Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 2016;375: DOI: /NEJMoa

2 Re: Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting This supplemental file contains the following items: 1. Original protocol, activated ; Updated and final protocol on ; 2. Original statistical analysis plan is in the original protocol; final statistical analysis and plan,

3 Activation Date: xx/xx/xx ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY ALLIANCE A OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY (HEC): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL An Alliance trial conducted by CALGB, NCCTG*, and ACOSOG Supplied agent(s): olanzapine (Alliance IND ; NSC ) and placebo for olanzapine Study Chair Rudolph M. Navari, MD, PhD, FACP Indiana University School of Medicine South Bend 1234 Notre Dame Ave South Bend, IN Tel: Fax: navari.1@nd.edu Symptom Intervention Committee Chair Health Outcomes Committee Study Co-chair Charles L. Loprinzi, MD Kathryn J. Ruddy, MD Mayo Clinic Mayo Clinic Tel: Tel: cloprinzi@mayo.edu ruddy.kathryn@mayo.edu Primary Statistician Secondary Statistician Rui Qin, PhD Heshan Liu Tel: Tel: qin.rui@mayo.edu liu.heshan@mayo.edu Protocol Coordinator Data Manager Kimberly K. Thomas, MS Cristina Zabel Tel: Tel: kthoma16@uchicago.edu Fax: zabel.cristina@mayo.edu NCI Version Date: 03/17/2014 1

4 A Study Resources Expedited Adverse Event Reporting Medidata Rave imedidata portal OPEN (Oncology Patient Enrollment Network) Biospecimen Management System A Nursing Contact Joanne Lester Institution: The Ohio State University Tel: Protocol Contacts: A Pharmacy Contact Heidi D. Finnes, PharmD, BCOP Institution: Mayo Clinic Tel: Protocol-related questions may be directed as follows: Questions Questions regarding patient eligibility, treatment, and dose modification: Questions related to data submission, RAVE or patient follow-up: Questions regarding the protocol document: Questions related to IRB issues and model consent revisions: Questions regarding CTEP-AERS reporting: Contact (via ) Study Chair, Nursing Contact, Protocol Coordinator, and (where applicable) Data Manager Data Manager Protocol Coordinator Regulatory Affairs Manager: Director of Pharmaceutical and Regulatory Affairs Document History Update ## Effective Date: Date NCI Version Date: 03/17/2014 2

5 A CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION To submit site registration documents: CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA Phone CTSU Fax For patient enrollments: Please refer to the patient enrollment section for instructions on using the OPEN system. Submit study data directly to the Lead National Clinical Trial Network (NCTN) Group unless otherwise specified in the protocol: All participating sites will submit study data via Medidata Rave System. Do not submit study data or forms to CTSU Data Operations. Do not copy the CTSU on data submissions. The study protocol and all related forms and documents must be downloaded from the protocolspecific Web page of the CTSU Member Web site located at Sites must use the current form version and adhere to the instructions and submission schedule outlined in the protocol. CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. For patient eligibility or treatment-related questions see the Protocol Contacts, Page 2. For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by phone or CTSU General Information Line , or All calls and correspondence will be triaged to the appropriate CTSU representative. For detailed information on the regulatory and monitoring procedures for CTSU sites please review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members website The CTSU Web site is located at NCI Version Date: 03/17/2014 3

6 A OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY (HEC): A Randomized, Double-Blind, Placebo-Controlled Trial Eligibility Criteria (see Section 3.0) Diagnosis of malignant disease. Overview No prior chemotherapy and scheduled to receive HEC (either cisplatin-containing regimen or anthracycline + cyclophosphamide [AC]). (See Section for additional details) Age 18 years. ECOG Performance Status 0, 1 or 2 No nausea or vomiting 24 hours prior to registration. Negative pregnancy test (serum or urine) done 7 days prior to registration, for women of childbearing potential only (per clinician discretion). No severe cognitive compromise. No known history of CNS disease (e.g. brain metastases, seizure disorder). No treatment with another antipsychotic agent such as risperidone, quetiapine, clozapine, phenothiazine or butyrophenone for 30 days prior registration or planned during protocol therapy. No chronic phenothiazine administration as an antipsychotic agent (patients may receive prochloperazine and other phenothiazines as rescue antiemetic therapy). No concurrent use of amifostine. No concurrent abdominal radiotherapy. No concurrent use of quinolone antibiotic therapy. No chronic alcoholism (as determined by the investigator). No known hypersensitivity to olanzapine. No known cardiac arrhythmia, uncontrolled congestive heart failure or acute myocardial infarction within the previous six months. No diagnosis of diabetes mellitus (e.g., on insulin or an oral hypoglycemic agent). Required Initial Laboratory Values Absolute 1500/mm 3 neutrophil count (ANC) Serum Creatinine 2.0 mg/dl SGOT or SGPT 3 x upper limit of normal (ULN) NCI Version Date: 03/17/2014 4

7 A Schema 5-HT3# (Day 1) + HEC Randomize Dex (Day 1-4) + Fosaprepitant* (Day 1) + 5-HT3# (Day 1) + Record Nausea (linear visual analogue scale) and Complete Response Dex (Day 1-4) + Fosaprepitant* (Day 1) + (no emesis, no rescue) Cycle Length = 1 Day NOTE: Cycle is an Alliance data management tool to facilitate consistent remote data entry. # palonosetron, ondansetron, or granisetron * or oral aprepitant for 3 days Please refer to the full protocol text for a complete description of the eligibility criteria and treatment plan. NCI Version Date: 03/17/2014 5

8 A Section Table of Contents 1.0 BACKGROUND STUDY RATIONALE STUDY DESIGN AND TREATMENT REGIMEN REGISTRATION QUALITY OF LIFE (QOL) MEASUREMENTS OBJECTIVES PRIMARY OBJECTIVE SECONDARY OBJECTIVE(S) PATIENT SELECTION ON-STUDY GUIDELINES ELIGIBILITY CRITERIA PATIENT REGISTRATION REGISTRATION REQUIREMENTS STRATIFICATION FACTORS AND TREATMENT ASSIGNMENTS STUDY CALENDAR DATA AND SPECIMEN SUBMISSION DATA COLLECTION AND SUBMISSION TREATMENT PLAN/INTERVENTION DEFINITIONS OF DEVIATIONS IN PROTOCOL PERFORMANCE DATA COLLECTION AND FORMS DOSE AND TREATMENT MODIFICATIONS, UNBLINDING ANCILLARY THERAPY, CONCOMITANT MEDICATIONS, AND SUPPORTIVE CARE DOSE MODIFICATIONS UNBLINDING PROCEDURES ADVERSE EVENTS ROUTINE ADVERSE EVENT REPORTING EXPEDITED ADVERSE EVENT REPORTING (CTEP-AERS) DRUG INFORMATION OLANZAPINE (ZYPREXA ) OR PLACEBO NURSING GUIDELINES PLACEBO MEASUREMENT OF EFFECT END OF TREATMENT/INTERVENTION DURATION OF TREATMENT: ONE CYCLE MANAGING INELIGIBLE AND CANCELED PATIENTS AND MAJOR PROTOCOL VIOLATIONS EXTRAORDINARY MEDICAL CIRCUMSTANCES STATISTICAL CONSIDERATIONS STUDY OVERVIEW SAMPLE SIZE, ACCRUAL TIME AND STUDY DURATION SUPPLEMENTARY ANALYSIS PLANS STUDY MONITORING STUDY REPORTING DESCRIPTIVE FACTORS - NONE NCI Version Date: 03/17/2014 Page

9 A INCLUSION OF WOMEN AND MINORITIES CORRELATIVE AND COMPANION STUDIES NONE GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING NONE REFERENCES APPENDIX I CONSENT FORM APPENDIX II REGISTRATION FATIGUE/UNISCALE ASSESSMENTS APPENDIX III PATIENT QUESTIONNAIRE APPENDIX IV BASELINE NAUSEA AND VOMITING QUESTIONNAIRE APPENDIX V NAUSEA AND VOMITING DAILY DIARY/QUESTIONNAIRE APPENDIX VI DAILY TELEPHONE CONTACT NCI Version Date: 03/17/2014 7

10 A BACKGROUND 1.1 Study Rationale Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life and is perceived by patients as a major adverse effect of the treatment [1]. The use of 5-hydroxytryptamine 3 (5-HT 3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV [2]. Recent studies have demonstrated additional improvement in the control of acute CINV and also delayed CINV with the use of three new agents, palonosetron, a second generation 5-HT 3 receptor antagonist [3], aprepitant, the first agent available in the drug class of neurokinin-1 (NK-1) receptor antagonists [4,5], and olanzapine, an antipsychotic which blocks multiple neurotransmitters in the central nervous system [6-8]. Palonosetron is a second generation 5-HT 3 receptor antagonist which has anti-emetic activity at both central and gastrointestinal sites. In comparison to the first generation 5-HT 3 receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT 3 receptors [9,10]. These differences may explain palonosetron s efficacy in delayed CINV compared to the first generation receptor antagonists [3]. A high level of efficacy and an excellent safety profile has been demonstrated in a number of studies [3,9,11-14]. Based on these studies, palonosetron is recommended by multiple international antiemetic guidelines [15-17] for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy (HEC) and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). Aprepitant is an NK-1 receptor antagonist which blocks the emetic effects of substance-p [4,5,18]. When combined with a standard regimen of the corticosteroid dexamethasone and a 5-HT 3 receptor antagonist, aprepitant is effective in the prevention of CINV in patients receiving HEC [5,18]. This regimen is recommended in the guidelines of multiple international groups for the control of CINV in patients receiving HEC [15-17]. The intravenous form of aprepitant, fosaprepitant, has recently been approved by the FDA. One intravenous dose of fosaprepitant prior to chemotherapy has been shown to be equivalent to the daily three day oral dose of aprepitant [19]. Palonosetron and aprepitant have been combined with dexamethasone for the prevention of CINV in a phase II study of fifty-eight patients who received MEC [20]. This three drug antiemetic regimen was found to be safe and highly effective in preventing CINV in the acute, delayed, and overall periods. Olanzapine is an FDA approved antipsychotic that blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT 2a, 5-HT 2c, 5-HT 3, 5-HT 6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors [21,22]. Common side effects are sedation and weight gain [23,24], as well as an association with the onset of diabetes mellitus [25]. Olanzapine s activity at multiple receptors, particularly at the D2, 5-HT 2c, and 5-HT 3 receptors which appear to be involved in nausea and emesis, suggests that it may have significant anti-emetic properties. A recent single institution phase III trial demonstrated that olanzapine, when combined with a single dose of dexamethasone and a single dose of palonosetron, was very effective in controlling acute and delayed CINV in patients receiving HEC [7] as illustrated in Figures 1a and 1b. There was excellent control of nausea without the use of multiple days of dexamethasone. In addition, a 8 NCI Version Date: 03/17/2014

11 A phase III study showed the addition of olanzapine to the 5-HT 3 receptor antagonist azasetron and dexamethasone improved delayed CINV in patients receiving HEC (Figures 2a and 2b) or MEC (Figures 3a and 3b) [8]. A recent study compared olanzapine to metoclopramide for the treatment of breakthrough emesis and nausea in patients receiving HEC and guideline-directed antiemetic prophylaxis [26]. Olanzapine was significantly better than metoclopramide for the treatment of breakthrough emesis and nausea. This was the first phase III study on the treatment of breakthrough emesis and nausea (Figure 4). Figure 1a. Complete response of patients receiving olanzapine, palonosetron, and dexamethasone or aprepitant, palonosetron, and dexamethasone prior to HEC. Figure 1b. Percent of patients with no nausea after receiving olanzapine, palonosetron, and dexamethasone or aprepitant, palonosetron, and dexamethasone. Figure 2a. Complete response of patients receiving olanzapine, azasetron, and dexamethasone or azasetron and dexamethasone prior to HEC. Figure 2b. Percent of patients with no nausea after receiving olanzapine, azasetron, and dexamethasone or azasetron, and dexamethasone. NCI Version Date: 03/17/2014 9

12 A Figure 3a. Complete response of patients receiving olanzapine, azasetron, and dexamethasone or azasetron and dexamethasone prior to MEC Figure 3b. Percent of patients with no nausea after receiving olanzapine, azasetron, and dexamethasone or azasetron, and dexamethasone. Figure 4. Percentage of patients with breakthrough CINV treated with olanzapine (OLN) or metoclopramide (METO) with no emesis or no nausea over a 72 hour observation period. As study investigators, we are very impressed with the results that have been seen in clinical trials evaluating olanzapine for the prevention and treatment of chemotherapy induced nausea and vomiting. Nonetheless, in order to confirm the results from reported trials that support the value of olanzapine [6-8, 26], a multi-institution, double-blind, placebo-controlled clinical trial is needed. International guideline committee reports have suggested that further study is in order, but have not been impressed enough to endorse this drug as an effective agent when added to standard therapy. Given this, we believe that we should see what this drug does to improve results over what is seen using standard practice. Since multiple smaller studies support the potential value of olanzapine for preventing and treating chemotherapy-induced nausea and vomiting, we considered multiple study designs including: Treatment of established chemotherapy-induced nausea/vomiting Using olanzapine in patients who had unacceptable nausea vomiting with one chemotherapy cycle and were about to receive another Comparing it to aprepitant NCI Version Date: 03/17/

13 A Conducting a placebo-controlled trial without aprepitant (conducting a trial comparing olanzapine to placebo and omitting aprepitant in both arms of the trial) Using it with less corticosteroids (using a reduced dose of corticosteroids in the trial) After much discussion with multiple parties over several months, we decided on the design presented in this protocol. We proposed 4 days of dexamethasone in this trial because standard practice is to use 4 days of dexamethasone, as per ASCO, NCCN, and MASCC guidelines [15-17]. We extensively discussed using a single day of dexamethasone or allowing this to be physician s choice, but the 4 day choice was chosen to be consistent with the current guidelines. Patients receiving HEC, including the combination of cyclophosphamide and doxorubicin, appear to have a significant amount of nausea post chemotherapy [7, 27] despite prophylactic anti-emetics. An effective anti-nausea agent is needed for this patient population. The potential short term toxicity of olanzapine is sedation [21,22]. The long term toxicities include weight gain and hyperglycemia in some patients who take olanzapine for 3-6 months [21-24]. In the published phase II and phase III prophylactic CINV studies [6-8], there has been no evidence that weight gain and hyperglycemia occur when using olanzapine as a preventative agent for CINV during the five days post chemotherapy. In addition, there were no Grade III or IV toxicities reported in any of the clinical trials and accrual was not impacted in any of the phase II or Phase III trials. Sedation will be monitored with the treatment cycle. We will not monitor weight gain or hyperglycemia, since patients will be treated with olanzapine for only 4 days. With regards to potential drug interactions, olanzapine has been given without any apparent clinical toxicities with other antiemetics such as dexamethasone and 5-HT 3 receptor antagonists [6-8]. While we are unaware of any studies that have combined olanzapine with aprepitant, given that the various targeted receptors, mechanisms of action, and metabolism of each of these agents (aprepitant and olanzapine) are markedly different, significant interactions would not be anticipated. Supporting this contention, a Micromedex 2.0 search of interactions among all of these drugs (olanzapine, aprepitant, palonosetron, ondansetron, granisetron and dexamethasone) confirms that there are none, aside from the well-known phenomenon that increased systemic exposure to dexamethasone occurs with the concurrent use of dexamethasone and aprepitant. The purpose of this study is to measure the efficacy of olanzapine in the prevention of CINV (particularly nausea) in patients receiving HEC. Olanzapine or placebo will be added to the guideline directed antiemetics for HEC regimens to determine if the control of nausea and emesis can be significantly improved during the 120 hours post chemotherapy. The current guidelines recommend any of the currently available 5-HT 3 receptor antagonists (palonosetron, ondansetron, or granisetron). It is particularly important for this be conducted as a cooperative group study, as opposed to being conducted by a pharmaceutical company, since nausea control is not an on-label indication for olanzapine and the present study is designed to increase our knowledge concerning new mechanisms of nausea control, not to support a label extension for olanzapine. In addition, olanzapine is generic and quite inexpensive. 1.2 Study Design and Treatment Regimen All patients eligible for the study receiving HEC will receive a 5-HT# receptor antagonist (palonosetron 0.25 mg IV, or granisetron 1mg IV or 2mg PO, or ondansetron 8mg IV or PO) on day one, dexamethasone (12 mg PO, day one; 8 mg PO, days 2-4) and an NK-1 receptor antagonist, day one; plus olanzapine (10 mg/day, days 1 to 4) or a matching placebo (days 1 to 4). The NK-1 receptor antagonist may be in the form of intravenous fosaprepitant (150 mg, day one) or oral aprepitant (125 mg, day 1; 80 mg, days 2, 3). The protocol doses of the 5-HT3 receptor antagonists, NCI Version Date: 03/17/

14 A dexamethasone, and aprepitant listed above are standard doses recommended by various international anti-emetics guidelines [15-17]. The protocol doses of olanzapine were determined from the various studies in the literature [2, 6-8, 28]. In a phase I trial of olanzapine as a prophylactic antiemetic, Passik et al [28] determined that 10 mg/day for four days was a dose without toxicity and minimal sedation. Navari et al [6] used a loading dose of olanzapine (daily for two days prior to chemotherapy), but subsequently determined that a loading dose was not necessary for efficacy and demonstrated that 10mg /day for four days beginning with the day of chemotherapy was highly efficacious in the prevention of nausea and emesis [6,7]. Patients will be stratified according to gender, their chemotherapy regimen, and the specific 5-HT 3 receptor antagonist used. Protocol therapy will be instituted for single day chemotherapy (see Section 7) for one cycle only. Patients will be permitted to take rescue therapy of the treating investigator s choice for nausea and/or emesis/retching, based on clinical circumstances. Multiple other study designs were extensively discussed at multiple meetings and by group phone calls and in writing, over several months, before the group consensus settled on the currently described study design. Concepts considered included studying HEC versus moderately emetogenic chemotherapy versus both; evaluating one cycle therapy versus several cycles of therapy; using nausea versus vomiting versus both as primary end points; mandating aprepitant versus allowing use to be patient/physician choice; comparing olanzapine to aprepitant; using olanzapine to treat nausea and vomiting that occurred after chemotherapy versus as an agent to prevent the problem. 1.3 Registration Quality of Life (QOL) Measurements QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance studies and will be assessed upon registration in this study. Fatigue and overall well-being clearly can impact how well patients will do in terms of being able to tolerate and experience nausea and vomiting [29]. Our group and others have done extensive work indicating that these simple measures of fatigue and overall QOL impact survival and other treatment outcomes [30-32]. This work has involved over fifty clinical trials and patient populations across the cancer spectrum. A recent meta-analysis (n=13,874) showed that 36 of 39 studies indicated that analogues of patient reported outcomes were significantly associated with overall survival [33]. A literature review of over 100 studies from 1982 to 2008 indicated that patient reported outcomes measures were significant independent predictors of survival duration [34]. Osoba [35] provides an overall rationale for the use of these measures in all clinical trials. If there is an imbalance in QOL or fatigue at baseline across treatment arms, it is universally recognized that it could confound the treatment comparison (Draft Guideline on Adjustment for Baseline Covariates, European Medicines Agency, EMA/295050/2013; pdf). As such, it is important to include these variables as covariates in the efficacy testing to demonstrate the robustness of the results and produce more efficient estimates of efficacy. NCI Version Date: 03/17/

15 A OBJECTIVES 2.1 Primary objective To compare between the two study arms the number of patients with no nausea for the acute (0-24 hours post-chemotherapy), delayed ( hours post-chemotherapy) and overall periods (0-120 hours post-chemotherapy) for patients receiving HEC. 2.2 Secondary objective(s) To compare between the two study arms the complete response (CR) (no emetic episodes and no use of rescue medication) in the acute, delayed, and overall periods To compare between the two study arms, the incidences of potential toxicities that have been ascribed to olanzapine. 3.0 PATIENT SELECTION For questions regarding eligibility criteria, see the Contact Information page. Please note that the Study Chair cannot grant waivers to eligibility requirements. 3.1 On-Study Guidelines This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All relevant medical and other considerations should be taken into account when deciding whether this protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although they will not be considered formal eligibility (exclusion) criteria, physicians should recognize that the following may seriously increase the risk to the patient entering this protocol: Psychiatric illness that would prevent the patient from giving informed consent. Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient. Patients with a currently active second malignancy other than non-melanoma skin cancers. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for 3 years. Patients who cannot swallow oral formulations of the agent(s). In addition: Women of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. NCI Version Date: 03/17/

16 A Eligibility Criteria Diagnosis of malignant disease No prior chemotherapy and scheduled to receive HEC (either cisplatin-containing regimen or anthracycline + cyclophosphamide [AC]). Cisplatin at a dose of 70mg/m 2, with or without other chemotherapy agent(s) OR Age 18 years. Anthracycline (60 mg/m 2 ) plus cyclophosphamide(600 mg/m 2 ) ECOG Performance Status 0, 1 or Required Initial Laboratory Values 120 days prior to registration. Serum Creatinine 2.0 mg/dl SGOT or SGPT 3 x upper limit of normal (ULN) Absolute neutrophil count (ANC) 1500/mm No nausea or vomiting 24 hours prior to registration Negative pregnancy test (serum or urine) done 7 days prior to registration, for women of childbearing potential only (per clinician discretion) No severe cognitive compromise No known history of CNS disease (e.g. brain metastases, seizure disorder) No treatment with another antipsychotic agent such as risperidone, quetiapine, clozapine, phenothiazine or butyrophenone 30 days prior to registration or planned during protocol therapy No chronic phenothiazine administration as an antipsychotic agent (patients may receive prochloperazine and other phenothiazines as rescue anti-emetic therapy) No concurrent use of amifostine No concurrent abdominal radiotherapy No concurrent use of quinolone antibiotic therapy No chronic alcoholism (as determined by the investigator) No known hypersensitivity to olanzapine No known cardiac arrhythmia, uncontrolled congestive heart failure or acute myocardial infarction within the previous six months No history of uncontrolled diabetes mellitus (e.g. on insulin or an oral hypoglycemic agent). NCI Version Date: 03/17/

17 A PATIENT REGISTRATION 4.1 Registration Requirements Informed consent: the patient must be aware of the neoplastic nature of his/her disease and willingly consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human protection committee approval of this protocol and a consent form is required prior to patient consent and registration. 4.2 Patient Registration/Randomization CTSU registration requirements This study is supported by the NCI Cancer Trials Support Unit (CTSU). Prior to the recruitment of a patient for this study, investigators must be registered members of a National Clinical Trials Network (NCTN) Group. Each investigator must have an NCI investigator number and must maintain an active investigator registration status through the annual submission of a complete investigator registration packet (FDA Form 1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These forms are available on the CTSU Web site (enter credentials at then click on the Register tab) or by calling the PMB at Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can enroll patients. Study centers can check the status of their registration packets by querying the Regulatory Support System (RSS) site registration status page of the CTSU member web site by entering credentials at Requirements for Alliance A site registration: CTSU IRB Certification CTSU IRB/Regulatory Approval Transmittal Sheet Patient Enrollment through OPEN Patient registration can occur only after pre-treatment evaluation is complete, eligibility criteria have been met, and the study site is listed as approved in the CTSU RSS. Patients must have signed and dated all applicable consents and authorization forms. All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study. OPEN can be accessed at or from the OPEN tab on the CTSU members side of the website at Prior to accessing OPEN site staff should verify the following: All eligibility criteria have been met within the protocol stated timeframes. Site staff should use the OPEN Enrollment forms provided on the group or CTSU web site as a tool to verify eligibility. All patients have signed an appropriate consent form and HIPAA authorization form (if applicable). NCI Version Date: 03/17/

18 A Access requirements for OPEN: Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM account. This is the same account (user id and password) used for the CTSU members' web site. To perform registrations, the site user must have been assigned the 'Registrar' role on the relevant Group or CTSU roster. To perform registrations on protocols for which you are a member of the Lead Group, you must have an equivalent 'Registrar' role on the Lead Group roster. Role assignments are handled through the Groups in which you are a member To perform registrations to trials accessed via the CTSU mechanism (i.e., non-lead Group registrations) you must have the role of Registrar on the CTSU roster. Site and/or Data Administrators can manage CTSU roster roles via the new Site Roles maintenance feature under RSS on the CTSU members' web site. This will allow them to assign staff the "Registrar" role. Note: The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records. Further instructional information is provided on the OPEN tab of the CTSU members side of the CTSU website at or at For any additional questions contact the CTSU Help Desk at or ctsucontact@westat.com. 4.3 Stratification Factors and Treatment Assignments Stratification Factors Gender: Male vs. Female Chemotherapy Regimen: cisplatin-containing regimen vs. anthracycline + cyclophosphamide (AC) HT 3 Receptor Antagonist: palonosetron vs. ondansetron vs. granisetron Treatment Assignments The factors defined in will be used as stratification factors After the patient has been registered into the study, the values of the stratification factors will be recorded, and the patient will be assigned to one of the following treatment groups using the Pocock and Simon dynamic allocation procedure which balances the marginal distributions of the stratification factors between the treatment groups [36]. 5-HT 3 receptor antagonist (palonosetron, ondansetron, or granisetron) + dexamethasone + aprepitant/fosaprepitant + placebo 5-HT 3 receptor antagonist (palonosetron, ondansetron, or granisetron) + dexamethasone + aprepitant/fosaprepitant + olanzapine To ensure both the patient and the medical professionals who care for the patient are blinded to the identity of the treatment assignment, the Registration Specialist will follow the double-blinding procedures outlined in Section 8.3. NCI Version Date: 03/17/

19 A Procedures for Double-Blinding the Treatment Assignment After the treatment assignment has been ascertained in the OPEN application, the patient s study medication code number will be displayed on the confirmation of registration screen The pharmacist or designated contact person at the treating site will maintain records that indicate the identity of the patient and their corresponding study medication code number. 5.0 STUDY CALENDAR Prior to Registration Days 1-6 Tests & Observations History and physical, weight, ECOG PS X Height X Adverse Event Assessment X 3 Registration Fatigue/Uniscale Assessment (Appendix II) X 1 Patient Questionnaire (Appendices III-V) X 1 X 2 Nurse/Research Coordinator Contact (Appendix VI) X 3 Laboratory Studies Serum or Urine HCG X 4 Creatinine, SGOT,SGPT ANC X 5 1 To be completed after registration and prior to treatment. 2 Patient to complete daily on days 2-6. Nurse/Research Coordinator to contact the patient on days 2-4 only. Please call the patient at the same time of day as the chemotherapy was given on day 1 (+/- 1 hour). 3 Nurse/Research Coordinator will contact each patient each day (days 2-4) to remind the patient to complete forms, answer questions, and to query adverse events. Adverse events experienced by patients on day 1 and day 2 will be collected during the nurse phone call on day 2. 4 For women of childbearing potential (see Section 3.2.7). Must be done 7 days prior to registration. 5 To be completed 120 days prior to registration. NCI Version Date: 03/17/

20 A DATA AND SPECIMEN SUBMISSION 6.1 Data collection and submission This study will use Medidata Rave for remote data capture (RDC) of all study data. The Rave system can be accessed through the imedidata portal at For additional information regarding account setup or training, please visit the training section of the Alliance Web site. Copies of forms and a data submission schedule are also available for download on the CTSU Web site. 7.0 TREATMENT PLAN/INTERVENTION Protocol treatment is to begin 14 days of registration. Protocol therapy will be instituted for single day chemotherapy for one cycle only. Patients will be permitted to take rescue therapy of the treating investigator s choice for nausea and/or emesis/retching, based on clinical circumstances. Agent Dose Route Day palonosetron OR ondansetron OR 0.25 mg 8 mg IV IV OR PO Day 1 pre-chemo granisetron 1 mg (IV) OR 2 mg PO IV OR PO dexamethasone 12 mg PO Day 1 pre-chemo dexamethasone 8 mg PO Once daily on Days 2-4 (start in AM with breakfast the day after treatment) NK-1 receptor antagonist: fosaprepitant OR aprepitant 150 mg OR 125 mg (80 mg) IV OR PO olanzapine or placebo 10 mg Oral Day 1 pre-chemo OR Day 1 pre-chemo (Once daily on Days 2-3) Once daily on Days 1-4 (prechemotherapy on days of chemotherapy) 7.1 Definitions of Deviations in Protocol Performance Major Deviations A "major deviation" is a situation in which patient safety or outcome is compromised. Minor Deviations A "minor deviation" is a discrepancy from the protocol that is not of sufficient magnitude to prevent adequate evaluation of the patient and does not cause the patient to be excluded from the statistical evaluation. 7.2 Data Collection and Forms The patient will complete the Baseline Nausea and Vomiting Questionnaire on day one, prior to the start of treatment. The patient will also complete the Nausea and Vomiting Daily Diary/Questionnaire on days 2-6 at the same time of day as the chemotherapy was given on day 1 (+/- 1 hour). NCI Version Date: 03/17/

21 A DOSE AND TREATMENT MODIFICATIONS, UNBLINDING 8.1 Ancillary therapy, concomitant medications, and supportive care Patients should receive full supportive care while on this study. This includes blood product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical conditions. All blood products and concomitant medications such as antidiarrheals, analgesics, and/or antiemetics received from the first day of study treatment administration until 30 days after the final dose will be recorded in the medical records. 8.2 Dose Modifications If the patient experiences a significant adverse event (per patient and physician discretion) felt to potentially be related to the study product (olanzapine/placebo), then the study product should be stopped and this should be recorded. 8.3 Unblinding Procedures Protocol-specified Unblinding: Trial participants may be unblinded upon completion of protocol therapy and submission of all of their questionnaire results. Any potential toxicity of the study agent (olanzapine/placebo) needs to be determined and recorded prior to unblinding of the investigator and/or patient. Contact the Alliance Registration Office at during regular business hours Emergency Unblinding Procedures: A trial participant s treatment assignment can be unblinded in emergent situations with the approval of the appropriate Alliance Executive Officer (or designee) only if unblinding would influence management of the situation, e.g., if a child has swallowed a vial of pills. Study Chairs, Primary Statisticians and other Alliance staff are not permitted to approve emergency unblinding requests. Treating sites should call the Executive Officer at , pager If an Alliance Executive Officer (or designee) is not available, the treating physician should assume that the trial participant is on the active agent and then follow-up with an Alliance Executive Officer (or designee) on the next business day. 9.0 ADVERSE EVENTS The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical research, as required by Federal Regulations. Adverse events must be described and graded using the terminology and grading categories defined in the NCI s Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The CTCAE is available at Attribution to protocol treatment for each adverse event must be determined by the investigator and reported on the required forms, using the codes provided. 9.1 Routine adverse event reporting Adverse event data collection and reporting, which are required as part of every clinical trial are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Solicited adverse events: None NCI Version Date: 03/17/

22 A Expedited adverse event reporting (CTEP-AERS) Investigators are required by Federal Regulations to report serious adverse events as defined below. Alliance investigators are required to notify the Alliance Central Protocol Operations Program Office, the Study Chair, and their Institutional Review Board if a patient has an adverse event requiring expedited reporting. All such events must be reported in an expedited manner using the CTEP Adverse Event Reporting System (CTEP-AERS). The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 will be utilized for reporting. The CTCAE is identified and located on the CTEP website at: All treatment areas should have access to a copy of the CTCAE version 4.0. A copy can be downloaded from the CTEP website The Alliance requires investigators to route all expedited adverse event reports through the Alliance Central Protocol Operations Program Office for Alliance-coordinated studies. Be sure to read this entire protocol section, as requirements are described in both the table and bullet points following the table. In the case of a conflict, the additional instructions or exclusions supersede the table Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND 30 Days of the Last Dose of Treatment 1 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR ) An adverse event is considered serious if it results in ANY of the following outcomes: 1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR ; ICH E2A and ICH E6). ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below. Hospitalization Grade 1 Timeframes Grade 2 Timeframes Grade 3 Timeframes Grade 4 & 5 Timeframes Resulting in Hospitalization 24 hrs Not resulting in Hospitalization 24 hrs Not required 10 Calendar Days 10 Calendar Days 24-Hour; 5 Calendar Days NCI Version Date: 03/17/

23 A Expedited AE reporting timelines are defined as: o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-AERS 24 hours of learning of the AE, followed by a complete expedited report 5 calendar days of the initial 24-hour report. o 10 Calendar Days - A complete expedited report on the AE must be submitted 10 calendar days of learning of the AE. 1 Serious adverse events that occur more than 30 days after the last dose of treatment require reporting as follows: Expedited 24-hour notification followed by complete report 5 calendar days for: All Grade 4, and Grade 5 AEs that are at least possibly related to treatment Expedited 10 calendar day reports for: Grade 2 adverse events resulting in hospitalization that are at least possibly related to treatment Grade 3 adverse events that are at least possibly related to treatment Additional Instructions or Exclusions: Deaths clearly due to progressive cancer should NOT be reported via CTEP-AERS but should be reported via routine reporting methods in RAVE Alliance A uses a drug under an Alliance IND. These reporting requirements should be followed for either arm in this trial. All new malignancies must be reported through CTEP-AERS whether or not they are thought to be related to previous or current treatment. This includes solid tumors (including non-melanoma skin malignancies), hematologic malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE version 4.0, new malignancies (both second and secondary) should be reported as one of the following: leukemia secondary to oncology chemotherapy; myelodysplastic syndrome; treatment-related secondary malignancy; or neoplasms benign, malignant and unspecified-other. Whenever possible, the CTEP-AERS reports for new malignancies should include tumor pathology, history of prior tumors, prior treatment/current including duration, any associated risk factors or evidence regarding how long the new malignancy may have been present, when and how the new malignancy was detected, molecular characterization or cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy treatment and outcome, if available. All pregnancies and suspected pregnancies occurring in female patient during therapy or within 28 days after completion of treatment on A must be reported via CTEP-AERS using the event term pregnancy, puerperium and perinatal conditions other, pregrnancy (Grade 3) CTEP-AERS reports should be amended upon completion of the pregnancy to report pregnancy outcome (e.g., normal, spontaneous abortion, therapeutic abortion, fetal death, congenital abnormalities) The CTEP-AERS report should be amended for any neonatal deaths or complications occurring within 28 days of birth independent of attribution. Infant deaths occurring after 28 days considered to be related to in utero to the agent used in this trial should be reported via CTEP- AERS DRUG INFORMATION 10.1 Olanzapine (Zyprexa ) or placebo Procurement: Olanzapine and placebo will be purchased by Mayo funds and supplied to the Alliance research base pharmacy. NCI Version Date: 03/17/

24 A Olanzapine 10 mg tablets (Dr. Reddy s) will be purchased for use in this trial. The tablets will be overencapsulated by Clinical Encapsulation Services of Schenectady, NY. The capsules will also contain microcrystalline cellulose as a filler material. A placebo capsule will also be prepared by Clinical Encapsulation Services of Schenectady, NY. This capsule will match the appearance of the overencapsulated 10mg olanzapine product. Each participating Alliance affiliate will order a starter supply of blinded olanzapine/placebo from the research base pharmacy. Fax the Alliance Clinical Drug Order/Return Form to: Medical Oncology Pharmacist Mayo Clinic Gonda Rochester, MN FAX (507) Registration Office personnel will monitor the supply of blinded olanzapine and placebo at each participating affiliate and will arrange for the research base pharmacy staff to send further supplies to the affiliate as needed. Outdated or remaining drug/product should be destroyed on-site per procedures in place at each institution. Formulation: Commercial olanzapine tablets contain 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg. Inactive ingredients are crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The color coating contains hydromellose, polyethylene glycol 400, titanium dioxide, FD&C Blue No. 2. Storage and Stability: Olanzapine tablets are stored at controlled room temperature, 20º to 25ºC (68º to 77ºF). Protect olanzapine tablets from light and moisture. Administration: Olanzapine will be taken as a single dose once daily Days 1 through 4 without regard to meals (prior to chemotherapy on day of chemotherapy administration and once daily in the morning thereafter). Drug Interactions: Olanzapine is a major substrate of CYP1A2 and a minor substrate of CYP2D6. Carbamazepine, a potent inducer of CYP1A2 caused a 50% increase in the clearance of olanzapine. Omeprazole and rifampin may cause an increase in olanzapine clearance. The effects of olanzapine may be decreased by potent inducers of CYP1A2 and should be avoided if possible. Fluvoxamine, an inhibitor of CYP1A2, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant fluvoxamine. Fluoxetine, an inhibitor of CYP2D6, causes a smaller increase (mean 16%) in the maximum concentration of olanzapine and a small decrease in the clearance of olanzapine (mean 16%). The magnitude of impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine. Olanzapine may potentiate the effects of antihypertensives, CNS acting medications and alcohol. Olanzapine may antagonize the effects of levodopa and dopamine agonists. Olanzapine is an inhibitor of CYP1A2 (weak), CYP2C19 (weak), CYP2C9 (weak), CYP2D6 (weak), CYP3A4 (weak). NCI Version Date: 03/17/

25 A Pharmacokinetics: a) Absorption Readily absorbed reaches peak concentrations in approximately 6 hours following an oral dose. Food does not affect the rate or extent of olanzapine absorption. b) Distribution Linear kinetics with half-life of 21 to 54 hours and apparent plasma clearance from 12 to 47 L/hr. Olanzapine is extensively distributed throughout the body with a Vd of approximately 1000 L. It is 93% bound to plasma proteins (primarily albumin and α 1-acid glycoprotein. c) Metabolism Direct glucuronidation and cytochrome P450 mediated oxidation via CYP1A2 (major) and CYP2D6 (minor) are the primary metabolic pathways for olanzapine. d) Excretion Urine (57%, 7% as unchanged drug); feces (30%). There is a 40% increase in olanzapine clearance in smokers, 30% decrease in females. Adverse Events All of the adverse events discussed below have been associated with olanzapine, but would be considered unexpected in the context of this trial. [U.S. Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Other warnings and precautions: suicide (particularly when used with fluoxetine), neuroleptic malignant syndrome, hyperglycemia, hyperlipidemia, weight gain, tardive dyskinesia, orthostatic hypotension, leukopenia, neutropenia, agranulocytosis, seizures, cognitive or motor impairment, hyproprolactinemia. The following toxicity information regards chronic daily use of olanzapine and is not likely applicable for drug use of only 4 days: Common known potential toxicities >10%: Central nervous system: somnolence, extrapyramidal symptoms, dizziness, headache, fatigue, insomnia Endocrine/metabolic: prolactin increased Gastrointestinal: weight gain, appetite increased, xerostomia, constipation Hepatic: ALT increased Neuromuscular/skeletal: weakness Miscellaneous: accidental injury Less common known potential toxicities 1-10%: Cardiovascular: chest pain, hypertension, peripheral edema, postural hypotension, tachycardia Central nervous system: fever, personality changes, restlessness Dermatologic: bruising Endocrine/metabolic: breast-related events (discharge, enlargement, galactorrhea, gynecomastia, lactation disorder), menstrual-related events (amenorrhea, hypomenorrhea, menstruation delayed, oligomenorrhea), sexual function-related events (anorgasmia, ejaculation delayed, erectile dysfunction, changes in libido, abnormal orgasm, sexual dysfunction) Gastrointestinal: abdominal pain, diarrhea, flatulence, nausea, vomiting Genitourinary: incontinence, UTI Hepatic: hepatic enzymes increase NCI Version Date: 03/17/

26 A Neuromuscular/skeletal: abnormal gait, akathisia, articulation impairment, back pain, falling, hypertonia, joint/extremity pain, muscle stiffness, tremor Ocular: amblyopia Respiratory: cough, epistaxis, pharyngitis, respiratory tract infection, rhinitis, sinusitis Rare, less than 1% (limited to important or life threatening): Acidosis, agranulocytosis, anaphylactic reaction, angioedema, apnea, atelectasis, atrial fibrillation, cerebrovascular accident, congestive heart failure, deafness, diabetes mellitus, diabetic ketoacidosis, diabetic coma, dystonia, encephalopathy, facial paralysis, glaucoma, heart arrest, heart failure, hemorrhage, hepatitis, hypercholesterolemia, hyper/hypoglycemia, hyper/hypokalemia, hyperlipidemia, hyper/hyponatremia, hypertriglyceridemia, hyperuricemia, hyper/hypoventilation, hypoproteinemia, hypoxia, jaundice, ileus, ketosis, leukocytosis (eosinophilia), leukopenia, liver damage (cholestatic or mixed), liver fatty deposit, lung edema, lymphadenopathy, myasthenia, myopathy, neuralgia, neuroleptic malignant syndrome, neutropenia, pancreatitis, paralysis, pulmonary embolus, rash, rhabdomyolysis, seizure, sudden death, suicide attempt, syncope, tardive dyskinesia, thrombocythemia, thrombocytopenia, transient ischemic attack, venous thrombotic events Nursing Guidelines Olanzapine has several drug to drug interactions, many of which can cause an increase in olanzapine clearance and increase the side effects of olanzapine. Assess patient s medication list for any possible drug to drug interactions. Discuss with study doctor Remind patients to report any side effects, noting that there have been a large number of side effects reported with chronic use of this drug, that we do not think will be applicable for short term, intermittent, use Placebo A matching placebo will be provided. It will be identical in appearance to the over-encapsulated olanzapine. The opaque gelatin capsule will contain microcrystalline cellulose MEASUREMENT OF EFFECT Data from the patient questionnaire (Appendices III-V) will be used to measure treatment effect END OF TREATMENT/INTERVENTION 12.1 Duration of Treatment: One cycle 12.2 Managing ineligible and canceled patients and major protocol violations Data must be submitted per Section 5.0 for patients deemed ineligible or canceled. See also the Forms Packet for full details of data submission requirements Extraordinary Medical Circumstances If, at any time the constraints of this protocol are detrimental to the patient's health and/or the patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In this event: Document the reason(s) for discontinuation of therapy on data forms. Follow the patient for protocol endpoints as required by the Study Calendar. NCI Version Date: 03/17/

27 A STATISTICAL CONSIDERATIONS 13.1 Study Overview This is a randomized placebo-controlled phase III clinical trial to determine the added effect of olanzapine in combination with palonosetron (or ondansetron or granisetron), dexamethasone, and fosaprepitant (aprepitant) to prevent CINV after patients receiving HEC. This trial implements a group sequential design with one interim analysis for superiority and futility, respectively. The sample size calculation and simulation for operating characteristics are conducted using EAST version Sample Size, Accrual Time and Study Duration Sample Size A previous study [7] demonstrated the proportion of non-olanzapine-receiving patients with no nausea during the overall period was about 40%. Considering a 17.5% increase as a clinically meaningful effect size, we will need a sample size of 332 patients (166 patients per arm) to achieve 90% power to detect the above effect size at the 5% significance level using a two-sided chi-squared test for a fixed sample size clinical trial. This sample size will be inflated to 338 patients (169 patients per arm) after adding an interim analysis for superiority and futility. In order to account for ineligible, cancel and major violations, the total sample size will be further inflated by 10% to 372 patients (186 patients per arm) Accrual Rate and Accrual Duration The proposed study is a standard antiemetic study for which patient accrual should be very timely and efficient. There are no complex accrual issues and no demands for extensive resources in the protocol. The investigators have extensive experience in conducting phase II and phase III antiemetic studies. The Alliance Symptom Intervention Committee expressed marked interest in participating in this trial. Assuming an accrual rate of 20 patients per month in the Alliance, the patient accrual will be completed in 18.5 months Primary Endpoint Completion Date for ClinicalTrials.gov Reporting For purposes of ClinicalTrials.gov reporting, the Primary Endpoint Completion Date (PECD) for this study is the time the last patient registered has been followed for at least 5 days Statistical Design and Analysis for the Primary Endpoint Primary Endpoint No nausea is defined as a response of 0 in the nausea item of Nausea and Vomiting Daily Diary/Questionnaire in the acute (0-24 hours), delayed ( hours), and overall (0-120 hours) periods. NCI Version Date: 03/17/

28 A Statistical Design Interim Analysis Decision Rule Interim analysis will be conducted when 50% patients are enrolled and have completed the Nausea and Vomiting Daily Diary/Questionnaire. The Lan-DeMets family [37] of alpha and beta spending functions corresponding to the O Brien- Fleming boundary are used for controlling overall type I and type II error rates. Superiority will be concluded if p-value and futility will be concluded if p- value The second stage of this clinical trial shall continue if p-value is in (0.003, 0.844) Final Analysis Decision Rule Final analysis will be conducted when all target patients are enrolled and have completed the Nausea and Vomiting Daily Diary/Questionnaire. Superiority will be concluded if p-value <0.049 and futility will be concluded if p-value Study Operating Characteristics Simulation studies of 10,000 clinical trials are conducted for the proposed group sequential design. The probabilities of early stopping (after interim analysis) and empirical powers for various effect sizes are summarized in the following table. Effect Interim Analysis Early Final Analysis Power Scenario Size Superiority Futility Stopping Superiority Futility % 25.9% 0.9% 26.8% 62.8% 10.4% 88.7% % 16.6% 1.9% 18.5% 61.5% 20.1% 78.1% % 38.0% 0.4% 38.4% 57.6% 4.0% 95.6% Analysis Plan A modified intent-to-treat principle [38] will be applied for statistical analysis of efficacy in evaluable patients. Evaluable patients are defined as all patients meeting the eligibility criteria who did not cancel prior to receiving treatment and had no major violations The proportions of patients with no nausea between treatment arms will be examined sequentially by the chi-squared tests for the overall period, and then, acute, and delayed periods. The hierarchical order of overall, then acute and delayed periods is determined by clinical importance. A serial gatekeeping procedure [39] will be applied to maintain the overall significance level at the specified level as determined by the Lan-DeMets family of alpha spending function: NCI Version Date: 03/17/

29 A H 11: No nausea rates are the same between treatment arms during overall period. H 21: No nausea rates are the same between treatment arms during acute period. H 22: No nausea rates are the same b t t t t d i d l d Step 1. The null hypothesis of H 11 serves as a gatekeeper; Step 2. The null hypotheses of H 21 and H 22 are tested only after H 11 has been rejected. As the inference of H 11 may depend on whether or not some hypotheses (H 21 or H 22) are rejected in the subsequent family, we will adopt the Simes gatekeeping procedure rather than Bonferroni gatekeeping procedure. A SAS macro %GateKeeper will be utilized to implement the decision matrix algorithm for adjusted p-values Generalized linear models will be explored to incorporate stratification factors, baseline fatigue/qol and other patient characteristics Supplementary Analysis Plans Secondary Endpoints Nausea scores (0-10) repeatedly measured by the Nausea and Vomiting Daily Diary/Questionnaire Complete response (no emetic episodes and no use of rescue medication) during the acute, delayed and the overall periods as measured by the Nausea and Vomiting Daily Diary/Questionnaire Potential toxicities as ascribed to olanzapine as measured by the Nausea and Vomiting Daily Diary/Questionnaire Frequency of rescue medication repeatedly measured by the Nausea and Vomiting Daily Diary/Questionnaire Secondary Analysis Multiplicity will not be adjusted for secondary analyses, hence, statistically significant findings from secondary analyses are exploratory in nature and therefore shall be interpreted as such. Descriptive statistics and graphical approaches will form the basis for most secondary analyses The repeated measures analyses and growth curve models will be used to account for the factor of day and time trend in nausea score Similar analysis as primary endpoint will be conducted for complete response during acute, delayed and overall periods Potential toxicities of undesired sedation and appetite increase will be analyzed by repeated measures analyses and growth curve models to account for the factor of day and time trend The repeated measures analyses and growth curve models will be performed to account for the factor of day and time trend in ordinal medication. NCI Version Date: 03/17/

30 A Study Monitoring Adverse Event Stopping Rule The stopping rule specified below is based on the knowledge available at study development. We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the study re-opening to accrual or (2) at any time during the conduct of the trial and in consideration of newly acquired information regarding the adverse event profile of the treatment(s) under investigation. The study team may choose to suspend accrual because of unexpected adverse event profiles that have not crossed the specified rule below. Accrual will be temporarily suspended to this study if at any time we observe events considered at least possibly related to study treatment (i.e., an adverse event with attribute specified as possible, probable, or definite) that satisfy the following criteria: If 7 or more of the first 20 treated patients (or 35% of all patients after 20 patients have been accrued) experience a grade 3 or higher non-hematologic adverse event and the adverse event rate is higher in the active treatment arm. If 3 or more of the first 20 treated patients (or 15% of all patients after 20 patients have been accrued) experience a grade 4 or higher non-hematologic adverse event and the adverse event rate is higher in the active treatment arm Accrual Monitoring Stopping Rule Slow Accrual Patient accrual will be closely monitored by the investigators and secondary statistician on a monthly basis. If the accrual rate falls below 50% of expected accrual rate, investigators will carefully review feedback from sites and consider taking measures to encourage patient enrollment Target Accrual of Patients Receiving Cisplatin-Containing regimen 13.6 Study Reporting In order to reach a target accrual of 200 patients receiving cisplatin-containing regimen, we will monitor patient accrual by the grouping factor of chemotherapy regimen. If the patient accrual to AC is so rapid that it jeopardizes the target accrual to cisplatin-containing regimen, we will temporary close to AC to ensure target accrual to cisplatin-containing regimen This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an NCI-approved functioning body. Reports containing efficacy, adverse event, and administrative information will be provided to the DSMB every month as per NCI guidelines Results Reporting on ClinicalTrials.gov: At study activation, this study will have been registered within the ClincialTrials.gov web site. The Primary and Secondary Endpoints (i.e., Outcome Measures ) along with other required information for this study will be reported on ClinicalTrials.gov Descriptive Factors - None 13.8 Inclusion of Women and Minorities This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. There is no information currently available regarding differential effects of this regimen in subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences NCI Version Date: 03/17/

31 A to exist. Therefore, although the planned analysis will, as always, look for differences in treatment effect based on racial and gender groupings, the sample size is not increased in order to provide additional power for subset analyses. The geographical region served by the Alliance, has a population which includes approximately 13.5% minorities. Based on prior Alliance studies involving similar disease sites, we expect about 11.6% of patients will be classified as minorities by race and about 60% of patients will be women. Expected sizes of racial by gender subsets for patients randomized to this study are shown in the following table. Accrual Targets Ethnic Category Sex/Gender Females Males Total Hispanic or Latino Not Hispanic or Latino Ethnic Category: Total of all subjects Racial Category American Indian or Alaskan Native Asian Black or African American Native Hawaiian or other Pacific Islander White Racial Category: Total of all subjects Ethnic Categories: Racial Categories: Hispanic or Latino a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race. The term Spanish origin can also be used in addition to Hispanic or Latino. Not Hispanic or Latino American Indian or Alaskan Native a person having origins in any of the original peoples of North, Central, or South America, and who maintains tribal affiliations or community attachment. Asian a person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific Islanders in previous data collection strategies.) Black or African American a person having origins in any of the black racial groups of Africa. Terms such as Haitian or Negro can be used in addition to Black or African American. Native Hawaiian or other Pacific Islander a person having origins in any of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. White a person having origins in any of the original peoples of Europe, the Middle East, or North Africa CORRELATIVE AND COMPANION STUDIES NONE 15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING NONE NCI Version Date: 03/17/

32 A REFERENCES 1. Bloechl-Daum B, Deuson RR, Panagiotis M et al, Delayed nausea and vomiting continue to reduce patients quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment, J Clin Oncol. 24 (2006) Navari RM, Pharmacological management of chemotherapy-induced nausea and vomiting: focus on recent developments, Drugs. 69 (2009) Navari RM, Palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer, Future Oncol. 6 (2010) Curran MP, Robinson DM, Aprepitant: a review of its use in the prevention of nausea and vomiting. Drugs. 69 (2009) Sankhala KK, Pandya DM, Sarantopoulos J et al, Prevention of chemotherapy induced nausea and vomiting: a focus on aprepitant, Expert Opin Drug Metab Toxicol. 12 (2009) Navari RM, Einhorn LH, Loehrer PJ et al, A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting, Support Care Cancer. 13 (2005) Navari RM, Gray SE, Kerr AC, Olanzapine versus aprepitant for the prevention of chemotherapyinduced nausea and vomiting: a randomized phase III trial, J Support Oncol. 9 (2011) Tan L, Liu J, Liu X et al, Clinical research of olanzapine for the prevention of chemotherapyinduced nausea and vomiting, J Exp Clin Cancer Res. 28 (2009) Eisenberg P, MacKintosh FR, Ritch P et al, Efficacy, safety, and pharmacokinetics of palonosetron in patients receiving highly emetogenic, cisplatin-based chemotherapy: a doseranging, clinical study, Ann Oncol. 15 (2004) Rojas C, Thomas AG, Alt J et al, Palonosetron triggers 5-HT 3 receptor internalization and causes prolonged inhibition of receptor function, J Pharmacol. 626 (2010) Aapro MS, Grunberg SM, Manikhas GM et al, A phase III, double blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy, Ann Oncol. 17 (2006) NCI Version Date: 03/17/

33 A Eisenberg P, Figueroa-Vadillo J, Zamora R et al, Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5HT3 receptor antagonist: Results of a phase III, single dose trial versus dolasetron, Cancer. 98 (2003) Gralla R, Lichinitser M, Van der Vegt S et al, Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized Phase II trial comparing single dose of palonosetron with ondansetron, Ann Oncol. 14 (2003) Saito M, Aogi K, Sekine I, Palonosetron plus dexamethasone versus granisetron plus dexamethasone for the prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomized, comparative phase III trial, Lancet Oncol. 10 (2009) Kris MG, Hesketh PJ, Somerfield MR et al, American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006, J Clin Oncol. 24 (2006) NCCN National Comprehensive Cancer Network, Antiemesis: Clinical Practice Guidelines in Oncology (2010) v Roila F, Herrstedt J, Aapro M et al, Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference, Ann Oncol. 21 (Suppl 5) (2010) Navari RM, Pathogenesis-based treatment of chemotherapy-induced nausea and vomiting: Two new agents, J Support Oncol. 1 (2003) Grunberg S, Chua D, Maru A et al, Single-dose fosaprepitant for the prevention of chemotherapyinduced nausea and vomiting associated with cisplatin therapy: randomized, double blind study protocol EASE, J Clin Oncol. 10 (2011) Grote T, Hajdenberg Cartnell A et al, Combination therapy for chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: palonosetron, dexamethasone, and aprepitant, J Support Oncol. 4 (2006) NCI Version Date: 03/17/2014

34 A Bymaster FP, Calligaro D, Falcone J et al, Radioreceptor binding profile of the atypical antipsychotic olanzapine, Neuropsychopharmacology. 14 (1996) Bymaster FP, Falcone JF, Bauzon D et al, Potent antagonism of 5HT3 and 5HT 6 receptors by olanzapine, Eur J Pharmacol. 430 (2001) Allison DB, Casey DE, Antipsychotic-associated weight gain: A review of the literature, J Clin Psychiatry. 62 (2001) Hale AS, Olanzapine, Br J Hosp Med. 58 (1997) Goldstein LE, Sporn J, Brown S et al, New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment, Psychosomatics. 40 (1999) Navari RM, Nagy CK, Gray SE, Olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, Supportive Care Cancer. 21 (2013) Navari RM, Treatment of chemotherapy-induced nausea, Community Oncol. 9 (2012) Passik S, Navari RM, Loehrer PJ et al. A phase I trial of olanzapine for the prevention of delayed emesis in cancer patients receiving chemotherapy. Cancer Investigation, 22: , Barsevick A. M., Cleeland CS et al. ASCPRO recommendations for the assessment of fatigue as an outcome in clinical trials. J Pain Symptom Manage, 39: , Stauder MC, Romero Y et al. Overall survival and self-reported fatigue in patients with esophageal cancer. Support Care Cancer 21: , Sloan J A, Zhao X et al. Relationship between deficits in overall quality of life and non-smallcell lung cancer survival. J Clin Oncol 30: , Innominato PF, Giacchetti S et al. Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer. Cancer 119: , Gotay CC, Kawamoto CT et al. The prognostic significance of patient-reported outcomes in cancer clinical trials. J Clin Oncol 26: , NCI Version Date: 03/17/

35 A Montazeri A. Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to Health Qual Life Outcomes 7: 102, Osoba D. Health-related quality of life and cancer clinical trials. Ther Adv Med Oncol 3: Pocock SJ, Simon R. Sequential Treatment Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial. Biometrics 31(1): , 1975 Mar. 37. Lan, K. K. G. and D. L. Demets (1983). "Discrete Sequential Boundaries for Clinical-Trials." Biometrika 70(3): Abraha, I. and A. Montedori (2010). "Modified intention to treat reporting in randomised controlled trials: systematic review." BMJ 340: c Dmitrienko, A., G. Molenberghs, et al. (2005). Analysis of Clinical Trials Using SAS: A Practical Guide. Cary, NC, SAS Institute. NCI Version Date: 03/17/

36 A APPENDIX I CONSENT FORM NCI Consent Form Template Version Date: May 12, 2013 NOTES FOR LOCAL INVESTIGATORS*: The goal of the informed consent process is to provide people with sufficient information for making informed choices about participating in research. The consent form provides a summary of the study, of the individual's rights as a study participant, and documents their willingness to participate. The consent form is, however, only one piece of an ongoing exchange of information between the investigator and study participant. For more information about informed consent, review the "Recommendations for the Development of Informed Consent Documents for Cancer Clinical Trials" prepared by the Comprehensive Working Group on Informed Consent in Cancer Clinical Trials for the National Cancer Institute. The Web site address for this document is A blank line,, indicates that the local investigator should provide the appropriate information before submitting to the Institutional Review Board. *These notes for investigators are instructional and should not be included in the consent form sent to Institutional Review Boards. Study Title for Study Participants: A221301, OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY (HEC) You are being asked to participate in this study because treatments for cancer can cause the side effect of nausea and vomiting. People who do not take part in this study will receive standard medications that have been approved by the Food and Drug Administration for nausea and vomiting. What are my other choices if I do not take part in this study? If you decide not to take part in this study, you have other choices. For example: you may choose to have the usual approach described above you may choose to take part in a different study, if one is available Why is this study being done? You have cancer and will be receiving chemotherapy that may cause nausea and vomiting. The purpose of this study is to test whether olanzapine can reduce nausea and vomiting. Olanzapine is a medication which has been approved by the Federal Drug Administration (FDA) for the treatment of specific mental illnesses and has been used in many patients over the past 15 years, but it is not FDA approved to treat nausea and vomiting. Over the past five years, it has been demonstrated in multiple scientific studies involving small numbers of patients to have anti-nausea and anti-vomiting effects in patients receiving chemotherapy. The purpose of this study is to determine if the use of this medication can significantly reduce nausea and vomiting in a large number of patients receiving chemotherapy. The effects of olanzapine will be compared to a placebo. A placebo is a pill that looks like the study drug but contains no medication. There will be about 372 people taking part in this study. NCI Version Date: 03/17/

37 A What are the study groups? This study has two study groups. Group 1 will receive the study drug olanzapine and Group 2 will receive a placebo, a pill that looks like the study drug but contains no medication. A computer will by chance assign you to treatment groups in the study. This is called randomization. This is done by chance because no one knows if one study group is better or worse than the other. This study has two study groups. Group 1 will get the chemotherapy drugs cisplatin or cyclophosphamide and doxorubicin, the usual chemotherapy drugs used for your type of cancer, as well as usual anti-nausea/vomiting drugs: - Ondansetron (8 mg orally or intravenously) or granisetron (1 mg intravenously or 2 mg orally) or palonosetron (0.25 mg intravenously) on the day of chemotherapy, plus - Dexamethasone (12 mg orally on the day of chemotherapy and 8 mg orally days 2, 3, 4 post chemotherapy), plus - Fosaprepitant (150 mg intravenously on the day of chemotherapy) or aprepitant (125 mg orally on the day of chemotherapy and 80 mg orally on days 2 and 3 post chemotherapy), plus - A placebo. Group 2 will get the chemotherapy drugs cisplatin or cyclophosphamide and doxorubicin, the usual chemotherapy drugs used for your type of cancer, as well as the following anti-nausea/vomiting drugs: - Ondansetron (8 mg orally or intravenously) or granisetron (1 mg intravenously or 2 mg orally) or palonosetron (0.25 mg intravenously) on the day of chemotherapy, plus - Dexamethasone (12 mg orally on the day of chemotherapy and 8 mg orally days 2, 3, 4 post chemotherapy), plus - Fosaprepitant (150 mg intravenously on the day of chemotherapy) or aprepitant (125 mg orally on the day of chemotherapy and 80 mg orally on days 2 and 3 post chemotherapy), plus - A study drug called olanzapine (10 mg orally on the day of chemotherapy and 10 mg orally on days 2, 3, 4 post chemotherapy). How long will I be in this study? You will receive the olanzapine for four days. After you finish the daily oral olanzapine for four days, your doctor will continue to watch you for side effects for an additional day. What extra tests and procedures will I have if I take part in this study? Most of the exams, tests, and procedures you will have are part of the usual approach for your cancer. However, there are some extra tests that you will need to have if you take part in this study. NCI Version Date: 03/17/

38 A Before you begin the study: You will need to have the following tests to find out if you can be in the study: Review of your medical history Physical examination including height, weight, performance status evaluation (ability to perform daily functions) Review of your current and past medications Standard blood tests (approximately 3 tablespoons of blood will be drawn) Pregnancy test if you are a woman of childbearing potential During the study: You will be completing patient questionnaires on day 1 prior to treatment and at approximately the same time as your chemotherapy was given each day for the next five days following the day of chemotherapy, days 2 through 6. You will be asked to complete a one page short questionnaire on the amount of nausea, vomiting, and/or sedation you have experienced in the previous 24 hour period. The questionnaire should take less than 10 minutes to complete each day. What possible risks can I expect from taking part in this study? Likely Side Effects of Olanzapine (when taken for 4 days): Most of the studies that have been done with 4 days of olanzapine have reported that the only evident side effect has been sedation (sleepiness). Below are listed side effects associated with this medication when it is taken for weeks to months. Possible Side Effects of Olanzapine (when taken for weeks to months) COMMON, SOME MAY BE SERIOUS In 100 people receiving olanzapine, more than 20 and up to 100 may have: Blurred vision, arm and leg swelling, restlessness, tingling of the hands and feet OCCASIONAL, SOME MAY BE SERIOUS In 100 people receiving olanzapine, from 4 to 20 may have: Sedation (sleepiness, muscle stiffness, mask-like face, impaired vision, and difficulty swallowing) RARE, AND SERIOUS In 100 people receiving olanzapine, 3 or fewer may have: Bladder pain, bruising, headache, lower back pain, muscle tension NCI Version Date: 03/17/

39 A What possible benefits can I expect from taking part in this study? It is not possible to know at this time if the study drug(s)/ approach is better than the usual approach so this study may or may not help you. This study will help researchers learn things that will help people in the future. Can I stop taking part in this study? Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let the study doctor continue to provide your medical information to the organization running the study. The study doctor will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. The study doctor may take you out of the study: If your health changes and the study is no longer in your best interest If new information becomes available If you do not follow the study rules If the study is stopped by the sponsor, Institutional Review Board or the Food and Drug Administration. What are my rights in this study? Taking part in this study is your choice. No matter what decision you make, and even if your decision changes, there will be no penalty to you. You will not lose medical care or any legal rights. For questions about your rights while in this study, call the (insert name of center) Institutional Review Board at (insert telephone number). (Note to Local Investigator: Contact information for patient representatives or other individuals at a local institution who are not on the Institutional Review Board or research team but take calls regarding clinical trial questions can also be listed here.) What are the costs of taking part in this study? The olanzapine/placebo will be supplied at no charge while you take part in this study. It is possible that the olanzapine/placebo may not continue to be supplied while you are on the study. Although not likely, if this occurs, your study doctor will talk to you about your options. You and/or your health plan/insurance company will need to pay for all of the other costs of treating your cancer while in this study, including the cost of tests, procedures, or medicines to manage any side effects, unless you are told that certain tests are supplied at no charge. Before you decide to be in the study, you should check with your health plan or insurance company to find out exactly what they will pay for. You will not be paid for taking part in this study. NCI Version Date: 03/17/

40 A What happens if I am injured or hurt because I took part in this study? If you are injured or hurt as a result of taking part in this study and need medical treatment, please tell your study doctor. The study sponsors will not offer to pay for medical treatment for injury. Your insurance company may not be willing to pay for study-related injury. If you have no insurance, you would be responsible for any costs. If you feel this injury was a result of medical error, you keep all your legal rights to receive payment for this even though you are in a study. Who will see my medical information? Your privacy is very important to us and the researchers will make every effort to protect it. Your information may be given out if required by law. For example, certain states require doctors to report to health boards if they find a disease like tuberculosis. However, the researchers will do their best to make sure that any information that is released will not identify you. Some of your health information, and/or information about your specimen, from this study will be kept in a central database for research. Your name or contact information will not be put in the database. There are organizations that may inspect your records. These organizations are required to make sure your information is kept private, unless required by law to provide information. Some of these organizations are: The Alliance for Clinical Trials in Oncology (ALLIANCE) The National Cancer Institute (NCI) The Institutional Review Board, IRB, is a group of people who review the research with the goal of protecting the people who take part in the study. The Food and Drug Administration and the National Cancer Institute in the U.S., and similar ones if other countries are involved in the study. Where can I get more information? You may visit the NCI Web site at for more information about studies or general information about cancer. You may also call the NCI Cancer Information Service to get the same information at: CANCER ( ). A description of this clinical trial will be available on as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time. Who can answer my questions about this study? You can talk to the study doctor about any questions or concerns you have about this study or to report side effects or injuries. Contact the study doctor (insert name of study doctor[s]) at (insert telephone number). NCI Version Date: 03/17/

41 A My Signature Agreeing to Take Part in the Main Study I have read this consent form or had it read to me. I have discussed it with the study doctor and my questions have been answered. I will be given a signed copy of this form. I agree to take part in the main study. Participant s signature Date of signature (The following signature and date lines for the person(s) conducting the discussion may be included at the discretion of the study sponsor.) Signature of person(s) conducting the informed consent discussion Date of signature NCI Version Date: 03/17/

42 Alliance A Page 1 of 1 APPENDIX II REGISTRATION FATIGUE/UNISCALE ASSESSMENTS At patient registration, this form is to be administered by a nurse/cra, completed by the patient, and recorded on the Registration Fatigue/Uniscale Assessments Form (see Forms Packet). If needed, this appendix can be adapted to use as a source document. A booklet containing this assessment does not exist please do not order this booklet. How would you describe: Your level of fatigue, on the average in the past week including today? No Fatigue Fatigue as bad as it can be Your overall quality of life in the past week including today? As bad as it can be As good as it can be NCI Version Date: 03/17/

43 Alliance A APPENDIX III PATIENT QUESTIONNAIRE PATIENT INFORMATION SHEET TREATMENT Patient Completed Quality of Life Booklet (Baseline) You have been given a booklet to complete for this study. The booklet contains some questions about your quality of life as a patient receiving treatment for cancer. Your answers will help us to better understand how the treatment you are receiving is affecting the way you feel. 1. This booklet is to be completed day 1 during your clinic visit prior to treatment. 2. The booklet contains 1 set of questions: a. Baseline Nausea and Vomiting Questionnaire 3. Directions on how to complete this set of questions are written on the top of the page. 4. Please return your booklet when you are finished. Thank you for taking the time to help NCI Version Date: 03/17/

44 Alliance A PATIENT INFORMATION SHEET TREATMENT Patient Completed Quality of Life Booklet (days 2-6) You have been given a booklet to complete for this study. The booklet contains some questions about your quality of life as a patient receiving treatment for cancer. Your answers will help us to better understand how the treatment you are receiving is affecting the way you feel. 1. This booklet is to be completed days 2-6 (the 5 days following your chemotherapy). 2. The booklet contains 1 set of questions: a. Nausea and Vomiting Daily Diary/Questionnaire 3. Directions on how to complete this set of questions are written on the top of the page. 4. You may call a member of the study team to answer any questions you might have. You will be given a name and telephone number. You can call anytime with any concerns or questions. A nurse/research coordinator will also call you days 2-5 and they can answer questions you might have. 5. It is very important that you return the booklet to us, whether you finish the study or not. 6. When the booklet is complete, return it in the provided envelope. Thank you for taking the time to help NCI Version Date: 03/17/

45 Alliance A APPENDIX IV BASELINE NAUSEA AND VOMITING QUESTIONNAIRE Date: / / For the following 3 questions, please circle the one number (0-10) that best describes the way you felt over the past 24 hours. 1. Please rate your worst nausea over the past 24 hours No nausea at all Nausea as bad as it can be 2. Please rate any undesired sedation trouble that you had over the past 24 hours No undesired sedation at all Undesired sedation as bad as it can be 3. Please rate any undesired appetite increase that you had over the past 24 hours No undesired appetite increase at all Undesired appetite increase as bad as it can be NCI Version Date: 03/17/

46 Alliance A APPENDIX V NAUSEA AND VOMITING DAILY DIARY/QUESTIONNAIRE Date: / / Check one option in each box, then continue and answer questions 1-3 below. Last 24 hours Nausea (check one) *Vomiting (check one) Number of extra nausea/vomiting pills taken because you developed nausea/vomiting None None None Mild Once One Moderate Twice Two Severe More than twice More than two *A single vomiting episode is defined as: a single vomit of solid or liquid stomach contents a single retch, or dry heave, that did not produce solid or liquid stomach contents any episode of continuous vomiting or retching Note: Episodes separated from each other by the absence of retching or vomiting for at least 1 minute should be considered separate emetic episodes. For the following 3 questions, please circle the one number (0-10) that best describes the way you felt over the past 24 hours. 1. Please rate your worst nausea over the past 24 hours No nausea at all Nausea as bad as it can be 2. Please rate any undesired sedation trouble that you had over the past 24 hours No undesired sedation at all Undesired sedation as bad as it can be 3. Please rate any undesired appetite increase that you had over the past 24 hours No undesired appetite increase at all Undesired appetite increase as bad as it can be NCI Version Date: 03/17/

47 Alliance A APPENDIX VI DAILY TELEPHONE CONTACT Nurse/Research Coordinator Contact Days 2 and 3 Daily Telephone contact (check one) Day 2 Day 3 Date of telephone contact or date of attempt to contact was made (dd MMM yyyy) - _- Were you able to contact the patient? Yes No (If no, then end form) If contacted, list the Time of day: HH:MM : Verify the following with the subject: Dexamethasone 8 mg PO QD taken per protocol? (check one) Yes No If No, provide reason Aprepitant 80 mg PO QD taken per protocol? (check one) Yes No NA If No, provide reason Study medication (olanzapine or placebo) 10 mg PO QD taken per protocol? (check one) Yes No If No, provide reason Rescue Medication taken? (check one) Yes No (If yes) Agent Name Dose Units of measure Number of doses the past 24 hours (Yesterday) Number of doses the current day Number of vomiting episodes over the past 24 hours Symptom Assessment: (Where 0 is none and 10 is as bad as it can be.) Worst nausea over the past 24 hours (circle one) Undesired sedation trouble over the past 24 hours (circle one) Undesired appetite increase over the past 24 hours (circle one) Did patient have any adverse events? (check one) Yes No If yes, fill out AE: Record all adverse events that meet the following criteria: grade 2 with attribution of possible, probable or definite and all grade 3, 4 and 5 regardless of attribution. Comments Please remind the patient to complete the patient diary. If possible, have the patient complete their questionnaire form while on the phone call. Please explain the rescue nausea medication information specifically Number of extra (PRN) nausea/vomiting pills taken. NCI Version Date: 03/17/

48 Alliance A Nurse/Research Coordinator Contact Day 4 Daily Telephone contact Date of telephone contact or date of attempt to contact was made: (dd MMM yyyy) - _- Were you able to contact the patient? Yes No (If no, then end form) If contacted, list the Time of day HH:MM : Verify the following with the subject: Dexamethasone 8 mg PO QD taken per protocol? (check one) Yes No If No, provide reason Study medication (Olanzapine or placebo) 10 mg PO QD taken per protocol? (check one) Yes No If No, provide reason Rescue Medication taken? (check one) Yes No (If yes) Agent Name Dose Units of measure Number of doses the past 24 hours (Yesterday) Number of doses the current day Number of vomiting episodes over the past 24 hours Symptom Assessment (Where 0 is none and 10 is as bad as it can be.) Worst nausea over the past 24 hours (circle one) Undesired sedation trouble over the past 24 hours (circle one) Undesired appetite increase over the past 24 hours (circle one) Did patient have any adverse events? (check one) Yes No If yes, fill out AE: Record all adverse events that meet the following criteria: grade 2 with attribution of possible, probable or definite and all grade 3, 4 and 5 regardless of attribution. Comments Please remind the patient to complete the patient diary. If possible, have the patient complete their questionnaire form while on the phone call. Please explain the rescue nausea medication information specifically Number of extra (PRN) nausea/vomiting pills taken. NCI Version Date: 03/17/

49 Protocol Update #01 02/15/2015 ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY PROTOCOL UPDATE TO ALLIANCE A OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY (HEC): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (Supplied agent(s): olanzapine (Alliance IND ; NSC ) and placebo for olanzapine) X Update: Eligibility changes X Therapy / Dose Modifications / Study Calendar changes X Informed Consent changes Scientific / Statistical Considerations changes Status Change: Activation Closure Suspension / temporary closure Reactivation Data Submission / Forms changes X Editorial / Administrative changes X Other IRB review of this update is required within 90 days. Expedited review is allowed. Please follow your local IRB guidelines. The Alliance does not require patient reconsent, but women of child bearing potential previously enrolled should be informed. UPDATES: Changes throughout the protocol The following changes have been made to reflect administrative and formatting revisions: Hyperlinks have been removed from web addresses and s. Alliance has been added to the header for Alliance A Cover Page At the top of the cover page, the legacy groups have been removed as all CALGB, NCCTG, and ACOSOG active studies are now conducted as Alliance studies. The address and phone number for the study chair has been updated. The fax number for the study data manager has been corrected. 1

50 The clinicaltrials.gov ID number has been added for this study. Per NCI request, the participating organization has been added. The protocol coordinator has been changed to Nathaniel Root Study Resources (Page 2) The website address has been updated for Expedited Adverse Event Reporting. For the Protocol-related questions table the last two rows have been updated with new contact information. Activation date update #1 have been added to the document history. CTSU Resources (Page 3) The CTSU table has been revised to include updated standard language from CTSU. Schema (Page 5) Olanzapine (Days 1-4) and Placebo (Days 1-4) have been added to the appropriate boxes in the schema. Section 1.2: Study Design and Treatment Regimen (Pages 11 & 12) In the first paragraph, The study is designed and measured using dexamethasone PO. If an institution typically gives IV dexamethasone, then the institution s standing protocol must be changed for study participants to receive dexamethasone PO. There is no exception to this study detail, was added. Section 3.1: On-Study Guidelines (Page 13) Uncontrolled diabetes mellitus has been removed from the second bullet point as it is listed in the eligibility criteria. Section 3.2: Eligibility Criteria (Page 14) This paragraph has been added as additional guidance for sites evaluating patient s eligibility of this study: Use the spaces provided to confirm a patient s eligibility by indicating Yes or No as appropriate. It is not required to complete or submit the following pages. Section 3.2.2: Eligibility Criteria (Page 14) The first bullet has been updated to specify Cisplatin, given on a single day, at a dose of Section 3.2.7: Eligibility Criteria (Page 14) The first sentence has been revised to eliminate per clinician discretion : Negative pregnancy test (serum or urine) done 7 days prior to registration, for women of childbearing potential only (per clinician discretion). This paragraph has been added to further expand the definition of child bearing potential: A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Section : Eligibility Criteria (Page 15) and Schema (Page 5) The following criteria has been revised as follows: No history of uncontrolled diabetes mellitus. (e.g. on insulin or an oral hypoglycemic agent) i.e., no recent diabetic ketoacidosis; Patients are eligible if they have controlled diabetes on diet, oral agents, and/or insulin. Section 4.0: Patient Registration (Page 15) Subsections have been added and renumbered in this section due to the addition of CTSU template language. 2

51 Sections 4.1, 4.2, and 4.3: CTSU Registration Procedures (Page 15) These sections have been added per updated CTSU standard language. Section 4.4: Registration Requirements (Page 16) This section has been revised to include guidance for ordering patient questionnaire booklets. Section 4.5: Patient Registration/Randomization Procedures (Page 16) This section has been revised to be consistent with Alliance standard language regarding patient registration and randomization. Section 4.6.2: Treatment Assignments (Page 17) The reference to has been updated to the correct section Section : Procedures for Double-Blinding the Treatment Assignment (Page 18) The following has been added to the end of the paragraph to include instructions for when a study medication code number is not displayed, If the code number is not displayed, contact the Registration Office at or random01@mayo.edu. Section 5.0: Study Calendar (Page 18) The first paragraph has been added as additional guidance for sites regarding test and procedures. The following has been added as a * footnote to clarify the time prior to registration that history and physical examination may be performed: History and physical examination completed prior to registration may be used if obtained 16 days prior to treatment. The Nurse/Research Coordinator line has been removed from the table and footnotes 2 and 3 have been rewritten for clarity. The Nurse/Research Coordinator are to contact patients on days 2-5, weekends and holidays included. Section 6.0: Data and Specimen Submission (Page 19) This section has been renamed (formerly Data and Specimen Submission ) as specimens are not collected for shipment in this study and has been revised to include Alliance standard language for data submission. Section 7.0: Treatment Plan/Intervention (Page 20) The table has been reformatted to better display the treatment plan. The dosing range for ondansetron has been changed to 8-16mg as this range of dosing has been suggested by multiple guidelines. Additional information regarding dexamethasone route of administration and the times of day that olanzapine/placebo may be taken has been added as footnotes to the table. Section 7.2: Data Collection and Forms (Page 20) The sentence Only the Baseline Nausea and Vomiting Questionnaire should be completed on day 1, has been added for clarity. Sections 8.3, 8.3.1, and 8.3.2: Unblinding Procedures (Page 22) These sections have been revised to include updated Alliance standard language for emergency unblinding procedures.) Section 9.0: Adverse Events (Page 22) The sentence Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details on AE reporting procedures, has been added to the end of the first paragraph. 3

52 Section 9.1: Routine Adverse Event Reporting (Page 22) The sentence Adverse events are reported in a routine manner at scheduled times according to the study calendar in Section 5.0. For this trial, the A Adverse Events form is used for routine AE reporting in Rave, has been added to the end of the first paragraph. Section 9.2: Expedited Adverse Event Reporting (CTEP-AERS) (Page 22) This section has been revised to include additional guidance to sites regarding reporting of adverse events. Section 10.1: Olanzapine (Zyprexa ) or placebo (Page 25) Under Storage and Stability, the following sentences have been added to provide additional information regarding olanzapine: Olanzapine tablets are stored at controlled room temperature, 20º to 25ºC (68º to 77ºF). The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20º to 25ºC (68º to 77ºF) that results in a mean kinetic temperature calculated to be not more than 25ºC and that allows for excursions between 15º and 30ºC (59º and 86ºF) that are experienced in pharmacies, hospitals, and warehouses. Protect olanzapine tablets from light and moisture. Section 10.2: Nursing Guidelines (Page 27) The subsection has been added to specify the number of tablets per bottle for both the study drugs. Appendix I: Consent Form (Page 37) NCI Consent Form Template Version Date: May 12, 2013, has been removed from the top of the first page as the correct version date is indicated in the footer. Appendix I: Consent Form - What are the study groups? (Page 38) The following revision has been made to the first sentence: This study has two study groups. Group 1 will receive the study drug olanzapine and a placebo (a pill that looks like the study drug but contains no medication) and Group 2 will receive a placebo, a pill that looks like the study drug but contains no medication the study drug olanzapine. Appendix I: Consent Form - How long will I be in this study? (Page 38) The following revision has been made to the first sentence: You will receive either the olanzapine or placebo (depending on your group assignment) for four days. The following has been added as the second sentence to clarify that patients will be contacted for AEs: You will be contacted on days 2-5 and asked how you are feeling. Appendix I: Consent Form - Possible Side Effects of Olanzapine (when taken for weeks to months) (Page 40) The following paragraph, which had been inadvertently omitted from the model consent form, was added at the end of this section: Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this study. The drug used in this study could be very damaging to an unborn baby. Check with the study doctor about what types of birth control, or pregnancy prevention, to use while in this study. A replacement protocol document has been issued ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 4

53 ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY ALLIANCE A OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY (HEC): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL Supplied agent(s): olanzapine (Alliance IND ; NSC ) and placebo for olanzapine ClinicalTrials.gov Identifier: NCT Study Chair Rudolph M. Navari, MD, PhD, FACP Indiana University School of Medicine South Bend 1234 Notre Dame Ave South Bend, IN Tel: Fax: rmnavari@gmail.com Symptom Intervention Committee Chair Health Outcomes Committee Study Co-chair Charles L. Loprinzi, MD Kathryn J. Ruddy, MD Mayo Clinic Mayo Clinic Tel: Tel: cloprinzi@mayo.edu ruddy.kathryn@mayo.edu Primary Statistician Secondary Statistician Rui Qin, PhD Heshan Liu Tel: Tel: qin.rui@mayo.edu liu.heshan@mayo.edu Protocol Coordinator Data Manager Nathaniel Root Cristina Zabel Tel: Tel: rootnl@uchicago.edu Fax: zabel.cristina@mayo.edu Participating Organizations: ALLIANCE/ Alliance for Clinical Trials in Oncology 1 NCI Version Date: 01/27/2015 Update #01

54 Alliance A Study Resources Expedited Adverse Event Reporting Medidata Rave imedidata portal OPEN (Oncology Patient Enrollment Network) Biospecimen Management System A Nursing Contact Joanne Lester Institution: The Ohio State University Tel: Protocol Contacts: A Pharmacy Contact Heidi D. Finnes, PharmD, BCOP Institution: Mayo Clinic Tel: Protocol-related questions may be directed as follows: Questions Questions regarding patient eligibility, treatment, and dose modification: Questions related to data submission, RAVE or patient follow-up: Questions regarding the protocol document: Questions related to IRB issues and model consent revisions: Questions regarding CTEP-AERS reporting: Contact (via ) Study Chair, Nursing Contact, Protocol Coordinator, and (where applicable) Data Manager Data Manager Protocol Coordinator Alliance Regulatory Inbox Regulatory Affairs Manager: (773) Document History Effective Date: Pre-Activation 04/22/2014 Activation 08/15/2014 Update #01 02/15/ NCI Version Date: 01/27/2015 Update #01

55 Alliance A CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION To submit site registration documents: CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA Phone CTSU Fax For patient enrollments: Please refer to the patient enrollment section for instructions on using the OPEN system. Submit study data directly to the Lead National Clinical Trial Network (NCTN) Group unless otherwise specified in the protocol: All participating sites will submit study data via Medidata Rave System. Do not submit study data or forms to CTSU Data Operations. Do not copy the CTSU on data submissions. The study protocol and all related forms and documents must be downloaded from the protocolspecific Web page of the CTSU Member Web site located at Sites must use the current form version and adhere to the instructions and submission schedule outlined in the protocol. CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. For patient eligibility or treatment-related questions see the Protocol Contacts, Page 2. For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by phone or CTSU General Information Line , or All calls and correspondence will be triaged to the appropriate CTSU representative. For detailed information on the regulatory and monitoring procedures for CTSU sites please review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members website The CTSU Web site is located at 3 NCI Version Date: 01/27/2015 Update #01

56 Alliance A OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY (HEC): A Randomized, Double-Blind, Placebo-Controlled Trial Eligibility Criteria (see Section 3.0) Diagnosis of malignant disease. Overview No prior chemotherapy and scheduled to receive HEC (either cisplatin-containing regimen or anthracycline + cyclophosphamide [AC]). (See Section for additional details) Age 18 years. ECOG Performance Status 0, 1 or 2 No nausea or vomiting 24 hours prior to registration. Negative pregnancy test (serum or urine) done 7 days prior to registration, for women of childbearing potential only (per clinician discretion). No severe cognitive compromise. No known history of CNS disease (e.g. brain metastases, seizure disorder). No treatment with another antipsychotic agent such as risperidone, quetiapine, clozapine, phenothiazine or butyrophenone for 30 days prior registration or planned during protocol therapy. No chronic phenothiazine administration as an antipsychotic agent (patients may receive prochloperazine and other phenothiazines as rescue antiemetic therapy). No concurrent use of amifostine. No concurrent abdominal radiotherapy. No concurrent use of quinolone antibiotic therapy. No chronic alcoholism (as determined by the investigator). No known hypersensitivity to olanzapine. No known cardiac arrhythmia, uncontrolled congestive heart failure or acute myocardial infarction within the previous six months. No history of uncontrolled diabetes, i.e., no recent diabetic ketoacidosis; Patients are eligible if they have controlled diabetes on diet, oral agents, and/or insulin. Required Initial Laboratory Values Absolute 1500/mm 3 neutrophil count (ANC) Serum Creatinine 2.0 mg/dl SGOT or SGPT 3 x upper limit of normal (ULN) 4 NCI Version Date: 01/27/2015 Update #01

57 Alliance A Schema 5-HT 3# (Day 1) + Dex (Day 1-4) + Fosaprepitant* (Day 1) + Record Nausea (linear visual analogue scale) HEC Randomize Placebo (Days 1-4) 5-HT 3# (Day 1) + Dex (Day 1-4) + and Complete Response (no emesis, no rescue) Fosaprepitant* (Day 1) + Olanzapine (Days 1-4) Cycle Length = 1 Day NOTE: Cycle is an Alliance data management tool to facilitate consistent remote data entry. # palonosetron, ondansetron, or granisetron * or oral aprepitant for 3 days Please refer to the full protocol text for a complete description of the eligibility criteria and treatment plan. 5 NCI Version Date: 01/27/2015 Update #01

58 Alliance A Section Table of Contents 1.0 BACKGROUND STUDY RATIONALE STUDY DESIGN AND TREATMENT REGIMEN REGISTRATION QUALITY OF LIFE (QOL) MEASUREMENTS OBJECTIVES PRIMARY OBJECTIVE SECONDARY OBJECTIVE(S) PATIENT SELECTION ON-STUDY GUIDELINES ELIGIBILITY CRITERIA PATIENT REGISTRATION REGISTRATION REQUIREMENTS STRATIFICATION FACTORS AND TREATMENT ASSIGNMENTS STUDY CALENDAR DATA AND SPECIMEN SUBMISSION DATA COLLECTION AND SUBMISSION TREATMENT PLAN/INTERVENTION DEFINITIONS OF DEVIATIONS IN PROTOCOL PERFORMANCE DATA COLLECTION AND FORMS DOSE AND TREATMENT MODIFICATIONS, UNBLINDING ANCILLARY THERAPY, CONCOMITANT MEDICATIONS, AND SUPPORTIVE CARE DOSE MODIFICATIONS UNBLINDING PROCEDURES ADVERSE EVENTS ROUTINE ADVERSE EVENT REPORTING EXPEDITED ADVERSE EVENT REPORTING (CTEP-AERS) DRUG INFORMATION OLANZAPINE (ZYPREXA ) OR PLACEBO NURSING GUIDELINES PLACEBO MEASUREMENT OF EFFECT END OF TREATMENT/INTERVENTION DURATION OF TREATMENT: ONE CYCLE MANAGING INELIGIBLE AND CANCELED PATIENTS AND MAJOR PROTOCOL VIOLATIONS EXTRAORDINARY MEDICAL CIRCUMSTANCES STATISTICAL CONSIDERATIONS STUDY OVERVIEW SAMPLE SIZE, ACCRUAL TIME AND STUDY DURATION SUPPLEMENTARY ANALYSIS PLANS STUDY MONITORING STUDY REPORTING DESCRIPTIVE FACTORS - NONE NCI Version Date: 01/27/2015 Update #01 Page

59 Alliance A INCLUSION OF WOMEN AND MINORITIES CORRELATIVE AND COMPANION STUDIES NONE GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING NONE REFERENCES APPENDIX I CONSENT FORM APPENDIX II REGISTRATION FATIGUE/UNISCALE ASSESSMENTS APPENDIX III PATIENT QUESTIONNAIRE APPENDIX IV BASELINE NAUSEA AND VOMITING QUESTIONNAIRE APPENDIX V NAUSEA AND VOMITING DAILY DIARY/QUESTIONNAIRE APPENDIX VI DAILY TELEPHONE CONTACT NCI Version Date: 01/27/2015 Update #01

60 Alliance A BACKGROUND 1.1 Study Rationale Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life and is perceived by patients as a major adverse effect of the treatment [1]. The use of 5-hydroxytryptamine 3 (5-HT 3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV [2]. Recent studies have demonstrated additional improvement in the control of acute CINV and also delayed CINV with the use of three new agents, palonosetron, a second generation 5-HT 3 receptor antagonist [3], aprepitant, the first agent available in the drug class of neurokinin-1 (NK-1) receptor antagonists [4,5], and olanzapine, an antipsychotic which blocks multiple neurotransmitters in the central nervous system [6-8]. Palonosetron is a second generation 5-HT 3 receptor antagonist which has anti-emetic activity at both central and gastrointestinal sites. In comparison to the first generation 5-HT 3 receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT 3 receptors [9,10]. These differences may explain palonosetron s efficacy in delayed CINV compared to the first generation receptor antagonists [3]. A high level of efficacy and an excellent safety profile has been demonstrated in a number of studies [3,9,11-14]. Based on these studies, palonosetron is recommended by multiple international antiemetic guidelines [15-17] for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy (HEC) and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). Aprepitant is an NK-1 receptor antagonist which blocks the emetic effects of substance-p [4,5,18]. When combined with a standard regimen of the corticosteroid dexamethasone and a 5-HT 3 receptor antagonist, aprepitant is effective in the prevention of CINV in patients receiving HEC [5,18]. This regimen is recommended in the guidelines of multiple international groups for the control of CINV in patients receiving HEC [15-17]. The intravenous form of aprepitant, fosaprepitant, has recently been approved by the FDA. One intravenous dose of fosaprepitant prior to chemotherapy has been shown to be equivalent to the daily three day oral dose of aprepitant [19]. Palonosetron and aprepitant have been combined with dexamethasone for the prevention of CINV in a phase II study of fifty-eight patients who received MEC [20]. This three drug antiemetic regimen was found to be safe and highly effective in preventing CINV in the acute, delayed, and overall periods. Olanzapine is an FDA approved antipsychotic that blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT 2a, 5-HT 2c, 5-HT 3, 5-HT 6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors [21,22]. Common side effects are sedation and weight gain [23,24], as well as an association with the onset of diabetes mellitus [25]. Olanzapine s activity at multiple receptors, particularly at the D2, 5-HT 2c, and 5-HT 3 receptors which appear to be involved in nausea and emesis, suggests that it may have significant anti-emetic properties. A recent single institution phase III trial demonstrated that olanzapine, when combined with a single dose of dexamethasone and a single dose of palonosetron, was very effective in controlling acute and delayed CINV in patients receiving HEC [7] as illustrated in Figures 1a and 1b. There was excellent control of nausea without the use of multiple days of dexamethasone. In addition, a 8 NCI Version Date: 01/27/2015 Update #01

61 Alliance A phase III study showed the addition of olanzapine to the 5-HT 3 receptor antagonist azasetron and dexamethasone improved delayed CINV in patients receiving HEC (Figures 2a and 2b) or MEC (Figures 3a and 3b) [8]. A recent study compared olanzapine to metoclopramide for the treatment of breakthrough emesis and nausea in patients receiving HEC and guideline-directed antiemetic prophylaxis [26]. Olanzapine was significantly better than metoclopramide for the treatment of breakthrough emesis and nausea. This was the first phase III study on the treatment of breakthrough emesis and nausea (Figure 4). Figure 1a. Complete response of patients receiving olanzapine, palonosetron, and dexamethasone or aprepitant, palonosetron, and dexamethasone prior to HEC. Figure 1b. Percent of patients with no nausea after receiving olanzapine, palonosetron, and dexamethasone or aprepitant, palonosetron, and dexamethasone. Figure 2a. Complete response of patients receiving olanzapine, azasetron, and dexamethasone or azasetron and dexamethasone prior to HEC. Figure 2b. Percent of patients with no nausea after receiving olanzapine, azasetron, and dexamethasone or azasetron, and dexamethasone. 9 NCI Version Date: 01/27/2015 Update #01

62 Alliance A Figure 3a. Complete response of patients receiving olanzapine, azasetron, and dexamethasone or azasetron and dexamethasone prior to MEC Figure 3b. Percent of patients with no nausea after receiving olanzapine, azasetron, and dexamethasone or azasetron, and dexamethasone. Figure 4. Percentage of patients with breakthrough CINV treated with olanzapine (OLN) or metoclopramide (METO) with no emesis or no nausea over a 72 hour observation period. As study investigators, we are very impressed with the results that have been seen in clinical trials evaluating olanzapine for the prevention and treatment of chemotherapy induced nausea and vomiting. Nonetheless, in order to confirm the results from reported trials that support the value of olanzapine [6-8, 26], a multi-institution, double-blind, placebo-controlled clinical trial is needed. International guideline committee reports have suggested that further study is in order, but have not been impressed enough to endorse this drug as an effective agent when added to standard therapy. Given this, we believe that we should see what this drug does to improve results over what is seen using standard practice. Since multiple smaller studies support the potential value of olanzapine for preventing and treating chemotherapy-induced nausea and vomiting, we considered multiple study designs including: Treatment of established chemotherapy-induced nausea/vomiting Using olanzapine in patients who had unacceptable nausea vomiting with one chemotherapy cycle and were about to receive another Comparing it to aprepitant 10 NCI Version Date: 01/27/2015 Update #01

63 Alliance A Conducting a placebo-controlled trial without aprepitant (conducting a trial comparing olanzapine to placebo and omitting aprepitant in both arms of the trial) Using it with less corticosteroids (using a reduced dose of corticosteroids in the trial) After much discussion with multiple parties over several months, we decided on the design presented in this protocol. We proposed 4 days of dexamethasone in this trial because standard practice is to use 4 days of dexamethasone, as per ASCO, NCCN, and MASCC guidelines [15-17]. We extensively discussed using a single day of dexamethasone or allowing this to be physician s choice, but the 4 day choice was chosen to be consistent with the current guidelines. Patients receiving HEC, including the combination of cyclophosphamide and doxorubicin, appear to have a significant amount of nausea post chemotherapy [7, 27] despite prophylactic anti-emetics. An effective anti-nausea agent is needed for this patient population. The potential short term toxicity of olanzapine is sedation [21,22]. The long term toxicities include weight gain and hyperglycemia in some patients who take olanzapine for 3-6 months [21-24]. In the published phase II and phase III prophylactic CINV studies [6-8], there has been no evidence that weight gain and hyperglycemia occur when using olanzapine as a preventative agent for CINV during the five days post chemotherapy. In addition, there were no Grade III or IV toxicities reported in any of the clinical trials and accrual was not impacted in any of the phase II or Phase III trials. Sedation will be monitored with the treatment cycle. We will not monitor weight gain or hyperglycemia, since patients will be treated with olanzapine for only 4 days. With regards to potential drug interactions, olanzapine has been given without any apparent clinical toxicities with other antiemetics such as dexamethasone and 5-HT 3 receptor antagonists [6-8]. While we are unaware of any studies that have combined olanzapine with aprepitant, given that the various targeted receptors, mechanisms of action, and metabolism of each of these agents (aprepitant and olanzapine) are markedly different, significant interactions would not be anticipated. Supporting this contention, a Micromedex 2.0 search of interactions among all of these drugs (olanzapine, aprepitant, palonosetron, ondansetron, granisetron and dexamethasone) confirms that there are none, aside from the well-known phenomenon that increased systemic exposure to dexamethasone occurs with the concurrent use of dexamethasone and aprepitant. The purpose of this study is to measure the efficacy of olanzapine in the prevention of CINV (particularly nausea) in patients receiving HEC. Olanzapine or placebo will be added to the guideline directed antiemetics for HEC regimens to determine if the control of nausea and emesis can be significantly improved during the 120 hours post chemotherapy. The current guidelines recommend any of the currently available 5-HT 3 receptor antagonists (palonosetron, ondansetron, or granisetron). It is particularly important for this be conducted as a cooperative group study, as opposed to being conducted by a pharmaceutical company, since nausea control is not an on-label indication for olanzapine and the present study is designed to increase our knowledge concerning new mechanisms of nausea control, not to support a label extension for olanzapine. In addition, olanzapine is generic and quite inexpensive. 1.2 Study Design and Treatment Regimen All patients eligible for the study receiving HEC will receive a 5-HT# receptor antagonist (palonosetron 0.25 mg IV, or granisetron 1mg IV or 2mg PO, or ondansetron 8mg IV or PO) on day one, dexamethasone (12 mg PO, day one; 8 mg PO, days 2-4) and an NK-1 receptor antagonist, day one; plus olanzapine (10 mg/day, days 1 to 4) or a matching placebo (days 1 to 4). The NK-1 receptor antagonist may be in the form of intravenous fosaprepitant (150 mg, day one) or oral aprepitant (125 mg, day 1; 80 mg, days 2, 3). The protocol doses of the 5-HT3 receptor antagonists, 11 NCI Version Date: 01/27/2015 Update #01

64 Alliance A dexamethasone, and aprepitant listed above are standard doses recommended by various international anti-emetics guidelines [15-17]. The study is designed and measured using dexamethasone PO. If an institution typically gives IV dexamethasone, then the institution s standing protocol must be changed for study participants to receive dexamethasone PO. There is no exception to this study detail. The protocol doses of olanzapine were determined from the various studies in the literature [2, 6-8, 28]. In a phase I trial of olanzapine as a prophylactic antiemetic, Passik et al [28] determined that 10 mg/day for four days was a dose without toxicity and minimal sedation. Navari et al [6] used a loading dose of olanzapine (daily for two days prior to chemotherapy), but subsequently determined that a loading dose was not necessary for efficacy and demonstrated that 10mg /day for four days beginning with the day of chemotherapy was highly efficacious in the prevention of nausea and emesis [6,7]. Patients will be stratified according to gender, their chemotherapy regimen, and the specific 5-HT 3 receptor antagonist used. Protocol therapy will be instituted for single day chemotherapy (see Section 7) for one cycle only. Patients will be permitted to take rescue therapy of the treating investigator s choice for nausea and/or emesis/retching, based on clinical circumstances. Multiple other study designs were extensively discussed at multiple meetings and by group phone calls and in writing, over several months, before the group consensus settled on the currently described study design. Concepts considered included studying HEC versus moderately emetogenic chemotherapy versus both; evaluating one cycle therapy versus several cycles of therapy; using nausea versus vomiting versus both as primary end points; mandating aprepitant versus allowing use to be patient/physician choice; comparing olanzapine to aprepitant; using olanzapine to treat nausea and vomiting that occurred after chemotherapy versus as an agent to prevent the problem. 1.3 Registration Quality of Life (QOL) Measurements QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance studies and will be assessed upon registration in this study. Fatigue and overall well-being clearly can impact how well patients will do in terms of being able to tolerate and experience nausea and vomiting [29]. Our group and others have done extensive work indicating that these simple measures of fatigue and overall QOL impact survival and other treatment outcomes [30-32]. This work has involved over fifty clinical trials and patient populations across the cancer spectrum. A recent meta-analysis (n=13,874) showed that 36 of 39 studies indicated that analogues of patient reported outcomes were significantly associated with overall survival [33]. A literature review of over 100 studies from 1982 to 2008 indicated that patient reported outcomes measures were significant independent predictors of survival duration [34]. Osoba [35] provides an overall rationale for the use of these measures in all clinical trials. If there is an imbalance in QOL or fatigue at baseline across treatment arms, it is universally recognized that it could confound the treatment comparison (Draft Guideline on Adjustment for Baseline Covariates, European Medicines Agency, EMA/295050/2013; pdf). As such, it is important to include these variables as covariates in the efficacy testing to demonstrate the robustness of the results and produce more efficient estimates of efficacy. 12 NCI Version Date: 01/27/2015 Update #01

65 Alliance A OBJECTIVES 2.1 Primary objective To compare between the two study arms the number of patients with no nausea for the acute (0-24 hours post-chemotherapy), delayed ( hours post-chemotherapy) and overall periods (0-120 hours post-chemotherapy) for patients receiving HEC. 2.2 Secondary objective(s) To compare between the two study arms the complete response (CR) (no emetic episodes and no use of rescue medication) in the acute, delayed, and overall periods To compare between the two study arms, the incidences of potential toxicities that have been ascribed to olanzapine. 3.0 PATIENT SELECTION For questions regarding eligibility criteria, see the Contact Information page. Please note that the Study Chair cannot grant waivers to eligibility requirements. 3.1 On-Study Guidelines This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All relevant medical and other considerations should be taken into account when deciding whether this protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although they will not be considered formal eligibility (exclusion) criteria, physicians should recognize that the following may seriously increase the risk to the patient entering this protocol: Psychiatric illness that would prevent the patient from giving informed consent. Medical condition such as uncontrolled infection (including HIV) or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient. Patients with a currently active second malignancy other than non-melanoma skin cancers. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for 3 years. Patients who cannot swallow oral formulations of the agent(s). In addition: Women of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. 13 NCI Version Date: 01/27/2015 Update #01

66 Alliance A Eligibility Criteria Use the spaces provided to confirm a patient s eligibility by indicating Yes or No as appropriate. It is not required to complete or submit the following pages Diagnosis of malignant disease No prior chemotherapy and scheduled to receive HEC (either cisplatin-containing regimen or anthracycline + cyclophosphamide [AC]). Cisplatin, given on a single day, at a dose of 70mg/m 2, with or without other chemotherapy agent(s) OR Age 18 years. Anthracycline (60 mg/m 2 ) plus cyclophosphamide(600 mg/m 2 ) ECOG Performance Status 0, 1 or Required Initial Laboratory Values 120 days prior to registration. Serum Creatinine 2.0 mg/dl SGOT or SGPT 3 x upper limit of normal (ULN) Absolute neutrophil count (ANC) 1500/mm No nausea or vomiting 24 hours prior to registration Negative pregnancy test (serum or urine) done 7 days prior to registration, for women of childbearing potential only. A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) No severe cognitive compromise No known history of CNS disease (e.g. brain metastases, seizure disorder) No treatment with another antipsychotic agent such as risperidone, quetiapine, clozapine, phenothiazine or butyrophenone 30 days prior to registration or planned during protocol therapy No chronic phenothiazine administration as an antipsychotic agent (patients may receive prochloperazine and other phenothiazines as rescue anti-emetic therapy) No concurrent use of amifostine No concurrent abdominal radiotherapy No concurrent use of quinolone antibiotic therapy No chronic alcoholism (as determined by the investigator) No known hypersensitivity to olanzapine. 14 NCI Version Date: 01/27/2015 Update #01

67 Alliance A No known cardiac arrhythmia, uncontrolled congestive heart failure or acute myocardial infarction within the previous six months No history of uncontrolled diabetes mellitus, i.e., no recent diabetic ketoacidosis; Patients are eligible if they have controlled diabetes on diet, oral agents, and/or insulin. 4.0 PATIENT REGISTRATION 4.1 CTEP Investigator Registration Procedures Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all investigators participating in any NCI-sponsored clinical trial to register and to renew their registration annually. Registration requires the submission of: a completed Statement of Investigator Form (FDA Form 1572) with an original signature a current Curriculum Vitae (CV) a completed and signed Supplemental Investigator Data Form (IDF) a completed Financial Disclosure Form (FDF) with an original signature Fillable PDF forms and additional information can be found on the CTEP website at For questions, please contact the CTEP Investigator Registration Help Desk by at pmbregpend@ctep.nci.nih.gov. 4.2 CTSU Site Registration Procedures / CTEP-IAM Account The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application is a web-based application intended for use by both Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-IAM application to register (both initial registration and annual re-registration) with CTEP and to obtain a user account. Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator Registration Procedures above for information on registering with CTEP as an Investigator, which must be completed before a CTEP-IAM account can be requested.) An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications, including the CTSU members website. Additional information can be found on the CTEP website at For questions, please contact the CTEP Associate Registration Help Desk by at ctepreghelp@ctep.nci.nih.gov. 4.3 CTSU Registration Procedures This study is supported by the NCI Cancer Trials Support Unit (CTSU). IRB Approval: Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be approved to enroll patients. Study centers can check the status of their 15 NCI Version Date: 01/27/2015 Update #01

68 Alliance A registration packets by querying the Regulatory Support System (RSS) site registration status page of the CTSU members website by entering credentials at For sites under the CIRB initiative, IRB data will automatically load to RSS. Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are not required to submit separate IRB approval documentation to the CTSU Regulatory Office for initial, continuing or amendment review. This information will be provided to the CTSU Regulatory Office from the CIRB at the time the site s Signatory Institution accepts the CIRB approval. The Signatory site may be contacted by the CTSU Regulatory Office or asked to complete information verifying the participating institutions on the study. Other site registration requirements (i.e., laboratory certifications, protocol-specific training certifications, or modality credentialing) must be submitted to the CTSU Regulatory Office or compliance communicated per protocol instructions Submitting Regulatory Requirements Submit completed forms along with a copy of your IRB Approval (for sites not participating via the NCI CIRB), Model Informed Consent (for sites not participating via the NCI CIRB), and any other required documentation (see above) to the CTSU Regulatory Office, where they will be entered and tracked in the CTSU RSS. CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA Phone: Fax: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 4.4 Patient Registration Requirements Informed consent: the patient must be aware of the neoplastic nature of his/her disease and willingly consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human protection committee approval of this protocol and a consent form is required prior to patient consent and registration. Patient completed booklets: Patient questionnaire booklets are to be ordered prior to the registration of any patients. Patient completed booklets can be ordered by downloading and completing the booklet ordering form (located under the supplemental documents section of the A Alliance website) and faxing the form to Attn: Operational Support Clerk at Samples of the questionnaires are found in Appendices III-V, which are to be used for reference and IRB submission only. They are not to be used for patient completion. 4.5 Patient Registration/Randomization Procedures CTSU registration requirements Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site user must have an active CTEP-IAM account (check at and a 'Registrar' role on either the LPO or participating organization roster. 16 NCI Version Date: 01/27/2015 Update #01

69 Alliance A All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in the Rave database. OPEN can be accessed at or from the OPEN tab on the CTSU members side of the website at A user manual is available for OPEN users on the CTSU site. Prior to accessing OPEN, site staff should verify the following: All eligibility criteria have been met within the protocol stated timeframes. All patients have signed an appropriate consent form and HIPAA authorization form (if applicable). Note: The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records. Further instructional information is provided on the OPEN tab of the CTSU members side of the CTSU website at or at For any additional questions contact the CTSU Help Desk at or ctsucontact@westat.com. 4.6 Stratification Factors and Treatment Assignments Stratification Factors Gender: Male vs. Female Chemotherapy Regimen: cisplatin-containing regimen vs. anthracycline + cyclophosphamide (AC) HT 3 Receptor Antagonist: palonosetron vs. ondansetron vs. granisetron Treatment Assignments The factors defined in will be used as stratification factors After the patient has been registered into the study, the values of the stratification factors will be recorded, and the patient will be assigned to one of the following treatment groups using the Pocock and Simon dynamic allocation procedure which balances the marginal distributions of the stratification factors between the treatment groups [36]. 5-HT 3 receptor antagonist (palonosetron, ondansetron, or granisetron) + dexamethasone + aprepitant/fosaprepitant + placebo 5-HT 3 receptor antagonist (palonosetron, ondansetron, or granisetron) + dexamethasone + aprepitant/fosaprepitant + olanzapine To ensure both the patient and the medical professionals who care for the patient are blinded to the identity of the treatment assignment, the Registration Specialist will follow the double-blinding procedures outlined in Section NCI Version Date: 01/27/2015 Update #01

70 Alliance A Procedures for Double-Blinding the Treatment Assignment After the treatment assignment has been ascertained in the OPEN application, the patient s study medication code number will be displayed on the confirmation of registration screen. If the code number is not displayed, contact the Registration Office at or random01@mayo.edu The pharmacist or designated contact person at the treating site will maintain records that indicate the identity of the patient and their corresponding study medication code number. 5.0 STUDY CALENDAR Laboratory and clinical parameters during treatment are to be followed using individual institutional guidelines and the best clinical judgment of the responsible physician. It is expected that patients on this study will be cared for by physicians experienced in the treatment and supportive care of patients on this trial. Prior to Registration Days 1-6 Tests & Observations History and physical, weight, ECOG PS X Height X Adverse Event Assessment X 3 Registration Fatigue/Uniscale Assessment (Appendix II) X 1 Patient Questionnaire (Appendices III-V) X 1 X 2 Laboratory Studies Serum or Urine HCG X 4 Creatinine, SGOT,SGPT ANC X 5 * History and physical exam completed prior to registration may be used if obtained 16 days prior to treatment. 1 To be completed after registration and prior to treatment. 2 Patient is to complete the diary on days 2-6. Nurse/Research Coordinator will contact the patient on days 2-5 only (weekends & holidays included) to remind the patient to complete the diary. The Nurse/Research Coordinator should call the patient at the same time of day as the chemotherapy was given on day 1 (+/- 1 hour) (See Appendix VI). 3 Nurse/Research Coordinator will contact each patient each day (days 2-5, weekends & holidays included) to remind the patient to complete forms, answer questions, and to query adverse events. Adverse events experienced by patients on day 1 and day 2 will be collected during the nurse phone call on day 2. 4 For women of childbearing potential (see Section 3.2.7). Must be done 7 days prior to registration. 5 To be completed 120 days prior to registration. 18 NCI Version Date: 01/27/2015 Update #01

71 Alliance A DATA AND SPECIMEN SUBMISSION 6.1 Data collection and submission Data collection for this study will be done exclusively through the Medidata Rave clinical data management system. Access to the trial in Rave is granted through the imedidata application to all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave via imedidata, the site user must have an active CTEP-IAM account (check at and the appropriate Rave role (Rave CRA, Read- Only, Site Investigator) on either the LPO or participating organization roster at the enrolling site. Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation from imedidata. To accept the invitation, site users must log into the Select Login ( using their CTEP-IAM user name and password, and click on the accept link in the upper right-corner of the imedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (elearnings), and can be accessed by clicking on the link in the upper right pane of the imedidata screen. Users who have not previously activated their imedidata/rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from imedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on imedidata/rave is available on the CTSU members website under the Rave tab at or by contacting the CTSU Help Desk at or by at ctsucontact@westat.com. A Schedule of Forms is available on the Alliance study webpage, within the Case Report Forms section. 19 NCI Version Date: 01/27/2015 Update #01

72 Alliance A TREATMENT PLAN/INTERVENTION Protocol treatment is to begin 14 days of registration. Protocol therapy will be instituted for single day chemotherapy for one cycle only. Patients will be permitted to take rescue therapy of the treating investigator s choice for nausea and/or emesis/retching, based on clinical circumstances. NOTE: Chemotherapy is to be given on Day 1 of protocol treatment. Agent Day 1 a Day 2 Day 3 Day 4 1. Palonosetron OR 0.25 mg Ondansetron, OR Granisetron 8-16 mg IV OR PO 1 mg IV, OR 2 mg PO Dexamethasone b 12 mg PO 8 mg PO c 8 mg PO c 8 mg PO c 3. Fosaprepitant, OR 150 mg IV Aprepitant 125 mg PO 80 mg PO 80 mg PO - 4. Olanzapine or 10 mg PO 10 mg PO placebo d 10 mg PO d 10 mg PO d a On Day 1, all agents are to be given prior to chemotherapy. b The study is designed and measured using dexamethasone PO. If an institution typically gives IV dexamethasone, then the institution s standing protocol must be changed for study participants to receive dexamethasone PO. There is no exception to this study detail. c On Days 2-4, dexamethasone is to be taken in the morning with breakfast. d On days 2-4, olanzapine/placebo may be taken the morning or at bedtime. The patient should record the time of day in the patient diary. 7.1 Definitions of Deviations in Protocol Performance Major Deviations A "major deviation" is a situation in which patient safety or outcome is compromised. Minor Deviations A "minor deviation" is a discrepancy from the protocol that is not of sufficient magnitude to prevent adequate evaluation of the patient and does not cause the patient to be excluded from the statistical evaluation. 7.2 Data Collection and Forms The patient will complete the Baseline Nausea and Vomiting Questionnaire on day one, prior to the start of treatment. The patient will also complete the Nausea and Vomiting Daily Diary/Questionnaire on days 2-6 at the same time of day as the chemotherapy was given on day 1 (+/- 1 hour). Only the Baseline Nausea and Vomiting Questionnaire should be completed on day DOSE AND TREATMENT MODIFICATIONS, UNBLINDING 8.1 Ancillary therapy, concomitant medications, and supportive care Patients should receive full supportive care while on this study. This includes blood product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 20 NCI Version Date: 01/27/2015 Update #01

73 Alliance A conditions. All blood products and concomitant medications such as antidiarrheals, analgesics, and/or antiemetics received from the first day of study treatment administration until 30 days after the final dose will be recorded in the medical records. 8.2 Dose Modifications If the patient experiences a significant adverse event (per patient and physician discretion) felt to potentially be related to the study product (olanzapine/placebo), then the study product should be stopped and this should be recorded. 8.3 Unblinding Procedures Unblinding can be done only in cases of an emergency or at the end of protocol treatment. Follow the directions below to unblind patient treatment. Please note that if a treatment assignment is unblinded, the patient must discontinue protocol therapy Protocol-specified Unblinding: Trial participants may be unblinded upon the end of protocol treatment. Contact the Alliance Registration Office at during regular business hours. Upon confirmation by the Primary Statistician (or designee) that the treatment has ended, the treatment assignment may be unblinded. No Alliance Executive Officer approval is required Emergency Unblinding Procedures: Emergency unblinding requests for A should be made directly to the Alliance Executive Officer on call. This memorandum describes changes to the emergency unblinding procedure. Institution staff should contact the Alliance Executive Officer on call by calling , pressing 1 to speak with an operator and then asking for pager ID 8625 to return their call. The institution must provide the following information to the Alliance Executive Officer: -Alliance study ID (A221301) -Alliance patient ID number -Patient initials (e.g., L,FM ) -Name and telephone number of treating physician -Name and contact information of person requesting unblinding procedure -Name and contact information of person to inform of treatment assignment -Reason for unblinding request 9.0 ADVERSE EVENTS Please remember that emergency unblinding requests may be authorized only by an Alliance Executive Officer, and emergency unblinding applies only if unblinding would influence management of the medical situation. The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical research, as required by Federal Regulations. Adverse events must be described and graded using the terminology and grading categories defined in the NCI s Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The CTCAE is available at Attribution to protocol 21 NCI Version Date: 01/27/2015 Update #01

74 Alliance A treatment for each adverse event must be determined by the investigator and reported on the required forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details on AE reporting procedures. 9.1 Routine Adverse Event Reporting Adverse event data collection and reporting, which are required as part of every clinical trial are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times according to the study calendar in Section 5.0. For this trial, the A Adverse Event form is used for routine AE reporting in Rave. Solicited adverse events: None 9.2 Expedited Adverse Event Reporting (CTEP-AERS) Investigators are required by Federal Regulations to report serious adverse events as defined below. Alliance investigators are required to notify the Investigational Drug Branch (IDB), the Alliance Central Protocol Operations Program Office, the Study Chair, and their Institutional Review Board if a patient has a reportable serious adverse event. The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 will be utilized for AE reporting. The CTCAE is identified and located on the CTEP website at: All appropriate treatment areas should have access to a copy of the CTCAE. All reactions determined to be reportable in an expedited manner must be reported using the Cancer Evaluation Program Adverse Event Reporting System (CTEP-AERS). For further information on the NCI requirements for SAE reporting, please refer to the NCI Guidelines for Investigators: Adverse Event Reporting Requirements document published by the NCI. Note: All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause should be provided. 22 NCI Version Date: 01/27/2015 Update #01

75 Alliance A Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND 30 Days of the Last Dose of Treatment 1 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR ) An adverse event is considered serious if it results in ANY of the following outcomes: 1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR ; ICH E2A and ICH E6). ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below. Hospitalization Grade 1 Timeframes Resulting in Hospitalization 24 hrs Not resulting in Hospitalization 24 hrs Not required Grade 2 Timeframes 10 Calendar Days Grade 3 Timeframes 10 Calendar Days Grade 4 & 5 Timeframes 24-Hour; 5 Calendar Days Expedited AE reporting timelines are defined as: o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-AERS 24 hours of learning of the AE, followed by a complete expedited report 5 calendar days of the initial 24-hour report. o 10 Calendar Days - A complete expedited report on the AE must be submitted 10 calendar days of learning of the AE. 1 Serious adverse events that occur more than 30 days after the last dose of treatment require reporting as follows: Expedited 24-hour notification followed by complete report 5 calendar days for: All Grade 4, and Grade 5 AEs that are at least possibly related to treatment Expedited 10 calendar day reports for: Grade 2 adverse events resulting in hospitalization that are at least possibly related to treatment Grade 3 adverse events that are at least possibly related to treatment 23 NCI Version Date: 01/27/2015 Update #01

76 Alliance A Additional Instructions or Exclusions: All adverse events reported via AERS (i.e., serious adverse events) should also be forwarded to your local IRB, according to local IRB policies. Grade 1-3 nausea or vomiting and hospitalization resulting from such do not require AERS reporting, but should be reported via routine AE reporting. Grade 3 nausea or vomiting does not require AERS reporting, but should be reported via routine AE reporting Grade 1-3 diarrhea and hospitalization resulting from such do not require AERS reporting, but should be reported via routine AE reporting Grade 3 diarrhea does not require AERS reporting, but should be reported via routine AE reporting Grade 1-3 mucositis and hospitalization resulting from such do not require AERS reporting, but should be reported via routine AE reporting Grade 3 mucositis does not require AERS reporting, but should be reported via routine AE reporting Grade 1-3 dehydration and hospitalization resulting from such do not require AERS reporting, but should be reported via routine AE reporting Grade 3 dehydration does not require AERS reporting, but should be reported via routine AE reporting Grade 1-3 fatigue and hospitalization resulting from such do not require AERS reporting, but should be reported via routine AE reporting. Grade 3 fatigue does not require AERS reporting, but should be reported via routine AE reporting Grade 1-3 hematosuppression (leukopenia, neutropenia, lymphopenia, anemia, and thrombocytopenia) with hospitalization resulting from such do not require AERs reporting, but should be reported via routine AE reporting Grade 3 hematosuppression (leukopenia, neutropenia, lymphopenia, anemia, and thrombocytopenia) does not require AERs reporting, but should be reported via routine AE reporting Deaths clearly due to progressive cancer should NOT be reported via CTEP-AERS but should be reported via routine reporting methods in RAVE Alliance A uses a drug under an Alliance IND. These reporting requirements should be followed for either arm in this trial. All new malignancies must be reported through CTEP-AERS whether or not they are thought to be related to previous or current treatment. This includes solid tumors (including non-melanoma skin malignancies), hematologic malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE version 4.0, new malignancies (both second and secondary) should be reported as one of the following: leukemia secondary to oncology chemotherapy; myelodysplastic syndrome; treatment-related secondary malignancy; or neoplasms benign, malignant and unspecified-other. Whenever possible, the CTEP-AERS reports for new malignancies should include tumor pathology, history of prior tumors, prior treatment/current including duration, any associated risk factors or evidence regarding how long the new malignancy may have been present, when and how the new malignancy was detected, molecular characterization or cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy treatment and outcome, if available. 24 NCI Version Date: 01/27/2015 Update #01

77 Alliance A All pregnancies and suspected pregnancies occurring in female patient during therapy or within 28 days after completion of treatment on A must be reported via CTEP-AERS using the event term pregnancy, puerperium and perinatal conditions other, pregrnancy (Grade 3) CTEP-AERS reports should be amended upon completion of the pregnancy to report pregnancy outcome (e.g., normal, spontaneous abortion, therapeutic abortion, fetal death, congenital abnormalities) The CTEP-AERS report should be amended for any neonatal deaths or complications occurring within 28 days of birth independent of attribution. Infant deaths occurring after 28 days considered to be related to in utero to the agent used in this trial should be reported via CTEP- AERS DRUG INFORMATION 10.1 Olanzapine (Zyprexa ) or placebo Procurement: Olanzapine and placebo will be purchased by Mayo funds and supplied to the Alliance research base pharmacy. Olanzapine 10 mg tablets (Dr. Reddy s) will be purchased for use in this trial. The tablets will be over encapsulated by Clinical Encapsulation Services of Schenectady, NY. The capsules will also contain microcrystalline cellulose as a filler material. A placebo capsule will also be prepared by Clinical Encapsulation Services of Schenectady, NY. This capsule will match the appearance of the overencapsulated 10mg olanzapine product. Each participating Alliance affiliate will order a starter supply of blinded olanzapine/placebo from the research base pharmacy. Fax the Alliance Clinical Drug Order/Return Form to: Medical Oncology Pharmacist Mayo Clinic Gonda Rochester, MN FAX (507) Registration Office personnel will monitor the supply of blinded olanzapine and placebo at each participating affiliate and will arrange for the research base pharmacy staff to send further supplies to the affiliate as needed. Outdated or remaining drug/product should be destroyed on-site per procedures in place at each institution. Formulation: Commercial olanzapine tablets contain 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg. Inactive ingredients are crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The color coating contains hydromellose, polyethylene glycol 400, titanium dioxide, FD&C Blue No. 2. Storage and Stability: Olanzapine tablets are stored at controlled room temperature, 20º to 25ºC (68º to 77ºF). The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20º to 25ºC (68º to 77ºF) that results in a mean kinetic temperature calculated to be not more than 25ºC and that allows for excursions between 15º and 30ºC (59º and 86ºF) that are experienced in pharmacies, hospitals, and warehouses. Protect olanzapine tablets from light and moisture. Administration: Olanzapine will be taken as a single dose once daily Days 1 through 4 without regard to meals (prior to chemotherapy on day of chemotherapy administration and once daily in the morning thereafter). 25 NCI Version Date: 01/27/2015 Update #01

78 Alliance A Drug Interactions: Olanzapine is a major substrate of CYP1A2 and a minor substrate of CYP2D6. Carbamazepine, a potent inducer of CYP1A2 caused a 50% increase in the clearance of olanzapine. Omeprazole and rifampin may cause an increase in olanzapine clearance. The effects of olanzapine may be decreased by potent inducers of CYP1A2 and should be avoided if possible. Fluvoxamine, an inhibitor of CYP1A2, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant fluvoxamine. Fluoxetine, an inhibitor of CYP2D6, causes a smaller increase (mean 16%) in the maximum concentration of olanzapine and a small decrease in the clearance of olanzapine (mean 16%). The magnitude of impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine. Olanzapine may potentiate the effects of antihypertensives, CNS acting medications and alcohol. Olanzapine may antagonize the effects of levodopa and dopamine agonists. Olanzapine is an inhibitor of CYP1A2 (weak), CYP2C19 (weak), CYP2C9 (weak), CYP2D6 (weak), CYP3A4 (weak). Pharmacokinetics: a) Absorption Readily absorbed reaches peak concentrations in approximately 6 hours following an oral dose. Food does not affect the rate or extent of olanzapine absorption. b) Distribution Linear kinetics with half-life of 21 to 54 hours and apparent plasma clearance from 12 to 47 L/hr. Olanzapine is extensively distributed throughout the body with a Vd of approximately 1000 L. It is 93% bound to plasma proteins (primarily albumin and α 1-acid glycoprotein. c) Metabolism Direct glucuronidation and cytochrome P450 mediated oxidation via CYP1A2 (major) and CYP2D6 (minor) are the primary metabolic pathways for olanzapine. d) Excretion Urine (57%, 7% as unchanged drug); feces (30%). There is a 40% increase in olanzapine clearance in smokers, 30% decrease in females. Adverse Events All of the adverse events discussed below have been associated with olanzapine, but would be considered unexpected in the context of this trial. [U.S. Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Other warnings and precautions: suicide (particularly when used with fluoxetine), neuroleptic malignant syndrome, hyperglycemia, hyperlipidemia, weight gain, tardive dyskinesia, orthostatic hypotension, leukopenia, neutropenia, agranulocytosis, seizures, cognitive or motor impairment, hyproprolactinemia. The following toxicity information regards chronic daily use of olanzapine and is not likely applicable for drug use of only 4 days: Common known potential toxicities >10%: Central nervous system: somnolence, extrapyramidal symptoms, dizziness, headache, fatigue, insomnia Endocrine/metabolic: prolactin increased Gastrointestinal: weight gain, appetite increased, xerostomia, constipation 26 NCI Version Date: 01/27/2015 Update #01

79 Alliance A Hepatic: ALT increased Neuromuscular/skeletal: weakness Miscellaneous: accidental injury Less common known potential toxicities 1-10%: Cardiovascular: chest pain, hypertension, peripheral edema, postural hypotension, tachycardia Central nervous system: fever, personality changes, restlessness Dermatologic: bruising Endocrine/metabolic: breast-related events (discharge, enlargement, galactorrhea, gynecomastia, lactation disorder), menstrual-related events (amenorrhea, hypomenorrhea, menstruation delayed, oligomenorrhea), sexual function-related events (anorgasmia, ejaculation delayed, erectile dysfunction, changes in libido, abnormal orgasm, sexual dysfunction) Gastrointestinal: abdominal pain, diarrhea, flatulence, nausea, vomiting Genitourinary: incontinence, UTI Hepatic: hepatic enzymes increase Neuromuscular/skeletal: abnormal gait, akathisia, articulation impairment, back pain, falling, hypertonia, joint/extremity pain, muscle stiffness, tremor Ocular: amblyopia Respiratory: cough, epistaxis, pharyngitis, respiratory tract infection, rhinitis, sinusitis Rare, less than 1% (limited to important or life threatening): Acidosis, agranulocytosis, anaphylactic reaction, angioedema, apnea, atelectasis, atrial fibrillation, cerebrovascular accident, congestive heart failure, deafness, diabetes mellitus, diabetic ketoacidosis, diabetic coma, dystonia, encephalopathy, facial paralysis, glaucoma, heart arrest, heart failure, hemorrhage, hepatitis, hypercholesterolemia, hyper/hypoglycemia, hyper/hypokalemia, hyperlipidemia, hyper/hyponatremia, hypertriglyceridemia, hyperuricemia, hyper/hypoventilation, hypoproteinemia, hypoxia, jaundice, ileus, ketosis, leukocytosis (eosinophilia), leukopenia, liver damage (cholestatic or mixed), liver fatty deposit, lung edema, lymphadenopathy, myasthenia, myopathy, neuralgia, neuroleptic malignant syndrome, neutropenia, pancreatitis, paralysis, pulmonary embolus, rash, rhabdomyolysis, seizure, sudden death, suicide attempt, syncope, tardive dyskinesia, thrombocythemia, thrombocytopenia, transient ischemic attack, venous thrombotic events Nursing Guidelines Olanzapine has several drug to drug interactions, many of which can cause an increase in olanzapine clearance and increase the side effects of olanzapine. Assess patient s medication list for any possible drug to drug interactions. Discuss with study doctor Remind patients to report any side effects, noting that there have been a large number of side effects reported with chronic use of this drug, that we do not think will be applicable for short term, intermittent, use Each bottle of study drug (olanzapine or placebo) will contain 4 tablets Placebo A matching placebo will be provided. It will be identical in appearance to the over-encapsulated olanzapine. The opaque gelatin capsule will contain microcrystalline cellulose. 27 NCI Version Date: 01/27/2015 Update #01

80 Alliance A MEASUREMENT OF EFFECT Data from the patient questionnaire (Appendices III-V) will be used to measure treatment effect END OF TREATMENT/INTERVENTION 12.1 Duration of Treatment: One cycle 12.2 Managing ineligible and canceled patients and major protocol violations Data must be submitted per Section 5.0 for patients deemed ineligible or canceled. See also the Forms Packet for full details of data submission requirements Extraordinary Medical Circumstances If, at any time the constraints of this protocol are detrimental to the patient's health and/or the patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In this event: Document the reason(s) for discontinuation of therapy on data forms. Follow the patient for protocol endpoints as required by the Study Calendar STATISTICAL CONSIDERATIONS 13.1 Study Overview This is a randomized placebo-controlled phase III clinical trial to determine the added effect of olanzapine in combination with palonosetron (or ondansetron or granisetron), dexamethasone, and fosaprepitant (aprepitant) to prevent CINV after patients receiving HEC. This trial implements a group sequential design with one interim analysis for superiority and futility, respectively. The sample size calculation and simulation for operating characteristics are conducted using EAST version Sample Size, Accrual Time and Study Duration Sample Size A previous study [7] demonstrated the proportion of non-olanzapine-receiving patients with no nausea during the overall period was about 40%. Considering a 17.5% increase as a clinically meaningful effect size, we will need a sample size of 332 patients (166 patients per arm) to achieve 90% power to detect the above effect size at the 5% significance level using a two-sided chi-squared test for a fixed sample size clinical trial. This sample size will be inflated to 338 patients (169 patients per arm) after adding an interim analysis for superiority and futility. In order to account for ineligible, cancel and major violations, the total sample size will be further inflated by 10% to 372 patients (186 patients per arm) Accrual Rate and Accrual Duration The proposed study is a standard antiemetic study for which patient accrual should be very timely and efficient. There are no complex accrual issues and no demands for extensive resources in the protocol. The investigators have extensive experience in conducting phase II and phase III antiemetic studies. The Alliance Symptom Intervention Committee expressed marked interest in participating in this trial. Assuming an accrual rate of 20 patients per month in the Alliance, the patient accrual will be completed in 18.5 months. 28 NCI Version Date: 01/27/2015 Update #01

81 Alliance A Primary Endpoint Completion Date for ClinicalTrials.gov Reporting For purposes of ClinicalTrials.gov reporting, the Primary Endpoint Completion Date (PECD) for this study is the time the last patient registered has been followed for at least 5 days Statistical Design and Analysis for the Primary Endpoint Primary Endpoint No nausea is defined as a response of 0 in the nausea item of Nausea and Vomiting Daily Diary/Questionnaire in the acute (0-24 hours), delayed ( hours), and overall (0-120 hours) periods Statistical Design Interim Analysis Decision Rule Interim analysis will be conducted when 50% patients are enrolled and have completed the Nausea and Vomiting Daily Diary/Questionnaire. The Lan-DeMets family [37] of alpha and beta spending functions corresponding to the O Brien- Fleming boundary are used for controlling overall type I and type II error rates. Superiority will be concluded if p-value and futility will be concluded if p- value The second stage of this clinical trial shall continue if p-value is in (0.003, 0.844) Final Analysis Decision Rule Final analysis will be conducted when all target patients are enrolled and have completed the Nausea and Vomiting Daily Diary/Questionnaire. Superiority will be concluded if p-value <0.049 and futility will be concluded if p-value Study Operating Characteristics Simulation studies of 10,000 clinical trials are conducted for the proposed group sequential design. The probabilities of early stopping (after interim analysis) and empirical powers for various effect sizes are summarized in the following table. Effect Interim Analysis Early Final Analysis Power Scenario Size Superiority Futility Stopping Superiority Futility % 25.9% 0.9% 26.8% 62.8% 10.4% 88.7% % 16.6% 1.9% 18.5% 61.5% 20.1% 78.1% % 38.0% 0.4% 38.4% 57.6% 4.0% 95.6% Analysis Plan A modified intent-to-treat principle [38] will be applied for statistical analysis of efficacy in evaluable patients. Evaluable patients are defined as all patients meeting the eligibility criteria who did not cancel prior to receiving treatment and had no major violations The proportions of patients with no nausea between treatment arms will be examined sequentially by the chi-squared tests for the overall period, and then, acute, and delayed periods. The hierarchical order of overall, then acute and delayed periods is determined by clinical importance. A serial gatekeeping procedure [39] will be applied to maintain the overall significance level at the specified level as determined by the Lan-DeMets family of alpha spending function: 29 NCI Version Date: 01/27/2015 Update #01

82 Alliance A H 11: No nausea rates are the same between treatment arms during overall period. H 21: No nausea rates are the same between treatment arms during acute period. H 22: No nausea rates are the same between treatment arms during delayed period. Step 1. The null hypothesis of H 11 serves as a gatekeeper; Step 2. The null hypotheses of H 21 and H 22 are tested only after H 11 has been rejected. As the inference of H 11 may depend on whether or not some hypotheses (H 21 or H 22) are rejected in the subsequent family, we will adopt the Simes gatekeeping procedure rather than Bonferroni gatekeeping procedure. A SAS macro %GateKeeper will be utilized to implement the decision matrix algorithm for adjusted p-values Generalized linear models will be explored to incorporate stratification factors, baseline fatigue/qol and other patient characteristics Supplementary Analysis Plans Secondary Endpoints Nausea scores (0-10) repeatedly measured by the Nausea and Vomiting Daily Diary/Questionnaire Complete response (no emetic episodes and no use of rescue medication) during the acute, delayed and the overall periods as measured by the Nausea and Vomiting Daily Diary/Questionnaire Potential toxicities as ascribed to olanzapine as measured by the Nausea and Vomiting Daily Diary/Questionnaire Frequency of rescue medication repeatedly measured by the Nausea and Vomiting Daily Diary/Questionnaire Secondary Analysis Multiplicity will not be adjusted for secondary analyses, hence, statistically significant findings from secondary analyses are exploratory in nature and therefore shall be interpreted as such. Descriptive statistics and graphical approaches will form the basis for most secondary analyses The repeated measures analyses and growth curve models will be used to account for the factor of day and time trend in nausea score Similar analysis as primary endpoint will be conducted for complete response during acute, delayed and overall periods Potential toxicities of undesired sedation and appetite increase will be analyzed by repeated measures analyses and growth curve models to account for the factor of day and time trend The repeated measures analyses and growth curve models will be performed to account for the factor of day and time trend in ordinal medication. 30 NCI Version Date: 01/27/2015 Update #01

83 Alliance A Study Monitoring Adverse Event Stopping Rule The stopping rule specified below is based on the knowledge available at study development. We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the study re-opening to accrual or (2) at any time during the conduct of the trial and in consideration of newly acquired information regarding the adverse event profile of the treatment(s) under investigation. The study team may choose to suspend accrual because of unexpected adverse event profiles that have not crossed the specified rule below. Accrual will be temporarily suspended to this study if at any time we observe events considered at least possibly related to study treatment (i.e., an adverse event with attribute specified as possible, probable, or definite) that satisfy the following criteria: If 7 or more of the first 20 treated patients (or 35% of all patients after 20 patients have been accrued) experience a grade 3 or higher non-hematologic adverse event and the adverse event rate is higher in the active treatment arm. If 3 or more of the first 20 treated patients (or 15% of all patients after 20 patients have been accrued) experience a grade 4 or higher non-hematologic adverse event and the adverse event rate is higher in the active treatment arm Accrual Monitoring Stopping Rule Slow Accrual Patient accrual will be closely monitored by the investigators and secondary statistician on a monthly basis. If the accrual rate falls below 50% of expected accrual rate, investigators will carefully review feedback from sites and consider taking measures to encourage patient enrollment Target Accrual of Patients Receiving Cisplatin-Containing regimen 13.6 Study Reporting In order to reach a target accrual of 200 patients receiving cisplatin-containing regimen, we will monitor patient accrual by the grouping factor of chemotherapy regimen. If the patient accrual to AC is so rapid that it jeopardizes the target accrual to cisplatin-containing regimen, we will temporary close to AC to ensure target accrual to cisplatin-containing regimen This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an NCI-approved functioning body. Reports containing efficacy, adverse event, and administrative information will be provided to the DSMB every month as per NCI guidelines Results Reporting on ClinicalTrials.gov: At study activation, this study will have been registered within the ClincialTrials.gov web site. The Primary and Secondary Endpoints (i.e., Outcome Measures ) along with other required information for this study will be reported on ClinicalTrials.gov Descriptive Factors None 13.8 Inclusion of Women and Minorities This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. 31 NCI Version Date: 01/27/2015 Update #01

84 Alliance A There is no information currently available regarding differential effects of this regimen in subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences to exist. Therefore, although the planned analysis will, as always, look for differences in treatment effect based on racial and gender groupings, the sample size is not increased in order to provide additional power for subset analyses. The geographical region served by the Alliance, has a population which includes approximately 13.5% minorities. Based on prior Alliance studies involving similar disease sites, we expect about 11.6% of patients will be classified as minorities by race and about 60% of patients will be women. Expected sizes of racial by gender subsets for patients randomized to this study are shown in the following table. Accrual Targets Ethnic Category Sex/Gender Females Males Total Hispanic or Latino Not Hispanic or Latino Ethnic Category: Total of all subjects Racial Category American Indian or Alaskan Native Asian Black or African American Native Hawaiian or other Pacific Islander White Racial Category: Total of all subjects Ethnic Categories: Racial Categories: Hispanic or Latino a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race. The term Spanish origin can also be used in addition to Hispanic or Latino. Not Hispanic or Latino American Indian or Alaskan Native a person having origins in any of the original peoples of North, Central, or South America, and who maintains tribal affiliations or community attachment. Asian a person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific Islanders in previous data collection strategies.) Black or African American a person having origins in any of the black racial groups of Africa. Terms such as Haitian or Negro can be used in addition to Black or African American. Native Hawaiian or other Pacific Islander a person having origins in any of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. White a person having origins in any of the original peoples of Europe, the Middle East, or North Africa. 32 NCI Version Date: 01/27/2015 Update #01

85 Alliance A CORRELATIVE AND COMPANION STUDIES None 15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING None 33 NCI Version Date: 01/27/2015 Update #01

86 Alliance A REFERENCES 1. Bloechl-Daum B, Deuson RR, Panagiotis M et al, Delayed nausea and vomiting continue to reduce patients quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment, J Clin Oncol. 24 (2006) Navari RM, Pharmacological management of chemotherapy-induced nausea and vomiting: focus on recent developments, Drugs. 69 (2009) Navari RM, Palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer, Future Oncol. 6 (2010) Curran MP, Robinson DM, Aprepitant: a review of its use in the prevention of nausea and vomiting. Drugs. 69 (2009) Sankhala KK, Pandya DM, Sarantopoulos J et al, Prevention of chemotherapy induced nausea and vomiting: a focus on aprepitant, Expert Opin Drug Metab Toxicol. 12 (2009) Navari RM, Einhorn LH, Loehrer PJ et al, A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting, Support Care Cancer. 13 (2005) Navari RM, Gray SE, Kerr AC, Olanzapine versus aprepitant for the prevention of chemotherapyinduced nausea and vomiting: a randomized phase III trial, J Support Oncol. 9 (2011) Tan L, Liu J, Liu X et al, Clinical research of olanzapine for the prevention of chemotherapyinduced nausea and vomiting, J Exp Clin Cancer Res. 28 (2009) Eisenberg P, MacKintosh FR, Ritch P et al, Efficacy, safety, and pharmacokinetics of palonosetron in patients receiving highly emetogenic, cisplatin-based chemotherapy: a doseranging, clinical study, Ann Oncol. 15 (2004) Rojas C, Thomas AG, Alt J et al, Palonosetron triggers 5-HT 3 receptor internalization and causes prolonged inhibition of receptor function, J Pharmacol. 626 (2010) Aapro MS, Grunberg SM, Manikhas GM et al, A phase III, double blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy, Ann Oncol. 17 (2006) Eisenberg P, Figueroa-Vadillo J, Zamora R et al, Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5HT3 receptor antagonist: Results of a phase III, single dose trial versus dolasetron, Cancer. 98 (2003) Gralla R, Lichinitser M, Van der Vegt S et al, Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized Phase II trial comparing single dose of palonosetron with ondansetron, Ann Oncol. 14 (2003) Saito M, Aogi K, Sekine I, Palonosetron plus dexamethasone versus granisetron plus dexamethasone for the prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomized, comparative phase III trial, Lancet Oncol. 10 (2009) Kris MG, Hesketh PJ, Somerfield MR et al, American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006, J Clin Oncol. 24 (2006) NCCN National Comprehensive Cancer Network, Antiemesis: Clinical Practice Guidelines in Oncology (2010) v NCI Version Date: 01/27/2015 Update #01

87 Alliance A Roila F, Herrstedt J, Aapro M et al, Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference, Ann Oncol. 21 (Suppl 5) (2010) Navari RM, Pathogenesis-based treatment of chemotherapy-induced nausea and vomiting: Two new agents, J Support Oncol. 1 (2003) Grunberg S, Chua D, Maru A et al, Single-dose fosaprepitant for the prevention of chemotherapyinduced nausea and vomiting associated with cisplatin therapy: randomized, double blind study protocol EASE, J Clin Oncol. 10 (2011) Grote T, Hajdenberg Cartnell A et al, Combination therapy for chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: palonosetron, dexamethasone, and aprepitant, J Support Oncol. 4 (2006) Bymaster FP, Calligaro D, Falcone J et al, Radioreceptor binding profile of the atypical antipsychotic olanzapine, Neuropsychopharmacology. 14 (1996) Bymaster FP, Falcone JF, Bauzon D et al, Potent antagonism of 5HT3 and 5HT 6 receptors by olanzapine, Eur J Pharmacol. 430 (2001) Allison DB, Casey DE, Antipsychotic-associated weight gain: A review of the literature, J Clin Psychiatry. 62 (2001) Hale AS, Olanzapine, Br J Hosp Med. 58 (1997) Goldstein LE, Sporn J, Brown S et al, New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment, Psychosomatics. 40 (1999) Navari RM, Nagy CK, Gray SE, Olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, Supportive Care Cancer. 21 (2013) Navari RM, Treatment of chemotherapy-induced nausea, Community Oncol. 9 (2012) Passik S, Navari RM, Loehrer PJ et al. A phase I trial of olanzapine for the prevention of delayed emesis in cancer patients receiving chemotherapy. Cancer Investigation, 22: , Barsevick A. M., Cleeland CS et al. ASCPRO recommendations for the assessment of fatigue as an outcome in clinical trials. J Pain Symptom Manage, 39: , Stauder MC, Romero Y et al. Overall survival and self-reported fatigue in patients with esophageal cancer. Support Care Cancer 21: , Sloan J A, Zhao X et al. Relationship between deficits in overall quality of life and non-smallcell lung cancer survival. J Clin Oncol 30: , Innominato PF, Giacchetti S et al. Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer. Cancer 119: , Gotay CC, Kawamoto CT et al. The prognostic significance of patient-reported outcomes in cancer clinical trials. J Clin Oncol 26: , Montazeri A. Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to Health Qual Life Outcomes 7: 102, Osoba D. Health-related quality of life and cancer clinical trials. Ther Adv Med Oncol 3: Pocock SJ, Simon R. Sequential Treatment Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial. Biometrics 31(1): , 1975 Mar. 35 NCI Version Date: 01/27/2015 Update #01

88 Alliance A Lan, K. K. G. and D. L. Demets (1983). "Discrete Sequential Boundaries for Clinical-Trials." Biometrika 70(3): Abraha, I. and A. Montedori (2010). "Modified intention to treat reporting in randomised controlled trials: systematic review." BMJ 340: c Dmitrienko, A., G. Molenberghs, et al. (2005). Analysis of Clinical Trials Using SAS: A Practical Guide. Cary, NC, SAS Institute. 36 NCI Version Date: 01/27/2015 Update #01

89 Alliance A APPENDIX I CONSENT FORM NOTES FOR LOCAL INVESTIGATORS*: The goal of the informed consent process is to provide people with sufficient information for making informed choices about participating in research. The consent form provides a summary of the study, of the individual's rights as a study participant, and documents their willingness to participate. The consent form is, however, only one piece of an ongoing exchange of information between the investigator and study participant. For more information about informed consent, review the "Recommendations for the Development of Informed Consent Documents for Cancer Clinical Trials" prepared by the Comprehensive Working Group on Informed Consent in Cancer Clinical Trials for the National Cancer Institute. The Web site address for this document is A blank line,, indicates that the local investigator should provide the appropriate information before submitting to the Institutional Review Board. *These notes for investigators are instructional and should not be included in the consent form sent to Institutional Review Boards. Study Title for Study Participants: A221301, OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY (HEC) You are being asked to participate in this study because treatments for cancer can cause the side effect of nausea and vomiting. People who do not take part in this study will receive standard medications that have been approved by the Food and Drug Administration for nausea and vomiting. What are my other choices if I do not take part in this study? If you decide not to take part in this study, you have other choices. For example: you may choose to have the usual approach described above you may choose to take part in a different study, if one is available Why is this study being done? You have cancer and will be receiving chemotherapy that may cause nausea and vomiting. The purpose of this study is to test whether olanzapine can reduce nausea and vomiting. Olanzapine is a medication which has been approved by the Federal Drug Administration (FDA) for the treatment of specific mental illnesses and has been used in many patients over the past 15 years, but it is not FDA approved to treat nausea and vomiting. Over the past five years, it has been demonstrated in multiple scientific studies involving small numbers of patients to have anti-nausea and anti-vomiting effects in patients receiving chemotherapy. The purpose of this study is to determine if the use of this medication can significantly reduce nausea and vomiting in a large number of patients receiving chemotherapy. The effects of olanzapine will be compared to a placebo. A placebo is a pill that looks like the study drug but contains no medication. There will be about 372 people taking part in this study. 37 NCI Version Date: 01/27/2015 Update #01

90 Alliance A What are the study groups? This study has two study groups. Group 1 will receive a placebo, a pill that looks like the study drug but contains no medication and Group 2 will receive the study drug olanzapine,. A computer will by chance assign you to treatment groups in the study. This is called randomization. This is done by chance because no one knows if one study group is better or worse than the other. This study has two study groups. Group 1 will get the chemotherapy drugs cisplatin or cyclophosphamide and doxorubicin, the usual chemotherapy drugs used for your type of cancer, as well as usual anti-nausea/vomiting drugs: - Ondansetron (8 mg orally or intravenously) or granisetron (1 mg intravenously or 2 mg orally) or palonosetron (0.25 mg intravenously) on the day of chemotherapy, plus - Dexamethasone (12 mg orally on the day of chemotherapy and 8 mg orally days 2, 3, 4 post chemotherapy), plus - Fosaprepitant (150 mg intravenously on the day of chemotherapy) or aprepitant (125 mg orally on the day of chemotherapy and 80 mg orally on days 2 and 3 post chemotherapy), plus - A placebo. Group 2 will get the chemotherapy drugs cisplatin or cyclophosphamide and doxorubicin, the usual chemotherapy drugs used for your type of cancer, as well as the following anti-nausea/vomiting drugs: - Ondansetron (8 mg orally or intravenously) or granisetron (1 mg intravenously or 2 mg orally) or palonosetron (0.25 mg intravenously) on the day of chemotherapy, plus - Dexamethasone (12 mg orally on the day of chemotherapy and 8 mg orally days 2, 3, 4 post chemotherapy), plus - Fosaprepitant (150 mg intravenously on the day of chemotherapy) or aprepitant (125 mg orally on the day of chemotherapy and 80 mg orally on days 2 and 3 post chemotherapy), plus - A study drug called olanzapine (10 mg orally on the day of chemotherapy and 10 mg orally on days 2, 3, 4 post chemotherapy). How long will I be in this study? You will receive either olanzapine or placebo for four days. You will be contacted on days 2-5 and asked how you are feeling. After you finish the daily oral olanzapine for four days, your doctor will continue to watch you for side effects for an additional day. What extra tests and procedures will I have if I take part in this study? Most of the exams, tests, and procedures you will have are part of the usual approach for your cancer. However, there are some extra tests that you will need to have if you take part in this study. 38 NCI Version Date: 01/27/2015 Update #01

91 Alliance A Before you begin the study you will need to have the following tests to find out if you can be in the study: Review of your medical history Physical examination including height, weight, performance status evaluation (ability to perform daily functions) Review of your current and past medications Standard blood tests (approximately 3 tablespoons of blood will be drawn) Pregnancy test if you are a woman of childbearing potential During the study: You will be completing patient questionnaires on day 1 prior to treatment and at approximately the same time as your chemotherapy was given each day for the next five days following the day of chemotherapy, days 2 through 6. You will be asked to complete a one page short questionnaire on the amount of nausea, vomiting, and/or sedation you have experienced in the previous 24 hour period. The questionnaire should take less than 10 minutes to complete each day. What possible risks can I expect from taking part in this study? Likely Side Effects of Olanzapine (when taken for 4 days): Most of the studies that have been done with 4 days of olanzapine have reported that the only evident side effect has been sedation (sleepiness). Below are listed side effects associated with this medication when it is taken for weeks to months. Possible Side Effects of Olanzapine (when taken for weeks to months) COMMON, SOME MAY BE SERIOUS In 100 people receiving olanzapine, more than 20 and up to 100 may have: Blurred vision, arm and leg swelling, restlessness, tingling of the hands and feet OCCASIONAL, SOME MAY BE SERIOUS In 100 people receiving olanzapine, from 4 to 20 may have: Sedation (sleepiness, muscle stiffness, mask-like face, impaired vision, and difficulty swallowing) RARE, AND SERIOUS In 100 people receiving olanzapine, 3 or fewer may have: Bladder pain, bruising, headache, lower back pain, muscle tension 39 NCI Version Date: 01/27/2015 Update #01

92 Alliance A Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this study. The drug used in this study could be very damaging to an unborn baby. Check with the study doctor about what types of birth control, or pregnancy prevention, to use while in this study. What possible benefits can I expect from taking part in this study? It is not possible to know at this time if the study drug(s)/ approach is better than the usual approach so this study may or may not help you. This study will help researchers learn things that will help people in the future. Can I stop taking part in this study? Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let the study doctor continue to provide your medical information to the organization running the study. The study doctor will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. The study doctor may take you out of the study: If your health changes and the study is no longer in your best interest If new information becomes available If you do not follow the study rules If the study is stopped by the sponsor, Institutional Review Board or the Food and Drug Administration. What are my rights in this study? Taking part in this study is your choice. No matter what decision you make, and even if your decision changes, there will be no penalty to you. You will not lose medical care or any legal rights. For questions about your rights while in this study, call the (insert name of center) Institutional Review Board at (insert telephone number). (Note to Local Investigator: Contact information for patient representatives or other individuals at a local institution who are not on the Institutional Review Board or research team but take calls regarding clinical trial questions can also be listed here.) What are the costs of taking part in this study? The olanzapine/placebo will be supplied at no charge while you take part in this study. It is possible that the olanzapine/placebo may not continue to be supplied while you are on the study. Although not likely, if this occurs, your study doctor will talk to you about your options. You and/or your health plan/insurance company will need to pay for all of the other costs of treating your cancer while in this study, including the cost of tests, procedures, or medicines to manage any side effects, unless you are told that certain tests are supplied at no charge. Before you decide to be in the study, you should check with your health plan or insurance company to find out exactly what they will pay for. 40 NCI Version Date: 01/27/2015 Update #01

93 Alliance A You will not be paid for taking part in this study. What happens if I am injured or hurt because I took part in this study? If you are injured or hurt as a result of taking part in this study and need medical treatment, please tell your study doctor. The study sponsors will not offer to pay for medical treatment for injury. Your insurance company may not be willing to pay for study-related injury. If you have no insurance, you would be responsible for any costs. If you feel this injury was a result of medical error, you keep all your legal rights to receive payment for this even though you are in a study. Who will see my medical information? Your privacy is very important to us and the researchers will make every effort to protect it. Your information may be given out if required by law. For example, certain states require doctors to report to health boards if they find a disease like tuberculosis. However, the researchers will do their best to make sure that any information that is released will not identify you. Some of your health information, and/or information about your specimen, from this study will be kept in a central database for research. Your name or contact information will not be put in the database. There are organizations that may inspect your records. These organizations are required to make sure your information is kept private, unless required by law to provide information. Some of these organizations are: The Alliance for Clinical Trials in Oncology (ALLIANCE) The National Cancer Institute (NCI) The Institutional Review Board, IRB, is a group of people who review the research with the goal of protecting the people who take part in the study. The Food and Drug Administration and the National Cancer Institute in the U.S., and similar ones if other countries are involved in the study. Where can I get more information? You may visit the NCI Web site at for more information about studies or general information about cancer. You may also call the NCI Cancer Information Service to get the same information at: CANCER ( ). A description of this clinical trial will be available on as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time. Who can answer my questions about this study? You can talk to the study doctor about any questions or concerns you have about this study or to report side effects or injuries. Contact the study doctor (insert name of study doctor[s]) at (insert telephone number). 41 NCI Version Date: 01/27/2015 Update #01

94 Alliance A My Signature Agreeing to Take Part in the Main Study I have read this consent form or had it read to me. I have discussed it with the study doctor and my questions have been answered. I will be given a signed copy of this form. I agree to take part in the main study. Participant s signature Date of signature (The following signature and date lines for the person(s) conducting the discussion may be included at the discretion of the study sponsor.) Signature of person(s) conducting the informed consent discussion Date of signature 42 NCI Version Date: 01/27/2015 Update #01

95 Alliance A Page 1 of 1 APPENDIX II REGISTRATION FATIGUE/UNISCALE ASSESSMENTS At patient registration, this form is to be administered by a nurse/cra, completed by the patient, and recorded on the Registration Fatigue/Uniscale Assessments Form (see Forms Packet). If needed, this appendix can be adapted to use as a source document. A booklet containing this assessment does not exist please do not order this booklet. How would you describe: Your level of fatigue, on the average in the past week including today? No Fatigue Fatigue as bad as it can be Your overall quality of life in the past week including today? As bad as it can be As good as it can be 43 NCI Version Date: 01/27/2015 Update #01

96 Alliance A APPENDIX III PATIENT QUESTIONNAIRE PATIENT INFORMATION SHEET TREATMENT Patient Completed Quality of Life Booklet (Baseline) You have been given a booklet to complete for this study. The booklet contains some questions about your quality of life as a patient receiving treatment for cancer. Your answers will help us to better understand how the treatment you are receiving is affecting the way you feel. 1. This booklet is to be completed day 1 during your clinic visit prior to treatment. 2. The booklet contains 1 set of questions: a. Baseline Nausea and Vomiting Questionnaire 3. Directions on how to complete this set of questions are written on the top of the page. 4. Please return your booklet when you are finished. Thank you for taking the time to help 44 NCI Version Date: 01/27/2015 Update #01

97 Alliance A PATIENT INFORMATION SHEET TREATMENT Patient Completed Quality of Life Booklet (days 2-6) You have been given a booklet to complete for this study. The booklet contains some questions about your quality of life as a patient receiving treatment for cancer. Your answers will help us to better understand how the treatment you are receiving is affecting the way you feel. 1. This booklet is to be completed days 2-6 (the 5 days following your chemotherapy). 2. The booklet contains 1 set of questions: a. Nausea and Vomiting Daily Diary/Questionnaire 3. Directions on how to complete this set of questions are written on the top of the page. 4. You may call a member of the study team to answer any questions you might have. You will be given a name and telephone number. You can call anytime with any concerns or questions. A nurse/research coordinator will also call you days 2-5 and they can answer questions you might have. 5. It is very important that you return the booklet to us, whether you finish the study or not. 6. When the booklet is complete, return it in the provided envelope. Thank you for taking the time to help 45 NCI Version Date: 01/27/2015 Update #01

98 Alliance A APPENDIX IV BASELINE NAUSEA AND VOMITING QUESTIONNAIRE Date: / / For the following 3 questions, please circle the one number (0-10) that best describes the way you felt over the past 24 hours. 1. Please rate your worst nausea over the past 24 hours No nausea at all Nausea as bad as it can be 2. Please rate any undesired sedation trouble that you had over the past 24 hours No undesired sedation at all Undesired sedation as bad as it can be 3. Please rate any undesired appetite increase that you had over the past 24 hours No undesired appetite increase at all Undesired appetite increase as bad as it can be 46 NCI Version Date: 01/27/2015 Update #01

99 Alliance A APPENDIX V NAUSEA AND VOMITING DAILY DIARY/QUESTIONNAIRE Date: / / Check one option in each box, then continue and answer questions 1-3 below. Last 24 hours Nausea (check one) *Vomiting (check one) Number of extra nausea/vomiting pills taken because you developed nausea/vomiting None None None Mild Once One Moderate Twice Two Severe More than twice More than two *A single vomiting episode is defined as: a single vomit of solid or liquid stomach contents a single retch, or dry heave, that did not produce solid or liquid stomach contents any episode of continuous vomiting or retching Note: Episodes separated from each other by the absence of retching or vomiting for at least 1 minute should be considered separate emetic episodes. For the following 3 questions, please circle the one number (0-10) that best describes the way you felt over the past 24 hours. 1. Please rate your worst nausea over the past 24 hours No nausea at all Nausea as bad as it can be 2. Please rate any undesired sedation trouble that you had over the past 24 hours No undesired sedation at all Undesired sedation as bad as it can be 3. Please rate any undesired appetite increase that you had over the past 24 hours No undesired appetite increase at all Undesired appetite increase as bad as it can be 47 NCI Version Date: 01/27/2015 Update #01

100 Alliance A APPENDIX VI DAILY TELEPHONE CONTACT Nurse/Research Coordinator Contact Days 2 and 3 Daily Telephone contact (check one) Day 2 Day 3 Date of telephone contact or date of attempt to contact was made (dd MMM yyyy) - _- Were you able to contact the patient? Yes No (If no, then end form) If contacted, list the Time of day: HH:MM : Verify the following with the subject: Dexamethasone 8 mg PO QD taken per protocol? (check one) Yes No If No, provide reason Aprepitant 80 mg PO QD taken per protocol? (check one) Yes No NA If No, provide reason Study medication (olanzapine or placebo) 10 mg PO QD taken per protocol? (check one) Yes No If No, provide reason Rescue Medication taken? (check one) Yes No (If yes) Agent Name Dose Units of measure Number of doses the past 24 hours (Yesterday) Number of doses the current day Number of vomiting episodes over the past 24 hours Symptom Assessment: (Where 0 is none and 10 is as bad as it can be.) Worst nausea over the past 24 hours (circle one) Undesired sedation trouble over the past 24 hours (circle one) Undesired appetite increase over the past 24 hours (circle one) Did patient have any adverse events? (check one) Yes No If yes, fill out AE: Record all adverse events that meet the following criteria: grade 2 with attribution of possible, probable or definite and all grade 3, 4 and 5 regardless of attribution. Comments Please remind the patient to complete the patient diary. If possible, have the patient complete their questionnaire form while on the phone call. Please explain the rescue nausea medication information specifically Number of extra (PRN) nausea/vomiting pills taken. 48 NCI Version Date: 01/27/2015 Update #01

101 Alliance A Nurse/Research Coordinator Contact Day 4 Daily Telephone contact Date of telephone contact or date of attempt to contact was made: (dd MMM yyyy) - _- Were you able to contact the patient? Yes No (If no, then end form) If contacted, list the Time of day HH:MM : Verify the following with the subject: Dexamethasone 8 mg PO QD taken per protocol? (check one) Yes No If No, provide reason Study medication (Olanzapine or placebo) 10 mg PO QD taken per protocol? (check one) Yes No If No, provide reason Rescue Medication taken? (check one) Yes No (If yes) Agent Name Dose Units of measure Number of doses the past 24 hours (Yesterday) Number of doses the current day Number of vomiting episodes over the past 24 hours Symptom Assessment (Where 0 is none and 10 is as bad as it can be.) Worst nausea over the past 24 hours (circle one) Undesired sedation trouble over the past 24 hours (circle one) Undesired appetite increase over the past 24 hours (circle one) Did patient have any adverse events? (check one) Yes No If yes, fill out AE: Record all adverse events that meet the following criteria: grade 2 with attribution of possible, probable or definite and all grade 3, 4 and 5 regardless of attribution. Comments Please remind the patient to complete the patient diary. If possible, have the patient complete their questionnaire form while on the phone call. Please explain the rescue nausea medication information specifically Number of extra (PRN) nausea/vomiting pills taken. 49 NCI Version Date: 01/27/2015 Update #01

102 1 A221301: Olanzapine For The Prevention of Chemotherapy Induced Nausea And Vomiting (CINV) in Patients Receiving Highly Emetogenic Chemotherapy (HEC): A Randomized, Double-Blind, Placebo-Controlled Trial PI: Rudolph M. Navari, MD Lead Stat: Qin Rui, PhD MS: Heshan Liu SPA: Angelina D. Tan Statistical Summary Data Frozen: 8/21/2015 Summary Last updated: 8/27/2015 Purpose: The purpose of this study is to compare between the two study arms the number of patients with no nausea for the acute (0-24 hours post-chemotherapy), delayed ( hours post-chemotherapy) and overall periods (0-120 hours post-chemotherapy) for patients receiving HEC. Trial Design: This is a randomized placebo-controlled phase III clinical trial to determine the added effect of olanzapine in combination with palonosetron (or ondansetron or granisetron), dexamethasone, and fosaprepitant (aprepitant) to prevent CINV after patients receiving HEC. This trial implements a group sequential design with one interim analysis for superiority and futility, respectively. The stratification factors for this study are gender (male vs. female), chemotherapy regimen (cisplatin-containing regimen vs. anthracycline + cyclophosphamide (AC) and 5-HT3 receptor antagonist (palonosetron vs. ondansetron vs. granisetron). Patient Population: This study was opened on 08/05/2014 and closed to accrual on 3/16/ patients (202 receiving Olanzapine (arm A) and 199 receiving placebo (arm B)) were enrolled on this study between 08/20/2014 and 03/16/2015. There were 18 cancellations (8 arm A, 10 arm B), 3 major violation (2 arm A, 1 arm B) on this study. All 21 patients were excluded from study analysis. Out of the 380 eligible patients, 365 patients have completed study treatment and 12 patients discontinued study treatment due to the following reasons: patient refusal (2 pts, 0.5%), adverse events (4 pts, 1.1%), and other reason (6 pts, 1.6%). (Notes: we re still waiting for 3 end of tretament forms). Table 1 shows the sites of enrollment. Table 2 shows baseline patient characteristics. Table 3 shows the reasons of patients who ended the treatment. Table of Contents: Page Figure 1: Patient Consort Diagram Table 1: Patient Enrollment Table 2: Patient Characteristics Table 3: End of Treatment Reason Primary Analysis: Table 4: Primary Endpoint Summary Table 5: Odds Ratio from Generalized Linear Model Predicting No Nausea Secondary Analysis: Figure 2: Predicted and Observed Mean Plots across arm for Nausea Table 6: Mixed Effect Regression Model predicting Nausea Table 7: Summary of Complete Response Table 8: Odds Ratio from Generalized Linear Model Predicting Complete Response Figure 3: Predicted and Observed Mean Plots across arm for Sedation Trouble Table 9: Mixed Effect Regression Model predicting Sedation Trouble Figure 4: Predicted and Observed Mean Plots across arm for Appetite Increased Table 10: Mixed Effect Regression Model predicting Appetite Increased

103 2 Supplementatry Analysis: Table 11: Daily Toxicities reported per PRO Table 12: Summary of Change from Baseline for Toxicities reported per PRO Table 13: Nausea Severity/Vomiting and Number of Extra Nausea/Vomiting Pills Taken Figure 5: Mean plots of Nausea Figure 6: Mean plots of Sedation Trouble Figure 7: Mean plots of Appetite Increased Figure 8a: Bug plots of Raw Score for Nausea Figure 8b: Bug plots of Change from Baseline Scores for Nausea Figure 9a: Bug plots of Raw Score for Sedation Trouble Figure 9b: Bug plots of Change from Baseline Scores for Sedation Trouble Figure 10a: Bug plots of Raw Score for Appetite Increased Figure 10b: Bug plots of Change from Baseline Scores for Appetite Increased Adverse Event Analysis: Table 14: Adverse Events Summary

104 Figure 1: Patient Consort Diagram 3

105 4 Table 1: Patient Enrollment Olanzapine (N=192) Placebo (N=188) Total (N=380) Registration Member Coborn 0 (0.0%) 1 (0.5%) 1 (0.3%) Altru ND 2 (1.0%) 2 (1.1%) 4 (1.1%) Rapid 1 (0.5%) 1 (0.5%) 2 (0.5%) U VT 1 (0.5%) 1 (0.5%) 2 (0.5%) EMMC 3 (1.6%) 3 (1.6%) 6 (1.6%) Ellis Fischel 3 (1.6%) 1 (0.5%) 4 (1.1%) Mount NY021 3 (1.6%) 3 (1.6%) 6 (1.6%) RI Hosp 2 (1.0%) 1 (0.5%) 3 (0.8%) Sinai Balt 0 (0.0%) 1 (0.5%) 1 (0.3%) University IL 2 (1.0%) 2 (1.1%) 4 (1.1%) WellSpan PA 3 (1.6%) 2 (1.1%) 5 (1.3%) SUNY 0 (0.0%) 1 (0.5%) 1 (0.3%) Inova Fairfax 1 (0.5%) 3 (1.6%) 4 (1.1%) Baptist KY 2 (1.0%) 1 (0.5%) 3 (0.8%) Avera 4 (2.1%) 2 (1.1%) 6 (1.6%) University MN 0 (0.0%) 1 (0.5%) 1 (0.3%) Edwards WV 4 (2.1%) 1 (0.5%) 5 (1.3%) Bay Area Tumor Institute NCORP 4 (2.1%) 3 (1.6%) 7 (1.8%) Colorado Cancer Research Program 1 (0.5%) 1 (0.5%) 2 (0.5%) Dana-Farber/Partners Care NCTN LAPS 0 (0.0%) 1 (0.5%) 1 (0.3%) Mayo Clinic NCTN LAPS 4 (2.1%) 4 (2.1%) 8 (2.1%) Michigan NCORP 7 (3.6%) 8 (4.3%) 15 (3.9%) Roswell Park Cancer Institute NCTN LAPS 1 (0.5%) 1 (0.5%) 2 (0.5%) Southeast Cancer Control Consortium 4 (2.1%) 4 (2.1%) 8 (2.1%) University of North Carolina at Chapel H 3 (1.6%) 3 (1.6%) 6 (1.6%) University of Oklahoma Health Science Ce 1 (0.5%) 2 (1.1%) 3 (0.8%) Huntsman Cancer Institute / University o 1 (0.5%) 1 (0.5%) 2 (0.5%) William Beaumont Hospital 2 (1.0%) 5 (2.7%) 7 (1.8%) Virginia Commonwealth University MBCCOP 1 (0.5%) 0 (0.0%) 1 (0.3%) Geisinger Cancer Institute NCI Community 1 (0.5%) 1 (0.5%) 2 (0.5%) Hawaii Minority Underserved NCORP 3 (1.6%) 3 (1.6%) 6 (1.6%) Medical University of South Carolina Min 3 (1.6%) 3 (1.6%) 6 (1.6%) Columbus NCI Community Oncology Research 3 (1.6%) 3 (1.6%) 6 (1.6%) Dayton 5 (2.6%) 5 (2.7%) 10 (2.6%) Wichita NCI Community Oncology Research 5 (2.6%) 5 (2.7%) 10 (2.6%) Wisconsin NCI Community Oncology Researc 15 (7.8%) 16 (8.5%) 31 (8.2%) Heartland Cancer Research NCORP 40 (20.8%) 36 (19.1%) 76 (20.0%) Metro-Minnesota NCI Community Oncology R 9 (4.7%) 8 (4.3%) 17 (4.5%) Sanford NCI Community Oncology Research 13 (6.8%) 12 (6.4%) 25 (6.6%) NCORP of the Carolinas (Greenville Healt 2 (1.0%) 2 (1.1%) 4 (1.1%) Delaware/Christiana Care NCI Community O 10 (5.2%) 10 (5.3%) 20 (5.3%) Iowa-Wide Oncology Research Coalition NC 6 (3.1%) 7 (3.7%) 13 (3.4%) Cancer Research for the Ozarks NCORP 9 (4.7%) 10 (5.3%) 19 (5.0%) Pacific Cancer Research Consortium NCORP 1 (0.5%) 1 (0.5%) 2 (0.5%) Lafayette Family Cancer Center-EMMC 4 (2.1%) 6 (3.2%) 10 (2.6%)

106 5 Table 1: Patient Enrollment Olanzapine (N=192) Placebo (N=188) Total (N=380) Baptist Health Network 3 (1.6%) 0 (0.0%) 3 (0.8%) (report generated on 25AUG2015) Table 2: Patient Characteristics Olanzapine (N=192) Placebo (N=188) Total (N=380) p value Age N Mean (SD) 55.9 (10.7) 55.2 (11.2) 55.6 (10.9) Median Q1, Q3 49.5, , , 63.0 Range ( ) ( ) ( ) Race White 172 (89.6%) 171 (91.0%) 343 (90.3%) Black or African American 9 (4.7%) 9 (4.8%) 18 (4.7%) Asian 5 (2.6%) 4 (2.1%) 9 (2.4%) American Indian or Alaska Native 3 (1.6%) 1 (0.5%) 4 (1.1%) Not reported: patient refused or not available 3 (1.6%) 2 (1.1%) 5 (1.3%) Unknown: Patient unsure 0 (0.0%) 1 (0.5%) 1 (0.3%) Gender Female 139 (72.4%) 136 (72.3%) 275 (72.4%) Male 53 (27.6%) 52 (27.7%) 105 (27.6%) Receptor Antagonist Palonosetron 145 (75.5%) 143 (76.1%) 288 (75.8%) Ondasetron 46 (24.0%) 44 (23.4%) 90 (23.7%) Granisetron 1 (0.5%) 1 (0.5%) 2 (0.5%) Chemotherapy regimen Cisplatin-containing regimen 71 (37.0%) 65 (34.6%) 136 (35.8%) Anthracycline and cyclophosphamide (AC) 121 (63.0%) 123 (65.4%) 244 (64.2%) ECOG Performance Status Missing (78.0%) 144 (76.6%) 293 (77.3%) 1 40 (20.9%) 41 (21.8%) 81 (21.4%) 2 2 (1.0%) 3 (1.6%) 5 (1.3%) Primary site of disease Breast 120 (62.5%) 122 (64.9%) 242 (63.7%) Lung 27 (14.1%) 22 (11.7%) 49 (12.9%) Other 45 (23.4%) 44 (23.4%) 89 (23.4%)

107 6 Table 2: Patient Characteristics Olanzapine (N=192) Placebo (N=188) Total (N=380) Your overall quality of life in the past week including today? (0=As bad as it can be, 10=As good as it can be) N Mean (SD) 7.6 (2.4) 7.9 (2.5) 7.7 (2.4) Median Q1, Q3 7.0, , , 10.0 Range ( ) ( ) ( ) Your level of fatigue, on the average in the past week including today? (0=No Fatigue, 10=Fatigue as bad as it can be) N Mean (SD) 2.5 (2.3) 2.3 (2.2) 2.4 (2.3) Median Q1, Q3 1.0, , , 4.0 Range ( ) ( ) ( ) (report generated on 27AUG2015) 1 Wilcoxon 2 Fisher Exact p value Table 3: End of Treatment Reason Olanzapine (N=192) Placebo (N=188) Total (N=380) p value Off treatment reason Missing Treatment (Intervention) Completed Per Protocol 182 (95.3%) 183 (98.4%) 365 (96.8%) Patient Withdrawal/Refusal After Beginning Protocol Treatment 1 (0.5%) 1 (0.5%) 2 (0.5%) Adverse Events/Side Effects/Complications 4 (2.1%) 0 (0.0%) 4 (1.1%) Other 4 (2.1%) 2 (1.1%) 6 (1.6%) (report generated on 25AUG2015) Fisher Exact

108 Results: Primary Analysis: The primary endpoint is no nausea, which is defined as a response of 0 in the nausea item of Nausea and Vomiting Daily Diary/Questionnaire in the acute (0-24 hours), delayed ( hours), and overall (0-120 hours) periods. The proportion of patients who had no nausea was significantly greater for the Olanzapine regimen compared to the Placebo regimen for the acute period (24h post-chemotherapy) (74% vs. 45%, p=0.0015), for the delayed period (days h postchemotherapy) (42% vs. 25%, p=0.0015), and for the overall period (0-120 h) (37% vs. 22%, p=0.0015). See Table 4. 7 Olanzapine (N=192) Table 4: Primary Endpoint Summary Placebo (N=188) Total (N=380) p value Overall Adjusted P-value per Simes Gatekeeping Acute Nausea < Missing No Nausea 135 (73.8%) 82 (45.3%) 217 (59.6%) Had Nausea 48 (26.2%) 99 (54.7%) 147 (40.4%) Delayed Nausea Missing No Nausea 75 (42.4%) 45 (25.4%) 120 (33.9%) Had Nausea 102 (57.6%) 132 (74.6%) 234 (66.1%) Overall Nausea Missing No Nausea 66 (37.3%) 39 (21.9%) 105 (29.6%) Had Nausea 111 (62.7%) 139 (78.1%) 250 (70.4%) (report generated on 25AUG2015) 1 Chi-Square Generalized linear models was explored to incorporate baseline fatigue/qol, stratification factors and other patient characteristics.(table 5) The patients receiving Olanzapine are 5.26 (CI: ) times more often to have no nausea than those receiving placebo (P<0.001). White patients are 0.5 (CI: 0.29, 1.01) times less often to have no nausea than non-white patients (P=0.0542). Gender, 5-HT3 receptor antagonist, chemotherapy regimen, baseline overall QOL and fatigue had no significant effect on no nausea rate. Age is found to have statistically significant effect on no nausea (P<0.0001), however the effect is very small since the odds ratio is close to 1. Table 5: Odds Ratio from Generalized Linear Model Predicting No Nausea Label L'Beta Estimate Confidence Limits P value AGE <.0001 Arm(Olanzapine vs. Placebo) <.0001 Race( White vs non-white) Gender( Female vs Male) HT3(Ondansetron vs Palonosetron) Chemotherapy regimen (AC vs Cisplatin) Overall QOL Fatigue

109 Nausea 8 Secondary Analysis: Nausea scores (0-10) repeatedly measured by the Nausea and Vomiting Daily Diary/Questionnaire, the repeated measures analyses and growth curve models was used to account for the factor of day and time trend in nausea score. The model selected is a mixed-effect model controlling baseline nausea score including covariates of arm, time, time^2, arm by time interaction with random intercept, linear and quadratic effect and unstructured variance-covariance pattern by REML methods based on the criteria likelihood ratio test, AIC and BIC. Comparing the estimated mean plot from the selected model and the observed mean plot, the model is a good fit (Figure 1) Figure 2: Predicted and Observed Mean Plot Across Arm for Nausea Predicted OLN Predicted PLA Observed OLN Observed PLA Table 6: Mixed Effect Regression Model predicting Nausea Parameter ( fixed effect) REML estimate SE P Constant < Baseline Nausea Day Day Arm (Olanzapine vs. Placebo) < Arm*Day The difference in the nausea score at day 1 after receiving treatment between Olanzapine and placebo group is about , indicating that Olanzapine have very immediate effect on controlling nausea symptom during acute period. (Table 6) P-values for all the interaction of arm by time are less than 0.05(P=0.0068), thus we have strong evidence to conclude that the trends across time vary significantly by group. The average daily symptom worsening is bigger in Olanzapine group with the average difference equal to

110 In general, Olanzapine is effective in alleviating nausea symptom. The most effective period for the drug is during the first 24 hours (acute period) after chemotherapy, and the drug will gradually decrease its effectiveness during delayed period (Table 6). Similar analysis as primary endpoint was conducted for complete response during acute, delayed and overall periods. Complete response was significantly improved for the Olanzapine patients compared to Placebo patients for the acute (86% vs. 65%, p<0.0001), the delayed (67% vs. 52%, p<0.0073), and the overall periods (64% vs. 41%, p<0.0001). See Table 7. 9 Olanzapine (N=192) Table 7: Summary of Complete Response Placebo (N=188) Total (N=380) p value Adjusted P-value per Simes Gatekeeping Acute Response < < Missing No Response 26 (14.3%) 64 (35.4%) 90 (24.8%) Complete Response 156 (85.7%) 117 (64.6%) 273 (75.2%) Delayed Response Missing No Response 54 (33.1%) 80 (47.6%) 134 (40.5%) Complete Response 109 (66.9%) 88 (52.4%) 197 (59.5%) Overall Response < < Missing No Response 59 (36.4%) 101 (59.4%) 160 (48.2%) Complete Response 103 (63.6%) 69 (40.6%) 172 (51.8%) (report generated on 25AUG2015) 1 Chi-Square Generalized linear model on complete response was explored to incorporate baseline fatigue/qol, stratification factors and other patient characteristics. (Table 8) The patients receiving Olanzapine are 5.48 (CI: ) times more often to have complete response than those receiving placebo (P<0.0001). Patients on AC regimen are 1.83 (CI: ) times more often to have complete response than those on Cisplatin regimen. Race, gender, 5-HT3 receptor antagonist, baseline overall QOL and fatigue had no significant effect on complete response rate. Age is found to have statistically significant effect on complete response (P<0.0001), however the effect is very small since the odds ratio is close to 1. Table 8: Odds Ratio from Generalized Linear Model Predicting Complete Response Label L'Beta Estimate Confidence Limits P value AGE <.0001 Arm(Olanzapine vs. Placebo) <.0001 Race( White vs non-white) Gender( Female vs Male) HT3 (Ondansetron vs Palonosetron) Chemotherapy regimen (AC vs Cisplatin) Overall QOL Fatigue

111 Sedation Potential toxicities of undesired sedation were analyzed by repeated measures analyses and growth curve models to account for the factor of day and time trend. The repeated measures analyses and growth curve models was used to account for the factor of day and time trend in sedation trouble score. The model selected is a mixed-effect model controlling baseline sedation trouble score including covariates of arm, time, time^2, arm by time interaction with random intercept, linear and quadratic effect and unstructured variance-covariance pattern by REML methods based on the criteria likelihood ratio test, AIC and BIC. Comparing the estimated mean plot from the selected model and the observed mean plot, the model is a good fit (Figure 3) 10 Figure 3: Predicted and Observed Mean Plot Across Arm for Undesired Sedation Predicted OLN Predicted PLA Observed OLN Observed PLA The difference in the sedation trouble score at day 1 after receiving treatment between Olanzapine and placebo group is about 1.4, indicating that Olanzapine have very immediate side effect of sedation trouble within 24 hours after receiving treatment during acute period. (Table 9) P-values for all the interaction of arm by time are less than 0.001(P=0.0004), thus we have strong evidence to conclude that the trends across time vary significantly by group. The average daily symptom worsening is smaller in Olanzapine group with the average difference equal to

112 Appetite Olanzapine has side effect of sedation trouble, especially during acute period after chemotherapy, and the side effect will gradually decrease itself during delayed period (Table 9). Table 9: Mixed Effect Regression Model Predicting Sedation Trouble Parameter ( fixed effect) REML estimate SE P Constant Baseline Sedation trouble <.0001 Day Day Arm (Olanzapine vs. Placebo) Arm*Day Potential toxicities of undesired appetite increase were analyzed by repeated measures analyses and growth curve models to account for the factor of day and time trend. The repeated measures analyses and growth curve models was used to account for the factor of day and time trend in appetite increase score. The model selected is a mixed-effect model controlling baseline appetite increase score including covariates of arm, time, time^2, arm by time interaction with random intercept, linear and quadratic effect and unstructured variance-covariance pattern by REML methods based on the criteria likelihood ratio test, AIC and BIC. Comparing the estimated mean plot from the selected model and the observed mean plot, the model is a good fit (Figure 4) 11 Figure 4: Predicted and Observed Mean Plot Across Arm for Appetite Increased Predicted OLN Predicted PLA Observed OLN Observed PLA

113 P-values for all the interaction of arm by time are not statistically significant (p=0.2239), thus the trends across time doesn t vary significantly by group. Daily change in appetite increase is not statistically significant (p=0.1215), suggesting that there is no significant daily increase in appetite symptom during follow-up period. Olanzapine was not found to have statistically significant side effect on appetite increase after controlling baseline appetite increase score. (p=0.9645) (Table 10) 12 Table 10: Mixed Effect Regression Model Predicting Appetite Increased Parameter ( fixed effect) REML estimate SE P Constant Baseline appetite <.0001 Day Day Arm (Olanzapine vs. Placebo) Arm*Day The repeated measures analyses and growth curve models were performed to account for the factor of day and time trend in ordinal medication. The number of medication have been combined to two category, since less than 5% of patients take two or more than two extra nausea/vomiting pills. So generalized linear models on the number of rescue medication was explored to incorporate baseline fatigue/qol, stratification factors and other patient characteristics, the results is the same as the complete response (no emetic episodes and no use of rescue medication) See Table 8.

114 13 Supplementary Analysis: Scores Comparison between Arms Table 11 shows the summary of daily toxicities reported per Patient Reported Outcome. Patients on Olanzapine reported significantly less nausea at day 2 to day 6, significantly higher sedation trouble at day 2; and significantly more undesired appetite increase at day 3 to day 6. Patients on Olanzapine reported less than one point worsen in nausea at day 2 to day 6 from baseline as compared to placebo with 1.3 to 1.7 points worsen in nausea. On average, Olanzapine patients reported about 2 points worsen in sedation trouble at day 2 from baseline as compared to patients on placebo (mean=1.9 vs. 0.7, p=0.0040), See Table 12 There were at least 10% more patients on Olanzapine compared to Placebo patients reported no nausea at day 2 to 6; and not taking extra nausea/vomiting pills for nausea/vomiting at day 2 to 4. See Table 13. Table 11: Daily Toxicities reported per PRO Olanzapine (N=192) Placebo (N=188) Total (N=380) p value Day 1: Nausea N Mean (SD) 0.2 (0.8) 0.3 (1.1) 0.3 (1.0) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) Day 2: Nausea < N Mean (SD) 0.7 (1.5) 2.0 (2.7) 1.3 (2.2) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Day 3: Nausea < N Mean (SD) 0.8 (1.7) 1.8 (2.4) 1.3 (2.1) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Day 4: Nausea < N Mean (SD) 0.9 (1.7) 1.8 (2.4) 1.4 (2.1) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Day 5: Nausea N Mean (SD) 1.0 (1.8) 1.6 (2.3) 1.3 (2.1) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Day 6: Nausea

115 14 Table 11: Daily Toxicities reported per PRO Olanzapine (N=192) Placebo (N=188) Total (N=380) N Mean (SD) 1.0 (1.9) 1.6 (2.4) 1.3 (2.1) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) p value Day 1: Sedation Trouble N Mean (SD) 0.4 (1.2) 0.5 (1.5) 0.5 (1.3) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) Day 2: Sedation Trouble N Mean (SD) 2.3 (3.2) 1.2 (2.2) 1.7 (2.8) Median Q1, Q3 0.0, , , 3.0 Range ( ) ( ) ( ) Day 3: Sedation Trouble N Mean (SD) 1.6 (2.5) 1.4 (2.3) 1.5 (2.4) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Day 4: Sedation Trouble N Mean (SD) 1.5 (2.3) 1.4 (2.3) 1.4 (2.3) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Day 5: Sedation Trouble N Mean (SD) 1.2 (2.1) 1.2 (2.1) 1.2 (2.1) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Day 6: Sedation Trouble N Mean (SD) 0.9 (1.8) 1.3 (2.2) 1.1 (2.0) Median Q1, Q3 0.0, , , 1.0 Range ( ) ( ) ( )

116 15 Table 11: Daily Toxicities reported per PRO Olanzapine (N=192) Placebo (N=188) Total (N=380) p value Day 1: Appetite Increase N Mean (SD) 0.6 (1.7) 0.3 (0.9) 0.4 (1.4) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) Day 2: Appetite Increase N Mean (SD) 0.7 (1.6) 0.5 (1.5) 0.6 (1.6) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) Day 3: Appetite Increase N Mean (SD) 0.7 (1.5) 0.6 (1.7) 0.7 (1.6) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) Day 4: Appetite Increase N Mean (SD) 1.0 (1.8) 0.7 (1.7) 0.8 (1.8) Median Q1, Q3 0.0, , , 1.0 Range ( ) ( ) ( ) Day 5: Appetite Increase N Mean (SD) 1.0 (1.8) 0.7 (1.7) 0.8 (1.8) Median Q1, Q3 0.0, , , 1.0 Range ( ) ( ) ( ) Day 6: Appetite Increase N Mean (SD) 1.1 (2.0) 0.7 (1.7) 0.9 (1.9) Median Q1, Q3 0.0, , , 1.0 Range ( ) ( ) ( ) (report generated on 25AUG2015) 1 Wilcoxon

117 16 Table 12: Summary of Change from Baseline for Toxicities reported per PRO Olanzapine (N=192) Placebo (N=188) Total (N=380) p value Nausea: Change from Baseline at Day 2 < N Mean (SD) 0.5 (1.6) 1.7 (2.7) 1.1 (2.3) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Nausea: Change from Baseline at Day 3 < N Mean (SD) 0.6 (1.7) 1.5 (2.4) 1.1 (2.1) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Nausea: Change from Baseline at Day N Mean (SD) 0.7 (1.7) 1.5 (2.5) 1.1 (2.2) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Nausea: Change from Baseline at Day N Mean (SD) 0.8 (1.8) 1.3 (2.4) 1.1 (2.1) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Nausea: Change from Baseline at Day N Mean (SD) 0.9 (2.0) 1.3 (2.5) 1.1 (2.2) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Undesired Sedation: Change from Baseline at Day N Mean (SD) 1.9 (3.4) 0.7 (2.2) 1.3 (2.9) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Undesired Sedation: Change from Baseline at Day N Mean (SD) 1.2 (2.6) 0.9 (2.3) 1.0 (2.5) Median Q1, Q3 0.0, , , 2.0

118 17 Table 12: Summary of Change from Baseline for Toxicities reported per PRO Olanzapine (N=192) Placebo (N=188) Total (N=380) Range ( ) ( ) ( ) p value Undesired Sedation: Change from Baseline at Day N Mean (SD) 1.1 (2.4) 0.9 (2.3) 1.0 (2.3) Median Q1, Q3 0.0, , , 2.0 Range ( ) ( ) ( ) Undesired Sedation: Change from Baseline at Day N Mean (SD) 0.8 (2.1) 0.7 (2.1) 0.8 (2.1) Median Q1, Q3 0.0, , , 1.0 Range ( ) ( ) ( ) Undesired Sedation: Change from Baseline at Day N Mean (SD) 0.6 (1.8) 0.8 (2.1) 0.7 (2.0) Median Q1, Q3 0.0, , , 1.0 Range ( ) ( ) ( ) Undesired Appetite: Change from Baseline at Day N Mean (SD) 0.2 (2.2) 0.2 (1.5) 0.2 (1.8) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) Undesired Appetite: Change from Baseline at Day N Mean (SD) 0.2 (1.9) 0.3 (1.7) 0.3 (1.8) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) Undesired Appetite: Change from Baseline at Day N Mean (SD) 0.5 (2.2) 0.4 (1.7) 0.5 (1.9) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) Undesired Appetite: Change from Baseline at Day N Mean (SD) 0.5 (2.2) 0.4 (1.6) 0.5 (2.0)

119 18 Table 12: Summary of Change from Baseline for Toxicities reported per PRO Olanzapine (N=192) Placebo (N=188) Total (N=380) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) p value Undesired Appetite: Change from Baseline at Day N Mean (SD) 0.6 (2.3) 0.4 (1.7) 0.5 (2.0) Median Q1, Q3 0.0, , , 0.0 Range ( ) ( ) ( ) (report generated on 25AUG2015) Wilcoxon Table 13: Nausea Severity/Vomiting and number of extra nausea/vomiting pills taken Olanzapine (N=192) Placebo (N=188) Total (N=380) p value Day 2: Nausea Severity < Missing None 139 (76.4%) 93 (52.0%) 232 (64.3%) Mild 36 (19.8%) 61 (34.1%) 97 (26.9%) Moderate 6 (3.3%) 19 (10.6%) 25 (6.9%) Severe 1 (0.5%) 6 (3.4%) 7 (1.9%) Day 3: Nausea Severity Missing None 130 (72.2%) 86 (48.3%) 216 (60.3%) Mild 39 (21.7%) 70 (39.3%) 109 (30.4%) Moderate 10 (5.6%) 17 (9.6%) 27 (7.5%) Severe 1 (0.6%) 5 (2.8%) 6 (1.7%) Day 4: Nausea Severity Missing None 123 (71.1%) 91 (51.1%) 214 (61.0%) Mild 39 (22.5%) 63 (35.4%) 102 (29.1%) Moderate 10 (5.8%) 22 (12.4%) 32 (9.1%) Severe 1 (0.6%) 2 (1.1%) 3 (0.9%) Day 5: Nausea Severity Missing None 122 (69.7%) 94 (55.3%) 216 (62.6%) Mild 43 (24.6%) 60 (35.3%) 103 (29.9%) Moderate 7 (4.0%) 13 (7.6%) 20 (5.8%) Severe 3 (1.7%) 3 (1.8%) 6 (1.7%) Day 6: Nausea Severity

120 19 Table 13: Nausea Severity/Vomiting and number of extra nausea/vomiting pills taken Olanzapine (N=192) Placebo (N=188) Total (N=380) Missing None 117 (67.6%) 96 (56.1%) 213 (61.9%) Mild 42 (24.3%) 50 (29.2%) 92 (26.7%) Moderate 14 (8.1%) 19 (11.1%) 33 (9.6%) Severe 0 (0.0%) 6 (3.5%) 6 (1.7%) p value Day 2: Vomiting Frequency Missing None 179 (98.4%) 174 (96.1%) 353 (97.2%) Once 2 (1.1%) 3 (1.7%) 5 (1.4%) Twice 0 (0.0%) 1 (0.6%) 1 (0.3%) More than twice 1 (0.5%) 3 (1.7%) 4 (1.1%) Day 3: Vomiting Frequency Missing None 177 (98.3%) 169 (94.9%) 346 (96.6%) Once 2 (1.1%) 3 (1.7%) 5 (1.4%) Twice 1 (0.6%) 2 (1.1%) 3 (0.8%) More than twice 0 (0.0%) 4 (2.2%) 4 (1.1%) Day 4: Vomiting Frequency Missing None 169 (98.3%) 166 (93.3%) 335 (95.7%) Once 1 (0.6%) 5 (2.8%) 6 (1.7%) Twice 2 (1.2%) 3 (1.7%) 5 (1.4%) More than twice 0 (0.0%) 4 (2.2%) 4 (1.1%) Day 5: Vomiting Frequency Missing None 169 (97.1%) 159 (92.4%) 328 (94.8%) Once 3 (1.7%) 7 (4.1%) 10 (2.9%) Twice 1 (0.6%) 1 (0.6%) 2 (0.6%) More than twice 1 (0.6%) 5 (2.9%) 6 (1.7%) Day 6: Vomiting Frequency Missing None 161 (94.2%) 152 (88.4%) 313 (91.3%) Once 5 (2.9%) 8 (4.7%) 13 (3.8%) Twice 2 (1.2%) 7 (4.1%) 9 (2.6%) More than twice 3 (1.8%) 5 (2.9%) 8 (2.3%) Day 2: No. of Nausea/Vomiting Pills < Missing None 156 (85.7%) 117 (64.6%) 273 (75.2%) One 21 (11.5%) 35 (19.3%) 56 (15.4%) Two 3 (1.6%) 19 (10.5%) 22 (6.1%) More than two 2 (1.1%) 10 (5.5%) 12 (3.3%)

121 20 Table 13: Nausea Severity/Vomiting and number of extra nausea/vomiting pills taken Olanzapine (N=192) Placebo (N=188) Total (N=380) p value Day 3: No. of Nausea/Vomiting Pills Missing None 158 (87.8%) 124 (69.7%) 282 (78.8%) One 11 (6.1%) 24 (13.5%) 35 (9.8%) Two 7 (3.9%) 20 (11.2%) 27 (7.5%) More than two 4 (2.2%) 10 (5.6%) 14 (3.9%) Day 4: No. of Nausea/Vomiting Pills Missing None 141 (82.9%) 124 (70.5%) 265 (76.6%) One 16 (9.4%) 24 (13.6%) 40 (11.6%) Two 10 (5.9%) 17 (9.7%) 27 (7.8%) More than two 3 (1.8%) 11 (6.3%) 14 (4.0%) Day 5: No. of Nausea/Vomiting Pills Missing None 145 (83.8%) 131 (76.6%) 276 (80.2%) One 19 (11.0%) 23 (13.5%) 42 (12.2%) Two 5 (2.9%) 7 (4.1%) 12 (3.5%) More than two 4 (2.3%) 10 (5.8%) 14 (4.1%) Day 6: No. of Nausea/Vomiting Pills Missing None 143 (83.6%) 130 (76.0%) 273 (79.8%) One 12 (7.0%) 16 (9.4%) 28 (8.2%) Two 12 (7.0%) 11 (6.4%) 23 (6.7%) More than two 4 (2.3%) 14 (8.2%) 18 (5.3%) (report generated on 25AUG2015) Chi-Square

122 21 Figures 5-7 show the mean plots of nausea, undesired appetite and sedation trouble. Figures 8-10 show the bug plots of raw score and change from baseline scores for nausea, undesired appetite and sedation trouble. Mean Score Olanzapine Placebo Figure 5: Mean plots of Nausea by Day (0=None and 10=As bad as it can be) Day Olanzapine Placebo

123 22 Mean Score Olanzapine Placebo Figure 6: Mean plots of Sedation Trouble by Day (0=None and 10=As bad as it can be) Day Olanzapine Placebo Mean Score Olanzapine Placebo Figure 7: Mean plots of Undesired Appetite by Day (0=None and 10=As bad as it can be) Day Olanzapine Placebo

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