Version di 67 - July, CONFIDENTIAL

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1 The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced : results of GOIRC randomized phase II study and pooled analysis with NVALT7 trial Ardizzoni, et al DOI: /JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors ( only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly.

2 Randomized phase II study of pemetrexed versus pemetrexed (prt. GOIRC 02/2006) (EudraCT number: ) Version di 67 - July,

3 Study coordinator Dr. Andrea Ardizzoni Oncologia Medica Azienda Ospedaliero-Universitaria, Parma Via Gramsci Parma Italy Medical advisor Dr. Marcello Tiseo Azienda Ospedaliero-Universitaria, Parma Via Gramsci Parma Italy Administrative Office Dr. Roberta Camisa Azienda Ospedaliero-Universitaria, Parma Via Gramsci Parma Italy Version di 67 - July,

4 Table of contents ABBREVIATIONS AND DEFINITIONS BACKGROUND AND INTRODUCTION INVESTIGATIONAL AGENTS PEMETREXED (ALIMTA) CARBOPLATIN OBJECTIVES OF THE TRIAL PRIMARY OBJECTIVE SECONDARY OBJECTIVES END-POINTS PRIMARY END-POINT SECONDARY END-POINTS TRIAL DESIGN PATIENT SELECTION CRITERIA INCLUSION CRITERIA EXCLUSION CRITERIA THERAPEUTIC REGIMENS, TOXICITY AND DOSE MODIFICATIONS DRUG ADMINISTRATION PREMEDICATION, FOLIC ACID AND VITAMIN B 12 SUPPLEMENTATION DOSE MODIFICATIONS Hematologic Toxicity Non-hematologic toxicity Creatinine Clearance Treatment delays as a result of insufficient folic acid or vitamin B 12 supplementation CONCOMITANT THERAPY Non-steroidal anti-inflammatory drugs Leucovorin Therapy for diarrhea Therapy for febrile neutropenia Therapy for anemia Folic acid and vitamin B 12 supplementation DURATION OF THERAPY CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP BEFORE TREATMENT START DURING TREATMENT AFTER THE END OF TREATMENT (FOLLOW-UP) SUMMARY TABLE CRITERIA OF EVALUATION DEFINITIONS RESPONSE EVALUATION CRITERIA (RECIST) TOXICITY EVALUATION Serious adverse events Toxic deaths TIME TO PROGRESSION AND SURVIVAL EVALUATION STATISTICAL CONSIDERATIONS STATISTICAL DESIGN Version di 67 - July,

5 10.2 RANDOMIZATION AND STRATIFICATIONS STATISTICAL ANALYSIS DATA MONITORING INVESTIGATOR AUTHORIZATION PROCEDURE PATIENT REGISTRATION/RANDOMIZATION PROCEDURE FORMS AND PROCEDURES FOR COLLECTING DATA CASE REPORT FORMS AND SCHEDULE FOR COMPLETION DATA FLOW REPORTING ADVERSE EVENTS DEFINITIONS REPORTING PROCEDURE Non-serious adverse events and/or non-serious adverse drug reactions Serious adverse events or serious adverse drug reactions QUALITY ASSURANCE CONTROL OF DATA CONSISTENCY AUDITS CENTRAL REVIEW PROCEDURES ETHICAL CONSIDERATIONS PATIENT PROTECTION SUBJECT IDENTIFICATION INFORMED CONSENT ADMINISTRATIVE RESPONSIBILITIES THE STUDY COORDINATOR THE DATA CENTER TRIAL SPONSORSHIP AND FINANCING TRIAL INSURANCE PUBLICATION POLICY REFERENCES APPENDIX A APPENDIX B APPENDIX C APPENDIX D APPENDIX E APPENDIX F Version di 67 - July,

6 Study synopsis NAME OF ACTIVE SUBSTANCES Title of the study Study Coordinator Clinical phase PEMETREXED (ALIMTA) AND CARBOPLATIN RANDOMIZED PHASE II STUDY OF PEMETREXED VERSUS PEMETREXED AND CARBOPLATIN AS SECOND LINE CHEMOTHERAPY IN ADVANCED NON-SMALL-CELL LUNG CANCER (NSCLC) Dr. Andrea Ardizzoni Oncologia Medica Azienda Ospedaliero-Universitaria, Parma Via Gramsci Parma Italy Phase II Study period (date of first inclusion/last inclusion) Objectives Methodology Number of patients Primary Objective: To compare time to progression between the combination pemetrexed-carboplatin and pemetrexed alone in previously treated patients with locally advanced or metastatic NSCLC. Secondary Objectives: - To assess differences in terms of response rate between the combination pemetrexed-carboplatin and pemetrexed alone. - To assess differences in terms of duration of response between the combination pemetrexed-carboplatin and pemetrexed alone. - To assess differences in terms of toxicity between the combination pemetrexed-carboplatin and pemetrexed alone. - To assess differences in terms of survival between the combination pemetrexed-carboplatin and pemetrexed alone. Multicenter, open-label, randomized phase II trial comparing the combination pemetrexed-carboplatin versus pemetrexed alone in the second-line treatment of advanced NSCLC. Countries: Italy and EU 115 (per treatment group) patients. Version di 67 - July,

7 Inclusion criteria Exclusion criteria The patient must give written (personally signed and dated) informed consent before completing any study related procedure. Males or females 18 years. Histologically or cytologically confirmed non-squamous. Unresectable stage IIIB, stage IV and unresectable local relapse or metastatic disease, with evidence of disease progression after first line chemotherapy which should have included a platinum agent. ECOG performance status 2. Life expectancy 12 weeks. Adequate hematological, hepatic and renal functions: neutrophils 1.5 x 10 9 /L platelets 100 x 10 9 /L total bilirubin 1.5 ULN AP, AST and ALT 3.0 ULN AP, AST and ALT 5.0 ULN is acceptable if the liver has tumor involvement creatinine clearance 45 ml/min Prior treatment with only 1 chemotherapy regimen for the treatment of advanced disease which should have included a platinum agent (prior treatment with gefitinib/erlotinib as maintenance after 1 st line chemotherapy is allowed and not considered as a chemotherapy regimen). At least 4 weeks from prior chemotherapy with complete recovery from first line chemotherapy side effects to < Grade 2. Prior radiotherapy allowed, only in case of presence of at least one measurable lesion outside an irradiated area. Radiotherapy must have been completed at least 2 weeks before registration. At baseline, presence of at least one measurable target lesion: lesion that can be accurately measured in at least one dimension i.e. longest diameter as 20 mm with conventional CT scan or as 10 mm with spiral CT scan (RECIST Criteria). All radiology studies must be performed within 28 days prior to randomization. Absence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule. Prior treatment with pemetrexed. Patients who are: pregnant or lactating; at risk of pregnancy during the study. This must be checked by pregnancy test at study entry. The patient must be receiving a medically accepted contraceptive regimen. Patients with any underlying medical condition that might be aggravated by treatment or which cannot be controlled i.e. patients with active serious infection, diabetes mellitus, patients with concurrent heart failure [New York Version di 67 - July,

8 Heart Association (NYHA) class II-III-IV, or with progressive or unstable angina, patients who have had myocardial infarction within 6 months, and/or poorly controlled hypertension, or pericardial effusion. Documented brain metastases unless the patient has completed local therapy for central nervous system metastases and has been off corticosteroids for at least two weeks before enrollment. History of another malignancy within the past five years except basal cell carcinoma of the skin or carcinoma in situ of the cervix. Treatment with any investigational drug within the 30 days prior to registration. Concomitant treatment with any other anticancer drug. Known hypersensitivity to the study drugs or to drugs with similar chemical structures. Inability to interrupt aspirin or other non-steroidal antiinflammatory agents 2 days before, the day of, and 2 days after the dose of pemetrexed single agent or pemetrexed plus carboplatin. If a patient is taking an NSAID (COX-2 inhibitors included) or salicylate with a long half-life (for example, naproxen, piroxicam, diflunisal, nabumetone, rofecoxib or celecoxib) it should not be taken 5 days before the dose of pemetrexed (8-day period for long-acting agents such as piroxicam), the day of, and 2 days after the dose of pemetrexed single agent or pemetrexed plus carboplatin. Patients will be randomized (1:1) to receive either: Pemetrexed 500 mg/m 2 i.v. over approximately 10 minutes on day 1 of a 21 days cycle (Arm A control arm). Drug administration Duration of treatment Premedication and vitamin supplementation or Pemetrexed 500 mg/m 2 i.v. over approximately 10 minutes on day 1 and Carboplatin AUC 5 i.v. over approximately 30 minutes on day 1 (beginning approximately 30 minutes after the end of the pemetrexed infusion) of a 21 days cycle (Arm B experimental arm). Treatment will be repeated every 3 weeks for a maximum of 4 courses in the absence of progressive disease, unacceptable toxicity or patient refusal. Folic Acid: 350 to 600 g or equivalent oral dose daily beginning approximately 1 to 2 weeks prior to the first dose of pemetrexed or pemetrexed-carboplatin and continuing daily until 3 weeks after the last dose of pemetrexed. Vitamin B 12 : 1000 µg intramuscular injection approximately 1 to 2 weeks prior to the first dose of pemetrexed or pemetrexed-carboplatin and approximately every 9 weeks until 3 weeks after the last dose of pemetrexed. Dexamethasone (or equivalent): 4 mg orally twice per day; it Version di 67 - July,

9 should be taken on the day before, the day of, and the day after each dose of pemetrexed or pemetrexed-carboplatin, unless clinical contraindications exist. Higher or additional doses are permitted for reasons other than routine rash prophylaxis (i.e. anti-emetic prophylaxis). Tumor assessment will be performed according to the RECIST method. Assessment of measurable disease will be performed at baseline and every 2 cycles. Confirmation of an objective response has to be performed 4 weeks after documentation. Criteria for evaluation Safety will be assessed at each cycle by: Physical examination, including PS and body weight assessment; Complete blood cell count + platelet counts; Serum chemistry; Regular reporting of adverse events (AEs) graded by the Common Terminology Criteria for Adverse Event version 3.0 (CTCAE) ( Statistical considerations Follow-up The primary end-point in this trial is the time to progression (TTP). The median time to progression for the control arm (pemetrexed alone) is assumed to be 3 months based on data from Hanna et al 17. A total of 230 patients will be included in the study (115 in each arm) and patients will be followed until 190 of them have progressed in both arms together. This will provide 80% power to detect (at alpha = 0.05 two-sided log-rank test) a decrease of the hazard of progression in the combined arm of 33% (hazard ratio = 0.67). With an accrual of 80 patients per year, 230 patients could be randomized in 36 months and the analysis could be done immediately after, since the required number of events will be observed by the end of accrual. The total duration of the study will be 36 months. Efficacy will be analyzed by both intent-to-treat and for evaluable patients. Kaplan Meier method will be used to calculate the time to progression and the overall survival. Patients characteristics and safety will be analyzed by descriptive methods. A meta-analysis of this study plus an identical one running in The Netherlands, to assess the impact on survival of adding carboplatin to pemetrexed, is also planned. The follow-up period is the time from 30 days after last study treatment administration until evidence of progressive disease or final analysis or death. Survival information will be collected approximately every 3 months until death or final analysis. Version di 67 - July,

10 Abbreviations and definitions ALIMTA ALT ANC AP AST AUC Compliance CrCl CT CTCAE DHFR DLT GARFT GCP GFR Investigator IRB/ERB Legal Representative MRI MTD NSAID NSCLC PD trade name for the multi-targeted antifolate (LY231514, pemetrexed) alanine transaminase absolute neutrophil count alkaline phosphatase aspartate transaminase area under the curve Adherence to all the trial-related requirements, good clinical practice requirements and the applicable regulatory requirements. creatinine clearance computed tomography Common Terminology Criteria for Adverse Event dihydrofolate reductase dose limiting toxicity glycinamide ribonucleotide formyl transferase good clinical practice glomerular filtration rate A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. Institutional review board/ethical review board: a board or committee (institutional, regional, or national) composed of medical professional and nonmedical members whose responsibility is to verify that the safety, welfare, and human rights of the subjects participating in a clinical trial are protected. An individual or judicial or other body authorized under applicable law to consent, on behalf of a prospective subject, to the patient s participation in the clinical trial. magnetic resonance imaging maximum tolerated dose Non-Steroidal Anti-Inflammatory Drug non-small-cell lung cancer progressive disease Version di 67 - July,

11 PR RECIST SAE Study Entry Terms partial response Response Evaluation Criteria in Solid Tumors serious adverse event Screen: the act of determining if an individual meets minimum requirements to become part of a pool of potential candidates for participation in a clinical trial. In this study, screening involves diagnostic procedures and/or tests (for example, diagnostic psychological tests, x-rays, blood draws). For this type of screening, informed consent for these screening procedures and/or tests shall be obtained; this consent may be separate from obtaining consent for the study. Enter/Consent: the act of obtaining informed consent for participation in a clinical trial from patients deemed eligible or potentially eligible to participate in the clinical trial. Patients entered into a trial are those who sign the informed consent document directly or through their legally acceptable representatives. Enroll: the act of assigning a patient to a treatment. Patients who are enrolled in the trial are those who have been assigned to a treatment. TS WBC WHO thymidylate synthase white blood cell (leukocyte count) World Health Organization Version di 67 - July,

12 1. Background and introduction 1.1 Advanced Non-Small-Cell Lung Cancer (NSCLC) Lung cancer is the third most common malignancy and the first leading cause of cancer death in the Western world. In year 2002, over 800,000 people worldwide died of non-small cell lung cancer (NSCLC). More people die of lung cancer than of colon, breast, and prostate cancers altogether. NSCLC accounts for 75-80% of lung cancer cases 1. In the past twenty years, chemotherapy together with radiotherapy and surgery is the mainstay of NSCLC treatment, improving survival in locally advanced and advanced NSCLC stages 2. Recently, the encouraging results provided by adjuvant chemotherapy in NSCLC, suggest its use also in early disease stages 3. The increasing use of chemotherapy in NSCLC is due to the improved activity and tolerability of the new third generation drugs that allow administration of more than one line of chemotherapy 4. Platinum-based chemotherapy is the standard treatment and doublets with third generation drugs are the treatment of choice in NSCLC patients 5. Several prospective trials and meta-analyses have proved compellingly that chemotherapy does lead to a small, but statistically significant, improvement in survival when compared with best supportive care only. In the Non-Small-Cell Lung Cancer Collaborative Group meta-analysis, a 27% reduction of the death risk and 10% improvement in 1-year survival have been found when platinum-based chemotherapy has been compared with best supportive care 6. In addition, randomized studies comparing chemotherapy with best supportive care have shown that chemotherapy reduces cancer-related symptoms and does not compromise the quality of life 7. Recently, several randomized studies have shown that addition of platinum to any other third generation agent (vinorelbine, gemcitabine, docetaxel and paclitaxel) results in improved outcome 4,7. Although the current treatment practice for patients with metastatic disease includes addition of third generation agents to a platinum agent, no combination has emerged as the gold standard for efficacy and tolerability. Five randomized trials compared third generation regimens and their conclusions were that no differences in activity (response rates 20-30%), in efficacy (median survival 8-10 months) and in toxicity exist among the different doublets Second-line chemotherapy in advanced NSCLC An increasing number of patients with advanced non-small cell lung cancer (NSCLC) progressing after front-line chemotherapy are still in good performance status and willing to receive further treatment. The role of second line chemotherapy in the treatment of advanced NSCLC has been recognized only recently 13. The aims of second line chemotherapy consist mainly in symptoms palliation and, possibly, survival improvement. Several drugs have been tested in this setting of treatment, but the only two agents registered for second line chemotherapy of advanced NSCLC are docetaxel and, recently, pemetrexed. Docetaxel was first agent approved for the second line treatment of advanced NSCLC. The approval was owing to the demonstration of survival superiority over best supportive care (BSC) or single agent vinorelbine or ifosfamide in two prospective North American trials 14,15. When compared with best supportive care alone (study TAX 317), second line treatment with docetaxel 75 mg/m 2 significantly improved the median survival (7.5 vs 4.6 months, p = 0.010), the 1-year survival rate (37 vs 12%, p = 0.003) and lengthened time to disease progression (12.3 vs 7 weeks, p = 0.004). Docetaxel was safe, offered clinically meaningful benefit to patients and was associated with better quality of life compared to BSC 14. These findings are in keeping with results of study TAX 320 in which heavily pre-treated patients with advanced NSCLC were randomized to receive Version di 67 - July,

13 docetaxel 100 mg/m 2, docetaxel 75 mg/m 2 or a comparator arm of either vinorelbine or ifosfamide. Treatment with either dose of docetaxel significantly increased the proportion of patients without disease progression at 26 weeks. Significant differences favoring docetaxel in terms of response rate and time to progression for both docetaxel dosages and in 1-year survival for 75 mg/m 2 (32 vs 19%, p = 0.025) were also observed. Prior exposure to paclitaxel did not lessen the response rate or survival advantage of docetaxel in this second-line setting. Moreover, it was shown that docetaxel improved symptoms and quality of life compared to both vinorelbine and ifosfamide 15. Despite some methodological drawbacks in these registration studies, docetaxel has become a standard of care in the second line treatment of advanced NSCLC as recommended by all clinical guidelines 5. In addition, docetaxel has become the standard reference regimen for further registration studies with novel agents in this setting. Limitations in the second line use of docetaxel rely mainly in its toxicity, particularly fatigue and neutropenia. Other single agents have been evaluated as second-line treatment in NSCLC, but have not tested in phase III trials 13. The only other agent that has been developed for this indication is the Multi- Target Antifolate (MTA) pemetrexed (ALIMTA). 1.3 Pemetrexed (ALIMTA) in second-line NSCLC Pemetrexed inhibits at least three enzymes involved in DNA synthesis and folate metabolism: thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). Pemetrexed as single agent has been investigated for anti-tumor activity in patients with advanced NSCLC who were either previously untreated or previously treated. In a phase II study, patients with advanced NSCLC, who had progressed during or within 3 months after completion of first-line chemotherapy, were treated with pemetrexed 500 mg/m 2 every 3 weeks and were stratified by prior treatment (cisplatin-containing regimen vs no cisplatin regimen) 16. For all patients the objective response rate was 8.9% with a median survival time of 5.7 months; in particular, about prior treatment, the response rate was higher in the platinum-naïve patients (14.3 vs 4.5%), however, the median survival was 6.4 months in patients pre-treated with cisplatin and 4 months in platinumnaïve. Pemetrexed was well tolerated, with vitamin supplementation (folic acid 350-1,000 g orally daily and vitamin B 12 1,000 g i.m. every 9 weeks). The favorable results obtained in this trial led to a large phase III randomized study comparing pemetrexed with docetaxel in the second line treatment of advanced NSCLC 17. In this trial 571 patients with advanced NSCLC previously treated were randomized to receive pemetrexed 500 mg/m 2 i.v. day 1 or docetaxel 75 mg/m 2 i.v. day 1, both every 3 weeks. This trial, the largest ever conducted in this setting, indicates similar response rate (9.1 vs 8.8% for pemetrexed and docetaxel, respectively) and no meaningful difference between arms in primary efficacy parameters (median progression free survival 2.9 months for each arm and median survival 8.3 vs 7.9 months for pemetrexed and docetaxel, respectively). There was no significant difference in the distribution of numbers of patients reporting changes in the ASBI (Average Symptom Burden Index) between the two arms of the study. There were several clinically and statistically significant differences between the two agents in their toxicity profiles in favor of pemetrexed, in particular in hematological toxicity, hospitalization and growth factor use. Owing to these results, pemetrexed has been the second drug approved by the US FDA for second line treatment of advanced NSCLC. 1.4 The rational for combination pemetrexed-carboplatin in second-line NSCLC In spite of the superiority of single agent over best supportive care in second-line NSCLC, the prognosis of these patients remains poor with a median survival of 6-7 months, justifying the Version di 67 - July,

14 evaluation of new regimens in this setting. An open question in the second-line treatment of NSCLC remains the possible superiority of combination chemotherapy over single agent, as it has been clearly demonstrated in first-line. Particularly, the addition of platinum to either docetaxel or pemetrexed should be further investigated especially in patients with prior response/stable disease to platinum-based first-line chemotherapy. Pemetrexed has shown anti-tumor activity in combination with other chemotherapy agents, including gemcitabine, vinorelbine, taxanes, cisplatin and carboplatin 18. In particular about combination with carboplatin, the growth inhibitory effects were shown to be additive, regardless of the order of exposure in NCI-H460 non-small cell lung carcinoma, SKOV-3 ovarian carcinoma and HT29 colorectal carcinoma cells (Lilly Research Laboratories NCPR04). Calvert et al reported results of a phase I trial in chemotherapy-naïve patients with pleural mesothelioma. The maximum tolerated dose (MTD) was pemetrexed 500 mg/m 2 plus carboplatin AUC 5 with dose-limiting toxicity (DLT) of neutropenia. Other side effects included thrombocytopenia, anemia, skin rash and reversible transaminase elevation 19. Two phase II trials evaluated the combination pemetrexed-carboplatin in advanced NSCLC 20,21. Zinner et al investigated this combination in 50 chemo-naïve patients with advanced NSCLC (pemetrexed 500 mg/m 2 plus carboplatin AUC 6 every 3 weeks with vitamin supplementation) 20. Response rate was 24% and median time to progression was 5.4 months, with a very favorable toxicity; only 28% of patients had grade 3 or 4 hematological toxicity and only 6% of grade 3 or 4 non-hematological toxicity. In a multicenter phase II randomized study, 80 chemo-naïve patients with advanced NSCLC received pemetrexed (500 mg/m 2 ) plus carboplatin (AUC 6) or pemetrexed (500 mg/m 2 ) plus oxaliplatin (120 mg/m 2 ) on day 1 of a 21-day cycle 21. The combination pemetrexed-carboplatin demonstrated a response rate of 33% with 44% of stable disease. Main grade 3-4 hematological toxicities in the pemetrexed-carboplatin arm included neutropenia in 26% of patients, febrile neutropenia in 3%, thrombocytopenia in 18% and anemia in 8%. Main nonhematological toxicities included grade 3 fatigue (8%) and stomatitis (3%). Aim of the present phase II trial is to compare the combination pemetrexed-carboplatin to pemetrexed alone as second line chemotherapy in patients with advanced NSCLC. In this multicenter, open label, randomized phase II trial, pemetrexed 500 mg/m 2 and carboplatin AUC 5 will be administered on day 1 every 3 weeks until progression of disease or for a maximum of 4 courses in the experimental arm. The control arm will be pemetrexed as single agent at 500 mg/m 2 on day 1 every 3 weeks until progression of disease or for a maximum of 4 courses. 2. Investigational agents 2.1 Pemetrexed (ALIMTA) Name Pemetrexed (ALIMTA, Eli Lilly) Chemical structure Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2- amino-4,7-dihydro-4-oxo-1h-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O6 7H2O and a molecular weight of Mechanism of action Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its anti- Version di 67 - July,

15 neoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Experimental anti-tumor activity Pemetrexed has shown activity in multiple tumor types when given as a single agent once every 21 days at either 500 mg/m 2 or 600 mg/m 2. Phase II trials of pemetrexed have demonstrated activity in malignant pleural mesothelioma, pancreatic cancer, colorectal cancer, breast cancer, head and neck cancer, cervical cancer and non-small cell lung cancer (NSCLC). Pemetrexed has demonstrated broad activity and acceptable toxicity as a single agent. In addition, pemetrexed was evaluated in combination with the following chemotherapeutic agents: cisplatin, 5-FU, vinorelbine, gemcitabine, irinotecan, docetaxel, carboplatin, paclitaxel, oxaliplatin, doxorubicin, epirubicin and cyclophosphamide. Pharmacokinetics The pharmacokinetics of pemetrexed administered as a single agent in doses ranging from 0.2 to 838 mg/m 2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The total systemic clearance of pemetrexed is 91.8 ml/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 ml/min). The clearance decreases, and exposure (AUC) increases, as renal function decreases. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles. Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment. Toxicity The most frequently observed adverse events were anorexia, asthenia, nausea, vomiting, diarrhea, constipation, fever, rash, alopecia, pain, dyspnea, anemia, stomatitis, thrombocytopenia, transaminase increased, abdominal pain and leucopenia. The dose limiting toxicities (DLTs) on schedule of 10-minute infusion once every 21 days were neutropenia, thrombocytopenia, and fatigue. Patients who developed rashes received dexamethasone 4 mg twice daily for 3 days starting 1 day prior to treatment with pemetrexed, which improved or prevented the rash during subsequent cycles of therapy. Pemetrexed is not a vesicant. There is no specific antidote for extravasation of pemetrexed. Pemetrexed extravasation should be managed with local standard practice for extravasation as with other non-vesicants agent. Several studies have investigated the relationship between folic acid and toxicity of antifolate agents, as pemetrexed. These studies have concluded that the addition of folic acid significantly reduces toxicity while preserving the anti-tumor activity of the drug. In initial phase I and II trials, pemetrexed was administered at 500 and 600 mg/m 2 every 21 days without folic acid or vitamin B 12 supplementation. Myelosuppression was the principal drug-related toxicity, with a frequency of Grade 3-4 neutropenia of 40% to 50% and Grade 3-4 thrombocytopenia of 15% (n = 880). A recent safety assessment of the impact of folic acid and vitamin B 12 supplementation on the severe toxicities related to pemetrexed therapy has been completed. The analysis focused on those severe hematologic (Grade 4 neutropenia and thrombocytopenia) and non-hematologic (Grade 3-4 infection, diarrhea, and mucositis) toxicities associated with pemetrexed therapy. The incidence of Version di 67 - July,

16 both Grade 4 hematologic and Grade 3-4 non-hematologic toxicities decreased markedly in those patients supplemented with vitamins. These data indicate a marked improvement in the incidence of severe toxicities associated with pemetrexed therapy when patients are supplemented with folic acid and vitamin B 12. Table 1. Frequency of severe toxicities related to pemetrexed therapy in patients with and without folic acid and vitamin B 12 supplementation occurring within the first 7 cycles. Without folic acid/b 12 supplementation (n=394) With folic acid/b 12 supplementation (n=196) P value* Grade 4 hematologic and Grade 3-4 non-hematologic toxicities 33% 12% < Grade 4 neutropenia 28% 9% < Grade 4 thrombocytopenia 6% 1% Grade 3-4 mucositis 5% 0.5% Grade 3-4 diarrhea 5% 4% NS Grade 3-4 infection 3% 1% NS Grade 4 neutropenia + Grade 3-4 3% 0% mucositis Grade 4 neutropenia + Grade 3-4 3% 1% NS diarrhea Grade 4 neutropenia + Grade 3-4 infection 1% 1% NS Abbreviation: NS = not statistically significant. * Chi-Square test. Drug Interactions Chemotherapeutic Agents - Carboplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed. Vitamins - Co-administration of oral folic acid or intramuscular vitamin B12 does not affect the pharmacokinetics of pemetrexed. Drugs Metabolized by Cytochrome P450 Enzymes - Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9 and CYP1A2. No studies were conducted to determine the cytochrome P450 isozyme induction potential of pemetrexed, because pemetrexed used as recommended (once every 21 days) would not be expected to cause any significant enzyme induction. Aspirin - Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown. Ibuprofen - Daily ibuprofen doses of 400 mg qid reduce pemetrexed s clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown. Version di 67 - July,

17 Pharmaceutical data Supplied Pemetrexed (ALIMTA) for injection is available in sterile single-use vials containing 500 mg for i.v. use. Storage and stability Pemetrexed for injection, should be stored at 25 C; excursions permitted to C. Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8 C, or at 25 C, excursions permitted to C. When prepared as directed, reconstituted and infusion solutions of pemetrexed contain no antimicrobial preservatives. Discard unused portion. Pemetrexed is not light sensitive. Solution preparation As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of pemetrexed. The use of gloves is recommended. If a solution of pemetrexed contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed contacts the mucous membranes, flush thoroughly with water. Use aseptic technique during the reconstitution and further dilution of pemetrexed for intravenous infusion administration. Reconstitute 500 mg vials with 20 ml of 0.9% sodium chloride injection (preservative free) to give a solution containing 25 mg/ml pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. The ph of the reconstituted pemetrexed solution is between 6.6 and 7.8. The appropriate volume of reconstituted pemetrexed solution should be further diluted to 100 ml with 0.9% sodium chloride injection (preservative free) and administered as an intravenous infusion over 10 minutes. Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% sodium chloride injection (preservative free). Pemetrexed is physically incompatible with diluents containing calcium, including Lactated Ringer s Injection, USP and Ringer s Injection, USP and therefore these should not be used. Co-administration of pemetrexed with other drugs and diluents has not been studied, and therefore is not recommended. Route of administration and infusion Pemetrexed diluited in 100 ml of sodium chloride must be infused either by peripheral vein or central venous line over 10 minutes. The administration of pemetrexed does not require prehydration. 2.2 Carboplatin Name Carboplatin Chemical structure Carboplatin (cis-diammine (1,1-cyclobutane dicarboxylato) platinum. Version di 67 - July,

18 Mechanism of action Carboplatin has a mechanism of action similar to that of cisplatin. Carboplatin induced the same platinum-dna adducts as those induced by cisplatin. Experimental anti-tumor activity Carboplatin has shown activity in multiple tumor types. Carboplatin is broadly active against various tumors in cell culture, including ovarian, germ cell, lung, colon, pancreatic and mammary carcinomas. Carboplatin, in general, shows a similar spectrum of cisplatin in vitro activity, but it is consistently 4- to 10-fold less potent in various tumor cell types. Carboplatin has demonstrated broad activity and acceptable toxicity as a single agent and in combination with several chemotherapeutic agents. Carboplatin have demonstrated activity in ovarian cancer, bladder cancer, germ cell tumors, breast cancer, head and neck cancer, cervical cancer, endometrial cancer and lung cancer. Pharmacokinetics The differences in pharmacokinetics observed between cisplatin and carboplatin depend primarily on the slower rate of conversion of carboplatin to a reactive species. Thus, the stability of carboplatin results in a low incidence of nephrotoxicity. Carboplatin diffuses rapidly into tissues after infusion, but it is more stable in plasma. Only 24% of a dose was reported to be bound to plasma protein at 4 hours post-infusion. The disappearance of platinum from plasma after short intravenous infusions of carboplatin has been reported to occur in a biphasic or triphasic manner. The half-lives for carboplatin ranges for T 1/2 from 12 to 98 minutes, for T 1/2 from 1.3 to 1.7 hours and from 8.2 to 40 hours for T 1/2. Carboplatin is excreted primarily in the urine as unchanged drug, with approximately 90% clearance after 24 hours. The renal clearance is closely correlated with glomerular filtration rate (GFR). This observation enabled Calvert to design a carboplatin dosing formula based on an individual patient s GFR. Toxicity The dose limiting toxicity of carboplatin is myelosuppression, particularly thrombocytopenia (severe in approximately 25% of cases), but neutropenia and anemia are frequently observed. Nausea and vomiting are less severe, shorter in duration and more easily controlled with standard anti-emetics than those symptoms typical after cisplatin treatment. Carboplatin may induce anaphylactic type reactions, facial edema, wheezing, tachycardia and hypotension. A correlation exists between clearance and glomerular filtration rate (GFR) that implies that the area under the concentration time cure for carboplatin (AUC), and, consequently, the toxicity and therapeutic effect of the drug are dictated by the pretreatment GFR and the dose administered. At standard doses of carboplatin, nephrotoxicity, neurotoxicity and ototoxicity are infrequent. Pharmaceutical data Supplied Carboplatin for injection is available in sterile single-use vials containing 50, 150 and 450 mg for i.v. use. Storage and stability It should be stored at room temperature 15 C to 25 C and protected from light. Version di 67 - July,

19 Solution preparation As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of carboplatin. The use of gloves is recommended. If a solution of carboplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. If carboplatin contacts the mucous membranes, flush thoroughly with water. Use aseptic technique during the reconstitution and further dilution of carboplatin for intravenous infusion administration. It should be diluted with 5% dextrose or 0.9% sodium chloride. Once diluted, it should be stored at room temperature or refrigerated. Because no antibacterial preservatives are contained in the formulation, it is recommended that any carboplatin solution be discarded after 8 hours from the time of dilution if stored at room temperature or after 24 hours if stored under refrigeration. The appropriate volume of reconstituted carboplatin solution should be further diluted to ml with 5% dextrose or 0.9% sodium chloride injection (preservative free) and administered as an intravenous infusion over 30 minutes-1 hour. Route of administration and infusion Carboplatin diluited in ml of 5% dextrose or sodium chloride must be infused either by peripheral vein or central venous line over 30 minutes-1 hour. The administration of carboplatin does not require prehydration. 3. Objectives of the trial 3.1 Primary objective To compare time to progression between the combination pemetrexed (500 mg/m 2 i.v. on day 1) and carboplatin (AUC 5 i.v. on day 1) given every 3 weeks (experimental arm) and pemetrexed alone (500 mg/m 2 i.v. on day 1) given every 3 weeks (control arm) in previously treated patients with locally advanced or metastatic NSCLC. 3.2 Secondary objectives To assess differences in terms of response rate between the combination pemetrexedcarboplatin and pemetrexed alone. To assess differences in terms of duration of response between the combination pemetrexedcarboplatin and pemetrexed alone. To assess differences in terms of toxicity between the combination pemetrexed-carboplatin and pemetrexed single alone. To assess differences in terms of survival between the combination pemetrexed-carboplatin and pemetrexed single alone. Version di 67 - July,

20 4. End-points 4.1 Primary end-point The primary end-point of this study is Time To Progression (TTP). 4.2 Secondary end-points The secondary end-points of this study are: Response Rate (RR); Duration of response; Toxicity; Overall Survival (OS). 5. Trial design This is a multicenter, open-label, randomized phase II trial comparing the combination pemetrexedcarboplatin versus pemetrexed alone in the second-line treatment of locally advanced or metastatic NSCLC. Patients will be randomly assigned (1:1) to treatment groups through a central randomization process using the following stratification factors: ECOG performance status (0 or 1 vs 2); prior response to first line chemotherapy (objective tumor response vs stable/progressive disease); interval from the end of prior chemotherapy (< 3 vs 3 months). Treatment will be given until progression of disease, unacceptable toxicity, patient refusal or for a maximum of 4 courses. Primary end-point is time to progression (TTP), defined as the time interval between the date of randomization and the date of progression/death or the last known date progression-free (censored). Secondary end-point are response rate that will be assessed every two cycles according to RECIST criteria (see section 9), duration of response, toxicity that will be reported according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) ( and overall survival (OS), defined as the time interval between the date of randomization and the date of death due to any cause or last follow-up (censored). The analyses of primary and secondary parameters will utilize a dataset that includes all the randomized patients, which constitute the intent-to-treat (ITT) population. Version di 67 - July,

21 6. Patient selection criteria 6.1 Inclusion criteria The patient must give written (personally signed and dated) informed consent before completing any study related procedure. Males or females 18 years. Histologically or cytologically confirmed non-squamous ; non-squamous histology includes adenocarcinoma, large cell carcinoma and other NSCLC histologies (those that are not clearly qualified as adenocarcinoma, large cell carcinoma or squamous cell carcinoma). Unresectable stage IIIB, stage IV and unresectable local relapse or metastatic disease, with evidence of disease progression after first line chemotherapy which should have included a platinum agent. ECOG performance status 2 (see Appendix A). Life expectancy > 12 weeks. Adequate hematological, hepatic and renal functions: neutrophils 1.5 x 10 9 /L platelets 100 x 10 9 /L total bilirubin 1.5 x ULN AP, AST and ALT 3.0 x ULN (AP, AST and ALT 5.0 x ULN is acceptable if the liver has tumor involvement) creatinine clearance 45 ml/min (based on the Cockcroft and Gault formula) Prior treatment with only 1 chemotherapy regimen for the treatment of advanced disease which should have included a platinum agent (prior treatment with gefitinib/erlotinib as maintenance therapy after 1 st line chemotherapy is allowed and not considered as a chemotherapy regimen). At least 4 weeks from prior chemotherapy with complete recovery from first line chemotherapy side effects to < Grade 2. Prior radiotherapy allowed, only in case of presence of at least one measurable lesion outside an irradiated area. Radiotherapy must have been completed at least 2 weeks before registration. At baseline, presence of at least one measurable target lesion: lesion that can be accurately measured in at least one dimension i.e. longest diameter as 20 mm with conventional CT scan or as 10 mm with spiral CT scan /RECIST Criteria). All radiology studies must be performed within 28 days prior to randomization. Version di 67 - July,

22 Absence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule. 6.2 Exclusion criteria Histologically or cytologically confirmed squamous. Prior treatment with pemetrexed. Patients who are: pregnant or lactating; at risk of pregnancy during the study. This must be checked by pregnancy test at study entry. The patient must be receiving a medically accepted contraceptive regimen. Patients with any underlying medical condition that might be aggravated by treatment or which cannot be controlled i.e. patients with active serious infection, diabetes mellitus, patients with concurrent heart failure [New York Heart Association (NYHA) class II-III-IV] (see Appendix B), or with progressive or unstable angina, patients who have had myocardial infarction within 6 months, and/or poorly controlled hypertension, or pericardial effusion. Documented brain metastases unless the patient has completed local therapy for central nervous system metastases and has been off corticosteroids for at least two weeks before enrollment. History of another malignancy within the past five years except basal cell carcinoma of the skin or carcinoma in situ of the cervix. Treatment with any investigational drug within the 30 days prior to registration. Concomitant treatment with any other anticancer drug. Known hypersensitivity to the study drugs or to drugs with similar chemical structures. Patients who have received > 25% Radiation Therapy to the bone marrow. Inability to interrupt aspirin or other non-steroidal anti-inflammatory agents 2 days before, the day of, and 2 days after the dose of pemetrexed single agent or pemetrexed plus carboplatin. If a patient is taking an NSAID (COX-2 inhibitors included) or salicylate with a long half-life (for example, naproxen, piroxicam, diflunisal, nabumetone, rofecoxib or celecoxib) it should not be taken 5 days before the dose of pemetrexed (8-day period for long-acting agents such as piroxicam), the day of, and 2 days after the dose of pemetrexed single agent or pemetrexed plus carboplatin. 7. Therapeutic regimens, toxicity and dose modifications 7.1 Drug administration Patients will be randomized (1:1) to receive either: Version di 67 - July,

23 Pemetrexed 500 mg/m 2 i.v. over approximately 10 minutes on day 1 of a 21 days cycle (Arm A control arm) (see Table 2). or Pemetrexed 500 mg/m 2 i.v. over approximately 10 minutes on day 1 and Carboplatin AUC 5* i.v. over approximately 30 minutes on day 1 (beginning approximately 30 minutes after the end of the pemetrexed infusion) of a 21 days cycle (Arm B experimental arm) (see Table 2). Treatment will be repeated every 3 weeks for a maximum of 4 courses in the absence of progressive disease, unacceptable toxicity and patient refusal. * Carboplatin AUC 5 i.v. infusion, based on the Calvert formula, with GFR (Glomerular Filtration Rate) estimated using calculated creatinine clearance (standard Cockcroft and Gault formula, see Appendix C) obtained prior to each cycle. Carboplatin dose (mg) = AUC 5 x (GFR + 25). 7.2 Premedication, folic acid and vitamin B 12 supplementation Premedication In order to reduce the incidence and severity of skin rash reaction, patients should receive steroid premedication with dexamethasone 4 mg or equivalent corticosteroid taken orally twice per day on the day before, the day of, and the day after each dose of pemetrexed (see Table 2). Prophylactic anti-emetic therapy, including 5-HT 3 antagonists and corticosteroids, is recommended. Folic acid supplementation Folic acid supplementation, 350 to 600 g or equivalent, should be taken orally daily beginning approximately 1 to 2 weeks prior to the first dose of pemetrexed or pemetrexed-carboplatin and continue daily until the patient discontinues from study therapy (see Table 2). Folic acid in one of the following formulations should be used, with preference in order from Option 1 to Option 3: to 600 g folic acid; 2. a multivitamin containing folic acid in the range of 350 g to 600 g (acceptable only if Option 1 is not available); 3. a dose of folic acid between 600 g and 1000 g (acceptable only if neither Option 1 or Option 2 is available). Sufficient folic acid treatment prior to study therapy administration is defined in section Vitamin B 12 supplementation A vitamin B 12 injection, 1000 g, must be given intramuscularly approximately 1 to 2 weeks prior to the first dose of pemetrexed or pemetrexed-carboplatin and should be repeated approximately every 9 weeks until the patient discontinues from study therapy (see Table 2). Sufficient vitamin B 12 treatment prior to study therapy administration is defined in section Version di 67 - July,