POLO study Olaparib as maintenance therapy for patients with gbrca-mutated metastatic pancreatic cancer. POLO study inclusion and

Transcription

1 Screening patients with pancreatic cancer for gbrca mutations POLO study Olaparib as maintenance therapy for patients with gbrca-mutated metastatic pancreatic cancer POLO study inclusion and exclusion criteria POLO study restrictions

2 Section 1 Screening patients with pancreatic cancer for gbrca mutations Screening patients with pancreatic cancer for gbrca mutations

3 Screening patients with pancreatic cancer for gbrca mutations Patients with metastatic pancreatic cancer need to be screened for gbrca1/2 mutations that are predicted to be deleterious or suspected to be deleterious (known or predicted to be detrimental/ lead to loss of function) Screening for gbrca mutations is ideally done at the same time as the histological confirmation of the disease, but can be done at any time from diagnosis up to a pause in first-line platinum-based chemotherapy Screening patients with pancreatic cancer for gbrca mutations gbrca screening can be done at any time between diagnosis and a pause in chemotherapy gbrca mutation status can be determined by prior local laboratory testing or by central testing using the Myriad BRACAnalysis test The Myriad BRACAnalysis test gives results available to oncologists within 14 days uses a blood sample is being reimbursed by AstraZeneca is backed by more than 20 years experience in genetic testing Family history, ethnicity or other characteristics should not limit screening Screening should not be limited by patient characteristics Please refer to the study protocol and laboratory manual for full details

4 Section 2 POLO study inclusion and exclusion criteria POLO study inclusion and exclusion criteria

5 POLO study inclusion and exclusion criteria POLO study inclusion and exclusion criteria Summary To be included in the POLO study, patients need to Be 18 years of age Have histologically or cytologically confirmed metastatic pancreatic adenocarcinoma Have a documented gbrca1 or gbrca2 mutation that is known or predicted to be detrimental Be receiving first-line platinum-based (cisplatin, carboplatin or oxaliplatin) chemotherapy for metastatic disease for a minimum of 16 weeks if platinum-based treatment was discontinued, chemotherapy must be continued until enrolment other drugs can be stopped as clinically indicated, but no new drugs can be added, and the last dose of chemotherapy must be completed 4 8 weeks before study drug treatment commences Show no evidence of disease progression at any time during first-line platinum-based chemotherapy (the tumour must have stabilised or improved during treatment) Have reached a point in their chemotherapy where both they and their physicians believe that having a pause or break from the chemotherapy treatment is appropriate Patients are excluded from the POLO study if They have gbrca1 and/or gbrca2 mutations that are considered to be non-detrimental Disease progression occurs between the first-line platinum-based chemotherapy and randomisation They have previously received a PARP inhibitor, including olaparib Inclusion criteria 1. Patients have provided informed consent prior to any study-specific procedures 2. Patients must be 18 years of age, male or female 3. Patients have histologically or cytologically confirmed pancreatic adenocarcinoma and are receiving initial chemotherapy for metastatic disease without evidence of disease progression on treatment 4. Patients with measurable and/or non-measurable disease or no evidence of disease assessed at baseline by computed tomography (CT; or MRI where CT is contraindicated) will be entered in this study. RECIST 1.1 has been modified to allow the assessment of progression due to new lesions in patients with no evidence of disease at baseline 5. Documented mutation in gbrca1 or gbrca2 is predicted to be deleterious or suspected to be deleterious (known or predicted to be detrimental/lead to loss of function) 6. Patients are on treatment with a first-line platinum-based (cisplatin, carboplatin or oxaliplatin) regimen for metastatic pancreatic cancer, have received a minimum of 16 weeks of continuous platinum treatment and have no evidence of progression based on investigator s opinion. Patients who have received at least 16 weeks of a platinum regimen and had the platinum discontinued for toxicity, but continued on the remaining drugs of their regimen, are also eligible if they have no evidence of disease progression within 4 weeks of their last dose of chemotherapy 7. Patients who have received platinum as potentially curative treatment for a prior cancer (e.g. ovarian cancer) or as adjuvant/neoadjuvant treatment for pancreatic cancer are eligible, provided at least 12 months have elapsed between the last dose of platinum-based treatment and initiation of the platinum-based chemotherapy for metastatic pancreatic cancer POLO study inclusion and exclusion criteria

6 POLO study inclusion and exclusion criteria POLO study inclusion and exclusion criteria 8. Patients must have normal organ and bone marrow function measured within 4 weeks prior to administration of study treatment as defined below Haemoglobin 9.0G/dl with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days Absolute neutrophil count 1.5X10 9 /l White blood cells >3x10 9 /l No features suggestive of mds/aml on peripheral blood smear Platelet count 100x10 9 /l Total bilirubin 1.5X institutional uln Aspartate aminotransferase (serum glutamic oxaloacetic transaminase)/alanine aminotransferase (serum glutamic pyruvic transaminase) 2.5X institutional uln value, unless liver metastases are present, in which case they must be 5x uln 9. Patients must have an ECOG performance status 0 or 1 at signing of informed consent 10. Women must be post-menopausal or, for women of childbearing potential, must have evidence of non-childbearing status: negative urine or serum pregnancy test. Post-menopausal is defined as Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments Luteinizing hormone (lh) and follicle-stimulating hormone (fsh) levels in the post-menopausal range for women under 50 years old Radiation-induced oophorectomy with last menses >1 year ago Chemotherapy-induced menopause with a >1-year interval since last menses Surgical sterilisation (bilateral oophorectomy or hysterectomy) 11. Patient is willing and able to comply with the study protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations 12. FFPE tumour sample is required from the primary tumour or a metastatic site if available, or three unstained cytology slides if available Exclusion criteria 1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or staff at the study site) 2. gbrca1 and/or gbrca2 mutations that are considered to be non-detrimental (e.g. variants of uncertain clinical significance, variant of unknown significance, genetic variant, favour polymorphism or benign polymorphism, etc.) 3. Progression of tumour between start of first-line platinum-based chemotherapy for metastatic pancreatic cancer and randomisation 4. Cytotoxic chemotherapy or non-hormonal targeted therapy within 28 days of cycle 1, day 1. Palliative radiotherapy must have been completed 14 or more days before cycle 1, day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases before and during the study, as long as these were started at least 2 weeks prior to study treatment 5. Previous randomisation in the present study 6. Exposure to an investigational product within 30 days or five half-lives (whichever is longer) prior to randomisation 7. Any previous treatment with a PARP inhibitor, including olaparib 8. A second primary cancer. EXCEPTIONS: adequately treated non-melanoma skin cancer; curatively treated in-situ cancer of the cervix; ductal carcinoma in situ; stage 1, grade 1 endometrial carcinoma; or other solid tumours, including lymphomas (without bone marrow involvement), curatively treated with no evidence of disease for 5 years prior to study entry 9. Resting ECG with QTc 450msec detected at two or more timepoints within a 24-hour period or family history of long QT syndrome. If ECG demonstrates QTc 450msec, the patient will be eligible only if the repeat ECG demonstrates QTc 450msec 10. Concomitant use of known potent CYP3A4/5 inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir POLO study inclusion and exclusion criteria

7 POLO study inclusion and exclusion criteria POLO study inclusion and exclusion criteria 11. Persistent toxicities (CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 3 peripheral neuropathy 12. Patients with MDS/AML 13. Major surgery within 2 weeks of starting study treatment; patients must have recovered from any effects of any major surgery 14. Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV) 15. Clinically significant uncontrolled medical conditions (e.g. active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, recent [3 months] myocardial infarction, extensive bilateral interstitial lung disease, psychiatric illness that would limit ability to comply with study procedures and any other medical condition that, in the opinion of the investigator, places the patient at unacceptable risk of toxicity). NB: diabetes that is controlled by medication does not exclude participation in the study 16. Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: disease outside the CNS is present; no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographical study; no history of intracranial haemorrhage or spinal cord haemorrhage; minimum of 2 weeks between completion of radiotherapy and cycle 1, day 1; and recovery from significant (grade 3) acute toxicity with no ongoing requirement for 10mg of prednisone per day or an equivalent dose of other corticosteroid 17. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication 18. Pregnant or breast-feeding women 19. Previous allogeneic bone marrow transplant 20. Patients with a known hypersensitivity to olaparib or any of the excipients of the product 21. Whole blood transfusions in the last 120 days prior to enrolment in the study that may interfere with gbrca testing (packed red blood cells and platelet transfusions are acceptable; for timing refer to inclusion criterion No. 8) POLO study inclusion and exclusion criteria

8 Section 3 POLO study restrictions POLO study restrictions

9 POLO study restrictions POLO study restrictions Contraception CYP3A4/5 restrictions Patients of childbearing potential and their partners, if sexually active, must agree to the use of two highly effective forms of contraception in combination while the patient is receiving study treatment and for 3 months after last dose of study drug For details please refer to the protocol Appendix E: Acceptable Birth Control Methods Medications that may NOT be administered Patients of childbearing potential must use two highly effective forms of contraception No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy [hormone replacement therapy (HRT) is acceptable], radiotherapy, biological therapy or other novel agents) is to be permitted while the patient is receiving study medication No other anti-cancer medications can be administered during the study Live virus and bacterial vaccines should not be administered while the patient is receiving study medication and during the 30-day follow-up period. An increased risk of infection by administration of the live virus and bacterial vaccines has been observed with conventional chemotherapy drugs, and the effects with olaparib are unknown The use of any natural/herbal products or other folk remedies should be discouraged, but use of these products, as well as use of all vitamins, nutritional supplements and all other concomitant medications, must be recorded Agents that modulate CYP3A4/5 should be avoided Olaparib is an investigational drug for which no data on in-vivo interactions are currently available. Based on in-vitro data and clinical exposure data, olaparib is considered unlikely to cause clinically significant drug interactions through inhibition or induction of CYP enzyme activity. In-vitro data have, however, also shown that the principal enzyme responsible for the formation of the three main metabolites of olaparib is CYP3A4/5 Consequently, to ensure patient safety, the following potent inhibitors of CYP3A4/5 must not be used during this study for any patient receiving olaparib ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir Although this is not an exhaustive list, it covers the known potent inhibitors that have most often previously been reported to be associated with clinically significant drug interactions For patients taking any of the above, the required wash-out period prior to starting olaparib is 1 week In addition, to avoid potential reductions in exposure due to drug interactions, the following CYP inducers should be avoided phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, phenobarbitone, nevirapine, modafinil and St John s Wort (Hypericum perforatum) POLO study restrictions

10 POLO study restrictions POLO study restrictions For patients taking any of the above, the required wash-out periods prior to starting olaparib are: for phenobarbitone, 5 weeks; and, for any of the others, 3 weeks After randomisation, if the use of any potent CYP inducers or inhibitors of CYP3A4/5 is considered necessary for the patient s safety and welfare, the investigator must contact the AstraZeneca Study Physician. A decision to allow the patient to continue in the study will be made on a case-by-case basis Administration of other anti-cancer agents Patients must not receive any other concurrent anti-cancer therapy, including investigational agents, while on study treatment Treatment with bisphosphonates or RANKL inhibitors for the prevention of skeletal-related events in patients with bone metastasis is permitted and must be started at least 5 days prior to randomisation Other concomitant treatment Any medication other than that described above, if considered necessary for the patient s safety and wellbeing, may be given at the discretion of the investigator and recorded in the appropriate sections of the Case Report Form Please refer to the study protocol for full details Anti-emetics/anti-diarrhoeals Should a patient develop nausea, vomiting and/or diarrhoea, then these symptoms should be reported as adverse events (see Section 6.3 of the study protocol) and appropriate treatment of the event given Anticoagulant therapy Patients who are taking warfarin may participate in this trial; however, it is recommended that prothrombin time (INR and APTT) be monitored carefully at least once per week for the first month, then monthly if the INR is stable. Subcutaneous heparin is permitted POLO study restrictions

11 Section 4

12 Summary POLO (NCT ) is a global phase III study of olaparib as maintenance therapy 1,2 POLO is a double-blind, randomised study - patients with gbrca-mutated metastatic pancreatic cancer will be randomised 3:2 to receive olaparib (300mg BID) monotherapy or placebo Study treatment is given as maintenance therapy following first-line platinum chemotherapy The primary study endpoint is first occurrence of PFS (PFS1) by central review Selected secondary endpoints are - overall survival - second occurrence of PFS (PFS2) by investigator assessment - overall response rate - disease control rate - safety and quality of life

13 Diagnosis of metastatic pancreatic cancer (histologically/cytologically confirmed) gbrca mutation KNOWN gbrca mutation UNKNOWN Part 1 screening: unknown gbrca mutation only gbrca screening anytime from diagnosis to a pause in chemotherapy First-line platinumbased chemotherapy Part 2 screening: known gbrca mutation screened against inclusion/exclusion criteria, within 28 days before randomisation gbrca mutation KNOWN R 3:2 Olaparib 300mg BID Placebo Treatment period Visits on days 8, 15, 22 and 29 (then every 4 weeks) RECIST assessments until disease progression (every 8 weeks for 40 weeks, then every 12 weeks) Progression: PFS1 (discontinuation of study treatment) No progression (discontinuation of study treatment) Death Lost to Withdrawal follow-up * of consent * Safety follow-up 30 days after the last dose of study treatment Off-treatment RECIST follow-up (every 8 or 12 weeks) for progression Progression Second progression: PFS2 survival follow-up every 8 weeks post first progression * Data for overall survival analysis gathered from hospital records/public death registries where available Please refer to Section 4.2 of the study protocol

14 Patients will be randomised to study treatment (olaparib or placebo) within 6 weeks of their last chemotherapy infusion Patients must be randomised within 6 weeks of their last dose of chemotherapy Study treatment should be initiated no sooner than 4 weeks and no later than 8 weeks after the last chemotherapy infusion Treatment will start 4 8 weeks after a patient s last dose of chemotherapy Following randomisation, patients will attend clinic visits weekly for the first 4 weeks of treatment (days 8, 15, 22 and 29). Patients will then attend clinic visits every 4 weeks while on study treatment Patients will have tumour assessments according to RECIST at baseline and every 8 weeks (±1 week) up to 40 weeks and then every 12 weeks (±1 week) relative to the date of randomisation until objective radiological disease progression according to modified RECIST criteria occurs All CT/MRI scans will be sent to Perceptive (AstraZenecaappointed clinical research organisation) for blinded independent central review. All treatment decisions will be based on site assessment of scans All scans will undergo blinded independent central review Once a patient has experienced disease progression, they will be followed for second progression (PFS2) every 8 weeks and then survival until the final analysis After disease progression, patients will be assessed every 8 weeks for second progression The primary study analysis will be carried out when approximately 87 progression events (as assessed by central review) have occurred; an interim futility analysis will be carried out when 50% of the planned PFS events have occurred Please see the study protocol for complete details of the study design Abbreviations not defined in text AML = acute myeloid leukaemia; APTT = active partial thromboplastin time; BID = twice daily; CNS = central nervous system; CTCAE = Common Terminology Criteria for Adverse Events; CYP = cytochrome P450; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formalin-fixed, paraffin-embedded; gbrca = germline BRCA; INR = international normalised ratio; MDS = myelodysplastic syndrome; MRI = magnetic resonance imaging; PARP = poly ADP ribose polymerase; PFS = progression-free survival; POLO = Pancreas OLaparib Ongoing trial; R = randomisation; RANKL = receptor activator of nuclear factor kappa-b ligand; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal References 1. Kindler HL, et al. J Clin Oncol 2015;33(Suppl.):Abstr TPS ClinicalTrials.gov. NCT show/nct Accessed August 2016 Questions? If you have any queries or would like any additional information, please contact Gershon Locker, MD, Senior Director of Clinical Research, AstraZeneca; Gershon.locker@astrazeneca.com

15 Date of preparation: October 2016