Platine, Avastin and OLAparib in 1st Line
Platine, Avastin and OLAparib in 1st Line
Randomized, Double-Blind, Phase III Trial of Olaparib vs. Placebo in Patients with Advanced
 FIGO Stage IIIB - IV High Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal
 Cancer treated with standard First-Line Treatment, Combining Platinum-Taxane Chemotherapy and
 Bevacizumab Concurrent with Chemotherapy and in Maintenance.
Patients with advanced FIGO stage IIIB - IV high grade serous or endometrioid ovarian,
 fallopian tube, or peritoneal cancer treated with standard first-line treatment, combining
 platinum-taxane chemotherapy and bevacizumab concurrent with chemotherapy and in maintenance.
Inclusion Criteria:

 I-1. Female Patient must be ≥18 years of age. I-2. Signed informed consent and ability to
 comply with treatment and follow-up.

 I-3. Patient with newly diagnosed I-3-1 Ovarian cancer, primary peritoneal cancer and/or
 fallopian-tube cancer,

 I-3-2 Histologically confirmed (based on local histopathological findings):

 -  high grade serous or

 -  high grade endometrioid or

 -  other epithelial non mucinous ovarian cancer in a patient with germline BRCA 1 or 2
 deleterious mutation I-3-3 at an advanced stage: FIGO stage IIIB, IIIC, or IV of the
 1988 FIGO classification.

 I-4. Patient who has completed prior to randomization first line platinum-taxane
 chemotherapy:

 1. Platinum-taxane based regimen must have consisted of a minimum of 6 treatment cycles
 and a maximum of 9. However if platinum based therapy must be discontinued early as a
 result of non hematological toxicity specifically related to the platinum regimen,
 (i.e. neurotoxicity, hypersensitivity etc.), patient must have received a minimum of 4
 cycles of the platinum regimen.

 2. Intravenous, intraperitoneal, or neoadjuvant platinum based chemotherapy is allowed;
 for weekly therapy, three weeks are considered one cycle. Interval debulking is
 allowed.

 I-5. Patient must have received prior to randomization a minimum of 3 cycles of bevacizumab
 in combination with the 3 last cycles of platinum-based chemotherapy. Only in case of
 interval debulking surgery, it is allowed to realize only 2 cycles of bevacizumab in
 combination with the last 3 cycles of platinium-based chemotherapy. Bevacizumab treatment
 should be administered at a dose 15mg/kg q3 weeks up to a total of 15 months.

 I-6. Patient must be prior to randomization without evidence of disease (NED) or in
 complete response (CR) or partial response (PR) from her first line treatment. There should
 be no clinical evidence of disease progression (physical exam, imagery, CA 125) throughout
 her first line treatment and prior to study randomization.

 I-7. Patient must be randomized at least 3 weeks and no more than 9 weeks after her last
 dose of chemotherapy (last dose is the day of the last infusion) and all major toxicities
 from the previous chemotherapy must have resolved to CTC AE grade 1 or better (except
 alopecia and peripheral neuropathy).

 I-8. Patient must have normal organ and bone marrow function:

 1. Hemoglobin ≥ 10.0 g/dL.

 2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.

 3. Platelet count ≥ 100 x 109/L.

 4. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).

 5. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and
 Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 x
 ULN, unless liver metastases are present in which case they must be ≤ 5 x ULN.

 6. Serum creatinine ≤ 1.25 x institutional ULN and creatinine clearance > 50 mL/min.

 7. Patient not receiving anticoagulant medication who has an International Normalized
 Ratio (INR) ≤1.5 and an Activated ProThrombin Time (aPTT) ≤1.5 x ULN.

 The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR
 or APTT is within therapeutic limits (according to site medical standard). If the
 patient is on oral anticoagulants, dose has to be stable for at least two weeks at the
 time of randomization.

 8. Urine dipstick for proteinuria < 2+. If urine dipstick i s ≥2+, 24-hour urine must
 demonstrate <1 g of protein in 24 hours.

 9. Normal blood pressure or adequately treated and controlled hypertension (systolic BP ≤
 140 mmHg and/or diastolic BP ≤ 90 mmHg).

 I-9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. I-10. Formalin
 fixed, paraffin embedded (FFPE) tumor sample from the primary cancer must be available for
 central BRCA testing and test result must be available for stratification.

 I-11. Postmenopausal or evidence of non-childbearing status for women of childbearing
 potential prior to the first dose of study treatment. (see appendix 4) I-12. For France
 only: In France, a subject will be eligible for randomization in this study only if either
 affiliated to, or a beneficiary of, a social security category.

 Exclusion Criteria:

 E-1. Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ
 cell tumors).

 E-2. Ovarian tumors of low malignant potential (e.g. borderline tumors), or mucinous
 carcinoma.

 E-3. Patient with synchronous primary endometrial cancer unless both of the following
 criteria are met:

 1. stage < II,

 2. Less than 60 years old at the time of diagnosis of endometrial cancer with stage IA or
 IB grade 1 or 2, or stage IA grade III endometrioid adenocarcinoma OR ≥ 60 years old
 at the time of diagnosis of endometrial cancer with stage IA grade 1 or 2 endometrioid
 adenocarcinoma.

 Patient with serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium is
 not eligible.

 E-4. Other malignancy within the last 5 years except: adequately treated non-melanoma skin
 cancer curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS).
 Patient with a history of localized malignancy diagnosed over 5 years ago may be eligible
 provided she completed her adjuvant systemic therapy prior to randomization and that the
 patient remains free of recurrent or metastatic disease.

 Patient with history of primary triple negative breast cancer may be eligible provided she
 completed her definitive anticancer treatment more than 3 years ago and she remains breast
 cancer disease free prior to start of study treatment.

 E-5. Patient with myelodysplastic syndrome/acute myeloid leukemia history E-6. Patient
 having experienced for at least one cycle, a delay > 2 weeks due to prolonged hematological
 recovery during the first line chemotherapy E-7. Patient receiving radiotherapy within 6
 weeks prior to study treatment E-8. Major surgery within 4 weeks of starting study
 treatment and patient must have recovered from any effects of any major surgery E-9.
 Previous allergenic bone marrow transplant. E-10. Any previous treatment with PARP
 inhibitor, including olaparib. E-11. Administration of other simultaneous chemotherapy
 drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous
 radiotherapy during the trial treatment period (hormonal replacement therapy is permitted
 as are steroidal antiemetics).

 E-12. Current or recent (within 10 days prior to randomization) chronic use of aspirin >
 325 mg/day.

 E-13. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole,
 ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.

 E-14. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.

 E-15. Clinically significant (e.g. active) cardiovascular disease, including:

 1. Myocardial infarction or unstable angina within ≤ 6 months of randomization,

 2. New York Heart Association (NYHA) ≥ grade 2congestive heart failure (CHF).

 3. Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled
 atrial fibrillation are eligible), or any clinically significant abnormal finding on
 resting ECG,

 4. Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with
 activities of daily living [ADL] requiring repair or revision).

 E-16. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-
 Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.

 E-17. History or evidence of hemorrhagic disorders within 6 months prior to randomization.

 E-18. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
 coagulation).

 E-19. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI
 of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected
 brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case
 of suspected spinal cord compression.

 E-20. History or evidence upon neurological examination of central nervous system (CNS)
 disease, unless adequately treated with standard medical therapy (e.g. uncontrolled
 seizures).

 E-21. Significant traumatic injury during 4 weeks prior to randomization. E-22. Non-healing
 wound, active ulcer or bone fracture. Patient with granulating incisions healing by
 secondary intention with no evidence of facial dehiscence or infection is eligible but
 require 3 weekly wound examinations.

 E-23. History of VEGF therapy related abdominal fistula or gastrointestinal perforation or
 active gastrointestinal bleeding within 6 months prior to the first study treatment.

 E-24. Current, clinically relevant bowel obstruction, including sub-occlusive disease,
 related to underlying disease.

 E-25. Patient with evidence of abdominal free air not explained by paracentesis or recent
 surgical procedure.

 E-26. Evidence of any other disease, metabolic dysfunction, physical examination finding or
 laboratory finding giving reasonable suspicion of a disease or condition that
 contraindicates the use of an investigational drug or puts the patient at high risk for
 treatment related complications.

 E-27. Pregnant or lactating women. E-28. Participation in another clinical study with an
 investigational product during her chemotherapy course immediately prior to randomization.

 E-29. Patient unable to swallow orally administered medication and patient with
 gastrointestinal disorders likely to interfere with absorption of the study medication.

 E-30. Patient with a known hypersensitivity to olaparib or any of the recipients of the
 product.

 E-31. Immunocompromised patient, e.g., with known active hepatitis (i.e. Hepatitis B or C)
 due to risk of transmitting the infection through blood or other body fluids or patient who
 is known to be serologically positive for human immunodeficiency virus (HIV).