PEMBRO With Chemo in Neo Adj Treatment of Ovarian Cancer . (NEOPEMBROV)

Inclusion Criteria:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Woman ≥ 18 and ≤ 75 years old on day of signing informed consent
3. Histologically confirmed diagnosis of epithelial ovarian carcinoma or fallopian tube carcinoma or primary peri-toneal carcinoma with the exception of mucinous histology. Histology should be obtained by laparoscopy (or by laparotomy).
4. High grade serous or endometrioid (see appendix 1 bis)
5. Advanced FIGO stage IIIC to IV patient not able to receive primary debulking surgery for which neo adjuvant chemotherapy with carboplatin and paclitaxel is recommended (primary debulking surgery has been denied after an evaluation through laparoscopy or laparotomy). Patients with extra abdominal metastasis (FIGO 2014 Stage IV) can be included in case of completely resectable metastasis.
6. Primary debulking surgery denied and maximum surgical effort of cytoreduction with the goal of no residual disease planned at interval debulking surgery. Sugarbaker index before inclusion must be less than 30
7. Eligible for carboplatin and paclitaxel chemotherapy in accordance with local standards of care following cy-toreductive surgery.
8. Interval complete surgery anticipated in a center with excellence.
9. ECOG performance status (PS) ≤ 2.
10. Life expectancy of at least 6 months,
11. Interval between diagnosis and enrolment (informed consent) ≤ 8 weeks,
12. Be willing to provide blood, and tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 8 weeks (56 days) prior to initiation of treatment on Day 1.
13. Demonstrate adequate organ function as defined in the table below, all screening labs should be performed within 7 days before randomization.

14. Adequate hematological laboratory value: Absolute neutrophil count (ANC): ≥1,500/mm3

    • Platelets : ≥100,000/mm3
    • Hemoglobin : ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)

15. Adequate renal laboratory value:

    • Serum creatinine and Measured or calculated creatinine clearance a (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (Creatinine clearance is calculated according to Cockcroft formula or to MDRD formula for patients older than 65 years-old. Glo-merular filtration rate or creatinine clearance according to MDRD formula is: GFR = 186 x (creatinine (μmol/l) x 0,0113)-1,154 x age- 0,203 x 0.742.)

16. Adequate hepatic laboratory value:

    • Serum total bilirubin: ≤ 1.5 X ULN OR
    • Direct bilirubin: ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    • LDH, CRP
    • AST (SGOT) and ALT (SGPT): ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

17. Adequate coagulation laboratory value:

    • International Normalized Ratio (INR) or Prothrombin Time (PT) : ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    • Activated Partial Thromboplastin Time (aPTT): ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
18. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
19. Female subjects of childbearing potential should be willing to use 1 or 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 4 months after the last dose of study medication and 6 months after the last dose of bevacizumab, or paclitaxel, or carboplatin. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. (see below NB: contraception requirement)
20. Patient should be beneficiary of healthcare coverage under the social security system.

Exclusion Criteria:

1. Histological diagnosis of malignant tumor of non-epithelial origin (e.g. germ cell tumor, sex cord-stromal tumor) of the ovary, the fallopian tube or peritoneum or borderline tumor of the ovary (tumor of low malignant potential).
2. Patients with extra abdominal metastasis (FIGO 2014 Stage IV) not completely resectable, as e.g. multiple parenchymal lung metastases (preferably histologically proven), non resectable lymph node metastases, brain me-tastases.
3. Prior systemic therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, oral targeted therapy, hormonal therapy),
4. Prior radiotherapy to the abdomen or prior radiotherapy to an extra-abdominal target volume that would bear the risk of increased toxicity of chemotherapy,
5. Serious illness or concomitant non-oncological disease such as neurologic, psychiatric or infectious disease, active ulcers (gastrointestinal tract, skin) or a laboratory abnormality that may Increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study,
6. Any contraindications for therapy with paclitaxel or carboplatin, e.g. a history of severe hypersensitivity reactions to paclitaxel or platinum-containing compounds and their excipients, or other drugs formulated with Pol-yoxyl 35Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
7. Diagnosis of immunodeficiency or receiving prolonged period of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
8. Known history of active Bacillus Tuberculosis (TB)
9. Hypersensitivity to pembrolizumab or any of its excipients.
10. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or no recovery (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
11. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
12. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
13. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
14. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
15. History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Active Hepatitis B (e.g., HbsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

17. Vaccination with a live vaccine within 30 days of planned start of study therapy.

    Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

18. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
19. Active infection requiring systemic therapy.
20. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
21. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule,
22. Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
23. Active alcohol or drug abuse,
24. Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 4 months after the last dose of trial treatment, and six months after the last dose of bevacizumab, or paclitaxel, or carboplatin.
25. Patient unable to give their consent by their own (guardianship and curatorship)