This study is to determine the efficacy of Olaparib, Pembrolizumab, Bevacizumab maintenance treatment by assessment of progression-free survival (6 months PFS rate), the hypothesis is as below.
*Hypothesis:  Olaparib Pembrolizumab, Bevacizumab maintenance treatment is synergistic in Secondary objective is to determine the efficacy of OlaparibPembrolizumab, Bevacizumab maintenance treatment by assessment of Overall survival, Time to progression, Time to first subsequent treatment (or death), Time to second subsequent treatment, and to evaluate the safety and tolerability of OlaparibPembrolizumab, Bevacizumab maintenance treatment. Also to identify molecular biomarkers that may be indicative of clinical response/resistance, safety, and/or the mechanism of action of pembrolizumab, olaparib, and bevacizumab.
- Olaparib 300mg, PO, twice daily [BID]
- Bevacizumab 15mg/kg or 7.5mg/kg , IV, every 3 weeks (Q3W) 
- Pembrolizumab 200mg starting from cycle 2, IV, every 3 weeks (Q3W)

Treatment

If the subject has enrolled, the drugs will be administered until PD as below.
- Pembrolizumab/200 mg/Q3W/IV infusion/Day 1 of each 3 week cycle from cycle 2/Experimental
- Olaparib/300mg/BID/Oral/during each treatment cycle/Experimental
- Bevacizumab/15mg/kg or 7.5mg/kg/Q3W/IV infusion/Q3W; Day 1 of each 3-week cycle/Background therapy

Arm Label

Target Number of Participant

Arm Type

Arm Description

- Pembrolizumab/200 mg/Q3W/IV infusion/Day 1 of each 3 week cycle from cycle 2/Experimental
- Olaparib/300mg/BID/Oral/during each treatment cycle/Experimental
- Bevacizumab/15mg/kg or 7.5mg/kg/Q3W/IV infusion/Q3W; Day 1 of each 3-week cycle/Background therapy

Gender

Age

Description

Type of Participant and Disease Characteristics 
1) Participant has histologically confirmed diagnosis of high-grade predominantly serous, endometrioid, carcinosarcoma, mixed mullerian with high-grade serous component, clear cell, or low-grade serous OC, primary peritoneal cancer, or fallopian tube cancer will be enrolled in this study (only up to 8 patients with clear cell carcinoma will be included and mucinous carcinoma will not be included).
2) Participant has received 2 previous courses of platinum-containing therapy, and has disease that was considered platinum sensitive following the penultimate (next to last) platinum course (more than 6 months’ period between penultimate platinum regimen and progression of disease)
3) Participant has responded to last the platinum regimen (complete or partial response), remains in response and is enrolled on study within 8 weeks of completion of the last platinum regimen
4) Participant is able to provide a newly obtained core or excisional biopsy of a tumor lesion for prospective testing of BRCA 1/2 and PD-L1 status prior to enrollment

Demographics
5) Female participants who are at least 20 years of age on the day of signing informed consent with
6) Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to enrollment.
Female participants: 
7) A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: 
a) Not a woman of childbearing potential (WOCBP) 
OR 
b) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days following the last dose of pembrolizumab and olaparib and at least 210 days following the last dose of chemotherapy or bevacizumab.

Information based Consent 
8) The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.  The participant may also provide consent for future biomedical research; however, the participant may participate in the main study without participating in future biomedical research.

Laboratory Values
9) Participant has adequate organ function as defined in the following table <Table 1>; all screening laboratory tests should be performed within 10 days prior to the start of study treatment.
<Table 1.  Adequate Organ Function Laboratory Values>
System Laboratory Value
Hematological 
Absolute neutrophil count (ANC) ≥1500/µL
Platelets ≥100 000/µL
Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
Renal 
Creatinine OR Measured or calculatedb creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
Hepatic 
Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
Coagulation 
International normalized ratio (INR) OR prothrombin time (PT), Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

Medical Conditions
1. Participant has mucinous, germ cell, or borderline tumor of the ovary.
2. Participant has a known or suspected deleterious mutation (germline or somatic) in either BRCA1 or BRCA2
3. Participant has a history of non-infectious pneumonitis that required treatment with steroids or currently has pneumonitis
4. Participant either has myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) or has features suggestive of MDS/AML.
5. Participant has a known additional malignancy that is progressing or has required active treatment within the past 3 years.  
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ, endometrial carinoma) that have undergone potentially curative therapy are not excluded.
Note: Participants with synchronous primary endometrial cancer or a past history of primary endometrial cancer that met the following conditions are not excluded: Stage not greater than IA: no more than superficial myometrial invasion.
6. Participant has known active CNS metastases and/or carcinomatous meningitis.  Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
7. Participant has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 
8. Participant has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
9. Participant has a known history of active TB (Bacillus Tuberculosis).
10. Participant has an active infection requiring systemic therapy.
11. Participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.  
12. Participant has had underwent chemotherapy to treat borderline tumor. 
13. Participant has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
14. Participant has a known history of Human Immunodeficiency Virus (HIV).  
15. Participant has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. 
16. Participant is either unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg. Gasterectomy, partial bowel obstruction, malabsorption)
17. Participant has uncontrolled hypertension, defined as systolic > 140 mmHg or diastolic  > 90 mmHg documented by 2 blood pressure readings taken at least 1 hour apart.
Note: Use of antihypertensive medications to control blood pressure is allowed. 
18. Participant has current, clinically relevant bowel obstruction, abdominal fistula or gastrointestinal perforation, related to underlying EOC.
19. Participant has a history of hemorrhage, hemoptysis or active gastrointestinal bleeding within 6 months prior to randomization. 
20.  WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3).  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.
Prior/ Concomitant Therapy
21. Participant has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
Note: Participant who received prior therapy with either olaparib or any other PARP inhibitor is allowed. Participant who received prior therapy with bevacizumab or anti-angiogenic agent is allowed.
22. Participant has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
23. Participant has severe hypersensitivity (≥Grade 3) to pembrolizumab, olaparib, or bevacizumab and/or any of its excipients.
24. Participant is currently receiving either strong (eg. Itraconzaole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. Ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued prior to starting olaparib and for the duration of the study. The required washout period prior to starting olaparib is 2 weeks.
Note: A current list of strong/moderate inhibitors of CYP3A4 can be found at the following website:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling
25. Participant is currently receiving either strong (eg. Phenobarbital, enzalutamide, phenytoin, rifampin, rifabutin, rifapentine, carbamazepine, nevirapine, and St John’s’ Wort)  or moderate (eg. Bosentan, efavirenz, modafinil) inducers of cytochrome P450 (CYP)3A4 that cannot be discontinued prior to starting olaparib and for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents.
Note: A current list of strong/moderate inducers of CYP3A4 can be found at the following website:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling

Prior/Concurrent Clinical Study Experience
26. Participant is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
Note:  Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

Diagnostic Assessments
27. Participant has resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg. Unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolyte disturbances, etc.), or participant has congenital long QT syndrome.
Other Exclusion
28. Participant has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation. Participant either had major surgery within 2 weeks of enrollment or has not recovered from any effects of any major surgery.
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
29. Participant has received prior radiotherapy within 2 weeks of start of study treatment.  Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.  A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
30. Participant has had allogenic tissue/solid organ transplant, has received previous allogenic bone-marrow transplant, or has received double umbilical cord transplantation. 
31. Participant, in the judgement of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study.

progression-free survival

6 months

Overall survival (OS)

Up to 1year

Time to tumour progression (TTP)

Up to 1year

Time to first subsequent treatment(or death)

The date of first documented first subsequent treatment or date of death, assessed up to 72 months

Time to second subsequent treatment

The date of first documented second subsequent treatment assessed up to 72 months

progression-free survival

Up to 1year