Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized, Double-Blind, Phase III Trial Olaparib vs. Placebo Patients With Advanced FIGO Stage IIIB-IV High Grade Serious or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer Treated Standard First-Line Treatment
Brief Summary: 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.


Options:
A: Inclusion criteria

1. Patients were diagnosed with ovarian cancer, fallopian tube cancer or primary peritoneal cancer confirmed by previous pathology, and the pathological type was non-mucinous adenocarcinoma.There were previous surgical wax preservation.
2. Initial platinum-resistant relapse, the recurrence time was less than 6 months after the last chemotherapy.
3. Complicated with malignant pleural effusion or ascites, or with recurrent lesions that can be evaluated clinically.
4. ECOG physical status score 0 or 1.
5. The expected survival time is ≥ 4 months.
6. In the previous treatment, there was no antivascular targeted therapy;
7. Patients without pleural effusion or ascites should be confirmed by CT or MRI according to the standard of RECIST1.1 version, requiring the patient to have at least one measurable focus as the target focus. If the target focus is a lymph node with a short diameter of more than 1.5 cm, and the target focus is not suitable for surgical treatment, the target focus has not received radiotherapy or relapsed in the radiotherapy field.
8. The baseline blood routine conforms to the following criteria:

   1. neutrophil count ≥ 1.5x109 /L;
   2. platelet count ≥ 100x109 PG L;
   3. hemoglobin ≥ 9g/dL (blood transfusion is allowed to achieve or maintain this target) .
9. Liver function meets the following criteria:

   1. total bilirubin\<1.5 normal limit (ULN);
   2. glutamic oxaloacetic transaminase (AST), glutamic pyruvic transaminase (ALT)\<2.5xULN, which is allowed\<5xULN in patients with liver metastasis.
10. Serum creatinine ≤ 1.25xULN or calculated creatinine clearance ≥ 50mL/min.

Exclusion criteria

1. Have received more than two chemotherapy regimens in the past.
2. Currently or recently (within 30 days before enrollment) using another research drug or participating in another clinical study.
3. other malignant tumors have occurred within 5 years (except adequately treated cervical carcinoma in situ or skin squamous cell carcinoma, or controlled basal cell carcinoma of the skin).
4. Patients with hypertension that cannot be reduced to normal range after antihypertensive treatment (systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥ 90 mmHg).
5. Suffer from myocardial ischemia or myocardial infarction above II grade and poorly controlled arrhythmias (including QTc interval ≥ 470ms in females).
6. According to the NYHA standard, there were previous or present cardiac insufficiency of grade II or above, or color Doppler echocardiography showed that the left ventricular ejection fraction ((LVEF)) was less than 50% or the lower limit of the normal value.
7. Abnormal coagulation function (INR\>1.5 or prothrombin time (PT) \> ULN+4 seconds or APTT\>1.5xULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy.
8. There were significant clinical bleeding symptoms or definite bleeding tendency in the first 3 months, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood or above, or suffering from vasculitis.
9. Major surgical operations or severe traumatic injuries, fractures or ulcers occurred within the first 4 weeks of randomization.
10. There are significant factors affecting oral drug absorption, such as inability to swallow, chronic diarrhea and intestinal obstruction.
11. Urine routine indicates urinary protein ≥++, or confirms 24-hour urinary protein ≥ 1.0g.
12. The researchers judged other conditions that may affect the conduct of clinical studies and the determination of research results.
13. Allergic or heterogeneous reactions to doxorubicin and / or related substances.
14. The cumulative dose of doxorubicin (including previous anthracycline, if any) is expected to reach or exceed 550 mg after 4 courses of doxorubicin liposome injection treatment.
15. Uncontrollable arrhythmias or electrocardiograms abnormalities determined by the lead researcher to be at risk.
16. A history of doxorubicin liposome therapy in recent half a year.
17. Have previously received local radiotherapy of the pelvis or lower abdomen.
B: 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).
C: Inclusion Criteria:

* with recurrent epithelial carcinoma of the ovary, fallopian tube or primary peritoneum
* At least 1 previous line of chemotherapy
* Measurable disease
* Patients have a normal organ and bone marrow function measured within 28 days of randomization
* WHO 0-2

Exclusion Criteria:

* Primary platinum-refractory disease
* Known hypersensitivity to olaparib
* Resting ECG with QTc \> 470 msec
* Concomitant use of known potent CYP3A4 inhibitors
* Symptomatic uncontrolled brain metastases
* Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
D: Inclusion Criteria:

* Female subjects, ≥18 years, histologically proven recurrent advanced epithelial ovarian, fallopian tube or primary peritoneal carcinomas
* Have either undergone a hysterectomy or bilateral oophorectomy/salpingectomy and/or have been postmenopausal for 24 consecutive months (i.e. who have not had menses at any time in the preceding 24 consecutive months without an alternative medical cause)
* Performance status 0-2
* Adequate organ function
* Life expectancy \>6 weeks
* Has received 2 or more lines of chemotherapy for ovarian cancer and patient is platinum resistant or platinum intolerant or not suitable for any further standard intravenous chemotherapy
* No previous oral cyclophosphamide, nintedanib, or other tyrosine kinase inhibitors such as cediranib but patients can have received anti-VEGF therapies such as bevacizumab as they will be stratified for this
* Measurable lesions according to RECIST 1.1 criteria or serum CA125 levels for evaluation by GCIG CA125 criteria are welcomed but not a prerequisite for inclusion as response will only be assessed for those with evaluable disease
* Able to give written informed consent and to complete QoL

Exclusion Criteria

* Carcinosarcoma or malignant tumour of non-epithelial origin (e.g. germ cell tumour, sex cord-stromal tumour) of the ovary, fallopian tube or peritoneum
* Clinically relevant non-healing wound, ulcer (intestinal tract, skin) or bone fracture
* Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other GI disorders or abnormalities that would interfere with drug absorption or inability to take oral medication
* Active brain metastases (i.e. symptoms deteriorating, changing condition in \< 4 weeks) or leptomeningeal disease. Trial entry is allowed if the brain metastases are stable (asymptomatic or condition stable for \> 4 weeks).
* Dexamethasone for brain metastases is allowed if administered as stable dose for \> 4 weeks before randomisation (if \< 4 weeks then the patient is not eligible)
* Clinically relevant therapy-related toxicity from previous chemotherapy and radiotherapy
* History of major thromboembolic event within the last 6 months, such as pulmonary embolism or proximal deep vein thrombosis, unless on stable therapeutic anticoagulation (\>3 months if on warfarin, PT / INR needs to be monitored regularly as per table 8.1 in protocol)
* Known inherited or acquired bleeding disorder
* Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within the past 6 months, congestive heart failure \> NYHA II, severe peripheral vascular disease, significantly relevant pericardial effusion
* History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 6 months
* Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels
* Laboratory values indicating an increased risk for adverse events:

  1. calculated GFR \< 45 ml/min. Sites can use any calculation method according to local practice.
  2. absolute neutrophil count (ANC) \< 1.5x109/L
  3. platelets \< 100 x109/L
  4. haemoglobin \< 90 g/L
  5. proteinuria CTCAE 2 or greater
  6. total bilirubin \> x 2 ULN
  7. ALT and/or AST \> 1.5 x ULN
  8. unless liver metastases present when ALT or AST \> 2.5 ULN
  9. International normalized ratio (INR) \> 2 or activated partial thromboplastin time (APTT) \>1.5 x ULN in the absence of therapeutic anticoagulation. INR \> 4 or APTT \> 2.5 x ULN in presence of therapeutic anticoagulation
* Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal or antiviral therapy), including hepatitis B and/or C infection, HIV- infection
* Poorly controlled diabetes mellitus or patient on sulphonylurea-type hypoglycaemics (e.g. gliclazide) as main diabetic control (as contraindicated with cyclophosphamide)
* Previous breast cancer patients are permitted only if diagnosis and any chemotherapy treatment for this was \> 5 years previously and there is no evidence of metastatic breast cancer at trial entry (Please contact UCL CTC / CI if patient still on hormone treatment for breast cancer).
* Other malignancy diagnosed within the past 5 years. In exception to this rule, the following malignancies may be included:

  1. non-melanoma skin cancer (if adequately treated)
  2. cervical carcinoma in situ (if adequately treated)
  3. prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met: G1 or G2, no LVSI and FIGO (2010) stage IA only
* Serious illness or concomitant non-oncological disease such as neurologic, psychiatric or infectious disease 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
* Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule e.g. active alcohol or drug abuse
* Any contraindications for therapy with cyclophosphamide, e.g. a history of severe hypersensitivity reactions to listed excipients for cyclophosphamide treatment with other investigational drugs
* Patients should not commence trial treatment within 6 weeks of any major surgical procedure
* Participation in another clinical trial testing a drug within the past four weeks before start of therapy or concomitantly with this trial
* Chemotherapy, including immunotherapy or monoclonal antibody treatment (VEGF) within 4 weeks of starting study treatment
* Hormone treatment for ovarian cancer within 2 weeks of starting study treatment (ongoing HRT is allowable)
* Any previous tyrosine kinase inhibitor treatment that has predominantly anti-angiogenic action
* Radiotherapy within 3 months not allowed except when given for symptom control \>28d previously. All patients receiving any radiotherapy will require evidence of recurrent ovarian cancer outside the irradiated field either on imaging or via rising CA125
* Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients of nintedanib

Answer: B