Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Molecular Driven Phase II Trial of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib, Selected According to HRD Status, in Patients With Advanced (Stage III B-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer Preceded by a Phase I Dose Escalation Study on Rucaparib-Bevacizumab Combination
Brief Summary: This trial is a randomized, open-label Phase I-2 multi-center study designed to evaluate the effect of Carboplatin-Paclitaxel-Bevacizumab (in combination and maintenance) vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib (Rucaparib only in maintenance) vs Carboplatin-Paclitaxel-Rucaparib (Rucaparib only in maintenance) on progression-free survival in patients with advanced high grade ovarian cancer treated according to HRD status . The trial will test the hypothesis that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib and the Carboplatin-Paclitaxel-Rucaparib arms will improve the progression-free survival in comparison to standard Carboplatin-Paclitaxel-Bevacizumab in HRD negative (HR proficient) patients and that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib will improve PFS with respect to Carboplatin-Paclitaxel-Rucaparib in HRD positive patients. The randomized phase of the study will be preceded by a single arm Phase I study which will be conducted only in the National Cancer Institute of Milan, aiming at evaluating the MTD of the combination Rucaparib-Bevacizumab. Once the MTD has been reached, the randomized study will start.


Options:
A: Inclusion Criteria:

1. Women aged \>=18 years at the time of study inclusion;
2. Patients with newly diagnosed, histologically confirmed, high grade serous, high grade endometrioid, FIGO stage IIIB-C-IV epithelial ovarian cancer, primary peritoneal cancer and / or Fallopian-tube cancer. Patients with mixed histology (carcinosarcoma) are eligible providing that high grade tumor represent more than 50% of the total histology.

   Stage III patients should have had one attempt at optimal debulking surgery (upfront or interval debulking). Stage IV patients must have had either a biopsy and/or upfront or interval debulking surgery;
3. Archival tumor tissue available. At progression fresh biopsy is optional for patients willing to submit ;
4. ECOG Performance Status of 0-1;
5. Measurable and not measurable disease;
6. Adequate renal and hepatic function, defined as:

   * Total serum bilirubin ≤ 1.5 institutional ULN unless patient has Gilbert's syndrome in which case total serum bilirubin must be \<2 ULN for the institution AST and/or ALT ≤ 2.5 x ULN for the institution. (or ≤ 5 x ULN if liver metastases are present);
   * Alkaline phosphatase \< 1.5 x ULN for the institution (if \> 1.5 x ULN, then alkaline phosphatase liver fraction must be \< 1.5 ULN)
   * Serum creatinine ≤ 1.5 x ULN for the institution (or calculated creatinine clearance ≥ 45 mL/min/1.73 m2);
7. Adequate bone marrow function, defined as:

   * Total leukocytes 2.5 x 109/L;
   * ANC 1.5 x 109/L;
   * Platelet count 100 x 109/L;
8. Able to understand and give written informed consent;
9. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

Exclusion Criteria:

1. Women who are pregnant or lactating;
2. Presence of brain or other central nervous system metastases, not adequately controlled by treatment;
3. Prior Anticancer treatment;
4. Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 3 weeks prior to randomization;
5. Another primary malignancy except for:

   1. Curatively treated non-melanoma skin cancer;
   2. Breast cancer treated curatively ≥5 years ago, or other solid tumor treated curatively ≥5 years ago, without evidence of recurrence;
   3. Synchronous endometrioid endometrial cancer (except for Stage 1A G1/G2);
6. Known active HIV, hepatitis B or C infection;
7. Concurrent treatment with immunosuppressive or investigational agents;
8. History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or subarachnoid haemorrhage within _6 months prior to the first study treatment);
9. Clinically significant (i.e. active) cardiovascular disease, including:

   * Myocardial infarction or unstable angina within _6 months prior to the first study treatment;
   * New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF);
   * Serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia);
   * Peripheral vascular disease \> grade 3 (i.e.symptomatic and interfering with activities of daily living requiring repair or revision);
10. Serious active infection requiring i.v. antibiotics at enrolment;
11. Known hypersensitivity to any of the study drugs or excipients (including cremophor and hamster Ovary cell products);
12. Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications;
13. Prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with absorption of study drug;
14. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first dose of Rucaparib or have on-going requirements for these medications.
B: Inclusion Criteria:

* Has histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
* Has received 1 or 2 prior lines of systemic therapy for ovarian cancer (OC), including at least 1 prior platinum-based therapy. Participants may have received a prior poly (ADP-ribose) polymerase inhibitor (PARPi), anti-PD-1/anti-PD-L1 therapy, bevacizumab, or hormonal therapy; these will not be considered a separate line of therapy. Any chemotherapy regimen change due to toxicity in the absence of disease progression will be considered part of the same line of therapy.
* Has provided documented informed consent for the study.
* Has radiographic evidence of disease progression within 6 months (180 days) after the last dose of platinum-based chemotherapy for OC (i.e., platinum-resistant disease).
* Is a candidate for paclitaxel chemotherapy (and bevacizumab, if using).
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 3 days before randomization.
* For a female participant, she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP and uses a contraceptive method that is highly effective (with a failure rate of \<1% per year).
* Has radiographically evaluable disease, either measurable or nonmeasurable per RECIST 1.1, as assessed by the local site investigator.
* Archival tumor tissue sample or newly obtained core or incisional/excisional biopsy of a tumor lesion not previously irradiated has been provided.
* Have adequate organ function.

Exclusion Criteria:

* Has nonepithelial cancers, borderline tumors, mucinous, seromucinous that is predominantly mucinous, malignant Brenner's tumor and undifferentiated carcinoma.
* Has primary platinum-refractory disease, defined as disease that has progressed per radiographic imaging while receiving or within 28 days of the last dose of first-line platinum-based therapy.
* Has prior disease progression on weekly paclitaxel alone.
* Has received \>2 prior lines of systemic therapy for OC.
* Has received prior systemic anticancer therapy including investigational agents or maintenance therapy (including bevacizumab maintenance therapy), within 4 weeks before randomization.
* Has received prior radiation therapy within 2 weeks of start of study intervention.
* Has not recovered adequately from surgery and/or any complications from the surgery.
* Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor,\[GM-CSF\] or recombinant erythropoietin) within 4 weeks before randomization.
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
* Has received investigational agent or has used an investigational device within 4 weeks prior to study intervention.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Has severe hypersensitivity (≥Grade 3) to pembrolizumab, paclitaxel, or bevacizumab (if using) and/or any of their excipients.
* Has an active autoimmune disease that has required systemic treatment in the past 2 years.
* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has an active infection requiring systemic therapy.
* Has a known history of human immunodeficiency virus (HIV) infection.
* Has a known history of Hepatitis B or known active Hepatitis C virus infection.
* Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study.
* Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
* Participant, in the judgement of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study.
* Has had an allogenic tissue/solid organ transplant.

For bevacizumab treatment

* Has uncontrolled hypertension.
* Has current, clinically relevant bowel obstruction including related to underlying epithelial OC, abdominal fistula or gastrointestinal perforation, intra-abdominal abscess, or evidence of rectosigmoid involvement by pelvic exam.
* Has a history of thrombotic disorders, hemorrhage, hemoptysis, or active gastrointestinal bleeding within 6 months before randomization.
C: Inclusion Criteria:

* Histologically proven epithelial ovarian cancer, epithelial fallopian tube cancer, or primary peritoneal cancer
* Prior treatment with only 1 platinum based chemotherapy regimen
* Eastern Cooperative Oncology Group status of not more than 2
* Progression more than 6 months after the start of initial chemotherapy treatment

Exclusion Criteria:

* Treatment with more than 1 prior chemotherapy regimen
* Progression within 6 months after starting initial chemotherapy
* Prior exposure to anthracyclines
* Unwilling or unable to have central venous catheter
* Known clinically relevant central nervous system metastasis
D: Inclusion Criteria:

* Female 18 years of age or older at the time the written informed consent is obtained
* Gynecologic Oncology Group (GOG) Performance Status of 0 or 1
* Life expectancy \>= 3 months (per investigator opinion)
* Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (Subjects with pseudomyxoma , mesothelioma, unknown primary tumor, sarcoma, or neuroendocrine histology, with borderline ovarian cancer, ie, subjects with low malignant potential tumors, and with clear cell or mucinous histology are excluded)
* Subjects must have undergone surgery for ovarian cancer, primary peritoneal cancer, or fallopian tube cancer including at least a unilateral oophorectomy
* Radiologically evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with modifications
* Subjects must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, high-dose therapy, consolidation therapy, bevacizumab or extended therapy administered after surgical or non-surgical assessment.
* Adequate organ and hematological function
* Generally well controlled blood pressure with systolic blood pressure \<= 140 mmHg and diastolic blood pressure \<= 90 mmHg prior to randomization. The use of anti-hypertensive medications to control hypertension is permitted
* Radiographically documented disease progression either on or following the last dose of prior chemotherapy regimen for epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer

Exclusion Criteria:

* Subjects who have received more than 3 previous regimens of anti-cancer therapy for epithelial ovarian, primary peritoneal or fallopian tube cancers
* Subjects who have received paclitaxel as consolidation therapy, maintenance, or monotherapy are excluded
* Subjects with primary platinum-refractory disease
* Subjects with platinum-free interval (PFI) \> 12 months from their last platinum based therapy
* Radiotherapy \<= 14 days prior to randomization. Subjects must have recovered from all radiotherapy-related toxicities
* Previous abdominal or pelvic radiotherapy
* History of arterial or venous thromboembolism within 12 months prior to randomization
* History of clinically significant bleeding within 6 months prior to randomization
* History of central nervous system metastasis
* Has not yet completed a 21 day washout period prior to randomization for any previous anti cancer systemic therapies (30 days for prior bevacizumab)
* Enrolled in or has not yet completed at least 30 days (prior to randomization) since ending other investigational device or drug, or currently receiving other investigational treatments
* Unresolved toxicities from prior systemic therapy that are Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 \>= Grade 2 in severity except alopecia
* Known active or ongoing infection (except uncomplicated urinary tract infection \[UTI\]) within 14 days prior to randomization
* Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor
* Treatment within 30 days prior to randomization with strong immune modulators including but not limited to systemic cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, thalidomide, and lenalidomide
* Clinically significant cardiovascular disease within 12 months prior to randomization
* Major surgery within 28 days prior to randomization or still recovering from prior surgery
* Minor surgical procedures, except placement of tunneled central venous access device within 3 days prior to randomization. Diagnostic laparoscopy is regarded as a minor surgical procedure.

Answer: A