Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Prospective Randomised Phase III Trial to Evaluate Optimal Treatment Duration of First-line Bevacizumab in Combination With Carboplatin and Paclitaxel in Patients With Primary Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer
Brief Summary: The purpose of this study is to determine whether the early and continuous addition of bevacizumab for up to 30 months to the standard chemotherapy is more effective than the early and continuous addition of bevacizumab for up to 15 months.


Options:
A: Inclusion Criteria:

1. Female subjects who are at least 18 years of age at the time of informed consent
2. CA125 less than or equal to 3 x upper limit of normal (ULN) \[105 units per millilitre (U/mL)\] confirmed within 2 weeks of randomization using a centralized laboratory assay
3. A histologically confirmed diagnosis of high-grade serous epithelial ovarian cancer including primary peritoneal and fallopian tube malignancies; all other histologies, including mixed histology, are excluded
4. Have been treated with debulking surgery and a first-line platinum-based chemotherapy regimen
5. Maintenance therapy during the first platinum-free interval is allowed; however, the last dose must have been at least 21 days prior to Randomization.
6. Must be in a first relapse and have evaluable disease by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan, according to RECIST 1.1 (subjects with measurable disease per RECIST 1.1 or radiographically visible and evaluable disease). Subjects with only ascites or pleural effusion are excluded.
7. Must have relapsed radiographically between 6 months and 36 months of completion of first-line platinum chemotherapy
8. Must be a candidate for treatment with either carboplatin plus paclitaxel or carboplatin plus PLD with no medical contraindications present as outlined in the product labels for the selected regimen to be used in this study
9. Have a life expectancy of at least 6 months, as estimated by the investigator
10. Other significant medical conditions must be well-controlled and stable in the opinion of the investigator for at least 30 days prior to Randomization
11. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
12. Subjects being enrolled to receive paclitaxel plus carboplatin treatment must have neuropathic function (sensory and motor less than or equal to Grade 2 according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (2010)
13. Laboratory results within the 2 weeks prior to Randomization must be as follows:

    * Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10\^9/L
    * Platelet count greater than or equal to 100 x 10\^9/L
    * Hemoglobin greater than or equal to 9 g/dL
    * Creatinine less than 1.5 x ULN (CTCAE Grade 1)
    * Bilirubin less than 1.5 x ULN (CTCAE Grade 1)
    * Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) less than 3 x ULN
    * Alkaline Phosphatase less than 2.5 x ULN (CTCAE Grade 1)
    * Baseline albumin greater than or equal to Lower Limit of Normal
14. Subjects of childbearing potential must be surgically sterile or consent to use a medically acceptable method of contraception throughout the study period. All females will be considered to be of childbearing potential unless they are postmenopausal (eg, amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). If a patient of childbearing potential is neither surgically sterile nor postmenopausal, a highly-effective contraceptive method (ie, a method that can achieve a failure rate of less than 1 percent (%) per year when used consistently and correctly) must start either before or at Screening and continue throughout the entire study period and for 6 months after the last dose of Test Article is administered. Pregnant and/or lactating females are excluded

Exclusion Criteria:

1. Known central nervous system (CNS) tumor involvement
2. Evidence of other active invasive malignancy requiring treatment other than surgery in the past 3 years
3. Clinically significant heart disease (eg, congestive heart failure of New York Heart Association Class 3 or 4 angina, not well controlled by medication, or myocardial infarction within 6 months)
4. Electrocardiogram (ECG) demonstrating clinically significant arrhythmias that are not adequately medically managed (Note: subjects with chronic atrial arrhythmia, ie, atrial fibrillation or paroxysmal supraventricular tachycardia \[SVT\], are eligible)
5. Active serious systemic disease, including active bacterial or fungal infection
6. Active viral hepatitis or active human immunodeficiency virus (HIV) infection. Asymptomatic positive serology is not exclusionary.
7. Other concurrent immunotherapy (eg, immunosuppressants or chronic use of systemic corticosteroids, with the exception that low-dose corticosteroids \[50 mg/day prednisone or equivalent corticosteroid\] are allowed; these should be discussed with the Medical Monitor)
8. Known allergic reaction to a prior monoclonal antibody therapy or have any documented Anti-Drug Antibody (ADA) response; additionally known allergic reaction to the concomitant chemotherapies selected by the investigator for planned treatment in this study unless desensitization is planned
9. Previous treatment with farletuzumab or other folate receptor targeting agents
10. Previous treatment with cancer vaccine therapy
11. For subjects being enrolled to receive PLD plus carboplatin, prior treatment with anthracyclines or anthracenodiones
12. Breast-feeding, pregnant, or likely to become pregnant during the study
13. Any medical or other condition that, in the opinion of the investigator, would preclude the subject's participation in a clinical study including medical contraindications as outlined in the product labels for the chemotherapies selected by the investigator for planned treatment in this study
14. Patients who have had secondary debulking surgery or any second line therapy
15. Currently enrolled in another clinical study or used any investigational drug or device within 30 days (or 5 x half-life for investigational drugs where the half-life is known) preceding informed consent
B: Inclusion Criteria:

* Female patients with newly diagnosed, histologically confirmed, high risk advanced (FIGO stage III - IV) BRCA mutated high grade serous or high grade endometrioid ovarian cancer, primary peritoneal cancer and / or fallopian - tube cancer who have completed first line platinum based chemotherapy (intravenous or intraperitoneal).
* Stage III patients must 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.
* Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
* Patients who have completed first line platinum (e.g. carboplatin or cisplatin), containing therapy (intravenous or intraperitoneal) prior to randomisation:
* Patients must have, in the opinion of the investigator, clinical complete response or partial response and have no clinical evidence of disease progression on the post treatment scan or rising CA-125 level, following completion of this chemotherapy course. Patients with stable disease on the post-treatment scan at completion of first line platinum-containing therapy are not eligible for the study.
* Patients must be randomized within 8 weeks of their last dose of chemotherapy

Exclusion Criteria:

* BRCA1 and/or BRCA2 mutations that are considered to be non detrimental (e.g. "Variants of uncertain clinical significance" or "Variant of unknown significance" or "Variant, favor polymorphism" or "benign polymorphism" etc).
* Patients with early stage disease (FIGO Stage I, IIA, IIB or IIC)
* Stable disease or progressive disease on the post-treatment scan or clinical evidence of progression at the end of the patient's first line chemotherapy treatment.
* Patients where more than one debulking surgery has been performed before randomisation to the study. (Patients who, at the time of diagnosis, are deemed to be unresectable and undergo only a biopsy or oophorectomy but then go on to receive chemotherapy and interval debulking surgery are eligible).
* Patients who have previously been diagnosed and treated for earlier stage ovarian, fallopian tube or primary peritoneal cancer.
* Patients who have previously received chemotherapy for any abdominal or pelvic tumour, including treatment for prior diagnosis at an earlier stage for their ovarian, fallopian tube or primary peritoneal cancer. (Patients who have received prior adjuvant chemotherapy for localised breast cancer may be eligible, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease).
* Patients with synchronous primary endometrial cancer unless both of the following criteria are met: 1) stage \<2 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 3 endometrioid adenocarcinoma OR ≥ 60 years old at the time of diagnosis of endometrial cancer with Stage IA grade 1 or 2 endometrioid adenocarcinoma. Patients with serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium are not eligible.
C: The following eligibility criteria pertain to patients enrolling into PART 2 of the study:

Inclusion:

* Have a histologically confirmed diagnosis of high grade serous or Grade 2 or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer
* Received at least 3 prior chemotherapy regimens. Non-chemotherapy regimens and maintenance therapies administered as single agent treatment will not count as a chemotherapy regimen
* Relapsed/progressive disease as confirmed by CT scan
* Have biopsiable and measurable disease. Note: biopsy is optional for patients known to harbor a deleterious gBRCA mutation
* Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue available for planned analyses

Exclusion:

* History of prior cancers except for those that have been curatively treated, with no evidence of cancer currently (provided all chemotherapy was completed \>6 months prior and/or bone marrow transplant \>2 years prior to first dose of rucaparib).
* Prior treatment with any PARP inhibitor
* Symptomatic and/or untreated central nervous system metastases
* Pre-existing duodenal stent and/or any other gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
* Hospitalization for bowel obstruction within 3 months prior to enrollment
D: Inclusion Criteria:

* Signed written informed consent obtained prior to initiation of any study specific procedures and treatment as confirmation of the patients awareness and willingness to comply with the study requirements
* Primary diagnosis is confirmed by specialized pathology review (Germany only)
* Females aged ≥ 18 years
* Histologically confirmed, newly diagnosed

  * Epithelial ovarian carcinoma
  * Fallopian tube carcinoma
  * Primary peritoneal carcinoma AND FIGO stage IIb - IV (all grades and all histological types)
* Patients should have already undergone surgical debulking, by a surgeon experienced in the management of ovarian cancer, with the aim of maximal surgical cytoreduction according to the GCIG Conference Consensus Statement. There must be no planned surgical debulking prior to disease progression. Patients with stage III and IV disease in whom initial surgical debulking was not appropriate or possible will still be eligible providing

  * the patient has a histological diagnosis and
  * debulking surgery prior to disease progression is not foreseen
* Patients must be able to commence cytotoxic chemotherapy within 8 weeks of cytoreductive surgery. The first dose of bevacizumab can be omitted in both arms if the investigator decides to start chemotherapy within 4 weeks of surgery.
* ECOG 0-2
* Life expectancy \> 3 months
* Adequate bone marrow function (within 14 days prior to randomization)

  * ANC ≥ 1.5 x 10\^9/L
  * PLT ≥ 100 x 10\^9/L
  * Hb ≥ 9 g/dL (can be post-transfusion)
* Adequate coagulation parameters (within 14 days prior to randomization)

  * Patients not receiving anticoagulant medication who have an INR ≤ 1.5 and an aPTT ≤ 1.5 x ULN
  * The use of full-dose oral or par-enteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to institution medical standard) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of randomization.
* Adequate liver function (within 14 days prior to randomization)

  * Serum bilirubin ≤ 1.5 x ULN
  * Serum transaminases ≤ 2.5 x ULN
* Urine dipstick for proteinuria \< 2+. If urine dipstick is ≥ 2+, 24 hour urine must demonstrate ≤ 1 g of protein in 24 hours
* Adequate postoperative GFR \> 40 ml/min (estimates based on the Cockroft-Gault or Jelliffe formula are sufficient)

Exclusion Criteria:

* Non-epithelial origin of the ovary, the fallopian tube or the peritoneum
* Borderline tumours (tumours of low malignant potential) and FIGO stage Ia - IIa tumours
* Planned intraperitoneal cytotoxic chemotherapy
* Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy)
* Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of bevacizumab (allowing for the fact that bevacizumab can be omitted from the first cycle of chemotherapy). It is strongly recommended that an interval of 7 days is left between the insertion of any central venous access devices (CVADs) and the onset of bevacizumab treatment.
* Any planned surgery during the study treatment period plus 4 additional weeks to allow for bevacizumab clearance
* Uncontrolled hypertension (sustained elevation of BP systolic \> 150mmHg and/or diastolic \> 100mmHg despite antihypertensive therapy)
* Any previous radiotherapy to the abdomen or pelvis
* Significant traumatic injury during 4 weeks preceding the potential first dose of bevacizumab
* 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.
* History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy e.g. uncontrolled seizures
* Previous Cerebro-Vascular Accident (CVA), Transient Ischaemic Attack (TIA) or Sub-Arachnoid Haemorrhage (SAH) within 6 months prior to randomization
* Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least 6 months afterwards
* Pregnant or lactating women
* Treatment with other investigational agents, or participation in another clinical trial testing a drug within the past 4 weeks before start of therapy concomitantly with this trial
* Malignancies other than ovarian cancer within 5 years prior to randomization, except for adequately treated

  * carcinoma in situ of the cervix
  * and/or basal cell skin cancer
  * and/or non-melanomatous skin cancer
  * carcinoma in situ of the breast
  * and/or early endometrial carcinoma as specified below. Patients may have received previous adjuvant chemotherapy for other malignancies e.g. breast or colorectal carcinoma if diagnosed over 5 years ago with no evidence of subsequent recurrence.
* Patients with synchronous primary endometrial carcinoma, or a past history of primary endometrial carcinoma, are excluded unless ALL of the following criteria for describing the endometrial carcinoma are met

  * Disease stage FIGO stage ≤ IA (tumour invades less than one half of the myometrium)
* Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cell products or other recombinant human or humanised antibodies
* Non healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require 3 weekly wound examinations
* History or evidence of thrombotic or hemorrhagic disorders within 6 months prior to randomization
* Clinically significant cardiovascular disease, including

  * Myocardial infarction or unstable angina within 6 months of randomization
  * NYHA ≥ Grade 2 Congestive Heart Failure (CHF)
  * Poorly controlled cardiac arrhythmia despite medication (patients with rate-controlled atrial fibrillation are eligible)
  * Grade ≥ 3 peripheral vascular disease (i.e. symptomatic and interfering with activities of daily living requiring repair or revision)
* Current or recent (within 10 days prior to randomization) chronic use of aspirin \> 325 mg/day
* Pre-existing sensory or motor neuropathy ≥ Grade 2
* Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications

Answer: D