Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Open Label Phase II Study of Weekly Gemcitabine Plus Pazopanib Versus Weekly Gemcitabine Alone in the Treatment of Patients With Persistent or Relapsed Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma
Brief Summary: Ovarian cancer is the leading cause of gynecologic cancer deaths, and the fifth most common cause of cancer deaths in women. While approximately 75% of patients with epithelial ovarian cancer will respond to first-line chemotherapy with platinum and paclitaxel, most patients with advanced stage epithelial ovarian cancer will experience disease recurrence. Pazopanib is a novel agent has recently been approved for the treatment of subjects with advanced renal cell carcinoma (RCC), and preclinical studies suggest it may be effective in other cancers such as ovarian cancer. Therefore, the purpose of this study is to test the efficacy and safety of a novel agent, pazopanib, as an adjunct to a standard treatment, gemcitabine, for recurrent or persistent ovarian cancer. This is an open label study in which subjects will be randomized 1:1 to receive 4 cycles of either gemcitabine, or gemcitabine with pazopanib. Gemcitabine will be administered as an IV infusion weekly on days 1 and 8 of a 21 day cycle. Subjects randomized to receive pazopanib will take 800 mg daily during the 21 day cycle. All subjects will be monitored for toxicity and other indicators of safety (labs, physical exams, vitals) at intervals throughout the treatment cycles. Subjects will be followed for up to 5 years following the conclusion of treatment to evaluate efficacy. The primary endpoints of the study are progression free survival and overall survival, which will be assessed at three years.


Options:
A: Inclusion Criteria:

* Patient must have epithelial ovarian, fallopian tube, or primary peritoneal cancer
* Patients must have received ≥2 and not more than 5 prior therapies, including at least 1 line of therapy containing bevacizumab (or biosimilar).
* Patients must be considered platinum-resistant, defined as progression within 6 months from completion of a platinum-containing therapy
* Patient must be considered appropriate for treatment with weekly paclitaxel monotherapy as the next line of therapy.
* Patient must be willing and able to provide an FFPE archival or core tumor sample for determination of biomarker status on the Xerna™ TME Panel biomarker assay (positive or negative) prior to study treatment.
* Presence of at least one measurable lesion, as defined by RECIST v1.1.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 Adequate organ function

Exclusion Criteria:

* Non-epithelial ovarian carcinoma.
* Ovarian tumors with low malignant potential (i.e., borderline tumors).
* Primary platinum-refractory disease (defined as progression during or within 4 weeks after completion of the first platinum regimen).
* Patient has received an anti-angiogenic product other than bevacizumab or biosimilar.
* Patient has congestive heart failure
* Patient has a history of myocardial infarction, cerebral vascular accident, or transient ischemic attacks within 6 months
* Patient has a history of cardiac ischemia or heart failure within 6 months
* Baseline B-type natriuretic peptide (BNP) value \>100 pg/mL or N-terminal-proBNP (NT-proBNP) value of \> 125 pg/mL.
* LVEF \<50%.
* Peak tricuspid velocity \>3.0 m/s on Doppler ECHO.
* Clinically significant ECG abnormality, as assessed by the investigator
* Blood pressure (BP) \>140/90 mmHg
* History of bowel obstruction, including sub-occlusive disease, related to the underlying disease
* Hemoptysis \>2.5 mL within 8 weeks prior
* Major surgical procedure, or significant traumatic injury within 28 days
* Uncontrolled seizure disorder or active neurologic disease
* Patients with a cardiac aneurysm.
B: Inclusion Criteria:

1. Pathologically and radiologically confirmed stage IV or postoperative recurrence ovarian cancer.
2. Age of 18-70, Karnofsky score higher than 80.
3. No severe functional damage of major organ, normal liver and kidney function.
4. Peritoneal adhesion. (1) peritoneal adhesions diagnosed by microlaparoscopy or abdominal operations, and classification according to Nair criteria is performed. (1) must be met. (2) Peritoneal adhesion symptoms, intermittent abdominal pain, abdominal distension, nausea and vomiting, hard to pass stools or gas; (3) Peritoneal adhesion signs，abdominal distension, abdominal tenderness, reduced or absent bowel sounds; (4) B ultrasound or CT or MRI show peritoneal adhesion or adhesion-related complications.

Exclusion Criteria:

1. Complete intestinal obstruction and suitable for surgery.
2. Patients known to be allergic to bevacizumab or any of the components of the drug.
3. Other ongoing anti-tumor treatment.
4. Heart disease with significant clinical symptoms, such as: congestive heart failure, coronary heart disease with symptom, arrhythmia hardly be controlled by drugs, myocardial infarction in 6 months, or heart failure
5. Active wound infection and a history of uncontrolled psychiatric illness.

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C: Inclusion Criteria:

1. Signed written informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient's awareness and willingness to comply with the study requirements.
2. Female patients ≥ 18 years with histologically confirmed primary advanced invasive high grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO stage IIIA2 without nodal involvement) according to recent FIGO classification (= FIGO stage IIIB - IV according to FIGO 2009 classification).
3. All patients must have had either upfront primary debulking surgery OR plan to undergo chemotherapy with interval debulking surgery.
4. Patients must have available tumor samples to be sent to central laboratory as formalin-fixed, paraffin-embedded (FFPE) sample for determination of BRCA status prior to randomization for stratification.
5. Patients must be able to commence systemic therapy within 8 weeks of cytoreductive surgery.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
7. Estimated life expectancy \> 3 months.
8. Adequate bone marrow function (within 28 days prior to day 1, cycle 1)

   * Absolute Neutrophil Count (ANC) ≥ 1.5 x 10\^9/L
   * Platelets (PLT) ≥ 100 x 10\^9/L
   * Hemoglobin (Hb) ≥ 9 g/dL (can be post-transfusion)
9. Adequate coagulation parameters (within 28 days prior to day 1, cycle 1)

   * Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) ≤ 1.5 and an Activated ProThrombin Time (aPTT) ≤ 1.5 x institutional upper limit of normal (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 institution medical standard) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of day 1, cycle 1.
10. Adequate liver and kidney function (within 28 days prior to day 1, cycle 1)

    * Total bilirubin ≤ 1.5 x ULN (≤ 2.0 x ULN in patients with known Gilbert's syndrome) OR direct bilirubin ≤ 1.0 x ULN.
    * 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 case of liver metastases values must be ≤ 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.
    * Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation.
11. Patients must have normal blood pressure (BP) or adequately treated and controlled BP, with a systolic BP of ≤ 140 mmHg and diastolic BP of ≤ 90 mmHg for eligibility. Patients must have a BP of ≤ 140/90 mmHg taken in the clinic setting by a medical professional within 4 weeks prior to day 1, cycle 1.
12. Negative urine or serum pregnancy test within 7 days prior to day 1, cycle 1 in women of childbearing potential (WOCBP), confirmed prior to treatment on day 1.
13. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method with a failure rate of \< 1% per year during the treatment period and for at least 6 months after administration of the last dose of medication.

    A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or uterus).

    Examples of contraceptive methods with a failure rate of \< 1% per year include but are not limited to bilateral tubal ligation and/or occlusion, male sterilization, and intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, that include the completion of patient-reported outcomes questionnaires.

Exclusion Criteria:

1. Non-epithelial tumor origin of the ovary.
2. Ovarian tumors of low malignant potential (e.g. borderline tumors) and low grade tumors.
3. Planned intraperitoneal cytotoxic chemotherapy.
4. Malignancies other than ovarian cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS rate \> 90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ of the breast, or stage I p53 wild type endometrial cancer).
5. Prior systemic treatment for ovarian cancer.
6. Prior treatment with Poly adenosine diphosphate ribose polymerase (PARP) inhibitor.
7. 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).
8. Prior randomization in this trial.
9. Major surgery within 1 week of starting study treatment or patient who has not completely recovered from the effects of any major surgery. Core biopsy or other minor surgical procedure within 7 days prior to day 1, cycle 1 is permitted.
10. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to day 1, cycle 1) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to day 1, cycle 1) in case of suspected spinal cord compression.
11. Significant traumatic injury during 4 weeks preceding the potential first dose of bevacizumab.
12. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to day 1, cycle 1.
13. History or evidence of thrombotic or hemorrhagic disorders within 3 months prior to day 1, cycle 1.
14. History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy e.g. uncontrolled seizures.
15. Pregnant or lactating women.
16. Treatment with any other investigational agent, or participation in another clinical trial testing a drug within 4 weeks or 5 times the half-life of the drug, whichever is longer, prior to day 1, cycle 1 or concomitantly with this trial.
17. Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cell products or other recombinant human or humanized antibodies. Known hypersensitivity to niraparib, paclitaxel and carboplatin and its components or excipients.
18. 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.
19. Clinically significant cardiovascular disease, including

    * Myocardial infarction or unstable angina within 6 months of day 1, cycle 1
    * New York Heart Association (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 activity of daily living (ADL) requiring repair or revision)
    * Significant vascular disease including aortic aneurysm requiring surgical repair
20. Pre-existing sensory or motor neuropathy ≥ Grade 2.
21. Any prior history of hypertensive crisis (CTCAE grade 4) or hypertensive encephalopathy.
22. Patients with a history of or current Nephrotic syndrome.
23. Bowel obstruction (including subocclusive disease).
24. History of abdominal fistula or tracheoesophageal fistula or gastrointestinal perforation or active gastrointestinal bleeding or anastomotic insufficiency within 6 months of day 1, cycle 1.
25. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of niraparib.
26. 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.
27. Any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
28. Previous allogeneic bone marrow transplant or previous solid organ transplantation.
29. Current or recent (within 10 days prior to day 1, cycle 1) chronic use of aspirin \> 325 mg/day. Patients treated with other inhibitors of platelet aggregation such as clopidogrel, prasugrel, ticlopidine, tirofibane or dipyridamole should not be included into the trial.
30. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. This includes also any psychiatric disorder that prohibits obtaining informed consent.
31. Patient has known active hepatitis B or hepatitis C.
32. Patient has a history of Posterior Reversible Encephalopathy Syndrome (PRES).
D: Inclusion Criteria:

* Must be at least 18 years old
* Must have measurable or detectable ovarian, fallopian or primary peritoneal cancer
* Must have been treated previously with carboplatin, cisplatin or another organoplatinum compound

Exclusion Criteria:

* Women who are pregnant or nursing
* History of congenital long QT syndrome
* Active bleeding or at risk of a bleeding disorder
* Other significant medical condition or history of medical condition which may put the patient at risk

Answer: D