Please select the eligibility criteria that correspond to the clinical trial below.
Title: Bevacizumab and Carboplatin for Patients With Platin Resistant Epithelial Ovarian Cancer. A Phase II Study.
Brief Summary: This is a phase II trial to investigate the effect of bevacizumab and carboplatin in patients with platin resistant ovarian cancer.


Options:
A: Inclusion Criteria:

1. Histologically verified epithelial ovarian cancer, primary tubae- or primary peritoneal cancer (Stage I-IV)
2. Carboplatin resistant ovarian cancer previously treated with a maximum of three different cytostatic regimens (single substance or in combination).
3. Age ≥ 18 years.
4. Performance status 0-2.
5. Measurable disease according to CA125 GCIG criteria (Gynaecologic Cancer Intergroup) or RECIST (Response Evaluation Criteria in Solid Tumors) (See appendix I+II)
6. Adequate bonemarrow, liver and kidney function and coagulation parameters (within seven days of start of treatment).
7. ANC ≥ 1.5\*109
8. Thrombocytes ≥ 100\*10\^9/L
9. Haemoglobin (Hb) ≥ 6 mmol/l
10. Se-bilirubin (BR) ≤ 1.5\*ULN (Upper Limit of Normal)
11. Se-transaminase ≤ 2.5\*ULN
12. Se-creatinin ≤ 1.5\*ULN
13. Urin stix for protein \<2+ (If stix shows protein ≥2+ urin must be measured 24 hours where the protein content must be under 1 g.)
14. INR ≤1.5
15. APTT ≤ 1.5\*ULN
16. Signed informed consent form.

Exclusion Criteria:

1. Patients who have received other types of experimental treatment or participated in a clinical study less than 28 days prior to this study.
2. Pregnant or breastfeeding women. A negative pregnancy test is mandatory for fertile women.
3. Fertile women, who do not wish to use safe contraception (e.g., birth control pills, coil, gestagen deposit injection, subdermal implantation, hormonal vagina ring, and transdermal deposit band-aid).
4. Untreated bowel obstruction or massive gastrointestinal tumors verified by CT scan.
5. Other present or previous malignant disease apart from curatively treated non-melanoma skin cancer or other types of cancer with minimal risk of relapse.
6. CNS-metastases.
7. Underlying medical disease not adequately treated (diabetes, cardiovascular disease).
8. Uncontrolled hypertension (persistent BP \> 150/100 despite antihypertensive treatment).
9. Surgery incl. open biopsy less than 4 weeks before expected first dose of Bevacizumab.
10. Patients with non-healing wounds or fractures.
11. Previous cerebrovascular attack (TVA), transient ischaemic attack (TIA) or subarachnoidal bleeding (SAH) within last six months.
12. Thromboembolic or haemorrhagic disease in the anamnesis.
13. Clinically significant cardiovascular disease including Myocardial infarction or unstable angina less than 6 months prior to treatment

    * New York heart Association NYHA class ≥ 2
    * Poorly controlled cardial arrythmia despite medical treatment
    * Peripheral vascular disease, grade 3 or above.
14. Present or previous chronical use of Aspirin (less than 10 days before start of treatment) Aspirin \> 325 mg daily.
15. Present or recent use of full dose oral or parenteral anticoagulant or thrombolytic medicine.
16. Preexisting neuropathy, sensoric or motoric ≥ grade 2.
17. Decreased hearing.
18. Bleeding tumor.
19. Hypersensitivity to the active substance or one or more of the other substances contained in the protocol drugs.
20. Hypersensitivity to products from ovarian cells (CHO) from Chinese hamster or other recombinant or humanized antibodies.
B: Inclusion Criteria:

* No evidence of disease on CT/MRI following treatment for recurrent ovarian, fallopian tube, or peritoneal cancer.
* High-grade papillary serous carcinoma of the ovary, fallopian tube or peritoneum. Histological confirmation of the original primary tumor is required.
* CA-125 within normal range.
* Age greater than or equal to 18 years.
* 1 prior line of therapy (cytotoxic therapy only) in the recurrent setting is allowed. Bevacizumab in the upfront setting allowed, however Bevacizumab or other VEGF pathway targeted therapy in the recurrent setting is not allowed. Hormonal therapy does not count as a prior line.
* Recovered from effects of recent surgery, radiotherapy, and chemotherapy.
* ECOG performance status ≤ 2

Organ and marrow function as defined below:

* Absolute neutrophil count ≥1,250/mcL
* Platelets ≥100,000/mcL
* Bilirubin ≤ 1.5 x ULN
* AST (SGOT) / ALT (SGPT) ≤ 2.5 x institutional upper limit of normal Alkaline phosphatase ≤ to 2.5 x ULN
* Creatinine ≤ 1.5 x institutional upper limit
* Less than or equal to 1+ proteinuria on two consecutive dipsticks taken no less than 1 week apart, or \< 1 gm protein on 24-hour urine collection or a urine protein:creatinine ratio of \< 1.
* INR \< 1.5; if on anticoagulation: INR is required to be between 2 and 3.

Patient must receive one of these three regimens for their platinum sensitive disease (number of cycles should not have exceeded 8 cycles of 1 regimen in the recurrent setting):

* Platinum (Carboplatin or Cisplatin) and Taxane (Paclitaxel or Docetaxel) Carboplatin and Gemcitabine
* Carboplatin and Liposomal Doxorubicin
* Females not of childbearing potential or has documentation of a negative pregnancy test prior to the start of the study treatment are eligible. Sexually active pre-menopausal female subjects must agree to use adequate, highly effective contraceptive measures, while on study and for 45 days after the last dose of last study drug. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; (b) oral, implantable or injectable contraceptives plus one barrier method; or (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).
* Able and willing to sign a written informed consent document.

Exclusion Criteria:

* Prior therapy with bevacizumab or other VEGF pathway targeted therapy in the recurrent setting. Bevacizumab in the upfront setting is allowed.
* Receiving any other study agents.
* Subjects with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible. Subjects with prior cancer treated with a curative intent with no evidence of recurrent disease 5 years following diagnosis and judged by the investigator to be at low risk of recurrence are eligible. Subjects with any other concomitant or prior malignancies are ineligible.
* Serious non-healing wounds or ulcers at the time of registration.
* History of abdominal fistula or gastrointestinal perforation.
* Active bleeding.
* Clinically significant cardiovascular disease.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to Tivozanib.
* Symptomatic left ventricular dysfunction or baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram (ECHO) ≤ 50 % lower limit of institutional normal (LLN).
* Uncontrolled hypertension: systolic blood pressure of \>140 mmHg or diastolic blood pressure of \>90 mmHg documented on 2 consecutive measurements taken at least 24 hours apart.
* Myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug.
* History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation).
* Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication).
* Coronary or peripheral artery bypass graft within 6 months of screening.
* History of Class III or IV congestive heart failure, as defined by the New York Heart Association.
* Central nervous system metastases.

Note: Subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable without steroid treatment for at least 3 months following prior treatment may be enrolled.
C: 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.
D: Inclusion Criteria:

* Histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage (67) III or IV ovarian epithelial cancer or primary peritoneal cancer at presentation. Patients must have achieved a clinical complete response (disappearance of all clinical and radiological evidence of tumor) after only one regimen (4-6 cycles) of platinum and taxane-based standard chemotherapy received after tumor debulkment.
* Normal serum CA125 (cancer-associated tumor marker) level within 7 days of first dose of sorafenib.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* All scans used to document complete response must be done within 30 days prior to randomization.
* Patients must be able to swallow and retain oral medication.

Exclusion Criteria:

* Patients with any residual cancer tissue after the completion of chemotherapy detectable by standard Computed tomography (CT) or magnetic resonance imaging (MRI).
* Prior local radiotherapy, neoadjuvant chemotherapy or intraperitoneal chemotherapy.
* Histologic subtypes of ovarian cancer other than epithelial (i.e. sarcoma, lymphoma, germ cell).
* Major surgery, open biopsy, or significant traumatic injury within 30 days prior to randomization.

Answer: A