Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II Study of Tivozanib as Maintenance Therapy, Post-Chemotherapy, in Patients With Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Brief Summary: This research study is evaluating a drug called tivozanib as a possible treatment for ovarian, fallopian tube or primary peritoneal cancer.

Angiogenesis is the formation of new blood vessels. Tumors need blood vessels to grow and spread. Tivozanib is an anti-angiogenesis medicine that fights cancer by cutting off a tumor's blood supply so that it does not get the blood and nutrients it needs to grow.

In this research study, the Investigators are looking to see whether tivozanib works as a maintenance therapy for ovarian, fallopian tube or primary peritoneal carcinoma in participants who have achieved a complete response following chemotherapy. Maintenance therapy is given after a disease has responded to previous treatment. It is given to help prevent the spread or recurrence of the tumor.


Options:
A: Inclusion Criteria:

* Female patients with histologically diagnosed serous ovarian cancer or recurrent serous ovarian cancer.
* Patients must have completed at least 2 previous courses of platinum containing therapy; the patient must have been platinum sensitive to the penultimate chemo regimen.
* For the last chemotherapy course prior to enrolment on the study, patients must have demonstrated an objective stable maintained response (partial or complete response) and this response needs to be maintained until completion of chemotherapy.
* Patients must be treated on the study within 8 wks of completion of their final dose of the platinum containing regimen.

Exclusion Criteria:

* Previous treatment with PARP inhibitors including AZD2281
* Patients with low grade ovarian carcinoma.
* Patients who have had drainage of their ascites during the final 2 cycles of their last chemotherapy regimen prior to enrolment on the study
* Patients receiving any chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study entry (or a longer period depending on the defined characteristics of the agents used).
B: Inclusion Criteria:

* Histologically or cytologically documented invasive epithelial ovarian, primary peritoneal, or fallopian tube cancer
* Radiographically documented disease progression either on or following the last dose of the prior regimen for epithelial ovarian, primary peritoneal, or fallopian tube cancer
* Subjects must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound.
* Female 18 years of age or older at the time the written informed consent is obtained
* Adequate organ and hematological function

Exclusion Criteria:

* Subjects who have received more than 3 previous regimens of anti cancer therapy for epithelial ovarian, primary peritoneal or fallopian tube cancer
* Subjects treated with prior pegylated liposomal doxorubicin (PLD) or any anthracycline-based or mitoxantrone-based chemotherapy
* Subjects with primary platinum-refractory disease
* Subjects with platinum-free interval (PFI) \> 12 months from their last platinum based therapy
* History of central nervous system metastasis
* Major surgery within 28 days prior to randomization or still recovering from prior surgery
C: 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.
D: Inclusion Criteria:

* Female subjects ≥ 18 years of age.
* Histologically confirmed progressive or recurrent endometrial cancer or ovarian cancer with previously identified ARID1A tumor mutations.

  a. Any ARID1A mutation is eligible and any CLIA Next generation sequencing test is allowable for eligibility.
* Archival tumor tissue specimen available. Histological tissue specimen (tissue block or 8-10 unstained slides) must be available (specimen can be the sample at diagnosis or taken at relapse). Otherwise, patient must agree to have tumor biopsy to obtain sufficient tissue for histological assessment. If unable to be safely biopsied and patient desires enrollment, may be enrolled per MM discretion.
* A subset of patients (15 ovarian samples and 15 endometrial samples) should agree to have optional tumor biopsy for translational studies assessment. If unable to be safely biopsied and patient desires enrollment, may be enrolled per medical monitor discretion. Tissue collection for the optional translational biopsies will continue until a total of 30 viable samples have been collected (15 endometrial and 15 ovarian). Patient agrees to have blood draw at pre-treatment and post-treatment (end of study) for translational studies assessment.
* Patients who have progressed after ≥1 prior platinum containing 5.2 regimen.
* Patient must agree to have blood draw at pre- and post-treatment for correlative studies.
* Measurable disease by RECIST criteria v1.1.
* ECOG performance status 0 or 1.
* Patients should have no major existing co-morbidities or medical conditions that will preclude therapy in the view of the principal investigator.
* Life expectancy \> 12 weeks.
* Adequate bone marrow, hepatic and renal function as defined by the following values within 14 days prior to starting treatment:

  1. Hemoglobin \>9 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
  2. Platelet count ≥ 100 x 109/L with no platelet transfusion in the past 28 days.
  3. Creatinine clearance ≥50 mL/min (estimated using Cockcroft-Gault equation).
  4. Total bilirubin ≤1.5 x institutional upper limit (ULN) (where bilirubin rise \> 1.5 x ULN due to Gilbert's syndrome a conjugated bilirubin ≤1.5 x ULN is required).
  5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5 x ULN if no demonstrable liver metastases or ≤5 times ULN if patient has documented liver metastases.
* Women of child-bearing potential who are confirmed NOT to be pregnant. This should be evidenced by a negative urine or serum pregnancy test within 72 hours prior to start of trial treatment. Patients will be considered to be not of child-bearing potential if they are:

  1. Post-menopausal - defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, OR women under 50 years old who have been amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and have serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the post-menopausal range for the institution.
  2. Able to provide documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  3. Radiation or chemotherapy-induced oophorectomy or menopause with \> 1 year since last menses.
* Patient is willing and able to comply with the protocol for the duration of the study. including undergoing treatment and scheduled visits and examinations.
* Able to swallow, absorb, retain oral medication.
* Able to provide written, informed consent.
* Patients must have recovered from any effects of any major surgery and not have an open wound, active ulcer, or fistula.

Exclusion Criteria:

* Patients with localized advanced disease without other measurable lesion and could be treated with curative intent.
* Other malignancy within the last 5 years that would be expected to impact on overall survival. Prior malignancy with no expected impact on overall survival are allowed.
* Patients with myelodysplastic syndrome/acute myeloid leukemia history or with features suggestive of MDS/AML.
* Patients receiving radiotherapy within 2 weeks prior to study treatment.
* Major surgery within 4 weeks of starting study treatment.
* Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
* Any previous treatment with PARP inhibitor, including niraparib.
* Clinically significant (e.g. active) cardiovascular disease, uncontrolled high blood pressure. Uncontrolled high blood pressure defined as values ≥160/100 or symptomatic, refer to CTCAE.
* Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub- Arachnoids Hemorrhage (SAH) within 6 months prior to study treatment.
* Patients with increased risk of bleeding or history or evidence of hemorrhagic disorders within 6 months prior to study treatment.
* Resting ECG with QTc \> 470 msec on 2 or more time points within a 24-hour period or family history of long QT syndrome
* Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) \> grade 2) caused by previous cancer therapy, excluding alopecia.
* Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
* Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
* Pregnant or lactating woman.
* Participation in another clinical study with an investigational product during the chemotherapy course within 30 days prior to study treatment.
* Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
* Patients with a known hypersensitivity to investigational drugs or excipients.
* Clinical/radiological evidence of bowel obstruction (e.g. hospitalization) or symptoms of sub-acute bowel obstruction within 6 weeks prior to trial entry.

Answer: C