Tivozanib in Recurrent, Platinum-Resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Inclusion Criteria:

• Patients must have recurrent or persistent, platinum resistant epithelial ovarian, fallopian tube or primary peritoneal carcinoma; platinum-resistant disease is defined as a recurrence within 6 months of completing adjuvant, platinum-based chemotherapy

Patients must have measurable disease or non-measurable (detectable) disease:

Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be greater than or equal to 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray; lymph nodes must be greater than or equal to 15 mm in short axis when measured by CT or MRI

Non-measurable (detectable) disease in a patient is defined in this protocol as one who does not have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria but does have a cancer antigen 125 (CA-125) greater than or equal to two times the upper normal limit within the last 60 days (confirmatory at baseline) and at least one of the following conditions:

Ascites and/or pleural effusion attributed to tumor
Hypermetabolic lesions on positron emission tomography (PET) scan
Patients with measurable disease must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Recovery from effects of recent surgery, radiotherapy, or chemotherapy:

Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection [UTI])
Any other prior therapy directed at the malignant tumor, including chemotherapy, biological/targeted (non-cytotoxic) agents and immunologic agents, must be discontinued at least three weeks prior to registration
At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: laparotomy, laparoscopy, thoracotomy, video assisted thorascopic surgery (VATS); there is no restriction on minor procedures (e.g., minor: central venous access catheter placement, ureteral stent placement or exchange, paracentesis, thoracentesis)
Patients must have had one prior taxane and platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organo platinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic (biologic/targeted agents, such as bevacizumab) or extended therapy administered after surgical or non-surgical assessment; there is no maximum number of prior regimens;
patients may not have had any prior systemic therapy (including interleukin-2, interferon-alpha, chemotherapy, bevacizumab, investigational or licensed drug that targets vascular endothelial growth factor [VEGF] or VEGF receptors/pathway or are mammalian target of rapamycin [mTOR] inhibitors) for treatment of recurrent ovarian cancer
Patients must have signed an approved informed consent and authorization permitting the release of personal health information
Patients must meet pre-entry requirements
A female is eligible to participate if she is of non-childbearing potential or as documentation of a negative pregnancy test prior to the start of the study treatment; 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)

Exclusion Criteria:

• Age < 18 years

Patients who have had previous treatment with tivozanib
Hemoglobin < 9.0 g/dL
Absolute neutrophil count (ANC) < 1500 per mm^3
Platelet count < 100,000 per mm^3
Total bilirubin > 1.5 × upper limit of normal (ULN) (or > 2.5 x ULN for subjects with asymptomatic Gilbert's syndrome)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis)
BOTH total bilirubin > ULN AND AST/ALT > ULN
Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis)
Creatinine > 2.0 × ULN
Prothrombin time (PT) such that international normalized ratio (INR) > 1.5 x ULN (unless a patient is on therapeutic warfarin) or a partial thromboplastin time (PTT) > 1.5 x ULN
Proteinuria > 3+ by urinalysis or urine dipstick

Significant cardiovascular disease, including:

Symptomatic left ventricular dysfunction or baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram (ECHO) of =< 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
Non-healing wound, bone fracture, or skin ulcer
Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug
Serious/active infection or infection requiring parenteral antibiotics
Corrected QT interval (QTc) of > 480 msec using Bazett's formula
Radiotherapy or minor surgical procedure within 2 weeks, or major surgical procedure within 4 weeks prior to administration of first dose of study drug; inadequate recovery from prior surgical procedure

Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug, including but not limited to:

Deep vein thrombosis
Pulmonary embolism
Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
Peripheral arterial ischemia > grade 2 (per National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4.0)

Significant bleeding disorders within 6 months prior to administration of first dose of study drug, including but not limited to:

Hematemesis, hematochezia, melena or other gastrointestinal bleeding >= grade 2 (per CTCAE version 4.0)
Hemoptysis or other pulmonary bleeding >= grade 2 (per CTCAE Version 4.0)
Hematuria or other genitourinary bleeding >= grade 2 (per CTCAE Version 4.0)
Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast; subjects are considered to have a currently active malignancy if they have completed anti-cancer therapy and have not been disease free for > 2 years
Pregnant or lactating females
History of genetic or acquired immune suppression disease such as human immunodeficiency virus (HIV); subjects on immune suppressive therapy for organ transplant
Life-threatening illness or organ system dysfunction compromising safety evaluation
Requirement for hemodialysis or peritoneal dialysis
Inability to swallow capsules, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of study drugs, major resection of the stomach or small bowel, or gastric bypass procedure
Known hypersensitivity to drugs chemically related to tivozanib hydrochloride or sunitinib or their excipients
Psychiatric disorder or altered mental status precluding informed consent or protocol-related testing