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

PRIMARY OBJECTIVES:

I. To determine the clinical activity of tivozanib in patients with platinum-resistant, recurrent ovarian, fallopian tube or primary peritoneal cancer.

SECONDARY OBJECTIVES:

I. Determining the potential survival advantage and characterizing the safety of single agent tivozanib in patients with platinum-resistant ovarian cancer.

OUTLINE:

Patients receive tivozanib hydrochloride orally (PO) once daily (QD) on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

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