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