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

Study Overview
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Brief Summary
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This phase II trial studies how well tivozanib works in treating patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer. Tivozanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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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.

Official Title
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The Efficacy and Safety of Tivozanib in Recurrent, Platinum-Resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Conditions
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Recurrent Epithelial Ovarian Cancer, Recurrent Fallopian Tube Cancer, Recurrent Primary Peritoneal Cancer

Intervention / Treatment
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* Drug: Tivozanib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Tivozanib)<br>Tivozanib 1.5mg orally given daily for 3 weeks with one week off to complete a 4 week cycle until disease progression or adverse effects prohibit further therapy | Drug: Tivozanib<br>* 1.5 mg Given PO (orally)days 1-21 or every 28 day cycle<br>* Other names: Oral VEGF receptor tyrosine kinase inhibitor AV-951;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the number of patients with complete response plus those with partial response as measured by RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Time taken to reach first best response. Range 1-4 cycles (1 cycle = 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | The Kaplan-Meier method will be utilized to estimate the median and overall distribution of PFS and will be defined from the start of treatment until the first documentation of progressive disease or death, whichever occurs first.. | Up to 36 months | 
| Number of Patients Who Experienced Adverse Events in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | Adverse events will be assessed by NCI CTCAE v 4.03. Adverse event that were determined to be serious adverse events (either grade 3, 4, or 5) related to study drug were collected. Grading is as follows:In general the following severity definitions are true: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death. | During treatment and up to 30 days after completion of study treatment. Range of cycles 1-32 (1 cycle =28 days). | 
| Overall Survival (OS) in Platinum-resistant Ovarian Cancer to Treatment With Single Agent Tivozanib | OS is defined from the start of treatment until date of death from any cause or date of last contact. | Up to approximately 42 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovary, Cancer, Recurrent, Fallopian Tube, Primary Peritioneal, Phase II, Platinum Resistant