A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma

Study Overview
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Brief Summary
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This is an open-label, single arm, multicenter study. Subjects will be stratified by histology (clear cell versus non-clear cell). Enrollment of non-clear cell subjects will be limited to ≤ 30% of the entire study population.

Detailed Description
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This is a Phase 2, open-label, single arm, multi-center, study of orally administered tivozanib to approximately 100 subjects with advanced renal cell carcinoma (RCC). This study is designed to evaluate biomarkers in blood and archived tissue samples, and their correlation with clinical activity and/or treatment-related toxicity in subjects with advanced RCC, and estimate the percentage of tivozanib-treated subjects who are progression-free at 6 months, overall response rate (ORR), progression free survival (PFS), safety and tolerability, and pharmacokinetics (PK). Subjects will be stratified by histology (clear cell vs. non-clear cell). Enrollment of non-clear cell subjects will be limited to ≤ 30% of the entire study population. Study enrollment is anticipated to complete in approximately 9 months. Treatment duration is estimated to last approximately 6 months from the subject's first dose of tivozanib with a follow-up period of 30 days. After 6 months, treatment with tivozanib may continue by participation in a rollover protocol (AV-951-09-901). Maximum duration of subject participation in this Phase 2 study is approximately 8 months.

Official Title
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A Phase 2 and Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Tivozanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 year old males or females Subjects with unresectable locally recurrent or metastatic renal cell carcinoma (RCC) Histologically or cytologically confirmed clear cell renal cell carcinoma (≥ 50% clear cell) or non-clear cell RCC (all histologies) Subjects must have undergone prior nephrectomy (complete or partial) for excision of the primary tumor. Measurable disease per RECIST criteria Version 1.1 (see Appendix A) Treatment naïve subjects or subjects who have received no more than one prior systemic treatment (immunotherapy, including interferon-alfa or interleukin-2 based therapy, chemotherapy, hormonal therapy or an investigational agent) for metastatic RCC. Eastern Cooperative Oncology Group performance status of 0 or 1, and life expectancy ≥ 3 months If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment Willingness to provide archival paraffin embedded tumor tissue, if available. Ability to give written informed consent and comply with protocol requirements Exclusion Criteria: Any prior vascular endothelial growth factor (VEGF)-directed therapy including VEGF antibody (eg, bevacizumab), VEGF receptor tyrosine kinase inhibitor (eg, sunitinib, sorafenib, axitinib, pazopanib, etc.), VEGF trap (eg, aflibercept), or any other agent or investigational agent targeting the VEGF pathway. Any prior therapy with an agent targeting the mechanistic target of rapamycin pathway (eg, temsirolimus, everolimus, etc) Primary central nervous system (CNS) malignancies or CNS metastases; subjects with previously treated brain metastasis will be allowed if the brain metastasis have been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery). Any of the following hematologic abnormalities: Hemoglobin < 9.0 g/dL Absolute neutrophil count (ANC) < 1500 per mm3 Platelet count < 100,000 per mm3 International Normalized Ratio >1.5 or partial thromboplastin time >1.5 × upper limit of normal (ULN) Any of the following serum chemistry abnormalities: Total bilirubin > 1.5 × ULN (or > 2.5 × ULN for subjects with Gilbert's syndrome) Aspartate aminotransferase or alanine aminotransferase > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis) Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis) Creatinine > 2.0 × ULN Proteinuria > 3+ by urinalysis or urine dipstick Significant cardiovascular disease, including: Active clinically symptomatic left ventricular failure. Uncontrolled hypertension: Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg on 2 or more antihypertensive medications, 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 (ie, 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 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. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug. 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 CTCAE Version 3.0) 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 3.0) Hemoptysis or other pulmonary bleeding Grade 2 (per CTCAE Version 3.0) 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 not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for >2 years. Pregnant or lactating females. History of genetic or acquired immune suppression disease such as 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 pills, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of tivozanib, major resection of the stomach or small bowel, or gastric bypass procedure. Psychiatric disorder or altered mental status precluding informed consent or protocol-related testing. Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for 30 days after the last dose of study drug. All fertile male and female subjects must agree to use a highly effective method of contraception (including their partner). Effective birth control includes: intrauterine device plus one barrier method or 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). (Note: Oral,implantable, or injectable contraceptives

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Tivozanib<br>Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks. | Drug: Tivozanib<br>* Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Clinical Activity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib. | To Evaluate CD68, HIF (hypoxia induced factor) 1/HIF2, VEGF A, VEGF-B, VEGF-C, VEGF-D, HGF (hepatocyte growth factor), CAIX, and PLGF (placental growth factor) levels and a biomarker signature based on transcriptional profiles. | Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1. | 
| Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Treatment-related Toxicity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib. | To Evaluate biomarkers like VEGF-A, VEGF-B, VEGF-C, VEGF-D, HGF, and PLGF levels, protein expression and metabolite patterns. | Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1. | 
| Number of Tivozanib-treated Subjects Who Are Progression-free at 6 Months | Subjects were considered to be progression-free at 6 months if they did not have disease progression or death by Day 182 and if they had an evaluation of confirmed PR, unconfirmed PR, or SD on or after Day 144. | Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Objective Response Rate (ORR) | Objective response rate (ORR) is defined as the proportion of evaluable subjects who had a best overall response of complete response (CR) or partial response (PR). Based on RECIST v1.1 for target lesions, CR is the disappearance of all target lesions, reduction in short axis of any pathological lymph nodes (whether target or non-target) to < 10 mm and PR is at least a 30% decrease from baseline in the sum of diameters of target lesions. | Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). | 
| Kaplan-Meier Estimate of Progression-free Survival (PFS) | PFS is defined as the duration in days from the date of first dose of study drug to the date of first documentation of Progressive Disease (PD) or death (whichever came first), censored at the last tumor assessment documenting the absence of PD prior to the start of further anti-cancer therapy. Based on RECIST v1.1, progressive Disease (PD) is defined as an increase of at least 20%, and an absolute increase of at least 5 mm, in the sum of diameters of target lesions, taking as reference the smallest sum on study. | Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib). | 
| Number of Subjects With Adverse Events | Subjects were monitored throughout the treatment and 30 day follow-up period for occurrence of adverse events as well as for changes in clinical status, vital signs, and laboratory data. Safety parameters to be measured/assessed include eligibility assessment, medical history, performance status evaluation, vital signs, physical examination, subjective reports, hematology, serum chemistries, thyroid function tests, coagulation parameters, urinalysis, pregnancy test, and ECG. | Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AV-951, Tivozanib, RCC, Biomarkers, Advanced Renal Cell Carcinoma