A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma
Condition: Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Tivozanib
Intervention description: 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.
Intervention MeSH terms: Tivozanib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 105.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: AV-951; Tivozanib; RCC; Biomarkers; Advanced Renal Cell Carcinoma

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. ≥ 18 year old males or females

          2. Subjects with unresectable locally recurrent or metastatic renal cell carcinoma (RCC)

          3. Histologically or cytologically confirmed clear cell renal cell carcinoma (≥ 50% clear
             cell) or non-clear cell RCC (all histologies)

          4. Subjects must have undergone prior nephrectomy (complete or partial) for excision of
             the primary tumor.

          5. Measurable disease per RECIST criteria Version 1.1 (see Appendix A)

          6. 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.

          7. Eastern Cooperative Oncology Group performance status of 0 or 1, and life expectancy ≥
             3 months

          8. If female and of childbearing potential, documentation of negative pregnancy test
             prior to enrollment

          9. Willingness to provide archival paraffin embedded tumor tissue, if available.

         10. Ability to give written informed consent and comply with protocol requirements

        Exclusion Criteria:

          1. 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.

          2. Any prior therapy with an agent targeting the mechanistic target of rapamycin pathway
             (eg, temsirolimus, everolimus, etc)

          3. 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).

          4. 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)

          5. 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

          6. 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

          7. Non-healing wound, bone fracture, or skin ulcer.

          8. 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

          9. Serious/active infection or infection requiring parenteral antibiotics.

         10. Inadequate recovery from any prior surgical procedure or major surgical procedure
             within 4 weeks prior to administration of first dose of study drug.

         11. 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)

         12. 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)

         13. 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.

         14. Pregnant or lactating females.

         15. History of genetic or acquired immune suppression disease such as HIV; subjects on
             immune suppressive therapy for organ transplant.

         16. Life-threatening illness or organ system dysfunction compromising safety evaluation.

         17. Requirement for hemodialysis or peritoneal dialysis.

         18. 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.

         19. Psychiatric disorder or altered mental status precluding informed consent or
             protocol-related testing.

         20. 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