A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma
Condition: Advanced Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: tivozanib (AV-951); Sorafenib
Intervention description: Tivozanib: 1.5 mg orally once daily. 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.; Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Intervention MeSH terms: Sorafenib; Tivozanib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 517.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is an open-label, randomized, controlled, multi-national, multi-center, parallel-arm
      trial comparing tivozanib to sorafenib in subjects with advanced RCC. The study is designed
      to compare the PFS, OS, ORR, DR, safety and tolerability, and kidney specific symptoms/health
      outcome measurements of tivozanib and sorafenib.
    

Eligibility criteria:

        Inclusion Criteria:

          1. ≥ 18-years of age.

          2. Subjects with recurrent or metastatic RCC.

          3. Subjects must have undergone prior nephrectomy (complete or partial) for excision of
             the primary tumor.

          4. Histologically or cytologically confirmed RCC with a clear cell component (subjects
             with pure papillary cell tumor or other non-clear cell histologies, including
             collecting duct, medullary, chromophobe, mixed tumor containing predominantly
             sarcomatoid cells, and unclassified RCC are excluded).

          5. Measurable disease per the RECIST criteria Version 1.0.

          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.
             Postoperative or adjuvant systemic therapy will not be counted as a prior therapy
             unless recurrence is detected within 6 months of completion of treatment, in which
             case it will be counted as a prior therapy for metastatic disease.

          7. ECOG 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. Ability to give written informed consent and comply with protocol requirements.

        Exclusion Criteria:

          1. Any prior 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 mTOR pathway (eg, temsirolimus,
             everolimus, etc)

          3. Primary 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 hematologic abnormalities (as noted in the protocol).

          5. Any serum chemistry abnormalities (as noted in the protocol).

          6. Significant cardiovascular disease.

          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.

         12. Significant bleeding disorders within 6 months prior to administration of first dose
             of study drug.

         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 or sorafenib, major resection of the
             stomach or small bowel, or gastric bypass procedure.

         19. Psychiatric disorder or altered mental status precluding informed consent or necessary
             testing.

         20. Sexually active pre-menopausal female subjects (and female partners of male subjects)
             must use adequate contraceptive measures, while on study and for 50 days after the
             last dose of study drug. Sexually active male subjects must use adequate contraceptive
             measures, while on study for at least 90 days after the last dose of drug. All fertile
             male and female subjects and their partners must agree to use a highly effective
             method of contraception (including their partner). Effective birth control includes
             (a) IUD plus one barrier method; or (b) 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 may be
             affected by cytochrome P450 interactions, and are not considered effective for this
             study.)