A Phase 3, Randomized, Controlled, Multi-Center, Open-Label Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma (TIVO-1)
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.
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,
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
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.)