A Phase II Multi-Center Study of Bevacizumab in Combination With Ixabepilone in Subjects With Advanced Renal Cell Carcinoma
- Substantial preclinical antitumor synergy supports the exploration of the combination
of antiangiogenic compounds (including sunitinib and bevacizumab) plus ixabepilone. In
Vivo, synergistic activity between ixabepilone and bevacizumab has been demonstrated
using the 151-B human renal carcinoma xenograft model and this synergy compares
favorably with other antiangiogenic inhibitors (i.e. sunitinib).
- Combination therapies of bevacizumab with chemotherapy demonstrated improved benefit
compared with single-agent cytotoxics in multiple animal models and in humans.
- Clinical activity of both compounds used as single agents has been demonstrated in a
broad spectrum of solid tumors. Bevacizumab and ixabepilone, when used as a single
agent, have demonstrated substantial activity in renal cell carcinoma. Ixabepilone is
currently being evaluated in a Phase II study (CCR/NCI, Tito Fojo MD, PhD, PI) in stage
IV renal carcinoma, with encouraging preliminary activity.
- Phase II studies with bevacizumab and ixabepilone suggest the absence of overlapping
- Development of a well-tolerated and active bevacizumab/ixabepilone combination has the
potential to further improve the treatment of metastatic renal cell carcinoma (mRCC),
and could represent a second-line option after sunitinib or sorafenib are no longer of
benefit or are intolerable.
- Determine the objective response rate of the combination of ixabepilone and bevacizumab
in patients with relapsed or refractory mRCC.
- Determine progression-free survival.
- Characterize the toxicity of the combination of ixabepilone and bevacizumab in patients
- Determine changes in biomarkers and evaluate correlation with clinical outcomes.
- Pathologic confirmation of renal cell carcinoma (clear cell histology) by the
Laboratory of Pathology, NCI or the Medical University of South Carolina..
- Presence of metastatic renal carcinoma, after progression or intolerance to VEGFR
inhibitors (sunitinib and/or sorafenib).
- Adequate organ and bone marrow function.
- Multi-center, open labeled phase II study
- Following a Simon two-stage optimal design, a maximum of 58 patients with metastatic
RCC will be accrued over a period of 24 months.
- Ixabepilone will be administered daily as a one hour infusion on five successive days
(daily x 5), every three weeks (one cycle equals 3 weeks or 21 days). The starting dose
will be a daily dose of 6 mg/m(2)/day, for a total per cycle dose of 30 mg/m(2).
- In addition, 15 mg/kg bevacizumab will be administered intravenously on day 1 of each
cycle. The first infusion of bevacizumab will be 90 minutes in duration, the second 60
minutes in duration, and in all subsequent cycles bevacizumab will be infused over 30
minutes if prior infusions are well tolerated.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Response rate per RECIST.
Antonio T Fojo, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|Medical University of South Carolina||Charleston, South Carolina 29425-0721|