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Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma
Article first published online: 4 OCT 2010
Copyright © 2010 American Cancer Society
Volume 117, Issue 4, pages 758–767, 15 February 2011
How to Cite
Rini, B. I., Stein, M., Shannon, P., Eddy, S., Tyler, A., Stephenson, J. J., Catlett, L., Huang, B., Healey, D. and Gordon, M. (2011), Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer, 117: 758–767. doi: 10.1002/cncr.25639
- Issue published online: 3 FEB 2011
- Article first published online: 4 OCT 2010
- Manuscript Accepted: 3 AUG 2010
- Manuscript Revised: 6 JUL 2010
- Manuscript Received: 7 APR 2010
- metastatic renal cell carcinoma;
- phase 1;
- antiangiogenic therapy
On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated.
Adult patients with mRCC who had received ≤1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics.
Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report.
In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses >6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. Cancer 2011. © 2010 American Cancer Society.