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A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma †
Version of Record online: 8 MAR 2011
Copyright © 2011 American Cancer Society
Volume 117, Issue 18, pages 4194–4200, 15 September 2011
How to Cite
Harzstark, A. L., Small, E. J., Weinberg, V. K., Sun, J., Ryan, C. J., Lin, A. M., Fong, L., Brocks, D. R. and Rosenberg, J. E. (2011), A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma . Cancer, 117: 4194–4200. doi: 10.1002/cncr.25931
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009; Orlando, Florida.
- Issue online: 2 SEP 2011
- Version of Record online: 8 MAR 2011
- Manuscript Accepted: 14 DEC 2010
- Manuscript Revised: 11 DEC 2010
- Manuscript Received: 2 NOV 2010
- renal cell carcinoma;
- clear cell;
- mammalian target of rapamycin (mTOR) inhibitor;
- tyrosine kinase inhibitor;
- combination therapy
The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma.
Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined.
Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib.
The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma. Cancer 2011;. © 2011 American Cancer Society.