PMID- 22169794 OWN - NLM STAT- MEDLINE DCOM- 20120621 LR - 20181201 IS - 1938-0682 (Electronic) IS - 1558-7673 (Linking) VI - 10 IP - 1 DP - 2012 Mar TI - Phase I trial of everolimus plus sorafenib for patients with advanced renal cell cancer. PG - 26-31 LID - 10.1016/j.clgc.2011.11.002 [doi] AB - BACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, and sorafenib, a RAF kinase inhibitor, has shown efficacy in renal cell cancer (RCC) as single agents. We conducted a phase I study to evaluate the maximum tolerated dose (MTD) of combining these agents for potential additive or synergistic effects when treating progressive metastatic RCC (mRCC). PATIENTS AND METHODS: The 15 patients enrolled in the study had predominantly clear cell RCC (cRCC) and progressive measurable disease with previous treatment that included immunotherapy, tyrosine kinase inhibitors, and/or everolimus. Patients received daily everolimus and twice-daily sorafenib at escalating dose levels of 2.5 mg/400 mg (cohort 1), 5 mg/400 mg (cohort 2), and 10 mg/400 mg (cohort 3), and they were evaluated weekly for toxicity and every 8 weeks for response, using computed tomography/positron emission tomography (CT/PET) and CT at baseline and at first staging. RESULTS: In cohort 1, 2 of 6 patients experienced dose-limited toxicity (DLT) of thrombocytopenia/leukopenia and pneumonitis. In cohort 2, 1 of 6 patients experienced a DLT of pulmonary embolism, and the 3 patients in cohort 3 experienced no DLTs. The MTD was 10 mg/400 mg. Common adverse events included grade 1/2 hand-foot syndrome. Using Response Evaluation Criteria in Solid Tumors (RECIST), 1 patient achieved a pathologic complete response (CR), 1 patient achieved a radiographic CR, and 1 patient achieved a surgical CR. Seven patients achieved stable disease; 10 patients had decreased fluorine-18 fluorodeoxyglucose uptake. Median progressive-free survival was 5.6 months; overall survival was 7.9 months. CONCLUSION: The MTD of daily everolimus 10 mg and twice-daily sorafenib 400 mg is safe and effective for progressive mRCC. CI - Copyright (c) 2012 Elsevier Inc. All rights reserved. FAU - Amato, Robert J AU - Amato RJ AD - Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston (Medical School), Memorial Hermann Cancer Center, Houston, TX 77030, USA. FAU - Flaherty, Amber L AU - Flaherty AL FAU - Stepankiw, Mika AU - Stepankiw M LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20111213 PL - United States TA - Clin Genitourin Cancer JT - Clinical genitourinary cancer JID - 101260955 RN - 0 (Benzenesulfonates) RN - 0 (Phenylurea Compounds) RN - 0 (Pyridines) RN - 25X51I8RD4 (Niacinamide) RN - 9HW64Q8G6G (Everolimus) RN - 9ZOQ3TZI87 (Sorafenib) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Benzenesulfonates/administration & dosage MH - Carcinoma, Renal Cell/*drug therapy/secondary MH - Everolimus MH - Female MH - Follow-Up Studies MH - Humans MH - Kidney Neoplasms/*drug therapy/pathology MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Niacinamide/analogs & derivatives MH - Phenylurea Compounds MH - Pyridines/administration & dosage MH - Sirolimus/administration & dosage/analogs & derivatives MH - Sorafenib MH - Treatment Outcome EDAT- 2011/12/16 06:00 MHDA- 2012/06/22 06:00 CRDT- 2011/12/16 06:00 PHST- 2011/07/29 00:00 [received] PHST- 2011/10/20 00:00 [revised] PHST- 2011/11/07 00:00 [accepted] PHST- 2011/12/16 06:00 [entrez] PHST- 2011/12/16 06:00 [pubmed] PHST- 2012/06/22 06:00 [medline] AID - S1558-7673(11)00102-9 [pii] AID - 10.1016/j.clgc.2011.11.002 [doi] PST - ppublish SO - Clin Genitourin Cancer. 2012 Mar;10(1):26-31. doi: 10.1016/j.clgc.2011.11.002. Epub 2011 Dec 13.