Phase I trial of RAD001 (everolimus) plus sunitinib in patients with metastatic renal cell carcinoma
Authors: G. S. Kroog, D. R. Feldman, G. V. Kondagunta, M. S. Ginsberg, P. M. Fischer, M. J. Trinos, S. Patil, N. M. Ishill, R. J. Motzer
Journal: Journal of Clinical Oncology (2009)

5037^ Background: RAD001 (everolimus) and sunitinib (SUTENT) both have activity in metastatic renal cell carcinoma (mRCC). Combining RAD001 and sunitinib may increase antitumor efficacy by maximizing inhibition of HIF-dependent signaling. The safety and maximum tolerated dose (MTD) of sunitinib in combination with RAD001 was assessed in this phase I trial. Methods:Cohorts of 3–6 patients (pts) with mRCC received sunitinib at 37.5 or 50 mg daily for 4 weeks (wks) followed by 2 wks off with RAD001 administered either daily (2.5 or 5 mg) or weekly (20 or 30 mg). Predetermined dose-limiting toxicities (DLTs) were assessed in the first 6-wk cycle. Serum levels of RAD001 and sunitinib were measured for pts on weekly RAD001. Results: Of 20 pts (median age 62; 13 clear cell (cc) and 7 non-cc RCC) enrolled, 19 are evaluable for DLT including 3 in cohort 1 (2.5 mg RAD001 daily/ 37. 5 mg sunitinib), 2 in cohort 2 (5 mg RAD001 daily/ 37. 5 mg sunitinib), 5 in cohort 3 (20 mg RAD001 weekly/ 37. 5 mg sunitinib; 1 pt too early to evaluate), 6 in cohort 4 (30 mg RAD001 weekly/ 37. 5 mg sunitinib), and 3 in cohort 5 (30 mg RAD001 weekly/ 50 mg sunitinib). On daily RAD001 dosing, 2/2 patients on 5 mg/day experienced grade (G) 3 DLT (thrombocytopenia and mucositis; vomiting). On weekly RAD001 dosing, 2/3 patients on cohort 5 experienced G3 DLT (mucositis; thrombocytopenia with bleeding). 1/6 patients on cohort 4 experienced G3 DLT (febrile neutropenia and mucositis). Therefore, the MTD was cohort 4. However, with chronic treatment, only 1/6 pts at cohort 4 tolerated treatment beyond 4 cycles. Toxicities observed with chronic dosing include: G3 strep viridans endocarditis, G3 gastrointestinal hemorrhage with G4 anemia, and G4 pulmonary embolism. Therefore, we treated 3 more pts at cohort 3. All 6 pts remaining on study, including 2 dose reduced from other cohorts, are on 20 mg RAD001 weekly/ 37. 5 mg sunitinib. 3/5 pts with confirmed partial responses have non-cc RCC (2 chromophobe; 1 papillary). RAD001 blood levels (Cmax and AUC) at 20–30 mg/week were comparable to those seen at 50–70 mg/week in a single agent study. Conclusions: The combination of 20 mg RAD001 weekly/ 37. 5 mg sunitinib is recommended for phase II and shows responses in non-cc RCC. [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .