Multicenter, single-arm, two-stage phase II trial of everolimus (RAD001) with imatinib in imatinib-resistant patients (pts) with advanced GIST.
Authors: P. Hohenberger, S. Bauer, V. Gruenwald, J. T. Hartmann, E. Jaeger, O. G. Ottmann, C. Hosius, C. May, A. Pustowka, P. Reichardt
Journal: Journal of Clinical Oncology (2010)

10048^ Background: In 2002, imatinib was approved for treating adult patients with KIT (CD 117)-positive unresectable and/or metastatic GIST and is since then considered as gold standard. For pts failing imatinib at a dose of 400 mg/day, dose escalation to 800 mg/day is recommended before switching to second-line treatment with sunitinib. Combination studies on imatinib plus RAD001 have revealed that their synergistic actions may safely and effectively inhibit GIST growth. RAD001 phase I study data suggest that more frequent dosing is likely to achieve a significant increase in the previously observed pharmacodynamic and synergistic effects. Methods: A multicenter, single-arm, Simon two-stage, phase II trial was conducted to determine the efficacy and safety of RAD001 plus imatinib in GIST pts whose disease has recurred or progressed under 400 mg/day of imatinib during at least a 2 months treatment period. Daily doses were 2.5 mg for RAD001 and 600 mg for imatinib, respectively/day. PFS at week 16 was the primary objective. To continue into stage 2, ≥ 7 responders (SD, CR. PR) out of 24 pts were required. Results: 28 patients (17 male and 11 female) were screened, and 27 pts entered the treatment between Jan 2007 and Sep 2008. Mean age was 59y (range 30–80y ). Mean time between diagnosis and randomization was 39,9 months. Primary site of GIST: stomach = 14, small intestine = 8, duodenum = 2, rectum, oesophagus, mesentery, other = 1. The best response at 16 weeks was SD, detected in 9 pts. 18 pts showed PD at 16 weeks. One patient harbouring an exon 12 mutation is still free of progression at 33 months. Manageable adverse events were experienced in 100% pts with anemia, diarrhea, nausea, flatulence, vomiting, and fatigue being the most common. Conclusions: Based on the number of responders (9 SD/27 pts) the statistical goal to continue into the second stage was reached. No toxicity-related discontinuation of treatment was observed. Due to the absence of any partial responses and an increasing number of treatment options for imatinib-resistant GIST pts, the second stage of the trial was not initiated. However, the drug combination can still be considered an option in selected single pts. 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. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis 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 2010 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.