Multicenter, triple-arm, single-stage, phase II trial to determine the efficacy and safety of everolimus (RAD001) in patients with refractory bone or soft tissue sarcomas including GIST.
Authors: S. Richter, D. Pink, P. Hohenberger, H. Schuette, P. G. Casali, A. Pustowka, P. Reichardt
Journal: Journal of Clinical Oncology (2010)

10038^ Background: RAD001 is an orally available inhibitor of mTOR. The PI3K (mTOR) pathway is frequently deregulated in human cancers. The mTOR pathway is involved in the production of pro-angiogenic factors (e.g. VEGF) and inhibits endothelial cell growth and proliferation directly. Recent data with the mTOR inhibitor ridaforolimus demonstrated a single-agent activity in a broad range of sarcomas. Methods: A multicenter, single-stage phase II trial was conducted to determine the efficacy and safety of RAD001 in patients with refractory sarcomas. Patients (pts.) were included in three different arms consisting of bone and soft-tissue sarcomas (I), GIST (II), and alveolar soft part sarcoma (III), respectively. Each arm will be analyzed independently. Arm III is ongoing and data will not be presented. RAD001 was administered once daily at a dose of 10mg. The primary objective was efficacy defined as the proportion of patients with either CR, PR, or SD according to RECIST after 16 weeks. Results: 61 patients (26 male and 25 female; median age 56, [range 26-79]) were included (11 bone, 26 soft tissue sarcomas, 24 GIST). 30 patients (15 bone and soft tissue sarcoma, 15 GIST) are currently evaluable. Treatment was generaly well tolerated with grade 1/2-toxicity in the majority of patients (skin toxicity 18 pts [60%], mucositis 14 pts [47%], fatigue 16 pts [53%], elevation of liver transaminases 15 pts [50%], nausea/vomiting 12 pts [40%], anaemia 9 pts [30%]). Grade 3/4 toxicities occured in 9 patients (pneumonitis, mucositis and anemia in 2 patients each [7%], thrombopenia, lymphopenia and elevation of liver transaminases in 1 patient each [3% respectively]). Efficacy (CR, PR or SD) was seen in 2 / 15 pts. (13%, arm I), and 4 / 15 pts. (27%, arm II), respectively. Conclusions: RAD001 shows acceptable toxicity and displays limited clinical activity in heavily pretreated patients with bone and soft tissue sarcomas. The efficacy in imatinib- and sunitinib-refractory GIST is promising. Full analysis of all patients will be presented. 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 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.