Multicenter phase II study of RAD001 for previously treated metastatic gastric cancer (MGC): Preliminary results
Authors: K. Muro, N. Boku, Y. Yamada, T. Nishina, T. Doi, H. Takiuchi, T. Tajima, A. Takahashi, Y. Fujita, A. Ohtsu
Journal: Journal of Clinical Oncology (2008)

4541 Background: RAD001 (everolimus) is an oral inhibitor of the mTOR (mammalian target of rapamycin) serine-threonine kinase, a downstream component of the PI3K/AKT signaling pathway that plays a critical role in regulation of protein synthesis and ultimately in cell growth, metabolism and proliferation, as well as angiogenesis. This pathway is deregulated in gastric cancer cells and RAD001 has shown anti- cancer effect in in vitro and in vivo models of gastric cancer. Remarkable response was seen in a MGC pt entered in the previous phase I study. To evaluate the activity and safety of RAD001 monotherapy, a multi-center phase II study for pretreated pts with MGC was conducted. Methods: Eligibility criteria included histologically proven MGC with at least 1 measurable lesion per RECIST; 1 or 2 prior chemotherapy regimens; documented progressive disease during/after last prior chemotherapy; and ECOG PS =0 or 1. RAD001 was administered orally once daily at a dose of 10 mg per day. The primary efficacy endpoint was disease control rate (DCR) defined as CR, PR or stable disease (SD) lasting at least 8 weeks, according to RECIST. A Simon 2-stage design (null hypothesis DCR≤30%, 5% type 1 error [one-sided] and 85% power to detect the alternative hypothesis of 50% DCR) was adopted: 21 per-protocol pts in the first stage followed by expanding to 48 per-protocol pts if 8 or more had DC in the first stage. Secondary endpoints included objective response rate, PFS and safety. The influence of gastrectomy on pharmacokinetics and safety was also investigated. Results: As of Dec 12 2007, 24 pts were enrolled: 16 male; median age 63.5 (35–77) years; 1/2 prior regimen (63/38%); prior treatment with fluorouracils (Fus) (TS-1, capecitabine, etc.) + platinum [P] (38%), Fus + P + taxane [T] or CPT-11 (21%), Fus only (33%), and other (8%). Pts have received a median of 52 days of RAD001 (range 6–105+) and 16 pts are still on treatment. Independent radiological review was done in 17 pts who had completed 8 weeks follow-up for efficacy: 10 pts had SD lasting 8 or more weeks (one pt had 29% tumor shrinkage) and 7 pts showed disease progression before week 8. In addition, tumor shrinkage >20% has been reported at week 4 and 8 in 2 pts still to be independently reviewed. Most commonly reported Aes were grade 1/2 stomatitis, rash, anorexia, and fatigue. Grade 3 stomatitis, anorexia, hyponatraemia, and diarrhea were seen in one pt each. No pt required treatment discontinuation due to drug-related Aes. Preliminary PK analysis indicated no significant influence of gastrectomy on plasma drug concentrations based on the comparison between pts with and without gastrectomy. Conclusions: These preliminary results showed that RAD001 monotherapy is generally well tolerated with promising activity in pts with previously treated MGC warranting a continuation of the trial to the second stage. The second stage of the trial is now underway. No significant financial relationships to disclose.