Final Report of a Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Abstract 3567 Background: Acute lymphoblastic leukemia (ALL) is an aggressive lymphoproliferative disorder, responsive to frontline standard induction and consolidation chemotherapy. However, the prognosis of patients (pts) with relapsed/refractory ALL is extremely poor. Deregulation of the PI3K/Akt/mTOR signal transduction pathway is central to leukemic cell growth, proliferation and survival, and has been implicated in ALL pathogenesis. In a recent phase II study of pts with relapsed/refractory non-Hodgkin lymphoma, single agent mTOR inhibitor everolimus showed ORR 30% and acceptable toxicity in 77 heavily pretreated pts (Witzig TE et al, Leukemia 2011; 25,341–7). The purpose of this study was to establish the safety and efficacy of everolimus in combination with hyper-CVAD in pts with relapsed/refractory ALL, and to study effects of everolimus on AKT/mTOR signaling in ALL blasts. Methods: In this single center phase I/II study, pts aged 10 years or older with relapsed/refractory ALL or lymphoblastic lymphoma were treated with oral everolimus at a daily dose of 5 mg or 10 mg in combination with the standard hyper-CVAD regimen (Kantarjian HM et al, J Clin Oncol. 2000 Feb;18(3):547–61) until disease progression or unacceptable toxicity. Primary endpoints were to establish safety (after 2 cycles) and efficacy. Secondary endpoints included assessments of pharmacodynamics and pharmacokinetics. Results: Twelve pts have been enrolled and are evaluable for response. Median was age 24 years (range, 11–59). Five pts had T-ALL and 7 had Philadelphia chromosome negative precursor-B-ALL. Median number of prior treatments was 2 (range, 1–4); 5 pts were 1st salvage attempts. Three pts received everolimus 5 mg/day and 9 were treated with 10 mg/day continuously in combination with hyper-CVAD. Median number of cycles given was 2 (range, 1–4). Median follow-up was 12 months (range, 7–23). Three pts achieved CR (all were 1st salvage attempts) and 1 patient had CRi (second salvage); 2 pts achieved PR. No responses were seen beyond second salvage. Of the 9 pts completing 2 cycles, both EFS and OS were not reached for 3 pts in the 1st salvage, and were 8.5 weeks and 18.5 weeks respectively for pts in second salvage and beyond (P=.01 and P=0.04). Of the 12 pts (including 3 only treated with one cycle), both EFS and OS were not reached for 3 pts in the 1st salvage, and were 10 weeks and 18 weeks respectively for pts in second salvage and beyond (P=0.17 and P=0.05). Treatment-related toxicities in the 9 pts evaluable for MTD (completed 2 cycles) included 3 episodes of grade 3 mucositis, which was a dose-limiting toxicity, 3 episodes of grade 4 infections (sepsis) and 9 episodes of grade 3 infections (neutropenic fever, pneumonia, bacteremia). There was no deaths on-study. Inhibition of mTOR signaling (p-pS6K) was observed in 5 of 8 (62%) patient samples tested, at both the 5 and 10 mg dose levels, suggesting that 5 mg is sufficient to block the pathway. Lack of inhibition of p-pEBP1 and pAKT argues for potential benefit of second generation mTOR inhibitors or dual PI3K/mTOR inhibitors. Conclusions: We conclude that administration of hyper-CVAD plus everolimus is well-tolerated. The study warrants further investigation of next generation mTOR inhibitors in combination with hyper-CVAD for ALL in relapsed and frontline settings. Disclosures: Cortes: Novartis: Consultancy, Research Funding.