E. Stein, M. Tallman, D. Pollyea
Oct 1, 2014
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Influential Citations
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Cancer Research
Abstract
Background: Cancer metabolism represents an emerging field of novel cancer target discovery. Somatic point mutations in the metabolic enzymes isocitrate dehydrogenase 1/2 (IDH1/2) confer a novel gain-of-function in cancer cells, which results in the accumulation and secretion of the onco-metabolite, R-2-hydroxyglutarate (2-HG). High levels of 2-HG have been shown to inhibit α᠄KG dependent dioxygenases including histone and DNA demethylases, which regulate the epigenetic state of cells and result in altered cellular differentiation. IDH2 mutations have been identified in a spectrum of solid tumors and hematologic malignancies including chondrosarcoma, glioblastoma, acute myeloid leukemia (AML), and myelodyplastic syndromes (MDS). AG-221 is the first IDH mutant inhibitor in clinical trials; it is an oral, potent, reversible, and selective inhibitor of the mutated IDH2 protein. In a primary human AML xenograft model, AG-221 treatment reduced 2-HG levels and demonstrated a dose dependent survival benefit. Early results of the ongoing first in human phase I study of AG-221 in patients with advanced IDH2 mutant positive hematologic malignancies are reported here. Study Methods: This phase I study of oral AG-221 is designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) including assessment of 2-HG levels, and clinical activity in patients with advanced hematologic malignancies. AG-221 is administered orally 2 times per day (BID) in continuous 28-day cycles. Sequential cohorts of up to 5 PK-evaluable patients are enrolled at higher dose levels, followed by multiple planned expansion cohorts. The eligible patient population includes those with relapsed or refractory AML, myelodysplastic syndromes (MDS,) and elderly untreated AML that harbor an IDH2 mutation. Blood and bone marrow is collected at multiple time points for determination of the PK and PD effects of AG-221. Response assessments via bone marrow examination are performed on Days 15, 29, 57, and every 56 days (2 cycles) thereafter. Study Status and Results: The study was activated in September 2013. As of February 26th 2014, a total of 19 patients have been enrolled; 18 with AML and 1 with MDS. All patients were IDH2-mutant positive by local testing. AG-221 doses administered included 30 mg BID (n=7), 50 mg BID (n=5), 75 mg BID (n=5), and 100 mg QD (n=2). Two patients were added to the 30 mg BID cohort to replace PK-unevaluable patients. Fourteen of 19 patients remain on study drug treatment. Therapy has been well tolerated; with no dose-limiting toxicities reported. The maximum tolerated dose has not been reached. Possible drug-related severe adverse events were reported in two patients: grade 2 hyperleukocytosis and grade 3 confusion. In the first cohort there were three deaths due to sepsis within 30 days of study drug termination. One of these was attributed as possibly related to study drug treatment. Preliminary analysis of PK at 30 and 50 mg doses demonstrated excellent oral AG-221 exposure and a mean plasma half-life of greater than 40 hours. Evaluation of the PD response demonstrated sustained reduction in 2-HG plasma levels of up to 97% following AG-221 dosing in cohort 1 and 2. Ten AML patients are evaluable for efficacy at this time: (N=5 at 30 mg BID, N=5 at 50 mg BID), 5 men and 5 women, with a median age (range) of 62.5 years (53-74). Eight patients had an R140Q mutation and two had a R172K mutation. The median number of prior regimens was 2 (1-4) including one patient who had relapsed after an allogeneic bone marrow transplant. Currently, 6 of 10 patients have had objective responses, including 2 complete remissions defined by the International Working Group Criteria (1 at 30mg BID and 1 at 50mg BID). The four other responses are ongoing and will be updated. Marked differentiation of myeloblasts into mature forms, consistent with preclinical models, was associated with responses. Only one patient experienced disease progression. One patient with a CR was removed from study to undergo allogeneic BMT. Five of the 6 responding patients remain on AG-221. Dose escalation continues along with exploration of a once daily dosing regimen. Expansion cohorts are being planned. Conclusions: AG-221, a novel, oral, potent IDH2 mutant inhibitor is well tolerated and shows promising initial clinical and pharmacodynamic activity in patients with relapsed and refractory IDH2 mutant hematologic malignancies, even in the lowest dose cohort. These data provide early validation of mutant IDH2 as a therapeutic target in hematologic malignancies. Additional safety and efficacy data from the ongoing study will be presented. Clinical Trial Information: NCT01915498 Citation Format: Eytan Stein, Martin Tallman, Daniel A. Pollyea, Ian W. Flinn, Amir T. Fathi, Richard M. Stone, Ross L. Levine, Samuel Agresta, David Schenkein, Hua Yang, Bin Fan, Kate Yen, Stephane De Botton. Clinical safety and activity in a phase I trial of AG-221, a first in class, potent inhibitor of the IDH2-mutant protein, in patients with IDH2 mutant positive advanced hematologic malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT103. doi:10.1158/1538-7445.AM2014-CT103