Phase I/II trial of the MEK1/2 inhibitor GSK1120212 (GSK212) in patients (pts) with relapsed/refractory myeloid malignancies: Evidence of activity in pts with RAS mutation.

Abstract

6506 Background: Signaling through the RAS/RAF/MEK pathway is activated in many human cancers. GSK212 is a potent, selective allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A phase I/II study of a single, daily, oral dosing regimen was conducted to define the recommended phase II dose (RP2D) and evaluate pharmacokinetics, toxicity and preliminary activity in pts with previously treated hematologic malignancies. Results reported are from the RP2D; 2mg/day. Methods: Pts with relapsed/refractory AML, MDS, ALL or CMML with WBC <30,000/µL and adequate hepatic, renal and cardiac function were eligible for this study. Pts were prospectively screened for KRAS mutations at amino acids 12 and 13 using a PCR-based kit and for NRAS mutations at amino acids12, 13, and 61 using sequence analysis. Clinical response was assessed using International Working Group (2003 and 2006) criteria for AML and MDS. Results: 45 pts (30 AML, 12 MDS transformed to AML) received 2mg GSK212 daily. 73% were male; median age 62 (range 21–87) and 93% had received prior therapy. GSK212 exhibited long effective half-life with small peak/trough ratios and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Drug-related adverse events (AEs; >10%) were diarrhea 29% (n=13; 24% Grade 1/2, 4% Grade 3), and rash 22% (n=10; 20% Grade 1/2, 2% Grade 3), myelosuppression was not noted. AEs possibly related to inhibition of MEK signaling were blurred vision (n=3; 4% Grade 1, 2% grade 3) and decreased cardiac ejection fraction (n=1; Grade 3). Conclusions: GSK212 demonstrates encouraging signs of clinical activity with manageable AEs in pts with previously treated AML characterized by somatic RAS mutations. Recruitment of pts with N or KRAS mutant AML/MDS and CMML is ongoing. Best response n=39* N or KRAS mutated n=13 RAS wt or unk n=26 CR/CRp 3 (23%) 0 MLFS 1 (8%) 0 PR 0 2 (8%) HI/HI-N/HI-P 1 (8%) 4 (15%) SD# 7 (54%) 9 (35%) PD 1 (8%) 11 (42%) ORR 31% (95% CI 9%, 61%) 8% (95% CI 1%, 25%) * 6 pts not evaluable were RAS wt/unk; 5 had screen assessments only; 1 lacked follow-up. #Investigator assessed. Abbreviation: MLFS, morphologic leukemia-free state.