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Borthakur G et al. Proc ASCO 2011;Abstract 6506.

Phase I/II Trial of the MEK1/2 Inhibitor GSK1120212 (GSK212) in Patients with Relapsed/ Refractory Myeloid Malignancies: Evidence of Activity in Pts with RAS Mutation. Borthakur G et al. Proc ASCO 2011;Abstract 6506. Background.

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Borthakur G et al. Proc ASCO 2011;Abstract 6506.

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  1. Phase I/II Trial of the MEK1/2 Inhibitor GSK1120212 (GSK212) in Patients with Relapsed/Refractory Myeloid Malignancies: Evidence of Activityin Pts with RAS Mutation Borthakur G et al. Proc ASCO 2011;Abstract 6506.

  2. 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. • Study Objectives: • Define the recommended Phase II dose (RP2D) of GSK212. • Evaluate pharmacokinetics, toxicity and preliminary activity in patients with previously treated hematologic malignancies. Borthakur G et al. Proc ASCO 2011;Abstract 6506.

  3. Phase I/II Study Design Phase 1 — Dose escalation Phase 2 — Expansion Cohort 1RAS-mutant AML MDS 2 mg QDn = 9 1 mg QDn = 2 RP2D Cohort 2RAS wild type or unknown 3 mg loading1 mg QDn = 3 Cohort 3RAS-mutant CMML 3 + 3 doseescalation Recommended Phase II dose = 2 mg QD ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; MDS, myelodysplatic syndrome Borthakur G et al. Proc ASCO 2011;Abstract 6506.

  4. Patient Characteristics: 2 mg/Day Dose Borthakur G et al. Proc ASCO 2011;Abstract 6506.

  5. Clinical Activity • MLFS = morphologic leukemic-free state • ORR = CR/CRp/MLFS/PR 6 patients not evaluable Borthakur G et al. Proc ASCO 2011;Abstract 6506.

  6. Select Adverse Events* * Occurring in greater than 20% of patients Borthakur G et al. Proc ASCO 2011;Abstract 6506.

  7. Events of Special Interest • Decrease in LVEF • Six percent (3/47) of patients had drug-related left ventricular dysfunction (1 Grade 1 event and 2 Grade 2 events). • Transaminase elevations • Two patients had drug held due to transaminase elevations — on rechallenge, 1 positive and 1 negative. • Ocular toxicity • Central Serous Retinopathy: Fluid accumulation in the macular region between retinal pigment epithelium and out segment. • One patient developed a reversible retinopathy. Borthakur G et al. Proc ASCO 2011;Abstract 6506.

  8. Author Conclusions • Acceptable safety profile: • Monotherapy safety profile suggests potential to combine with other antileukemic therapies • Preliminary efficacy: • Overall response rates of 25 percent (4 of 16) among patients with RAS mutation • Enrolling patients with RAS-mutant AML, MDS and CMML: • Centralized RAS mutation analysis • Up to 30 sites in US and Europe open to accrual Borthakur G et al. Proc ASCO 2011;Abstract 6506.

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