MEK (mitogen-activated extracellular signal-related kinase) is downstream of the RAS/RAF pathway and is activated by many upstream oncogenic drivers. GSK1120212 is a potent and selective allosteric inhibitor of MEK 1 and 2 kinases. In vitro, GSK1120212 inhibited proliferation of myeloid cell lines selectively as compared to lymphoid cell lines. This 2 part study of a single daily oral dosing regimen was conducted to define the recommended Phase 2 dose, evaluate pharmacokinetics, and assess preliminary activity in patients with relapsed or refractory AML, MDS, ALL or CMML.
Subjects with WBC< 30,000/uL who met hepatic, renal and cardiac function criteria were eligible for participation. GSK1120212 was given orally, once daily in the following dose cohorts: 3mg loading dose followed by 1mg/day (n=3), 1mg/day without loading dose (n=1), and 2mg/day without loading dose (n=9). The loading dose was discontinued after cohort 1, based on findings in the phase I solid tumor study (J Clin Oncol 28:15s, 2010 (suppl, abstr 2503).
Fourteen subjects (10 with AML, 2 MDS transformed to AML, 1 MDS, 1 ALL) entered the trial. Eight were male, and median age was 65 years (range 33 to 85). Pharmacokinetic analysis showed that, upon repeat dosing, GSK1120212 exposure increased in a dose-proportional manner, had a small peak:trough ratio of approximately 4 and an effective half-life of approximately 7.7 days. Steady state concentrations were reached by day 15. Both single and repeat dose pharmacokinetics of GSK1120212 appeared to be similar to a phase I study in patients with solid tumors. Systemic exposure exceeded concentrations that inhibited in vitro leukemic cell proliferation. At the 2mg/day dose level (n=9), drug-related adverse events were diarrhea (7 overall; 6-Grade 1/2, 1-Grade 3), rash (3-Grade 1/2), fatigue (4-Grade 1/2), visual changes (3 Grade 1/2). One subject experienced a Grade 2 reversible serous retinopathy associated visual changes which resolved after drug discontinuation. One dose limiting toxicity was seen in a subject with disease-related Grade 4 thrombocytopenia and pneumonia who experienced a Grade 5 cerebrovascular accident possibly related to drug. One subject in the 2mg/day cohort achieved a CR; peripheral blast count was reduced from 30% at baseline to 0% and bone marrow blast count was reduced from 50% at baseline to 3%. During this time, platelet count increased from 48K to a maximum of 276K. Initial salutary effect was seen after 2 weeks on therapy and duration of CR was 4 weeks bone marrow blast count was 3% and 5%, respectively, at the beginning and end of the 4 week CR duration.
GSK1120212 administered at 2mg/day orally was tolerable in subjects with relapsed or refractory AML and other leukemias. This dose regimen achieved plasma concentrations sufficient for target inhibition and showed preliminary anti-leukemic clinical activity. Based on these results, a phase II study in AML, MDS and CMML has been initiated.
Borthakur:GlaxoSmithKline: Research Funding. Foran:GlaxoSmithKline: Research Funding. Kadia:GlaxoSmithKline: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Wissel:GlaxoSmithKline: Employment. Cox:GlaxoSmithKline: Employment. Xu:GlaxoSmithKline: Employment. Bauman:GlaxoSmithKline: Employment. Baccus:GlaxoSmithKline: Research Funding. Connor:GlaxoSmithKline: Research Funding. Cortes:GlaxoSmithKline: Research Funding. Kantarjian:GlaxoSmithKline: Research Funding.
Asterisk with author names denotes non-ASH members.