Preliminary Clinical, Pharmacokinetic (PK) and Pharmacodynamic (PD) Results of the Safety Run-In Part of a Phase II Trial of Orally Available MEK-Inhibitor MSC1936369 in Patients (Pts) with Advanced Hematological Malignancies (HM)

MSC1936369 is a selective non-competitive inhibitor of MEK1/2 with anti-proliferative activity in leukemia cell lines and in human tumor xenograft models with activation of mitogen-activated protein kinase (MAPK) signaling. We present the preliminary data of the safety run-in part of the phase II trial, in which the primary objective is to determine the maximum tolerated dose (MTD) for different dosing schedules (S). Methods: MSC1936369 was administered orally twice per day (BID), either on days 1–5, 8–12, 15–19 and 22–26 (S1) or on days 1–21 (S2) of a 28-day cycle. Dose escalation within each S followed a modified Fibonacci scheme with 3+3 cohorts. PK samples and peripheral blood leukemia blasts for the measurement of phosphorylated extracellular signal-regulated kinase (pERK) were collected for all pts. Results: 48 pts have been treated, 25 in S1 (8–42 mg BID) and 23 in S2 (8–60 mg BID). Pt characteristics, treatment exposure, and safety signals were similar in both Ss. The median age was 67 years (range 22–80), 66% were male and the Eastern Cooperative Oncology Group Performance Status was 0/1/2 in 25%/58%/17% of pts, respectively. Underlying HMs were: acute myeloid leukemia (AML, n=41), myelodysplastic syndrome (MDS, n=3) and other (n=4). Cytogenetics were known for 42/44 pts with MDS (n=3) and AML (n=39): 3 were favorable, 21 intermediate and 18 unfavorable. RAS mutation was present in 5 pts (not reported in others), of whom 2 also carried a FLT3 mutation. Six additional pts had a FLT3 mutation. The median duration of treatment was 3.7 weeks (range 0.1–77). The MTD has not been reached in either S. One dose-limiting toxicity (DLT) of grade 2 angioedema was seen in S1 at 42 mg BID. The most common non-hematological adverse events (AEs): infections (56%), diarrhea (46%), skin rash (38%), nausea (27%), pyrexia (25%), peripheral edema (21%), dizziness (21%), aspartate aminotransferase increase (21%) and transient visual disorders (with underlying serous retinal detachment in most cases) (21%). Plasma concentrations increased proportionally with dose. Sustained pERK inhibition during the dosing period was observed in blasts and lymphocytes starting at 23 mg BID. Transient clearance or 50% decrease of blasts in bone marrow and peripheral blood have been detected in 6 pts (MDS n=2, AML n=4), 2 RAS mutated. Conclusions: MSC1936369 in intermittent Ss is well tolerated with reversible mild or moderate AEs, PD effect during dosing and signals of activity have been seen. Dose escalation continues in intermittent Ss. Continuous dosing is being introduced. Molecular genotyping is ongoing.

Ravandi:EMD Serono Inc: Research Funding. Luepfert:Merck KGaA: Employment. Asatiani:Merck Serono SA: Employment. Donica:Merck Serono SA: Employment. Kantarjian:Novartis, Pfizer, BMS: Consultancy, Research Funding. Smith:infinity, genzyme, synta, celator, BMS, novartis: Research Funding; celgene, BMS, novartis: Membership on an entity's Board of Directors or advisory committees.