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

MSC1936369 is 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 preliminary data from the ongoing safety run in part of a phase II trial. The primary objective of the safety run in part of the trial is to determine the maximum tolerated dose (MTD) for each of 2 different schedules (S).

Patients with advanced hematological malignancies received MSC1936369 orally twice per day, either on days 1–5, 8–12, 15–19 and 22–26 (S1) or on days 1–21 (S2) of a 28-day cycle. For each S independent dose escalation in 3+3 cohorts followed a modified Fibonacci scheme. PK samples and peripheral blood leukemia blasts to measure phosphorylated extracellular signal-regulated kinase (pERK) were collected for all patients.

11 patients were treated in each S at the following dose levels: 8mg, 15mg and 23 mg twice per day. Patient characteristics: median age [range] 64 years [22–73] S1, 67 years [30–76] S2; males 67% S1,70% S2; ECOG PS (0/1/2) 11%/56%/33% S1, 50%/50%/0% S2. The most frequent hematological malignancy was acute myeloid leukemia (AML) 7 patients in S1 and 11 in S2, 3 patients had newly diagnosed AML unsuitable for standard chemotherapy, 15 patients had relapsed/refractory AML. Cytogenetic analysis is available for 15/18 patients: 1 favorable, 8 intermediate, 6, unfavorable. RAS mutation was detected in 3 patients, 2 of whom also carried a FLT3 mutation. At the time of analysis patients had remained on treatment for a median of 4 weeks [range 0.1–17] in S1, and 6 [3-13] weeks in S2. Safety data were available for 19 patients. The most common non-hematological adverse events were diarrhea (44% S1, 40% S2), nausea/vomiting (33% S1, 30% S2) and pyrexia (33% S1, 20% S2). Febrile neutropenia was reported in 10% of patients in S1 and 40% in S2. To date no dose-limiting toxicity (DLT) has been observed. Serous macular detachment (SMD) with transient visual disturbances was reported in 2 patients in S2. SMD is reversible with treatment interruption. Plasma concentrations increase proportionally to dose. pERK inhibition in blasts is being analyzed. Stable disease lasting 12 weeks or more has been reported in 3 patients with relapsed/refractory AML, 1 of 3 patients had transient clearance of blasts from peripheral blood.

MSC1936369 has reversible mild or moderate adverse events when administered twice per day to patients with hematological malignancies. Assessment of the PD effect in blasts and clinical efficacy is ongoing. Dose escalation continues.

Ravandi:Merck Serono: Research Funding. Asatiani:Merck Serono: Employment. Gianella-Borradori:Merck Serono: Employment. Longerey: Merck Serono: Employment.