Multicenter, Dose-Escalation Study of the Investigational Drug Tak-733, An Oral Mek inhibitor, in Patients (PTS) with Advanced Solid Tumors: Preliminary Phase 1 Results

Background TAK-733 is an investigational, orally available, selective, non-ATP-competitive, allosteric inhibitor of MEK1/2 shown to have anti-tumor activity in multiple xenograft models. In this first-in-human ph 1 study (NCT00948467), we evaluated safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and efficacy of TAK-733 in pts with advanced solid tumors. Methods Pts aged ≥18 y, with ECOG PS 0–2 and radiographically or clinically evaluable tumors were eligible. Pts received TAK-733 QD on d 1–21 in 28-d cycles; doses escalated in a modified 3 + 3 design based on dose-limiting toxicities (DLTs) in cycle 1 to determine MTD. Plasma and blood samples for PK and PD analysis were collected pre-dose on d 1, 8, 15 and 21 and post-dose d 1 and 21 in cycle 1. Results As of March 16, 2012, 44 pts median age 58 (range 24 - 75) and 50% male, received TAK-733 (dose mg, [n]: 0.2, [1]; 0.4, [1]; 0.8, [2]; 1.6, [2]; 3.2, [4]; 4.4, [4]; 6, [4]; 8.4, [9]; 11.8, [8]; 16, [9]). 2 pts had DLTs (11.8 and 16.0 mg; both Grade 3 acneiform rash); MTD has not been reached. Pts received a median of 2 cycles (range 1-11, 6 pts ≥6 cycles). Safety and PK data are shown in the table. Maximum inhibition (Emax) of ERK phosphorylationin peripheral blood lymphocytes ranged from 21-95% (TAK-733; 0.2-16 mg QD), median Emax were 63%, 78%, and 92% at 8.4, 11.8, and 16 mg, respectively. In 32 evaluable pts, 1 pt (16 mg dose) with melanoma (BRAF L597R) had partial response confirmed at cycle 6 (RECIST v1.1) and is still on treatment at cycle 8; 12 pts had a best response of stable disease. Conclusions These preliminary data indicate that TAK-733 is generally well tolerated and pharmacodynamically active with signs of anti-tumor activity in pts with advanced non-hematologic malignancies. Dose escalation is continuing to determine the MTD. AEs, NCI-CTCAE v4.0 N = 44 Drug-related AE, n (%) 37 (84) ≥15% Dermatitis acneiform 19 (43) Diarrhoea 8 (18) Grade ≥3 drug-related AE, n (%) 7 (16) ≥5% Dermatitis acneiform 2 (5) Creatine phosphokinase evaluation 2 (5) PK data N = 41 Tmax, h 3 T1/2, h 53 Disclosure P.M. LoRusso: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Research Funding (Millennium Pharmaceuticals Inc.). A. Ribas: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Honoraria (Millennium Pharmaceuticals Inc.). J.A. Sosman: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Honoraria (Millennium Pharmaceuticals Inc.). B. Chmielowski: Consultancy within past 2 years (GSK, Genentech, Prometheus, CytRx, Morphotek). Membership on Board of Directors, Speakers Bureau, Advisory Committee (BMS, Genentech, Prometheus). P. Lipman: Employment (Millennium Pharmaceuticals Inc.). X. Zhou: Employment (Millennium Pharmaceuticals Inc.). V. Bozon: Employment (Millennium Pharmaceuticals Inc.). All other authors have declared no conflicts of interest.