A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours

Purpose: This phase 1b study determined the safety, tolerability, and recommended phase 2 dose (RP2D) and schedule of trametinib in combination with gemcitabine. Secondary objectives included assessment of clinical activity and steady-state pharmacokinetics. Methods: Adults with advanced solid tumours, adequate organ function and Eastern Cooperative Oncology Group performance status (ECOG PS) <= 1 were eligible. Once-daily oral trametinib (1 mg, 2 mg, 2.5 mg) was escalated in a 3 + 3 design with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 of 28-day cycles). During expansion, trametinib 2 mg was combined with gemcitabine. Pharmacokinetics samples were collected on Day 15 pre-dose and 1, 2, 4 and 6 h post-dose; tumour assessments were repeated every two cycles. Results: Between 8/2009 and 11/2010, 31 patients (pancreas = 11, breast = 6, non-small cell lung cancer (NSCLC) = 4, other = 10) were treated. Dose-limiting toxicities (DLTs) occurred in each cohort, and included febrile neutropenia, transaminase elevation and uveitis. The RP2D was declared as trametinib 2 mg daily with standard gemcitabine dosing. Common grade 3/4 toxicities at the RP2D included: neutropenia (38%), thrombocytopenia (19%) and transaminase elevation (14%). Of 10 patients with measurable pancreatic cancer, three partial responses (30%) were documented; two additional patients achieved objective responses (breast, complete response (CR); salivary glands, partial response (PR)). Pharmacokinetics suggested no change in exposures of either drug in combination. Conclusion: Administration of trametinib at its full monotherapy dose of 2 mg daily in combination with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 every 28 days) was feasible. Though most toxicities were manageable, the addition of trametinib may increase gemcitabine-associated myelosuppression. Future studies of this combination will require monitoring to maintain dose and schedule. (C) 2013 Elsevier Ltd. All rights reserved.