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 Co-operative Oncology Group performance status (ECOG PS) ⩽ 1 were eligible. Once-daily oral trametinib (1mg, 2mg, 2.5mg) 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 2mg was combined with gemcitabine. Pharmacokinetics samples were collected on Day 15 pre-dose and 1, 2, 4 and 6h 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 2mg 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 2mg 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.
Trial registration: ClinicalTrials.gov NCT01428427.
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