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Ref Type Journal Article
PMID (23583440)
Authors Infante JR, Papadopoulos KP, Bendell JC, Patnaik A, Burris HA, Rasco D, Jones SF, Smith L, Cox DS, Durante M, Bellew KM, Park JJ, Le NT, Tolcher AW
Title A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours.
Journal European journal of cancer (Oxford, England : 1990)
Vol 49
Issue 9
Date 2013 Jun
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Gemcitabine + Trametinib Phase Ib/II Actionable In a Phase Ib trial, the combination of Mekinist (trametinib) and Gemzar (gemcitabine) demonstrated safety and preliminary anti-tumor activity in patients with advanced solid tumors (PMID: 23583440). 23583440
Unknown unknown breast cancer not applicable Gemcitabine + Trametinib Phase Ib/II Actionable In a Phase Ib clinical trial, the combination of Mekinist (trametinib) and Gemzar (gemcitabine) demonstrated safety and preliminary anti-tumor activity in patients with advanced solid tumors, including one complete response in a patient with breast cancer (PMID: 23583440). 23583440
Unknown unknown pancreatic cancer not applicable Gemcitabine + Trametinib Phase Ib/II Actionable In a Phase Ib trial, a partial response was seen in 30% (3/11) of patients with pancreatic cancer after treatment with Mekinist (trametinib) in combination with Gemzar (gemcitabine) (PMID: 23583440). 23583440