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

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• 作者：Jeffrey R. Infante^a ; ^{jinfante@tnonc.com} ; Kyriakos P. Papadopoulos^b ; Johanna C. Bendell^a ; Amita Patnaik^b ; Howard A. Burris III^a ; Drew Rasco^b ; Suzanne F. Jones^a ; Lon Smith^b ; Donna S. Cox^c ; Michael Durante^c ; Kevin M. Bellew^c ; Joohyun (Jennifer) Park^c ; Ngocdiep T. Le^c ; Anthony W. Tolcher^b
• 关键词：Trametinib ; MAP kinase ; Gemcitabine ; MEK inhibitor ; GSK1120212
• 刊名：European Journal of Cancer
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：49
• 期：9
• 页码：2077-2085
• 全文大小：448 K

文摘

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 (1 mg, 2 mg, 2.5 mg) was escalated in a 3 + 3 design with standard gemcitabine dosing (1000 mg/m² 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/m² 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.