Entry Detail
| General information | |
| Database: | DB00148 |
| Objective: | Thisphase 1b study determined the safety, tolerability, and recommendedphase 2 dose (RP2D) and schedule of trametinib in combination with gemcitabine. assessment of clinical activity and steadystate pharmacokinetics. |
| Authors: | Infante JR, et al |
| Title: | a phase 1b study of trametinib, an oral Mitogenactivated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours. |
| Journal: | Eur J Cancer. |
| Year: | 2013 |
| PMID: | 23583440 |
| Trial Design | |
| Clinical Trial Id: | NCT01428427 |
| Agent: | trametinib |
| Target: | MEK2 Dual specificity mitogenactivated protein kinase kinase 1 |
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | trametinib+gemcitabine |
| Study Type: | a phase Ib, openlabel, singlearm, doseescalation study |
| Key Patients Feature: | Adults with advanced solid tumours, adequate organ function and Eastern Cooperative Oncology Group performance status (ECOG PS) 1 were eligible. Tumor types:pancreas = 11, breast = 6, non small cell lung cancer (non small cell lung cancer) = 4, other = 10 |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | Oncedaily 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 28day cycles). During expansion, trametinib 2mg was combined with gemcitabine. Pharmacokinetics samples were collected on Day 15 predose and 1, 2, 4 and 6h postdose; tumour assessments were repeated every two cycles. |
| Primary End Point: | primary: the safety, tolerability, and recommendedphase 2 dose (RP2D) and schedule of trametinib in combination with gemcitabine. |
| Secondary End Point: | Secondary:included assessment of clinical activity and steadystate pharmacokinetics. |
| Patients Number: | 31 |
| Trial Results | |
| DLT_MTD: | Doselimiting 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. |
| Objective Response Rate: | 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)). |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Common grade 3/4 toxicities at the RP2D included: neutropenia (38%), thrombocytopenia (19%) and transaminase elevation (14%). |
| Conclusions: | 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 they were manageable, the addition of trametinib may increase gemcitabineassociated myelosuppression. Future studies of this combination will require monitoring to maintain dose and schedule. |