A Phase Ib Study Of The Mek Inhibitor Gsk1120212 Combined With Gemcitabine In Patients With Solid Tumors: Interim Results

278 Background: GSK1120212 (212) is a reversible, allosteric inhibitor of MEK1/MEK2. The objectives of this open-label, single-arm study are to evaluate the safety, pharmacokinetics (PK), and anti-tumor activity of 212 + gemcitabine (gem), and to determine the recommended phase II regimen (RP2R) in patients (pts) with advanced solid tumors. Methods: 212 (1-2.5mg) is given continuously, orally, once daily. Gem (1,000mg/m 2 ) is infused on days 1, 8, and 15 every 28 days. Doses are escalated to the maximum tolerated dose (MTD) and followed by an expansion cohort to confirm the RP2R tolerability. Results: 28 pts received ≥ 1 dose of 212 + gem, including 8 pancreatic, 6 breast, and 4 non-small cell lung (NSCLC) cancer pts. The MTD and RP2R is 2mg 212 + 1,000mg/m 2 gem. Dose-limiting toxicities (DLTs) are G3/G4 febrile neutropenia (n=2), G3 AST elevation (n=2), and G2 uveitis (n=1). 16 serious adverse events (SAEs) were reported; 5 were considered to be related to study drugs (1 pneumonitis, 3 febrile neutropenia, 1 dyspnea). All DLTs and SAEs have resolved. The most common AEs at the RP2R (n=18) were rash (78%), fatigue (67%), thrombocytopenia (61%), neutropenia (50%), decreased appetite (50%), nausea (44%), diarrhea and constipation (39%); all ≤ G2 except thrombocytopenia (17% ≥ G3) and neutropenia (33% ≥ G3). Co-administration did not affect the PK profiles of 212 or gem. 25 pts had measurable disease at baseline. 1 pancreatic cancer pt with previous radiotherapy and 2 cycles of gem achieved a partial response and stayed on study for 6 months. 3 additional pancreatic cancer pts reported stable disease; 2 of which were on the study for 3.5-5 months and the third pt continues in the study. 1 triple-negative breast cancer pt, refractory to chemotherapy, and 1 parotid cancer pt experienced a complete response of their target lesions. Conclusions: 212 + gem is tolerable with an acceptable safety profile in this pt population, with evidence of clinical activity in pancreatic cancer. A randomized phase II study in previously untreated patients with metastatic pancreatic cancer is underway to investigate the clinical activity of this combination. [Table: see text]