STARTRK-1: Phase 1/2a study of entrectinib, an oral Pan-Trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.

2596 Background: Entrectinib (formerly RXDX-101), a potent and selective small molecule inhibitor of TrkA/B/C, ROS1, and ALK kinases, has demonstrated early clinical activity when orally administered intermittently under fasting conditions (ASCO 2014). In this abstract, we report a companion Phase 1/2a trial of entrectinib administered daily in the fed state. Methods: Pts with advanced solid tumors with molecular alterations in NTRK1/2/3, ROS1 or ALK were treated daily with entrectinib in the fed state. Pts with asymptomatic untreated brain metastases were allowed; pts may have received prior TKI therapy. Endpoints include safety, RP2D, PK, and tumor response Results: Entrectinib was well tolerated across all dose levels. No DLTs or significant safety issues were reported from any cohort. Of 15 pts treated, the majority reported only G1 or G2 AEs. 3 pts reported > G3 AEs (each unrelated to entrectinib). 1 SAE (unrelated) has been reported. Entrectinib was readily absorbed with median Tmax of 4 hr at steady state. Steady state was reached within 7 days of dosing and the estimated t1/2 was approximately 17 hrs. There were dose proportional exposure increases with moderate accumulation (~2x or less) at steady state. 15 pts with various molecular alterations identified by local lab testing were treated in the following dose cohorts (mg/m2): 100 (N = 5), 200 (N = 5), 400 (N = 5). Summary of alterations of enrolled pts: NTRK (point mutation = 5; amplification = 1; rearrangement = 1); ROS1 (SNP = 1); ALK (SNP = 2; ampl = 1; rearr = 4). 3 pts with ALK-rearranged NSCLC failed at least 2 prior ALK inhibitors. No pts with ROS1 rearrangements have been treated. No objective responses observed to date. Conclusions: Entrectinib, administered daily in fed condition, is well tolerated. In STARTRK-1, there have been no responses at doses ≤ 200 mg/m2 (400 mg/m2 cohort recently opened). Doses ≥ 400 mg/m2 were associated with responses in the ALKA-372-001 Phase 1 study. Dose escalation will continue until the RP2D is identified. Thereafter, Phase 2a cohort expansion will begin enrolling pts with NTRK1/2/3, ROS1, or ALK molecular alterations to assess antitumor activity. Clinical trial information: NCT02097810.