Phase 1 open label, dose escalation study of RXDX101, an oral pan-trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.

Abstract

2502 Background: RXDX-101 is an oral small molecule inhibitor of TrkA, TrkB and TrkC, as well as ROS1 and ALK, with high potency and selectivity. RXDX-101 has demonstrated potent pharmacological activity in preclinical studies and has the potential to be first-in-class against the Trk family of kinases. This study aims to determine the MTD, PD, PK, and anti-tumor activity in patients with advanced cancer with applicable molecular alterations. Methods: Phase 1 dose escalation in patients with advanced solid tumors. Patients were treated with RXDX-101, dosed orally once each day in a 4 day on, 3 day off schedule for 3 weeks, followed by a 7 day rest period, in continuous 28-day cycles. A minimum of 3 patients were enrolled at each dose level. Endpoints include safety, PK, and tumor response by RECIST. Results: 17 patients have been treated at 5 dose levels (100, 200, 400, 800, and 1200 mg/m2). RXDX-101 has been well tolerated to date; the MTD has not been reached in this trial. The most common AEs (all grade 1-2), considered possibly treatment-related, included paresthesias, nausea, dysgeusia, and diarrhea. No treatment related grade 3/4 AEs or SAEs were observed; one patient had grade 3 dyspnea considered to be disease-related. No DLTs seen to date. A patient with neuroblastoma (ALK+) has a PR and is in cycle 13. Two patients have prolonged stabilization of their disease and remain on treatment; a patient with NSCLC (ALK+) in cycle 11, and a patient with pancreatic cancer (ROS1+) in cycle 8. PK analysis shows maximum concentrations of RXDX-101 were generally achieved within 2 to 4 hours following dosing. Despite a degree of variability, RXDX-101 exposure (Cmax and AUC) increased with dose, with minimal accumulation following multiple doses. Average terminal half-life was ~21 hours across the dose range of 100 to 400 mg/m2/day, but increased to 32 hours in patients treated with 800 mg/m2/day; steady state was reached within 4-days. Conclusions: RXDX-101 has been well tolerated in patients with advanced solid tumors. Continued clinical development is supported by the tolerability and early evidence of antitumor activity in patients with relevant molecular alterations.