A pediatric phase I study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family.

Abstract

10510 Background: Larotrectinib is the first selective small-molecule inhibitor of TRKA, B, and C in clinical development. Data from the adult phase I trial demonstrate prolonged responses in patients (pts) with TRK fusions and a favorable tolerability profile. Methods: This multicenter, rolling 6 phase I study enrolled pts with refractory solid or CNS tumors aged ≥ 1 month – 21 years. Pts were dosed orally BID on a continuous 28-day schedule either by capsule or solution. Pharmacokinetic (PK)-directed intra-subject dose escalation was permitted, with exposures targeting the adult recommended Phase II dose (RP2D) of 100 mg BID. The primary objective was to define the MTD / RP2D; secondary objectives included PK and efficacy using RECIST v1.1. Results: As of December 31, 2016, 17 pts (12 with TRK fusions, 5 without TRK fusions) with a median age of 5.2 years (0.4 – 18.3) were enrolled to 3 dose levels. Pts were enrolled with fusions of all 3 NTRK genes: NTRK1 (n=6), NTRK2 (n=1), and NTRK3 (n=5) in heterogeneous tumor diagnoses: infantile fibrosarcoma (IFS) (n=6), other sarcoma (n=4), and papillary thyroid cancer (n=2). Most common AEs regardless of attribution were vomiting, diarrhea, and fatigue. While 8 (47%) pts experienced grade 3-4 AEs, none were attributed to larotrectinib. No DLTs were observed and an MTD was not established. Both formulations delivered dose-dependent PK comparable to the adult RP2D at dose level 3. 12 pts (10 with TRK fusions, 2 without TRK fusions) remain on treatment with median follow-up of 2.8 months (0.7 – 8.4). Among TRK fusion pts, the vast majority have achieved confirmed RECIST responses regardless of tumor diagnoses. No responses were seen in pts without TRK fusions (n=4). 5 pts discontinued therapy, including 2 with TRK fusions: 1 pt with IFS had sufficient response to allow tumor resection, and 1 pt with IFS progressed with a documented acquired resistance mutation. Conclusions: Larotrectinib has demonstrated a favorable tolerability profile and histology-independent efficacy in pediatric pts harboring TRK fusions. Updated safety and efficacy data will be presented, including the RP2D, response rate, duration of response, and use of larotrectinib in the pre-surgical setting. Clinical trial information: NCT02637687.