Phase I study of ceritinib in pediatric patients (Pts) with malignancies harboring a genetic alteration in ALK (ALK+): Safety, pharmacokinetic (PK), and efficacy results.

Abstract

10005 Background: Ceritinib is a potent ALK inhibitor with durable efficacy in adult pts with ALK-translocated non-small cell lung cancer. This report describes the results of a phase I study (NCT01742286) in pediatric pts with ALK-aberrant malignancies: anaplastic large cell lymphoma (ALCL); myofibroblastic tumor (MT)/inflammatory (IMT) rhabdomyosarcoma (RMS) and neuroblastoma (NB). In these tumors ALK aberrations differ: ALCL and IMT carry gene translocations, NB amplifications or mutations, and RMS copy number gain or no change. Methods: This trial enrolled pediatric pts ≥ 1 to <18 yrs. ALK gene aberration was required, except in ALCL and RMS, where ALK+ by immunohistochemistry was sufficient. In a fasted, dose-escalation phase, pts received ceritinib at 300–560 mg/m2/day to determine the recommended dose for expansion (RDE). Pts were assessed for safety, PK and efficacy. Results: Twenty-two pts were enrolled (22 centers in 10 countries) over 13 months including: 2 ALCL, 6 IMT, 1 MT, 7 NB, 6 RMS. Median age was 10 years (range 2-17), 14 were male and 3 were crizotinib-pretreated (1 NB, 2 IMT). Completion of the fasted escalation phase established a RDE of 510 mg/m2. Common adverse events (% Any Grade [G]; G3/4) were diarrhea (86.4; 9.1), vomiting (81.8; 0), nausea (54.4; 0), elevated ALT (45.5; 18.2), abdominal pain (40.9; 9.1), decreased appetite (40.9; 0), elevated AST (36.4; 18.2), pyrexia (36.4; 0), and fatigue (31.8; 0). Two pts had dose limiting toxicity at 560 mg/m2: G3 elevated ALT and persistent G2 abdominal pain. PK at the RDE (AUC and CL/F) was comparable to that reported for adults at this dose. Early data show responses in 2 of 2 pts with ALCL and 4 of 7 pts with MT/IMT (2 CR: 1 in a crizotinib-pretreated pt). To date, one pt with ALK F1174L mutated NB had shrinkage of a retroperitoneal mass; disease progressed in the brain, where lower ceritinib exposure is expected. Dose escalation with food is ongoing. Conclusions: The RDE in children is 510 mg/m2/day without food. The toxicity profile is similar to that in adults. Food may reduce gastrointestinal symptoms and allow further dose escalation. Ceritinib showed efficacy in pediatric pts with ALCL and MT/IMT. Clinical trial information: NCT01742286.