Phase 1 study of NEDD8 activating enzyme inhibitor pevonedistat in combination with chemotherapy in pediatric patients with recurrent or refractory solid tumors (ADVL1615).

Purpose: The objective of this study was to determine the recommended Phase 2 dose (RP2D) of pevonedistat, a first in class inhibitor of NEDD8 activating enzyme, in combination with irinotecan (IRN) and temozolomide (TMZ) in children with cancer.

Methods: This Phase 1 study used a rolling 6 design to evaluate escalating doses of pevonedistat in combination with standard doses of IRN and TMZ in pediatric patients with recurrent/refractory solid or CNS tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50 mg/m) and TMZ (orally, 100 mg/m), on days 8-12 of a 28-day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN/TMZ on days 1-5 of a 21-day cycle.

Results: Thirty patients enrolled; all were eligible and evaluable for toxicity. Six patients each enrolled on pevonedistat dose levels (DL) 1 (15 mg/m), 2 (20 mg/m), 3 (25 mg/m) and 4 (35 mg/m) as well as an expanded pharmacokinetic (PK) cohort at DL4. The maximum tolerated dose (MTD) was not exceeded. 2/12 (17 %) patients treated at the RP2D (35 mg/m) experienced a cycle 1 dose limiting toxicity (DLT). IRN is unlikely to affect the pharmacokinetics of pevonedistat. Two patients had a partial response and 6 patients had prolonged stable disease (> 6 cycles).

Conclusions: Pevonedistat in combination with IRN/TMZ is well tolerated in children with solid or CNS tumors. The RP2D of pevonedistat is 35 mg/m on days 1, 3, 5 in combination with IRN/TMZ.