Phase 1 Study of NEDD8 Activating Enzyme Inhibitor Pevonedistat in Combination With Chemotherapy in Pediatric Patients With Recurrent or Refractory Solid Tumors (ADVL1615)

Authors

• Jennifer H Foster
• Joel M Reid
• Charles Minard
• Sarah Woodfield
• Kristina Z Denic
• Emasenyie Isikwei
• Stephan D Voss
• Marvin Nelson
• Xiaowei Liu
• Stacey L Berg
• Elizabeth Fox
• Brenda J Weigel

Language

English

Publication Date

9-1-2024

Journal

European Journal of Cancer

DOI

10.1016/j.ejca.2024.114241

PMID

39096851

Abstract

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/m2) and TMZ (orally, 100 mg/m2), 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/m2), 2 (20 mg/m2), 3 (25 mg/m2) and 4 (35 mg/m2) 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/m2) 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/m2 on days 1, 3, 5 in combination with IRN/TMZ.

Keywords

Humans, Female, Male, Child, Antineoplastic Combined Chemotherapy Protocols, Adolescent, Neoplasms, Child, Preschool, Pyrimidines, Cyclopentanes, Neoplasm Recurrence, Local, Irinotecan, Temozolomide, Maximum Tolerated Dose, Drug Resistance, Neoplasm, Young Adult, NEDD8 Protein, Pediatric oncology, Phase 1, Sarcoma, CNS tumors, Drug development

Published Open-Access

yes

Recommended Citation

Foster, Jennifer H; Reid, Joel M; Minard, Charles; et al., "Phase 1 Study of NEDD8 Activating Enzyme Inhibitor Pevonedistat in Combination With Chemotherapy in Pediatric Patients With Recurrent or Refractory Solid Tumors (ADVL1615)" (2024). Faculty, Staff and Students Publications. 8322.
https://digitalcommons.library.tmc.edu/baylor_docs/8322