Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors

A. Craig Lockhart, Todd M. Bauer, Charu Aggarwal, Carrie B. Lee, R. Donald Harvey, Roger B. Cohen, Farhad Sedarati, Tsz Keung Nip, Hélène Faessel, Ajeeta B. Dash, Bruce J. Dezube, Douglas V. Faller, Afshin Dowlati

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Purpose This phase Ib study (NCT01862328) evaluated the maximum tolerated dose (MTD), safety, and efficacy of pevonedistat in combination with standard-of-care chemotherapies in patients with solid tumors. Methods Patients received pevonedistat with docetaxel (arm 1, n = 22), carboplatin plus paclitaxel (arm 2, n = 26), or gemcitabine (arm 3, n = 10) in 21-days (arms 1 and 2) or 28-days (arm 3) cycles. A lead-in cohort (arm 2a, n = 6) determined the arm 2 carboplatin dose. Dose escalation proceeded via continual modified reassessment. Results Pevonedistat MTD was 25 mg/m 2 (arm 1) or 20 mg/m 2 (arm 2); arm 3 was discontinued due to poor tolerability. Fifteen (23%) patients experienced dose-limiting toxicities during cycle 1 (grade ≥3 liver enzyme elevations, febrile neutropenia, and thrombocytopenia), managed with dose holds or reductions. Drug-related adverse events (AEs) occurred in 95% of patients. Most common AEs included fatigue (56%) and nausea (50%). One drug-related death occurred in arm 3 (febrile neutropenia). Pevonedistat exposure increased when co-administered with carboplatin plus paclitaxel; no obvious changes were observed when co-administered with docetaxel or gemcitabine. Among 54 response-evaluable patients, two had complete responses (arm 2) and 10 had partial responses (three in arm 1, one in arm 2a, six in arm 2); overall response rates were 16% (arm 1) and 35% (arm 2). High ERCC1 expression correlated with clinical benefit in arm 2. Conclusion Pevonedistat with docetaxel or with carboplatin plus paclitaxel was tolerable without cumulative toxicity. Sustained clinical responses were observed in pretreated patients receiving pevonedistat with carboplatin and paclitaxel. ClinicalTrials.gov identifier: NCT01862328.

Original languageEnglish (US)
Pages (from-to)87-97
Number of pages11
JournalInvestigational New Drugs
Volume37
Issue number1
DOIs
StatePublished - Feb 15 2019

Keywords

  • Advanced solid tumors
  • Clinical research
  • Pevonedistat
  • Phase Ib study
  • Standard-of-care chemotherapies

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors'. Together they form a unique fingerprint.

  • Cite this

    Lockhart, A. C., Bauer, T. M., Aggarwal, C., Lee, C. B., Harvey, R. D., Cohen, R. B., Sedarati, F., Nip, T. K., Faessel, H., Dash, A. B., Dezube, B. J., Faller, D. V., & Dowlati, A. (2019). Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors. Investigational New Drugs, 37(1), 87-97. https://doi.org/10.1007/s10637-018-0610-0