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

• Type of Material: Article
• Authors: A Craig Lockhart, University of Miami; Todd M. Bauer, Tennessee Oncology PLLC; Charu Aggarwal, University of Pennsylvania; Carrie B. Lee, University of North Carolina; R Donald Harvey, Emory University; Roger B. Cohen, University of Pennsylvania; Farhad Sedarati, Millennium Pharmaceuticals, Inc.; Tsz Keung Nip, akeda Development Centre EU; Hélène Faessel, Millennium Pharmaceuticals, Inc.; Ajeeta B. Dash, Millennium Pharmaceuticals, Inc.; Bruce J. Dezube, Millennium Pharmaceuticals, Inc.; Douglas V. Faller, Millennium Pharmaceuticals, Inc.; Afshin Dowlati, Case Western Reserve University
• Language: English
• Date: 2019-02-01
• Publisher: Springer Verlag (Germany)
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s10637-018-0610-0
• Title of Journal or Parent Work: Investigational New Drugs
• ISSN: 0167-6997
• Volume: 37
• Issue: 1
• Start Page: 87
• End Page: 97
• Grant/Funding Information: Research was sponsored by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
• Keywords: CELL LUNG-CANCER; Oncology; RESISTANCE; TAK-924/MLN4924; Clinical research; ERCC1; Pevonedistat; Phase Ib study; Pharmacology & Pharmacy; CHEMOTHERAPY; Life Sciences & Biomedicine; CULLIN-RING LIGASES; Science & Technology; DNA-REPAIR; Advanced solid tumors; NEDDYLATION; MLN4924; Standard-of-care chemotherapies; EXPRESSION
• Research Categories: Health Sciences, Oncology; Chemistry, Pharmaceutical

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.