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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.
- Source :
- Investigational New Drugs; Feb2019, Vol. 37 Issue 1, p87-97, 11p
- Publication Year :
- 2019
-
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<superscript>2</superscript> (arm 1) or 20 mg/m<superscript>2</superscript> (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. [ABSTRACT FROM AUTHOR]
- Subjects :
- ANTINEOPLASTIC agents
DOCETAXEL
THERAPEUTIC use of antimetabolites
CANCER chemotherapy
CLINICAL trials
DRUG dosage
DRUG side effects
DRUG toxicity
FATIGUE (Physiology)
ENZYME inhibitors
FEBRILE neutropenia
LIVER diseases
LONGITUDINAL method
MEDICAL quality control
NAUSEA
THROMBOCYTOPENIA
PACLITAXEL
TRANSCRIPTION factors
TUMORS
TUMOR classification
TERMINATION of treatment
TREATMENT effectiveness
CARBOPLATIN
INVESTIGATIONAL drugs
THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 01676997
- Volume :
- 37
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Investigational New Drugs
- Publication Type :
- Academic Journal
- Accession number :
- 135191307
- Full Text :
- https://doi.org/10.1007/s10637-018-0610-0