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Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Sarantopoulos, John Shapiro, Geoffrey I. Cohen, Roger B. Clark, Jeffrey W. Kauh, John Sae Wook Weiss, Glen J. Cleary, James M. Mahalingam, Devalingam Pickard, Michael D. Faessel, Hélène M. Berger, Allison J. Burke, Kristine Mulligan, George J. Dezube, Bruce J. Harvey, R. Donald |
| Copyright Year | 2016 |
| Abstract | PURPOSE To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies. EXPERIMENTAL DESIGN Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0. RESULTS Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥ 3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. CONCLUSIONS Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. |
| File Format | PDF HTM / HTML |
| DOI | 10.1158/1078-0432.CCR-15-1338 |
| PubMed reference number | 26423795 |
| Journal | Medline |
| Volume Number | 22 |
| Issue Number | 4 |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/early/2015/12/02/1078-0432.CCR-15-1338.full.pdf |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/22/4/847.full.pdf |
| Alternate Webpage(s) | https://doi.org/10.1158/1078-0432.CCR-15-1338 |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
