Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

Petros Grivas, Amir Mortazavi, Joel Picus, Noah M. Hahn, Matthew I. Milowsky, Lowell L. Hart, Ajjai Alva, Joaquim Bellmunt, Sumanta K. Pal, Richard M. Bambury, Peter H. O’Donnell, Sumati Gupta, Elizabeth A. Guancial, Guru P. Sonpavde, Demiana Faltaos, Diane Potvin, James G. Christensen, Richard C. Chao, Jonathan E. Rosenberg

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study. Methods: Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate. Results: Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [C max ] after TIW dosing of 0.2 ng/mL/mg). Conclusions: To the authors’ knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.

Original languageEnglish (US)
Pages (from-to)533-540
Number of pages8
JournalCancer
Volume125
Issue number4
DOIs
StatePublished - Feb 15 2019

Keywords

  • CREB binding protein (CREBBP)
  • E1A binding protein p300 (EP300)
  • histone deacetylase
  • mocetinostat
  • urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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