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

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 [Cmax ] 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.

Keywords: CREB binding protein (CREBBP); E1A binding protein p300 (EP300); histone deacetylase; mocetinostat; urothelial carcinoma.

Conflict of interest statement

Petros Grivas has served as consultant for Genentech/Roche, Bristol‐Myers Squibb, Merck and Company, AstraZeneca, EMD Serono, Clovis Oncology, Foundation Medicine, Driver Inc, Seattle Genetics, Dendreon, Bayer, Pfizer, Exelixis, QED Therapeutics, and Biocept and received research funding from Genentech/Roche, Bayer, Merck and Company, Mirati Therapeutics Inc, OncoGenex, Pfizer, Bristol‐Myers Squibb, AstraZeneca, and Clovis Oncology for work performed outside of the current study; his institution received research funding from Mirati Therapeutics for work performed as part of the current study. Amir Mortazavi has served as a consultant and advisory board member for Genentech/Roche, received honoraria from Motive Medical Intelligence, and his institution has received research funding from Acerta Pharma, Merck, Genentech/Roche, Novartis, Seattle Genetics, and Bristol‐Myers Squibb for work performed outside of the current study and from Mirati Therapeutics for work performed as part of the current study. Joel Picus's institution has received research funding from Mirati Therapeutics for work performed as part of the current study. Noah M. Hahn has served as a consultant for OncoGenex, AstraZeneca, Merck, Bristol‐Myers Squibb, Genentech, Inovio, Principia Biopharma, Ferring, TARIS, Eli Lilly, Advanced Health, Seattle Genetics, Rexahn Pharmaceuticals, and Pieris Pharmaceuticals, received honoraria from the Bladder Cancer Academy and his institution has received research funding from OncoGenex, Seattle Genetics, Merck, Genentech, Bristol‐Myers Squibb, AstraZeneca, Principia Biopharma, Pieris Pharmaceuticals, and Inovio for work performed outside of the current study and from Mirati Therapeutics for work performed as part of the current study. Matthew I. Milowsky has served as a consultant for BioClin Therapeutics and his institution has received research funding from Acerta Pharma, Astellas, Seattle Genetics, Bristol‐Myers Squibb, Incyte, Merck, Pfizer, and Roche/Genentech for work performed outside of the current study and from Mirati Therapeutics for work performed as part of the current study. Lowell L. Hart's institution has received research funding from Mirati Therapeutics for work performed as part of the current study. Ajjai Alva's institution has received research funding from Mirati Therapeutics for work performed as part of the current study. Joaquim Bellmunt has served as a consultant, member of the advisory board, and provided lectures for Merck; acted as a member of the advisory board and provided lectures for Roche and Pfizer; acted as a consultant and member of the advisory board for AstraZeneca and Pierre Fabre; and acted as a member of the advisory board for Bristol‐Myers Squibb for work performed outside of the current study; and his institution received research funding from Mirati Therapeutics for work performed as part of the current study. Sumanta K. Pal has served as a member of the advisory board for Exelixis, Bristol‐Myers Squibb, Astellas, GlaxoSmithKline, Novartis, and Pfizer and has acted as a member of the advisory board and received honoraria from Genentech for work performed outside of the current study; her institution received research funding from Mirati Therapeutics for work performed as part of the current study. Peter H. O'Donnell owns stock in Allergan; has received honoraria from Algeta ASA, American Medical Forum, Astellas, AstraZeneca/MedImmune, Genentech/Roche, Harrison Consulting, Inovio Pharmaceuticals, Janssen Biotech, Kantar Health, Merck, Novartis, Parexel, Quintiles, Seattle Genetics, and Xcenda; has received travel expenses from Merck; has provided expert testimony for Trinity Health and Temple Health; is a coinventor of a genomic prescribing system (patent pending); and his institution has received research funding from Genentech/Roche, Merck, Boehringer Ingelheim, Acerta Pharma, Seattle Genetics, Janssen Biotech, and AstraZeneca/MedImmune for work performed outside of the current study and from Mirati Therapeutics for work performed as part of the current study. Sumati Gupta's institution received research support from Bristol‐Myers Squibb, Clovis Oncology, Five Prime Therapeutics, Hoosier Oncology Group, Incyte, LSK BioPharma, Merck, Novartis, Pfizer, and Rexahn Pharmaceuticals for work performed outside of the current study and from Mirati Therapeutics for work performed as part of the current study. Elizabeth A. Guancial has served as a consultant for TARIS and as a member of the Speakers' Bureau for Genentech for work performed outside of the current study, and her institution received research funding from Mirati Therapeutics for work performed as part of the current study. Guru P. Sonpavde has served as a consultant for Bristol‐Myers Squibb, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, Pfizer, Biotheranostics, the National Comprehensive Cancer Network, and Astellas/Agensys; acted as a speaker for Clinical Care Options, Physicians Education Resource, Research to Practice, and OncLive; received author royalties from UpToDate; acted as a member of the Data Safety Monitoring Board for AstraZeneca and his institution has received research/clinical trial support from Celgene, Bayer, Onyx‐Amgen, Boehringer‐Ingelheim, Merck, and Pfizer for work performed outside of the current study. Demiana Faltaos is an employee of Mirati Therapeutics Inc. Diane Potvin has acted as a paid consultant for Mirati Therapeutics Inc. James G. Christensen and Richard C. Chao are employees and shareholders of Mirati Therapeutics Inc. Jonathan E. Rosenberg has received trial funding from Novartis and Genentech/Roche; has served as a consultant for Genentech/Roche, Bristol‐Myers Squibb, Merck, AstraZeneca, Inovio, Bayer, Seattle Genetics, Mirati Therapeutics Inc, BioClin, EMD Serono, QED Therapeutics, and Astellas; has received travel funding from Genentech/Roche; and his institution has received research funding from AstraZeneca, Genentech/Roche, Astellas, and Seattle Genetics for work performed outside of the current study and from Mirati Therapeutics for work performed as part of the current study.

© 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Figures

Figure 1

OncoPrint of genetic alterations in 150 of the 155 patients in whom genetic profiling of the tumor was feasible. Alterations included truncating mutations, gene amplifications, homozygous deletions, annotated recurrent missense mutations, and missense variants of uncertain significance (variants of unknown significance were excluded from the main study analysis) that were present in ≥10% of the population. The 150 patients included 144 patients who were tested centrally at Foundation Medicine and 6 patients who were tested at local institutions. An arrow (↓) denotes a patient enrolled in the clinical trial (reports from 5 patients tested locally were not available, including 4 patients who were prescreened using FoundationOne testing and including 2 enrolled patients). aIn cases of CCND1 amplification, this co‐occurred with fibroblast growth factor 3 (FGF3), FGF4, or FGF19 amplification in >80% of cases. In addition, a significant correlation for the co‐occurrence of retinoblastoma protein (RB1) and TP53 mutations and CREB binding protein (CREBBP) and STAG2 mutations and the mutual exclusivity of cyclin‐dependent kinase inhibitor 2A (CDKN2A) homozygous deletion and TP53 mutation or mouse double minute 2 homolog (MDM2) amplification and TP53 mutation was observed. ARID1A indicates AT‐rich interaction domain 1A; CDKN2A/B, cyclin‐dependent kinase inhibitor 2A/B; EP300, E1A binding protein p300; PIK3CA, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase, catalytic subunit alpha.

Figure 2

Patient disposition. aThe safety population and intent‐to‐treat (ITT) population included all patients who received at least 1 dose of the study medication. bThe population evaluable for efficacy included all patients in the ITT population who met prespecified entry criteria and had at least a baseline and 1 on‐study disease assessment that were adequate for evaluation using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1).