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Metastatic Urothelial Carcinoma and Inactivating Alterations of Acetyltransferase Genes

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Metastatic Urothelial Carcinoma and Inactivating Alterations of Acetyltransferase Genes Original Article Mocetinostat for Patients With Previously Treated, Locally Advanced/Metastatic Urothelial Carcinoma and Inactivating Alterations of Acetyltransferase Genes Petros Grivas, MD1; Amir Mortazavi, MD2; Joel Picus, MD3; Noah M. Hahn, MD4; Matthew I. Milowsky, MD5; Lowell L. Hart, MD6; Ajjai Alva, MD7; Joaquim Bellmunt, MD8; Sumanta K. Pal, MD9; Richard M. Bambury, MB10; Peter H. O’Donnell, MD11; Sumati Gupta, MD12; Elizabeth A. Guancial, MD13; Guru P. Sonpavde, MD8; Demiana Faltaos, PhD14; Diane Potvin, MSc15; James G. Christensen, PhD16; Richard C. Chao, MD17; and Jonathan E. Rosenberg, MD18 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/meta- static 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 pre- treated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting. Cancer 2019;125:533-540. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribu- tion and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. KEYWORDS: CREB binding protein (CREBBP), E1A binding protein p300 (EP300), histone deacetylase, mocetinostat, urothelial carcinoma. Corresponding author: Jonathan E. Rosenberg, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; [email protected] Petros Grivas’s current address: Division of Oncology, Department of Medicine, University of Washington School of Medicine; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Joaquim Bellmunt’s current address: Department of Medical Oncology, IMIM-Hospital del Mar Medical Research Institute, and Dept of Medical Oncology Harvard Medical School, Boston, Massachusetts. Elizabeth A. Guancial’s current address: Florida Cancer Specialists, Fort Myers, Florida. 1 Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; 3 Division of Oncology, Department of Medicine, Washington University in St. Louis, St Louis, Missouri; 4 Departments of Oncology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland; 5 Department of Medicine, Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6 Florida Cancer Specialists, Fort Myers, Florida; 7 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; 8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 9 Department of Medical Oncology, City of Hope, Duarte, California; 10 Department of Medical Oncology, Cork University Hospital, Cork, Ireland; 11 Department of Medicine, University of Chicago, Chicago, Illinois; 12 Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; 13 Department of Medicine, Wilmot Cancer Institute, University of Rochester, Rochester, New York; 14 Clinical Pharmacology, Mirati Therapeutics Inc, San Diego, California; 15 Biostatistics and Data Management, Mirati Therapeutics Inc, San Diego, California; 16 Research, Mirati Therapeutics Inc, San Diego, California; 17 Clinical Development, Mirati Therapeutics Inc, San Diego, California; 18 Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York. We thank the patients and their families who participated in this study, Josée Morin (Excelsus Statistics Inc, Montreal, Quebec, Canada) for her review of the article, and Mary Collier (Mirati Therapeutics Inc) for coordinating the conduct of the trial. This work was supported in part by National Cancer Institute Cancer Center Support grant P30 CA008748. Medical writing services were provided by Siân Marshall (Siantifix Limited, Cambridge, United Kingdom) and funded by Mirati Therapeutics Inc. Additional supporting information may be found in the online version of this article. DOI: 10.1002/cncr.31817, Received: July 16, 2018; Revised: September 7, 2018; Accepted: September 10, 2018, Published online December 20, 2018 in Wiley Online Library (wileyonlinelibrary.com) Cancer February 15, 2019 533 Original Article INTRODUCTION HDAC inhibitors may restore the expression of tumor Worldwide, urothelial carcinoma of the upper urinary suppressor genes, resulting in antitumor responses. tract and bladder results in 165,000 deaths annually.1 The This phase 2 study investigated single-agent moce- majority of patients with metastatic disease experience tinostat in patients with locally advanced or metastatic disease progression despite platinum-based chemother- urothelial carcinoma who previously were treated with apy, and salvage chemotherapy is reported to have only platinum-based chemotherapy and inactivating tumor modest efficacy.2,3 Recently, 5 immune checkpoint inhib- mutations or deletions in CREBBP and/or EP300. itors were approved for patients with platinum-refractory urothelial carcinoma and, although the anti–programmed cell death protein 1 (PD-1) agent pembrolizumab has im- MATERIALS AND METHODS proved overall survival (OS) versus chemotherapy in this Patients and Study Design setting, many patients do not benefit from such therapy.4 The current phase 2, open-label, single-arm, 3-stage, mul- Consequently, new treatment options are needed. ticenter study was conducted between November 2014 and Dysregulated histone acetylation is implicated in July 2016 (ClinicalTrials.gov identifier NCT02236195). the pathogenesis of several cancers, including urothelial Patients with histologically confirmed, locally advanced, carcinoma. Acetylation of chromatin by histone acetyl- unresectable or metastatic urothelial (transitional cell) transferases (HATs) generally is associated with elevated carcinoma who developed disease progression after receipt transcription, whereas deacetylation, mediated by histone of platinum-based chemotherapy were recruited. Eligible deacetylases (HDACs), is associated with repressed tran- patients had adequate bone marrow, hepatic, and renal scription.5,6 Histone acetylation can become dysregu- function and an inactivating mutation or deletion (ho- lated through the upregulation of HDACs and/or genetic mozygous or hemizygous) in CREBBP and/or EP300 (see inactivation of HATs, resulting in the silencing of tumor Supporting Materials). Genomic prescreening of tumor supressor and other genes.5,6 Inhibition of HDAC1 and tissue (primary or metastatic; archival tissue was permit- HDAC2 resulted in antitumor activity in urothelial car- ted if a fresh biopsy was not available) was performed cinoma in vitro, whereas elevated HDAC1 is linked with centrally using next-generation sequencing (Foundation poor prognosis in patients with urothelial carcinoma.7,8 Medicine, Cambridge, Massachusetts) or a sponsor- HDAC inhibitors have demonstrated promise in clinical approved, local sequencing platform (FoundationOne trials across a range of tumor types, and several have been [Foundation Medicine] and MSK-IMPACT [Memorial approved by the US Food and Drug Administration, Sloan Kettering Cancer Center, New York, New York]) including vorinostat for patients with cutaneous T-cell or next-generation sequencing (Oncopanel; Center for lymphoma, romidepsin for patients with cutaneous Advanced Molecular Diagnostics, Brigham and Women’s T-cell lymphoma and peripheral T-cell lymphoma, beli-
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