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 [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.

The Histone Deacetylase Inhibitor Romidepsin Spares Normal Tissues While Acting as an Effective Radiosensitizer in Bladder Tumors in Vivo

“…Mocetinostat, class I and IV, is also compromised by severe toxicities. 24 We previously published that IR þ panobinostat delayed bladder tumor growth but did not increase acute and late normal tissue toxicity; however, panobinostat is a pan-HDACi. 11 Thus, finding a more specific HDACi with a lesser extent of normal tissue toxicity in combination with radiation therapy might be better for patients.…”

Precision oncology in urothelial cancer

“…Dysregulated histone acetylation, via upregulation of histone deacetylases (HDACs) and inactivation of HATs, has been associated with cancer pathogenesis of many tumour types through suppression of tumour regulatory genes 40. Although some success has been demonstrated with the use of HDAC inhibitors in the treatment of T-cell lymphoma,40 a recent phase II trial (NCT02236195) involving the use of mocetinostat, an oral HDAC inhibitor, in patients with advanced urothelial cancer harbouring inactivating alterations of acetyltransferase genes, unfortunately failed to show activity in the second-line setting post platinum-based chemotherapy 41. From a total of 17 patients who were recruited into stage 1 of the trial, only one PR was seen among nine evaluable patients 41.…”

“…Although some success has been demonstrated with the use of HDAC inhibitors in the treatment of T-cell lymphoma,40 a recent phase II trial (NCT02236195) involving the use of mocetinostat, an oral HDAC inhibitor, in patients with advanced urothelial cancer harbouring inactivating alterations of acetyltransferase genes, unfortunately failed to show activity in the second-line setting post platinum-based chemotherapy 41. From a total of 17 patients who were recruited into stage 1 of the trial, only one PR was seen among nine evaluable patients 41. These findings highlight the sobering challenges of translating in vitro findings into therapeutically significant outcomes.…”

New and Emerging Therapies in the Management of Bladder Cancer

“…Disruption of this process is implicated in the pathogenesis of urothelial cancer and therefore may be a viable target for new therapies, such as histone deacetylase (HDAC) inhibitors and enhancer of zeste homolog 2 (EZH2) inhibitors 38 . Mocetinostat, a class I/IV HDAC inhibitor, was administered to 17 patients with mUC with progression after platinum-based chemotherapy and an inactivating mutation or deletion in CREBBP, EP300 39 , or both. The ORR was 11% in stage 1 and so the study was terminated.…”