A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma

Abstract

Summary Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70–110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18.9% (7.2, 32.2) for the DLBCL cohort (n = 41), and 11.5% (1.7, 20.7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54.1% and 73.1% of patients derived clinical benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, respectively. Progression-free survival ranged from 1.8 to 22.8 months and 11.8 to 26.3 months in responders with DLBCL and FL, respectively. The most frequent treatment-related adverse events were fatigue (75.0%), nausea (69.4%) and diarrhoea (61.1%). Although mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clinical benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.

The HDAC6‐selective inhibitor is effective against non‐Hodgkin lymphoma and synergizes with ibrutinib in follicular lymphoma

“…In a phase II study, eight of 20 patients with FL (40%) demonstrated response to vorinostat but among patients with DLBCL the response rate was 6% (1/18) . Interestingly, in a phase II study of patients with relapsed or refractory NHL, mocetinostat had a 23.5% response rate in patients with DLBCL and a 10% response rate in FL . Overall, these data prompt us to explore whether inhibitors of different classes of HDACs may work differentially in different NHL subtypes.…”

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ25‐35‐induced anxiety and cognitive deficits in a mouse model

“…The administration of MGCD0103 attenuated the anxiety and cognitive deficits that accompanied a decrease in serotonergic neuron loss in the raphe nucleus of oligomeric Aβ 25‐35 ‐treated mice. The most common manageable side effects of MGCD0103 therapy at doses 70‐110 mg (orally 3 times a week in 28‐day cycles) in tumor therapy are fatigue, nausea, and vomiting . The dose (0.5 mg/kg once daily) we applied to the mice in this study was much lower than the doses in the treatment of tumors.…”

“…The elimination half‐life in plasma of MGCD0103 is 7‐11 hours . Chronic intrathecal delivery (4 weeks Alzet minipumps) of MGCD0103 (30 or 60 nmol/d) was administrated into the spinal cord of nerve injury rats .…”

“…The elimination half-life in plasma of MGCD0103 is 7-11 hours. [22][23][24] Chronic intrathecal delivery (4 weeks Alzet minipumps) of MGCD0103 (30 or 60 nmol/d) was administrated into the spinal cord of nerve injury rats. 25 In addition, four HDACi (BML210, MGCD0103, PXD101, Droxinostat) in three different doses (high, medium, and low dose based on IC50) were screened using mouse primary hippocampal neuronal culture ( Figure S1).…”

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

“…Mocetinostat is an investigational HDAC inhibitor that targets class I and class IV HDACs (isoforms 1, 2, 3, and 11), and has demonstrated antitumor activity in patients with hematologic malignancies . In vivo, mocetinostat induces cell cycle arrest and apoptosis and inhibits tumor growth .…”