Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial

Abstract

BACKGROUND The prognosis of patients with relapsed Hodgkin lymphoma, especially those who relapsed after stem cell transplant, remains poor, and the development of new agents for this relatively young patient population represents an unmet medical need. In this study, we examined the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin lymphoma METHODS Patients with relapsed or refractory classical Hodgkin lymphoma aged 18 years or older were treated with mocetinostat administered as an oral dose three-times weekly, in 28-day cycles. Two dose cohorts were evaluated (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary objective was to estimate the disease control rate induced by mocetinostat, defined as CR, PR or SD (for at least 6 cycles) analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982 FINDINGS A total of 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, 28 additional patients were treated with a reduced dose of 85 mg to improve treatment tolerance. Based on intent to treat analysis, the overall disease control rate was 34.8% and 25% for the 110 mg and 85 mg groups, respectively. Thirty-four out of 42 (81%) patients who completed at least 2 cycles of therapy had a decrease in their tumor measurements. Forty-seven percent (24/51) discontinued therapy due to disease progression, 57% (16/28) in the 85 mg cohort and 34% in the 110 mg cohort. Twenty-four percent (12/51) discontinued due to adverse events, 32% (9/28) in the 85 mg cohort and 13% (3/23) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events included neutropenia, which was observed in 4 (17.4%) patients in the 110 mg group and in 3 (10.7%) patients in the 85 mg group; fatigue (in 5 (21.7%) of the 110 mg group vs 3 (10.7%) of the 85 mg group); and pneumonia (4 (17.4%) of the 110 mg group vs 2 (7.1% of the 85 mg group). Four patients, all in the 110 mg cohort, died during study, of whom two were considered possibly related to treatment. INTERPRETATION Mocetinostat 85 mg three-times weekly has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin lymphoma. FUNDING MethylGene Inc., Montreal, Canada; Celgene Corporation, Summit, New Jersey; Tufts Medical Center, Boston, MA

The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

“…121 These findings were paralleled in phase 2 studies of mocetinostat and panobinostat, in which treatment-induced decreases in TARC correlated with reductions in tumor burden and progression-free survival. 122,123 HDAC inhibition can also reinvigorate exhausted T cells in CHL by upregulating OX40 on RS cells 124 and by downregulating PD-1 expression on CD4+ and CD8+ T cells. 125 Finally, HDAC inhibition may selectively deplete Tregs by suppressing FoxP3…”

Single or tandem autologous stem-cell transplantation for first-relapsed or refractory Hodgkin lymphoma: 10-year follow-up of the prospective H96 trial by the LYSA/SFGM-TC study group

“…Besides BV, many new drugs, including histone deacetylase inhibitors (mocetinostat and panobinostat), 28,29 everolimus, 30 bendamustine, 31 and PD-1-blocking antibodies (nivolumab 32 and pembrolizumab 33 ), have shown activi ty in relapsed/refractory HL and could be used either to increase the rate of CR prior to ASCT, or as consolidation therapy after ASCT.…”

Új lehetőségek a refrakter és relabált Hodgkin-lymphomás betegek kezelésében

“…Terápiás lehetőségként a hisztondeacetiláz-gátlók használata szá-mos hematológiai betegségben kipróbálásra került. Jelenleg mintegy 18 HDACi ismert, amelyek közül a panobinostat, entinostat, mocetinostat és a vorinostat került kipróbálásra HL-ben, de, sajnos, nem váltotta be a hozzá fűzött reményeket, az ORR mindössze 16-27% [42,43,44].…”