A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma
Mené sur 25 et 30 patients atteints d'un lymphome réfractaire/récidivant, cet essai de phase I/II évalue la dose maximale tolérée et l'activité clinique de l'abexinostat, un inhibiteur d'histone désacétyase par voie orale
Purpose: Additional targeted therapies are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N=55) with single-agent abexinostat in relapsed/refractory lymphoma. Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30-60 mg/m2 twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/refractory follicular lymphoma (FL) or mantle cell lymphoma (MCL). Results: The recommended phase II dose was 45 mg/m2 twice daily (90 mg/m2 total), 7 days/week given every other week. Of the 30 FL and MCL patients enrolled in phase II, 25 (14 FL, 11 MCL) were response-evaluable. Tumor size was reduced in 86% of FL patients with an investigator-assessed ORR of 64.3% for evaluable patients (intent-to-treat [ITT] ORR 56.3%). Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2-22.3+). Of responding FL patients, 89% were on study/drug >8 months. In MCL, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment-related adverse events (phase II) with ≥10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths. Conclusions: The pan-HDACi, abexinostat, was very well tolerated and had significant clinical activity in FL, including highly durable responses in this multiply relapsed population.