Treatment of relapsed or refractory non-hodgkin lymphoma with the oral isotype-selective histone deacetylase inhibitor MGCD0103: Interim results from a phase II study

Abstract

8528 Background: MGCD0103 is an orally available selective inhibitor of histone deacetylases (HDACs) with significant biological activity in preclinical models of both solid tumors and hematopoietic cancers. Methods: Open-label, Phase II trial in adults (Trial 008) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Eligibility included: ≥1 site of measurable disease (≥2.0 cm), ECOG 0 or 1. MGCD0103 was given 3x/week starting at 110 mg; after 32 patients (pts) the starting dose was reduced to 85 mg. Tumor responses were determined every 2 cycles. PK was evaluated on Day 1, Cycle 1. Results: 50 pts received treatment; 33 DLBCL and 17 FL (median age [range], 61.5 years [32−80]; male, n=27; prior rituximab therapy: 96%; prior stem cell transplant: 33%). The response rate in pts with DLBCL met the protocol defined criteria for expansion beyond 21 pts, and enrollment of this cohort is now complete. Of 17 DLBCL pts with tumor reassessed by CT, most had tumor reduction, including 1 CR & 3 PRs (response rate 23.5%), with progression free survival (PFS) for responders ranging from 168 to >336 days. Five DLBCL pts with stable disease had PFS ranging from 112 to >336 days. One of 10 FL pts with tumor reassessment had a PR. All 50 pts were evaluable for safety: the most common toxicities grade ≥3 were fatigue (14%), neutropenia (12%), thrombocytopenia (10%), and anemia (6%). Comparison of data available to date of the 85 mg and 110 mg cohorts revealed 16% and 53% of patients, respectively, with ≥ grade 3 toxicity. MGCD0103 was rapidly absorbed (median Tmax = 1 hr), and disappeared biphasically (plasma t½, approximately 8 hrs). Similar exposures (Cmax & AUC) were observed at 85 (n=8) and 110 (n=17) mg, suggesting a trend towards saturable absorption. Inhibition of HDAC activity in PBMCs was seen in 13/18 pts (9/13 at 85 mg and 4/5 at 110 mg) and is similar between the group treated with 85 mg or with 110 mg. Conclusions: MGCD0103 demonstrated significant anti-cancer activity in relapsed or refractory NHL (DLCBL and FL subtypes) and had a manageable side effect profile. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MethylGene, Pharmion MethylGene MethylGene