Preliminary Results of An Ongoing Phase I Trial of Oral Belinostat a Novel Histone Deacetylase Inhibitor in Patients with Lymphoid Malignancies,

Belinostat (Bel) is a pan class I/II histone deacetylase inhibitor with broad preclinical activity. A phase I study of oral Bel in patients (pts) with solid tumors identified a maximum tolerated dose (MTD) of 750 mg orally (PO) daily on days (d) 1–14, of an every 21 day cycle. An allowance for intra-patient dose escalation was permitted as long as the higher dose level was deemed safe and not the maximum administrable dose. The current study was initiated to assess the safety and dosing of Bel in patients with relapsed or refractory Hodgkin and non-Hodgkin Lymphoma. Methods: 3–6 pts per dose cohort were enrolled on study, at the following doses: A 750; B 1000; C 1250; D1500;E 1750; F 2000mg/d. Pts who met eligibility criteria (ANC =; plts =) with evaluable disease were eligible. Definition of dose limiting toxicity (DLT) included: related non-hem grade (gr) 3/4 tox; gr 4 neutropenia > 5 d or with fever > 100.5 °F; gr 4 thrombocytopenia > 7 d.

28 pts, median age 48 (range 21–82),prior regimens: median 5,5 (range 0–13), (17 had BM transplants, including 5 pts with allogeneic) have been enrolled. Diagnoses include: HD (12 pts), mantle cell lymphoma (MCL;5 pts), other NHL (11 pts). Most frequent adverse events seen in > 50% of patients (regardless of attribution or gr) in 28 pts fully evaluable for toxicity: diarrhea (25 pts), anorexia/decreased appetite (24 pts), fatigue (23 pts), nausea (18 pts), vomiting (18 pts), cough (17 pts) and fever (15 pts). Non-hem gr 3 events included diarrhea in 9 pts (evenly distributed over the co-horts), grade 3 diarrhea at 1500 and 2000 mg dose were among the 4 DLT's. 5 pts with gr 3/4 thrombocytopenia (shift from baseline) were seen in cohort C, D, E. 16 pts are evaluable to date, and include r, 1 CR (duration: 2+cycles)in NHL patient, 1 PR (duration: 8 cycles) in HD patient, and stable disease have been noted in 12 patients (duration: 1–24 cycles, median 1,5). Aside from the 1 CR and 1 PR, tumor shrinkage between 25– 50% was noted in 8 pts.

Oral Bel can be delivered safely with a d 1–14, q3w schedule in pts with lymphoma at a daily dose higher than what has been established for pts with solid tumors. MTD for lymphoma pts was established at 1500 mg/d 1–14, q3w. The safety profile and early tumor shrinkage noted in both HD, MCL and other NHL warrants continued evaluation of Bel, especially in combination with other active compounds.

Foss:esai, allos, merck, celgene: Consultancy, Research Funding. Knoblauch:Topotarget: Employment.