Interim Results of a Phase 1 Trial of An Oral Histone Deacetylase Inhibitor Belinostat In Patients with Lymphoid Malignancies.

Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. A phase I study of oral Bel in patients (pts) with solid tumors found a recommended dose for day (d) 1–14, q3w, of 750 mg QD, with allowance for intra-patient dose escalation if limited toxicity. The current study was initiated to assess if the same dose could be utilized in pts with lymphoma.

safety and efficacy assessments of oral Bel in cohorts of 3–6 pts (A 750; B 1000; C 1250; D 1500, E 1750; F 2000), treated d 1–14, q3w in pts with relapsed/refractory non-Hodgkin lymphoma (NHL) or Hodgkin's disease (HD) with evaluable disease and acceptable organ functions.

21 pts, sex (9 F, 12 M) - median age 48 (range 21 – 81), prior regimens, median 5 (range 1 – 13), 12 had BM transplants, including 3 pt with allogeneic have been enrolled. Diagnoses included Mantle Cell lymphoma (MCL; 5 pts), HD (7 pts), other NHL (9 pts).

Median number of Belinostat cycles 3 (range 1–29) 1 pt remains on trial. In 21pts evaluable for tox the most frequent adverse events (regardless of attribution or grade) were: Diarrhea and fatigue (each in 18pts), vomiting (14 pts), cough and constipation (each in 12 pts), anxiety and decreased appetite (each in 11pts). Non-hem gr 3/4 events: 6 pts had gr 3 diarrhea – no dose dependency, – (1 grade 3 diarrhea at 1500-mg dose resulting in hospitalization - DLT) Gr 3 Abdominal pain; cholelithiasis; DVT; hyperthyroidism (each seen in 1 pt;), only gr 4 event was respiratory distress (1 pt in cohort C). Gr 4 Thrombocytopenia (2 pts - Cohort C and E) gr 3 Thrombocytopenia (4 pts - Cohorts, D, E, F) Gr 4 anemia (1 pt - cohort B) Gr 3 anemia (2 pts - Cohort C and D) Leucopenia grade 3 or 4 was not seen-. In 16 pts evaluable for efficacy, stable disease have been noted in 12 pts, including 4- pts with MCL, 4 pts with NHL and 4 with HD. 1 pt with HD had CR after C2 and was treated with additional 2 cycles.

Oral Bel can be administered 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. Protocol defined DLTs have been encountered in the dose range 750 – 2000mg in pts with lymphoma. Cohort D at 1500 mg was expanded due to 1 DLT (diarrhea). Cohort E at 1750 mg was tolerated without DLT and cohort F 2000 mg is currently being investigated. Final evaluation will include additional pts and possible dose escalation. The safety profile and early tumor shrinkage noted in MCL and HD warrants continued evaluation of Bel, especially in combination with other active compounds.

Foss:Allos Therapeutics, Inc.: Consultancy, Speaker. Neylon:Allos Therapeutics, Inc.: Honoraria. Knoblauch:TopoTarget: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.