Phase I study of chidamide (CS055/HBI-8000), a novel histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas

Abstract

3529 Background: Chidamide (CS055/HBI-8000) is a new benzamide type of histone deacetylase (HDAC) inhibitor with low nanomolar activity against HDAC1, 2, 3 and 10. This Phase I study evaluated the safety and tolerability of chidamide in patients (pts) with advanced solid tumors and lymphomas. Methods: 31 pts with refractory or relapsed advanced solid tumors (22) and lymphomas (9) were enrolled in this study. Escalating doses of 5, 10, 17.5, 25, 32.5 and 50 mg Chidamide (each with 3 to 7 pts) were administered orally either twice or three times per week for 4 consecutive weeks every 6 weeks. Results: No dose limiting toxicities (DLTs) were identified in the 2 x per week cohorts (22 pts) up to 50 mg; G2 and G3 hematological toxicities (leukopenia/neutropenia and thrombocytopenia) were observed at 50 mg. DLTs were reported as G3 diarrhea or vomiting in 2 pts in the 3 x per week cohort at 50 mg. Common adverse events were G1/G2, fatigue (n = 11), thrombocytopenia (n = 9), anorexia (n = 8), nausea/vomiting (n = 7), leukopenia/neutropenia (n = 6), hypochromia (n = 6), and diarrhea (n = 5). No cystitis, pericarditis, pericardial effusion or prolonged QTc intervals were observed. Single dose PK analysis in pts with 25, 32.5 and 50 mg revealed T1/2 of 16.8–18.3 h, Tmax of 1–2 h in most cases, and a dose-related increase in Cmax and AUC. Multiple dose PK analysis in pts with 32.5 mg 3 x per week suggested drug accumulation with this regimen. Significant induction of histone (H3) acetylation was observed in peripheral white blood cells, which lasted for 2–3 days in most pts after single dosing. 25 pts with total treatment cycles of 49 (range 1–6) were evaluable for efficacy. 4 pts with T-cell lymphomas (4/5 evaluable) and 1 pt with submandibular adenoid cystic carcinoma achieved PR, and 11 pts (2 B-cell lymphomas and 9 solid tumors) experienced SD. Conclusions: Chidamide was well-tolerated in pts with advanced solid tumors and lymphomas in the tested regimens. In addition, the compound exhibited a relatively long half-life, a long-lasting biomarker response and encouraging antitumor activity at well-tolerated doses. The overall phase I results recommend the 2 x per week regimen for phase II studies. [Table: see text]