Oral histone deacetylase inhibitor HBI-8000 (tucidinostat) in Japanese patients with relapsed or refractory non-Hodgkin’s lymphoma: phase I safety and efficacy

Abstract

Objective HBI-8000 (tucidinostat) is a novel, oral histone deacetylase inhibitor that selectivity inhibits Class I (histone deacetylase 1, 2, 3) and Class II (histone deacetylase 10) with direct anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It has been approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma. Methods This multicenter, prospective phase I dose-escalation trial evaluating the safety of twice weekly HBI-8000 was conducted in Japan. Eligible patients had non-Hodgkin’s lymphoma and no available standard therapy. The primary endpoint was maximum tolerated dose; secondary endpoints included anti-tumor activity, safety and pharmacokinetics. Results Fourteen patients were enrolled in the study. Twelve patients were assessed for dose-limiting toxicity: six patients in the 30 mg BIW cohort had no dose-limiting toxicitys; two of six patients in the 40 mg BIW cohort had asymptomatic dose-limiting toxicitys. Treatment was well tolerated; adverse events were predominantly mild to moderate hematologic toxicities and were managed with dose modification and supportive care. Thirteen patients were included in the efficacy analysis. Objective response was seen in five of seven patients in the 40 mg BIW cohort; three partial responders had adult T-cell leukemia-lymphoma. In the 30 mg BIW cohort, three of six patients had stable disease after the first cycle. Conclusions Treatment with HBI-8000 30 and 40 mg BIW were well-tolerated and safe, with hematological toxicities as expected from other studies of histone deacetylase inhibitor. The maximum tolerated dose and recommended dosage for phase II studies of HBI-8000 is 40 mg BIW. Preliminary efficacy results are encouraging.

Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results

“…In the present study, the dose of 40 mg BIW was determined based on the results from the phase I study of Japanese patients with non-Hodgkin lymphoma, in which 40 mg BIW was tolerable and the ORR for the 40 mg cohort was higher than that for the 30 mg cohort. 31 …”

“…Identifier: NCT02953652 ). The dose, 40 mg twice per week (BIW), was determined based on the result from the preceding phase I study for Japanese patients with non-Hodgkin lymphoma, 31 which was higher than that approved for patients with PTCL in China (30 mg BIW). The data described herein led to the approval of tucidinostat for R/R PTCL by the Japanese Ministry of Health, Labour and Welfare in 2021.…”

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

“…For example, functional dysregulation of histone acetyltransferases has been associated with cancer development, including B-cell [45,46] and T-cell lymphomas [47,48]. In humans, histone modifier gene mutations have been associated with inferior progression-free survival time in patients with T-cell lymphomas [48], and it has been demonstrated that HDAC regulates the expression of BCL6, involved in cell survival and/or differentiation in B-cell lymphoma [49], and HDAC inhibitors have been tried as therapy in humans [50][51][52]. In CML, repression of p16 tumour suppressor gene is regulated by histone H3 acetylation in vitro [53].…”

Targeting Class I Histone Deacetylases in Human Uterine Leiomyosarcoma

“…Tucidinostat (chidamide), as a Class I HDAC inhibitor, has been shown to inhibit a variety of cancer growth [ 41 , 42 , 43 , 44 , 45 , 46 ]. Therefore, we selected Tucidinostat in our in vitro cell model to assess its effect on uLMS cell growth.…”