Activity and safety of preclinical and a phase 1 study of purinostat mesylate, a uniquely potent and selective hdac i/iib inhibitor in relapsed or refractory lymphoma

Introduction: Purinostat Mesylate (PM) is a uniquely potent and selective HDAC I/IIb inhibitor. This study evaluated the efficacy and safety of PM in preclinical studies and phase 1 clinical trial for the treatment of relapsed or refractory (R/R) lymphoma. Methods: This open-label, non-randomized, first-in-human, phase 1 two-center trial enrolled adult patients with lymphoma who were refractory to or relapsed after ≥1 prior regimens. PM was administered by 30-minute intravenous infusion ranging from 4.0 mg/m2 to 15.0 mg/m2 in a standard 3 + 3 dose escalation design. Eligible patients received a single dose (Day 1) and multiple doses (Day 8, 11, and 15) followed by extended doses (Day 1, 4, 8, 11 in 21-day cycles). Additionally, multiple cell lines, xenograft mouse models of diffuse large B-cell lymphoma (DLBCL) were used to evaluate the PM activity and mechanism in vitro and in vivo. Results: A total of 18 R/R lymphoma patients were enrolled. Among them, 11 patients with R/R DLBCL achieved objective responses rate(ORR) of 63.6% and the disease control rate (DCR) was 72.7% (4 complete remissions [CR], and 3 partial remissions [PR]), and 1 stable disease [SD]). Notably, one patient with double-expression DLBCL who was refractory to two lines of therapy, including chidamide combined with R-CHOP and R-ICE regimen, obtained PR in cycle 3 and CR in cycle 5. Additionally, two out of 4 follicular lymphoma patients relapsed after 2∼3 lines therapy achieved ORR of 50%. Most adverse events (AEs) were grade 1 to 2 and recovered with observation or symptomatic manageme. The most common Grade ≥3 AEs were thrombocytopenia (n = 48.1%), neutropenia (n = 48.1%), and anemia (11.1%), which occurred primarily during the extended dosing stages. Dose limiting toxicities (DLTs) have not been observed with dose escalation to the protocol-set maximum dose of 15.0 mg/m2. Similarly, preclinical studies have also demonstrated the potent therapeutic activity of PM on DLBCL. In vitro, PM had better inhibitory activity against DLBCL cell lines than other HDAC inhibitors, such as chidamide and panobinostat. In several PDX models of DLBCL, the tumors of the PM-treated mice completely regressed, and the activity was significantly superior to selinexor, R-CHOP, and chidamide combined with R-CHOP, with controlled toxicity. Mechanistically, PM can significantly down-regulate the proteins c-MYC, EZH2, and mutated P53, which are closely related to the development of DLBCL. More importantly, we found that PM showed strong inhibitory activity against TP53-mutated DLBCL cell lines. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.