A Phase 1 Trial of Duvelisib and Oral Azacitidine in Relapsed/Refractory T‐Cell Lymphoma

Mature T-cell lymphomas (TCL) are aggressive malignancies with limited effective therapies. Duvelisib (DUV), a dual inhibitor of PI3K-δ and PI3K-γ, has shown promising activity in TCL. Azacitidine (AZA), a hypomethylating agent, has demonstrated efficacy in TCL and may enhance the activity of PI3K inhibitors through epigenetic modulation and immune regulation. We conducted a phase I, open-label, 3 + 3 dose-escalation study of oral duvelisib in combination with oral azacitidine (BMS-986345) in patients with relapsed or refractory TCL. The primary objective was to identify the maximum tolerated dose (MTD) of the combination. Fourteen patients (N = 14) were enrolled with a median age of 63.5 years. The median number of prior therapies was two. Grade ≥ 3 toxicities, expressed for the full treated population (N = 14), included neutropenia (29%), anemia (21%), AST elevation (21%), ALT elevation (14%), thrombocytopenia (14%), and leukocytosis (14%). Most adverse events were grade 1-2 and manageable. The ORR was 46% (N = 6), with 31% (N = 4) complete responses (CR) and 15% (N = 2) partial responses (PR). All four evaluable patients with a T-follicular-helper (TFH) phenotype achieved CR, a hypothesis-generating observation given the small denominator. Median PFS was 2.2 months (95% CI 1.8-NE) and median OS 10.2 months (95% CI 6.3-NE); however, median duration of response was not reached, and three responders were censored at the time of allogeneic transplant. On-treatment suppression of AKT phosphorylation was enhanced during combined therapy. Duvelisib plus oral azacitidine had a manageable safety profile and encouraging activity, particularly in the TFH subtype, where responses were deep and enabled a bridge to allogeneic transplant. Randomized evaluation focused on the TFH subtype is warranted. TRIAL REGISTRATION: NCT05065866.