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.