All‐Oral PI3Kδ and HDAC Inhibition with Parsaclisib Plus Chidamide and Step‐Down Maintenance in Relapsed or Refractory Peripheral T‐Cell Lymphoma: A Phase Ib Trial

ABSTRACT Single‐agent targeted therapies for relapsed or refractory peripheral T‐cell lymphoma (R/R peripheral T‐cell lymphoma [PTCL]) produce modest, short‐lived responses, underscoring the need for tolerable, chemotherapy‐free combinations. In an open‐label, single‐arm Phase Ib trial at two tertiary hospitals, we evaluated parsaclisib plus chidamide with step‐down maintenance. Adults with R/R PTCL received parsaclisib 10–20 mg once daily plus chidamide 20 mg twice weekly for 8 weeks using 3+3 escalation; patients without progression or unacceptable toxicity continued parsaclisib 2.5 mg once daily plus chidamide 20 mg twice weekly. Primary endpoints were Cycle 1 dose‐limiting toxicities (DLTs), treatment‐related adverse events, and recommended Phase II dose; antitumor activity and biomarker correlates were exploratory. Twelve screened patients were enrolled and treated. One Grade 3 hepatotoxicity DLT occurred; no maximum tolerated dose was reached; parsaclisib 20 mg once daily plus chidamide 20 mg twice weekly was selected for Phase II. No Grade 4 treatment‐related events or treatment‐related deaths occurred. Objective and complete response rates were 58% (95% CI, 28–85) and 42% (95% CI, 15–72). With 26.8 months’ median follow‐up, 2‐year progression‐free and overall survival rates were 33.3 and 66.7%. Exploratory analyses suggested TET2 alterations and natural killer‐cell expansion as correlates of durable remission. This regimen warrants prospective validation (ClinicalTrials.gov: NCT05083208).