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).