Background: Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ being developed for the treatment of hematologic malignancies. In preclinical investigations, duvelisib potently killed TCL cell lines with constitutive phospho-AKT (S473) and reprogrammed tumor-associated macrophages from an immunosuppressive to immunostimulatory phenotype in PTCL mouse xenograft models (Horwitz, Blood 2017). In a Phase 1 study duvelisib monotherapy demonstrated encouraging clinical activity and an acceptable safety profile (Flinn, Blood 2017), with an overall response rate (ORR) of 50% (3 complete responses [CRs], 5 partial responses [PRs]) in patients (pts) with PTCL (n = 16). These results suggest duvelisib monotherapy may provide a meaningful benefit in relapsed/refractory (RR) PTCL, a population in need of new and effective therapies. Methods: This Phase 2, open-label, study of duvelisib monotherapy in adult pts PTCL employs a Dose Optimization Phase (DOP) and an Expansion Phase (EP) (NCT03372057). The primary objectives are to identify the optimal dose of duvelisib and examine the efficacy, safety, and tolerability of duvelisib at the optimal dose. The study will enroll up to 120 pts with histologically confirmed PTCL subtypes of PTCL-NOS, angioimmunoblastic TCL, anaplastic large cell lymphoma, and natural-killer TCL. Disease responses will be measured by ¹⁸FDG-PET-CT scanning as assessed by an independent review committee per IWG criteria. The DOP, to be conducted at 4-6 centers in the U.S., will include 20 pts randomly assigned to 1 of 2 parallel cohorts. Cohort 1 will receive a starting dose of 25 mg duvelisib PO BID, with potential sequential escalation to 50 mg and then 75 mg based on responses and tolerance of therapy. Pts in Cohort 2 will receive 75 mg duvelisib PO BID. The EP, to be conducted globally at ~40 centers, will include pts treated at the optimal dose as determined from the DOP. The primary endpoint is ORR (CR + PR) in all pts receiving the optimal dose for at least 1 cycle in either phase. Secondary endpoints include AEs, duration of response, and PFS. This study is open for enrollment. Clinical trial information: NCT03372057