Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, Shows Activity in Patients with Relapsed/Refractory T-Cell Lymphoma
Authors: Horwitz Steven M. , Porcu Pierluigi , Flinn Ian , Kahl Brad S. , Sweeney Jennifer , Stern Howard M. , Douglas Mark , Allen Kerstin , Kelly Patrick , Foss Francine M. 
Published: October 2019

Abstract
Introduction: Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are uncommon lymphoid malignancies. Approved agents in the relapsed setting have overall response rates (ORR) in the range of 25-35%. Phosphoinositide-3-Kinases (PI3K) are pivotal in cell signaling and regulate multiple cellular functions relevant to oncogenesis. PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes with distinct roles in T-cell function. PI3K-δ and PI3K-γ are central to the growth and survival of certain T-cell malignancies and inhibition of PI3K is a therapeutic strategy for PTCL and CTCL. Duvelisib (IPI-145), an oral inhibitor of PI3K-δ and PI3K-γ, was studied in a phase 1 trial in hematologic malignancies with disease-specific expansion cohorts at the maximum tolerated dose (MTD). Responses were seen in a substantial number of patients with relapsed or refractory PTCL and CTCL.
Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of duvelisib administered twice daily (BID), continuously in 28-day cycles. Patients with relapsed or refractory leukemia or lymphoma received doses ranging from 8 mg to 100 mg BID. A disease-specific cohort at the MTD included PTCL and CTCL patients. The pharmacodynamics of duvelisib were assessed by early positron-emission tomography (PET) in a subset of patients and in serum through evaluation of a panel of cytokines, chemokines, and matrix metalloproteinase.
Results: Thirty-three patients with TCL (17 CTCL, 16 PTCL) received duvelisib primarily at the MTD of 75 mg BID (25 mg, n=1; 50 mg, n=1; 60 mg, n=4; 75 mg, n=25; 100 mg, n=2). The median age was 64 years (range: 34-86), and the median number of prior therapies was 4 (range: 1-11). The median time from last prior therapy to first dose of duvelisib was 1.05 months (range: 0.2-36). Thirty-one patients were evaluable for efficacy, with an ORR of 42% (13/31). The ORR in PTCL was 47% (7/15, 2 complete responses [CR], 5 partial responses [PR]) and in CTCL 38% (6/16, 6 PR). The median time to response was 1.9 months (range: 1.5-3.8). Median overall survival (OS) was 36.4 weeks (95% CI: 18.6, –) for patients with PTCL. The median OS was not yet reached for patients with CTCL. The median number of treatment cycles was 3.1 (range: 0.5-12.5), with 14 (42%) on treatment ≥4 cycles (16 weeks).
Pharmacodynamic results showed that within 8 days of starting treatment with duvelisib, modulation of serum cytokines and chemokines known to play a role in leukocyte migration and support the tumor microenvironment was observed. Furthermore, a reduction in standard uptake value (SUV) from baseline was observed in 6/11 patients evaluated by PET at Cycle 1 Day 22. (All 6 patients with reduction in SUV received duvelisib ≥60 mg BID).
Twenty-six (79%) patients had adverse events (AEs) ≥Grade 3, with the most common (≥10%) being increased ALT/AST (n=12, 36%), rash (combined terms) (n=7, 21%), and neutropenia (n=5, 15%). Ten (30%) patients discontinued treatment due to an AE, with the most common (>1 patient) being increased ALT/AST [n=5 (4 CTCL, 1 PTCL), 15%]. Three TCL patients died on treatment or within 30 days of the last dose of duvelisib, one due to disease progression, one who declined supportive therapy, and one due to HSV pneumonia (patient was not receiving HSV prophylaxis).
Conclusions: Duvelisib has shown clinical activity in patients with relapsed/refractory TCL (ORR 42%, including 2 CR) with an acceptable safety profile that supports continued assessment in this heavily pretreated patient population. The preliminary results support further evaluation of duvelisib in patients with TCL, including additional studies in both CTCL and PTCL to determine the optimal dose and identify appropriate combination therapy.

Disclosures
Horwitz: Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, SpectrumConsulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Off Label Use: ipi-145 is not an approved drug. Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals: Employment. Kelly:Infinity Pharmaceuticals: Employment. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau.