a Phase 1 Evaluation of Duvelisib (IPI-145), a PI3K-δ,γ Inhibitor, in Patients with Relapsed/Refractory iNHL
Authors: Flinn Ian , Oki Yasuhiro , Patel Manish , Horwitz Steven M. , Foss Francine M. , Sweeney Jennifer , Allen Kerstin , Douglas Mark , Steelman Lori , Dunbar Joi , Stern Howard M. , Kelly Patrick , Kahl Brad 
Published: October 2019

Abstract
Introduction: Signaling via PI3K-δ and PI3K-γ is essential for both normal and malignant B-cell and T-cell proliferation, survival, and migration. PI3K-δ and PI3K-γ have distinct and complimentary effects on malignant B-cells and nonmalignant immune cells important in tumor immunity and the tumor microenvironment. Duvelisib (IPI-145) is a novel targeted oral PI3K-δ,γ inhibitor in development for the treatment of hematologic malignancies. An ongoing Phase 1 study has demonstrated substantial clinical activity in patients (pts) with advanced hematologic malignancies, including pts with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL).
Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of duvelisib administered continuously in 28-day cycles. The optimal biological dose (supported by pharmacodynamic studies and clinical activity) selected for chronic administration in iNHL (25 mg BID) was further evaluated in expansion cohorts in R/R iNHL pts while additional testing up to the MTD (75 mg BID) was pursued to further characterize safety and activity. iNHL clinical responses were evaluated based on revised IWG (2007) criteria with additional criteria for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) where appropriate.
Results: A total of 32 pts with R/R iNHL (follicular lymphoma, marginal zone lymphoma and WM/LPL) were enrolled, including 16 pts dosed at 25 mg BID (1 pt received 15 mg BID). The median age was 65 years [range: 37-78] and 56% were male. Nineteen (59%) pts had ≥3 prior systemic therapies and 34% were <6 months from their most recent therapy. Baseline cytopenias ≥Grade 1 at study entry were: anemia n=19 (61%), neutropenia n=8 (26%), and thrombocytopenia n=8 (26%).
The R/R iNHL pts received duvelisib at doses ranging from 15 mg BID to 75 mg BID. Pharmacokinetic data demonstrated that exposure (AUC and Cmax) increased across the dose range evaluated. There was evidence of pharmacodynamic modulation based on reductions in serum cytokines and chemokines known to support the malignant B-cell microenvironment. Despite increasing exposure above 25 mg BID, cytokine and chemokine reductions were similar at doses of 25 mg BID or higher.
Consistent with the pharmacodynamic observations, clinical activity was observed in R/R iNHL pts at all doses of duvelisib evaluated (15 mg BID to 75 mg BID). In the efficacy evaluable population (n=31), the ORR was 65% with a best response of 5 complete responses (CR) (all follicular), 14 partial responses (PR), 1 minor response (MR), 9 stable disease (SD) and 2 progressive disease (PD), and with a median time to response of 1.8 months. For the subset of 15 evaluable pts treated at 25 mg BID (1 pt received 15 mg BID), the ORR was 73% (including 4 CRs). This pt subset has received a median of 11 treatment cycles (range: 1.1-28.7), with 47% (7/15) remaining on long-term treatment (1 to >2 years).
The overall safety profile has been consistent across the range of doses studied in R/R iNHL pts (median of 6 treatment cycles [range: 0.1-28.7]). The majority of adverse events (AEs) were Grade 1-2, reversible and/or clinically manageable. The most common ≥Grade 3 treatment-emergent AEs (≥15%, all causality) were ALT/AST increase (n=13 [41%]) with a median time to occurrence of 50 days (range: 5-448), and diarrhea (n=7 [22%]) with a median time to occurrence of 124 days (range: 36-434). In addition, transient ≥Grade 3 neutropenia was reported in 10 pts (31%), including 6 pts who entered the study with baseline neutropenia. The most common reasons for treatment discontinuation included AEs (10/32, 31%) and disease progression (7/32, 22%).
Conclusions: Duvelisib (IPI-145), a novel oral PI3K-δ,γ inhibitor, appears generally well tolerated with an acceptable safety profile across the dose range evaluated. Evidence of clinical activity in pts with R/R iNHL was observed with an ORR of 65% including CRs in 25% (5/20) of responding pts. Based on these promising results which suggest a positive benefit-risk in this pt population, registration trials in pts with iNHL evaluating 25 mg BID as a monotherapy or in combination with rituximab are ongoing or planned, respectively.

Disclosures
Flinn: Infinity Pharmaceuticals: Consultancy. Off Label Use: This is an investigational drug not FDA approved.. Oki:Infinity Pharmaceuticals Inc: Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, SpectrumConsulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Steelman:Infinity Pharmaceuticals: Employment. Dunbar:Infinity Pharmaceuticals Inc: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment. Kahl:Infinity Pharmaceuticals Inc: Consultancy, Research Funding.