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Clinical Trial
. 2018 Feb 22;131(8):877-887.
doi: 10.1182/blood-2017-05-786566. Epub 2017 Nov 30.

Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies

Ian W Flinn  1   2 , Susan O'Brien  3 , Brad Kahl  4 , Manish Patel  1   5 , Yasuhiro Oki  3 , Francine F Foss  6 , Pierluigi Porcu  7 , Jeffrey Jones  8 , Jan A Burger  3 , Nitin Jain  3 , Virginia M Kelly  9 , Kerstin Allen  9 , Mark Douglas  9 , Jennifer Sweeney  9 , Patrick Kelly  9 , Steven Horwitz  10
Affiliations
Clinical Trial

Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies

Ian W Flinn et al. Blood. .

Abstract

Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma (TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50% (n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was ∼1.8 months. Severe (grade ≥3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies. This trial was registered at clinicaltrials.gov as #NCT01476657.

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Conflict of interest statement

Conflict-of-interest disclosure: I.W.F. has received funding/grant support from Acerta Pharma, Agios Pharmaceuticals, BeiGene, Celgene, Constellation Pharmaceuticals, Curis Inc, Forma Therapeutics, Forty Seven Inc., Genentech, Gilead Sciences, Incyte Corporation, Infinity Pharmaecuticals, Janssen Pharmaceutical, Kite Pharma, Merck, Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics, Takeda Pharmaceuticals, TG Therapeutics, Inc., Trillium Therapeutics, Inc., and Verastem Inc. Y.O. received honoraria from Bristol-Myers Squibb and Takeda, and research funding from Infinity Pharmaceuticals, Inc., Rhizen Pharmaceuticals S.A., and Curis Inc. S.H. has received research funding/grant support from Celgene Corporation, Millennium Pharmaceuticals, Inc., Seattle Genetics, Spectrum Pharmaceuticals, Inc., and Infinity Pharmaceuticals, Inc., and consulting fees/honoraria from Celgene Corporation, Millennium Pharmaceuticals, Inc., Seattle Genetics, and Spectrum Pharmaceuticals, Inc. F.F.F. has received consulting fees and funding for a clinical study from Infinity Pharmaceuticals, Inc. K.A., M.D., J.S., and P.K. are former employees of Infinity Pharmaceuticals, Inc. B.K. has received consulting fees from Infinity Pharmaceuticals, Inc., Gilead Sciences, Inc., Pharmacyclics, Roche, Millennium Pharmaceuticals, Inc., Seattle Genetics, and CTI BioPharma. V.M.K. is a former employee of Infinity Pharmaceuticals, Inc., and currently a consultant for Verastem, Inc. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Mean duvelisib plasma concentrations following single-dose (cycle 1, day 1) and multiple-dose (cycle 2, day 1) administration. BID, twice daily; SD, standard deviation.
Figure 2.
Figure 2.
Study design. The first row of boxes shows the dose escalation cohort (n = 31) and the 4 dose-limiting toxicities of duvelisib (1 at 15 mg BID, 1 at 75 mg BID, and 2 at 100 mg BID). The MTD was found to be 75 mg BID. The lower 2 boxes represent the expansion cohorts (1 at 25 mg BID and 1 at 75 mg BID).
Figure 3.
Figure 3.
Reductions in key pharmacodynamic markers of inhibition and proliferation in CLL cells from patients with RR CLL/SLL and TN CLL. Phosphorylation of AKT at S473 was measured by flow cytometry in CD19+/CD5+ CLL cells obtained from whole blood collected at baseline (0 h) and at 1 h and 24 h postdose on C1D1. Ki-67, a marker of cell proliferation, was measured by flow cytometry on CD19+/CD5+ CLL cells obtained from whole blood collected predose (0 h) on C1D1 and C2D1). All data shown as percent positive.
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