Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ,γ, In Patients With Chronic Lymphocytic Leukemia
Authors: Flinn Ian , Patel Manish , Kahl Brad S. , Horwitz Steven M. , Foss Francine M. , Oki Yasuhiro , Porcu Pierluigi , Sweeney Jennifer , Allen Kerstin , Faia Kerrie , Harris Patricia , Dunbar Joi , Stern Howard M. , Kelly Patrick , O'Brien Susan 
Published: October 2019

Abstract

Introduction
IPI-145 is an oral, potent PI3K-δ,γ inhibitor currently in development for the treatment of hematologic (heme) malignancies. Biochemical /cellular and whole blood assays indicate that differential inhibition of the PI3K-δ and PI3K-γ isoforms is possible. An ongoing Phase 1 study (ClinicalTrials.gov NCT01476657) is evaluating patients (pts) with advanced heme malignancies and includes a subset of pts with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Preliminary results from the R/R CLL pts are reported here.

Methods and Patients
This Phase 1 study is designed to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and activity of orally administered IPI-145 BID in 28-day cycles. Sequential cohorts of pts with heme malignancies were enrolled in the dose escalation (DE) phase (completed), with 75 mg BID identified as the MTD. Two expansion cohorts (ECs) with R/R CLL pts are ongoing and examine 75 mg BID (MTD) and 25 mg BID; the latter dose was selected based on PK/PD showing complete suppression of PI3K-δ (>IC90) and inhibition of PI3K-γ (≥ IC50) at steady state. Of note, CLL pts with pancytopenia and/or prior exposure to PI3K- or BTK-inhibitors are allowed in these ECs. An EC of high-risk, treatment-naïve CLL pts is also ongoing at 25 mg BID. CLL responses are evaluated based on modified IWCLL (2008) criteria.

Results
As of July 2013, 155 pts have enrolled, including 44 pts with R/R CLL. Within the R/R CLL pts, 77% were male and 23% female, with a median (range) age of 67 years (51-82), and 93% with a baseline ECOG ≤1. Thirty-three (75%) R/R CLL pts had ≥3 prior systemic therapies and 62% were <6 months from their most recent therapy. Forty-four percent (44%) of pts tested (n=32) had TP53 mutation and/or 17p deletion.
Twenty-three R/R CLL pts received IPI-145 ≤25 mg BID (median [range] number of cycles 5.6 [1-21] and 43% remain on study) and 21 pts received 75 mg BID (median [range] number of cycles 3.6 [1–6] and 76% remain on study).
To date, there is no dose related increase in frequency or severity of AEs and SAEs. The most common ≥ Grade 3 AEs were transient neutropenia (n=9 [20%]; all in pts receiving ≤ 25 mg BID), anemia (n=4 [9%]), febrile neutropenia (n=3 [7%]), and pneumonitis (n=3 [7%]). Grade 3 ALT/AST increase occurred in 2 (5%) pts; no Grade 4 elevations occurred. The most frequently-occurring SAEs were respiratory and/or infectious events occurring in 11 (25%) pts total.
PK/PD data demonstrate exposure (AUC) increases proportionally through 75 mg BID, with maximum PD effects at doses ≥25 mg BID based on inhibition of pAKT, reductions in serum cytokines, chemokines and matrix metalloproteinases and reduction in adenopathy after 2 cycles of IPI-145 treatment.
Clinical activity has been observed in R/R CLL pts at all doses of IPI-145 studied from 8 mg to 75 mg BID and in pts with R/R high-risk disease (TP53 mut/17pdel). Treatment-related lymphocytosis is rapid, with the median ALC return to baseline within 6 cycles of treatment. Reduction in adenopathy occurs early with no apparent dose-dependence. Nodal responses (>50% reduction in adenopathy by CT assessment) occurred in 79% of pts after 2 treatment cycles. Best overall response (based on investigator assessment per IWCLL) in evaluable pts to date (median [range] number of cycles 5.1 [1-21.1]) is 52%, with 1 CR, 15 PR, 14 SD and 1 PD. The ORR for the 19 evaluable pts treated at ≤25 mg BID is 53% (10/19; including 1 CR) and 7 of the 8 SD pts achieving nodal response. Resolution of lymphocytosis may lead to an increase in best ORR for SD pts who remain on study. R/R pts with high-risk disease (TP53 mut/17pdel) had similar ORR.

Conclusions
IPI-145, an oral, potent PI3K-δ,γ inhibitor, appears well tolerated and has shown promising clinical activity in pts with R/R CLL across the range of doses examined. The PK/PD and clinical activity suggest that 25 mg BID is a biologically active dose in R/R CLL, and this dose has been selected for an upcoming randomized Phase 3 trial in R/R CLL. Updated data from treatment-naïve CLL pts who received IPI-145 at 25 mg BID and R/R CLL pts who received IPI-145 at 25 mg and 75 mg BID will be presented.

Disclosures:
Flinn: Infinity Pharmaceuticals, Inc.: Consultancy, Research Funding. Patel:Lilly, Medivation: Honoraria, Research Funding, Speakers Bureau; Infinity Pharmaceuticals, Inc.: Research Funding. Kahl:Infinity Pharmaceuticals, Inc.: Consultancy, Research Funding. Horwitz:Celgene, Allos, Seattle Genetics, Bristol-Myers Squibb, Genzyme, Kyowa, Janssen, Johnson & Johnson, Millenium: Consultancy; Celgene, Allos, Seattle Genetics, Kyowa, Infinty, Millenium: Research Funding. Foss:Eisai, Celgene, Spectrum, Millenium: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Oki:Infinity Pharmaceuticals, Inc.: Research Funding. Porcu:United States Cutaneous Lymphoma Consortium (USCLC) Cutaneous Lymphoma Foundation (CLF): Membership on an entity’s Board of Directors or advisory committees; Infinity Pharmaceuticals, Inc.: Research Funding. Sweeney:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals, Inc.: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Harris:Infinity Pharmaceuticals, Inc.: Employment. Dunbar:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals, Inc.: Employment. O'Brien:Infinity Pharmaceuticals, Inc.: Research Funding.