Preclinical and phase I studies of KA2237, a selective and potent inhibitor of PI3K β/δ in relapsed refractory B cell lymphoma

Abstract

PI3-kinase p110δ is mainly expressed in lymphocytes and is an attractive therapeutic target in B cell lymphomas. Targeting p110β may further suppress tumor growth and overcome escape mechanisms. KA2237 is an oral, potent, dual p110β/p110δ inhibitor. In preclinical studies, KA2237 inhibited p110β- and p110δ-dependent AKT activation and suppressed proliferation of diverse hematological and epithelial tumors. Twenty-one patients received KA2237 in a first-in-human phase I study (NCT02679196; diffuse large B cell, n = 8; follicular, n = 5; mantle cell, n = 3; chronic lymphocytic leukemia/small lymphocytic lymphoma, n = 3; marginal zone, n = 1; Waldenstrom’s, n = 1). Median age 69; median prior therapies 3. Eighty-six percent of patients experienced treatment-related adverse events (TRAEs). Forty-three percent of patients experienced grade ≥3 TRAEs, with rash (n = 3), pneumonia (n = 3), transaminitis (n = 2), and pneumonitis (n = 2) being most common. Thirty-three percent discontinued treatment due to adverse events. KA2237 induced objective responses in indolent and aggressive lymphoma (overall response rate 37%; complete response n = 4, partial response n = 3).

Keywords:

• PI3-kinase
• B cell lymphoma
• clinical trial

Author contributions

LJN is Principal Investigator for the clinical study and wrote the manuscript; SSN, RED, FS, and MW performed translational studies; LJN, SSN, FS, MW, NHF, JW, HJL, and FH contributed patients; ARLC and FAS designed and optimized the drug; JD analyzed pharmacokinetic data; KH and EAB directed preclinical development and analyzed preclinical data; AW and LL designed preclinical experiments; HMJ represented the Sponsor in directing the clinical trial, analyzed clinical data and wrote the manuscript; PAB analyzed preclinical and clinical data and wrote the manuscript. All authors reviewed and approved the final manuscript.

Disclosure statement

LJN has received honorarium from Bayer, BMS/Celgene, Epizyme, Genentech, Gilead/Kite, Janssen, Morphosys, Novartis, Pfizer, and TG Therapeutics. She has received research support from BMS/Celgene, Epizyme, Genentech, Janssen, Karus Therapeutics, Lam Therapeutics, Novartis, Pfizer, and TG Therapeutics. SSN served as Advisory Board member or consultant for Kite, a Gilead Company, Merck, Bristol-Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, and Unum Therapeutics; received research support from Kite, a Gilead Company, Bristol-Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, and Acerta; received royalties from Takeda Pharmaceuticals; and has intellectual property related to cell therapy.

Additional information

Funding

This study was funded by Karus Therapeutics Ltd.