Preclinical and Phase I Studies of KA2237, a Selective and Potent Inhibitor of PI3K Β/δ in Relapsed Refractory B Cell Lymphoma.

PI3-kinase p110 delta is mainly expressed in lymphocytes and is an attractive therapeutic target in B cell lymphomas. Targeting p110 beta may further suppress tumor growth and overcome escape mechanisms. KA2237 is an oral, potent, dual p110 beta/p110 delta inhibitor. In preclinical studies, KA2237 inhibited p110 beta- and p110 delta-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).