TY - JOUR
T1 - Preclinical and phase I studies of KA2237, a selective and potent inhibitor of PI3K β/δ in relapsed refractory B cell lymphoma
AU - Nastoupil, Loretta J.
AU - Neelapu, Sattva S.
AU - Davis, Richard Eric
AU - Samaniego, Felipe
AU - Fowler, Nathan H.
AU - Westin, Jason
AU - Lee, Hun Ju
AU - Wang, Michael
AU - Hagemeister, Fredrick
AU - Cecil, Alexander R.L.
AU - Dow, James
AU - Haque, Kemal
AU - Silva, Franck A.
AU - Whale, Andrew
AU - Lensun, Letitia
AU - Bone, Elisabeth A.
AU - McElwaine-Johnn, Hilary
AU - Beer, Philip A.
N1 - Publisher Copyright:
© 2021 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2021
Y1 - 2021
N2 - 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).
AB - 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).
KW - B cell lymphoma
KW - PI3-kinase
KW - clinical trial
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U2 - 10.1080/10428194.2021.1957874
DO - 10.1080/10428194.2021.1957874
M3 - Article
C2 - 34365878
AN - SCOPUS:85112088340
SN - 1042-8194
VL - 62
SP - 3452
EP - 3462
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 14
ER -