TY - JOUR
T1 - Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy
AU - Mato, Anthony R.
AU - Ghosh, Nilanjan
AU - Schuster, Stephen J.
AU - Lamanna, Nicole
AU - Pagel, John M.
AU - Flinn, Ian W.
AU - Barrientos, Jacqueline C.
AU - Rai, Kanti R.
AU - Reeves, James A.
AU - Cheson, Bruce D.
AU - Barr, Paul M.
AU - Kambhampati, Suman
AU - Lansigan, Frederick
AU - Pu, Jeffrey J.
AU - Skarbnik, Alan P.
AU - Roeker, Lindsey
AU - Fonseca, Gustavo A.
AU - Sitlinger, Andrea
AU - Hamadeh, Issam S.
AU - Dorsey, Colleen
AU - LaRatta, Nicole
AU - Weissbrot, Hanna
AU - Luning Prak, Eline T.
AU - Tsao, Patricia
AU - Paskalis, Dana
AU - Sportelli, Peter
AU - Miskin, Hari P.
AU - Weiss, Michael S.
AU - Svoboda, Jakub
AU - Brander, Danielle M.
N1 - Funding Information:
Conflict-of-interest disclosure: A.R.M. has acted as a consultant or advisor for AbbVie, Adaptive Biotechnologies, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Loxo Oncology, Pharmacyclics, Regeneron, Sunesis, TG Therapeutics (consulting and Data and Safety Monitoring Board), and Curio Biotech and has received research funding from AbbVie, Adaptive Biotechnologies, Acerta/AZ, DTRM Biopharma, Genentech, Johnson & Johnson, Loxo Oncology, Pharmacyclics, Regeneron, Sunesis, TG Therapeutics, Aprea Therapeutics, Aptose Biosciences, and Pfizer. N.G. has acted as a consultant or advisor for Celgene, Gilead Sciences, Janssen Pharmaceuticals, Pharmacyclics, Seattle Genetics, and TG Therapeutics; is a member of the speaker's bureau for AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Gilead Sciences, Janssen Pharmaceuticals, Pharmacyclics, and Seattle Genetics; and has received research funding from Celgene, Forty Seven Inc., Genentech, Pharmacyclics, and TG Therapeutics. S.J.S. has acted as a consultant or advisor for Allogene Therapeutics, AstraZeneca, BeiGene, Celgene, Genentech/Hoffman-La Roche, Loxo Oncology, Novartis, and Tessa Therapeutics; is a member of the speaker's bureau for DAVA Oncology; and has received research funding from Genentech/Hoffman-La Roche. N. Lamanna has acted as a consultant or advisor for AbbVie, AstraZeneca, BeiGene, Celgene, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Juno, and Pharmacyclics and has received research funding from AbbVie, AstraZeneca, BeiGene, Genentech, Juno Therapeutics, MingSight Pharmaceuticals, Oncternal Therapeutics, TG Therapeutics, and Verastem Oncology. J.M.P. has received research funding from AstraZeneca, Gilead Sciences, and Pharmacyclics. J.A.R. has acted as a consultant or advisor for Bayer and is a member of the speaker's bureau for Celgene, Eisai, and Janssen Oncology. B.D.C. has acted as a consultant or advisor for AbbVie, Astellas Pharma, AstraZeneca, Bayer, Celgene, Epizyme, Gilead Sciences, Karyopharm Therapeutics, MorphoSys, Parexel, Pharmacyclics/Janssen Pharmaceuticals, Symbio, and TG Therapeutics; has received research funding from AbbVie, Acerta Pharma, Bristol Myers Squibb, Gilead Sciences, Roche/Genentech, Seattle Genetics, TG Therapeutics, and Trillium Therapeutics; and has had travel, accommodations, and expenses paid by Symbio. P.M.B. has acted as a consultant or advisor for AbbVie, Celgene, Genentech, Infinity Pharmaceuticals, Janssen Pharmaceuticals, Merck, MorphoSys, Novartis, Pharmacyclics, Seattle Genetics, and TG Therapeutics and has received research funding from Pharmacyclics. A.P.S. has acted as a consultant or advisor for AbbVie, AstraZeneca, Celgene, Genentech, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Pharmacyclics, and Seattle Genetics; is a member of the speaker's bureau for AbbVie, AstraZeneca, BeiGene, Celgene, Gilead Sciences, Genentech, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Kite, Pharmacyclics, Seattle Genetics, and Verastem Oncology; and has received research funding from AbbVie, Acerta, AstraZeneca, Bristol Myers Squibb, Janssen Pharmaceuticals, Pharmacyclics, TG Therapeutics, and Verastem Oncology. L.R. has received honoraria from Projects in Knowledge and the Vaniam Group; has stock and other ownership interests in Abbott Laboratories and AbbVie; and has received research funding from Aptose Biosciences. G.A.F. has received honoraria from, has acted as a consultant or advisor for, is a member of the speaker's bureau for, has received research funding from, and has had travel, accommodations, and expenses paid by Amgen and Celgene and has received research funding from TG Therapeutics. D.P., P.S., and H.P.M. are employees of and hold stock and other ownership interests in TG Therapeutics. M.S.W. holds a leadership position at and holds stock and other ownership interests in TG Therapeutics. J.S. has received honoraria from AstraZeneca, Bristol Myers Squibb, Imbrium Therapeutics, Kite, Kyowa, Pharmacyclics, and Seattle Genetics and has received research funding from Bristol Myers Squibb, Incyte, Pharmacyclics, Seattle Genetics, and TG Therapeutics. D.M.B. has acted as a consultant or advisor for AbbVie, ArQule, AstraZeneca, Genentech, Pharmacyclics, Pfizer, Teva, TG Therapeutics, and Verastem Oncology and has received research funding from AbbVie, ArQule, Ascentage Pharma, AstraZeneca, BeiGene, DTRM Biopharma, Genentech, Juno Therapeutics/Celgene/Bristol Myers Squibb, MEI Pharma, Pharmacyclics, TG Therapeutics, Tolero Pharmaceuticals, and Verastem Oncology. The remaining authors declare no competing financial interests.
Funding Information:
This work was supported by TG Therapeutics, Inc.
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/5/20
Y1 - 2021/5/20
N2 - Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1–not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki–intolerant CLL population can result in durable well-tolerated responses.
AB - Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1–not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki–intolerant CLL population can result in durable well-tolerated responses.
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UR - http://www.scopus.com/inward/citedby.url?scp=85107087324&partnerID=8YFLogxK
U2 - 10.1182/blood.2020007376
DO - 10.1182/blood.2020007376
M3 - Article
C2 - 33259589
AN - SCOPUS:85107087324
VL - 137
SP - 2817
EP - 2826
JO - Blood
JF - Blood
SN - 0006-4971
IS - 20
ER -