TY - JOUR
T1 - Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia
AU - Lunning, Matthew
AU - Vose, Julie
AU - Nastoupil, Loretta
AU - Fowler, Nathan
AU - Burger, Jan A.
AU - Wierda, William G.
AU - Schreeder, Marshall T.
AU - Siddiqi, Tanya
AU - Flowers, Christopher R.
AU - Cohen, Jonathon B.
AU - Sportelli, Peter
AU - Miskin, Hari P.
AU - Weiss, Michael S.
AU - O'Brien, Susan
N1 - Funding Information:
The authors thank the patients and caregivers for their participation in this study. They extend further thanks to Michael Chen of TCM Groups, Inc., for assistance with statistical analyses. Medical writing support was provided by Allison Cherry of Nexus Global Group Science, LLC, and funded by TG Therapeutics.
Funding Information:
Kite, Acerta, Nordic Nanovector, and AstraZeneca. L.N. has received personal fees, research support, and honorarium from TG Therapeutics and Celgene, and personal fees and honorarium from Gilead, Novartis, and Spectrum Pharmaceuticals. N.F. had an advisory role with Celgene, Roche, and Janssen; and received grants from AbbVie. J.A.B. has received grants from Pharmacyclics and Gilead and honoraria from Janssen. T.S. has received grants and nonfinancial support from TG Therapeutics. C.R.F. had a paid consultancy role with Spectrum, Cel-gene, Denovo Biopharma, Seattle Genetics, Gilead, Bayer, Karyopharm, AstraZeneca, and Beigene; an unpaid consultancy role with Genentech/ Biogen Idec/Roche and Millennium/Takeda; received research funding from AbbVie, Acerta, Celgene, Gilead, Infinity Pharmaceuticals, Janssen, Millennium/Takeda, Spectrum, Onyx Pharmaceuticals, and Pharmacy-clics; and received payments for educational materials from Clinical Care Options, Educational Concepts, PRIME Oncology, and Research to Practice. J.B.C. has received grants from Seattle Genetics, Takeda, Novartis, American Society of Hematology, and Lymphoma Research Foundation; and received personal fees from Seattle Genetics and Genentech. S.O. had a consultancy role with Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Inc., Vaniam Group, LLC, AbbVie, Alexion Pharmaceuticals, Gilead, Pharmacyclics LLC, an AbbVie Company, TG Therapeutics, Pfizer, and Sunesis; and has received research support from Kite, Regeneron, Acerta, Gilead, Phar-macyclics LLC, an AbbVie Company, TG Therapeutics, Pfizer, and Sunesis. P.S., H.P.M., and M.S.W. report employment and equity ownership with TG Therapeutics. The remaining authors declare no competing financial interests.
Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/11/21
Y1 - 2019/11/21
N2 - Targeting both CD20 and phosphatidylinositol 3-kinase (PI3K), a protein that is critically involved in B-cell maturation, could be an efficacious strategy for treating B-cell malignancies. The safety of the next-generation compounds umbralisib, a PI3K-d inhibitor, plus ublituximab, an anti-CD20 monoclonal antibody (combination referred to as U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase 1/1b study. Phase 1 dose escalation was performed with a 3 1 3 design to establish the maximum tolerated dose. In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 or 1200 mg (initial formulation) or 400 to 1200 mg (micronized formulation) in the phase 1 dose escalation portion, and at 800 to 1200mg in the phase 1b portion until progression, toxicity, or study removal. The maximum tolerated dose was not reached in either the CLL or NHL cohort, and only 1 dose-limiting toxicity was observed. U2 had low instances of grade 3 or higher diarrhea (8%), pneumonia (8%), or hepatic toxicity (4%). Treatment discontinuation due to adverse events occurred in 13% of patients, and umbralisib dose reductions occurred in 15% of patients. The overall response rate for all patients was 46% with 17% complete responses. The median duration of response was 20 months (95% confidence interval, 11.3-not reached). U2 was well tolerated, and no new safety signals were observed over single-agent umbralisib. Preliminary efficacy with this combination is promising and warrants further investigation.
AB - Targeting both CD20 and phosphatidylinositol 3-kinase (PI3K), a protein that is critically involved in B-cell maturation, could be an efficacious strategy for treating B-cell malignancies. The safety of the next-generation compounds umbralisib, a PI3K-d inhibitor, plus ublituximab, an anti-CD20 monoclonal antibody (combination referred to as U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase 1/1b study. Phase 1 dose escalation was performed with a 3 1 3 design to establish the maximum tolerated dose. In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 or 1200 mg (initial formulation) or 400 to 1200 mg (micronized formulation) in the phase 1 dose escalation portion, and at 800 to 1200mg in the phase 1b portion until progression, toxicity, or study removal. The maximum tolerated dose was not reached in either the CLL or NHL cohort, and only 1 dose-limiting toxicity was observed. U2 had low instances of grade 3 or higher diarrhea (8%), pneumonia (8%), or hepatic toxicity (4%). Treatment discontinuation due to adverse events occurred in 13% of patients, and umbralisib dose reductions occurred in 15% of patients. The overall response rate for all patients was 46% with 17% complete responses. The median duration of response was 20 months (95% confidence interval, 11.3-not reached). U2 was well tolerated, and no new safety signals were observed over single-agent umbralisib. Preliminary efficacy with this combination is promising and warrants further investigation.
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U2 - 10.1182/blood.2019002118
DO - 10.1182/blood.2019002118
M3 - Article
C2 - 31558467
AN - SCOPUS:85075562689
SN - 0006-4971
VL - 134
SP - 1811
EP - 1820
JO - Blood
JF - Blood
IS - 21
ER -