Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia

Abstract

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-δ 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 + 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 1200 mg 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. This study was registered at www.clinicaltrials.gov as #NCT02006485.

Conflict of interest statement

Conflict-of-interest disclosure: M.L. has received grants from Celgene, Curis, Janssen Scientific Affairs LLC, Juno Therapeutics, Pharmacyclics, and TG Therapeutics; and had a consultancy role with AbbVie, ADC Therapeutics, AstraZeneca/Acerta, Bayer, Celgene, Genentech, Gilead Sciences Inc., Janssen/Pharmacyclics, Juno Therapeutics, Kite, Portola, Sanofi-Genzyme, Seattle Genetics, Spectrum, TG Therapeutics, and Verastem. J.V. had a consultancy role with AbbVie, Novartis, Epizyme, Roche, Legend Pharmaceuticals, Kyopharm, Sandoz, Janssen/Pharmacyclics, 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, Celgene, 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 Pharmacyclics; 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, Pharmacyclics 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.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Study schema.

Figure 2.

Best percent change from baseline in disease burden. The best percent change in tumor size for 68 patients eligible for efficacy analysis was determined by the principal investigators. One patient was not evaluable for change in tumor size due to lack of a post-baseline scan. Each bar represents an individual patient. Patients are grouped according to histology. MCL, mantle cell lymphoma; RT, Richter’s transformation. *Post-baseline scan was not available for 1 patient with MCL.