Key Points

  • Umbralisib plus ublituximab exhibited low rates of immune-mediated toxicities associated with other PI3K-δ inhibitors.

  • This combination had promising preliminary activity across a broad range of B-cell malignancies, including a 17% complete response rate.

Targeting both CD20 and phosphoinositol-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 (U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase I/Ib study. Phase I dose-escalation was performed with a 3+3 design to establish the maximum tolerated dose (MTD). In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 mg or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 mg or 1200 mg (standard formulation) or 400 mg to 1200 mg (micronized formulation) in the Phase I dose-escalation portion, and at 800 mg to 1200 mg in the phase Ib portion until progression, toxicity, or study removal. The MTD was not reached in either CLL or NHL cohort and only one dose-limiting toxicity was observed. U2 had low instances of grade {greater than or equal to}3 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% CI: 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 is registered at www.ClinicalTrials.gov (NCT02006485).

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