A phase 2 study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib in patients with chronic lymphocytic leukemia (CLL): A minimal residual disease (MRD)-driven, time-limited approach

ABSTRACT

Background: While time-limited novel agent combinations have demonstrated high overall response rates and durable responses for patients with chronic lymphocytic leukemia (CLL), they also have high rates of adverse events and possibly overtreat many favorable risk patients. Meanwhile, patients receiving indefinite ibrutinib monotherapy are at risk for cumulative toxicity and acquired resistance with continuous exposure. To address these challenges, we utilized an 'add-on' approach to combination therapy after a period of ibrutinib monotherapy exposure. We examined the addition of umbralisib (a selective PI3Kδ and casein kinase-1epsilon [CK1ϵ] inhibitor) and ublituximab (a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity;U2) to ibrutinib in CLL patients with detectable minimal residual disease (MRD) after an initial period of treatment with ibrutinib monotherapy. With this strategy, we aimed to induce undetectable MRD (uMRD), minimize the risk of developing BTKi resistance mutations, stop all CLL-directed therapy, and achieve a durable treatment-free observation (TFO) period in CLL patients who would most benefit from combination therapy. Methods: This is a phase II, multicenter, open label clinical trial (NCT04016805). Eligible patients were receiving ongoing ibrutinib, in any line of therapy, for a minimum duration of 6 months and had detectable residual CLL in the peripheral blood via MRD assay (flow cytometry with a cutoff of 10