A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax (U2-Ven) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Background: Despite the effectiveness of novel agents in treating CLL, prolonged single agent use can lead to drug resistance, toxicity, challenges with adherence, and considerable financial burden. Combinations may provide deeper prolonged remissions using defined treatment durations. Umbralisib (Umbra) is a novel and highly specific PI3Kδ/CK1ε dual inhibitor, while ublituximab (Ubli) is a glycoengineered monoclonal antibody targeting a unique epitope on CD20. A randomized Phase 3 study of the Umbra + Ubli (U2) combination in patients (pts) with treatment naïve and previously treated CLL, UNITY-CLL, was recently determined to have met its primary endpoint at a pre-planned interim analysis. Integrating the BCL2 inhibitor venetoclax (Ven) into the U2 backbone is hypothesized to reduce the risk of acquired drug resistance (Choudhary, Cell Death Dis 2015), achieve higher levels of undetectable minimal residual disease (MRD), and reduce the risk of tumor lysis syndrome (TLS). Phase 1 results established the recommended Phase 2 doses to be: Umbra 800 mg QD; Ubli 900 mg and Ven 400 mg QD (Barr et al., ASH 2019). The Phase 2 component evaluated the safety, efficacy and MRD negativity rates in relapsed or refractory CLL pts.