A Study of Lonitoclax (ZE50-0134) in Relapsed or Refractory B-cell Malignancies

This is an open-label, multicenter Phase 1 study with two sequential parts. Part 1 is a non-randomized dose-escalation study in participants with relapsed or refractory CLL/SLL or select low-grade lymphomas. A standard 3+3 design is used to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of lonitoclax (ZE50-0134), and to identify a biologically effective dose and/or maximum tolerated dose. Planned dose levels include once-daily and twice-daily regimens. Dose Levels 6a and 6b may enroll concurrently. Dose-limiting toxicities are evaluated during Cycle 1. To reduce the risk of tumor lysis syndrome, participants receive intravenous hydration beginning on Day -1 and a 3-day step-up dosing regimen as inpatients. After step-up dosing, the assigned lonitoclax dose is administered orally once daily or twice daily in a fed state. Each treatment cycle is 28 days. Part 2 is a randomized dose-expansion portion in venetoclax-naive participants with relapsed or refractory CLL/SLL. Approximately 15 participants are assigned to each of two selected dose levels: the biologically effective dose or maximum tolerated dose and one lower dose level, provided activity is observed. Part 2 evaluates safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity to support selection of a recommended Phase 2 dose. Treatment is continuous for up to 12 cycles. Participants deriving clinical benefit may continue treatment for up to 24 cycles at the investigator's discretion with Medical Monitor approval. Participants are followed for safety after treatment and for disease progression, subsequent treatment, and survival.