This Phase 1, open-label, multicenter study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of lonitoclax (ZE50-0134) in adults with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and select low-grade B-cell lymphomas.
The study has two sequential parts. Part 1 uses dose escalation to determine the biologically effective dose and/or maximum tolerated dose of lonitoclax. Participants receive a 3-day step-up regimen followed by continuous once-daily or twice-daily oral dosing in 28-day cycles. Part 2 is a randomized dose-expansion comparison of two selected lonitoclax dose levels in venetoclax-naive participants with relapsed or refractory CLL/SLL. Treatment may continue for up to 12 cycles and, for participants deriving clinical benefit, for up to 24 cycles with approval from the Medical Monitor.
Men and women aged 18 years or older.
Part 1: Relapsed or refractory CLL or SLL, as defined by iwCLL, after at least 2 prior therapies that included a covalent Bruton tyrosine kinase inhibitor (BTKi) and venetoclax, or after the participant declined venetoclax; or progressive low-grade lymphoma, including marginal zone lymphoma or lymphoplasmacytic lymphoma (including Waldenstrom macroglobulinemia), after at least 1 prior therapy that included either a BTKi or CD20 antibody-based therapy.
Part 2: Relapsed or refractory CLL or SLL, as defined by iwCLL, after at least 1 prior therapy that included a BTKi; participants must be venetoclax naive.
Disease requiring therapy in the investigator's opinion.
Part 2 only: Prior venetoclax treatment.
Known active Richter transformation. Participants previously treated for Richter transformation may be eligible if they have been in remission for more than 2 years, have no evidence of Richter transformation, and have CLL only.
Known hypersensitivity to lonitoclax, its excipients, or an agent administered in association with the study.
Clinically significant cardiac disease, including congestive heart failure greater than New York Heart Association Class II; uncontrolled coronary artery disease; unstable angina; new-onset angina or myocardial infarction within 6 months before first dose; major regional wall-motion abnormalities on baseline echocardiography; or cardiac arrhythmias requiring antiarrhythmic treatment other than beta-blockers or digoxin.
Sequential
Lonitoclax (ZE50-0134)
DrugLonitoclax is supplied as immediate-release white opaque soft gelatin capsules in 25 mg, 100 mg, and 250 mg strengths. Participants receive a 3-day step-up regimen followed by the assigned oral dose once daily (QD) or twice daily (BID) in a fed state, administered within 1 hour of food. Each cycle is 28 days. Treatment continues for up to 12 cycles and may continue for up to 24 cycles in participants deriving clinical benefit, at the investigator's discretion with Medical Monitor approval. Participants receive inpatient monitoring and tumor lysis syndrome prophylaxis during the initial step-up period.
12
Treatment groupsSee each treatment group below.
Incidence and severity of treatment-emergent adverse events and serious adverse events
Number and percentage of participants with treatment-emergent adverse events, serious adverse events, clinically significant laboratory abnormalities, adverse events related to lonitoclax, and adverse events leading to treatment discontinuation. Adverse events are graded using NCI CTCAE Version 5.0.
Incidence of dose-limiting toxicities in Part 1
Number and percentage of Part 1 participants experiencing a protocol-defined dose-limiting toxicity during the dose-limiting toxicity assessment period.
Determination of the biologically effective dose and/or maximum tolerated dose
The selected dose is determined from the totality of safety, dose-limiting toxicity, pharmacokinetic, pharmacodynamic, and early response data across Part 1 dose cohorts according to the protocol-defined dose-escalation rules.
Overall Response Rate (ORR)
Proportion of participants whose best overall response is partial response or better, as assessed by the investigator using iwCLL criteria for CLL, Lugano criteria for SLL and other applicable low-grade lymphomas, or Waldenstrom response criteria, as applicable.
Duration of response (DOR)
For participants with partial response or better, time from the first documented response until disease progression or death from any cause.
Progression-free survival (PFS)
Time from first dose until disease progression by the applicable disease-specific response criteria or death from any cause.
Time to next treatment (TTNT)
Time from first dose of lonitoclax to initiation of a non-protocol anticancer treatment for CLL/SLL or death.
Rate of undetectable measurable residual disease in blood and bone marrow
Proportion of evaluable participants with undetectable measurable residual disease by flow cytometry and/or next-generation sequencing, including bone marrow assessment after 12 cycles.
Change from baseline in caspase 3 activation
Change in caspase 3 activation in CLL or lymphoma cells and exploratory relationship with lonitoclax pharmacokinetics and clinical response.
Change from baseline in immune-cell populations
Change in absolute numbers of CD8 T cells, natural killer cells, and normal B cells during lonitoclax treatment.
Molecular and protein markers associated with resistance or response
Exploratory evaluation of serial samples for BCL2, BAX, and other escape mutations; expression of alternative BCL2-family proteins; alternative biomarkers; and clonal evolution in relation to response, progression, and resistance.
Click on the lead sponsor to view all of their trials.
