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

NCT06708897 | Recruiting Phase 1 FDA Drug

• 1 other identifier: ZE50-0134-0002
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

CLL / SLL; SLL (Small Lymphocytic Lymphoma); CLL (Chronic Lymphocytic Leukemia); Marginal Zone Lymphoma(MZL); Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

Keywords

Lonitoclax; ZE50-0134; BCL2 inhibitor; relapsed or refractory; dose escalation; dose expansion; dose optimization; BTK inhibitor; venetoclax; tumor lysis syndrome

Outcome Measures

Primary Outcomes (3)

• 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.

  From first dose through 30 days after the last dose; treatment may continue for up to 24 cycles (28 days per cycle).

• 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.

  Cycle 1 (Days 1-28).

• 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.

  After completion of Cycle 1 for evaluable participants in each Part 1 dose cohort.

Secondary Outcomes (6)

• Overall Response Rate (ORR)

  From first dose through end of treatment, up to 24 cycles (28 days per cycle).

• Duration of response (DOR)

  From first documented response until progression, death, withdrawal, loss to follow-up, or sponsor termination; assessed during treatment and long-term follow-up.

• Progression-free survival (PFS)

  From first dose until progression, death, withdrawal, loss to follow-up, or sponsor termination; assessed during treatment and long-term follow-up.

• Time to next treatment (TTNT)

  From first dose until initiation of new anticancer treatment, death, withdrawal, loss to follow-up, or sponsor termination.

• Maximum observed plasma concentration (Cmax) of lonitoclax

  Cycle 1 Days 1-4, 8, 15, and 22; Cycle 2 Days 1-2; and end-of-treatment/early-termination sampling as applicable.

Other Outcomes (5)

• Rate of undetectable measurable residual disease in blood and bone marrow

  Peripheral blood at the ends of Cycles 3, 6, 9, and 12; bone marrow at the end of Cycle 12.

• Change from baseline in caspase 3 activation

  Screening/baseline through Cycle 1 Day 4.

• Change from baseline in immune-cell populations

  Baseline; Cycle 1 Day 1; Cycle 2 Day 1; Cycle 4 Day 1; Cycle 7 Day 1; and safety follow-up/end of treatment/early termination, as applicable.

Study Arms (12)

Part 1: Dose Level -1 - 75 mg QD

EXPERIMENTAL

Optional de-escalation cohort. Participants receive lonitoclax 25 mg once daily on Day 1, 50 mg once daily on Day 2, and 75 mg once daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 1 - 100 mg QD

EXPERIMENTAL

Participants receive lonitoclax 25 mg once daily on Day 1, 50 mg once daily on Day 2, and 100 mg once daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 2 - 200 mg QD

EXPERIMENTAL

Participants receive lonitoclax 50 mg once daily on Day 1, 100 mg once daily on Day 2, and 200 mg once daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 3 - 400 mg QD

EXPERIMENTAL

Participants receive lonitoclax 50 mg once daily on Day 1, 100 mg once daily on Day 2, and 400 mg once daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 4 - 600 mg QD

EXPERIMENTAL

Participants receive lonitoclax 50 mg once daily on Day 1, 100 mg once daily on Day 2, and 600 mg once daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 5 - 800 mg QD

EXPERIMENTAL

Participants receive lonitoclax 50 mg once daily on Day 1, 100 mg once daily on Day 2, and 800 mg once daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 6a - 1000 mg QD

EXPERIMENTAL

Participants receive lonitoclax 100 mg once daily on Day 1, 250 mg once daily on Day 2, and 1000 mg once daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles. Dose Levels 6a and 6b may enroll concurrently.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 6b - 500 mg BID

EXPERIMENTAL

Participants receive lonitoclax 50 mg twice daily on Day 1, 100 mg twice daily on Day 2, and 500 mg twice daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles. Dose Levels 6a and 6b may enroll concurrently.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 7b - 750 mg BID

EXPERIMENTAL

Participants receive lonitoclax 100 mg twice daily on Day 1, 250 mg twice daily on Day 2, and 750 mg twice daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles.

Drug: Lonitoclax (ZE50-0134)

Part 1: Dose Level 8b - 1000 mg BID

EXPERIMENTAL

Participants receive lonitoclax 100 mg twice daily on Day 1, 250 mg twice daily on Day 2, and 1000 mg twice daily on Day 3 and thereafter. Treatment is administered orally in a fed state in 28-day cycles.

Drug: Lonitoclax (ZE50-0134)

Part 2: Selected Dose A - BED/MTD

EXPERIMENTAL

Participants with relapsed or refractory CLL/SLL who are venetoclax naive are randomized to a selected lonitoclax dose corresponding to the biologically effective dose or maximum tolerated dose identified in Part 1. The selected regimen may be once daily or twice daily. Approximately 15 participants are planned.

Drug: Lonitoclax (ZE50-0134)

Part 2: Selected Dose B - One Dose Level Lower

EXPERIMENTAL

Participants with relapsed or refractory CLL/SLL who are venetoclax naive are randomized to one lonitoclax dose level below the biologically effective dose or maximum tolerated dose selected in Part 1, provided activity is observed. The selected regimen may be once daily or twice daily. Approximately 15 participants are planned.

Drug: Lonitoclax (ZE50-0134)

Interventions

Lonitoclax (ZE50-0134) DRUG

Lonitoclax 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.

Part 1: Dose Level -1 - 75 mg QD; Part 1: Dose Level 1 - 100 mg QD; Part 1: Dose Level 2 - 200 mg QD; Part 1: Dose Level 3 - 400 mg QD; Part 1: Dose Level 4 - 600 mg QD; Part 1: Dose Level 5 - 800 mg QD; Part 1: Dose Level 6a - 1000 mg QD; Part 1: Dose Level 6b - 500 mg BID; Part 1: Dose Level 7b - 750 mg BID; Part 1: Dose Level 8b - 1000 mg BID; Part 2: Selected Dose A - BED/MTD; Part 2: Selected Dose B - One Dose Level Lower

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women aged 18 years or older.
• Disease as defined below:
• 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.
• Adequate bone marrow, liver, and renal function during screening:
• Absolute neutrophil count greater than 0.75 x 10\^9/L; for participants with documented bone marrow involvement, at least 0.5 x 10\^9/L.
• Platelet count greater than 50 x 10\^9/L; for participants with documented bone marrow involvement, at least 30 x 10\^9/L.
• AST and ALT no greater than 3.0 times the upper limit of normal.
• Total bilirubin no greater than 1.5 times the upper limit of normal. Participants with suspected or known Gilbert disease may have total bilirubin up to 3 times the upper limit of normal if predominantly unconjugated.
• Creatinine- or cystatin C-based glomerular filtration rate at least 60 mL/min, or at least 40 mL/min with a normal urine neutrophil gelatinase-associated lipocalin level. Estimated GFR is calculated using the Modification of Diet in Renal Disease formula.
• Eastern Cooperative Oncology Group performance status of 0, 1, or 2.
• For women of childbearing potential, a negative serum or urine pregnancy test within 7 days before the first dose and a negative result before each treatment cycle. Pregnancy testing is not required for women older than 50 years with at least 12 months of amenorrhea; women aged 50 years or younger with at least 6 months of spontaneous amenorrhea and follicle-stimulating hormone greater than 40 mIU/mL; or permanently sterilized women, including hysterectomy, bilateral salpingectomy, or uterine ablation.
• Women and men of reproductive potential must agree to use highly effective contraception from signing informed consent until 90 days after the last dose of study drug.
• Ability to understand and willingness to sign written informed consent, including consent for genetic biomarker analyses from tissue and plasma, before study-specific procedures.

You may not qualify if:

• 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.
• Known active cytomegalovirus, hepatitis B virus, or hepatitis C virus infection.
• HIV-positive disease that is not adequately controlled by antiviral therapy. Participants with adequately controlled HIV may enroll.
• Known active SARS-CoV-2 infection. Prior infection is allowed if the participant completely recovered more than 14 days previously.
• Active clinically serious infection of Grade greater than 2 requiring parenteral therapy. Participants may be eligible after the infection resolves.
• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura within 28 days before enrollment.
• Allogeneic bone marrow transplant within 4 months before first dose. Immunosuppressive therapy related to the transplant must be completed before enrollment.
• Active cancer that limits expected survival to less than 2 years or requires anticancer therapy concomitantly with study treatment. Exceptions may include resected localized skin, breast, or prostate cancer and malignancies treated with hormonal or immune therapies alone; secondary cancers should be discussed with the Medical Monitor.
• Physical examination or laboratory finding that contraindicates investigational therapy or otherwise places the participant at excessively high treatment risk in the investigator's opinion.
• Requirement for ongoing immunosuppressive therapy, including systemic corticosteroids, for cancer or another condition. Topical or inhaled corticosteroids and low-dose systemic steroids of no more than 20 mg prednisone equivalent per day are permitted for comorbid conditions. Short courses above this dose before first dose and during Week 1 may be used for tumor flare.
• Major surgery or significant trauma within 4 weeks before first dose.
• Breastfeeding. Breastfeeding must be discontinued before and during treatment and for at least 3 months after treatment ends.

Sponsors & Collaborators

• Lomond Therapeutics Holdings, Inc.: lead

Study Sites (5)

Norton Cancer Institute, St. Matthews Campus

Louisville, Kentucky, 40207, United States

RECRUITING

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

RECRUITING

University of Cincinnati

Cincinnati, Ohio, 45221, United States

RECRUITING

The Ohio State University

Columbus, Ohio, 43210, United States

RECRUITING

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell, Marginal Zone; Waldenstrom Macroglobulinemia; Recurrence; Tumor Lysis Syndrome

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Central Study Contacts

Ekaterina Dokukina, PhD MD

CONTACT

+1 858 353 4108; kdokukina@eileanther.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1 is a non-randomized sequential 3+3 dose-escalation study. Part 2 begins after dose selection and randomizes participants in parallel between two selected lonitoclax dose levels.

Study Record Dates

• First Submitted: November 22, 2024
• First Posted: November 27, 2024
• Study Start: April 8, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): July 1, 2028
• Last Updated: July 31, 2026

Record last verified: 2026-07

Locations

US (5)