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

Official title

Phase 1 Study of Lonitoclax (ZE50-0134) in Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), and Select Low-grade Lymphomas

Overview

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.

Detailed description

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.

Interventions

• Drug Lonitoclax (ZE50-0134)
  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. Parti

Primary outcome measures

• Incidence and severity of treatment-emergent adverse events and serious adverse events [Time frame: 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 [Time frame: Cycle 1 (Days 1-28).]
• Determination of the biologically effective dose and/or maximum tolerated dose [Time frame: After completion of Cycle 1 for evaluable participants in each Part 1 dose cohort.]

Secondary outcome measures (6)

• Overall Response Rate (ORR) [Time frame: From first dose through end of treatment, up to 24 cycles (28 days per cycle).]
• Duration of response (DOR) [Time frame: 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) [Time frame: 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) [Time frame: 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 [Time frame: Cycle 1 Days 1-4, 8, 15, and 22; Cycle 2 Days 1-2; and end-of-treatment/early-termination sampling as applicable.]
• Area under the plasma concentration-time curve (AUC) of lonitoclax [Time frame: Cycle 1 Days 1-3 and Cycle 2 Day 1, based on protocol-specified serial PK sampling.]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.
• QT interval corrected using Fridericia's formula greater than 470 milliseconds that cannot be corrected with electrolyte replacement, hydration, or medication modification. This criterion does not apply to participants with a pacemaker.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 5 centers

• Norton Cancer Institute, St. Matthews Campus — Louisville
• University of North Carolina at Chapel Hill — Chapel Hill
• University of Cincinnati — Cincinnati
• The Ohio State University — Columbus
• UT Southwestern Medical Center — Dallas

Identifiers

NCT: NCT06708897 · ZE50-0134-0002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗