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

Prior treatment

• 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.
• 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 SARS-CoV-2 infection. Prior infection is allowed if the participant completely recovered more than 14 days previously.
• 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.
• Major surgery or significant trauma within 4 weeks before first dose.

Other illness

• Known hypersensitivity to lonitoclax, its excipients, or an agent administered in association with the study.
• 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.
• Active clinically serious infection of Grade greater than 2 requiring parenteral therapy. Participants may be eligible after the infection resolves.
• 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.

Lab values

• Physical examination or laboratory finding that contraindicates investigational therapy or otherwise places the participant at excessively high treatment risk in the investigator's opinion.
• 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.

Other

• Breastfeeding. Breastfeeding must be discontinued before and during treatment and for at least 3 months after treatment ends.

• 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.