Inclusion Criteria:
1. Men and women aged 18 years or older.
2. 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.
3. Disease requiring therapy in the investigator's opinion.
4. 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.
5. Eastern Cooperative Oncology Group performance status of 0, 1, or 2.
6. 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.
7. 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.
8. 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:
1. Part 2 only: Prior venetoclax treatment.
2. 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.
3. Known hypersensitivity to lonitoclax, its excipients, or an agent administered in association with the study.
4. 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.
5. Known active cytomegalovirus, hepatitis B virus, or hepatitis C virus infection.
6. HIV-positive disease that is not adequately controlled by antiviral therapy. Participants with adequately controlled HIV may enroll.
7. Known active SARS-CoV-2 infection. Prior infection is allowed if the participant completely recovered more than 14 days previously.
8. Active clinically serious infection of Grade greater than 2 requiring parenteral therapy. Participants may be eligible after the infection resolves.
9. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura within 28 days before enrollment.
10. Allogeneic bone marrow transplant within 4 months before first dose. Immunosuppressive therapy related to the transplant must be completed before enrollment.
11. 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.
12. Physical examination or laboratory finding that contraindicates investigational therapy or otherwise places the participant at excessively high treatment risk in the investigator's opinion.
13. 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.
14. Major surgery or significant trauma within 4 weeks before first dose.
15. Breastfeeding. Breastfeeding must be discontinued before and during treatment and for at least 3 months after treatment ends.
16. 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.
