A Study of AZD0486 Monotherapy or in Combination With Other Anti-Cancer Agents for Mature B-Cell Malignancies

Inclusion Criteria

• Participants with CLL must require treatment according to the international workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.
• SLL: at least 1 measurable site per Lugano.
• Absolute lymphocytes <10,000.
• Cohort 1A and 1C: at least 2 prior lines of systemic therapy for CLL/SLL.
• Cohort 1B: at least 1 prior line of therapy and is bruton tyrosine kinase inhibitor (BTKi)-sensitive. Substudy 2 Specific Inclusion Criteria:
• MCL diagnosis per WHO.
• Clinical Stage II, III, or IV by Ann Arbor Classification.
• At least 1 measurable site per Lugano.
• ALC < 10,000.
• Cohort 2A and 2C: Relapse or progressed after 2 or more lines of therapy including BTKi. Substudy 3 Specific Inclusion Criteria:
• Large B-cell lymphoma per WHO 2022.
• R/R B-NHL after at least 1 prior line of therapy.
• International Prognostic Index (IPI) 2-5.
• At least 1 measurable site as per Lugano.
• Left ventricular ejection fraction (LVEF) >50%.
• Contraception at least 90 days after last dose of AZD0486 or 4 months after last dose of vincristine, and 6 months after the last dose of cyclophosphamide, or doxorubicin. Exclusion Criteria: Master Exclusion Criteria applicable to all substudies:
• Central nervous system (CNS) lymphoma.
• Surgery within 14 days of study drug.
• Clinically significant cardiovascular (CV) disease.
• Unresolved Grade >2 AEs from prior anticancer therapy (except alopecia or fatigue).
• Any anticancer therapy within 5 half-lives or 21 days (whichever is shorter) prior to treatment.
• Radiation therapy within 28 days.
• Prior CAR T-cell therapy or autologous-haematopoietic stem cell transplant (HSCT) within 12 weeks or prior T-cell engager (TCE) within 8 weeks.
• Prior Grade > 3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) event.
• Prior allogeneic HSCT or solid organ transplantation within 24 weeks of starting Cycle 1 Day 1. Substudy 1 Specific

Exclusion Criteria

• CLL transformation to more aggressive lymphoma.
• Cohort 1B: bleeding diathesis, CYP3A inhibitor or inducer, history of ICH or stroke within 24 weeks, GI malabsorption, receiving vitamin K antagonist. Substudy 3 Specific Exclusion Criteria:
• Mediastinal grey-zone lymphoma, Burkitt, Richter's transformation, primary effusion large B-cell lymphoma (LBCL).
• Cumulative dose of anthracycline >150 mg/m2.