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

Inclusion Criteria:

Master Inclusion Criteria applicable to all substudies:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

• Contraception during treatment and at least 6 months after final dose.

• Confirmed CD19 expression if prior anti-CD19 therapy.

Substudy 1 Specific Inclusion Criteria:

• Participants with CLL must require treatment according to the international workshopon Chronic Lymphocytic Leukemia (iwCLL) criteria.

• SLL: at least 1 measurable site per Lugano.

• Absolute lymphocytes <10,000.

• Cohort 1A: at least 2 prior lines of therapy, including a Bruton tyrosine kinaseinhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i).

• Cohort 1B: at least 1 prior line of therapy and is 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: Relapse or progressed after 2 or more lines of therapy including BTKi.

• Cohort 2B: Relapse or progressed after 1 or more line of therapy, not including aBTKi.

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 12 months after last dose of R-CHOP or 6 months after lastdose of AZD0486.

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) priorto treatment.

• Radiation therapy within 28 days.

• Prior CAR-T or auto-haematopoietic stem cell transplant (HSCT) within 12 weeks orprior T-cell engager (TCE) within 8 weeks.

• Prior Grade > 3 cytokine release syndrome (CRS) or immune effector cell-associatedneurotoxicity syndrome (ICANS) event.

Substudy 1 Specific Exclusion Criteria:

• CLL transformation to more aggressive lymphoma

• Cohort 1B: bleeding diathesis, CYP3A inhibitor or inducer, history of ICH or strokewithin 6 months, GI malabsorption, receiving vitamin K antagonist

Substudy 2 Specific Exclusion Criteria:

• Cohort 2B: bleeding diathesis, CYP3A inhibitor or inducer, history of ICH or strokewithin 6 months, GI malabsorption, receiving vitamin K antagonist

Substudy 3 Specific Exclusion Criteria:

• Mediastinal grey-zone lymphoma, Burkitt, Richter's transformation, primary effusionlarge B-cell lymphoma (LBCL)

• Cumulative dose of anthracycline >150 mg/m2