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

The purpose of this study is to assess the safety and efficacy of AZD0486 administered as monotherapy or in combination with other anticancer agents in participants with hematological malignancies.

This is open-label, multi-center study to evaluate the safety and preliminary efficacy of AZD0486 administered as monotherapy and in combination with other anticancer agents in participants with mature B-cell hematologic malignancies.

This master study currently includes 3 substudies and each substudy focusing on a defined population:

Substudy 1: Relapsed/refractory (R/R) Chronic lymphocytic leukaemia (CLL)/ Small lymphocytic leukaemia (SLL) Substudy 2: R/R Mantle-cell lymphoma (MCL) Substudy 3: Large B-cell lymphoma (LBCL) or R/R B-cell non-Hodgkin lymphoma (B-NHL) (not applicable to US)

The study will have the following sequential periods:

1. Screening period of 28 days
2. Treatment period
3. Follow-up period

Eligibility Criteria:
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 workshop on 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 kinase inhibitor (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 a 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 12 months after last dose of R-CHOP or 6 months after last dose 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) prior to treatment.
* Radiation therapy within 28 days.
* Prior CAR-T or auto-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.

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 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 stroke within 6 months, 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