The purpose of this study is to assess the safety and efficacy of surovatamig (formerly 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 surovatamig 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 lymphoma (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

Inclusion Criteria:

Master Inclusion Criteria applicable to all substudies:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Contraception use during treatment and at least 90 days 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 lymphocyte count (ALC) <25000 cells/mcL.
• 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 < 25000 cells/mcL.
• Cohort 2A and 2C: Relapse or progressed after 2 or more lines of therapy including BTKi.

Substudy 3 Specific Inclusion Criteria:

• At least 1 measurable site as per Lugano.

• Left ventricular ejection fraction (LVEF) ≥50%.

• Participant must be no older than 79 years of age at the time of signing ICF.

• Contraception at least 90 days after last dose of surovatamig or 4 months after last dose of vincristine, and 6 months after the last dose of cyclophosphamide, or doxorubicin.

• Cohort 3A:

  1. Histologically confirmed diagnosis of previously untreated large B-cell Lymphoma (LBCL) per WHO 2022.
  2. R/R B-NHL after at least 1 prior lines of systemic therapy.
  3. International Prognostic Index (IPI) 2-5.

• Cohort 3B:

  1. Histologically confirmed diagnosis of previously untreated large B-cell Lymphoma (LBCL) per WHO 2022.
  2. IPI score of 2 to 5.

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 systemic 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.
• Active, significant, uncontrolled infection or autoimmune disease requiring systemic therapy including participants with known history of haemophagocytic lymphohistiocytosis (HLH).

Substudy 1 Specific Exclusion Criteria:

• CLL/SLL transformation to more aggressive form of 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.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via there quest portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure."Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.