A Phase I/II Study of AZD4512 Monotherapy or in Combination With Anticancer Agents in Participants With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

Core Inclusion Criteria

• Eligible patients must be adults (≥18 years)
• Additional criteria include measurable disease by Lugano 2014, ECOG performance status ≤2, and adequate organ and bone marrow function (as specified by blood counts, cardiac ejection fraction, renal and hepatic parameters, and coagulation indices).

Module 1 Monotherapy Inclusion criteria

• Documented histologically confirmed diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as per World Health Organization (WHO) 2022 classification. In the dose escalation phase, any B-NHL subtype is allowed (excluding some subtypes), while the backfill phase restricts inclusion to defined subtypes: large B-cell lymphomas (as defined as Diffuse large B-cell lymphoma (DLBCL), Grade 3b Follicular lymphoma (FL), high-grade B-cell lymphoma (HGBCL) NOS, DLBCL/HGBCL with MYC and BCL2 rearrangements, primary mediastinal Large B-cell lymphoma, T-cell/histiocyte-rich LBCL, and transformed indolent lymphoma) and mantle cell lymphoma.
• Patients with LBCL must have relapsed or refractory disease after at least two prior lines of systemic therapy and lack additional standard options with established benefit. Additionally patients must have progressed after both anti CD20 and at least one systemic chemotherapy regimen, and have considered-or be ineligible for-CAR-T, T cell engager, and stem cell transplant modalities Participants with MCL must have previously received an anti-CD20 based therapy, and BTKi

Module 2 Surovatamig Combination Inclusion criteria

• Documented histologically confirmed diagnosis of LBCL as defined as: DLBCL ( not otherwise specified), Grade 3b FL, DLBCL/high grade B-cell lymphoma with MYC and BCL2 rearrangements, High grade B-cell lymphoma (not other specified), Primary mediastinal LBCL, T-cell/histiocyte-rich LBCL, Transformations of indolent B-cell lymphoma.
• Participants who have received previous CD19-directed therapy must have locally assessed confirmation (after completion of the CD19-directed therapy) to demonstrate presence of CD19 expression by immunohistochemistry or flow cytometry.
• Patients must have relapsed or refractory disease after at least two prior lines of systemic therapy and lack additional standard options with established benefit. Additionally patients must have progressed after both anti-CD20 and at least one systemic chemotherapy regimen, and have considered-or be ineligible for-CAR-T, T cell engager, and stem cell transplant modalities

Core Exclusion Criteria

• Active CNS involvement from their B-NHL. Exclusion also applies to those who have received CAR-T , within 6 months or T cell engager therapies within 90 days prior to C1D1, any investigational drug or other systemic anticancer therapies (except low-dose corticosteroids, ≤10mg prednisone/day) within 21 days or 5 half-lives, and curative radiation within 14 days (localized palliative radiotherapy is allowed).
• Other exclusions include: allogeneic HSCT within 180 days (unless stable without active GVHD for ≥2 months), autologous HSCT within 90 days (unless resolved toxicities), major surgery within 28 days, use of strong CYP3A inhibitors within 14 days or 5 half-lives before the dosing date, use of QTc-prolonging agents within 5 half-lives before the dosing date, or other malignancies within two years. Patients with unresolved ≥ Grade 2 AEs from prior therapy (except specified tolerable conditions), serious uncontrolled medical conditions, active infection within 14 days, or history/suspicion of significant ILD/pneumonitis are also excluded.
• Females who are pregnant or breastfeeding are not eligible.
• Previous dosing with AZD4512

Module 1 Exclusion Criteria Patients are excluded if they have a diagnosis of post transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, CLL/SLL, Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma

Module 2 Exclusion Criteria

Participants will be excluded if they have:

• Clinically significant central nervous system (CNS) pathologies, including neurological, neurodegenerative, psychiatric, or other severe mental health conditions.
• Active or prior CNS involvement related to autoimmune disease.
• Leukemic presentation of non-Hodgkin lymphoma (NHL), with circulating malignant lymphoid cells in peripheral blood.
• A history of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). • Prior Grade ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) following CAR T-cell or T-cell engager (TCE) therapy, or any unresolved CRS/ICANS.
• Prior exposure to surovatamig.
• Diagnosis of Richter's transformation