A Phase I/II Open-Label Multi-Centre Master Protocol to Evaluate the Safety and Efficacy of AZD0486 Monotherapy or in Combination With Other Anticancer Agents in Participants With Mature B-Cell Malignancies
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Study Summary
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.
To assess safety and tolerability and determine the RP2D (recommended Phase II dose) of AZD0486 (administered as IV or SC) as monotherapy and in combination with other anticancer agents across mature B-cell malignancies\
To evaluate the safety and preliminary efficacy of AZD0486 as monotherapy and in combination with other anticancer drugs in patients with hematological malignancies
This study aims to evaluate the safety, tolerability, PK, and potential biological and clinical activity of AZD0486 as a monotherapy and in combination with other anticancer agents in patients with R/R mature B-cell hematologic malignancies, with a focus on determining the optimal dose and dosing regimen for AZD0486 SC or IV monotherapy or combination therapy.
To assess safety and tolerability and determine the RP2D (recommended Phase II dose) of AZD0486 (administered as IV or SC) as monotherapy and in combination with other anticancer agents across mature B-cell malignancies
Substudy 1 evaluates SC AZD0486 in R/R CLL/small lymphocytic lymphoma and includes a monotherapy cohort (1A; ≥2 prior lines of therapy [pLOT] with Bruton tyrosine kinase inhibitor exposure) and a cohort that receives combination with acalabrutinib (1B; ≥1 pLOT). Substudy 2 evaluates SC AZD0486 in R/R mantle cell lymphoma and includes a monotherapy cohort (2A; ≥2 pLOT) and a cohort that receives combination with acalabrutinib (2B; ≥1 pLOT). Substudy 3 evaluates AZD0486 in combination with R-CHOP in pts with untreated large B-cell lymphoma with International Prognostic Index ≥2, or R/R B-cell non-Hodgkin lymphoma with ≥1 pLOT.
To assess fixed-duration subcutaneous (SC) AZD0486 monotherapy in B-cell malignancies and fixed-duration SC or intravenous AZD0486 in combination with other anticancer agents.
- 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:
- Histologically confirmed diagnosis of previously untreated large B-cell Lymphoma (LBCL) per WHO 2022.
- R/R B-NHL after at least 1 prior lines of systemic therapy.
- International Prognostic Index (IPI) 2-5.
- Cohort 3B:
- Histologically confirmed diagnosis of previously untreated large B-cell Lymphoma (LBCL) per WHO 2022.
- IPI score of 2 to 5.
- 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.
Clinical Study Information for Healthcare Providers
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