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
Chronic Lymphocytic Leukaemia
Small Lymphocytic Lymphoma
Mantle-cell Lymphoma
Large B-cell Lymphoma
B-cell Non-Hodgkin Lymphoma
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 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:
- Screening period of 28 days
- Treatment period
- 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 lymphocytes <10,000.
- 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 < 10,000.
- Cohort 2A and 2C: Relapse or progressed after 2 or more lines of therapy including 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 90 days after last dose of AZD0486 or 4 months after last dose of vincristine, and 6 months after the last dose of cyclophosphamide, or doxorubicin.
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-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.
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 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.
HaematologyCTU.HPH@ramsayhealth.com.au
08 9346 6637
Professor Chan Cheah
AstraZeneca
Phase 1
Phase 2
D7407C00001
NCT06564038