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

Phase 1

Not yet recruiting

• Conditions: Large B-cell Lymphoma; B-cell Non-Hodgkin Lymphoma; Mantle-cell Lymphoma; Chronic Lymphocytic Leukaemia; Small Lymphocytic Leukaemia
• Interventions: Drug: AZD0486; Drug: Acalabrutinib; Drug: Prednisone; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Vincristine; Drug: Doxorubicin

• Registration Number: NCT06564038
• Lead Sponsor: AstraZeneca

Brief 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.

Detailed Description

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:
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Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Status Verified: 2024-08
• Study First Submitted: 2024-08-19
• Study First Submitted QC: 2024-08-19
• Last Update Submitted: 2024-08-19
• Study First Posted: 2024-08-21
• Last Update Posted: 2024-08-21
• Study Start: 2024-09-13
• Primary Completion: 2031-01-31
• Study Completion: 2031-01-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 180

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Substudy 1 (RR CLL/SLL): Cohort 1B (AZD0486 + Acalabrutinib)	AZD0486	Participants will receive AZD0486 as SC injection. Participants will receive acalabrutinib tablet orally twice daily.
Substudy 1 (RR CLL/SLL): Cohort 1A (AZD0486 Monotherapy)	AZD0486	Participants will receive AZD0486 monotherapy as subcutaneous (SC) injection.
Substudy 2 (RR MCL): Cohort 2B (AZD0486 + Acalabrutinib)	AZD0486	Participants will receive AZD0486 monotherapy as SC injection. Participants will receive acalabrutinib tablet orally twice daily.
Substudy 2 (RR MCL): Cohort 2A (AZD0486 Monotherapy)	AZD0486	Participants will receive AZD0486 monotherapy as SC injection.
Substudy 3 (LBCL): AZD0486 + R-CHOP	AZD0486	Participants will receive AZD0486 as intravenous (IV) infusion in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as per standard of care. For participants achieving CR or PR, AZD0486 will be administered every 3 weeks.
Substudy 1 (RR CLL/SLL): Cohort 1B (AZD0486 + Acalabrutinib)	Acalabrutinib	Participants will receive AZD0486 as SC injection. Participants will receive acalabrutinib tablet orally twice daily.
Substudy 2 (RR MCL): Cohort 2B (AZD0486 + Acalabrutinib)	Acalabrutinib	Participants will receive AZD0486 monotherapy as SC injection. Participants will receive acalabrutinib tablet orally twice daily.
Substudy 3 (LBCL): AZD0486 + R-CHOP	Prednisone	Participants will receive AZD0486 as intravenous (IV) infusion in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as per standard of care. For participants achieving CR or PR, AZD0486 will be administered every 3 weeks.
Substudy 3 (LBCL): AZD0486 + R-CHOP	Rituximab	Participants will receive AZD0486 as intravenous (IV) infusion in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as per standard of care. For participants achieving CR or PR, AZD0486 will be administered every 3 weeks.
Substudy 3 (LBCL): AZD0486 + R-CHOP	Cyclophosphamide	Participants will receive AZD0486 as intravenous (IV) infusion in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as per standard of care. For participants achieving CR or PR, AZD0486 will be administered every 3 weeks.
Substudy 3 (LBCL): AZD0486 + R-CHOP	Vincristine	Participants will receive AZD0486 as intravenous (IV) infusion in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as per standard of care. For participants achieving CR or PR, AZD0486 will be administered every 3 weeks.
Substudy 3 (LBCL): AZD0486 + R-CHOP	Doxorubicin	Participants will receive AZD0486 as intravenous (IV) infusion in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as per standard of care. For participants achieving CR or PR, AZD0486 will be administered every 3 weeks.

Primary Outcome Measures

Name	Time	Method
Number of Participants with Dose Limiting Toxicity (DLTs)	Up to 2 months	Safety and tolerability of AZD0486 as monotherapy and in combination with other anticancer agents across mature B-cell malignancies.
Number of Participants with Adverse Events, Serious Adverse Events and Adverse Events of Special Interest	Up to 6 years 4 months	Safety and tolerability of AZD0486 as monotherapy and in combination with other anticancer agents across mature B-cell malignancies.

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DoR)	Up to 6 years 4 months	DoR is defined as time from the date of first documented response until date of documented progression based on response criteria for iwCLL 2018 and Lugano 2014 assessed by investigator, relapse or death (substudy 1) and time from the date of first documented response until date of documented progression based on Lugano 2014 Response Criteria by investigator...
Number of Participants with Anti-drug Antibody (ADA) for AZD0486	Up to 90 days after last dose	The incidence of immunogenicity of SC AZD0486 as monotherapy and in combination with other anti-cancer agents will be evaluated.
Objective Response Rate (ORR)	Up to 6 years 4 months	ORR is defined as percentage of participants achieving either a partial response (PR) or complete response (CR) based on response criteria for International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 and Lugano 2014 assessed by investigator (substudy 1) and percentage of participants achieving CR as best response based on Lugano 2014 Response Crit...
Trough Plasma Concentration (Ctrough)	Up to 90 days after last dose	The PK (Ctrough) of AZD0486 as monotherapy and in combination with other anti-cancer agents will be evaluated.
Half Life (t1/2) of AZD0486	Up to 90 days after last dose	The PK (t1/2) of AZD0486 as monotherapy and in combination with other anti-cancer agents will be evaluated.
Clearance (CL) of AZD0486	Up to 90 days after last dose	The PK (CL) of AZD0486 as monotherapy and in combination with other anti-cancer agents will be evaluated.
Complete Response (CR) Rate	Up to 6 years 4 months	CR rate is defined as percentage of participants achieving CR as best response based on response criteria for iwCLL 2018 and Lugano 2014 assessed by investigator (substudy 1) and percentage of participants achieving CR as best response based on Lugano 2014 Response Criteria by investigator assessment (substudies 2 and 3).
Time to Reach Maximum Concentration (Tmax)	Up to 90 days after last dose	The PK (Tmax) of AZD0486 as monotherapy and in combination with other anti-cancer agents will be evaluated.
Maximum Observed Concentration (Cmax)	Up to 90 days after last dose	The PK (Cmax) of AZD0486 as monotherapy and in combination with other anti-cancer agents will be evaluated.
Area Under the Concentration-time Curve (AUC)	Up to 90 days after last dose	The PK (AUC) of AZD0486 as monotherapy and in combination with other anti-cancer agents will be evaluated.
Minimum Observed Concentration (Cmin)	Up to 90 days after last dose	The PK (Cmin) of AZD0486 as monotherapy and in combination with other anti-cancer agents will be evaluated.