A trial to learn if AZD0486 alone or with other anticancer drugs is safe and works in adults with certain blood cancers

Phase 1/2

Recruiting

• Conditions: Large B-Cell Lymphoma; Chronic Lymphocytic Leukaemia; Small Lymphocytic Lymphoma; Mantle Cell Lymphoma

• Registration Number: 2024-515034-33-00
• Lead Sponsor: AstraZeneca AB

Brief Summary

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

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:

Substudy 1: Relapsed/refractory (R/R) Chronic lymphocytic leukaemia (CLL)/ Small lymphocytic leukaemia (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

Study Timeline

• Study First Posted: 2025-01-07
• Last Update Posted: 2025-03-12

Recruitment & Eligibility

• Status: Ongoing, recruiting
• Sex: Not specified
• Target Recruitment: 135

Inclusion Criteria

All sub- studies: Age >18 years

Sub-study 2: MCL diagnosis per WHO

Sub-study 2: Stage II, III, or IV per Ann Arbor classification

Sub-study 2: At least 1 measurable site per Lugano

Sub-study 2: ALC < 10,000

Sub- study 2, Cohort 2A: Relapse after 2 or more lines of therapy including BTKi

Sub-study 2, Cohort 2B: Relapse or progressed after 1 or more line of therapy, not including a BTKi

Sub-study 3: Large B-cell lymphoma per WHO 2022 or R/R B-NHL after at least 1 prior line of therapy

Sub-study 3: IPI 2-5

Sub-study 3: At least 1 measurable site as per Lugano

Sub-study 3: LVEF >50%

All sub- studies: ECOG performance status 0 to 2

Sub-study 3: Contraception at least 12 months after last dose of R-CHOP or 6 months after last dose of AZD0486

All sub-studies: Contraception during treatment and at least 6 months after final dose

All sub- studies: Confirmed CD19 expression if prior anti-CD19 therapy

Sub-study 1: CLL/SLL diagnosis and meets iwCLL criteria for treatment

Sub-study 1: SLL: at least 1 measurable site per Lugano

Sub-study 1: Absolute lymphocytes <10,000

Sub-study 1, Cohort 1A: at least 2 prior lines of therapy, including BTKi and BCL2i

Sub-study 1, Cohort 1B: at least 1 prior line of therapy and BTKi sensitive or naïve

Exclusion Criteria

All sub- studies: CNS lymphoma

Sub-study 1, Cohort 1B: bleeding diathesis, CYP3A inhibitor or inducer, history of ICH or stroke within 6 months, GI malabsorption, receiving vitamin K antagonist

Sub-study 2, Cohort 2B: bleeding diathesis, CYP3A inhibitor or inducer, history of ICH or stroke within 6 months, GI malabsorption, receiving vitamin K antagonist

Sub-study 3: Mediastinal grey-zone lymphoma, Burkitt, Richter’s transformation, primary effusion LBCL

Sub-study 3: Cumulative dose of anthracycline >= 150 mg/m2

All sub- studies: Surgery within 14 days of study drug

All sub- studies: Clinically significant CV disease

All sub- studies: Unresolved Grade >=2 AEs from prior anticancer therapy (except alopecia or fatigue)

All sub-studies: Any anticancer therapy within 5 half-lives or 21 days (whichever is shorter) prior to treatment

All sub-studies: Radiation therapy within 28 days

All sub-studies: Prior CAR-T or auto-HSCT within 12 weeks or prior TCE within 8 weeks

All sub-studies: Prior Grade >= 3 CRS or ICANS event

Sub-study 1: CLL transformation to more aggressive lymphoma

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Primary Outcome Measures

Name	Time	Method
Incidence, nature and severity of AEs/SAEs based on NCI CTCAE v5.0/ASTCT criteria; changes in laboratory data, and vital signs compared with baseline		Incidence, nature and severity of AEs/SAEs based on NCI CTCAE v5.0/ASTCT criteria; changes in laboratory data, and vital signs compared with baseline
Incidence of Dose Limiting Toxicity (DLTs)		Incidence of Dose Limiting Toxicity (DLTs)
Incidence and severity of AESIs		Incidence and severity of AESIs
Incidence and nature of study drug discontinuation, dose reduction and dose delay due to AEs		Incidence and nature of study drug discontinuation, dose reduction and dose delay due to AEs

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 assessment, relapse or death (substudies 2 and 3).
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 Criteria by investigator assessment (substudies 2 and 3).
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.

Trial Locations

Locations (19)

Institute Of Hematology And Blood Transfusion; 🇨🇿 Prague, Czechia

Fakultni Nemocnice Ostrava; 🇨🇿 Ostrava, Czechia

Vseobecna Fakultni Nemocnice V Praze; 🇨🇿 Prague, Czechia

Region Midtjylland; 🇩🇰 Aarhus N, Denmark

Rigshospitalet; 🇩🇰 Copenhagen Oe, Denmark

Aalborg University Hospital; 🇩🇰 Aalborg, Denmark

Klinikum der Universitaet Muenchen AöR; 🇩🇪 Munich, Germany

Universitaetsklinikum Schleswig-Holstein AöR; 🇩🇪 Kiel, Germany

Universitaetsklinikum Wuerzburg AöR; 🇩🇪 Wuerzburg, Germany

Hospital Universitario Fundacion Jimenez Diaz; 🇪🇸 Madrid, Spain

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Institute Of Hematology And Blood Transfusion

🇨🇿Prague, Czechia

Robert Pytlik

Site contact

+420775630341

Robert.Pytlik@uhkt.cz