Clinical trial NCT06564038: A Study of AZD0486 Monotherapy or in Combination With Other Anti-Cancer Agents for Mature B-Cell Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Chronic Lymphocytic Leukaemia
Small Lymphocytic Leukaemia
Mantle-cell Lymphoma
Large B-cell Lymphoma
B-cell Non-Hodgkin Lymphoma
Keywords: IgG4 fully human CD19xCD3 bispecific T-cell engager
B cell lymphoma
Subcutaneous
AZD0486
Acalabrutinib
Prednisone
Rituximab
Cyclophosphamide
Vincristine
Doxorubicin
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2024-08-21
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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:

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

Eligibility criteria: 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.

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

Primary outcomes:
measure: Number of Participants with Adverse Events, Serious Adverse Events and Adverse Events of Special Interest
timeFrame: Up to 6 years 4 months
measure: Number of Participants with Dose Limiting Toxicity (DLTs)
timeFrame: Up to 2 months
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to 6 years 4 months
measure: Complete Response (CR) Rate
timeFrame: Up to 6 years 4 months
measure: Duration of Response (DoR)
timeFrame: Up to 6 years 4 months
measure: Maximum Observed Concentration (Cmax)
timeFrame: Up to 90 days after last dose
measure: Area Under the Concentration-time Curve (AUC)
timeFrame: Up to 90 days after last dose
measure: Minimum Observed Concentration (Cmin)
timeFrame: Up to 90 days after last dose
measure: Time to Reach Maximum Concentration (Tmax)
timeFrame: Up to 90 days after last dose
measure: Trough Plasma Concentration (Ctrough)
timeFrame: Up to 90 days after last dose
measure: Half Life (t1/2) of AZD0486
timeFrame: Up to 90 days after last dose
measure: Clearance (CL) of AZD0486
timeFrame: Up to 90 days after last dose
measure: Number of Participants with Anti-drug Antibody (ADA) for AZD0486
timeFrame: Up to 90 days after last dose
Other outcomes:
Locations:
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New Brunswick
country: United States
facility: Research Site
state: New Jersey
city: New York
country: United States
facility: Research Site
state: New York
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Providence
country: United States
facility: Research Site
state: Rhode Island
city: Heidelberg
country: Australia
facility: Research Site
city: Melbourne
country: Australia
facility: Research Site
city: Nedlands
country: Australia
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Jinan
country: China
facility: Research Site
city: Tianjin
country: China
facility: Research Site
city: Zhengzhou
country: China
facility: Research Site
city: Ostrava - Poruba
country: Czechia
facility: Research Site
city: Praha 2 - Nové Město
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Aalborg
country: Denmark
facility: Research Site
city: Aarhus N
country: Denmark
facility: Research Site
city: Copenhagen
country: Denmark
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Saint Cloud
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Wuerzburg
country: Germany
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Matsuyama-shi
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Palma de Mallorca
country: Spain
facility: Research Site
city: Santiago de Compostela
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Changhua
country: Taiwan
facility: Research Site
city: Kaohsiung City
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Derriford
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
Study officials:
References: