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

Overview

The purpose of this study is to assess the safety and efficacy of surovatamig (formerly 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 surovatamig 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:

1. Screening period of 28 days 2. Treatment period 3. Follow-up period

Interventions

• Drug Surovatamig
  Surovatamig will be administered as either SC injection or IV infusion.
• Drug Prednisone (or equivalent)
  Prednisone (or equivalent) will be administered either oral or IV infusion as per standard of care.
• Drug Rituximab
  Rituximab will be administered as IV infusion as per standard of care.
• Drug Cyclophosphamide
  Cyclophosphamide will be administered as IV infusion as per standard of care.
• Drug Vincristine
  Vincristine will be administered as IV infusion as per standard of care.
• Drug Doxorubicin
  Doxorubicin will be administered as IV infusion as per standard of care.
• Drug Acalabrutinib
  Acalabrutinib will be administered orally

Primary outcome measures

• Number of Participants with Adverse Events, Serious Adverse Events and Adverse Events of Special Interest [Time frame: Up to 6 years 4 months]
• Number of Participants with Dose Limiting Toxicity (DLTs) [Time frame: Up to 2 months]

Secondary outcome measures (11)

• Overall Response Rate (ORR) [Time frame: Up to 6 years 4 months]
• Complete Response (CR) Rate [Time frame: Up to 6 years 4 months]
• Duration of Response (DoR) [Time frame: Up to 6 years 4 months]
• Maximum Observed Concentration (Cmax) [Time frame: Up to 90 days after last dose]
• Area Under the Concentration-time Curve (AUC) [Time frame: Up to 90 days after last dose]
• Minimum Observed Concentration (Cmin) [Time frame: Up to 90 days after last dose]
• Time to Reach Maximum Concentration (tmax) [Time frame: Up to 90 days after last dose]
• Trough Plasma Concentration (Ctrough) [Time frame: Up to 90 days after last dose]
• Half Life (t1/2) of surovatamig [Time frame: Up to 90 days after last dose]
• Clearance (CL) of surovatamig [Time frame: Up to 90 days after last dose]
• Number of Participants with Anti-drug Antibody (ADA) for surovatamig [Time frame: Up to 90 days after last dose]

Eligibility criteria

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 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.

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 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 13 centers

• Research Site — Boston
• Research Site — Hackensack
• Research Site — New Brunswick
• Research Site — New York
• Research Site — New York
• Research Site — Charlotte
• Research Site — Charlotte
• Research Site — Columbus
• … and 5 more centers

Germany · 6 centers

• Research Site — Cologne
• Research Site — Homburg
• Research Site — Kiel
• Research Site — Mainz
• Research Site — München
• Research Site — Würzburg

South Korea · 6 centers

• Research Site — Busan
• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul

Spain · 6 centers

• Research Site — Barcelona
• Research Site — Madrid
• Research Site — Madrid
• Research Site — Palma de Mallorca
• Research Site — Santiago de Compostela
• Research Site — Valencia

China · 5 centers

• Research Site — Beijing
• Research Site — Guangzhou
• Research Site — Jinan
• Research Site — Tianjin
• Research Site — Zhengzhou

France · 5 centers

• Research Site — Clermont-Ferrand
• Research Site — Montpellier
• Research Site — Paris
• Research Site — Saint-Cloud
• Research Site — Villejuif

Denmark · 4 centers

• Research Site — Aalborg
• Research Site — Aarhus N
• Research Site — Copenhagen
• Research Site — Odense C

Taiwan · 4 centers

• Research Site — Changhua
• Research Site — Kaohsiung City
• Research Site — Tainan
• Research Site — Taipei

United Kingdom · 4 centers

• Research Site — Derriford
• Research Site — London
• Research Site — Oxford
• Research Site — Southampton

Australia · 3 centers

• Research Site — Heidelberg
• Research Site — Melbourne
• Research Site — Nedlands

Czechia · 3 centers

• Research Site — Ostrava - Poruba
• Research Site — Prague
• Research Site — Praha 2 - Nové Město

Japan · 3 centers

• Research Site — Kōtoku
• Research Site — Matsuyama
• Research Site — Nagoya

Italy · 2 centers

• Research Site — Bologna
• Research Site — Milan

Identifiers

NCT: NCT06564038 · D7407C00001 · 2024-515034-33-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗