Acalabrutinib Monotherapy vs Investigator's Choice of Treatment in Patients With CL Leukaemia and Heart Failure

NCT06651970 | Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: D8223C00016
• Study Type: interventional
• Target: 60
• Locations: 6 countries
• Sites: 23

Brief Summary

This will be a global Phase IV, open-label, randomised study to evaluate the safety and tolerability of acalabrutinib (monotherapy, 100 mg orally \[po\], twice daily \[bd\]) compared to investigator's choice of treatment, in patients with CLL (TN or R/R) and moderate to severe cardiac impairment. All patients will have cardiac impairment as defined by LVEF of \< 50%. Randomisation will be stratified by LVEF \> 40% vs ≤ 40% to stratify for moderate and severe cardiac impairment, which for this study are defined as follows: Severe cardiac impairment: in those with LVEF ≤ 40% Moderate cardiac impairment: in those with LVEF \> 40% to \< 50%. The study is planned to take place in approximately 20 centres globally. The study will be conducted in centres that have established close collaboration between the Haematology and Cardiology divisions, preferably with a cardio-oncologist on the team. An IDMC will be responsible for making recommendations for study continuation.

Conditions

Chronic Lymphocytic Leukaemia; Heart Failure

Keywords

Hemic Diseases; Lymphatic Diseases

Outcome Measures

Primary Outcomes (7)

• Safety endpoints 1: To evaluate the incidence of CV (CardioVascular) adverse events leading to drug discontinuation after acalabrutinib treatment compared to investigators choice of treatment.

  Frequency and time to discontinuation of any study treatment due to worsening in cardiovascular function or cardiovascular AEs.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Safety endpoints 2: To evaluate the duration on treatment prior to drug discontinuation due to CV adverse events after acalabrutinib treatment compared to investigators choice of treatment.

  Incidence of Grade 4 and 5 cardiovascular events of interest.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Safety endpoints 3: To evaluate the incidence of life threatening and fatal cardiac events of interest after acalabrutinib treatment compared to investigators choice of treatment.

  Incidence and relationship to study treatment of Grade ≥ 3 AEs.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Safety endpoints 4: To evaluate the frequency of grade≥3 Adverse events after acalabrutinib treatment compared to investigators choice of treatment.

  Incidence and relationship to study treatment of Adverse events of special interest (AESI) defined per Acalabrutinib IB

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Safety endpoints 5: To evaluate the frequency of AESI per Acalabrutinib IB after acalabrutinib treatment compared to investigators choice of treatment.

  Incidence and relationship to study treatment of Non-cardiovascular AE that led to discontinuation of any study treatment.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Safety endpoints 6: To evaluate the rate of discontinuation due to non-CV adverse events after acalabrutinib treatment compared to investigators choice of treatment.

  Incidence and relationship to study treatment of Events of clinical interest (ECI) per acalabrutinib IB

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Safety endpoints 7: To evaluate the rate of any serious adverse event after acalabrutinib treatment compared to investigators choice of treatment.

  Incidence and relationship to study treatment of Serious adverse events (SAEs).

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

Secondary Outcomes (5)

• Efficacy Endpoints 1:To evaluate the overall survival after acalabrutinib treatment compared to investigators choice of treatment.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Efficacy Endpoints 2:To evaluate the overall response rate after acalabrutinib treatment compared to investigators choice of treatment.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Efficacy Endpoints 3: To evaluate the duration of response after acalabrutinib treatment compared to investigators choice of treatment.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Efficacy Endpoints 4: To evaluate the progression free survival after acalabrutinib treatment compared to investigators choice of treatment.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

• Efficacy Endpoints 5:To evaluate the event free survival after acalabrutinib treatment compared to investigators choice of treatment.

  Visits are screening+ 8 visits( every 4 weeks) and then every 16 weeks until termination of the study which would be 4 years from the last subject randomized.

Study Arms (2)

Treatment Arm A (Acalabrutinib Monotherapy)

ACTIVE COMPARATOR

All participants randomised to Arm A will receive treatment with the investigational product acalabrutinib.

Drug: Acalabrutinib

Treatment Arm B

OTHER

Patients in Arm B will receive investigator's choice of treatment its duration will be based on standard duration of therapy for that regimen or until disease progression/patient withdrawal/study termination, whichever occurs first.

Other: Investigator's choice of treatment

Interventions

Acalabrutinib DRUG

Acalabrutinib Monotherapy

Also known as: Calquence

Treatment Arm A (Acalabrutinib Monotherapy)

Investigator's choice of treatment OTHER

control arm treatment type will be defined by the PI prior to randomisation

Also known as: Investigator's choice of treatment : i.e venetoclax, Rituximab, Obinutuzumab, Zanubrutinib etc.

Treatment Arm B

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women ≥ 18 years of age, at the time of signing the informed consent.
• Eastern Cooperative Oncology Group performance status of 0 to 3
• Left ventricular ejection fraction assessed by ECHO \< 50%.
• Diagnosis of CLL
• Treatment naïve or relapsed/refractory patients who received no more than 2 prior lines of systemic anti-CLL treatment.
• Active disease per iwCLL 2018 criteria that requires treatment.
• Meet the following laboratory parameters:
• Absolute neutrophil count (ANC) ≥ 500 cells/μL (0.50 × 109/L).
• Platelet count ≥ 30,000 cells/μL (30 × 109/L).
• Serum aspartate aminotransferase and ALT ≤ 3.0 × ULN.
• Total bilirubin ≤ 1.5 × ULN unless directly attributable to Gilbert's syndrome.
• Estimated creatinine clearance (ie, estimated glomerular filtration rate \[eGFR\] using Cockcroft-Gault) ≥ 40 mL/min, or serum creatinine ≤ 2 × ULN.
• Women and men who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib.
• Patients must be willing and able to adhere to the study visit schedule, understand, and comply with other protocol requirements, and provide written informed consent and authorisation to use protected health information (in accordance with national and local patient privacy regulations). Note: vulnerable patients, as defined in the ICH GCP, are not allowed on this protocol (eg, prisoners or institutionalised patients).

You may not qualify if:

• Known active CNS leukaemia, leptomeningeal disease or spinal cord compression. In case of R/R patients with prior history of CNS localisation of leukaemia who received treatment are eligible provided that there is no evidence of CNS involvement at study entry as documented by cerebrospinal fluid (CSF) cytology and/or brain MRI.
• Ongoing Richter's transformation.
• Prior exposure to a BTKi.
• Major surgery within 30 days before first dose of study treatment.
• Uncontrolled haemolytic anaemia.
• Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study treatment.
• Received a live virus vaccination within 28 days of first dose of study treatment.
• History of or ongoing confirmed PML.
• History of prior malignancy except for the following:
• Prior history of malignancy with no evidence of active disease present for more than
• years before screening or felt to be at low risk for recurrence by treating physician.
• (b) Adequately treated lentigo maligna melanoma without current evidence of disease or adequately resected non-melanomatous skin cancer (ie, basal cell carcinoma or squamous cell carcinoma of the skin). (c) Curatively treated in situ carcinoma of the cervix or carcinoma in situ of the prostate at any time prior to study without current evidence of disease. 10 Unable to swallow tablets or malabsorption syndrome, or disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• Active uncontrolled systemic infection (bacterial, fungal, viral or other) or clinically significant localised infection. 12 Known history of infection with human immunodeficiency virus (HIV). 13 Serologic status reflecting active HepB or HepC infection.
• Patients with HepB core antibody positive who are surface antigen negative or who are HepC antibody positive will need to have a negative polymerase chain reaction (PCR) result before randomisation and must be willing to undergo deoxyribonucleic acid (DNA) PCR testing during the study.
• Patients who are HepB surface antigen positive or HepB PCR positive and those who are HepC PCR positive will be excluded. 14 History of stroke or intracranial haemorrhage within 6 months prior to randomisation.

Sponsors & Collaborators

• AstraZeneca: lead
• Fortrea: collaborator
• CALYX Inc.: collaborator
• eResearch Technology, Inc.: collaborator
• CISCRP: collaborator

Study Sites (23)

Research Site

Charlotte, North Carolina, 28204, United States

WITHDRAWN

Research Site

Columbus, Ohio, 43210, United States

RECRUITING

Research Site

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Research Site

Brno, 625 00, Czechia

RECRUITING

Research Site

Hradec Králové, 500 05, Czechia

WITHDRAWN

Research Site

Prague, 10034, Czechia

RECRUITING

Research Site

Cagliari, 09121, Italy

RECRUITING

Research Site

Florence, 50134, Italy

RECRUITING

Research Site

Milan, 20122, Italy

RECRUITING

Research Site

Milan, 20132, Italy

RECRUITING

Research Site

Pavia, 27100, Italy

RECRUITING

Research Site

Perugia, 06156, Italy

RECRUITING

Research Site

Krakow, 30-727, Poland

RECRUITING

Research Site

Poznan, 60-693, Poland

RECRUITING

Research Site

Barcelona, 08003, Spain

RECRUITING

Research Site

Madrid, 28040, Spain

RECRUITING

Research Site

Seville, 41009, Spain

RECRUITING

Research Site

Bournemouth, BH7 7DW, United Kingdom

NOT YET RECRUITING

Research Site

Oxford, OX3 7LE, United Kingdom

RECRUITING

Research Site

Plymouth, PL6 8DH, United Kingdom

RECRUITING

Research Site

Romford, RM7 0AG, United Kingdom

RECRUITING

Research Site

Stockton, TS19 8PE, United Kingdom

WITHDRAWN

Research Site

Sutton Coldfield, B74 3UP, United Kingdom

RECRUITING

MeSH Terms

Conditions

Leukemia, B-Cell; Heart Failure; Lymphatic Diseases

Interventions

acalabrutinib; Rituximab; obinutuzumab

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

AstraZeneca Clinical Study Information Center

CONTACT

1-877-240-9479; information.center@astrazeneca.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 20, 2024
• First Posted: October 22, 2024
• Study Start: February 4, 2025
• Primary Completion (Estimated): August 16, 2030
• Study Completion (Estimated): August 16, 2030
• Last Updated: April 15, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Locations

CZ (3); GB (6); US (3); PL (2); ES (3); IT (6)