Acalabrutinib Monotherapy vs Investigator’s Choice of Treatment in Patients with Chronic Lymphocytic Leukaemia and Moderate to Severe Cardiac Impairment

Study identifier:D8223C00016

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Will Be Recruiting

Official Title

A Multicentre, Open-label, Randomised, Phase IV Study to Investigate Acalabrutinib Monotherapy Compared to Investigator’s Choice of Treatment in Adults (> 18 Years) With Chronic Lymphocytic Leukaemia and Moderate to Severe Cardiac Impairment

Medical condition

Chronic Lymphocytic Leukaemia and Moderate to Severe Cardiac Impairment

Phase

Phase 4

Healthy volunteers

Study drug

Acalabrutinib

Sex

All

Estimated Enrollment

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 15 Oct 2024

Estimated Primary Completion Date: 16 Aug 2030

Estimated Study Completion Date: 09 Oct 2030

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Other

Verification:

Verified 01 Aug 2024 by AstraZeneca

Collaborators

Fortrea Inc., Calyx IM and IRT `= Perceptive Informatics LLC,d/b/a Calyx, Clario, Merge, CISCRP

Inclusion and exclusion criteria

Inclusion Criteria

1 Men and women ≥ 18 years of age, at the time of signing the informed consent.
2 Eastern Cooperative Oncology Group performance status of 0 to 3
3 Left ventricular ejection fraction assessed by ECHO < 50%.
4 Diagnosis of CLL (Hallek et al, 2018)
5 Treatment naïve or relapsed/refractory patients who received no more than 2 prior lines of
systemic anti-CLL treatment.
6 Active disease per iwCLL 2018 (Hallek et al, 2018) criteria that requires treatment.
7 Meet the following laboratory parameters:
(a) Absolute neutrophil count (ANC) ≥ 500 cells/μL (0.50 × 109/L).
(b) Platelet count ≥ 30,000 cells/μL (30 × 109/L).
(c) Serum aspartate aminotransferase and ALT ≤ 3.0 × ULN.
(d) Total bilirubin ≤ 1.5 × ULN unless directly attributable to Gilbert’s syndrome.
(e) Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using
Cockcroft-Gault) ≥ 40 mL/min, or serum creatinine ≤ 2 × ULN.
8 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.
9 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).

Exclusion Criteria

1 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.
2 Ongoing Richter’s transformation.
3 Prior exposure to a BTKi.
4 Major surgery within 30 days before first dose of study treatment.
5 Uncontrolled haemolytic anaemia.
6 Received any investigational drug within 30 days or 5 half-lives (whichever is shorter)
before first dose of study treatment.
7 Received a live virus vaccination within 28 days of first dose of study treatment.
8 History of or ongoing confirmed PML.
9 History of prior malignancy except for the following:
(a) Prior history of malignancy with no evidence of active disease present for more than
3 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.
11 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.
(a) 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.
(b) 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.
15 History of bleeding diathesis (eg, haemophilia, von Willebrand disease).
16 Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
(eg, phenprocoumon) within 7 days of first dose of study treatment. Direct anti-X
(DOACs) or low molecular weight heparins (LMWH, eg, enoxaparin) on stable dosing
schedule is allowed.
17 Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor/inducer. The
use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks
of the first dose of study treatment is prohibited.
18 Breastfeeding or pregnant.
19 Concurrent participation in another therapeutic clinical trial.
20 Uncontrolled cardiac/cardiovascular disease including the following:
- Uncontrolled cardiac tachyarrhythmias (sinus, atrial or ventricular) that require
new/additional therapy within the last month.
- Clinically significant outlying QT interval corrected by Fridericia’s formula (QTcF)
values; QTcF > 470 ms or QTcF < 330 ms.
- Unstable ischaemic heart disease (IHD), recent (< 3 months): episode of acute
coronary syndrome, including acute myocardial infarction and unstable angina
pectoris.
- Percutaneous coronary intervention, or coronary artery bypass graft within the last
month.
21 Uncontrolled hypertension despite optimal management.
22 Current life-threatening illness, medical conditions, organ system dysfunction or lifestyle
habits which, in the investigator’s opinion, could compromise the patient’s safety or
ability to adhere to the study protocol.

Randomised controlled study: Treatment phase: Patients will receive treatment with either acalabrutinib 100 mg po tablets bd (until unacceptable toxicity or progression) or investigator’s choice of treatment (chlorambucil, venetoclax, ibrutinib, zanabrutinib, rituximab or Obinutuzumab etc). For the control arm the treatment type and duration will be defined by the PI prior to randomisation. Each treatment cycle is 28 days/4 weeks. Haematology visits (labs, physical exam), will be performed at the first day of each cycle for the first 8 cycles and every 4 cycles there after. Response assessment will be performed by the PI in accordance with modified iwCLL 2018 criteria (Hallek et al, 2018) every 4 cycles (16 weeks). Imaging and BM testing only as deemed appropriate by PI. Safety assessments will be performed at every visit. Cardiology assessments will be performed at the end of cycle 1 (C2D1) and 3 (C4D1) and thereafter every 4 cycles (16 weeks). These assessments will include: • A cardiology consult. • ECHO, 12-lead ECG and 24-hour Holter. • Cardiac biomarkers. • Any additional testing will be performed as clinically indicated. Cardiac MRI post-screening will be performed every year. Decisions for permanent withdrawal or modifications to treatment due to cardiac AEs will be made by PI after close consultation with the cardiologist. Post-Treatment Phase: Safety assessments Once treatment is discontinued due to any of the reasons mentioned above, a safety follow-up (SFU) will occur within 45 days of the last dose of treatment. This will occur regardless of the patient developing progressive disease or initiation a new anti-CLL therapy during that timespan. The evaluation will include: • Cardiology consult • Cardiac biomarkers • 12-lead ECG, ECHO and 24 hour Holter • Cardiac MRI (if not performed in the last 6 months). The subsequent safety assessments will continue until disease progression, WoC, death or termination of study whichever occurs first. These will mirror the in-treatment schedule, with cardiology consults including ECHO, ECG, cardiac biomarkers and 24 hour Holter performed every 16 weeks and yearly cardiac MRI. Once patient has progressive disease they will be contacted to assess survival status every 16 weeks. Response assessments Patients that discontinue treatment prior to progression will continue to be evaluated for disease progression every 16 weeks. The response assessment will be per iwCLL 2018 guidelines and will be performed by the PI. Bone marrow testing and imaging will continue to remain optional and per PI discretion. Once patient has progressive disease they will be contacted every 16 weeks for survival status and information on any new anti-cancer therapy until WoC, death, termination of study by Sponsor whichever occurs first.

No locations available

Arms	Assigned Interventions
Active Comparator: Treatment Arm A (Acalabrutinib Monotherapy) All participants randomised to Arm A will receive treatment with the investigational product acalabrutinib.	Drug: Acalabrutinib Acalabrutinib Monotherapy
Other: Treatment Arm B 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: Unknow control arm treatment type will be defined by the PI prior to randomisation

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Investigators

Principal Investigator

Paolo Prospero NA GHIA