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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

18 Dec 2024 → ongoing

Decision date (initial)

2024-11-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB, Sweden

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Efficacy

To evaluate the safety and tolerability of acalabrutinib monotherapy vs investigator’s choice of treatment in patients with treatment naïve or
relapsed/refractory chronic lymphocytic leukaemia and moderate to severe cardiac impairment.

Secondary objectives 1

1. To evaluate the extent and duration of tumour response and survival after acalabrutinib vs investigator’s choice of treatment in patients with treatment naïve or relapsed/refractory chronic lymphocytic leukaemia and moderate to severe cardiac impairment

Conditions and MedDRA coding

Chronic Lymphocytic Leukaemia and Moderate to Severe Cardiac Impairment

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Men and women ≥ 18 years of age, at the time of signing the informed consent.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3.
3. Left ventricular ejection fraction (LVEF) assessed by echocardiogram (ECHO) < 50%.
4. Diagnosis of CLL per (Hallek et al, 2018).
5. Treatment naïve (TN) or relapsed/refractory (R/R) 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: - Absolute neutrophil count (ANC) ≥ 500 cells/μL (0.50 × 109/L). - Platelet count ≥ 30,000 cells/μL (30 × 109/L). - Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (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 x ULN.
8. Women and men who are sexually active and can bear children must agree to use highly effective forms of contraception.Contraceptives used by men or women should follow the respective Prescribing Information requirements and be consistent with local regulations.
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 International Council for Harmonisation (ICH) Good Clinical Practice (GCP), are not allowed on this protocol (eg, prisoners or institutionalised patients).

Exclusion criteria 24

1. Known active central nervous system (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 CSF cytology and/or brain MRI.
2. 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.
3. Active uncontrolled systemic infection (bacterial, fungal, viral, or other) or clinically significant localised infection.
4. Known history of infection with human immunodeficiency virus (HIV).
5. Serologic status reflecting active HepB or HepC infection.Patients who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative DNA polymerase chain reaction (PCR) result before randomisation and must be willing to undergo DNA PCR testing during the study. Those who are HBsAg-positive or hepatitis B PCR positive will be excluded. Patients who are hepatitis C antibody positive will need to have a negative RNA PCR result before randomisation. Those who are hepatitis C PCR positive will be excluded.
6. History of stroke or intracranial haemorrhage within 6 months prior to randomisation.
7. History of bleeding diathesis (eg, haemophilia, von Willebrand disease).
8. 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.
9. 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.
10. Breastfeeding or pregnant.
11. Concurrent participation in another therapeutic clinical trial.
12. Ongoing Richter’s transformation.
13. Uncontrolled cardiac/cardiovascular disease including the following: Baseline cardiac troponin (cTnI or cTnT or hs-cTn) levels greater than the upper limit of normal (per the local laboratories reference range) that cannot be fully explained by non-ischemic conditions. 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.
14. Uncontrolled hypertension (> 140/90 mmHg) despite optimal management.
15. 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.
16. Prior exposure to a BTKi.
17. Major surgery within 30 days before first dose of study treatment.
18. Uncontrolled haemolytic anaemia.
19. Received any investigational drug within 30 days or 5-half-lives (whichever is shorter) before first dose of study treatment.
20. Received a live virus vaccination within 28 days of first dose of study treatment.
21. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
22. History of prior malignancy except for the following: - 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 the treating physician. - 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). - 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.
23. Hypersensitivity to the study treatments active substance or to any of the excipients listed in the Prescribing Information.
24. Any contraindication to the study treatments in Arm B as per the local Prescribing Information.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Frequency and time to discontinuation of any study treatment due to worsening in cardiovascular. function or cardiovascular Adverse events (AEs).
2. Incidence of Grade 4 and 5 cardiovascular events of interest.
3. Incidence and relationship to study treatment of: - Grade ≥ 3 AEs. - Serious adverse events (SAEs). - Adverse events of special interest (AESI) defined per acalabrutinib Invetigator’s Brochure (IB). - Non-cardiovascular AE that lead to discontinuation of any study treatment. - Events of clinical interest (ECI)as defined in the Statistical Analysis Plan (SAP).

Secondary endpoints 5

1. Overall survival (OS), defined as the time from randomisation to death from any cause.
2. Per iwCLL 2018 criteria (Hallek et al, 2018): Event-free survival (EFS), defined as the time from randomisation to disease progression, initiation of subsequent anti-CLL therapy, or death from any cause, whichever occurs first.
3. Overall response rate (ORR), defined as the proportion of patients with a complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR).
4. Duration of response (DOR), defined as the time from the first documented response (PR or better) to disease progression or death (by any cause in the absence of disease progression).
5. Progression‑free survival (PFS), defined as the time from randomisation to disease progression or death (by any cause in the absence of disease progression).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Third parties 6

Locations

4 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 35 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications