ACALABRUTINIB for Chronic lymphocytic leukaemia | Moderate to severe cardiac impairment

Stratification factors

• LVEF > 40% vs ≤ 40%

Inclusion criteria

• {"criterion_text":"- Men and women ≥ 18 years of age, at the time of signing the informed consent."}
• {"criterion_text":"- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3."}
• {"criterion_text":"- Left ventricular ejection fraction (LVEF) assessed by echocardiogram (ECHO) < 50%."}
• {"criterion_text":"- Diagnosis of CLL per (Hallek et al, 2018)."}
• {"criterion_text":"- Treatment naïve (TN) or relapsed/refractory (R/R) patients who received no more than 2 prior lines of systemic anti-CLL treatment."}
• {"criterion_text":"- Active disease per iwCLL 2018 (Hallek et al, 2018) criteria that requires treatment."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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

• {"criterion_text":"- 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."}
• {"criterion_text":"- Breastfeeding or pregnant."}
• {"criterion_text":"- Concurrent participation in another therapeutic clinical trial."}
• {"criterion_text":"- Ongoing Richter’s transformation."}
• {"criterion_text":"- 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. \tClinically 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."}
• {"criterion_text":"- Uncontrolled hypertension (> 140/90 mmHg) despite optimal management."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Prior exposure to a BTKi."}
• {"criterion_text":"- Major surgery within 30 days before first dose of study treatment."}
• {"criterion_text":"- Uncontrolled haemolytic anaemia."}
• {"criterion_text":"- Received any investigational drug within 30 days or 5-half-lives (whichever is shorter) before first dose of study treatment."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Received a live virus vaccination within 28 days of first dose of study treatment."}
• {"criterion_text":"- History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Hypersensitivity to the study treatments active substance or to any of the excipients listed in the Prescribing Information."}
• {"criterion_text":"- Any contraindication to the study treatments in Arm B as per the local Prescribing Information."}
• {"criterion_text":"- Active uncontrolled systemic infection (bacterial, fungal, viral, or other) or clinically significant localised infection."}
• {"criterion_text":"- Known history of infection with human immunodeficiency virus (HIV)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- History of stroke or intracranial haemorrhage within 6 months prior to randomisation."}
• {"criterion_text":"- History of bleeding diathesis (eg, haemophilia, von Willebrand disease)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}

Primary endpoints

• {"endpoint_text":"- Frequency and time to discontinuation of any study treatment due to worsening in cardiovascular. function or cardiovascular Adverse events (AEs).","definition_or_measurement_approach":"Frequency and time to discontinuation will be recorded; assessments based on occurrence of cardiovascular AEs leading to treatment discontinuation as captured during study visits and safety monitoring."}
• {"endpoint_text":"- Incidence of Grade 4 and 5 cardiovascular events of interest.","definition_or_measurement_approach":"Incidence of grade 4 and 5 cardiovascular events will be collected and graded per CTCAE (implicitly) and reported as events of interest."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Incidence and investigator-assessed relationship to study treatment will be captured; AESIs defined per acalabrutinib Investigator’s Brochure; ECIs per SAP."}

Secondary endpoints

• {"endpoint_text":"- Overall survival (OS), defined as the time from randomisation to death from any cause.","definition_or_measurement_approach":"OS measured as time (days) from randomisation until death from any cause; censoring per protocol."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"EFS per iwCLL 2018: time from randomisation to progression, start of next anti-CLL therapy, or death."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"ORR is proportion of patients achieving CR, CRi, nPR or PR per response assessment (iwCLL criteria)."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"DOR measured from first documented PR or better to progression or death."}
• {"endpoint_text":"- Progression‑free survival (PFS), defined as the time from randomisation to disease progression or death (by any cause in the absence of disease progression).","definition_or_measurement_approach":"PFS measured as time from randomisation to progression or death; assessments per iwCLL 2018 criteria."}

Methods

• Patient Recruitment Engagement provided by Merge (listed as third party with duty 'Patient Recruitment Engagement') — no specific channels described in source.
• Recruitment arrangements and materials available (documents listed: K1_Recruitment arrangements, K2_Recruitment material_Patient Brochure, K2_Study Overview Flipchart) — materials associated with country Part II applications.

Poland

Earliest CTIS Part Ii Submission Date

28-06-2024

Latest Decision Or Authorization Date

26-09-2024

Processing Time Days

90

Number Of Sites

2

Number Of Participants

5

Italy

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

23-07-2024

Processing Time Days

50

Number Of Sites

6

Number Of Participants

6

Czechia

Earliest CTIS Part Ii Submission Date

04-11-2024

Latest Decision Or Authorization Date

28-11-2024

Processing Time Days

24

Number Of Sites

3

Number Of Participants

11

Spain

Earliest CTIS Part Ii Submission Date

30-05-2024

Latest Decision Or Authorization Date

22-07-2024

Processing Time Days

53

Number Of Sites

3

Number Of Participants

11

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Fortrea Inc.

Responsibilities

Third Party Vendor set up management; sponsor duties codes present (1,11,12,15,2,6,7,8)

Name

Perceptive Eclinical Limited

Responsibilities

Operational role (sponsor duty code 3)

Name

Perceptive Informatics Inc.

Responsibilities

Imaging and reading

Name

Eresearchtechnology Inc.

Responsibilities

Cardio ECG & reading

Name

Merge

Responsibilities

Patient Recruitment Engagement

Name

Medidata Solutions Inc.

Third parties

• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"Third Party Vendor set up management; sponsor duties codes present (1,11,12,15,2,6,7,8)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Merge","duties_or_roles":"Patient Recruitment Engagement","organisation_type":"Industry"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Cardio ECG & reading","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Perceptive Eclinical Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"Imaging and reading","organisation_type":"Pharmaceutical company"}