A Randomized Study of Acalabrutinib and Venetoclax in Newly Diagnosed Chronic Lymphocytic Leukemia Patients at High Risk of Infection or Early Treatment
- Trial ID
- 2024-511072-33-00
- Protocol
- PreVent-ACaLL
- Sponsor
- Region Hovedstaden
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate **Grade ≥3-infection-free survival** in the treatment arm compared to the observation arm 12 weeks after finishing treatment (24 weeks after treatment initiation) in patients with **Chronic Lymphocytic Leukemia** (CLL). This non-inferiority analysis aims to ensure the safety of the combination treatment in this preemptive trial population. Additionally, in an optional phase 3 part, the study will assess Grade ≥3-infection-free and CLL-treatment-free survival 2 years after enrollment. These objectives are clinically relevant as they focus on the safety and efficacy of the treatment regimen in preventing severe infections and delaying the need for further CLL treatment.
Secondary objectives include:
- Grade ≥3-infection-free and CLL-treatment-free survival at the end of treatment, 1 year, and 2 years after enrollment.
- Rate of overall survival (OS) and cause of death.
- Treatment-free survival.
- Rate and CTCAE V5.0 grade of infections.
- Response rate and duration according to IWCLL criteria.
- Treatment-related adverse events, including type, frequency, and severity during and for 2 years after treatment.
- Immune function as assessed by immune phenotyping, functional TruCulture assays, and measurements of cytokine levels.
- MRD levels in bone marrow and peripheral blood.
- Quality of life during and for 2 years after treatment, assessed by QLQC30 and CLL16.
Participants
The clinical trial involves participants diagnosed with **Chronic Lymphocytic Leukemia** (CLL) according to IWCLL criteria within one year prior to randomization. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group Performance Status of 0-2. Participants are required to have adequate bone marrow function, liver function, and creatinine clearance. The trial population is selected based on their high risk of infection and/or progressive treatment within two years according to CLL-TIM, and they must not fulfill IWCLL treatment indication. Participants must have a life expectancy greater than two years and be willing and able to adhere to study procedures, including swallowing capsules without difficulty. The sponsor has not provided the total number of participants. The trial includes individuals who are considered a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a combination treatment involving **venetoclax** and **acalabrutinib** in patients newly diagnosed with **Chronic Lymphocytic Leukemia** (CLL) who are at high risk of infection and/or early treatment but do not meet the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) treatment criteria. This is a randomized, controlled, and double-blind study, structured to ensure rigorous assessment of the treatment's impact on infection-free survival. The trial is set to span a total duration of approximately eight years, with an estimated recruitment start date in September 2019 and an anticipated end date in September 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a diagnosis of CLL within one year prior to randomization, adequate bone marrow and liver function, and a life expectancy of more than two years. Following the screening, participants will be randomized into either the treatment arm or the observation arm. The primary objective is to compare Grade ≥3 infection-free survival between these two groups 12 weeks after completing the treatment, which corresponds to 24 weeks post-treatment initiation.
Throughout the trial, follow-up visits will be conducted to monitor the participants' health status, adherence to the treatment protocol, and any adverse events. These visits will also include assessments of immune function through immune phenotyping and cytokine level measurements. The end-of-study visit will mark the conclusion of the participant's involvement, where final evaluations will be conducted to assess overall survival, treatment-free survival, and response rates according to IWCLL criteria.
Participant involvement is expected to last up to two years, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial's design ensures that all participants are monitored closely to maintain safety and integrity throughout the study period.
Treatment
The clinical trial involves the administration of **Venclyxto** (venetoclax) in three different dosages: 10 mg, 50 mg, and 100 mg film-coated tablets. **Venclyxto** is a chemical compound provided by AbbVie Deutschland GmbH & Co. KG. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose for the 10 mg tablet is 20 mg, with a total maximum dose of 140 mg over a treatment period of 1 week. For the 50 mg tablet, the maximum daily dose is 50 mg, with a total maximum dose of 350 mg over a treatment period of 1 week. The 100 mg tablet has a maximum daily dose of 400 mg, with a total maximum dose of 5300 mg over a treatment period of 10 weeks. Compliance with the dosing schedule is monitored throughout the trial.
Additionally, the trial includes the administration of **Calquence** (acalabrutinib), a chemical compound provided by AstraZeneca AB. **Calquence** is available in the form of 100 mg hard capsules, administered orally. The maximum daily dose is 200 mg, with a total maximum dose of 16800 mg over a treatment period of 12 weeks. Participant compliance with the dosing regimen is closely monitored to ensure adherence to the treatment protocol.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial. The study focuses on the combination of **acalabrutinib** and **venetoclax** for the treatment of newly diagnosed patients with chronic lymphocytic leukemia (CLL) at high risk of infection and/or early treatment, who do not fulfill IWCLL treatment criteria. The trial aims to evaluate the safety and efficacy of this combination therapy, with a primary objective of assessing grade ≥3 infection-free survival in the treatment arm compared to the observation arm.
Efficacy
Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoint is **Grade ≥3-Infection-free survival** in the treatment arm compared to the observation arm, evaluated 12 weeks after finishing treatment, which corresponds to 24 weeks after treatment initiation. This endpoint will be analyzed using a non-inferiority approach as detailed in the statistical analysis plan to ensure the safety of the combination treatment in this preemptive trial population.
Secondary endpoints include **Grade ≥3-infection free, CLL-treatment-free survival** at the end of treatment, as well as 1 year and 2 years after enrollment. Additional secondary endpoints encompass overall survival and cause of death, treatment-free survival, rate and CTCAE grade of infections, response rate and duration according to IWCLL criteria, and treatment-related adverse events, including type, frequency, and severity during and for 2 years after treatment. Furthermore, immune function will be assessed through immune phenotyping, functional TruCulture assays, and measurements of cytokine levels.
Inclusion and Exclusion Criteria
Inclusion Criteria
- CLL diagnosed according to IWCLL criteria within one year prior to randomization
- High risk of infection and/or progressive treatment within 2 years according to CLL-TIM
- IWCLL treatment indication not fulfilled
- Life expectancy > 2 years
- Age at least 18 years
- Ability and willingness to provide written informed consent and adhere to study procedures and treatment
- Adequate bone marrow function as indicated by platelets above 100 x 10E9, hemoglobin above 10 g/dL and neutrophils above 1 x 10E9
- Creatinine clearance above 30 mL/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault
- Adequate liver function as indicated by a total bilirubin≤ 2 x, AST or ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
- Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration (signature date on informed consent).
- Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
- Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 30 days after the last dose of investigational drugs.
- Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
- Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information.
Exclusion Criteria
- Prior CLL treatment (including monoclonal antibodies, chemotherapy, small molecules, including CD20 antibodies, BTK inhibitors and bcl-2 inhibitors for any indication)
- Transformation of CLL (Richter’s transformation)
- Previous autoimmune disease as AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura) treated with immune suppression or uncontrolled AIHA or ITP
- History of progressive multifocal leukoencephalopathy
- HIV infection (a negative test required)
- Known active infection
- Malignancies other than CLL requiring systemic therapies (except anti-hormonal therapies) or considered to impact survival
- Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonists
- History of bleeding disorders or current platelet inhibitors or anticoagulant therapy
- History of clinically significant cardiovascular disease such as arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening (counting from signature date on informed consent), or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening.
- History of stroke or intracranial hemorrhage within 6 months prior to (signature date on informed consent).
- Use of investigational agents which might interfere with the study drug within 28 days prior to first day of treatment/C1D1.
- Vaccination with live vaccines within 28 days prior to first day of treatment/C1D1.
- Major surgery less than 30 days before start of treatment. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
- Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
- Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly).
- Fertile men or women of childbearing potential unless: surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 30 days after the end of study treatment.
- Legal incapacity.
- Persons who are in dependence to the sponsor or an investigator
- Persons not considered fit for the trial by the investigator
- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
- Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x ULN.
- Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 01 Sept 2019 | 30 |
 The Netherlands | Not Recruiting | 01 Sept 2019 | — |
 Sweden | Not Recruiting | 01 Sept 2019 | 15 |
| Netherlands | — | — | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Venclyxto 10 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 20 | 1 | PRD6353818 |
Calquence 100 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 200 | 12 | PRD8485701 |
Venclyxto 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 10 | PRD6353834 |
Venclyxto 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 50 | 1 | PRD6353826 |