Phase II Multicenter Study of Acalabrutinib in Elderly or Frail Patients with Treatment-Naïve or Relapsed/Refractory Chronic Lymphocytic Leukemia
- Trial ID
- 2023-507002-14-00
- Protocol
- CLL-Frail
- Sponsor
- University Of Cologne
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this trial is to evaluate the **efficacy** of acalabrutinib in patients aged 80 years or older, or those with a FRAIL scale score greater than 2, who have been diagnosed with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). This is clinically relevant as it addresses the treatment needs of a vulnerable population with limited therapeutic options.
Secondary objectives include:
- Objective response rate (ORR) at final restaging approximately 24 months after therapy initiation.
- Overall survival (OS).
- Progression-free survival (PFS).
- Event-free survival (EFS).
- Duration of response.
- Time to next CLL treatment (TTNT).
- Feasibility parameters, including treatment modifications, discontinuation reasons, and treatment exposure metrics.
- Safety parameters, focusing on the type, frequency, and severity of adverse events (AEs), adverse events of special interest (AESI), and adverse events of particular interest (AEPI), such as falls and delirium, and their relationship to the study treatment.
Participants
The clinical trial involves participants diagnosed with **chronic lymphocytic leukemia** (CLL), specifically those who are treatment-naïve or have relapsed/refractory CLL. The study population includes both male and female subjects aged 80 years or older, or those considered too frail for intensive or standard treatment, as defined by a frailty score greater than 2 on the FRAIL scale. The trial does not involve a vulnerable population. Participants must have a life expectancy of at least three months and a maximum of one previous treatment for CLL. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations, such as diet and physical activity, are not specified. The selection criteria ensure that participants have adequate liver and marrow function, and are free from active hepatitis B or C infections. The trial aims to assess the efficacy of acalabrutinib in this specific cohort of CLL patients.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **acalabrutinib** in patients aged 80 years or older, or those considered frail, with **chronic lymphocytic leukemia** (CLL). This is a prospective, multicenter, phase II trial. The study employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to last approximately 24 months, with an estimated recruitment start date of June 1, 2021, and an estimated end date of June 30, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, frailty score, and previous treatment history. Following the screening, eligible participants will be enrolled and randomized to receive the study medication. The primary endpoint is the overall response rate at the initial response assessment, approximately six months after the initiation of therapy. Secondary endpoints include overall survival, progression-free survival, and safety parameters, among others.
Study visits will occur at regular intervals, with follow-up visits scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur at the conclusion of the treatment period, approximately 24 months after the initiation of therapy. Participants are expected to be involved in the study for the entire duration unless specific conditions necessitate early termination, such as significant adverse events or withdrawal of consent.
The trial will involve the administration of **Calquence 100 mg film-coated tablets** or **hard capsules**, with a maximum daily dose of 200 mg. The treatment period is set for a maximum of 168 weeks. Participants must adhere to the study protocol and visit schedule to remain in the trial. Conditions that may lead to early termination include non-compliance with the protocol, development of severe adverse events, or any other medical condition that, in the investigator's judgment, warrants discontinuation of the study medication.
Treatment
The clinical trial involves the administration of **acalabrutinib**, a small molecule drug classified as a Bruton’s tyrosine kinase inhibitor. The experimental medication is provided in two pharmaceutical forms: **Calquence 100 mg film-coated tablets** and **Calquence 100 mg hard capsules**. Both forms are intended for **oral use**. The maximum daily dose for each form is 200 mg, with a total maximum dose of 235,200 mg over the course of the treatment period. The treatment duration is set for a maximum of 168 days. The specific labelling and packaging have been adapted for the clinical trial to ensure compliance and accurate dosing.
**Calquence 100 mg film-coated tablets** are manufactured by AstraZeneca AB and are chemically derived. The tablets are designed to be taken orally, with a recommended dosage of 100 mg twice daily, ensuring a total daily intake of 200 mg. The administration schedule is consistent throughout the trial period, and participant compliance is monitored through regular assessments and pill counts.
**Calquence 100 mg hard capsules** are also produced by AstraZeneca AB and share the same active ingredient, **acalabrutinib**. These capsules are similarly administered orally, with a dosage of 100 mg twice daily. The administration and monitoring protocols for the capsules mirror those of the film-coated tablets, ensuring uniformity in treatment delivery and participant adherence.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The focus remains solely on evaluating the efficacy of **acalabrutinib** in the specified patient cohort. Compliance with the dosing schedule is critical, and adherence is tracked through participant self-reporting and clinical evaluations.
Efficacy
The efficacy of acalabrutinib in the clinical trial will be assessed primarily through the **Overall Response Rate (ORR)** at the initial response assessment, which is scheduled for cycle 7, day 1, approximately six months after the initiation of therapy. Secondary endpoints include ORR at final restaging (cycle 25, day 1, approximately 24 months after initiation), overall survival (OS), progression-free survival (PFS), event-free survival (EFS), duration of response, and time to next CLL treatment (TTNT). Feasibility parameters such as treatment modification, reasons for treatment discontinuation, total cumulative dose, dose intensity, and time on treatment will also be evaluated. Safety parameters will include the type, frequency, and severity of adverse events (AEs), adverse events of special interest (AESI), and adverse events of particular interest (AEPI), including falls and delirium, which are typical adverse geriatric outcomes. These efficacy and safety parameters will be collected and analyzed to determine the effectiveness of acalabrutinib in the specified patient cohort.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥80 years AND/OR considered too frail for intensive/standard treatment defined by a frailty score of >2 on the FRAIL scale via the patient´s assessment.
- Have documented CLL requiring treatment according to iwCLL 2018 criteria.
- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
- GFR >30ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 – age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method. Please note: Patients currently on hemodialysis are excluded from participating in the trial.
- Adequate liver function as indicated by a total bilirubin ≤ 3 x, AST/ ALT ≤ 3 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
- Adequate marrow function independent of growth factor or transfusion support as follows, unless cytopenia is due to marrow involvement of CLL: i. Absolute neutrophil count ≥ 1.0 × 10^9/L. ii. Platelet counts ≥ 30 × 10^9/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator); platelet count should be ≥ 10 × 10^9/L if there is bone marrow involvement. iii. Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to marrow involvement of CLL).
- 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/every three months if persistently negative until 12 months after last month of treatment), negative testing for hepatitis C RNA within 6 weeks prior to registration.
- Life expectancy ≥ 3 months.
- Maximum of 1 previous treatment for CLL.
- In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treat-ment in the CLL-Frail trial: i. chemotherapy ≥ 28 days, ii. antibody treatment ≥ 14 days, iii. kinase inhibitors (see also exclusion criterion 6), BCL2-antagonists or immuno-modulatory agents ≥ 3 days, iv. corticosteroids may be applied until the start of the study therapy, these have to be reduced to an equivalent of ≤ 20mg prednisolone per day during treatment.
- Signed informed consent and, in the investigator’s judgment, able to comply with the study protocol.
Exclusion Criteria
- >1 prior CLL-specific therapy (corticosteroid treatment is not counted as prior treatment; within the last 10 days before start of study treatment, only corticosteroid dose equivalents up to 20 mg prednisolone are permitted).
- Transformation of CLL to aggressive NHL (Richter’s transformation or pro-lymphocytic leukaemia).
- Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).
- Patients with uncontrolled autoimmune haemolytic anaemia or immune thrombocytopenia.
- Prior exposure to acalabrutinib.
- Progression during previous treatment with another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Bruton´s Tyrosine Kinase (BTK) and Phospholipase C Gamma 2 (PLCg2).
- Uncontrolled concomitant malignancy, i.e. any concomitant malignancy that may compromise the assessment of CLL stage and the response assessment of the study treatment.
- Eastern Cooperative Oncology Group Performance Status (ECOG) performance status >3.
- Uncontrolled or active infection (including positive SARS-Cov-2 PCR result).
- Patients with known infection with human immunodeficiency virus (HIV).
- Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 3 months of screening, or any class 4 cardiac disease as defined by the New York Heart Association Functional Classification at Screening. Please note: Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll in the study.
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
- Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathesis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hemorrhage ≤ 6 months.
- Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
- Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists. Please note: Switch to alternative anticoagulants for vitamin K antagonists is permitted.
- Inability to swallow tablets.
- Legal incapacity.
- Prisoners or subjects who are institutionalized by regulatory or court order.
- Persons who are in dependence to the sponsor or an investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Jun 2021 | 16 |
 Germany | Not Recruiting | 01 Jun 2021 | 37 |
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 |
|---|---|---|---|---|---|---|
Calquence 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 200 | 168 | PRD10242588 |
Calquence 100 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 200 | 168 | PRD8485702 |