Phase 2 Study on Acalabrutinib Discontinuation and Restart in Frail, Treatment-Naïve Elderly Patients with Chronic Lymphocytic Leukemia (CLL)
- Trial ID
- 2024-513936-80-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine whether discontinuing **acalabrutinib** after 18 months in treatment-naïve patients with chronic lymphocytic leukemia (CLL) affects progression-free survival (PFS) at one year following treatment interruption. This is clinically relevant as it may inform treatment strategies for elderly patients, potentially optimizing therapeutic outcomes and minimizing unnecessary exposure to medication.
Secondary objectives include:
- Investigating the impact of acalabrutinib withdrawal on time to next treatment (TTNT) and overall survival (OS).
- Assessing the quality of life of patients.
- Evaluating the tolerance profile of the treatment.
- Determining the overall response rate to re-treatment with acalabrutinib after discontinuation in the experimental arm.
Participants
The clinical trial involves **elderly patients** over the age of 70 diagnosed with **Chronic Lymphocytic Leukemia (CLL)** or **Small Lymphocytic Lymphoma (SLL)**. The study population includes both male and female participants, with no specific vulnerable populations selected. Participants are required to have adequate hematology and liver function values, and an **Eastern Cooperative Oncology Group (ECOG)** performance status of 2 or less. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as therapy-controlled cardiovascular comorbidities and anticoagulation are acknowledged, with certain restrictions on anticoagulant therapies. The trial population was selected based on specific inclusion criteria, including untreated CLL or SLL requiring treatment according to the iwCLL 2018 criteria, and a life expectancy of more than six months. The study does not focus on any particular dietary or physical activity requirements.
Plans and Procedures
The clinical trial is designed as an **open-label**, phase 2 study aimed at investigating the effects of stopping and restarting **acalabrutinib** in frail patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The primary objective is to determine whether discontinuing acalabrutinib after 18 months affects progression-free survival (PFS) at one year post-treatment interruption. The trial is expected to run from November 2021 to June 2028, with the estimated duration of participant involvement being up to 60 months, depending on individual response and progression.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age over 70 years, adequate hematology and liver function, and a life expectancy greater than six months. Following the screening, eligible participants will be enrolled and randomized to receive acalabrutinib, administered orally in the form of either 100 mg hard capsules or film-coated tablets. The treatment phase will last for 18 months, after which acalabrutinib will be discontinued to evaluate the primary endpoint of PFS.
Follow-up visits will be scheduled regularly to monitor the participants' health status, assess disease progression using the iwCLL 2018 criteria, and evaluate secondary endpoints such as overall survival (OS), time to next treatment (TTNT), quality of life (QoL), and overall response rate (ORR) to re-treatment. The end-of-study visit will occur at the conclusion of the trial or upon early termination, which may be necessitated by disease progression, adverse events, or withdrawal of consent. Participants will be censored at the last disease assessment or initiation of the next treatment if they remain alive and progression-free.
Treatment
The clinical trial involves the administration of **acalabrutinib**, an experimental medication, in two pharmaceutical forms: hard capsules and film-coated tablets. The hard capsules, marketed under the name Calquence 100 mg, are designed for **oral use**. Each capsule contains 100 mg of acalabrutinib, a chemical substance with the active ingredient identified by the European Union substance number SUB182073. The maximum daily dose for participants is 200 mg, with a total maximum dose of 336,000 mg over a treatment period of up to 60 days. The capsules are manufactured by AstraZeneca AB and are not formulated for pediatric use.
The film-coated tablets, also marketed as Calquence 100 mg, are similarly intended for oral administration. Each tablet contains 100 mg of the active substance acalabrutinib. The dosing regimen mirrors that of the hard capsules, with a maximum daily dose of 200 mg and a total maximum dose of 336,000 mg over a 60-day treatment period. These tablets are also produced by AstraZeneca AB and are not designed for pediatric patients. Both forms of the medication are chemically derived and have been authorized for use in the European Union under the marketing authorization number EU/1/20/1479/003.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The primary objective of the trial is to assess the impact of discontinuing acalabrutinib after 18 months on progression-free survival in treatment-naïve patients with chronic lymphocytic leukemia (CLL).
Efficacy
Efficacy in the clinical trial titled "FILOCLL14 - STAIR: Open-label, phase 2 study investigating the STop and restart Acalabrutinib In fRrail patients with previously untreated Chronic Lymphocytic Leukemia (CLL)" will be assessed using several parameters. The primary endpoint is **Progression-Free Survival (PFS)** at one year post-**Acalabrutinib** discontinuation. PFS is defined as the time from randomization to disease progression or death from any cause, with progression evaluated using the iwCLL 2018 criteria. Patients who are alive and progression-free will be censored at the last disease assessment or at the initiation of the next treatment.
Secondary endpoints include Overall Survival (OS), Time to Next Treatment (TTNT), Quality of Life (QoL), and Overall Response Rate (ORR) to re-treatment. OS is defined as the time from randomization to death from any cause, with patients alive censored at the last follow-up. TTNT is the time from randomization to the initiation of the next treatment required for symptomatic CLL, with the need for restarting therapy validated by an independent board review based on iwCLL 2018 criteria. QoL will be evaluated using the EORTC QLQ-C30 questionnaire. ORR to re-treatment is defined as the proportion of re-treated patients achieving a best response of complete remission, complete remission with incomplete marrow recovery, nodular partial remission, or partial remission per iwCLL 2018 criteria.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age > 70 years or older
- ECOG performance status ≤ 2
- Previously untreated CLL or SLL
- CLL or SLL requiring treatment according to the iwCLL 2018 criteria
- Total CIRS score > 6 and / or 30 < CrCl < 69 mL/min
- Both patients with or without TP53 disruption 17p deletion and/or TP53 mutations) can be included
- Patients can be included whatever their IGHV mutational status
- Patients with therapy-controlled cardiovascular comorbidities and/or anticoagulation (novel oral anticoagulant alone, aspirin alone, heparin alone) can be included (patients treated by vitamin K antagonist or dual anti-platelet therapy cannot be included)
- Life expectancy > 6 months
- Adequate hematology values: absolute neutrophil count ≥ 0.75 x 109/L, platelet count ≥ 50 x 109/L (accordance to the coordinator if linked to the disease)
- Adequate liver function as indicated by a total bilirubin < 1.5, aspartate transaminase and alanine transaminase ≤ 3 the institutional upper limits of normal values, unless directly attributable to CLL, unless directly attributable to Gilbert’s syndrome
- Signed (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including specify biology analysis, and are willing to participate in the study.
Exclusion Criteria
- Hypersensitivity to the active substance
- Patients who are not vaccinated against COVID (2nd dose 15 days before inclusion)
- Known HIV seropositivity
- Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: 1). Uncontrolled and/or active systemic infection (viral, bacterial or fungal). 2). Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with subjects who are on ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment 2a). Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded. 2b). Subjects who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrollment. Those who are hepatitis C virus PCR positive will be excluded. 3). Active and uncontrolled autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA) (isolated positive DAT is not an exclusion criteria) and idiopathic thrombocytopenic purpura (ITP). 4). Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
- Patients treated by vitamin K antagonist or dual anti-platelet therapy
- History of bleeding diathesis (e.g. hemophilia or von Willebrand disease)
- History of confirmed progressive multifocal leukoencephalopathy (PML).
- Concurrent severe diseases which exclude the administration of therapy: 1). Heart insufficiency NYHA grade III/IV, LEVF < 50% and or RF < 30%, myocardial infarction within the past 6 months prior to study. 2). Significant cardiovascular disease such as symptomatic arrhythmias (including atrial fibrillation), congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional (Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll on study). 3). Severe chronic obstructive lung disease with hypoxemia. 4). History of stroke or intra-cranial hemorrhage within the last 6 months. 5). Severe diabetes mellitus. 6).Uncontrolled hypertension 7). Impaired renal function with creatinine clearance < 30 ml/min according the formula of Cockroft and Gault. 8). Patient who requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) unless of separate dosing of acalabrutinib capsules with antacids by at least 2 hours. Acalabrutinib capsules should be taken 2 hours before an H2-receptor antagonist. Avoid co-administration of acalabrutinib capsules with proton pump inhibitors. 9). Disease significantly affecting gastrointestinal function (malabsorption syndrome, stomach or small bowel resection). 10). Evidence for Richter syndrome. 11). Treatment with any of the following within 7 days prior to the first dose of study drug : steroid therapy for anti-neoplastic intent. 12). A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the patient’s participation in this study or interpretation of study outcomes. 13). Major surgery within 30 days prior to the first dose of study treatment. 14). History of prior other malignancy that could affect compliance with the protocol or interpretation of results, with the exception of the following: - curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study; - other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which patient is disease-free for ≥ 5 years without further treatment
- Adult under law-control
- Fertile male patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study
- No affiliation to social security
- Patient under psychiatric care
- Patient unable to express consent
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 12 Nov 2021 | 160 |
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 hard capsules | Test | HARD CAPSULES | ORAL USE | 200 | 60 | PRD8485701 |
Calquence 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 200 | 60 | PRD10242587 |