STop and Restart Acalabrutinib In fRail Patients With Previously Untreated Chronic Lymphocytic Leukemia

NCT ID: NCT04963946

Last Updated: 2025-12-03

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 160 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-18
• Study Completion Date: 2028-08-01

Brief Summary

The irreversible Bruton's Tyrosine Kinase (BTK) inhibitor acalabrutinib (ACA) has potent clinical activity as a single agent in patients with treatment naive and Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

However, a growing body of concerns is raising regarding the unlimited administration of targeted therapy as BTKi. First, long-term treatments expose the patients to increased risk of specific adverse events (infections, bleeding events or cardiovascular problems). Second, continuous administration might also increase the risk of clonal evolution and therapeutic resistance resulting from genetic alterations such as BTK or PLCG2 mutations. Discontinuation of therapy after a fixed period is expected to prevent these events.

Rapid and deep responses yielded by ACA in elderly patients pave the way of investigating a limited 18-months period schedule. This study aims to investigate the 1-year PFS upon ACA discontinuation and efficacy of restarting ACA upon symptomatic relapse.

Detailed Description

This multicenter, non comparative, randomized phase II trial aims at evaluating the impact of a stopping ACA strategy on PFS of CLL patients >70 years or with coexisting comorbidities.

Patients will receive continuous Acalabrutinib (ACA) at 100 mg bid for 18 months. Dose adaptations will be made according to labels.

In case of first occurrence of grade ≥3 non-hematological toxicity, febrile grade ≥3 neutropenia or grade ≥4 hematological toxicity treatment must be stopped until recovering grade 1 or baseline state.

• 1st and second occurrence : restart at 100 mg twice daily
• 3rd occurrence : restart at 100 mg once daily
• 4th occurrence : discontinue acalabrutinib

At month 19 day 1, patients will be randomized (1:2) in two arms:

• Arm 1 = Control arm (acalabrutinib) continuing acalabrutinib until disease progression or unacceptable toxicity or
• Arm 2 = Experimental arm (watch and monitor) without ACA (see trial design).

Upon progression in the experimental arm, all patients will be re-treated with ACA at the last received dose after central reviewing of treatment criteria.

Upon progression in the control arm, patients will receive next line therapy at the discretion of their physicians and according to iwCLL 2018 criteria.

Patients will be monitored every three months until M31 then every 6 months until M60 or progression for both response and toxicity according to CTCAE v.5.

Minimal/Measurable Residual Disease (MRD) assessment will be done at month 19 day 1 in the peripheral blood.

CT-scan will be performed at baseline, then at month 19 day 1 and every 6 months within the year after randomization.

Conditions

Untreated Chronic Lymphocytic Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

watch and monitor

After 18 months of acalabrutinib treatment, patients will stop acalabrutinib treatment for watch and monitor until month 60. If progression disease, patients will be re-treated with ACA at the last received dose after central reviewing of treatment criteria.

Group Type: EXPERIMENTAL

Stop ACA

Intervention Type: DRUG

discontinuation of acalabrutinib after 18 months in treatment-naïve CLL patients

Acalabrutinib

After 18 months of acalabrutinib treatment, patients will continue acalabrutinib treatment until month 60. If progression disease or unacceptable toxicity, patients will receive next line therapy at the discretion of their physicians and according to iwCLL 2018 criteria

Group Type: ACTIVE_COMPARATOR

ACA Continuation

Intervention Type: DRUG

continuation of acalabrutinib at the same dose

Interventions

Stop ACA

discontinuation of acalabrutinib after 18 months in treatment-naïve CLL patients

Intervention Type: DRUG

ACA Continuation

continuation of acalabrutinib at the same dose

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age > 70 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status < 2
• Previously untreated CLL or Small Lymphocytic Lymphoma (SLL)
• CLL or SLL requiring treatment according to the iwCLL 2018 criteria2
• Total Cumulative Illness Rating Scale (CIRS) score > 6 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.
• 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
• 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

• Known HIV seropositivity
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

• Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
• 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

1. 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 Polymerase Chain Reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.

2. 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

• 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 :

• heart insufficiency New York Heart Association (NYHA) grade III/IV, Left Ventricular Ejection Fraction (LEVF) < 50% and or Recirculation Fraction (RF) < 30%, myocardial infarction within the past 6 months prior to study
• Significant cardiovascular disease such as symptomatic arrhythmias, 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)
• severe chronic obstructive lung disease with hypoxemia
• history of stroke or intra-cranial hemorrhage within the last 6 months
• severe diabetes mellitus
• uncontrolled hypertension
• impaired renal function with creatinine clearance < 30 ml/min according the formula of Cockcroft and Gault
• Patient who 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 in this study.
• Disease significantly affecting gastrointestinal function (malabsorption syndrome, stomach or small bowel resection)
• Evidence for Richter syndrome
• Treatment with any of the following within 7 days prior to the first dose of study drug: steroid therapy for anti-neoplastic intent.
• 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
• Major surgery within 30 days prior to the first dose of study treatment.
• 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

• Minimum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

French Innovative Leukemia Organisation

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Loïc Ysebaert, Pr

Role: PRINCIPAL_INVESTIGATOR

French Innovative Leukemia Organisation

Romain GUIEZE, Pr

Role: PRINCIPAL_INVESTIGATOR

French Innovative Leukemia Organisation

Locations

Chu Angers

Angers, , France

ARGENTEUIL - Centre hospitalier Victor Dupouy

Argenteuil, , France

Ch Avignon

Avignon, , France

Ch Cote Basque

Bayonne, , France

BOBIGNY - Hôpital Avicenne

Bobigny, , France

Hôpital Privé Sévigné

Cesson-Sévigné, , France

CHU Estaing - Hématologie Clinique Adulte

Clermont-Ferrand, , France

Corbeil-Essonnes -

Corbeil-Essonnes, , France

CHU Grenoble - Hématologie

Grenoble, , France

Centre Hospitalier du Mans

Le Mans, , France

Hôpital Saint Vincent de Paul

Lille, , France

Centre Léon Bérard - Hématologie

Lyon, , France

Institut Paoli-Calmettes - Hématologie Clinique

Marseille, , France

Centre Hospitalier Regional Metz Thionville

Metz, , France

Hôpital Saint-Eloi - Hématologie Clinique

Montpellier, , France

Hopital E.Muller

Mulhouse, , France

CHR ORLEANS - Hématologie

Orléans, , France

Hopital Pitie Salpetriere Service Hematologie Clinique - Pavillon de L'Enfant Et Adolescent

Paris, , France

CENTRE HOSPITALIER SAINTJEAN - Hématologie Clinique

Perpignan, , France

Bordeaux Pessac

Pessac, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

Hôpital de la Milétrie - Hématologie et Thérapie Cellulaire

Poitiers, , France

CERGY-PONTOISE - Centre Hospitalier René Dubos

Pontoise, , France

Chu Reims

Reims, , France

CHU Pontchaillou - Hématologie Clinique BMT-HC

Rennes, , France

Centre Henri Becquerel - Service Hématologie Clinique

Rouen, , France

Institut de Cancérologie Lucien Neuwirth

Saint-Priest-en-Jarez, , France

IUCT ONCOPOLE - Hématologie

Toulouse, , France

Hôpital Bretonneau - Hématologie et Thérapie Cellulaire

Tours, , France

CHU Nancy Brabois

Vandœuvre-lès-Nancy, , France

Vannes - Chba

Vannes, , France

VERSAILLES - Hôpital André Mignot

Versailles, , France

Countries

France

Other Identifiers

FILOCLL14 - STAIR

Identifier Type: -

Identifier Source: org_study_id