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NCT Number: NCT07099443

Determinants of the Response to BTK Degraders (BTKd) in Chronic Lymphocytic Leukemia

The aim of the REBELLE cohort - bio-collection is to collect samples from patients with Chronic Lymphocytic Leukemia candidates or those exposed to BTK degraders to evaluate the mechanisms of resistance to these new molecules. To do this, an additional blood or bone marrow sample to those planned in the context of patient care or a residual lymph node biopsy sample will be collected after signing consent.

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Key information

About this study

Chronic Lymphocytic Leukemia (CLL) is a malignant hematological disease of B cells, primarily observed in older adults. Although it is classified among indolent hematological malignancies, CLL exhibits significant heterogeneity, both in terms of its biological characteristics and its disease progression and the therapeutic strategies employed. In patients requiring treatment, the disease can relapse. Until recently, immunochemotherapy remained the standard treatment for this disease, but the last decade has seen the emergence of oral targeted therapies, such as Bruton's tyrosine kinase inhibitors (BKT1s) and BCL-2 inhibitors (BCL-2 inhibitors), which have profoundly altered patient prognosis. While the introduction of these two classes of drugs has led to improved prognosis, a rare but significant subgroup of patients, known as "double refractory," has emerged. These patients, exposed to both BKT and BCL-2 inhibitors and who have become refractory to both treatments, have a poor prognosis. To overcome this problem of resistance, molecules targeting the degradation of the BTK protein (BTKd) are currently under development. The main investigator propose the creation of a cohort and a biobank of samples from CLL patients who are candidates for or have been exposed to BTKd, in order to study the mechanisms of response and resistance to these molecules.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Patient with CLL candidates ou exposed to BTKd
  • Patient who has provided informed consent to participate in the study.
  • Patient covered by a social security health insurance plan

Exclusion criteria

  • Minor patients.
  • Adults under guardianship.
  • Protected persons.

Treatment and study plan

Non-Interventional Sample Collection and Analysis

Other

This study is observational. Biological samples are collected as part of standard care or for research purposes and analyzed to characterize resistance mechanisms. No treatment or intervention is administered as part of the study protocol.

Primary outcomes

  1. Characterization of resistance mechanisms to CLL patients candidates or exposed to BTKd.

    Time frame: Up to 5 years after inclusion

    The primary outcome is the in-depth characterization of tumor cells and their microenvironment in CLL patients candidates or exposed to BTKd. Analyses will be performed using cellular biology (e.g., flow cytometry), molecular biology (e.g., RNA sequencing), and bioinformatics (e.g., deconvolution). Functional studies include the development of preclinical ex vivo models (2D/3D culture) and gene editing of primary cells using CRISPR/Cas9 technology, based on the expertise of Team 11 at CRCI²NA.

    The study will include 60 patients over a 9-year enrollment period. Each participant will be followed for 5 years, resulting in a total study duration of 14 years.

Secondary outcomes

  1. Development of preclinical ex vivo culture models

    Time frame: Up to 5 years after inclusion

    Establishment of 2D and 3D ex vivo culture systems using primary CLL cells to replicate tumor behavior and evaluate functional characteristics.

  2. Genetic modification of primary CLL cells

    Time frame: Up to 5 years after inclusion

    Application of gene editing technologies (e.g., CRISPR/Cas9) to modify primary chronic lymphocytic leukemia cells in order to investigate gene function and resistance pathways.

  3. Genomic data analysis to identify resistance-related genes

    Time frame: Up to 5 years after inclusion

    Comprehensive genomic and transcriptomic profiling of CLL samples to identify genetic alterations and expression patterns associated with resistance to BTK degraders.

  4. Pharmacological targeting of novel candidate molecules

    Time frame: Up to 5 years after inclusion

    Functional validation of newly identified targets through pharmacological inhibition to assess their therapeutic potential in vitro using CLL models.

  5. Generation of knockout cell lines for genes of interest

    Time frame: Up to 5 years after inclusion

    Creation of gene knockout models in CLL cell lines via CRISPR/Cas9 to explore the biological role of specific resistance-associated genes.

  6. Generation of drug-resistant cell lines and comparative RNA sequencing

    Time frame: Up to 5 years after inclusion

    Development of CLL cell lines resistant to BTK degraders followed by RNA sequencing analysis to compare gene expression profiles between drug-sensitive lines and resistant cell lines.

  7. Reconstruction of the tumor microenvironment using co-culture systems

    Time frame: Up to 5 years after inclusion

    Establishment of co-culture models including immune (T lymphocytes, nurse-like cells) and/or stromal cells (from lymph nodes or bone marrow) to mimic the CLL tumor microenvironment.

Study contacts

Contact information is provided by the study sponsor or research team.

ANNE LOK, Dr

CONTACT

[email protected]

02.40.08.42.11

Benoit Tessoulin, Dr

CONTACT

[email protected]

02.40.08.23.96

Sponsors and collaborators

Lead sponsor

Nantes University Hospital

Other

Registry information

Acronym: REBELLE

Important dates

Study start
2025
Primary completion
2039
Study completion
2039
First posted
Aug 1, 2025
Registry last updated
Jul 8, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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