NCT03734198: IDA53

Evaluation of the Safety and Efficacy of the Association of Ibrutinib and Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia With p53 Dysfunction

Active, enrolled Phase 2 Last updated 26 November 2025

What this trial tests

Phase 2 trial testing Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia in 29 participants. Participants enrolled and being followed up; not accepting new ones.

Timeline

19 December 2018

Primary endpoint
17 June 2023

19 December 2025

Quick facts

Lead sponsor	French Innovative Leukemia Organisation
Phase	Phase 2
Status	Active, enrolled
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	29
Start date	19 December 2018
Primary completion	17 June 2023
Estimated completion	19 December 2025
Sites	24 locations across France

Drugs / interventions tested

• Ibrutinib (ibrutinib) — full drug profile →
• Daratumumab (daratumumab) — full drug profile →

Conditions studied

• Relapsed or Refractory Chronic Lymphocytic Leukemia — all drugs for Relapsed or Refractory Chronic Lymphocytic Leukemia →

Sponsor

French Innovative Leukemia Organisation — full company profile →

Who can join

18 and older, any sex, with Relapsed or Refractory Chronic Lymphocytic Leukemia. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

Ibrutinib, a first-in-class Bruton Tyrosine kinase (BTK) inhibitor, has become an established treatment in relapsed/refractory chronic lymphocytic leukemia (CLL). However, despite a considerable improvement of Progression Free Survival (PFS) and Overall Survival (OS) in comparison with historical controls, the prognosis of patients with 17p deletion (del17p) remains a concern, as it is clearly much less favourable than that of patient without del17p. Again, TP53 mutations correlated to poorer prognostic in Relapsed/Refractory (R/R) CLL patients treated with ibrutinib (Brown JR et al,2018). Despite these therapeutic advances, the treatment of CLL with TP53 disruption thus remains a difficult issue that warrants evaluation of alternative treatment strategies, in particular the use of ibrutinib in combination with other agents. A body of evidence suggests that targeting the extracellular molecule CD38 might be an interesting option. CD38 is a transmembrane glycoprotein with multiple receptor and enzymatic functions. The interaction of CD38 with its ligand CD31 (also known as Platelet Endothelial Cell Adhesion Molecule (PECAM-1)) not only plays a role in the binding and the migration of leucocytes through the endothelial cells wall but also triggers the activation of intracellular pathways involved in the differentiation and activation of B cells. Previous results strongly suggest that CD38 favours the expansion of CLL clones not only directly by transducing a proliferation signal but also by directing them to anatomic sites where they find favourable conditions for proliferation and survival.

Daratumumab is a first-in-class human IgG1ĸ monoclonal antibody (mAb) that binds CD38-expressing malignant cells with high affinity. Daratumumab induces tumor cell death through multiple mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP) and induction of apoptosis (de Weers et al, 2011). Recent data show that daratumumab may also display an immunomodulatory effect through depletion of a subset of immunosuppressive CD38+ Tregs (Krejcik et al, 2016). Early-stage clinical trials found daratumumab to be safe and to display encouraging clinical activity as a single agent in relapsed/refractory multiple myeloma (MM) patients (Lockhorst et al 2016, Lonial et al, 2016). Overall response rate was 31%, with rapid (median 1 month) and durable responses in this heavily pretreated MM population. Interestingly, no patient discontinued the treatment because of drug-related adverse events. These results led to approval of daratumumab in relapsed/refractory MM in December 2015. The clinical efficacy of daratumumab along with its very favourable safety profile supports its investigation in other lymphoproliferative malignancies. In particular, the expression of CD38 in poor prognosis CLL and the key role of CD38 in CLL biology provide a basis for examining the potential of daratumumab in this disease.

In preclinical studies, (Matas-Céspedes et al, 2016; Manna et al, 2017) Daratumumab efficiently kills CLL cell lines and patient-derived CLL cells by ADCC and ADCP in vitro. Daratumumab modulates CLL-T reg levels and increase cytotoxic effector T cells.

Rationale for combining ibrutinib with daratumumab:

These data suggest that combining ibrutinib with daratumumab might have a synergistic or additive effect. Both drugs inhibit B cell receptor (BCR) signalling via two different converging pathways, i.e. BTK and CD38/ZAP70/ERK (Deaglio et al, 2007). In vitro, Manna et al have shown that daratumumab is able to modulate BCR signaling.

Interestingly, the ibrutinib /daratumumab combination significantly enhanced mitochondrial-mediated apoptosis bth in CD38 high and CD38 low CLL cells (Manna et al, 2017).

Altogether, this provides a rationale for evaluating the safety and efficacy of the association of daratumumab with ibrutinib in high-risk relapsed/refractory patients for whom the standard-of-care using ibrutinib as a single agent has demonstrated limitations in terms of long-term disease control.

Primary objective of the study: to determine the efficacy of a treatment combining daratumumab and ibrutinib in a poor risk population of relapsed CLL patients with TP53 dysfunction.

Secondary objectives of the study : to determine the safety profile of daratumumab in combination with ibrutinib in CLL patients.

Inclusion period: 24 months Treatment duration (ibrutinib + daratumumab): continuous, until disease progression or unacceptable toxicity.

Follow-up period: will begin once the subject discontinues study treatment, during 2 years.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Adenosine Metabolism: Emerging Concepts for Cancer Therapy.
   Boison D, Yegutkin GG. · · 2019 · cited 251× · PMID 31821783 · DOI 10.1016/j.ccell.2019.10.007
2. Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy.
   Gohil SH, Iorgulescu JB, Braun DA, Keskin DB, et al · · 2021 · cited 218× · PMID 33277626 · DOI 10.1038/s41571-020-00449-x
3. Evaluating Daratumumab in the Treatment of Multiple Myeloma: Safety, Efficacy and Place in Therapy.
   Dima D, Dower J, Comenzo RL, Varga C. · · 2020 · cited 36× · PMID 32904669 · DOI 10.2147/cmar.s212526
4. The Many Facets of CD38 in Lymphoma: From Tumor-Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy.
   Calabretta E, Carlo-Stella C. · · 2020 · cited 28× · PMID 32225002 · DOI 10.3390/cells9040802
5. Role of mitochondria in physiological activities, diseases, and therapy.
   Wang L, Zhou X, Lu T. · · 2025 · cited 23× · PMID 40536597 · DOI 10.1186/s43556-025-00284-5
6. Trial Watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy.
   Petrazzuolo A, Maiuri MC, Zitvogel L, Kroemer G, et al · · 2022 · cited 23× · PMID 35655707 · DOI 10.1080/2162402x.2022.2077898
7. Single-Cell Analysis in Immuno-Oncology.
   Christodoulou MI, Zaravinos A. · · 2023 · cited 16× · PMID 37176128 · DOI 10.3390/ijms24098422
8. Current Status of Novel Agents for the Treatment of B Cell Malignancies: What's Coming Next?
   Tannoury M, Garnier D, Susin SA, Bauvois B. · · 2022 · cited 10× · PMID 36551511 · DOI 10.3390/cancers14246026