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

NCT03734198 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: IDA53-FILOCLL09
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 24

Brief Summary

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.

Conditions

Relapsed or Refractory Chronic Lymphocytic Leukemia

Keywords

p53 dysfunction

Outcome Measures

Primary Outcomes (1)

• Complete response rate (CR) at 12 months.

  Treatment response (ratio between the number of patients achieving complete response and the total number of patients included

  at 12 months

Secondary Outcomes (9)

• Occurrence of Tumor lysis syndrome

  At the first infusion of daratumumab (day 1 and day 2) and at the second infusion of daratumumab (day 8)

• Study treatment Emergent Adverse Events

  From the first treatment administration and during treatment period (ibrutinib and daratumumab)

• Response rate

  12 months after beginning study treatment

• Minimal residual disease (MRD) assessement

  During treatment :every 6 months after beginning study treatment until month 36 and 30 days after the last daratumumab infusion

• Progression Free Survival (PFS)

  from date of inclusion to the date of first-documented progression, assessed up to 2 years

Other Outcomes (1)

• Research of predictive biomarker and immune signatures in peripheral blood cells

  At baseline and up to 3 years

Study Arms (1)

Ibrutinib + daratumumab

EXPERIMENTAL

Prephase (D-27 to D0): ibrutinib 420 mg/day Cycle 1 (4 weeks): ibrutinib 420 mg/day from D1 to D28 + daratumumab 8 mg/kg D1 and D2, then 16 mg/kg at D8, D15, D22. Cycle 2 (4 weeks): ibrutinib 420 mg/day D1 to D28 + daratumumab 16 mg/kg at D1, D8, D15 and D22. Cycles 3 to 6 (4 weeks) : ibrutinib 420 mg/day D1 to D28 + daratumumab 16 mg/kg at D1 and D15. Cycles ≥ 7 (4 weeks) : ibrutinib 420 mg/day D1 to D28 + daratumumab 16 mg/kg at D1.

Drug: Ibrutinib; Drug: Daratumumab

Interventions

Ibrutinib DRUG

Ibrutinib will be given at the fixed dose of 420 mg daily for the duration of treatment.

Also known as: Ibrutinib treatment

Ibrutinib + daratumumab

Daratumumab DRUG

Daratumumab will be started 28 days after beginning of ibrutinib and will be administered at the standard dose of 16 mg/kg (divided over two days for the first infusion), then 16 mg/kg for the following infusions, weekly for 2 months, then every other week for 4 months and then once a month until progression or intolerance.

Also known as: Daratumumab perfusion

Ibrutinib + daratumumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Immunophenotypically confirmed diagnosis of CLL (criteria iwCLL Hallek et al. 2018)
• Progressive CLL according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
• Relapsed or refractory disease (≥ 1 previous line of treatment) with P53 genetic alteration (17p deletion and/or TP53 mutation).
• Age \> 18 years
• Eastern Cooperative Oncology Group electrocorticogram (ECOG) status 0-2
• Negative serum pregnancy test one week prior to treatment for premenopausal women
• Cumulative Illness Rating Scale (CIRS) ≤ 6
• Life expectancy \> 3 months.
• Possibility of follow-up
• Ability to understand the protocol
• Written informed consent of patient and treating physician

You may not qualify if:

• Previous treatment with ibrutinib.
• Patient refusal to perform bone marrow biopsy for evaluation point
• Prior other malignancy (except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the subject has been disease free for ≥ 2 years).
• Known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) \< 50 % of predicted normal. FEV testing is required for patients suspected of having COPD.
• Patients with active bacterial, viral, or fungal infection requiring systemic treatment.
• Patients with known infection with human immunodeficiency virus (HIV) or human T-lymphotropic virus type 1 (HTLV-1)
• Active B or C hepatitis (positive Hepatitis B Virus surface antigen (HBsAg) or Hepatitis B Virus (HBV) DNA for HBV; Positive Hepatitis C virus (HCV) RNA for HCV)
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies.
• Any other uncontrolled medical condition or comorbidity that might interfere with subject's participation.
• Concomitant dual antiplatelet therapy
• Concomitant treatment with both antiplatelet and anticoagulation therapy
• Treatment with other investigational agent or participating to another trial within 30 days prior to entering the study
• Hemoglobin \< 8 g/dL
• Absolute neutrophil count (ANC) \< 1000/mm3
• Platelets \< 30000/mm3

Sponsors & Collaborators

• French Innovative Leukemia Organisation: lead
• Janssen, LP: collaborator

Study Sites (24)

Chu Amiens Sud

Amiens, 80054, France

Location

CH Annecy Genevois - Hématologie A3

Annecy, 74374, France

Location

CHU Jean Minjoz - Hématologie

Besançon, 25000, France

Location

Hôpital Avicenne - Centre de Recherche Clinique

Bobigny, 93009, France

Location

CHU Caen - IHBN - Hématologie Clinique

Caen, 14033, France

Location

CHU Estaing - Hématologie Clinique Adulte

Clermont-Ferrand, 63000, France

Location

CHU Grenoble - Hématologie

Grenoble, 388043, France

Location

CHD Vendée

La Roche-sur-Yon, 85925, France

Location

Centre Hospitalier du Mans

Le Mans, 72000, France

Location

Centre Léon Bérard - Hématologie

Lyon, 69373, France

Location

CHLS - Lyon Pierre Bénite - Service Hématologie

Lyon, 69495, France

Location

Institut Paoli-Calmettes - Hématologie Clinique

Marseille, 13273, France

Location

Hôpital Saint-Eloi - Hématologie Clinique

Montpellier, 34295, France

Location

CHU Hôtel Dieu - Hématologie Clinique

Nantes, 44093, France

Location

Hôpital Pitié Salpétrière - Hématologie

Paris, 75651, France

Location

CHU Bordeaux - Hôpital Haut-Lévèque - CFM Maladies du sang

Pessac, 33604, France

Location

Hôpital de la Milétrie - Hématologie et Thérapie Cellulaire

Poitiers, 86021, France

Location

Hôpital Robert Debré - Hématologie Clinique

Reims, 51092, France

Location

CHU Pontchaillou - Hématologie Clinique BMT-HC

Rennes, 35033, France

Location

Centre Henri Becquerel - Service Hématologie Clinique

Rouen, 76038, France

Location

ICANS

Strasbourg, 67098, France

Location

IUCT ONCOPOLE - Hématologie

Toulouse, 31059, France

Location

Hôpital Bretonneau - Hématologie et Thérapie Cellulaire

Tours, 37044, France

Location

Hôpitaux de Brabois - Hématologie Adulte

Vandœuvre-lès-Nancy, 54511, France

Location

Related Links

• French Innovative Leukemia Organization (FILO) internet site

MeSH Terms

Conditions

Recurrence; Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ibrutinib; daratumumab

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease

Study Officials

• Alain DELMER, MD PD

  French Innovative Leukemia Organisation

  STUDY CHAIR

• Thérèse AURRAN-SCHEINLITZ, MD

  French Innovative Leukemia Organisation

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open label multicentre phase 2 study

Study Record Dates

• First Submitted: October 23, 2018
• First Posted: November 7, 2018
• Study Start: December 19, 2018
• Primary Completion: June 17, 2023
• Study Completion: December 19, 2025
• Last Updated: November 26, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (24)