Clinical Trials /

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

NCT03734198

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of the Safety and Efficacy of the Association of Ibrutinib and Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia With p53 Dysfunction
  • Official Title: A Phase II Pilot Study to Evaluate the Safety and Efficacy of the Association of Ibrutinib and Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia With p53 Dysfunction. IDA53 Trial

Clinical Trial IDs

  • ORG STUDY ID: IDA53-FILOCLL09
  • NCT ID: NCT03734198

Conditions

  • Relapsed or Refractory Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
IbrutinibIbrutinib treatmentIbrutinib + daratumumab
DaratumumabDaratumumab perfusionIbrutinib + daratumumab

Purpose

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.

Detailed Description

      This study will take place in several periods and phases of treatment:

        -  Observational period of selection of 28 days maximum

        -  Treatment period constituted:

             -  a first phase of treatment with ibrutinib alone (28 days): pre-phase,

             -  a formal protocol phase during which the two study drugs (ibrutinib and
                daratumumab) will be used together until progression of the disease or intolerance
                to treatment.

        -  2-year follow-up period that will begin after protocol processing has been stopped.

      Selection period (before starting treatment): exams performing to verify patients'
      eligibility.

        -  Collection of the medical history,

        -  Clinical examination with measurement of height and weight, vital signs (temperature,
           pulse / heart rate, blood pressure),

        -  Conventional blood tests to check all the functions of the body such as kidney, liver,
           etc

        -  Viral serologies (Human Immunodeficiency Virus (HIV) and hepatitis B and C) (10 ml).

        -  Blood Pregnancy Test for women who may have children,

        -  Specific blood tests to evaluate the disease and in particular to characterize the cells
           of LLC (mutational profile, search for chromosomal abnormalities and analysis of
           residual disease rate to have a reference point before the start of treatment will be
           made on leukemic cells),

        -  CT scan (thorax, abdomen and pelvis) to accurately search for and evaluate a deep tumor
           syndrome (lymph nodes, spleen in particular),

        -  Urine examination,

        -  Cardiological examination with an electrocardiogram (ECG)..

      Treatment period: the treatment period is divided into successive cycles of 28 days.

      Before starting ibrutinib and before each daratumumab cycle, a complete clinical examination
      and blood work will be performed.

      After 12 months of treatment, an evaluation report will be made with a complete clinical
      examination, a complete blood test, an urinalysis if necessary, a Computed Tomography (CT)
      scan, a myelogram and if necessary a marrow biopsy. Regularly after this assessment (every 6
      months until the end of the study), a report will be made with clinical examination, complete
      blood test, ECG, CT scan and if necessary, myelogram possibly associated with a marrow biopsy
      if justified and not previously carried out.

      After the end of the protocol treatment (progression of the disease, intolerance of the
      protocol treatment), a last evaluation will be carried out within 30 days after the last
      taking of the protocol treatment. This evaluation includes a complete clinical examination,
      biological tests (complete blood test) and a CT scan.

      Follow-up period the completed treatment you will then be followed in consultation every 6
      months for 2 years to evaluate the duration of the response to treatment and thus meet the
      objectives of the study.
    

Trial Arms

NameTypeDescriptionInterventions
Ibrutinib + daratumumabExperimentalPrephase (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.
  • Ibrutinib
  • Daratumumab

Eligibility Criteria

        Inclusion Criteria:

          -  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

        Exclusion Criteria:

          -  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.

          -  Moderate or severe persistent asthma within the two last years or currently
             uncontrolled asthma of any classification (American Lung Association criteria).
             Current controlled intermittent asthma or controlled mild persistent asthma is not an
             exclusion criterion.

          -  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

          -  Inadequate renal function: creatinine clearance < 50 ml/min (Cockcroft and Gault)

          -  Inadequate liver function: Aspartate Transaminase (ASAT), Alanine aminotransferase
             (ALT) > 2.5 x Upper Limit of Normal (ULN)

          -  Total bilirubin > 1.5 x ULN unless rise is due to Gilbert's syndrome or of non-hepatic
             origin.

          -  Active auto-immune haemolytic anemia

          -  Richter's transformation

          -  Evidence of central nervous system (CNS) involvement

          -  Pregnant or breastfeeding women.

          -  Adult under law-control

          -  Fertile male and female 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 affiliate to social security
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response rate (CR) at 12 months.
Time Frame:at 12 months
Safety Issue:
Description:Treatment response (ratio between the number of patients achieving complete response and the total number of patients included

Secondary Outcome Measures

Measure:Occurrence of Tumor lysis syndrome
Time Frame:At the first infusion of daratumumab (day 1 and day 2) and at the second infusion of daratumumab (day 8)
Safety Issue:
Description:Frequency and severity of tumor lysis syndrome
Measure:Study treatment Emergent Adverse Events
Time Frame:From the first treatment administration and during treatment period (ibrutinib and daratumumab)
Safety Issue:
Description:Incidence and severity of study treatment-Emergent Adverse Events utilizing National Cancer Institute - Common Terminology Criteria (NCI-CTC) criteria v4.03.
Measure:Response rate
Time Frame:12 months after beginning study treatment
Safety Issue:
Description:Overall response (OR) rate, partial response (PR) rate, PR with lymphocytosis rate
Measure:Minimal residual disease (MRD) assessement
Time Frame:During treatment :every 6 months after beginning study treatment until month 36 and 30 days after the last daratumumab infusion
Safety Issue:
Description:Presence of MRD measured by either quantitative PCR or flow cytometry
Measure:Progression Free Survival (PFS)
Time Frame:from date of inclusion to the date of first-documented progression, assessed up to 2 years
Safety Issue:
Description:time interval between the date of inclusion in the trial the date of progression of the illness or death
Measure:Overall Survival
Time Frame:from date of inclusion until the date of death, assessed up to 5 years
Safety Issue:
Description:time interval between the date of inclusion in the trial and the date of death
Measure:Duration of response
Time Frame:from the end of treatment to the date of progression, relapse or death, assessed up to 5 years
Safety Issue:
Description:time elapsed between the date of obtaining a maximal objective response (CR, PR or PR with persistent lymphocytosis) and the date of progression of the disease or death
Measure:CD38 expression in CLL cells
Time Frame:At baseline (day 0) and and before the first daratumumab perfusion (day 27)
Safety Issue:
Description:CD38 expression rate by immunophenotyping
Measure:Cumulative rate of Richter's syndrome
Time Frame:up to 5 years
Safety Issue:
Description:Number of patients who develop a Richter's syndrome

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:French Innovative Leukemia Organisation

Trial Keywords

  • p53 dysfunction

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