Clinical Trials /

Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia

NCT03679624

Description:

This study evaluates the safety and efficacy of daratumumab in combination with ibrutinib in patients with Waldenstrӧm's macroglobulinemia (WM). The study will evaluate this combination in two cohorts. Cohort A will comprise of ibrutinib naïve WM patients. Patients in this cohort may be treatment naïve or relapsed but who remain ibrutinib naïve. Cohort B will comprise of patients who are currently receiving ibrutinib but whose response to treatment has plateaued. In this cohort, daratumumab will be added on to ibrutinib in an attempt to deepen response.

Related Conditions:
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia
  • Official Title: A Phase II Study of Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia

Clinical Trial IDs

  • ORG STUDY ID: 1708018494
  • NCT ID: NCT03679624

Conditions

  • Waldenstrom Macroglobulinemia
  • Waldenstrom's Disease
  • Waldenström; Hypergammaglobulinemia
  • Waldenstrom's Macroglobulinemia Recurrent
  • Waldenstrom's Macroglobulinemia of Lymph Nodes
  • Waldenstrom's Macroglobulinaemia, Without Mention of Remission
  • Waldenstrom's Macroglobulinemia Refractory

Interventions

DrugSynonymsArms
IbrutinibIMBRUVICACohort A - Ibrutinib naive
DaratumumabDARZALEXCohort A - Ibrutinib naive

Purpose

This study evaluates the safety and efficacy of daratumumab in combination with ibrutinib in patients with Waldenstrӧm's macroglobulinemia (WM). The study will evaluate this combination in two cohorts. Cohort A will comprise of ibrutinib naïve WM patients. Patients in this cohort may be treatment naïve or relapsed but who remain ibrutinib naïve. Cohort B will comprise of patients who are currently receiving ibrutinib but whose response to treatment has plateaued. In this cohort, daratumumab will be added on to ibrutinib in an attempt to deepen response.

Detailed Description

      This is a multi-center, two cohort Phase 2 clinical trial investigating the effectiveness of
      adding daratumumab to ibrutinib in WM patients. Cohort A will consist of patients who are
      ibrutinib naïve and appropriate for ibrutinib based treatment. Cohort B will consist of
      patients who have achieved a response plateau less than a complete remission (CR) on single
      agent ibrutinib. Subjects in Cohort A will be identified by their treating physician and
      eligible for enrollment if they are treatment naïve or relapsed after 1 prior therapy for WM
      and eligible for ibrutinib based treatment.

      Subjects in Cohort B will be identified by their treating physician and eligible for
      enrollment if they have had at least 6 months of exposure to single agent ibrutinib and
      demonstrate an IgM response plateau defined by two IgM measurements, at least 8 weeks apart
      that have changed <15% from the previous mark. In Cohort B response assessment will be
      measured from initial IgM level prior to ibrutinib initiation.

      Enrolled subjects will be prescribed commercial ibrutinib, 420mg PO daily. The
      investigational agent, daratumumab will be administered based on FDA approved dosing in
      multiple myeloma (16mg/kg) with 8 weekly induction treatments during Cycles 1 and 2, followed
      by every other week dosing for Cycles 3-6, then monthly dosing from Cycle 7 until Cycle 25 at
      which point subjects will continue with ibrutinib as monotherapy until Cycle 52 (4 years
      total) which is the predefined study completion for enrolled subjects at which point they
      will complete follow-up. Study visits and response assessments with IgM measurements will
      occur with each cycle for the first year then every three cycles after cycle 13. Subjects
      with measureable extramedullary disease will have CT scans every 6 cycles until radiographic
      CR. Patients will be considered evaluable for response if they completed the initial 8 weeks
      of daratumumab induction therapy and evaluable for toxicity if receiving one dose of
      daratumumab. Patients will continue on combination therapy for 2 years or until disease
      progression or unacceptable toxicities at which point subjects will come off trial. Patients
      achieving a CR after two years of combination therapy will be given an option to continue
      with single agent commercial ibrutinib.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A - Ibrutinib naiveExperimentalCohort A will consist of subjects who are ibrutinib naïve and appropriate for ibrutinib based treatment. Treatment naïve subjects will be eligible to enroll in this cohort. All subjects in this cohort will receive ibrutinib plus daratumumab
  • Ibrutinib
  • Daratumumab
Cohort B - Ibrutinib response plateauExperimentalCohort B will consist of subjects who have had at least 6 months of exposure to single agent ibrutinib and who have demonstrated an IgM response plateau defined by two IgM measurements, at least 8 weeks apart that have changed <15% from the previous mark. All subjects in this cohort will receive ibrutinib plus daratumumab
  • Ibrutinib
  • Daratumumab

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must have a diagnosis of WM and meet the requirements for active therapy as
             defined by the 2nd International Workshop on Waldenstrom's Macroglobulinemia

          -  Age ≥18 years of age

          -  Ibrutinib naïve or previously treated patients currently on ibrutinib with a plateau
             in disease response are eligible to participate.

               1. Ibrutinib naïve subjects may be either treatment naïve or previously treated but
                  ibrutinib naïve to enter cohort 1.

               2. Subjects entering cohort 2 must have a plateau response on ibrutinib defined as ≥
                  6 months of ibrutinib treatment with 2 IgM measurements at least 2 months apart
                  with ≤ 15% change from the previous measurement. Subjects with progressive
                  disease are ineligible for enrollment.

          -  Subjects must have measurable disease defined by a serum IgM level ≥0.5g/dL

          -  Eastern Cooperative Oncology Group performance status of 0-2

          -  Hematology values must be within the following limits:

               1. Absolute neutrophil count (ANC) 1000/mm3 independent of growth factor support for
                  7 days of study entry if cytopenias are due to marrow involvement.

               2. Platelets 50,000/mm3 independent of transfusion support within 7 days of study
                  entry. TPO mimetics are not allowed to meet eligibility criteria.

               3. Hemoglobin ≥ 8g/dL, independent of transfusion support within 7 days of study
                  entry

          -  Biochemical values within the following limits:

             d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper
             limit of normal (ULN)

             e. Total bilirubin ≤ 2 x ULN unless bilirubin rise is due to Gilbert's syndrome or of
             non-hepatic origin

             f. Creatinine clearance (CLcr) > 25 ml/min

          -  Women of childbearing potential and men who are sexually active must be practicing a
             highly effective method of birth control during and after the study consistent with
             local regulations regarding the use of birth control methods for subjects
             participating in clinical trials. Men must agree to not donate sperm during and after
             the study. For females, these restrictions apply for 1 month after the last dose of
             study drug. For males, these restrictions apply for 3 months after the last dose of
             study drug.

          -  Women of childbearing potential must have a negative serum (beta-human chorionic
             gonadotropin (beta-hCG) or urine beta hCG pregnancy test at Screening. Women who are
             pregnant or breastfeeding are ineligible for this study.

          -  Subjects must be able to sign (or their legally-acceptable representatives must sign)
             an informed consent indicating that they understand the rational of the study and can
             participate in all study procedures.

        Exclusion Criteria:

          -  Subject does not have a recorded IgM level recorded within 3 months prior to ibrutinib
             initiation.

          -  Subjects in cohort B experiencing ongoing non hematologic toxicities attributable to
             ibrutinib > Grade 1 will be excluded from study entry.

          -  Major surgery or a wound that has not fully healed within 4 weeks of enrollment.

          -  Evidence of disease transformation at time of enrollment.

          -  Waldenstrom's complicated by amyloidosis

          -  Known central nervous system lymphoma.

          -  History of stroke or intracranial hemorrhage within 6 months prior to randomization.

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
             phenprocoumon).

          -  Requires chronic treatment with strong CYP3A inhibitors. Subjects that required strong
             CYP3A inhibitors but completed a course of treatment can be considered for enrollment
             after a washout period of 14 days prior to study drug administration.

          -  Requires strong CYP3A inducers. Subjects that required strong CYP3A inducers but
             completed a course of treatment can be considered for enrollment after a washout
             period of 14 days prior to study drug administration.

          -  Patients with history of Chronic Obstructive Pulmonary Disease or Reactive Airway
             disease must have PFTs with FEV1 calculated. Patients with a FEV1 ≤ 50% of predicted
             normal will be excluded.

          -  Clinically significant cardiovascular disease such as uncontrolled or symptomatic
             arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
             Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by
             the New York Heart Association Functional Classification.

          -  Vaccinated with live, attenuated vaccines within 4 weeks of randomization.

          -  Seropositive for human immunodeficiency virus (HIV).

          -  Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
             antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg
             negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or
             antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time
             polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.
             Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic
             findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic
             marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV
             DNA by PCR.

          -  Seropositive for hepatitis C (except in the setting of a sustained virologic response
             [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

          -  Any life-threatening illness, medical condition, or organ system dysfunction which, in
             the investigator's opinion, could compromise the subject's safety, interfere with the
             absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue
             risk.

          -  Active malignancy not treated with curative intent within 2 years of study entry.
             Nonmelanotic skin cancers and cervical carcinoma in situ are excluded from this
             criteria.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of combination treatment with ibrutinib and daratumumab as measured by the number of patients that experience 1 or more adverse event
Time Frame:3 years
Safety Issue:
Description:Number of patients that experience 1 or more adverse event

Secondary Outcome Measures

Measure:Major response rate in Cohort A
Time Frame:5 years
Safety Issue:
Description:Number of patients in Cohort A who achieve VGPR, PR, or CR
Measure:Deepening of response rate in Cohort B after daratumumab addition
Time Frame:5 years
Safety Issue:
Description:Number of patients in Cohort B who achieve a VGPR, PR, or CR from baseline IgM prior to ibrutinib
Measure:Duration of response
Time Frame:5 years
Safety Issue:
Description:Measured from time of first response to progression or death, measured in months.
Measure:Time to progression
Time Frame:5 years
Safety Issue:
Description:Measured from time of study drug administration to progression, measured in months.
Measure:Progression free survival
Time Frame:5 years
Safety Issue:
Description:Measured from time of study drug administration to progression or death, measured in months.
Measure:Overall survival
Time Frame:5 years
Safety Issue:
Description:Measured from time of study drug administration to death, measured in months.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Weill Medical College of Cornell University

Trial Keywords

  • treatment naive
  • relapsed
  • frontline
  • refractory
  • daratumumab
  • ibrutinib

Last Updated

January 9, 2020