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Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03679624
Recruitment Status : Recruiting
First Posted : September 20, 2018
Last Update Posted : August 14, 2020
Sponsor:
Collaborators:
Janssen Scientific Affairs, LLC
Mayo Clinic
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Tracking Information
First Submitted Date  ICMJE September 14, 2018
First Posted Date  ICMJE September 20, 2018
Last Update Posted Date August 14, 2020
Actual Study Start Date  ICMJE July 30, 2020
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 19, 2018)
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 ]
Number of patients that experience 1 or more adverse event
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2018)
  • Major response rate in Cohort A [ Time Frame: 5 years ]
    Number of patients in Cohort A who achieve VGPR, PR, or CR
  • Deepening of response rate in Cohort B after daratumumab addition [ Time Frame: 5 years ]
    Number of patients in Cohort B who achieve a VGPR, PR, or CR from baseline IgM prior to ibrutinib
  • Duration of response [ Time Frame: 5 years ]
    Measured from time of first response to progression or death, measured in months.
  • Time to progression [ Time Frame: 5 years ]
    Measured from time of study drug administration to progression, measured in months.
  • Progression free survival [ Time Frame: 5 years ]
    Measured from time of study drug administration to progression or death, measured in months.
  • Overall survival [ Time Frame: 5 years ]
    Measured from time of study drug administration to death, measured in months.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia
Official Title  ICMJE A Phase II Study of Daratumumab Plus Ibrutinib in Patients With Waldenstrӧm's Macroglobulinemia
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Ibrutinib
    Ibrutinib, 420mg orally, once daily
    Other Name: IMBRUVICA
  • Drug: Daratumumab
    Daratumumab, 16 mg/kg intravenously, weekly for 8 weeks, bi weekly for 16 weeks, then monthly for up to 19 months.
    Other Name: DARZALEX
Study Arms  ICMJE
  • Experimental: Cohort A - Ibrutinib naive
    Cohort 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
    Interventions:
    • Drug: Ibrutinib
    • Drug: Daratumumab
  • Experimental: Cohort B - Ibrutinib response plateau
    Cohort 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
    Interventions:
    • Drug: Ibrutinib
    • Drug: Daratumumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 19, 2018)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2024
Estimated Primary Completion Date October 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Amelyn Rodriguez, R.N. 212-746-1362 amr2017@med.cornell.edu
Contact: Rita Vaccaro, R.N. 212-746-0702 rig9021@med.cornell.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03679624
Other Study ID Numbers  ICMJE 1708018494
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Weill Medical College of Cornell University
Study Sponsor  ICMJE Weill Medical College of Cornell University
Collaborators  ICMJE
  • Janssen Scientific Affairs, LLC
  • Mayo Clinic
Investigators  ICMJE
Principal Investigator: John N. Allan, M.D. Weill Cornell Medicine
PRS Account Weill Medical College of Cornell University
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP