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Daratumumab, Carfilzomib, Lenalidomide and Low Dose Dexamethasone (DKRd) in Newly Diagnosed, Multiple Myeloma

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: NCT03500445
Recruitment Status : Recruiting
First Posted : April 18, 2018
Last Update Posted : October 8, 2019
Sponsor:
Collaborators:
Janssen Scientific Affairs, LLC
Amgen
Information provided by (Responsible Party):
University of Chicago

Tracking Information
First Submitted Date  ICMJE April 9, 2018
First Posted Date  ICMJE April 18, 2018
Last Update Posted Date October 8, 2019
Actual Study Start Date  ICMJE February 13, 2019
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 16, 2018)
  • Rate of stringent complete response (sCR) [ Time Frame: 8 months ]
  • Rate of minimal residual disease (MRD)-negative disease as assessed by Next Generation Sequencing [ Time Frame: 8 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Rate of stringent complete response (sCR) [ Time Frame: 8 months ]
  • Rate of MRD-negative disease as assessed by Next Generation Sequencing [ Time Frame: 8 months ]
Change History Complete list of historical versions of study NCT03500445 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2018)
  • Long term rate of MRD-negative disease [ Time Frame: 2 years ]
  • Duration of response [ Time Frame: 1 year ]
  • Rate of progression free survival [ Time Frame: 2 years ]
  • Time to progression [ Time Frame: 2 years ]
  • Overall survival rate [ Time Frame: 2 years ]
  • Overall response rate [ Time Frame: 2 years ]
  • Number of grade 2 or higher side effects as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 criteria [ Time Frame: 8 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Long term rate of MRD-negative disease [ Time Frame: 5 years ]
  • Duration of response [ Time Frame: 1 year ]
  • Rate of progression free survival [ Time Frame: 5 years ]
  • Time to progresssion [ Time Frame: 5 years ]
  • Overall survival rate [ Time Frame: 5 years ]
  • Overall response rate [ Time Frame: 5 years ]
  • Number of grade 2 or higher side effects as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 criteria [ Time Frame: 8 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Daratumumab, Carfilzomib, Lenalidomide and Low Dose Dexamethasone (DKRd) in Newly Diagnosed, Multiple Myeloma
Official Title  ICMJE Open-label, Single-arm, Phase 2 Study of Initial Treatment With Daratumumab (Darzalex), Carfilzomib (Kyprolis), Lenalidomide (Revlimid) and Low Dose Dexamethasone (DKRd) in Newly Diagnosed, Multiple Myeloma Requiring Systemic Chemotherapy
Brief Summary The purpose of this study is to determine response rate after 8 cycles of D-KRd (daratumumab, carfilzomib, lenalidomide (Revlimid) and dexamethasone in patients with multiple myeloma.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myeloma
  • Multiple Myeloma
Intervention  ICMJE
  • Drug: Daratumumab

    Daratumumab (16 mg/kg) will be administered as an IV infusion:

    • Cycle 1-2: 16 mg/kg weekly
    • Cycles 3-8: 16 mg/kg IV infusion every 2 weeks
    • Cycles 9-24: 16 mg/kg IV infusion Day 1
    Other Name: DARZALEX®
  • Drug: Carfilzomib

    Carfilzomib will be given as an IV infusion over 30 minutes:

    • Cycle 1: 20 mg/m2 Days 1, 2; 36 mg/m2 Days 8, 9, 15, 16. Alternatively, intermediate dose escalation (to 27mg/m2 on days 8, 9 of cycle 1) will be allowed at the treating physician's discretion.
    • Cycle 2-9: 36 mg/m2 (or best tolerated dose) Days 1, 2, 8, 9, 15 and 16
    • Cycles 9-24: 36 mg/m2 (or best tolerated dose) Days 1, 2, 15 and 16
    Other Name: KYPROLIS®
  • Drug: Lenalidomide

    Lenalidomide will be taken orally as follows:

    • Cycles 1-24: 25 mg (or best tolerated dose) PO Days 1-21

    Other Name: REVLIMID®
  • Drug: Dexamethasone

    Dexamethasone will be administered prior to carfilzomib (on days that they coincide), as follows:

    • Cycles 1-9: 40 mg PO (subjects ≤ 75 years) or 20 mg PO (subjects ≥ 75 years) per week
    • Cycles 9-24: 20 mg PO per week

    During weeks when daratumumab is given: 40 mg dexamethasone weekly, 20 mg prior to daratumumab infusion and 20 mg PO the day after

    During weeks with no daratumumab, single dose of 20 mg on day 1

Study Arms  ICMJE Experimental: Treatment Arm (D-KRd)
Interventions:
  • Drug: Daratumumab
  • Drug: Carfilzomib
  • Drug: Lenalidomide
  • Drug: Dexamethasone
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: April 9, 2018)
75
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2023
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy

    • Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids or lenalidomide or bortezomib-based regimens does not disqualify the patient (the treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle of Proteasome Inhibitor / Immunomodulatory-based therapy)

  • Both transplant and non-transplant candidates are eligible.
  • Diagnosis of symptomatic multiple myeloma as per current International Myeloma Working Group (IMWG) uniform criteria prior to initial treatment
  • Monoclonal plasma cells in the Bone Marrow (BM) ≥ 10% or presence of a biopsy-proven plasmacytoma
  • Measurable disease, prior to initial treatment as indicated by one or more of the following:

    • Serum M-protein ≥ 1 g/dL
    • Urine M-protein ≥ 200 mg/24 hours
    • If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable
    • Serum freelite measurable disease as per current IMWG criteria
  • Bone marrow specimen will be required at study entry; available DNA sample from pre-induction BM will be used for calibration step for MRD evaluation by gene sequencing.
  • Males and females ≥ 18 years of age
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Adequate hepatic function, with bilirubin ≤ 1.5 x upper limit of normal (ULN) and aspirate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
  • Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 x 109/L.
  • Calculated creatinine clearance (by Cockroft-Gault) ≥ 50 mL/min or serum creatinine below 2 g/dL
  • Woman of childbearing potential must have 2 negative pregnancy tests prior to initiating lenalidomide.
  • Woman of childbearing potential must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 30 days after discontinuation from the study.
  • Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 90 days following discontinuation from the study even if he has undergone a successful vasectomy.
  • All study participants in the US must be consented to and registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS®) program and be willing and able to comply with the requirements of Revlimid REMS®.
  • Voluntary written informed consent.

Exclusion Criteria:

  • Frail non-transplant candidates, defined as in Palumbo et al, Blood 2015.
  • Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as <1.0 g/dL M-protein in serum, <200 mg/24 hr urine M-protein, and no measurable disease as per IMWG by Freelite.
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Amyloidosis
  • Plasma cell leukemia
  • Waldenström's macroglobulinemia or Immunoglobulin M-producing (IgM) myeloma
  • Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
  • Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater
  • Potential subjects with evidence of progressive disease as per IMWG criteria
  • Patients not able to tolerate daratumumab, carfilzomib, lenalidomide or dexamethasone
  • Peripheral neuropathy ≥ Grade 2 at screening
  • Diarrhea > Grade 1 in the absence of antidiarrheals
  • Central Nervous System (CNS) involvement
  • Pregnant or lactating females
  • Major surgery within 3 weeks prior to first dose.
  • Myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  • Prior or concurrent pulmonary embolism
  • Known moderate or severe persistent asthma or known chronic obstructive pulmonary disease (COPD)

    • Known or suspected chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal
    • Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study.
  • Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening
  • Uncontrolled hypertension or diabetes
  • Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
  • Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
  • Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
  • Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03500445
Other Study ID Numbers  ICMJE IRB17-1097
Has Data Monitoring Committee No
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: Undecided
Responsible Party University of Chicago
Study Sponsor  ICMJE University of Chicago
Collaborators  ICMJE
  • Janssen Scientific Affairs, LLC
  • Amgen
Investigators  ICMJE
Principal Investigator: Andrzej Jakubowiak, MD, PhD University of Chicago
PRS Account University of Chicago
Verification Date October 2019

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