Carfilzomib, Lenalidomide, and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone (KRd vs. VRd) in Patients With Newly Diagnosed Multiple Myeloma (COBRA)

Sponsor
University of Chicago (Other)
Overall Status
Recruiting
CT.gov ID
NCT03729804
Collaborator
(none)
250
Enrollment
1
Location
2
Arms
67.6
Anticipated Duration (Months)
3.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized multicenter study that will compare two treatment regimens (Kyprolis, Revlimid, dexamethasone -KRD vs. Velcade, Revlimid, dexamethasone -VRD) for patients with newly diagnosed multiple myeloma.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
250 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Open-label Phase 3 Study of Carfilzomib, Lenalidomide, and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone (KRd vs. VRd) in Patients With Newly Diagnosed Multiple Myeloma (COBRA)
Actual Study Start Date :
May 7, 2019
Anticipated Primary Completion Date :
Dec 24, 2022
Anticipated Study Completion Date :
Dec 24, 2024

Arms and Interventions

ArmIntervention/Treatment
Experimental: KRD Arm

Patients assigned to this group will receive a combination of carfilzomib, lenalidomide, and dexamethasone in 28 day cycles. Doses will vary

Drug: Carfilzomib
Carfilzomib will be given by IV on Days 1, 2, 15 and 16 of each cycle during cycles 1-8. Carfilzomib will be given by IV on days 1, 2, 15 and 16 of each cycle during cycles 9-24.
Other Names:
  • Kyprolis
  • Drug: Lenalidomide
    Lenalidomide will be taken by mouth once a day for days 1-21 of each cycle during cycles 1-8. Lenalidomide will be taken by mouth once a day for days 1-21 of each cycle for cycles 9-24.
    Other Names:
  • CC-5013
  • Revlimid
  • Drug: Dexamethasone
    Dexamethasone will be taken by mouth on days 1, 8, 15 and 22 of each cycle during cycles 1-8. Dexamethasone will be taken by mouth on Days 1, 8, 15 and 22 of each cycle during cycles 9-24.

    Experimental: VRD Arm

    Patients assigned to this group will receive a combination of Bortezomib, lenalidomide and dexamethasone in 21-day cycles. Doses will vary

    Drug: Lenalidomide
    Lenalidomide will be taken by mouth once a day for days 1-21 of each cycle during cycles 1-8. Lenalidomide will be taken by mouth once a day for days 1-21 of each cycle for cycles 9-24.
    Other Names:
  • CC-5013
  • Revlimid
  • Drug: Dexamethasone
    Dexamethasone will be taken by mouth on days 1, 8, 15 and 22 of each cycle during cycles 1-8. Dexamethasone will be taken by mouth on Days 1, 8, 15 and 22 of each cycle during cycles 9-24.

    Drug: Bortezomib
    Bortezomib will be give by IV on days 1, 4, 8 and 11 of each cycle during cycles 1-8.
    Other Names:
  • Velcade
  • PS-341
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants with progression free survival with the group taking KRd versus VRd after randomization [5 years]

    Secondary Outcome Measures

    1. The rate of MRD-negative (minimal residual disease) at indicated time points of study after randomization [5 years]

    2. The combination of drugs (KRd vs VRd) with the best response using minimal residual disease analysis across entire treatment in high risk and low risk patients [5 years]

    3. The combination of drugs (KRd vs VRd) safety and tolerability based on patients response [5 years]

      The safety and tolerability of lenalidomide and carfilzomib will be evaluated by means of drug related Adverse Events reports.

    4. Evaluate the correlation between treatment outcome using KRd or VRd and pre-treatment [5 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy per
    International Myeloma Working Group criteria:

    • Patients must have received no prior chemotherapy for this disease; patients must have received no prior radiotherapy to a large area of the pelvis (more than half of the pelvis); prior steroid treatment is allowed provided treatment was not more than 2 weeks in duration and less than or equal to 160 mg dexamethasone; patients must not have received any prior treatment with bortezomib or lenalidomide

    1. Both transplant and non-transplant candidates are eligible. Transplant candidates must agree to defer transplant at time of consent.

    2. Diagnosis of symptomatic multiple myeloma as per current International Myeloma Working Group uniform criteria prior to initial treatment

    3. Monoclonal plasma cells in the BM 10% or presence of a biopsy-proven plasmacytoma

    4. Measurable disease, prior to initial treatment as indicated by one or more of the following:

    • Serum M-protein greater than or equal to 1 g/dL

    • Urine M-protein greater than or equal to 200 mg/24 hours

    • If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable

    1. Bone marrow specimen will be required at study entry; available DNA sample from pre-induction BM will be used for calibration step for Minimal Residual Disease evaluation by gene sequencing.

    2. Males and females 18 years of age or older.

    3. Eastern Cooperative Oncology Group performance status of 0-1

    4. Adequate hepatic function, with bilirubin less than or equal to 1.5 x ULN and aspirate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN

    5. ANC greater than or equal to 1.0 x 109/L, hemoglobin greater than or equal to 8 g/dL, platelet count greater than or equal to 75 x 109/L.

    6. Calculated creatinine clearance (by Cockroft-Gault) greater than or equal to 50 mL/min or serum creatinine below 2 g/dL

    7. FCBP must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled within 7 days).

    8. FCBP 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.

    9. 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.

    10. All study participants in the US must be consented to and registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®.

    11. Subjects must comply with pregnancy prevention and counseling

    12. Voluntary written informed consent.

    Exclusion Criteria:

    Patients meeting any of the following exclusion criteria are not eligible to enroll in this study.

    1. Frail non-transplant candidates, defined as in Palumbo et al, Blood 2015

    2. Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as less than 1.0 g/dL M-protein in serum, less than 200 mg/24 hr urine M-protein

    3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

    4. Amyloidosis

    5. Plasma cell leukemia

    6. Waldenström's macroglobulinemia or IgM myeloma

    7. 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)

    8. 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

    9. Potential subjects with evidence of progressive disease as per IMWG criteria

    10. Patients not able to tolerate daratumumab, carfilzomib, lenalidomide or dexamethasone

    11. Peripheral neuropathy greater than or equal to Grade 2 at screening

    12. Diarrhea greater than Grade 1 in the absence of antidiarrheals

    13. CNS involvement

    14. Patients who cannot undergo or unwilling to take thromoprophylaxis

    15. Uncontrolled or symptomatic angina, arrhythmia, hypertension, CHF, EF less than 40%, within 6 months prior to first dose

    16. Pregnant or lactating females

    17. Major surgery within 3 weeks prior to first dose.

    18. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities

    19. Prior or concurrent pulmonary embolism

    20. Known moderate or severe persistent asthma or known chronic obstructive pulmonary disease (COPD)

    21. Rate-corrected QT interval of electrocardiograph (QTc) greater than 470 msec on a 12-lead ECG during screening

    22. Uncontrolled diabetes

    23. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose

    24. 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.

    25. 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 less than Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone

    26. 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.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University Of Chicago Medicine Comprehensive Cancer CenterChicagoIllinoisUnited States60637

    Sponsors and Collaborators

    • University of Chicago

    Investigators

    • Principal Investigator: Andrzej Jakubowiak, MD, University of Chicago

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    University of Chicago
    ClinicalTrials.gov Identifier:
    NCT03729804
    Other Study ID Numbers:
    • IRB18-1243
    First Posted:
    Nov 5, 2018
    Last Update Posted:
    Jun 8, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jun 8, 2021