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Bortezomib or Carfilzomib With Lenalidomide and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Eastern Cooperative Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:
NCT01863550
First received: May 6, 2013
Last updated: September 16, 2014
Last verified: September 2014
  Purpose

This randomized phase III trial studies bortezomib, lenalidomide, and dexamethasone to see how well it works compared to carfilzomib, lenalidomide, and dexamethasone in treating patients with newly diagnosed multiple myeloma. Bortezomib and carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib or carfilzomib together with lenalidomide and dexamethasone may kill more cancer cells


Condition Intervention Phase
Stage I Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Drug: bortezomib
Drug: lenalidomide
Drug: dexamethasone
Drug: carfilzomib
Procedure: quality-of-life assessment
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase III Trial of Bortezomib, Lenalidomide and Dexamethasone (VRd) Versus Carfilzomib, Lenalidomide, Dexamethasone (CRd) Followed by Limited or Indefinite Lenalidomide Maintenance in Patients With Newly Diagnosed Symptomatic Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Eastern Cooperative Oncology Group:

Primary Outcome Measures:
  • Overall survival for the maintenance analysis [ Time Frame: From the maintenance randomization to death due to any cause or, censored at the date last known alive, assessed up to 15 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier (KM) method will be used to describe the overall survival function by arm.


Secondary Outcome Measures:
  • Progression-free survival for the maintenance analysis [ Time Frame: From the maintenance randomization until the earlier of progression or death due to any cause, assessed up to 15 years ] [ Designated as safety issue: No ]
    Weighted Cox regression will be used.

  • Progression-free survival for the induction analysis [ Time Frame: From the induction randomization until the earlier of progression or death due to any cause, assessed up to 15 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier method will be used to describe the progression-free survival function by arm using all data while ignoring maintenance.

  • Overall survival for the induction analysis [ Time Frame: From induction randomization to death due to any cause, or censored at the date last known alive, assessed up to 15 years ] [ Designated as safety issue: No ]
    The KM method will be used.

  • Response rates including partial response (PR), very good partial response (VGPR), immunofixation negative complete response (IF-CR) and complete response (CR) [ Time Frame: At 2.8 months ] [ Designated as safety issue: No ]
    Will be compared between induction arms using Fisher's exact test.

  • Response rates including PR, VGPR, IF-CR and CR [ Time Frame: At 8.3 months ] [ Designated as safety issue: No ]
    Will be compared between induction arms using Fisher's exact test.

  • Time to progression (TTP) for the induction analysis [ Time Frame: From the induction randomization to progression, or censored at the date of last disease evaluation for those without progression reported, assessed up to 15 years ] [ Designated as safety issue: No ]
    TTP distributions will be estimated by induction arm using Kaplan-Meier methods.

  • Duration of response (DOR) for the induction analysis [ Time Frame: From first objective response (partial response or better) since induction randomization until the earlier of progression or death due to any cause, or censored at date of last disease evaluation for those without events reported, assessed up to 15 years ] [ Designated as safety issue: No ]
    Duration of response will be estimated using Kaplan-Meier methods in the subset of patients achieving partial response or better while on induction therapy.

  • Incidence of overall grade 3 or higher non-hematologic toxicity and grade 3 or higher toxicity by type during induction, active maintenance and observation phases using CTCAE version 4.0 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
    Fisher's exact test will be used.

  • Incidence of grade 2 or higher peripheral neuropathy and cardiac toxicity during induction phase assessed using CTCAE version 4.0 [ Time Frame: Up to 36 weeks ] [ Designated as safety issue: Yes ]
    Fisher's exact test will be used.

  • Change in the Functional Assessment of Cancer Therapy-Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) for the transition to maintenance analysis [ Time Frame: From week 36 (the end) of induction therapy to week 24 (end of course 6) of maintenance therapy ] [ Designated as safety issue: No ]
    Will be analyzed using linear mixed models.

  • Change in the FACT-Ntx TOI for the short-term maintenance analysis [ Time Frame: From the end of 2 years of maintenance to 3 years post maintenance randomization ] [ Designated as safety issue: No ]
    Will be analyzed using linear mixed models.

  • Change in the FACT-Ntx TOI for the long-term maintenance analysis [ Time Frame: From the end of 2 years of maintenance to 5 years post maintenance randomization ] [ Designated as safety issue: No ]
    Will be analyzed using linear mixed models.

  • Change in the FACT-Ntx TOI for the end of induction analysis [ Time Frame: From baseline (induction randomization) to 36 weeks (end) of induction therapy ] [ Designated as safety issue: No ]
    Will be analyzed using linear mixed models.

  • Change in the FACT-Ntx TOI for the early induction analysis [ Time Frame: From baseline (induction randomization) to 2.8 months of induction therapy ] [ Designated as safety issue: No ]
    Will be analyzed using linear mixed models.

  • Levels and changes from related start of induction, active maintenance and observation phases [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Will be analyzed using linear mixed models.

  • Time to worsening of FACT-Ntx TOI for the induction analysis [ Time Frame: From the baseline assessment at induction randomization to a decrease of 7 points, assessed up to 15 years ] [ Designated as safety issue: No ]
    Will be analyzed with KM methods and Cox regression.

  • Time to worsening of Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM) for the maintenance analysis [ Time Frame: From the baseline assessment at maintenance randomization to a decrease of 4 points, assessed up to 15 years ] [ Designated as safety issue: No ]
    Will be analyzed with KM methods and Cox regression.


Estimated Enrollment: 756
Study Start Date: November 2013
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (bortezomib, lenalidomide, dexamethasone)
Patients receive bortezomib SC or IV on days 1, 4, 8, and 11 of courses 1-8 and days 1 and 8 of courses 9-12; lenalidomide PO daily on days 1-14; and dexamethasone PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of courses 1-8 and days 1, 2, 8, and 9 of courses 9-12. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: bortezomib
Given SC or IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Drug: lenalidomide
Given PO
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Other: laboratory biomarker analysis
Optional correlative studies
Experimental: Arm B (carfilzomib, lenalidomide, dexamethasone)
Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16; lenalidomide PO daily on days 1-21; and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.
Drug: lenalidomide
Given PO
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Drug: carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Other: laboratory biomarker analysis
Optional correlative studies
Experimental: Arm C (lenalidomide)
Patients receive lenalidomide PO daily on days 1-21. Treatment repeats every 4 weeks for 24 courses in the absences of disease progression or unacceptable toxicity.
Drug: lenalidomide
Given PO
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Other: laboratory biomarker analysis
Optional correlative studies
Experimental: Arm D (lenalidomide)
Patients receive lenalidomide PO daily on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Drug: lenalidomide
Given PO
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Other: laboratory biomarker analysis
Optional correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • STEP I: Patients must be diagnosed with symptomatic standard-risk multiple myeloma (SR-MM) as defined by all of the following:

    • No evidence of t(4;14), t(14;16),t(14;20), or deletion 17p on fluorescent in situ hybridization (FISH)
    • Standard risk gene expression profile (GEP)70 signature (only if GEP has been done and results are available)
    • Serum lactate dehydrogenase (LDH) =< 2 x upper limit of normal (ULN)
    • No more than 20% circulating plasma cells on white blood cell (WBC) differential or 2,000 plasma cells/microliter of peripheral blood
  • STEP I: Patients must have measurable or evaluable disease as defined by having one or more of the following:

    • >= 1g/dL monoclonal protein (M-protein) on serum protein electrophoresis
    • >= 200 mg/24 hrs of monoclonal protein on a 24 hour urine protein electrophoresis
    • Involved free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (< 0.26 or > 1.65)
    • Monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)
    • Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) assay, or bone marrow biopsy and or aspirate are required to be performed within 28 days prior to randomization

      • NOTE: UPEP (on a 24-hour collection) is required, no substitute method is acceptable; urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hr; please note that if both serum and urine M-components are present, both must be followed in order to evaluate response
      • NOTE: The serum free light chain test is required to be done if the patient does not have measurable disease in the serum or urine; measurable disease in the serum is defined as having a serum M-spike >= 1 g/dL; measurable disease in the urine is defined as having a urine M-spike >= 200mg/24 hr
  • STEP I: Hemoglobin >= 8 g/dL
  • STEP I: Untransfused platelet count >= 75,000 cells/mm^3
  • STEP I: Absolute neutrophil count >= 1000 cells/mm^3
  • STEP I: Calculated creatinine clearance >= 30 mL/min
  • STEP I: Bilirubin =< 1.5 mg/dL
  • STEP I: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 2.5 times the upper limit of normal
  • STEP I: Patients must have received no more than one cycle (4 weeks or less) of prior chemotherapy and no more than 160mg of prior dexamethasone for treatment of symptomatic myeloma; they should not have been exposed to lenalidomide, bortezomib or carfilzomib for treatment of symptomatic myeloma; prior radiation therapy to symptomatic lesions is allowed provided 14 days have elapsed from the completion of radiation therapy
  • STEP I: Prior systemic glucocorticoid use for the treatment of non-malignant disorders is permitted; prior or concurrent topical or localized glucocorticoid therapy to treat non-malignant comorbid disorders is permitted; note: concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day
  • STEP I: Patients must not have active, uncontrolled seizure disorder; patients must have had no seizures in the last 6 months
  • STEP I: Patients must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson Syndrome
  • STEP I: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 (PS 3 allowed if secondary to pain)
  • STEP I: Patients with monoclonal gammopathy of undetermined significance or asymptomatic multiple myeloma are not eligible
  • STEP I: Patients must not have grade 2 or higher peripheral neuropathy by Common Terminology Criteria for Adverse Events (CTCAE) 4.0
  • STEP I: Patients must not have active, uncontrolled infection
  • STEP I: Patients may have a history of current or previous deep vein thrombosis or pulmonary embolism but must be willing to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation
  • STEP I: Patients should not have New York Heart Association classification III or IV heart failure or myocardial infarction within the previous 6 months
  • STEP I: Patients with a history of prior malignancy are eligible provided they were treated with curative intent and do not require active therapy (currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix or breast are not excluded)
  • STEP I: Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
  • STEP I: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 4 weeks after stopping treatment
  • STEP I: The following patients will be excluded:

    • Pregnant women
    • Nursing women
  • STEP I: Human immunodeficiency virus (HIV) infection is not excluded; known HIV positive patients must meet the following criteria:

    • Cluster of differentiation (CD(4 cell count >= 350/mm^3
    • No history of acquired immune deficiency syndrome (AIDS)-related illness
    • Not currently prescribed zidovudine or stavudine
  • STEP I: Patient enrolling to this study must agree to register to the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist
  • STEP I: Patients must be willing to provide biological samples as required by the study
  • STEP II: Patients must not have experienced progression on step 1 induction therapy
  • STEP II: Step 2 registration must be within 28 days of completing step 1 therapy
  • STEP II: Patients must not have received any non-protocol therapy outside of the assigned induction therapy
  • STEP II: ECOG performance status 0, 1, or 2 (PS 3 allowed if secondary to pain)
  • STEP II: Any adverse event related to step 1 therapy must have resolved to grade 2 or less
  • STEP II: Hemoglobin >= 8 g/dL
  • STEP II: Platelet count >= 75,000 cells/mm^3
  • STEP II: Absolute neutrophil count >= 1000 cells/mm^3
  • STEP II: Calculated creatinine clearance >= 30 mL/min
  • STEP II: Bilirubin =< 1.5 mg/dL
  • STEP II: SGPT (ALT) and SGOT (AST) < 2.5 times the upper limit of normal
  • STEP II: FCBP must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
  • STEP II: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 4 weeks after stopping treatment
  • STEP II: The following patients will be excluded:

    • Pregnant women
    • Nursing women
  • STEP II: Patient enrolling to this study must agree to register to the mandatory RevAssist program and be willing and able to comply with the requirements of RevAssist
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01863550

Locations
United States, Massachusetts
Eastern Cooperative Oncology Group Recruiting
Boston, Massachusetts, United States, 02215
Contact: Shaji K. Kumar    507-538-7623    kumar.shaji@mayo.edu   
Principal Investigator: Shaji K. Kumar         
Sponsors and Collaborators
Eastern Cooperative Oncology Group
Investigators
Principal Investigator: Shaji Kumar Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier: NCT01863550     History of Changes
Other Study ID Numbers: E1A11, NCI-2012-02608, U10CA021115
Study First Received: May 6, 2013
Last Updated: September 16, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
BB 1101
Bortezomib
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Lenalidomide
Thalidomide
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents

ClinicalTrials.gov processed this record on November 27, 2014