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A Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) With VELCADE, Lenalidomide, and Dexamethasone (VRd) in Participants With Untreated Multiple Myeloma and for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy

NCT03652064

Description:

The purpose of this study to determine if the addition of daratumumab to bortezomib + lenalidomide + dexamethasone (VRd) will improve overall minimal residual disease (MRD) negativity rate compared with VRd alone.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) With VELCADE, Lenalidomide, and Dexamethasone (VRd) in Participants With Untreated Multiple Myeloma and for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy
  • Official Title: A Phase 3 Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) With VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects With Untreated Multiple Myeloma and for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy

Clinical Trial IDs

  • ORG STUDY ID: CR108529
  • SECONDARY ID: 2018-001545-13
  • SECONDARY ID: 54767414MMY3019
  • NCT ID: NCT03652064

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
DaratumumabJNJ-54767414, DARZALEXDaratumumab + VRd (D-VRd) and DRd
BortezomibVelcadeBortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
LenalidomideRevlimidBortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
DexamethasoneBortezomib + Lenalidomide + Dexamethasone (VRd) and Rd

Purpose

The purpose of this study to determine if the addition of daratumumab to bortezomib + lenalidomide + dexamethasone (VRd) will improve overall minimal residual disease (MRD) negativity rate compared with VRd alone.

Detailed Description

      This study will evaluate participants with newly diagnosed multiple myeloma (MM) for whom
      hematopoietic stem cell transplant is not planned as initial therapy. The data available from
      other available studies suggests that addition of daratumumab with Velcade (bortezomib),
      lenalidomide, and dexamethasone [VRd] is anticipated to improve the response rates and the
      depth of response and may lead to improved long-term outcomes in newly diagnosed participants
      with MM. Daratumumab targets CD38, a protein expressed on the surface of MM cells and other
      hematopoietic cells. Bortezomib is a proteasome inhibitor, which plays a critical role in the
      pathogenesis of MM. Lenalidomide has cytotoxic effects on myeloma cells and is capable of
      inducing apoptosis, or programmed cell death and dexamethasone induces apoptosis in MM cells.
      The rationale for the study is to utilize the subcutaneous (SC) formulation of daratumumab
      instead of the intravenous (IV) formulation, which is expected to provide similar exposure
      and is expected to limit additional toxicity to participants, treated with this quadruplet
      regimen. The study will consist of 3 phases: Screening (up to 28 days before randomization),
      Treatment phase (from Cycle 1 [21 days] Day 1 and continues until disease progression) and
      Follow up (Postintervention). Efficacy evaluations will include measurements of tumor
      burden/residual disease, myeloma proteins, bone marrow examinations, skeletal surveys,
      extramedullary plasmacytomas, and serum calcium corrected for albumin. Participants will
      undergo procedures like electrocardiogram (ECG), chest x-rays or full dose chest CT scans,
      Pulmonary function test (PFT), spirometry etc. during the course of study. Participants will
      also be monitored closely for adverse events (AEs), laboratory abnormalities, and clinical
      response. The duration of the study will be approximately 6.5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Bortezomib + Lenalidomide + Dexamethasone (VRd) and RdActive ComparatorParticipants will receive bortezomib 1.3 milligram per square meter (mg/m^2) as subcutaneous (SC) injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 (cycle of 28 days); dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond (each cycle is of 28 days) followed by lenalidomide-dexamethasone (Rd) until disease progression or unacceptable toxicity.
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
Daratumumab + VRd (D-VRd) and DRdExperimentalParticipants will receive daratumumab 1800 mg as SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3 through 8 and every 4 weeks for Cycle 9 and beyond; bortezomib 1.3 mg/m^2 as SC injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9; dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond followed by daratumumab-lenalidomide-dexamethasone (DRd) until disease progression or unacceptable toxicity.
  • Daratumumab
  • Bortezomib
  • Lenalidomide
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

        - Diagnosis of multiple myeloma as documented per International Myeloma Working Group
        (IMWG) criteria Monoclonal plasma cells in the bone marrow greater than or equal to (>=)10
        percentage (%) or presence of a biopsy proven plasmacytoma and documented multiple myeloma
        satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers
        of malignancy criteria. CRAB criteria: Hypercalcemia: serum calcium greater than (>) 0.25
        millimoles per liter (mmol/L) (>1 milligram per deciliter [mg/dL]) higher than upper limit
        of normal (ULN) or >2.75 mmol/L (>11 mg/dL); Renal insufficiency: creatinine clearance less
        than (<) 40 milliliter per minute (mL/min) or serum creatinine >177 micro millimoles per
        liter (umol/L) (>2 mg/dL); Anemia: hemoglobin >2 g/dL below the lower limit of normal or
        hemoglobin <10 g/dL; Bone lesions: one or more osteolytic lesions on skeletal radiography,
        computed tomography (CT), or positron emission tomography (PET)-CT.

        Biomarkers of Malignancy: Clonal bone marrow plasma cell percentage >=60%; Involved:
        uninvolved serum free light chain (FLC) ratio >=100; >1 focal lesion on magnetic resonance
        imaging (MRI) studies

          -  Must have measurable disease, as assessed by central laboratory

          -  Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

          -  A woman of childbearing potential must have 2 negative serum or urine pregnancy tests
             at Screening, first within 10 to 14 days prior to dosing and the second within 24
             hours prior to dosing

          -  A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
             reproduction during the study and for a period of 3 months after receiving the last
             dose of any component of the treatment regimen

        Exclusion Criteria:

          -  Frailty index of >=2 according to Myeloma Geriatric Assessment score

          -  Prior therapy for multiple myeloma other than a short course of corticosteroids (not
             to exceed 40 mg of dexamethasone, or equivalent per day, total of 160 mg dexamethasone
             or equivalent)

          -  Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years
             of date of randomization (exceptions are adequately treated basal cell or squamous
             cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other
             non-invasive lesion that in the opinion of the investigator, with concurrence with the
             sponsor's medical monitor, is considered cured with minimal risk of recurrence within
             3 years)

          -  Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the
             National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
             Version 5

          -  Focal radiation therapy within 14 days of randomization with the exception of
             palliative radiotherapy for symptomatic pain management. Radiotherapy within 14 days
             prior to randomization on measurable extramedullary plasmacytoma is not permitted even
             in the setting of palliation for symptomatic management
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Negative Minimal Residual Disease (MRD) Status
Time Frame:After randomization and prior to progressive disease (PD) or the start of subsequent anti-myeloma therapy approximately 2.5 years
Safety Issue:
Description:Percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirates using next generation sequencing (NGS) at 10^-5 threshold will be assessed.

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:From randomization to either disease progression or death whichever occurs first (approximately 6 years, or 9 years if the adaptive approach is decided at the interim)
Safety Issue:
Description:PFS is defined as the duration from date of randomization to either PD or death, whichever comes first. International Myeloma Working Group (IMWG) criteria for PD: Increase of 25 percentage (%) from lowest response value in any one of following: Serum M-component (absolute increase must be >= 0.5 gram per deciliter [g/dL],) Urine M-component (absolute increase must be >=200 mg/24 hours), participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >10 milligrams per deciliter [mg/dL]), participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC% (absolute percentage must be >=10%), definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or tissue plasmacytomas and development of hypercalcemia (serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
Measure:MRD Negative Rate
Time Frame:12,18 and 24 Months
Safety Issue:
Description:Percentage of participants who have achieved MRD negative status will be assessed and landmark timepoints (12, 18 and 24 months). MRD negativity will be evaluated as a potential surrogate for PFS and overall survival (OS) in multiple myeloma treatment.
Measure:Durable MRD Negative Rate
Time Frame:Throughout the study (approximately 6 year)
Safety Issue:
Description:Durable MRD negativity rate is defined as the number of participants who have achieved MRD negative status (at 10^-5) at 2 bone marrow aspirates examinations that are a minimum of 1 year apart, without any examination showing MRD positive status in between.
Measure:Overall Response Rate (ORR)
Time Frame:Up to the end of the study (approximately 6 years)
Safety Issue:
Description:ORR is defined as the percentage of participants who achieve partial response (PR) or better responses prior to subsequent anti-myeloma therapy in accordance with IMWG criteria, during or after the study treatment. IMWG criteria for PR: greater than or equal to (>=) 50 reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90 % or to less than (<) 200 mg/24 hours, If the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, >=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was >=30%. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.
Measure:Very Good Partial Response (VGPR) or Better Rate
Time Frame:Approximately 6 years
Safety Issue:
Description:VGPR or better rate is defined as the percentage of participants achieving VGPR and complete response (CR) (including stringent complete response [sCR]) prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or greater than or equal to (>=) 90 % reduction in serum M-protein plus urine M-protein <100 milligram per 24 hours (mg/24 hours); CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescence or 2- to 4 color flow cytometry.
Measure:Complete Response (CR) or Better Rate
Time Frame:Approximately 6 years
Safety Issue:
Description:CR or better rate is defined as the percentage of participants achieving CR or sCR prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment.
Measure:PFS on the Next Line of Therapy
Time Frame:Time from randomization to progression on the next line of treatment or death, whichever comes first (up to approximately 6 years, or 9 years if the adaptive approach is decided at the interim)
Safety Issue:
Description:The PFS on the next line of therapy is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first. Disease progression will be based on investigator judgment.
Measure:Overall Survival (OS)
Time Frame:From randomization until the participant's death from any cause (up to approximately 6 years, or 9 years if the adaptive approach is decided at the interim)
Safety Issue:
Description:OS is defined as the time from the date of randomization to the date of the participant's death due to any cause.
Measure:Time to Response
Time Frame:From randomization until PR or better until approximately 6 years
Safety Issue:
Description:Time to response is defined as the time between the randomization and the first efficacy evaluation at which the participant meets all criteria for PR or better.
Measure:Duration of Response (DOR)
Time Frame:From initial documentation of response to the date of PD until approximately 6 years
Safety Issue:
Description:DOR is calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of PD, as defined in the IMWG evaluation before the start of any subsequent anti-myeloma therapy.
Measure:Maximum Observed Serum Concentration (Cmax) of Daratumumab
Time Frame:Predose Cycle 1, Day 1 (C1D1), C3D1, C9D1, C12D1, and post dose C1D4, C3D4, Post-treatment Week 8 (Cycle 1 to 8 is of 21 days; Cycle 9 and onwards are of 28 days)
Safety Issue:
Description:The Cmax is the maximum observed serum concentration of daratumumab.
Measure:Minimum Observed Serum Concentration (Cmin) of Daratumumab
Time Frame:Predose, C1D1 (each cycle of 28 days), C3D1, C9D1, C12D1, and post dose C1D4, C3D4, Post-treatment Week 8 (Cycle 1 to 8 is of 21 days; Cycle 9 and onwards are of 28 days)
Safety Issue:
Description:The Cmin is the minimum observed serum concentration of daratumumab.
Measure:Number of Participants with Anit-daratumumab Antibodies
Time Frame:Predose, C1D1 (each cycle of 28 days), C9D1, C12D1, Post-treatment Week 8 (Cycle 1 to 8 is of 21 days; Cycle 9 and onwards are of 28 days)
Safety Issue:
Description:Number of participants with anti-daratumumab antibodies will be assessed.
Measure:Number of Participants with Anit-rHuPH20 Antibodies
Time Frame:Predose, C1D1 (each cycle of 28 days), C9D1, C12D1, Post-treatment Week 8 (Cycle 1 to 8 is of 21 days; Cycle 9 and onwards are of 28 days)
Safety Issue:
Description:Number of participants with anti-recombinant human hyaluronidase (rHuPH20) antibodies will be assessed.
Measure:Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 item (EORTC QLQ-C30)
Time Frame:Baseline, up to 6 years (end of study)
Safety Issue:
Description:The EORTC- QLQ-Core-30 includes 30 items that make up 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, and nausea/vomiting), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall period is 1 week ("past week") and responses are reported using a verbal and numeric rating scales. The item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms.
Measure:Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20-item (EORTC QLQ-MY20)
Time Frame:Baseline, up to 6 years (end of study)
Safety Issue:
Description:The EORTC QLQ-MY20 is a validated, self -administered instrument to assess QoL in persons with MM. This 20-item questionnaire measures the following domains: symptom scales, including disease symptoms (6 items) and symptoms related to side effects of treatment (10 items); function scale and future perspective (3 items); and body image (1 item).
Measure:Change from Baseline in HRQoL as Assessed by EuroQol Five Dimension Five Level Questionnaire (EQ-5D-5L)
Time Frame:Baseline, up to 6 years (end of study)
Safety Issue:
Description:The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The scores for the 5 separate questions are categorical and cannot be analyzed as cardinal numbers.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Janssen Research & Development, LLC

Last Updated

November 2, 2020