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Trial record 10 of 19 for:    multiple myeloma | Kraków, Poland

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

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ClinicalTrials.gov Identifier: NCT03652064
Recruitment Status : Recruiting
First Posted : August 29, 2018
Last Update Posted : February 8, 2019
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Daratumumab Drug: Bortezomib Drug: Lenalidomide Drug: Dexamethasone Phase 3

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 360 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 6, 2018
Estimated Primary Completion Date : March 29, 2024
Estimated Study Completion Date : April 30, 2025


Arm Intervention/treatment
Active Comparator: Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
Participants 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.
Drug: Bortezomib
Bortezomib 1.3 mg/m^2 will be administered by SC injection twice weekly on Days 1, 4, 8, and 11 of each 21-day cycle for Cycles 1-8.
Other Name: Velcade

Drug: Lenalidomide
Lenalidomide will be self-administered at a dose of 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 and beyond until disease progression or unacceptable toxicity whichever occurs first.
Other Name: Revlimid

Drug: Dexamethasone
Dexamethasone will be self-administered orally, 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for Cycles 1-8. During Cycle 9 and beyond dexamethasone, will be self-administered orally at a total dose of 40 mg on Days 1, 8, 15, 22 of each 28-day cycle.

Experimental: Daratumumab + VRd (D-VRd) and DRd
Participants 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.
Drug: Daratumumab
Daratumumab (1800 mg) will be administered by SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3-8. For Cycle 9 and beyond, participants will receive daratumumab 1800 mg SC once every 4 weeks until documented disease progression or unacceptable toxicity.
Other Names:
  • JNJ-54767414
  • DARZALEX

Drug: Bortezomib
Bortezomib 1.3 mg/m^2 will be administered by SC injection twice weekly on Days 1, 4, 8, and 11 of each 21-day cycle for Cycles 1-8.
Other Name: Velcade

Drug: Lenalidomide
Lenalidomide will be self-administered at a dose of 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 and beyond until disease progression or unacceptable toxicity whichever occurs first.
Other Name: Revlimid

Drug: Dexamethasone
Dexamethasone will be self-administered orally, 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for Cycles 1-8. During Cycle 9 and beyond dexamethasone, will be self-administered orally at a total dose of 40 mg on Days 1, 8, 15, 22 of each 28-day cycle.




Primary Outcome Measures :
  1. Percentage of Participants with Negative Minimal Residual Disease (MRD) Status [ Time Frame: After randomization and prior to progressive disease (PD) or subsequent anti-myeloma therapy approximately 2.5 years ]
    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 :
  1. 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) ]
    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.

  2. MRD Negative Rate at 1 Year [ Time Frame: 1 year after last participant first dose (approximately 2.5 year) ]
    Percentage of participants who have achieved MRD negative status at 1 year will be assessed. MRD negativity will be evaluated as a potential surrogate for PFS and overall survival (OS) in multiple myeloma treatment.

  3. Durable MRD Negative Rate [ Time Frame: Throughout the study (approximately 6 year) ]
    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.

  4. Overall Response Rate (ORR) [ Time Frame: Up to the end of the study (approximately 6 years) ]
    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.

  5. Very Good Partial Response (VGPR) or Better Rate [ Time Frame: Approximately 6 years ]
    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.

  6. Complete Response (CR) or Better Rate [ Time Frame: Approximately 6 years ]
    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.

  7. 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) ]
    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.

  8. 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) ]
    OS is defined as the time from the date of randomization to the date of the participant's death due to any cause.

  9. Time to Response [ Time Frame: From randomization until PR or better until approximately 6 years ]
    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.

  10. Duration of Response (DOR) [ Time Frame: From initial documentation of response to the date of PD until approximately 6 years ]
    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.

  11. Change from Baseline in Health-related Quality of Life (HRQoL) using EORTC Questionnaires [ Time Frame: Up to approximately 6 years ]
    European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 includes 30 items resulting in 5 functional scales (physical, role, emotional, cognitive, social), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). EORTC QLQ-MY20 20-items make up 4 scales: disease symptoms, side effects of treatment, future perspective, and body image. Item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms.

  12. Change from Baseline in Health-related Quality of Life (HRQoL) using EQ-5D-5L Questionnaire [ Time Frame: Up to approximately 6 years ]
    EuroQol Five Dimension (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).

  13. 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) ]
    The Cmax is the maximum observed serum concentration of daratumumab.

  14. 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) ]
    The Cmin is the minimum observed serum concentration of daratumumab.

  15. 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) ]
    Number of participants with anti-daratumumab antibodies will be assessed.

  16. 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) ]
    Number of participants with anti-recombinant human hyaluronidase (rHuPH20) antibodies will be assessed.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 for a maximum of 4 days, 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
  • Radiation therapy within 14 days of randomization

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03652064


Contacts
Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com

  Show 125 Study Locations
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Additional Information:
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03652064     History of Changes
Other Study ID Numbers: CR108529
2018-001545-13 ( EudraCT Number )
54767414MMY3019 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: August 29, 2018    Key Record Dates
Last Update Posted: February 8, 2019
Last Verified: February 2019

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Lenalidomide
Daratumumab
Thalidomide
Bortezomib
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones