Clinical trial NCT03652064: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Myeloma
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2018-08-29
Enrollment: 395
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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

Primary outcomes:
measure: Percentage of Participants with Negative Minimal Residual Disease (MRD) Status
timeFrame: After randomization and prior to progressive disease (PD) or the start of subsequent anti-myeloma therapy approximately 2.5 years
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: 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)
measure: MRD Negative Rate
timeFrame: 12,18 and 24 Months
measure: Durable MRD Negative Rate
timeFrame: Throughout the study (approximately 6 year)
measure: Overall Response Rate (ORR)
timeFrame: Up to the end of the study (approximately 6 years)
measure: Very Good Partial Response (VGPR) or Better Rate
timeFrame: Approximately 6 years
measure: Complete Response (CR) or Better Rate
timeFrame: Approximately 6 years
measure: PFS on the Next Line of Therapy
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: 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)
measure: Time to Response
timeFrame: From randomization until PR or better until approximately 6 years
measure: Duration of Response (DOR)
timeFrame: From initial documentation of response to the date of PD until approximately 6 years
measure: Maximum Observed Serum Concentration (Cmax) of Daratumumab
timeFrame: 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)
measure: Minimum Observed Serum Concentration (Cmin) of Daratumumab
timeFrame: 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)
measure: Number of Participants with Anit-daratumumab Antibodies
timeFrame: 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)
measure: Number of Participants with Anit-rHuPH20 Antibodies
timeFrame: 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)
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)
timeFrame: Baseline, up to 6 years (end of study)
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)
timeFrame: Baseline, up to 6 years (end of study)
measure: Change from Baseline in HRQoL as Assessed by EuroQol Five Dimension Five Level Questionnaire (EQ-5D-5L)
timeFrame: Baseline, up to 6 years (end of study)
Other outcomes:
Locations:
city: Cerritos
country: United States
facility: Innovative Clinical Research Inc
state: California
city: Jacksonville
country: United States
facility: Baptist MD Anderson
state: Florida
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology, Inc.
state: Indiana
city: Louisville
country: United States
facility: Norton Healthcare
state: Kentucky
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Grand Rapids
country: United States
facility: Cancer And Hematology Centers of Western Michigan PC
state: Michigan
city: Kansas City
country: United States
facility: Saint Lukes Hospital Saint Lukes Cancer Specialists
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Farmington
country: United States
facility: San Juan Oncology Associates
state: New Mexico
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Mineola
country: United States
facility: NYU Winthrop
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Corvallis
country: United States
facility: Good Samaritan Hospital Corvallis
state: Oregon
city: Pittsburgh
country: United States
facility: University Of Pittsburgh Medical Center UPMC Hillman Cancer Center
state: Pennsylvania
city: Spartanburg
country: United States
facility: Gibbs Cancer Center
state: South Carolina
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Campinas
country: Brazil
facility: Universidade Estadual De Campinas
city: Natal
country: Brazil
facility: Liga Norte Riograndense Contra O Cancer
city: Porto Alegre
country: Brazil
facility: Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da PUCRS
city: Rio de Janeiro
country: Brazil
facility: Ministerio da Saude Instituto Nacional do Cancer
city: Rio de Janeiro
country: Brazil
facility: Instituto de Educacao, Pesquisa e Gestao em Saude Instituto Americas (COI)
city: Sao Paulo
country: Brazil
facility: Instituto de Ensino e Pesquisa São Lucas
city: Sao Paulo
country: Brazil
facility: Real e Benemerita Associacao Portuguesa de Beneficencia
city: Sao Paulo
country: Brazil
facility: Instituto Brasileiro de Controle do Cancer - Sao Camilo Oncologia
city: Sao Paulo
country: Brazil
facility: Clinica Medica Sao Germano S/S LTDA
city: São Paulo
country: Brazil
facility: Hospital Santa Cruz
city: Calgary
country: Canada
facility: Arthur J E Child Comprehensive Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: The Gordon & Leslie Diamond Health Care Center
state: British Columbia
city: Halifax
country: Canada
facility: QEII Health Sciences Centre
state: Nova Scotia
city: Brampton
country: Canada
facility: Brampton Civic Hospital
state: Ontario
city: London
country: Canada
facility: Victoria Hospital
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Quebec
country: Canada
facility: CHU de Quebec L Hotel Dieu de Quebec
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Ostrava
country: Czechia
facility: Fakultni Nemocnice Ostrava
city: Plzen
country: Czechia
facility: Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Creteil N/a
country: France
facility: CHU Henri Mondor
city: La Roche sur Yon Cedex 9
country: France
facility: Centre Hospitalier Départmental La Roche sur Yon
city: Lille
country: France
facility: Hopital Claude Huriez
city: Marseille Cedex 9
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: CHU de Montpellier Hopital Saint Eloi
city: Pessac cedex
country: France
facility: CHU de Bordeaux - Hospital Haut-Leveque
city: Strasbourg
country: France
facility: Strasbourg Oncologie Libérale
city: Toulouse cedex 9
country: France
facility: Institut Universitaire du cancer de Toulouse-Oncopole
city: Aschaffenburg
country: Germany
facility: phase 3 - Hämatoonkologischer Studienkreis am Klinikum Aschaffenburg
city: Freiburg
country: Germany
facility: Universitatsklinikum Freiburg
city: Hamm
country: Germany
facility: St. Josef-Krankenhaus Hamm-Bockum-Hövel
city: Koblenz
country: Germany
facility: Institut für Versorgungsforschung
city: Leipzig
country: Germany
facility: Universitatsmedizin Leipzig
city: München
country: Germany
facility: Klinikum Großhadern der Ludwig-Maximilians-Universität
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,
city: Ashkelon
country: Israel
facility: Barzilai Medical Center
city: Hadera
country: Israel
facility: Hillel Yaffe Medical Center
city: Haifa
country: Israel
facility: Rambam Med.Center - Hematology Institute
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Kfar Saba
country: Israel
facility: Meir Hospital
city: Petah-Tiqva
country: Israel
facility: Rabin Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Sourasky (Ichilov) Medical Center
city: Fukuoka
country: Japan
facility: Fukuoka University Hospital
city: Gifu
country: Japan
facility: Ogaki Municipal Hospital
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
city: Kobe City
country: Japan
facility: Kobe City Medical Center General Hospital
city: Kumamoto shi
country: Japan
facility: National Hospital Organization Kumamoto Medical Center
city: Kyoto
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
city: Matsumoto
country: Japan
facility: National Hospital Organization Matsumoto Medical Center
city: Matsuyama
country: Japan
facility: Matsuyama Red Cross Hospital
city: Nagoya
country: Japan
facility: Nagoya City University Hospital
city: Okayama
country: Japan
facility: National Hospital Organization Okayama Medical Center
city: Osaka
country: Japan
facility: Japanese Red Cross Osaka Hospital
city: Shibukawa
country: Japan
facility: National Hospital Organization Shibukawa Medical Center
city: Shibuya
country: Japan
facility: Japanese Red Cross Medical Center
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer ziekenhuis-lokatie Dordwijk
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Brzozow
country: Poland
facility: Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im Ks B Markiewicza
city: Chorzow
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Kielce
country: Poland
facility: Swietokrzyskie Centrum Onkologii SPZOZ w Kielcach
city: Krakow
country: Poland
facility: NSSU Szpital Uniwersytecki w Krakowie
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej im sw Jana z Dukli
city: Poznan
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Poznaniu
city: Slupsk
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im Marii Sklodowskiej Curie Panstwowy Instytut Badawczy
city: Alcorcon
country: Spain
facility: Hosp. Univ. Fundacion Alcorcon
city: Barcelona
country: Spain
facility: Hosp. Del Mar
city: Guadalajara
country: Spain
facility: Hosp. Univ. de Guadalajara
city: Majadahonda
country: Spain
facility: Hosp. Univ. Pta. de Hierro Majadahonda
city: Pozuelo de Alarcon
country: Spain
facility: Hosp. Quiron Madrid Pozuelo
city: Terrassa
country: Spain
facility: Hosp. Mutua Terrassa
city: Ankara
country: Turkey
facility: Gulhane Egitim ve Arastirma Hastanesi
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Ankara
country: Turkey
facility: Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital
city: Ankara
country: Turkey
facility: Ankara University School of Medicine Cebeci Hospital
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Medical Faculty
city: Izmir
country: Turkey
facility: Dokuz Eylul University Medical Faculty
city: Samsun
country: Turkey
facility: Ondokuz Mayis University
city: Airdrie
country: United Kingdom
facility: Monklands District General Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital Wales
city: Colchester
country: United Kingdom
facility: Colchester Hospital University NHS
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary - Haematology
city: Londonderry
country: United Kingdom
facility: Altnagelvin Hospital
city: Oldham
country: United Kingdom
facility: The Royal Oldham Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References: