A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis
- Conditions
- Amyloidosis
- Interventions
- Registration Number
- NCT03201965
- Lead Sponsor
- Janssen Research & Development, LLC
- Brief Summary
The purpose of this study is to evaluate the efficacy and safety of daratumumab plus cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared with CyBorD alone in treatment of newly diagnosed amyloid light chain (AL) amyloidosis participants.
- Detailed Description
Participant involved in study for approx. 8 years duration includes Screening Phase (complete clinical evaluation will be done), Treatment Phase (monitoring of adverse events (AEs), laboratory abnormalities and clinical response), Post-Treatment Observation Phase (disease evaluations will be done) and a Long-term Follow-up Phase (Subsequent anticancer treatment, response to subsequent treatment, date of progression and survival status will be obtained every 16 weeks).The primary hypothesis is that daratumumab in combination with CyBorD will improve the overall complete hematological response rate compared to CyBorD alone in AL amyloidosis participants. Safety will be assessed by AEs, laboratory test results, electrocardiogram, vital sign measurements, physical examination, and Eastern Cooperative Oncology Group (ECOG) performance status.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 416
-
Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in congo red stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance
-
Measurable disease of amyloid light-chain (AL) amyloidosis as defined by at least one of the following:
- serum monoclonal (M)-protein greater than or equal (>=) 0.5 grams/deciliter (g/dL) by protein electrophoresis (routine serum protein electrophoresis and immunofixation [IFE] performed at a central laboratory)
- serum free light chain greater than or equal to (>=) 50 milligram/Liter (mg/L) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) >= 50 mg/L
-
One or more organs impacted by AL amyloidosis according to consensus guidelines
-
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
-
Prior therapy for AL amyloidosis or multiple myeloma including medications that target CD38, with the exception of 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure prior to randomization
-
Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, >= 60 percent (%) plasma cells in the bone marrow, or hypercalcemia
-
Evidence of significant cardiovascular conditions as specified below:
- NT-ProBNP > 8500 nanogram per liter (ng/L)
- New York Heart Association (NYHA) classification IIIB or IV heart failure
- Heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (eg, prior myocardial infarction with documented history of cardiac enzyme elevation and electrocardiogram [ECG] changes) or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy
- Inpatient admission to a hospital for unstable angina or myocardial infarction within the last 6 months prior to first dose or percutaneous cardiac intervention with recent stent within 6 months or coronary artery bypass grafting within 6 months
- For participants with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to randomization
- Participants with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/implantable cardioverter-defibrillators [ICD] is indicated but not placed (participants who do have a pacemaker/ICD are allowed on study)
- Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) > 500 milliseconds (msec). Participants who have a pacemaker may be included regardless of calculated QTc interval
- Supine systolic blood pressure < 90 millimeter of mercury (mmHg), or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 20 mmHg despite medical management (eg, midodrine, fludrocortisones) in the absence of volume depletion
-
Planned stem cell transplant during the first 6 cycles of protocol therapy are excluded. Stem cell collection during the first 6 cycles of protocol therapy is permitted
-
Known to be seropositive for human immunodeficiency virus (HIV)
-
Any one of the following:
- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (ie, participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded
- Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
-
Grade 2 sensory or Grade 1 painful peripheral neuropathy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description CyBorD alone (cyclophosphamide/bortezomib/dexamethasone) Cyclophosphamide Participants will receive dexamethasone (40 milligrams \[mg\] orally or intravenous \[IV\] dose), followed by cyclophosphamide (300 milligram per meter square \[mg/m\^2\] orally or IV dose), then bortezomib (1.3 mg/m\^2 subcutaneous injection) weekly on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. CyBorD alone (cyclophosphamide/bortezomib/dexamethasone) Bortezomib Participants will receive dexamethasone (40 milligrams \[mg\] orally or intravenous \[IV\] dose), followed by cyclophosphamide (300 milligram per meter square \[mg/m\^2\] orally or IV dose), then bortezomib (1.3 mg/m\^2 subcutaneous injection) weekly on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. CyBorD alone (cyclophosphamide/bortezomib/dexamethasone) Dexamethasone, 40 mg Participants will receive dexamethasone (40 milligrams \[mg\] orally or intravenous \[IV\] dose), followed by cyclophosphamide (300 milligram per meter square \[mg/m\^2\] orally or IV dose), then bortezomib (1.3 mg/m\^2 subcutaneous injection) weekly on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. CyBorD plus Daratumumab Daratumumab Participants will receive dexamethasone (20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing) followed by 1800 mg of daratumumab subcutaneously followed by cyclophosphamide (300 mg/m\^2 orally or IV dose weekly) and bortezomib (1.3 mg/m\^2 subcutaneous injection weekly) on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. Daratumumab will be administered weekly for the first 8 weeks (2 cycles), then every 2 weeks for 4 cycles (cycles 3-6), and then every 4 weeks until progression of disease or subsequent therapy for a maximum of 2 years.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Overall Complete Hematologic Response (CHR) Up to 2.4 years Overall CHR rate was defined as percentage of participants who achieved CHR, according to the International Amyloidosis Consensus Criteria. CHR: normalization of free light chain levels and ratio, negative serum, and urine immunofixation. If involved free light chain (iFLC) is less than (\<) upper limit of normal (ULN) and serum and urine Immunofixation electrophoresis (IFE) are negative, then neither a normal uninvolved free light chain (uFLC) level nor a normal free light chain (FLC) ratio are required for complete response (CR).
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (139)
CHU De Poitiers
🇫🇷Poitiers, France
Institut Paoli Calmettes
🇫🇷Marseille, France
Chu Hotel Dieu
🇫🇷Nantes cedex 01, France
Hopital Saint Louis
🇫🇷PARIS cedex 10, France
Centre hospitalier Lyon-Sud
🇫🇷Pierre - Bénite cedex, France
CHU Rangueil
🇫🇷Toulouse, France
Universitatsklinikum Essen
🇩🇪Essen, Germany
HOPA-Hämatologisch-Onkologische Praxis Altona MVZ GmbH
🇩🇪Hamburg, Germany
CHU Bretonneau
🇫🇷Tours cedex, France
CHU de Nancy_ Hopital Brabois
🇫🇷Vandoeuvre les Nancy, France
Charite Campus Benjamin Franklin
🇩🇪Berlin, Germany
Heinrich-Heine-Universität Düsseldorf
🇩🇪Düsseldorf, Germany
Universitaetsklinikum Heidelberg Medizinische Klinik V
🇩🇪Heidelberg, Germany
Hosp. Univ. de Canarias
🇪🇸San Cristóbal de La Laguna, Spain
Hosp. Univ. Dr. Peset
🇪🇸Valencia, Spain
South Elvsborg Hospital
🇸🇪Boras, Sweden
Skanes universitetssjukhus
🇸🇪Lund, Sweden
Ankara Universitesi Tip Fakultesi Cebeci Hastanesi
🇹🇷Ankara, Turkey
Akdeniz University Medical Faculty
🇹🇷Antalya, Turkey
Ondokuz Mayis Universitesi Tip Fakultesiy
🇹🇷Atakum, Turkey
Istanbul University Istanbul Medical Faculty
🇹🇷Istanbul, Turkey
Dokuz Eylul Universitesi Tip Fakultesi
🇹🇷Izmir, Turkey
Erciyes University Medical Faculty
🇹🇷Talas, Turkey
University Hospitals Birmingham NHS Trust,
🇬🇧Birmingham, United Kingdom
University College Hospital
🇬🇧London, United Kingdom
Box Hill Hospital
🇦🇺Box Hill, Australia
CHU Dijon
🇫🇷Dijon, France
Hopital Claude Huriez
🇫🇷Lille cedex, France
CHU de Limoges - Fédération Hépatologie
🇫🇷Limoges, France
Hosp Clinico Univ de Salamanca
🇪🇸Salamanca, Spain
Arthur J E Child Comprehensive Cancer Centre
🇨🇦Calgary, Alberta, Canada
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
City of Hope
🇺🇸Duarte, California, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
Stanford University
🇺🇸Stanford, California, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
Mayo Clinic
🇺🇸Jacksonville, Florida, United States
Winship Cancer Institute Emory University
🇺🇸Atlanta, Georgia, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Boston University Medical Center
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Barbara Ann Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Washington University School Of Medicine
🇺🇸Saint Louis, Missouri, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Weill Cornell Medical College
🇺🇸New York, New York, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Wake Forest University Health Sciences - Cardiovascular Medicine
🇺🇸Winston-Salem, North Carolina, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
The Ohio State University
🇺🇸Columbus, Ohio, United States
Oregon Health And Science University
🇺🇸Portland, Oregon, United States
University of Pennsylvania Medical Center
🇺🇸Philadelphia, Pennsylvania, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
University of Texas, MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Australia
Westmead Hospital
🇦🇺Westmead, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Australia
Institut Jules Bordet
🇧🇪Anderlecht, Belgium
UZ Gent
🇧🇪Gent, Belgium
Az Groeninge
🇧🇪Kortrijk, Belgium
Universitair Ziekenhuis Leuven
🇧🇪Leuven, Belgium
Hospital das Clinicas de Porto Alegre
🇧🇷Porto Alegre, Brazil
Sociedade Pernambucana de Combate ao Cancer
🇧🇷Recife, Brazil
Instituto de Educacao, Pesquisa e Gestao em Saude Instituto Americas (COI)
🇧🇷Rio de Janeiro, Brazil
Hospital Sao Rafael
🇧🇷Salvador, Brazil
Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto Hospital de Base
🇧🇷Sao Jose do Rio Preto, Brazil
Instituto de Assistencia Medica ao Servidor Publico Estadual IAMSPE
🇧🇷Sao Paulo, Brazil
Clinica Sao Germano
🇧🇷São Paulo, Brazil
Hospital Das Clinicas Da Faculdade De Medicina Da USP
🇧🇷São Paulo, Brazil
Alberta Health Services
🇨🇦Edmonton, Alberta, Canada
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
London Health Sciences Center
🇨🇦London, Ontario, Canada
University Health Network UHN Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
McGill University Health Centre
🇨🇦Montreal, Quebec, Canada
Peking University First Hospital
🇨🇳Beijing, China
Peking University People s Hospital
🇨🇳Beijing, China
First affiliated Hospital of Zhejiang University
🇨🇳Hangzhou, China
Ruijin Hospital Shanghai Jiao Tong University
🇨🇳Shanghai, China
The First Affiliated Hospital of Wenzhou Medical University
🇨🇳Wenzhou, China
Aarhus University Hospital
🇩🇰Aarhus N, Denmark
Dep. of Hematology, Rigshospitalet
🇩🇰Copenhagen, Denmark
Odense Universitets Hospital
🇩🇰Odense, Denmark
Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,
🇩🇪Tübingen, Germany
Universitätsklinikum Würzburg Med. Klinik U. Poliklinik Ii
🇩🇪Würzburg, Germany
Alexandra General Hospital of Athens
🇬🇷Athens, Greece
University General Hospital of Rio
🇬🇷Patra, Greece
Semmelweis Egyetem I.Belgyogyaszati Klinika
ðŸ‡ðŸ‡ºBudapest, Hungary
Del Pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet Szent Laszlo Telephely
ðŸ‡ðŸ‡ºBudapest, Hungary
Carmel Hospital
🇮🇱Haifa, Israel
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Sheba Medical Center
🇮🇱Ramat-Gan, Israel
Sourasky Medical Center
🇮🇱Tel-Aviv, Israel
Assaf Ha'Rofeh Medical Center
🇮🇱Zerifin, Israel
Policlinico di Bari
🇮🇹Bari, Italy
Istituto di Ematologia Serà gnoli azienda ospedaliera univeristaria Policlinico S.Orsola-Malpighi
🇮🇹Bologna, Italy
Casa di Cura La Maddalena
🇮🇹Palermo, Italy
Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Dipartimento Di Biotecnologie Cellulari Ed Ematologia-Università ''La Sapienza'',Policlinico Umberto I
🇮🇹Roma, Italy
A.O.U. Città della Salute e della Scienza
🇮🇹Torino, Italy
Fukushima Medical University Hospital
🇯🇵Fukushima, Japan
Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital
🇯🇵Hiroshima, Japan
Teine Keijinkai Hospital
🇯🇵Hokkaido, Japan
Kanazawa University Hospital
🇯🇵Kanazawa, Japan
Kumamoto University Hospital
🇯🇵Kumamoto-City, Japan
Kyoto Kuramaguchi Medical Center
🇯🇵Kyoto, Japan
Shinshu University Hospital
🇯🇵Matsumoto, Japan
Matsuyama Red Cross Hospital
🇯🇵Matsuyama, Japan
Nagoya City University Hospital
🇯🇵Nagoya, Japan
National Hospital Organization Okayama Medical Center
🇯🇵Okayama, Japan
Japanese Red Cross Medical Center
🇯🇵Shibuya, Japan
Tokushima University Hospital
🇯🇵Tokushima, Japan
Pusan National University Hospital
🇰🇷Busan, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Severance Hospital Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea Seoul St Marys Hospital
🇰🇷Seoul, Korea, Republic of
Centro de Investigación Farmacéutica Especializada
🇲🇽Guadalajara, Mexico
Hospital Universitario Dr Jose Eleuterio Gonzalez
🇲🇽Monterrey, Mexico
Haga ziekenhuis
🇳🇱Den Haag, Netherlands
UMCG
🇳🇱Groningen, Netherlands
Erasmus MC
🇳🇱Rotterdam, Netherlands
UMC Utrecht
🇳🇱Utrecht, Netherlands
Maxima Medisch Centrum
🇳🇱Veldhoven, Netherlands
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
🇵🇱Chorzow, Poland
SKPP UM w Poznaniu
🇵🇱Poznan, Poland
Instytut Hematologii i Transfuzjologii
🇵🇱Warszawa, Poland
Inst. Cat. D'Oncologia-Badalona
🇪🇸Badalona, Spain
Hosp Univ Vall D Hebron
🇪🇸Barcelona, Spain
Hosp Clinic de Barcelona
🇪🇸Barcelona, Spain
Hosp. Univ. Ramon Y Cajal
🇪🇸Madrid, Spain
Hosp Univ Fund Jimenez Diaz
🇪🇸Madrid, Spain
Hosp. Univ. 12 de Octubre
🇪🇸Madrid, Spain
Clinica Univ. de Navarra
🇪🇸Pamplona, Spain