Clinical trial NCT03201965: 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
Official title: A Randomized Phase 3 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 AL Amyloidosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Amyloidosis
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2017-06-28
Enrollment: 416
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 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.

Eligibility criteria: Inclusion Criteria:

* 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:

  1. 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)
  2. 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

Exclusion Criteria:

* 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:

  1. NT-ProBNP \> 8500 nanogram per liter (ng/L)
  2. New York Heart Association (NYHA) classification IIIB or IV heart failure
  3. 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
  4. 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
  5. For participants with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to randomization
  6. 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)
  7. 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
  8. 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:

  1. 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
  2. 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

Primary outcomes:
measure: Percentage of Participants With Overall Complete Hematologic Response (CHR)
timeFrame: Up to 2.4 years
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute Emory University
state: Georgia
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School Of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences - Cardiovascular Medicine
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health And Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Box Hill
country: Australia
facility: Box Hill Hospital
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
city: Westmead
country: Australia
facility: Westmead Hospital
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
city: Anderlecht
country: Belgium
facility: Institut Jules Bordet
city: Gent
country: Belgium
facility: UZ Gent
city: Kortrijk
country: Belgium
facility: Az Groeninge
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Porto Alegre
country: Brazil
facility: Hospital das Clinicas de Porto Alegre
city: Recife
country: Brazil
facility: Sociedade Pernambucana de Combate ao Cancer
city: Rio de Janeiro
country: Brazil
facility: Instituto de Educacao, Pesquisa e Gestao em Saude Instituto Americas (COI)
city: Salvador
country: Brazil
facility: Hospital Sao Rafael
city: Sao Jose do Rio Preto
country: Brazil
facility: Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto Hospital de Base
city: Sao Paulo
country: Brazil
facility: Instituto de Assistencia Medica ao Servidor Publico Estadual IAMSPE
city: São Paulo
country: Brazil
facility: Clinica Sao Germano
city: São Paulo
country: Brazil
facility: Hospital Das Clinicas Da Faculdade De Medicina Da USP
city: Calgary
country: Canada
facility: Arthur J E Child Comprehensive Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Alberta Health Services
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Toronto
country: Canada
facility: University Health Network UHN Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Beijing
country: China
facility: Peking University First Hospital
city: Beijing
country: China
facility: Peking University People s Hospital
city: Hangzhou
country: China
facility: First affiliated Hospital of Zhejiang University
city: Shanghai
country: China
facility: Ruijin Hospital Shanghai Jiao Tong University
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
city: Aarhus N
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Dep. of Hematology, Rigshospitalet
city: Odense
country: Denmark
facility: Odense Universitets Hospital
city: Dijon
country: France
facility: CHU Dijon
city: Lille cedex
country: France
facility: Hopital Claude Huriez
city: Limoges
country: France
facility: CHU de Limoges - Fédération Hépatologie
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Nantes cedex 01
country: France
facility: Chu Hotel Dieu
city: PARIS cedex 10
country: France
facility: Hopital Saint Louis
city: Pierre - Bénite cedex
country: France
facility: Centre hospitalier Lyon-Sud
city: Poitiers
country: France
facility: CHU De Poitiers
city: Toulouse
country: France
facility: CHU Rangueil
city: Tours cedex
country: France
facility: CHU Bretonneau
city: Vandoeuvre les Nancy
country: France
facility: CHU de Nancy_ Hopital Brabois
city: Berlin
country: Germany
facility: Charite Campus Benjamin Franklin
city: Düsseldorf
country: Germany
facility: Heinrich-Heine-Universität Düsseldorf
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Hamburg
country: Germany
facility: HOPA-Hämatologisch-Onkologische Praxis Altona MVZ GmbH
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg Medizinische Klinik V
city: Tübingen
country: Germany
facility: Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg Med. Klinik U. Poliklinik Ii
city: Athens
country: Greece
facility: Alexandra General Hospital of Athens
city: Patra
country: Greece
facility: University General Hospital of Rio
city: Budapest
country: Hungary
facility: Semmelweis Egyetem I.Belgyogyaszati Klinika
city: Budapest
country: Hungary
facility: Semmelweis Egyetem I.Belgyogyaszati Klinika
city: Budapest
country: Hungary
facility: Del Pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet Szent Laszlo Telephely
city: Haifa
country: Israel
facility: Carmel Hospital
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Ramat-Gan
country: Israel
facility: Sheba Medical Center
city: Tel-Aviv
country: Israel
facility: Sourasky Medical Center
city: Zerifin
country: Israel
facility: Assaf Ha'Rofeh Medical Center
city: Bari
country: Italy
facility: Policlinico di Bari
city: Bologna
country: Italy
facility: Istituto di Ematologia Seràgnoli azienda ospedaliera univeristaria Policlinico S.Orsola-Malpighi
city: Palermo
country: Italy
facility: Casa di Cura La Maddalena
city: Pavia
country: Italy
facility: Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo
city: Roma
country: Italy
facility: Dipartimento Di Biotecnologie Cellulari Ed Ematologia-Università ''La Sapienza'',Policlinico Umberto I
city: Torino
country: Italy
facility: A.O.U. Città della Salute e della Scienza
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Hiroshima
country: Japan
facility: Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital
city: Hokkaido
country: Japan
facility: Teine Keijinkai Hospital
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
city: Kumamoto-City
country: Japan
facility: Kumamoto University Hospital
city: Kyoto
country: Japan
facility: Kyoto Kuramaguchi Medical Center
city: Matsumoto
country: Japan
facility: Shinshu University Hospital
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: Shibuya
country: Japan
facility: Japanese Red Cross Medical Center
city: Tokushima
country: Japan
facility: Tokushima University Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St Marys Hospital
city: Guadalajara
country: Mexico
facility: Centro de Investigación Farmacéutica Especializada
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr Jose Eleuterio Gonzalez
city: Den Haag
country: Netherlands
facility: Haga ziekenhuis
city: Groningen
country: Netherlands
facility: UMCG
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Veldhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Chorzow
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
city: Poznan
country: Poland
facility: SKPP UM w Poznaniu
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Badalona
country: Spain
facility: Inst. Cat. D'Oncologia-Badalona
city: Barcelona
country: Spain
facility: Hosp Univ Vall D Hebron
city: Barcelona
country: Spain
facility: Hosp Clinic de Barcelona
city: Madrid
country: Spain
facility: Hosp. Univ. Ramon Y Cajal
city: Madrid
country: Spain
facility: Hosp Univ Fund Jimenez Diaz
city: Madrid
country: Spain
facility: Hosp. Univ. 12 de Octubre
city: Pamplona
country: Spain
facility: Clinica Univ. de Navarra
city: Salamanca
country: Spain
facility: Hosp Clinico Univ de Salamanca
city: San Cristóbal de La Laguna
country: Spain
facility: Hosp. Univ. de Canarias
city: Valencia
country: Spain
facility: Hosp. Univ. Dr. Peset
city: Boras
country: Sweden
facility: South Elvsborg Hospital
city: Lund
country: Sweden
facility: Skanes universitetssjukhus
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi Cebeci Hastanesi
city: Antalya
country: Turkey
facility: Akdeniz University Medical Faculty
city: Atakum
country: Turkey
facility: Ondokuz Mayis Universitesi Tip Fakultesiy
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Medical Faculty
city: Izmir
country: Turkey
facility: Dokuz Eylul Universitesi Tip Fakultesi
city: Talas
country: Turkey
facility: Erciyes University Medical Faculty
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Trust,
city: London
country: United Kingdom
facility: University College Hospital
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. doi: 10.1056/NEJMoa2028631.
citation: Palladini G, Kastritis E, Maurer MS, Zonder J, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Bumma N, Kaufman JL, Medvedova E, Kovacsovics T, Rosenzweig M, Sanchorawala V, Qin X, Vasey SY, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood. 2020 Jul 2;136(1):71-80. doi: 10.1182/blood.2019004460.