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

NCT ID: NCT03201965

Last Updated: 2025-11-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 416 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-05
• Study Completion Date: 2024-11-19

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.

Conditions

Amyloidosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CyBorD alone (cyclophosphamide/bortezomib/dexamethasone)

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.

Group Type: ACTIVE_COMPARATOR

Cyclophosphamide

Intervention Type: DRUG

Participants will receive 300 mg/m\^2 of cyclophosphamide as an oral or IV dose.

Bortezomib

Intervention Type: DRUG

Participants will receive 1.3 mg/m\^2 of bortezomib as an subcutaneous (SC) injection.

Dexamethasone, 40 mg

Intervention Type: DRUG

Participants of CyBorD alone arm will receive 40 mg dexamethasone orally or IV dose. Participants of CyBorD plus daratumumab arm will receive dexamethasone 20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing to make a total of 40 mg.

CyBorD plus 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.

Group Type: EXPERIMENTAL

Daratumumab

Intervention Type: DRUG

Participants will receive 1800 mg of daratumumab subcutaneously.

Interventions

Cyclophosphamide

Participants will receive 300 mg/m\^2 of cyclophosphamide as an oral or IV dose.

Intervention Type: DRUG

Bortezomib

Participants will receive 1.3 mg/m\^2 of bortezomib as an subcutaneous (SC) injection.

Intervention Type: DRUG

Dexamethasone, 40 mg

Participants of CyBorD alone arm will receive 40 mg dexamethasone orally or IV dose. Participants of CyBorD plus daratumumab arm will receive dexamethasone 20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing to make a total of 40 mg.

Intervention Type: DRUG

Daratumumab

Participants will receive 1800 mg of daratumumab subcutaneously.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Research & Development, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Janssen Research & Development, LLC Clinical Trial

Role: STUDY_DIRECTOR

Janssen Research & Development, LLC

Locations

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

St 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

Box Hill Hospital

Box Hill, , Australia

Sir Charles Gairdner Hospital

Nedlands, , Australia

Westmead Hospital

Westmead, , Australia

Princess Alexandra Hospital

Woolloongabba, , Australia

Institut Jules Bordet

Anderlecht, , Belgium

UZ Gent

Ghent, , 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

São José do Rio Preto, , Brazil

Clinica Sao Germano

São Paulo, , Brazil

Instituto de Assistencia Medica ao Servidor Publico Estadual IAMSPE

São Paulo, , Brazil

Hospital Das Clinicas Da Faculdade De Medicina Da USP

São Paulo, , Brazil

Arthur J E Child Comprehensive Cancer Centre

Calgary, Alberta, Canada

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

CHU Dijon

Dijon, , France

Hopital Claude Huriez

Lille, , France

CHU de Limoges - Fédération Hépatologie

Limoges, , France

Institut Paoli Calmettes

Marseille, , France

Chu Hotel Dieu

Nantes, , France

Hopital Saint Louis

Paris, , France

Centre hospitalier Lyon-Sud

Pierre-Bénite, , France

CHU De Poitiers

Poitiers, , France

CHU Rangueil

Toulouse, , France

CHU Bretonneau

Tours, , France

CHU de Nancy_ Hopital Brabois

Vandœuvre-lès-Nancy, , France

Charite Campus Benjamin Franklin

Berlin, , Germany

Heinrich-Heine-Universität Düsseldorf

Düsseldorf, , Germany

Universitatsklinikum Essen

Essen, , Germany

HOPA-Hämatologisch-Onkologische Praxis Altona MVZ GmbH

Hamburg, , Germany

Universitaetsklinikum Heidelberg Medizinische Klinik V

Heidelberg, , Germany

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

Pátrai, , Greece

Semmelweis Egyetem I.Belgyogyaszati Klinika

Budapest, , Hungary

Semmelweis Egyetem I.Belgyogyaszati Klinika

Budapest, , Hungary

Del Pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet Szent Laszlo Telephely

Budapest, , 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

Ẕerifin, , Israel

Policlinico di Bari

Bari, , Italy

Istituto di Ematologia Seràgnoli 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, , 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 City, , Japan

Tokushima University Hospital

Tokushima, , Japan

Centro de Investigación Farmacéutica Especializada

Guadalajara, , Mexico

Hospital Universitario Dr Jose Eleuterio Gonzalez

Monterrey, , Mexico

UMCG

Groningen, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Haga ziekenhuis

The Hague, , Netherlands

UMC Utrecht

Utrecht, , Netherlands

Maxima Medisch Centrum

Veldhoven, , Netherlands

Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich

Chorzów, , Poland

SKPP UM w Poznaniu

Poznan, , Poland

Instytut Hematologii i Transfuzjologii

Warsaw, , Poland

Pusan National University Hospital

Busan, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital Yonsei University Health System

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

The Catholic University of Korea Seoul St Marys Hospital

Seoul, , South Korea

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

Hosp Clinico Univ de Salamanca

Salamanca, , Spain

Hosp. Univ. de Canarias

San Cristóbal de La Laguna, , Spain

Hosp. Univ. Dr. Peset

Valencia, , Spain

South Elvsborg Hospital

Borås, , Sweden

Skanes universitetssjukhus

Lund, , Sweden

Ankara Universitesi Tip Fakultesi Cebeci Hastanesi

Ankara, , Turkey (Türkiye)

Akdeniz University Medical Faculty

Antalya, , Turkey (Türkiye)

Ondokuz Mayis Universitesi Tip Fakultesiy

Atakum, , Turkey (Türkiye)

Istanbul University Istanbul Medical Faculty

Istanbul, , Turkey (Türkiye)

Dokuz Eylul Universitesi Tip Fakultesi

Izmir, , Turkey (Türkiye)

Erciyes University Medical Faculty

Talas, , Turkey (Türkiye)

University Hospitals Birmingham NHS Trust,

Birmingham, , United Kingdom

University College Hospital

London, , United Kingdom

Countries

United States; Australia; Belgium; Brazil; Canada; China; Denmark; France; Germany; Greece; Hungary; Israel; Italy; Japan; Mexico; Netherlands; Poland; South Korea; Spain; Sweden; Turkey (Türkiye); United Kingdom

References

Suzuki K, Wechalekar AD, Kim K, Shimazaki C, Kim JS, Ikezoe T, Min CK, Zhou F, Cai Z, Chen X, Iida S, Katoh N, Fujisaki T, Shin HJ, Tran N, Qin X, Vasey SY, Tromp B, Weiss BM, Comenzo RL, Kastritis E, Lu J. Daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with newly diagnosed AL amyloidosis: subgroup analysis of ANDROMEDA. Ann Hematol. 2023 Apr;102(4):863-876. doi: 10.1007/s00277-023-05090-z. Epub 2023 Mar 2.

Reference Type: DERIVED

PMID: 36862168 (View on PubMed)

Minnema MC, Dispenzieri A, Merlini G, Comenzo RL, Kastritis E, Wechalekar AD, Grogan M, Witteles R, Ruberg FL, Maurer MS, Tran N, Qin X, Vasey SY, Weiss BM, Vermeulen J, Jaccard A. Outcomes by Cardiac Stage in Patients With Newly Diagnosed AL Amyloidosis: Phase 3 ANDROMEDA Trial. JACC CardioOncol. 2022 Nov 15;4(4):474-487. doi: 10.1016/j.jaccao.2022.08.011. eCollection 2022 Nov.

Reference Type: DERIVED

PMID: 36444227 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34192431 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32244252 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

54767414AMY3001

Identifier Type: OTHER

Identifier Source: secondary_id

2016-001737-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2024-511967-26-00

Identifier Type: REGISTRY

Identifier Source: secondary_id

CR108193

Identifier Type: -

Identifier Source: org_study_id