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

Amyloidosis Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03201965
• Other study ID #: CR108193
• Secondary ID: 2016-001737-2754
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 5, 2017
• Est. completion date: August 16, 2024

Study information

• Verified date: April 2024
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 416
• Est. completion date: August 16, 2024
• Est. primary completion date: February 14, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Amyloidosis

Intervention

Drug:
• Cyclophosphamide
Participants will receive 300 mg/m^2 of cyclophosphamide as an oral or IV dose.
• Bortezomib
Participants will receive 1.3 mg/m^2 of bortezomib as an subcutaneous (SC) injection.
• 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.
• Daratumumab
Participants will receive 1800 mg of daratumumab subcutaneously.

Locations

Country	Name	City	State
Australia	Box Hill Hospital	Box Hill
Australia	Sir Charles Gairdner Hospital	Nedlands
Australia	Westmead Hospital	Westmead
Australia	Princess Alexandra Hospital	Woolloongabba
Belgium	Institut Jules Bordet	Anderlecht
Belgium	UZ Gent	Gent
Belgium	Az Groeninge	Kortrijk
Belgium	Universitair Ziekenhuis Leuven	Leuven
Brazil	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
Canada	Alberta Health Services	Calgary	Alberta
Canada	Alberta Health Services	Edmonton	Alberta
Canada	London Health Sciences Center	London	Ontario
Canada	McGill University Health Centre	Montreal	Quebec
Canada	University Health Network (UHN) Princess Margaret Cancer Centre	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
China	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
Denmark	Aarhus University Hospital	Aarhus C
Denmark	Dep. of Hematology, Rigshospitalet	Copenhagen
Denmark	Odense Universitets Hospital	Odense
France	CHU Dijon	Dijon
France	Hopital Claude Huriez	Lille cedex
France	CHU de Limoges - Fédération Hépatologie	Limoges
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 De Poitiers	Poitiers
France	CHU Rangueil	Toulouse
France	CHU Bretonneau	Tours cedex
France	CHU de Nancy_ Hopital Brabois	Vandoeuvre les Nancy
Germany	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
Greece	Alexandra General Hospital of Athens	Athens
Greece	University General Hospital of Rio	Patra
Hungary	Del Pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet Szent Laszlo Telephely	Budapest
Hungary	Semmelweis Egyetem I.Belgyogyaszati Klinika	Budapest
Hungary	Semmelweis Egyetem I.Belgyogyaszati Klinika	Budapest
Israel	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
Italy	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
Japan	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
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul
Mexico	Centro de Investigación Farmacéutica Especializada	Guadalajara
Mexico	Hospital Universitario Dr Jose Eleuterio Gonzalez	Monterrey
Netherlands	Haga ziekenhuis	Den Haag
Netherlands	UMCG	Groningen
Netherlands	Erasmus MC	Rotterdam
Netherlands	UMC Utrecht	Utrecht
Netherlands	Maxima Medisch Centrum	Veldhoven
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich	Chorzów
Poland	SKPP UM w Poznaniu	Poznan
Poland	Instytut Hematologii i Transfuzjologii	Warszawa
Spain	Inst. Cat. D'Oncologia-Badalona	Badalona
Spain	Hosp. Clinic de Barcelona	Barcelona
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Hosp. Univ. Fund. Jimenez Diaz	Madrid
Spain	Hosp. Univ. Ramon Y Cajal	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
Sweden	South Elvsborg Hospital	Boras
Sweden	Skanes universitetssjukhus	Lund
Turkey	Ankara Universitesi Tip Fakultesi Cebeci Hastanesi	Ankara
Turkey	Akdeniz University Medical Faculty	Antalya
Turkey	Ondokuz Mayis Universitesi Tip Fakultesi	Atakum
Turkey	Istanbul University Istanbul Medical Faculty	Istanbul
Turkey	Dokuz Eylul Universitesi Tip Fakultesi	Izmir
Turkey	Erciyes University Medical Faculty	Talas
United Kingdom	University Hospitals Birmingham NHS Trust,	Birmingham
United Kingdom	University College Hospital	London
United States	Winship Cancer Institute Emory University	Atlanta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	University of Maryland	Baltimore	Maryland
United States	Boston University Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	Cleveland Clinic	Cleveland	Ohio
United States	The Ohio State University	Columbus	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	University of Texas, MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic	Jacksonville	Florida
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	University of Pennsylvania Medical Center	Philadelphia	Pennsylvania
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	University of California San Francisco	San Francisco	California
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Stanford University	Stanford	California
United States	Wake Forest University Health Sciences - Cardiovascular Medicine	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  China,  Denmark,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Spain,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Overall Complete Hematologic Response (CHR)	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).	Up to 2.4 years