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Note: This record shows only 22 elements of the WHO Trial Registration Data Set. To view changes that have been made to the source record, or for additional information about this trial, click on the URL below to go to the source record in the primary register.
Register: EUCTR
Last refreshed on: 10 December 2019
Main ID:  EUCTR2016-001737-27-GB
Date of registration: 11/01/2018
Prospective Registration: Yes
Primary sponsor: Janssen-Cilag International N.V.
Public title: 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
Scientific title: A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared With CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis
Date of first enrolment: 08/10/2018
Target sample size: 370
Recruitment status: Authorised-recruitment may be ongoing or finished
URL:  https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001737-27
Study type:  Interventional clinical trial of medicinal product
Study design: 
Controlled: yes
Randomised: yes
Open: yes
Single blind: no
Double blind: no
Parallel group: yes
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: no
Other: yes
Other specify the comparator: Active monitoring
Number of treatment arms in the trial: 2
 
Phase:  Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no
Countries of recruitment
Australia Belgium Brazil Canada China Denmark France Germany
Greece Hungary Israel Italy Japan Korea, Republic of Mexico Netherlands
Poland Romania Spain Sweden Turkey United Kingdom United States
Contacts
Name: Clinical Registry group   
Address:  Archimedesweg 29 2333 Leiden Netherlands
Telephone: +31715242166
Email: ClinicalTrialsEU@its.jnj.com
Affiliation:  Janssen-Cilag International N.V.
Name: Clinical Registry group   
Address:  Archimedesweg 29 2333 Leiden Netherlands
Telephone: +31715242166
Email: ClinicalTrialsEU@its.jnj.com
Affiliation:  Janssen-Cilag International N.V.
Key inclusion & exclusion criteria
Inclusion criteria:
1) 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) or older.
2) Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry (IHC) 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
Considerations for specific populations where other types of amyloidosis may be encountered:
- For male subjects 70 years of age or older who have cardiac involvement only, and subjects of African descent (black subjects), mass spectrometry typing of AL amyloid in a tissue biopsy is recommended to rule out other types of amyloidosis such as age-related amyloidosis or hereditary amyloidosis (ATTR mutation)
3) Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
-serum M-protein =0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation (IFE) performed at a central laboratory),
-serum free light chain =50 mg/L with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) =50 mg/L.
4) One or more organs impacted by AL amyloidosis according to consensus guidelines
5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
6) Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
a. Absolute neutrophil count =1.0 ×1000000000 /L;
b. Hemoglobin level =8.0 g/dL (=5 mmol/L); red blood cell transfusion allowed until 7 days before randomization
c. Platelet count =50 × 1000000000/L; Platelet transfusions are acceptable without restriction during the Screening period
d. Alanine aminotransferase level (ALT) =2.5 times the ULN
e. Aspartate aminotransferase (AST) =2.5 times the ULN
f. Total bilirubin level =1.5 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin =2 × ULN
g. Estimated glomerular filtration rate (eGFR) =20 mL/min/1.73m2.
Please note the eGFR is measured by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
7)Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective
contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing and continue for 1 year after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
8)During the study and for 1 year after stopping cyclophospham

Exclusion criteria:
1.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
2.Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, =60% plasma cells in the bone marrow, or hypercalcemia
3.Evidence of significant cardiovascular conditions as specified below:
a.NT-ProBNP >8500 ng/L
b.New York Heart Association (NYHA) classification IIIB or IV heart failure
c.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 ECG changes)or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy
d.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
e.For subjects with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to randomization
f.Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/ICD is indicated but not placed (Subjects who do have a pacemaker/ICD are allowed on study)
g.Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >500 msec.Subjects who have a pacemaker may be included regardless of calculated QTc interval
h.Supine systolic blood pressure <90 mm Hg, 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
4.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
5.History of malignancy (other than AL amyloidosis)within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas 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)
6.Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal.Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal
7.Moderate or severe persistent asthma within the past 2 years,or currently has uncontrolled asthma of any classification.(Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
8.Know to be seropositive for human immunodeficiency virus (HIV)
9.Any of the following:
a. seropositive for hepatitis B (defined by a positive test for hepati


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes
Health Condition(s) or Problem(s) studied
AL Amyloidosis (Newly Diagnosed Systemic AL Amyloidosis )
MedDRA version: 20.0 Level: PT Classification code 10002022 Term: Amyloidosis System Organ Class: 10021428 - Immune system disorders
Therapeutic area: Diseases [C] - Cancer [C04]
Intervention(s)

Product Name: Daratumumab co-formulated with recombinant human hyaluronidase (rHuPH20)
Product Code: JnJ 54767414
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DARATUMUMAB
CAS Number: 945721-28-8
Current Sponsor code: JnJ 54767414
Other descriptive name: HUMAX-CD38
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 120-

Primary Outcome(s)

Main Objective: The primary objective is to evaluate the efficacy of daratumumab plus CyBorD compared with CyBorD
alone in the treatment of newly diagnosed AL amyloidosis patients.

Secondary Objective: To evaluate the clinically observable composite endpoints for major organ deterioration progression-free survival (MOD-PFS) following treatment with daratumumab in combination with CyBorD compared with CyBorD alone
To evaluate the following efficacy measures following treatment with daratumumab in combination with CyBorD compared with CyBorD alone:
- Organ response rate (OrRR)
- Overall survival (OS)
- Time to and duration of response
To evaluate fatigue, mental functioning, and health-related quality of life following treatment with daratumumab in combination with CyBorD compared with CyBorD alone
To assess the safety and tolerability of daratumumab when administered in combination with CyBorD
To assess the pharmacokinetics of daratumumab and the immunogenicity of daratumumab and rHuPH20
To explore minimal residual disease (MRD) status in amyloidosis patients as a surrogate for hematologic progression-free survival (HemPFS) and OS or as a biomarker for relapse
Primary end point(s): The primary endpoint is overall complete hematologic response rate.
Timepoint(s) of evaluation of this end point: During cycles 1 through 6 every 28 days, then Cycle 7+ and during the observation phase Every 8 weeks until disease progression according to MOD-PFS criteria.
Secondary Outcome(s)

Secondary end point(s): - Major organ deterioration progression-free survival (MOD-PFS). This is a composite endpoint of clinically observable endpoints and will be defined from randomization to any one of the following events, whichever comes first:
1. Death
2. Clinical Manifestation of Cardiac Failure: Defined as development of dyspnea at rest (for at least 3 consecutive days) and due solely to amyloidosis cardiac deterioration, or need for cardiac transplant, left ventricular assist device (LVAD), or intra-aortic balloon pump (IABP)
3. Clinical Manifestation of Renal Failure: Defined as the development of end-stage renal disease (need for hemodialysis or renal transplant)
4. Development of hematologic PD as per consensus guidelines From CHR, abnormal free light chain ratio (light chain ratio must double) or from CHR/VGPR/PR, 50% increase in serum M-protein to >0.5 g/dL or 50% increase in urine M protein to >200 mg/day (a visible peak must be present)
Free light chain increase of 50% to >100 mg/L
- Organ response rate (OrRR) for kidney, heart, liver is defined as the proportion of baseline organ involved subjects who achieve confirmed organ response in each corresponding organ.
-Overall survival (OS) is measured from the date of randomization to the date of the subject's death. If the subject is alive or the vital status is unknown, then the subject's data will be censored at the date the subject was last known to be alive.
-CHR rate at 6 months is defined as the proportion of subjects who achieve a complete hematologic response at 6 months, according to the consensus guidelines for AL amyloidosis, during or after the study treatment.
- Improvement in fatigue is defined as the change from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Fatigue scale score, improvement in mental functioning is defined as the change from baseline in the 36- Item Short Form Survey version 2 (SF-36v2) Mental Component Summary (MCS), and improvement in health-related quality of life is defined as change from baseline in the EORTC QLQ-C30 Global Health Status scale score.
-Time to next treatment (TNT) defined as the time from the date of randomization to the start date of subsequent AL amyloidosis (nonprotocol) treatment. Death due to PD prior to subsequent therapy is considered as an event. Otherwise, TNT is censored at the date of death or the last date known to be alive.
-Hematologic VGPR or better rate is defined as the proportion of subjects who achieve hematologic CR or VGPR.
-Time to CHR (or VGPR or better) is defined as the time between the date of randomization and the first efficacy evaluation at which the subject has met all criteria for hematologic CR (or VGPR or better).
-Duration of CHR (or VGPR or better) is defined as the time between the date of initial documentation of CHR (or VGPR or better) to the date of first documented evidence of hematologic progressive disease. For
subjects who have not progressed, data will be censored at the last disease assessment.
-Time to cardiac response, time to renal response, and time to liver response. Defined as the time between the date of randomization and the first efficacy evaluation at which the subject has each corresponding organ response.
- Duration of organ response is defined as the time between the date of initial documentation of each corresponding organ response to the date of first documented evidence of the corresponding organ progressive disease. For subjects who have not had organ progression, data will be censored at the last disease assessment.
- Time to cardiac progression, time to renal progression, and time to liver progression.
Defined as the time from the date of randomization to the date of each corresponding organ progression per consensus guidelines.

Timepoint(s) of evaluation of this end point: During cycles 1 through 6 every 28 days, then Cycle 7+ and during the observation phase Every 8 weeks until disease progression according to MOD-PFS criteria.

Secondary ID(s)
2016-001737-27-DE
54767414AMY3001
NCT03201965
Source(s) of Monetary Support
Janssen Research & Development, LLC
Secondary Sponsor(s)
Ethics review
Status: Approved
Approval date:
Contact:
Results
Results available:
Date Posted:
Date Completed:
URL:
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