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
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
Sunagawa Yoshihiro
Janssen Pharmaceutical K.K.
5-2, Nishi-kanda 3-chome, Chiyoda-ku, Tokyo
+81-120-183-275
DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com
Medical Information Center
Janssen Pharmaceutical K.K.
5-2, Nishi-kanda 3-chome, Chiyoda-ku, Tokyo
+81-120-183-275
DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com
completed
July. 17, 2018
370
Interventional
Randomized
treatment purpose
4
- 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:
a) serum monoclonal (M)-protein greater than or equal (>=) to 0.5 grams/deciliter (g/dL) by protein electrophoresis (routine serum protein electrophoresis and immunofixation [IFE] performed at central laboratory)
b) 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:
a) NT-ProBNP > 8500 nanogram per liter (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 electrocardiogram [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 participants with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to randomization
f) 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)
g) 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
h) 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:
a) 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 realtime polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded
b) 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
20age old over
No limit
Both
Amyloidosis
investigational material(s)
Generic name etc : Cyclophosphamide, Bortezomib, dexamethasone plus Daratumumab
INN of investigational material : -
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Participants will receive dexamethasone (20mg 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.
control material(s)
Generic name etc : Cyclophosphamide, Bortezomib, dexamethasone
INN of investigational material : -
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Participants will receive dexamethasone (40milligrams [mg] orally or intravenous [IV]dose), followed by cyclophosphamide (300milligram 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.
efficacy
Percentage of Participants With Overall Complete Hematologic Response
Approximately 3 years
efficacy
Major Organ Deterioration Progression-Free Survival (MOD-PFS)
Major Organ Deterioration Progression-Free Survival (MOD-PFS)
efficacy
Progression-Free Survival (PFS)
Approximately 5 years
efficacy
Organ Response Rate (OrRR)
Approximately 5 years
efficacy
Overall Survival (OS)
Approximately 8 years
efficacy
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Fatigue Scale Score
Baseline, up to end of study (approximately 5 years)
efficacy
Change From Baseline in the 36-Item Short Form Survey version 2 (SF-36v2) Mental Component Summary (MCS)
Baseline, up to end of study (approximately 5 years)
efficacy
Change From Baseline in the EORTC QLQC30 Global Health Status Scale Score
Baseline, up to end of study (approximately 5 years)
efficacy
Time to Next Treatment (TNT)
Approximately 5 years
efficacy
Hematologic Very Good Partial Response or Better Rate
Approximately 3 years
efficacy
Time to Complete Hematologic Response
Approximately 3 years
efficacy
Time to Hematologic Very Good Partial Response (VGPR) or Better Response
Approximately 3 years
efficacy
Duration of Complete Hematologic Response
Approximately 5 years
efficacy
Duration of Hematologic Very Good Partial Response (VGPR) or Better Response
Approximately 5 years
efficacy
Time to Organ Response
Approximately 5 years
efficacy
Duration of Organ Response
Approximately 5 years
Janssen Pharmaceutical K.K.
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Matsuyama Red Cross Hospital Institutional Review Board
