Table 5: Details of the ANDROMEDA Study
Criteria
Description
Design and population
Study design
Phase III, randomized, open-label, active-controlled, multi-centre
Locations
109 sites in 22 countries (Australia, Belgium, Brazil, Canada, China, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, the Netherlands, Poland, Spain, South Korea, Sweden, Turkey, UK, and US)
Study duration
October 10, 2017, to ongoing
Patient enrolment: May 3, 2018, to August 15, 2019
Data cut-off date
February 14, 2020 (date of last observation for last patient recorded as part of the database for primary analysis)
Number of patients randomized (randomization ratio)
N = 388 (1:1)
Main inclusion criteria
Age ≥ 18 years
Histopathological diagnosis of systemic AL amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent in Congo red-stained tissue specimens or characteristic electron microscopy appearance
Measurable disease
Serum M-protein ≥ 0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation 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 ≥ 50 mg/L
Involvement in ≥ 1 organ(s)
Eastern Cooperative Oncology Group Performance Score of 0 to 2
Pre-treatment clinical laboratory values meeting the following criteria during the screening phase:
Absolute neutrophil count ≥ 1.0 × 109/L
Hemoglobin level ≥ 8.0 g/dL (≥ 5 mmol/L); red blood cell transfusion allowed until 7 days before randomization
Platelet count ≥ 50 × 109/L; platelet transfusions are acceptable without restriction during the screening period
Alanine aminotransferase level ≤ 2.5 times the ULN
Aspartate aminotransferase ≤ 2.5 times the ULN
Total bilirubin level ≤ 1.5 × ULN except for patients with Gilbert syndrome, in which case direct bilirubin ≤ 2 × ULN
Estimated glomerular filtration rate ≥ 20 mL/min/1.73 m2 measured using the Chronic Kidney Disease Epidemiology Collaboration equation
Main 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 before randomization
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
(continued)
Evidence of significant cardiovascular conditions
NT-ProBNP > 8,500 ng/L
New York Heart Association class IIIB or IV heart failure
Heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (e.g., prior myocardial infarction with documented history of cardiac enzyme elevation and electrocardiogram changes) or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy
Inpatient admission to a hospital for unstable angina or myocardial infarction within the last 6 months before first dose or percutaneous cardiac intervention with recent stent within 6 months or coronary artery bypass grafting within 6 months
For patients with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks before randomization
History of sustained ventricular tachycardia or aborted ventricular fibrillation or an atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker or implantable cardioverter defibrillator is indicated but not placed
Screening 12-lead electrocardiogram showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 500 ms; patients who have a pacemaker are included regardless of calculated QTc interval
Supine systolic blood pressure < 90 mm Hg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 20 mm Hg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion
Planned autologous stem cell transplant during the first 6 cycles treatment
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 and with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years)
Prior therapy for AL amyloidosis or multiple myeloma, including anti-CD38 medications (except for 160 mg dexamethasone, or equivalent corticosteroid, maximum exposure before randomization)
Drugs
Comparator
CyBorD: Cyclophosphamide (1.3 mg/m2 orally or intravenously), bortezomib (1.3 mg/m2 of body surface area), dexamethasone (40 mg orally or intravenously once weekly), for 6 cycles of 28 days each
Intervention
DCyBorD:
Cyclophosphamide (1.3 mg/m2 orally or intravenously), bortezomib (1.3 mg/m2 of body surface area), dexamethasone (40 mg orally or intravenously once weekly), for 6 cycles of 28 days each
plus
Daratumumab 1,800 mg per 15 mL administered SC, weekly in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter until disease progression or the start of subsequent therapy, or for a maximum of 24 cycles from start of the trial
Duration
Phase
Safety run-in (non-randomized)
2 years (n = 28) daratumumab SC weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years; CyBorD was given weekly for 6 cycles; patients received a median of 16 (range = 1 to 23) treatment cycles
Screening
Up to 28 days before treatment initiation
Open-label
CyBorD: 24 weeks
DCyBorD: 24 weeks for CyBorD and up to 24 months for daratumumab SC monotherapy
Follow-up
Ongoing
Outcomes
Primary end point
Hematologic CR assessed by an independent review committee
Secondary and exploratory end points
Secondary end points:
MOD-PFS/MOD-EFS
Organ response rate
Overall survival
Hematologic CR at 6 months
Hematologic VGPR-or-better rate
Time to hematologic response
Duration of hematologic response
Time to next treatment
Time to organ response
Duration of organ response
Time to organ progression
Improvement in fatigue
Exploratory end points:
Hematologic PFS
Minimal residual disease
Health-related quality of life
Medical resource utilization
Safety:
AEs
Grade 3 or 4 AEs
TEAE
Discontinuation due to TEAE
Death within 30 days of last dose of study treatment
Systemic administration-related reactions
Notes
Publications
Kastritis et al. (2021)7
AE = adverse event; AL = light chain; CR = complete response; CyBorD = cyclophosphamide, bortezomib, and dexamethasone; DCyBorD = daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone; EFS = event-free survival; MOD = major organ deterioration; NT-ProBNP = N-terminal pro-B-type natriuretic peptide; PFS = progression-free survival; SC = subcutaneous; TEAE = treatment-emergent adverse event; ULN = upper limit of normal; VGPR = very good partial response.
Source: Clinical Study Report for Darzalex.8
Hoặc