This study has been transitioned to CTIS with ID 2024-511967-26-00 check the CTIS register for the current data. Primary Objective: The primary objective is to evaluate the efficacy of daratumumab plus CyBorD compared with CyBorDalone in the…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is overall complete hematologic response rate.
Secondary outcome
The secondary efficacy endpoints include:
# 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).
Note: the development of a IgG Kappa spike on SPEP/IFE will not be considered
disease progression for subjects who have received daratumumab, DIRA testing
may be indicated.
From CHR, VGPR or 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
# Progression-free survival (PFS) is defined as the time from the date of
randomization to the date of first documentation of hematologic disease
progression, or organ (cardiac, renal, or liver) progression, or death due to
any cause, whichever occurs first according to central
laboratory results and judged by international consensus guidelines. For those
subjects who are still alive and have not yet progressed, the subject*s data
will be censored at the last disease assessment.
# Organ response rate (OrRR) for kidney, heart, liver is defined as the
proportion of baseline organ involved subjects who achieve 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.
# Improvement in fatigue is defined as the change from baseline in the EORTC
QLQ-C30
Fatigue scale score, improvement in mental functioning is defined as the change
from baseline in the SF-36v2 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 (non-protocol).
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 complete hematologic response (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).
For subjects without a hematologic CR (or VGPR or better), data will be
censored either at the date of progressive disease or, in the absence of
progressive disease, at the last disease assessment.
# Duration of complete hematologic response (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 organ response is defined as the time between the date of
randomization and the first efficacy evaluation at which the subject has each
corresponding organ response. For subjects without organ response, data will be
censored either at the date of the corresponding organ progressive disease or,
in the absence of organ progressive disease, at the last disease assessment.
# 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.
Background summary
refer to question/answer 4
Hypothesis: The primary hypothesis of this study is that daratumumab in
combination with CyBorD will improve the
overall complete hematological response rate compared to CyBorD alone, in
subjects with newly diagnosed
AL amyloidosis.The primary hypothesis of this study is that daratumumab in
combination with CyBorD
will improve the overall complete hematological response rate compared to
CyBorD alone, in subjects with
newly diagnosed AL amyloidosis.
Study objective
This study has been transitioned to CTIS with ID 2024-511967-26-00 check the CTIS register for the current data.
Primary 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 Objectives:
# To evaluate the clinically observable endpoints for major organ deterioration
(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:
* Progression-free survival (PFS)
* Organ response rate (OrRR)
* Overall survival (OS)
* Time 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 status in amyloidosis patients as a
surrogate for PFS and OS or as a biomarker for relapse
Exploratory Objectives
# To evaluate biomarkers of response following treatment with daratumumab in
combination with CyBorD compared with CyBorD alone
# To evaluate physical functioning, symptom improvement, functional improvement
and health utility following treatment with daratumumab in combination with
CyBorD compared with CyBorD alone
# To evaluate diastolic function following treatment with daratumumab in
combination with CyBorD compared with CyBorD alone
# To explore the pharmacokinetic/pharmacodynamic relationship of daratumumab,
such as exposure response relationship for efficacy/safety endpoints and/or
disease-related or mechanism-based biomarkers
Study design
This is a randomized, open-label, active-controlled, multicenter Phase 3 study
in subjects with newly
diagnosed amyloid light chain amyloidosis. Approximately 360 subjects will be
stratified by cardiac stage
(Stage I, II, and IIIa), countries that typically offer transplant for patients
with AL amyloidosis (List A or
List B), and renal function (CrCl >=60 mL/min or CrCl <60 mL/min) and then
assigned to receive either
CyBorD or CyBorD in combination with daratumumab. Subject participation will
include a Screening
Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term
Follow-up Phase.
Given the potential safety concern with regards to the use of IV daratumumab in
the amyloidosis population
(ie, volume overload), this study will utilize the daratumumab SC
co-formulation. Although the risk of
volume overload is predicted to be lower with SC daratumumab than with IV
infusion, patients with newly
diagnosed AL amyloidosis may still develop adverse events attributable to
hypervolemia (for example,
dyspnea, peripheral edema, etc) secondary to amyloid-induced cardiac or renal
insufficiency. Additionally,
daratumumab has not been co-administered with CyBorD. Therefore, prior to the
start of the randomized
portion of the study, a safety run-in will be conducted. Dosing of these
subjects will be staggered so that no
subject will receive their first dose sooner than 48 hours after the previously
enrolled subject. Safety
evaluation will be performed by the sponsor (and external academic
hematologists) after at least 10 subjects
have received at least 1 cycle of treatment. If no safety signal is observed,
particularly in regard to volume
overload, the randomized portion of the study will begin.
In the randomized portion of the study, subjects randomized to Treatment Arm A
will receive study
treatment with CyBorD. All treatment cycles are 4 weeks (28 days) in length.
CyBorD will be administered
for a maximum of 6 cycles (24 weeks).
Subjects randomized to Treatment Arm B will receive CyBorD plus daratumumab at
a fixed dose of
1800 mg. A maximum of 6 cycles (24 weeks) of CyBorD plus daratumumab will be
administered. After
Cycle 6, subjects may receive daratumumab monotherapy on Day 1 of subsequent
28-day cycles until
disease progression, start of subsequent therapy, or a maximum of 2 years from
the start of the study.
Intervention
Daratumumab 1800 mg will be administered subcutaneously through a syringe by a
manual push over
approximately 5 minutes. 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 from the start of the study.
Subjects will receive 300 mg/m2 cyclophosphamide (maximum weekly dose 500 mg)
as an oral or IV
weekly dose and 1.3 mg/m2 bortezomib as an SC injection weekly (Days 1, 8, 15,
22) in every 28-day cycle
for a maximum of 6 cycles.
Dexamethasone will be administered at a total dose of 40 mg weekly (ie, Days 1,
8, 15, 22). On days of
daratumumab dosing, subjects in Treatment Arm B will receive 20 mg on the day
of daratumumab dosing
as premedication and 20 mg on the day after daratumumab dosing. On weeks that
daratumumab is not
administered, or for subjects randomized to Treatment Arm A, dexamethasone is
to be given 40 mg weekly
on a single day or divided into 2 days.
Study burden and risks
Burden (both arm A and B): Hospital visits on a more frequent schedule than
standard, including additional assessments.
Risks (arm B): Adverse Events observed mostly related to the IV administration
of daratumumab are fever, fatigue, infusion-related reactions, diarrhea, cough,
headache, infection of the nose, sinuses and/or throat, nausea, swelling of
hands, feet or limbs, low white blood cell, platelets and/or red blood cell
counts and muscle spasms (refer to the patient information sheet for a complete
overview).
Adverse Events for daratumumab administered SC appear to be similar to those
reported in studies of daratumumab administered IV either alone or in
combination with other drugs, but with a lower incidence of
infusion/injection-related reactions (IRRs). In approximately 1 in 4 patients
with daratumumab administered SC an infusion-related reaction occurred.
Administration of daratumumab in the abdominal SC tissue was associated with
injection site erythema and hardening of the skin. This was observed in
approximately 30 to 40% of subjects.
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
Inclusion criteria
# 18 years of age or older.
# Histopathological diagnosis of amyloidosis based on detection by
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, if required
# 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 >=5.0 mg/dL with an abnormal kappa:lambda ratio or the
difference between involved and uninvolved free light chains (dFLC) >=5mg/ dL.
# One or more organs impacted by AL amyloidosis according to consensus
guidelines
# Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
# Laboratory values as defined by the protocol
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% plasma cells in the bone
marrow, or hypercalcemia
# 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 (AV) 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
# 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
# Any form of non-AL amyloidosis, including wild type or mutated (ATTR)
amyloidosis.
# History of malignancy (other than AL amyloidosis) within 3 years before the
date of
randomization (see exceptions in the protocol).
# 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
# Moderate or severe persistent asthma within the past 2 years, or
currently has uncontrolled asthma of any classification.
# Known to be seropositive for HIV, known to be seropositive for Hep B or known
to be seropositive for Hep C
# Grade 2 sensory or Grade 1 painful peripheral neuropathy
#Subjects who are taking CYP3A4 inducers must discontinue their use at least 5
half-lives prior to the first dose of study treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-511967-26-00 |
| EudraCT | EUCTR2016-001737-27-NL |
| ClinicalTrials.gov | NCT03201965 |
| CCMO | NL63074.056.17 |