The primary objective is to compare the efficacy of daratumumab when combined with lenalidomide and dexamethasone (DRd) to that of lenalidomide and dexamethasone (Rd), in terms of progression-free survival (PFS) in subjects with relapsed or…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Assessment of tumor response and disease progression will be conducted in
accordance with the IMWG response criteria. Disease evaluations will include
measurements of myeloma proteins, bone marrow examinations, skeletal surveys,
assessment of extramedullary plasmacytomas, and measurements of serum calcium
corrected for albumin. Survival status and subsequent anticancer treatment data
will also be collected.
Secondary outcome
PHARMACOKINETIC EVALUATIONS
Blood samples will be drawn from all subjects in the DRd group for estimation
of pharmacokinetic parameters of daratumumab.
IMMUNOGENICITY EVALUATIONS
Samples drawn from all subjects in the DRd group will be assessed for the
generation of antibodies to daratumumab.
BIOMARKER EVALUATIONS
Blood samples will be drawn from all subjects in both treatment groups to
better understand the mechanism of action and mechanism of resistance of
daratumumab. Minimal residual disease will be assessed for all subjects who
achieve a CR/sCR. Molecular subtyping will be done to evaluate daratumumab
response rates in high-risk multiple myeloma subpopulations if consent is given
for pharmacogenomics evaluation.
PHARMACOGENOMIC (DNA) EVALUATIONS
Samples from subjects in both treatment groups may be used for optional
pharmacogenomic evaluation to allow the identification of genetic factors that
may influence the pharmacodynamics, efficacy, safety, or tolerability of
daratumumab. Additional information on genetic parameters such as deletion 17p
(del17p), t(14;16), t(4;14), FGFR mutations, and BRAF mutations may be analyzed
to determine whether daratumumab treatment benefits these molecularly-defined
subpopulations.
SAFETY EVALUATIONS
Safety evaluations will include adverse event monitoring, physical
examinations, electrocardiogram (ECGs) monitoring, clinical laboratory
parameters (hematology and chemistry), blood pressure and temperature
measurements, and ECOG performance status.
Background summary
Daratumumab is a human IgG1* monoclonal antibody (mAb) that binds with high
affinity to a unique epitope on CD38. It is a targeted immunotherapy that
attacks tumor cells that overexpress CD38, a transmembrane glycoprotein, in a
variety of hematological malignancies including multiple myeloma.
The primary hypothesis is that daratumumab in combination with Rd will prolong
PFS as compared with Rd alone in subjects with relapsed or refractory multiple
myeloma.
Study objective
The primary objective is to compare the efficacy of daratumumab when combined
with lenalidomide and dexamethasone (DRd) to that of lenalidomide and
dexamethasone (Rd), in terms of progression-free survival (PFS) in subjects
with relapsed or refractory multiple myeloma.
The major secondary objectives are as follows:
* To compare the 2 treatment groups with respect to time to disease progression
(TTP), overall response rate (ORR), and overall survival (OS).
* To compare the 2 treatment groups with respect to the proportion of subjects
with a response of very good partial response (VGPR) or better.
* To compare the 2 treatment groups with respect to duration of and time to
response.
* To compare the 2 treatment groups with respect to time to subsequent
antimyeloma treatment.
* To assess the safety and tolerability of daratumumab when administered in
combination with Rd.
Other secondary objectives are to assess the pharmacokinetics of daratumumab in
combination with Rd; to assess the immunogenicity of daratumumab and rHuPH20
(for subjects receiving daratumumab SC); to determine ORR in molecular
subgroups based on translocations, mutations, and genetic signatures in CD138+
multiple myeloma cells; and to evaluate treatment effects on patient-reported
outcomes (PROs) including the EuroQol-5 Dimensions (EQ 5D 5L) and European
Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30.
Study design
This is a Phase 3, randomized, open-label, active-controlled, parallel-group,
multicenter study of daratumumab, lenalidomide, and low-dose dexamethasone
(DRd) compared with lenalidomide and low-dose dexamethasone (Rd) in subjects
with relapsed or refractory multiple myeloma. Approximately 560 subjects will
be randomized in a 1:1 ratio to receive either DRd or Rd. Randomization will be
stratified by International Staging System (ISS) (I, II, or III) at screening,
number of prior lines (1 vs. 2 or 3 vs. >3), and prior lenalidomide (no vs.
yes). Subject participation will include a Screening Phase, a Treatment Phase,
and a Follow-up Phase. Subjects will be treated until disease progression,
unacceptable toxicity, or other reasons. Per amendment INT-3 patients assigned
to treatment with lenalidomide and dexamethason will be offered the option for
daratumumab monotherapy in case of deterioration of their disease.
Per amendment INT-8 switch from IV to SC Daratumumab administration is allowed.
Intervention
The Treatment Phase consists of cycles of approximately 28 days. For subjects
assigned to DRd, daratumumab will be administered as an IV infusion /
subcutaneous.
The IV infusion is at a dose of 16 mg/kg weekly for 8 weeks, then every 2 weeks
for 16 weeks, and then every 4 weeks thereafter. Each subject*s dose will be
calculated based on the subject*s weight rounded to the nearest kilogram. For
all daratumumab infusions, subjects will receive preinfusion and postinfusion
medications for prevention of infusion-related reactions. For both treatment
groups, lenalidomide will be administered at a dose of 25 mg orally (PO) on
Days 1 through 21 of each 28-day cycle, and dexamethasone will be administered
at a total dose of 40 mg weekly (or 20 mg weekly for subjects >75 years or BMI
<18.5).
Following implementation of Protocol Amendment 8, subjects receiving treatment
with daratumumab IV will have the option to switch to daratumumab SC on Day 1
of any cycle, at the discretion of the investigator. Subjects with a known
allergy/intolerance to any of the components of the SC formulation, including
sorbitol, will not be eligible to switch to daratumumab SC. Note: throughout
this document, text has been added to highlight any differences between
daratumumab IV and daratumumab SC dosing, and where there is no clarification,
it is implied that the descriptions are the same for daratumumab IV and
daratumumab SC.
Study burden and risks
Burden will be higher for patients who will be randomized in the daratumumab
arm, due to frequent infusion sessions. For each whole body CT a moderate
radiation risk of 12mSv will be the case. Any drug and intervention has risks
and side effects which may vary from person to person. Side effects may be mild
or very severe. Most side effects will go away after treatment is stopped, but
some may be long lasting. Side effects seen on research studies can result from
a patient*s disease, the drug under study, other drugs, other diseases, or a
combination of these.
Graag Engelbertlaan 75
Breda 4837
NL
Graag Engelbertlaan 75
Breda 4837
NL
Listed location countries
Age
Inclusion criteria
- Must have documented multiple myeloma and measurable disease
- Must have received at least 1 prior line of therapy for multiple myeloma and
achieved a response (partial response or better) to at least one prior regimen
- Must have documented evidence of progressive disease as defined by the
International Myeloma Working Group criteria on or after their last regimen
- Must have an Eastern Cooperative Oncology Group Performance Status score of
0, 1, or 2
Exclusion criteria
- Has received any of the following therapies: daratumumab or other anti-CD38
therapies
- Has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic
half-lives of the treatment
- Disease shows evidence of refractoriness or intolerance to lenalidomide or if
previously treated with a lenalidomide-containing regimen the participant is
excluded if he or she discontinued due to any adverse event related to prior
lenalidomide treatment
- Has received autologous stem cell transplantation within 12 weeks before the
date of randomization, or previously received an allogenic stem cell transplant
(regardless of timing), or planning to undergo a stem cell transplant prior to
progression of disease
- History of malignancy (other than multiple myeloma) within 3 years before the
date of randomization
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 |
|---|---|
| Other | CR103663 / IND 100638 / NCT02076009 |
| EudraCT | EUCTR2013-005525-23-NL |
| CCMO | NL49227.041.14 |