This study has been transitioned to CTIS with ID 2023-507312-13-00 check the CTIS register for the current data. Primary ObjectiveThe primary objective is to determine if the addition of daratumumab to VELCADE (bortezomib),Revlimid (lenalidomide),…
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Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this study is:
Overall MRD negativity rate, which is defined as the proportion of subjects who
have achieved MRD negative status (at 10-5) by bone marrow aspirate after
randomization and prior to progressive disease (PD) or subsequent anti-myeloma
therapy. Subjects who have
achieved MRD negative status on or after PD or after the switch to subsequent
anti-myeloma therapy
before PD, will not be considered MRD negative in the primary endpoint
analysis.
Secondary outcome
Secondary efficacy endpoints are:
* PFS defined as the duration from the date of randomization to either
progressive disease (PD) or death, whichever comes first. Disease progression
will be determined according to the International Myeloma Working Group (IMWG)
criteria
For subjects who have not progressed and are alive, data will be censored at
the last disease evaluation before the start of any subsequent anti-myeloma
therapy.
* MRD negativity rate at 1 year.
* Durable MRD negativity rate is defined as the proportion of subjects who have
achieved MRD negative status (at 10-5) at 2 bone marrow aspirate examinations
that are a minimum of 1 year apart, without any examination showing MRD
positive status in between.
* Overall response rate is defined as the proportion of subjects who achieve PR
or better responses prior to subsequent anti-myeloma therapy in accordance with
the IMWG criteria, during or after the study treatment.
* VGPR or better rate is defined as the proportion of subjects achieving VGPR
and CR (including sCR) prior to subsequent anti-myeloma therapy in accordance
with the IMWG criteria during or after the study treatment.
* CR or better rate is defined as the proportion of subjects achieving CR or
sCR prior to subsequent anti-myeloma therapy in accordance with the
IMWG criteria during or after the study treatment.
* Progression-free survival on the next line of therapy is defined as the time
from randomization to progression on the next line of treatment or death,
whichever comes first. Disease progression will be based on investigator
judgment. Subjects who are still alive and not yet progressed on the next line
of treatment will be censored on the last date of followup.
* Overall survival is measured from the date of randomization to the date of
the subject*s death due to any cause. 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.
* Medical Resource utilization
* Time to response is defined as the time between the randomization and the
first efficacy evaluation at which the subject meets all criteria for PR or
better.
* Duration of response is calculated from the date of initial documentation of
a response (PR or better) to the date of first documented evidence of PD, as
defined in the IMWG evaluation before the start of any subsequent anti-myeloma
therapy.
* Clinical efficacy (i.e., overall MRD negativity rate and PFS) of D-VRd in
high-risk molecular subgroups compared with VRd alone.
* Change in health-related quality of life (HRQoL), symptoms, and functioning
using 2 European Organization for Research and Treatment of Cancer (EORTC)
questionnaires and utility and visual analog scale of the EuroQol Five
Dimension Questionnaire (EQ-5D-5L).
* Pharmacokinetic concentrations of daratumumab.
* Incidence of anti-daratumumab antibodies.
* Prevalence and incidence of anti-rHuPH20 antibodies.
Background summary
Daratumumab has multiple mechanisms of action, including the direct targeting
of tumor cells by selectively binding to cluster of differentiation 38 (CD38)
molecules, immune mediated activity
with antibody-dependent cellular cytotoxicity, antibody dependent cellular
phagocytosis and
complement-dependent cytotoxicity, decreased immunosuppression and CD38
enzymatic
inhibition. CD38 is highly expressed on myeloma cells but is expressed at
relatively low levels
on normal lymphoid and myeloid cells and in some tissues of non-hematopoietic
origin, making it a relevant target for the treatment of multiple myeloma.
Multiple myeloma is characterized by uncontrolled and progressive proliferation
of a plasma cell
clone. Patients with multiple myeloma produce a monoclonal protein
(paraprotein) comprising
monoclonal protein (M-protein) and free light chain (FLC), which is an
immunoglobulin (Ig) or
a fragment of one that has lost its function. The proliferation of myeloma
cells causes
displacement of the normal bone marrow. Normal Ig levels are compromised,
leading to
susceptibility to infections. Hypercalcemia, renal insufficiency or failure,
and neurological
complications are frequently reported signs and symptoms of the disease.
Treatment choices for multiple myeloma vary with age, performance status,
comorbidity, the
aggressiveness of the disease, and related prognostic factors. Newly diagnosed
patients with
multiple myeloma are typically categorized into 2 subpopulations usually
defined by their age
and suitability for intensive treatment. Younger patients (ie, <65 years of
age) typically receive
an induction regimen followed by treatment with high-dose chemotherapy and
autologous stem
cell transplantation (ASCT), followed by consolidation therapy and maintenance
treatment. For
those not considered suitable for high-dose chemotherapy and ASCT, longer-term
treatment with
multi-agent combinations including alkylators, high-dose steroids, and novel
agents are currently
considered standards of care.
While the treatment of newly diagnosed patients with multiple myeloma continues
to improve,
patients still are not cured. The most active combination to date is the VRd
regimen described
above. Due to prior results from studies with daratumumab in combination
with either bortezomib or lenalidomide in the relapsed/refractory setting, and
bortezomib in the
frontline setting, it is expected that the addition of daratumumab with VRd is
anticipated to improve the response
rates and the depth of response and may lead to improved long-term outcomes in
newly
diagnosed patients with multiple myeloma.
Study objective
This study has been transitioned to CTIS with ID 2023-507312-13-00 check the CTIS register for the current data.
Primary Objective
The primary objective is to determine if the addition of daratumumab to VELCADE
(bortezomib),Revlimid (lenalidomide), and dexamethasone (VRd) will improve
overall minimal residual disease (MRD) negativity rate compared with VRd alone.
Secondary Objectives
Key secondary objectives are:
* To determine if the addition of daratumumab to VRd will improve clinical
outcome as measured by:
* Progression-Free Survival (PFS)
* Durability of MRD negativity
* Rate of complete response (CR) or better
* To assess the safety profile of daratumumab + VRd (D-VRd)
Study design
This is a randomized, open-label, multicenter, Phase 3 study evaluating
subjects with newly diagnosed multiple myeloma and for whom transplant is not
planned. Approximately 360 subjects (180/arm) will be randomized 1:1. Subjects
in Arm A will receive VRd alone for eight 21-day cycles followed by
lenalidomide and dexamethasone (Rd) until disease progression or unacceptable
toxicity. Subjects in Arm B will receive D-VRd for eight 21-day cycles followed
by daratumumab, lenalidomide, and dexamethasone (DRd) therapy until disease
progression or unacceptable toxicity. Subjects will be
stratified at randomization by International Staging System (ISS) Stage and
age/transplant eligibility.
Intervention
Daratumumab 1800 mg SC will be administered to subjects in Arm B once every
week for Cycles 1 to 2, then every 3 weeks for Cycles 3-8. For Cycle 9 and
beyond, subjects will receive daratumumab 1800 mg SC once every 4 weeks until
documented disease progression or unacceptable toxicity.
Study burden and risks
For a detailed overview of all assessments done during the study, please see
the "Time and events schedule" in the protocol.
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
Inclusion criteria
Each potential subject must satisfy all of the following criteria to be
enrolled in the study:1.Newly diagnosed and not considered candidate for
high-dose chemotherapy with stem cell transplantation due to:*Being age
>=65years,or*age 18-65years with presence of comorbid condition(s) likely to
have a negative impact on tolerability of high-dose chemotherapy with SCT or
who refuse high-dose chemotherapy with SCT as initial treatment2.Diagnosis of
multiple myeloma as documented per International Myeloma Working Group
Criteria:Monoclonal plasma cells in the bone marrow >=10% or presence of a
biopsy proven plasmacytoma and documented multiple myeloma satisfying at least
one of the calcium,renal,anemia,bone(CRAB)criteria or biomarkers of malignancy
criteria:CRAB criteria:1.Hypercalcemia:serum calcium >;0.25mmol/L (>1mg/dL)
higher than upper limit of normal (ULN) or >;2.75mmol/L (>11mg/dL)2.Renal
insufficiency:creatinine clearance <40mL/min or serum creatinine >177 µmol/L
(>2mg/dL)3.Anemia:hemoglobin >2g/dL below the lower limit of normal or
hemoglobin <10g/dL4.Bone lesions:one or more osteolytic lesions on skeletal
radiography,computed tomography (CT),or positron emission tomography
(PET)-CTBiomarkers of Malignancy:a.Clonal bone marrow plasma cell percentage
>=60%b.Involved: uninvolved serum free light chain (FLC)ratio>=100c. >1 focal
lesion on magnetic resonance imaging (MRI) studies3.Must have measurable
disease,as assessed by central laboratory,defined by any of the following:-
IgG,IgA,IgM,IgD,or IgE multiple myeloma:Serum monoclonal paraprotein
(M-protein) level >=1.0g/dL or urine M-protein level >=200mg/24 hours;or- Light
chain multiple myeloma without measurable disease in serum or urine:Serum Ig
FLC >=10mg/dL and abnormal serum Ig kappa lambda FLC ratio4.Eastern cooperative
oncology group(ECOG) performance status score of 0,1 or25.Clinical laboratory
values meeting the following criteria during the Screening Phase:a.hemoglobin
>=7.5g/dL (>=5 mmol/L) (without prior RBC transfusion within 7days before the
laboratory test;recombinant human erythropoietin use is permitted)b.absolute
neutrophil count (ANC) >= 1.0x10^9/L (granulocyte colony stimulating factor
[G-CSF] use is permitted)c.platelet count >= 70x10^9/L for subjects in whom
<50% of bone marrow nucleated cells are plasma cells;otherwise platelet
count >50×10^9/L (transfusions are not permitted within 7days)d.aspartate
aminotransferase (AST)<=2.5xULNe.alanine aminotransferase (ALT)<=2.5xULNf.total
bilirubin <=1.5xULN,except in subjects with congenital bilirubinemia,such as
Gilbert syndrome (direct bilirubin <=2.0 x ULN)g.Estimated creatinine clearance
(CrCl) >=30 mL/min.Creatinine clearance can be calculated using the
Cockcroft-Gault (Appendix8),or eGFR (MDRD;Appendix9);or CKD-epi formula or for
subjects with over- or underweight, CrCl may be measured from a 24-hours urine
collection using the formula provided in Appendix 8h.If Cockcroft-Gault formula
is used and body mass index (BMI) is >or = 30 kg/m² then adjusted body weight
should be used in calculation (Appendix 8 section 10.8)corrected serum calcium
<=13.5 mg/dL (<=3.4 mM/L);or free ionized calcium <=6.5 mg/dL (<=1.6 mM/L)6.Female
subjects of reproductive childbearing potential must commit to either abstain
continuously from heterosexual sexual intercourse or to use 2 methods of
reliable birth control simultaneously during the Treatment Period,during any
dose interruptions,and for 3months after the last dose of any component of the
treatment regimen.Sexual abstinence is considered a highly effective method
only if defined as refraining from heterosexual intercourse during the entire
period of risk associated with the study drug.This birth control method must
include 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 4weeks prior to dosing.Reliable contraception is indicated even
where there has been a history of infertility,unless due to hysterectomy or
bilateral oophorectomy7.A woman of childbearing potential must have 2 negative
serum or urine pregnancy tests at Screening,first within 10to14 days prior to
dosing and the second within 24hours prior to dosing.For requirements during
the Treatment Phase8.A woman must agree not to donate eggs (ova, oocytes)for
the purposes of assisted reproduction during the study and for a period of
3months after receiving the last dose of any component of the treatment
regimen9.Male subjects of reproductive potential who are sexually active with
females of reproductive potential must always use a latex or synthetic condom
during the study and for 3months after discontinuing study treatment (even
after a successful vasectomy)10.Male subjects of reproductive potential must
not donate sperm during the study or for 3months after the last dose of study
treatmentPlease refer to Protocol for completed list of inclusion criteria
Exclusion criteria
Any potential subject who meets any of the following criteria will be excluded
from participating in the study:1. Frailty index of >=2 according to Myeloma
Geriatric Assessment score.2. Prior therapy for multiple myeloma other than a
short course of corticosteroids (not to exceed 40 mg of dexamethasone, or
equivalent per day, total of 160 mg dexamethasone or equivalent).3. Prior or
concurrent invasive malignancy (other than multiple myeloma) within 5 years of
date of randomization (exceptions are adequately treated basal cell or squamous
cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other
noninvasive 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).4. Peripheral neuropathy or neuropathic pain Grade 2
or higher, as defined by the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE) Version 5.5. Focal Radiation therapy
within 14 days of randomization with the exception of palliative radiotherapy
for symptomatic pain management. Radiotherapy within 14 days prior to
randomization on measurable extramedullary plasmacytima is not permitted even
in the setting of palliation for symptomatic management 6. Plasmapheresis
within 28 days of randomization.7. Clinical signs of meningeal involvement of
multiple myeloma.8. Chronic obstructive pulmonary disease (COPD) with a forced
expiratory volume in 1 second (FEV1) <50% of predicted. (FEV1 testing is
required for subjects suspected of having COPD).9. Moderate or severe
persistent asthma within the past 2 years,
uncontrolled asthma of any classification. (Subjects who have controlled
intermittent asthma or controlled mild persistent asthma are allowed in
the study).10. Subject is:
a. Known to be seropositive for human immunodeficiency virus (HIV).
b. seropositive for hepatitis B (defined by a positive test for hepatitis B
surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects
who are HBsAg negative but positive for antibodies to total hepatitis B core
antigen [anti- HBc] and/or antibodies to hepatitis B surface antigen
[anti-HBs]) must be screened using real-time polymerase chain reaction (PCR)
measurement of hepatitis B virus (HBV) DNA levels. Those who
are PCR positive will be excluded.
EXCEPTION: Subjects with serologic findings suggestive of HBV
vaccination (anti-HBs positivity as the only serologic marker) AND a
known history of prior HBV vaccination, do not need to be tested for HBV
DNA by PCR.
c. Known to be seropositive for hepatitis C virus (HCV; anti-HCV antibody
positive or HCV-RNA quantitation positive), except in the setting of a
sustained virologic response (SVR), defined as aviremia at least 12
weeks after completion of antiviral therapy.11. Concurrent medical or
psychiatric condition or disease (such as but
not limited to, systemic amyloidosis, POEMS, active systemic infection,
uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that
is likely to interfere with study procedures or results, or that in the
opinion of the investigator would constitute a hazard if enrolled in the
study.12. Has clinically significant cardiac disease, including:
* Myocardial infarction within 6 months before signing the informed
consent form (ICF), or unstable or uncontrolled disease/condition
related to or affecting cardiac function (eg, unstable angina, congestive
heart failure, New York Heart Association Class III-IV; Appendix 18)
* Uncontrolled cardiac arrhythmia or clinically significant
electrocardiogram (ECG) abnormalities
* Screening 12-lead ECG showing a baseline QT interval as corrected by
Frederica's formula (QTcF) >470 msec.13. Received a strong CYP3A4 inducer
within 5 half-lives prior to
Randomization14. Allergy, hypersensitivity, or intolerance to boron or mannitol,
corticosteroids, monoclonal antibodies or human proteins, or their
excipients, or sensitivity to mammalian-derived products or
lenalidomide.ehandelingskuur. Seksuele onthou
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 | CTIS2023-507312-13-00 |
| EudraCT | EUCTR2018-001545-13-NL |
| ClinicalTrials.gov | NCT03652064 |
| CCMO | NL67804.056.18 |