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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03710603




Registration number
NCT03710603
Ethics application status
Date submitted
8/10/2018
Date registered
18/10/2018

Titles & IDs
Public title
Daratumumab, VELCADE (Bortezomib), Lenalidomide and Dexamethasone Compared to VELCADE, Lenalidomide and Dexamethasone in Subjects With Previously Untreated Multiple Myeloma
Scientific title
A Phase 3 Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) vs VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects With Previously Untreated Multiple Myeloma Who Are Eligible for High-dose Therapy
Secondary ID [1] 0 0
EMN17/54767414MMY3014
Universal Trial Number (UTN)
Trial acronym
Perseus
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Daratumumab
Treatment: Drugs - velcade
Treatment: Drugs - Lenalidomide
Treatment: Drugs - dexamethasone

Active comparator: Velcade Lenalidomide dexamethasone (VRd) - VRd: subjects will receive VRd for induction and consolidation, followed by lenalidomide (R) maintenance until disease progression or unacceptable toxicity.

Experimental: Daratumumab + VRd (D-VRd) - D-VRd: Subjects will receive D-VRd for induction and consolidation followed by daratumumab and lenalidomide maintenance until disease progression or unacceptable toxicity. Minimal residual disease (MRD)-negative subjects in Arm B will stop therapy with daratumumab after sustained MRD negativity for 12 months and after a minimum of 24 months of maintenance therapy. These subjects will continue lenalidomide maintenance therapy until disease progression or unacceptable toxicity. After stopping daratumumab therapy, subjects with sustained MRD negativity should restart therapy with daratumumab if there is a recurrence of MRD or a confirmed loss of Complete Response (CR) without International Myeloma Working Group (IMWG)-defined disease progression. After reinitiating daratumumab, the subject will continue daratumumab and lenalidomide therapy until disease progression or unacceptable toxicity.


Treatment: Drugs: Daratumumab
Daratumumab will be given at a dose of 1800 mg SC weekly in Cycles 1 and 2, then every 2 weeks in Cycles 3-6. In maintenance Cycles 7+, subjects will receive daratumumab once every 4 weeks until disease progression or unacceptable toxicity. MRD-negative subjects will stop daratumumab after sustained MRD negativity for 12 months \& after a min. of 24 months of maintenance. Daratumumab should be restarted at recurrence of MRD or confirmed loss of CR without disease progression.

Treatment: Drugs: velcade
Bortezomib will be given at a dose of 1.3 mg/m2 SC twice a week (Days 1, 4, 8, and 11) in Cycles 1-6; four 28-day induction cycles (Cycles 1 to 4), and two 28-day consolidation cycles (Cycles 5-6). Subjects will not receive bortezomib after Cycle 6. On treatment days when both bortezomib and daratumumab are administered, bortezomib must be administered after the daratumumab administration.

Treatment: Drugs: Lenalidomide
Lenalidomide will be administered PO at 25 mg on Days 1 to 21 in Cycles 1-6; four 28-day induction cycles and two 28-day consolidation cycles. Following consolidation, subjects will then start maintenance therapy, during which they will receive lenalidomide 10 mg daily PO on Days 1 to 28 (continuously) of each 28-day cycle until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be increased to 15 mg daily, at the discretion of the investigator.

Treatment: Drugs: dexamethasone
Dexamethasone will be administered PO at 40 mg daily on Days 1-4 and Days 9-12 of each 28-day cycle during induction and consolidation (Cycles 1-6). On daratumumab administration days, during induction/consolidation, dexamethasone may be administered intravenously 1 hour before the daratumumab administration. On days when daratumumab is not administered, dexamethasone is administered PO. Dexamethasone tablets are to be taken with or immediately after a meal or snack, preferably in the morning.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression Free Survival (PFS)
Timepoint [1] 0 0
from randomization to the date of disease progression or death (approximately up to 9 years)
Secondary outcome [1] 0 0
Post-consolidation MRD negativity rate,
Timepoint [1] 0 0
at the end of consolidation, average of 9 months
Secondary outcome [2] 0 0
Overall Response Rate (ORR)
Timepoint [2] 0 0
post-induction (approx 4 months), post-transplant (approximately 7 months), post-consolidation (approximately 9 months), and overall assessed up to approximately 9 years
Secondary outcome [3] 0 0
Progression-free survival on the next line of therapy (PFS2)
Timepoint [3] 0 0
the time from randomization to progression on the next line of treatment or death, whichever comes first., assessed up to 9 years
Secondary outcome [4] 0 0
Overall Survival (OS)
Timepoint [4] 0 0
from the date of from randomization to the date the subject's death, assessed up to 9 years
Secondary outcome [5] 0 0
Time to response
Timepoint [5] 0 0
every 4 weeks up to 2 years, every 8 weeks up to 9 years
Secondary outcome [6] 0 0
Duration of response
Timepoint [6] 0 0
from the date of the initial documentation of a response (PR or better), or CR or better, or sCR, or MRD-negative status to the date of the first documented evidence of disease progression, as defined in the IMWG criteria, whichever occurs first.
Secondary outcome [7] 0 0
Pharmacokinetic concentrations of daratumumab
Timepoint [7] 0 0
cycle 1 Day 1&4, Cycle 3 day 1&4, Cycle 4 day 15, cycle 5 day 1&4, cycle 7,9&12 day 1, post treatment week 8 (each cycle is 28 days)
Secondary outcome [8] 0 0
Determine the incidence of anti-daratumumab antibodies (immunogenicity) for all subjects who receive at least 1 dose of daratumumab and determine the incidence of anti-rHuPH20 antibodies
Timepoint [8] 0 0
cycle 1,4,5,7&12 day 1, post treatment week 8 (each cycle is 28 days)
Secondary outcome [9] 0 0
Change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core module (EORTC QLQ-C30) score and the difference between-treatment arms
Timepoint [9] 0 0
Cycle 1&3 day1, pre-ASCT, Cycle 5 day 1, cycle 7 day 1 then every third cycle until PD (each cycle is 28 days), EOT, prior to PD, every 4 months (EQ-5D-5L only), start of subsequent therapy and 4 weeks after start of subsequent therapy.
Secondary outcome [10] 0 0
Change in EORTC QLQ- 20-item Multiple Myeloma module (MY-20) score and the difference between-treatment arms
Timepoint [10] 0 0
Cycle 1&3 day1, pre-ASCT, Cycle 5 day 1, cycle 7 day 1 then every third cycle until PD (each cycle is 28 days), EOT, prior to PD, every 4 months (EQ-5D-5L only), start of subsequent therapy and 4 weeks after start of subsequent therapy.
Secondary outcome [11] 0 0
EQ-5D-5L health utility values and the difference between-treatment arms
Timepoint [11] 0 0
Cycle 1&3 day1, pre-ASCT, Cycle 5 day 1, cycle 7 day 1 then every third cycle until PD (each cycle is 28 days), EOT, prior to PD, every 4 months (EQ-5D-5L only), start of subsequent therapy and 4 weeks after start of subsequent therapy.
Secondary outcome [12] 0 0
Stem cell yield after mobilization
Timepoint [12] 0 0
after mobilization, average of 5 months
Secondary outcome [13] 0 0
Time to engraftment post-ASCT
Timepoint [13] 0 0
post-ASCT, average of 7 months

Eligibility
Key inclusion criteria
1.18 to 70 years of age, inclusive.

2.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 >0.25 mmol/L (>1 mg/dL) higher than upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL)
2. Renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >177 µmol/L (>2 mg/dL)
3. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL
4. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or Positron-emission tomography (PET)-CT

Biomarkers of Malignancy:

a. Clonal bone marrow plasma cell percentage =60% b. Involved: uninvolved serum free light chain (FLC) ratio =100 c. >1 focal lesion on magnetic resonance imaging (MRI) studies

3.Measurable disease as defined by any of the following:

1. Serum monoclonal paraprotein (M-protein) level =1.0 g/dL or urine M-protein level =200 mg/24 hours; or
2. Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC =10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio

4.Newly diagnosed subjects for whom high-dose therapy and autologous stem cell transplantation (ASCT) is part of the intended treatment plan.

5.Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.

6.Clinical laboratory values meeting the following criteria during the Screening Phase (Screening hematology and chemistry tests should be repeated if done more than 3 days before C1D1):

Adequate bone marrow function:

1. Hemoglobin =7.5 g/dL (=4.65 mmol/L; prior red blood cell (RBC) transfusion or recombinant human erythropoietin use is permitted however transfusions are not permitted within 7 days of randomization to achieve this minimum hemoglobin count);
2. Absolute neutrophil count (ANC) =1.0 x 109/L (granulocyte-colony stimulating factor (G-CSF) use is permitted);
3. Platelet count =50 x 109/L if bone marrow is >50% involved in myeloma. Otherwise =75 x 109/L

Adequate liver function:

1. Aspartate aminotransferase (AST) =2.5 x ULN;
2. Alanine aminotransferase (ALT) =2.5 x ULN;
3. Total bilirubin =1.5 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin =1.5 x ULN)

Adequate renal function:

1. Estimated creatinine clearance =30 mL/min. Creatinine clearance may be calculated using Cockcroft-Gault, estimated Glomerular filtration rate (eGFR) (Modified Diet in Renal Disease (MDRD)), or Chronic Kidney Disease (CKD)-epi formula
2. Corrected serum calcium =13.5 mg/dL (=3.4 mmol/L); or free ionized calcium =6.5 mg/dL (=1.6 mmol/L)

7. 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 3 months 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 (IUD), 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 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.

8. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing.

9. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen.

10. 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 3 months after discontinuing study treatment (even after a successful vasectomy).

11. Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment.

12. Signed an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.

13. Able to adhere to the prohibitions and restrictions specified in this protocol
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior or current systemic therapy or stem cell transplant (SCT) for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
2. 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.
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 non-invasive 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. Radiation therapy within 14 days of randomization.
5. Plasmapheresis within 28 days of randomization.
6. Clinical signs of meningeal involvement of multiple myeloma.
7. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal (for subjects =65 years old FEV1 <50% or diffusing capacity of the lungs for carbon monoxide [DLCO] <50%)
8. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
9. Any of the following:

1. Seropositive for human immunodeficiency virus (HIV)
2. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are positive for antibodies to hepatitis B core antigen [antiHBc] and/or antibodies to hepatitis B surface antigen [antiHBs]) must be screened using real-time 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 (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by polymerase chain reaction (PCR).
3. Seropositive for hepatitis C (HCV) (anti-HCV antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response (SVR), defined as viremia at least 12 weeks after completion of antiviral therapy.
10. 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 the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
11. Any of the following:

1. myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)
2. uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities
3. screening 12-lead ECG showing a baseline QT interval >470 msec
4. left ventricular ejection fraction (LVEF) <40% for subjects age 65-70 years old
12. Received a strong CYP3A4 inducer within 5 half-lives prior to randomization
13. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Investigator's Brochure), or sensitivity to mammalian-derived products or lenalidomide.
14. Not able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
15. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen.
16. Major surgery within 2 weeks before randomization or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty is not considered major surgery.
17. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization or is currently enrolled in an interventional investigational study.
18. Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.
19. Gastrointestinal disease that may significantly alter the absorption of oral drugs
20. Vaccination with live attenuated vaccines within 4 weeks of first study agent administration
21. Unable or unwilling to undergo antithrombotic prophylactic treatment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
14/12/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/11/2029
Actual
Sample size
Target
Accrual to date
Final
690
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Alfred Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
- Melbourne
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Leuven
Country [2] 0 0
Czechia
State/province [2] 0 0
Ostrava
Country [3] 0 0
Denmark
State/province [3] 0 0
Odense
Country [4] 0 0
France
State/province [4] 0 0
Nantes
Country [5] 0 0
Greece
State/province [5] 0 0
Athens
Country [6] 0 0
Italy
State/province [6] 0 0
Ancona
Country [7] 0 0
Netherlands
State/province [7] 0 0
Rotterdam
Country [8] 0 0
Norway
State/province [8] 0 0
Oslo
Country [9] 0 0
Poland
State/province [9] 0 0
Kraków
Country [10] 0 0
Spain
State/province [10] 0 0
Barcelona
Country [11] 0 0
Switzerland
State/province [11] 0 0
Saint Gallen
Country [12] 0 0
Turkey
State/province [12] 0 0
Ankara

Funding & Sponsors
Primary sponsor type
Other
Name
European Myeloma Network B.V.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Janssen Research & Development, LLC
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03710603