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Clinical picture: MM (Multiple Myeloom)
Trial: HOVON-associated EMN17 Perseus Trial
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms
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- The Perseus Trial
• Erasmus MC Prof. dr. P. Sonneveld
• HagaZiekenhuis Dr P Ypma
• Albert Schweitzer Ziekenhuis Dr. M-D. Levin
• Amphia Ziekenhuis Dr. R. Boersma
• Vrije Universiteit Medisch Centrum Prof. dr. S. Zweegman
• Leids Universitair Medisch Centrum Dr. P. A. Von dem Borne
• Medisch Spectrum Twente Dr. M. R. Schaafsma
• TweeSteden ziekenhuis Dr Brada
• Universitair Medisch Centrum Groningen Dr. W.W.H. Roeloffzen
• Academisch Medisch Centrum Prof. dr. M.J. Kersten
• Universitair Medisch Centrum Utrecht Dr. M. C. Minnema
Type of study
Prospective randomized Phase III study
Type of monitoring for this study
Target number of patients
Date of activation
Will be submitted to Erasmus MC sept 2018
The primary objective is to determine if the addition of daratumumab to bortezomib, lenalidomide, and dexamethasone (VRd) will prolong progression-free survival (PFS) defined as the time from the date of randomization to the date of disease progression (assessed by International Myeloma Working Group [IMWG] criteria) or death, compared with VRd alone.
2. Patient eligibility criteria
18 to 70 years of age, inclusive.
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:
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 <40mL/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 PET CT
Biomarkers of Malignancy:
a. Clonal bone marrow plasma cell percentage ≥60%
b. Involved: uninvolved serum FLC ratio ≥100
>1 focal lesion on magnetic resonance imaging (MRI) studies
Measurable disease as defined by any of the following:
a. Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
b. 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
Newly diagnosed subjects for whom high-dose therapy and autologous stem cell transplantation is part of the intended treatment plan.
Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
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:
Adequate liver function:
Adequate renal function:
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.
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. For requirements during the Treatment Phase, refer to Section 4.3.
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.
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).
Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment.
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.
Able to adhere to the prohibitions and restrictions specified in this protocol
Prior or current systemic therapy or 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.
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.
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).
Radiation therapy within 14 days of randomization.
Plasmapheresis within 28 days of randomization.
Clinical signs of meningeal involvement of multiple myeloma.
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%)
Moderate or severe persistent asthma within the past 2 years (see Attachment 4), 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).
Any of the following:
a. 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 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 PCR.
c. Seropositive for hepatitis C (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.
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.
Any of the following:
a. 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)
b. uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities
c. screening 12-lead ECG showing a baseline QT interval >470 msec
d. left ventricular ejection fraction (LVEF) <40% for subjects age 65-70 years old
Received a strong CYP3A4 inducer within 5 half-lives prior to randomization (Flockhart 2016: http://medicine.iupui.edu/flockhart/)
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.
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.
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.
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.
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.
Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.
Gastrointestinal disease that may significantly alter the absorption of oral drugs
Vaccination with live attenuated vaccines within 4 weeks of first study agent administration
Unable or unwilling to undergo antithrombotic prophylactic treatment.
3. Registration (& randomization) of patients