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Clinical picture: MM (Multiple Myeloom)
Trial: HOVON 131 MM / IFM 2015-01
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms
Study of Daratumumab (JNJ-54767414 (HuMax® CD38) in Combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant Eligible Subjects with Newly Diagnosed Multiple Myeloma.
Intergroupe Francophone du Myelome (IFM) is the sponsor of this trial.
For more information regarding this trial, please visit the following website (login required):
Distribution of study documents, site initiation and monitoring will be performed by CRAs from Axonal. Please contact the CRA assigned to your hospital for more information:
Margot Gerrits (email@example.com)
Liesbeth Hammega (firstname.lastname@example.org)
Rutger van Noordenburg (email@example.com)
Type of study
Prospective randomized Phase III study
Type of monitoring for this study
Target number of patients
Date of activation
2. Patient eligibility criteria
Subject must be between 18 and 65 years of age.
Subject must have documented multiple myeloma satisfying the CRAB criteria and measurable disease as defined by:
- Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events:
* Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN or >2.75 mmol/L (>11 mg/dL)
* Renal insufficiency: creatinine clearance <40mL / min or serum creatinine >177 μmol/L (>2 mg/dL)
* Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL
* Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
* Clonal bone marrow plasma cell percentage ≥60%
* Involved: uninvolved serum free light chain ratio ≥100
* >1 focal lesion on MRI studies
- Measurable disease as defined by any of the following:
* IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
* IgA, IgE, IgD, or IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
* IgD multiple myeloma : serum M-protein level <0.5 g/dL and Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio; or
* Light chain multiple myeloma without measurable disease in the serum or the
urine: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation.
Subject must have an ECOG performance status score of 0, 1, or 2
Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
a) hemoglobin ≥7.5 g/dL (≥5 mmol/L; prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted);
b) absolute neutrophil count (ANC) ≥1.0 x 109/L (GCSF use is permitted);
c) AST ≤2.5 x upper limit of normal (ULN);
d) ALT ≤2.5 x ULN;
e) total bilirubin ≤1.5 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤1.5 x ULN);
f) calculated creatinine clearance ≥40 mL/min/1.73 m2;
g) corrected serum calcium ≤14 mg/dL (<3.5 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L);
h) platelet count ≥70 x 10^9/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count >50x10^9/L (transfusions are not permitted to achieve this minimum platelet count).
Women who are partners of men and of childbearing potential must be practicing one of
the following methods of birth control: subcutaneous hormonal implant, levonorgestrel-releasing intra-uterine system, edroxyprogesterone acetate depot, tubal sterilization, ovulation inhibitory progesterone only pills, or sexual intercourse with a
vasectomized male partner (vasectomy must be confirmed by 2 negative semen analyses). Or women will commit to absolute and continuous abstinence confirmed to her physician on a monthly basis. Childbearing potential is defined in Section 9.1.2 of the protocol. Contraception will start 4 weeks before the start of therapy, during therapy including dose interruptions, for 4 weeks after discontinuation of thalidomide and for 4 months
after discontinuation of daratumumab.
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.
Each subject (or their legally acceptable representative) must sign an informed consent
form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Subject has received daratumumab or other anti-CD38 therapies previously.
Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and (if determined) proportion of plasma cells in the bone marrow of
10% or less. Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of related organ or tissue impairment (ROTI) end organ damage.
Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
Subject has prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
Subject has 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 4.
Subject has had any prior or concurrent invasive malignancy (other than multiple myeloma) within 10 years of study start except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, localized prostate
adenocarcinoma diagnosed ≥3 years and without evidence of biochemical failure, or other cancer for which the subject has undergone potentially curative therapy and has no evidence of that disease for ≥10 years.
Subject has had radiation therapy within 14 days of randomization.
Subject has had plasmapheresis within 28 days of randomization.
Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
a) Subject has known chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
b) Subject has known moderate or severe persistent asthma within the past 2 years (see Attachment 5), 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).
Subject is known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C.
Subject has any concurrent medical or psychiatric condition or disease (eg, 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.
Subject has clinically significant cardiac disease, including:
- myocardial infarction within 1 year 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
- uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade ≥2) or clinically significant ECG abnormalities
- screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec
Subject has known allergies, hypersensitivity, or intolerance to boron or mannitol,
corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Investigator's Brochure), or known sensitivity to mammalian-derived products. Or subject has known hypersensitivity to thalidomide.
Subject has plasma cell leukemia (according to WHO criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
Subject is known or suspected of not being 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.
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 4 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 4 months after the last dose of any component of the treatment regimen.
Subject has had 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 are not considered major surgery.
Subject has 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.
Subject has contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.
Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
Subjects unable or unwilling to undergo antithrombotic prophylactic treatment.
3. Registration (& randomization) of patients
List of participating sites to which patients can be refered to:
NL - Alkmaar - MC Alkmaar
NL - Amersfoort - Meander MC
NL - Amsterdam - AMC
NL - Amsterdam - VUMC
NL - Amsterdam - OLVG
NL - Arnhem - Rijnstate
NL - Delft - RdGG
NL - Den Haag - Hagaziekenhuis
NL - Dordrecht - A. Schweitzer
NL - Deventer - Deventer zkh
NL - Eindhoven - Maxima Medisch Centrum
NL - Groningen - UMCG
NL - Heerlen - Zuyderland MC (Atrium MC)
NL - Hoofddorp - Spaarne ziekenhuis
NL - Leeuwarden - MC Leeuwarden
NL - Maastricht - AZ Maastricht
NL - Nieuwegein - Antonius Ziekenhuis
NL - Nijmegen - Radboudumc
NL - Rotterdam - Maasstadziekenhuis
NL - Rotterdam - Erasmus MC
NL - Tilburg - Elisabeth zkh
NL - Utrecht - UMCU
NL - Zwolle - Isala
4. Participating parties
Prof. Dr. P. Sonneveld