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Denosumab for High Risk SMM and SLiM CRAB Positive, Early Myeloma Patients (DEFENCE)

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ClinicalTrials.gov Identifier: NCT03792763
Recruitment Status : Not yet recruiting
First Posted : January 3, 2019
Last Update Posted : January 3, 2019
Sponsor:
Collaborators:
Amgen
Assign Data Management and Biostatistics GmbH
Information provided by (Responsible Party):
Arbeitsgemeinschaft medikamentoese Tumortherapie

Brief Summary:
This is a randomized, 2-arm phase II, placebo-controlled, multi-center study, where the investigators aim to evaluate whether the reported benefits of denosumab, delay of SRE and decrease in myeloma growth promotion, reduce the risk of progression of high-risk SMM and of early 'SLiM CRAB' myeloma into active, symptomatic CRAB positive myeloma or serological progression. In addition, tolerability of long-term treatment will be assessed.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA] Drug: Placebo 1.7 ml Subcutaneous Solution Phase 2

Detailed Description:

The aim of this study is to evaluate whether the transition of early Multiple Myeloma (High Risk Smouldering Multiple Myeloma SMM or "Ultra High Risk" SMM) or SLiM CRAB positive multiple myeloma to a symptomatic multiple myeloma (MM) can be reduced or delayed by the administration of denosumab.

With the exception of clinical studies, there are currently no standardized treatment options for SMM. Ultra-high risk SMM is already part of early active myeloma and is therefore in some cases treated according to a standard myeloma protocol (Revlimid-Dexamethasone, Velcade melphalan prednisone, melphalan prednisone thalidomide, or others). However, most practitioners recommend a wait-and-see strategy, since depending on the initial situation within two years only 58-95% of patients develop an 'active' MM and 5-42% of the patients had a stable disease and therefore do not necessarily have to be treated immediately.

Denosumab is a human monoclonal antibody (IgG2) which binds to RANKL with high affinity and specificity. RANKL (receptor activator of NF-κB Ligand) is a protein that is responsible for the formation, function and survival of osteoclasts (cell type responsible for bone resorption) Increased osteoclast activity, stimulated by RANKL, is a key mediator of the bone resorption in bone metastases and MM. Thus the activity of denosumab is resulting in a reduced number and function of osteoclasts and thus decreases the bone resorption and tumor-induced bone destruction.

After an initial phase of about 14 days (screening), the patients will be randomized 1:1 in one of the two study groups (arm A: denosumab or arm B: placebo). The study is double-blinded. The planned duration of therapy is 3 years. Patients receive denosumab or placebo every 4 weeks for 6 months, then every 3 months until a total of 3 years or progression.

After completion of the therapy, an observation and follow-up phase is carried out with patient visits every 3 months until the end of the treatment.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 164 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Placebo controlled, randomized
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Denosumab for High Risk SMM and SLiM CRAB Positive, Early Myeloma Patients- a Randomized, Placebo Controlled Phase II Trial "DEFENCE" (DEnosumab For the rEductioN of the Smoldering Myeloma transformatioN inCidence ratE)
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
Drug Information available for: Denosumab

Arm Intervention/treatment
Experimental: Arm A, denosumab

Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]

Every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM

Calcilac 500 mg/400 I.E. (Calcium/Vitamin D3) Concomitant medication, oral, 1 chewable tablet / day

Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
Administration every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM

Placebo Comparator: Arm B, placebo

Placebo 1.7 ml Subcutaneous Solution

SC every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM

Calcilac 500 mg/400 I.E. (Calcium/Vitamin D3) Concomitant medication, oral, 1 chewable tablet / day

Drug: Placebo 1.7 ml Subcutaneous Solution
Administration every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM




Primary Outcome Measures :
  1. Time to progression [ Time Frame: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months) ]
    Time from randomization to transformation to symptomatic, active MM (defined as progression to active multiple myeloma according to IMWG diagnosis criteria 2014) or progression of disease according to IMWG response criteria 2016


Secondary Outcome Measures :
  1. Percentage of patients transforming in 3 years [ Time Frame: 36 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months) ]
    Percentage of patients with high-risk SMM and early 'slim CRAB' positive MM transforming to CRAB positive multiple myeloma and/or developing serological progression (as defined by IMWG criteria 2016 for MM) within 3 years

  2. Overall survival [ Time Frame: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months) ]
    To determine the overall survival of patients receiving either denosumab or placebo

  3. Time to first skeletal-related event [ Time Frame: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months) ]
    To determine the time to first skeletal-related event for patients receiving either denosumab or placebo. • Imaging: low dose wbCT (details will be described in a separate guidance document) or PET-CT mandatory, whole body MRI recommended according to IMWG diagnosis criteria 2014 (after 3 and 6 months, and every 6 months thereafter).

  4. Incidence of bone lesions as MM defining events [ Time Frame: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months) ]
    To determine the incidence of bone lesions as MM defining events. • Imaging: low dose wbCT (details will be described in a separate guidance document) or PET-CT mandatory, whole body MRI recommended according to IMWG diagnosis criteria 2014 (after 3 and 6 months, and every 6 months thereafter).

  5. Time to first anti-myeloma treatment [ Time Frame: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months) ]
    To determine the time to first anti-myeloma treatment for patients receiving either denosumab or placebo



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 years
  • Able to provide written informed consent in accordance with federal, local, and institutional guidelines
  • Must meet criteria of high risk smoldering MM or early "SLiM CRAB" MM based on the criteria described below:
  • High-risk SMM is defined here according to the Mayo Clinical algorithm [1]:
  • Bone marrow clonal plasma cells ≥10% [2] +
  • Serum M protein ≥3.0g/dL [2] +
  • Serum free light chain ratio < 0.125 (but > 0.01) or ≥8 (but < 100), measured with "Binding site Kit"
  • Early 'SLiM CRAB' multiple myeloma
  • Patients must present with one or more of the following features
  • Bone marrow clonal plasma cells ≥ 60%, or
  • Serum FLC ratio ≥ 100 (k-LC leading) or ≤ 0.01 (l-LC leading), measured with "Binding site Kit", or
  • >1 Focal bone lesion of ≥5mm (not associated with osteolysis, detected by PET-CT or low dose whole body CT (ldwb-CT, mandatory); whole body MRI (recommended according to IMWG diagnosis criteria 2014, especially in those patients negative or with only one focal lesion in CT)
  • Time from diagnosis of high risk SMM or SLIM CRAB positive, early MM to study enrollment: <5 years

Exclusion Criteria:

  • ECOG >3
  • Active, symptomatic MM (fulfilling CRAB-criteria)
  • Non secretory MM
  • MGUS
  • Hypocalcemia (can be corrected by drug intervention before start of treatment)
  • Second malignancy within the past 5 years except:

    • Adequately treated basal cell or squamous cell skin cancer
    • Carcinoma in situ of the cervix
    • Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA over 12 months)
    • Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
    • Treated medullary or papillary thyroid cancer
    • Similar condition with an expectation of > 95% five-year disease-free survival
  • Active infection within the 14 days prior to randomization requiring systemic antibiotics and/or antiviral therapy
  • Known human immunodeficiency virus (HIV) seropositivity or active hepatitis C or hepatitis B infection (subjects with past hepatitis B virus [HBV] infection or resolved HBV infection defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti HBc] antibody test are eligible; subjects positive for hepatitis C virus [HCV] antibody are eligible only if polymerase chain reaction [PCR] is negative for HCV RNA.)
  • Participation in another interventional study within the 28 days prior to randomization
  • Any other clinically significant medical disease or social condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent, be compliant with study procedures, or provide accurate information.
  • Prior administration of denosumab
  • Prior exposure to any experimental or approved anti-myeloma agent
  • Use of oral bisphosphonates with a cumulative exposure of more than 1 year (wash out period for allowed bisphosphonate exposure 1 month)
  • More than 1 previous dose of IV bisphosphonate administration (wash out period for allowed bisphosphonate exposure 1 month)
  • Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
  • Active dental or jaw condition which requires oral surgery, including tooth extraction
  • Subject is pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment
  • Female subject of child bearing potential is not willing to use, in combination with her partner, 2 methods of highly effective contraception during treatment and for 7 months after the end of treatment
  • Male subject with partner of child bearing potential partner is not willing to use, in combination with his partner, 2 methods of highly effective contraception during treatment and for 10 months after the end of treatment
  • Known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium, or vitamin D)
  • Subject is receiving or is less than 30 days since ending other experimental device or drug (no marketing authorization for any indication).
  • Subject will not be available for follow-up assessment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03792763


Contacts
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Contact: Richard Greil, MD 004357255 ext 25801 r.greil@salk.at
Contact: Daniela Wolkersdorfer, PhD 0043662640 ext 4412 d.wolkersdorfer@agmt.at

Locations
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Austria
Landeskrankenhaus Steyr, Innere Medizin, Hämatologie, Onkologie
Steyr, Oberösterreich, Austria, 4400
Medizinische Universitaet Graz, Univ.-Klinik f. Innere Medizin, Onkologie
Graz, Austria, A-8036
Medizinische Universität Innsbruck Univ.-Klinik für Innere Medizin V Hämatologie und Onkologie
Innsbruck, Austria, 6020
LKH Hochsteiermark, Standort Leoben
Leoben, Austria, A-8700
BHS Linz: Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie
Linz, Austria, A-4020
IIIrd Medical Department, Private Medical University Hospital Salzburg
Salzburg, Austria, 5020
Medizinische Univ. Wien, Univ.Klinik f. Innere Medizin I, Hämatologie u. Hämostaseologie
Vienna, Austria, A-1090
Wilhelminenspital
Vienna, Austria, A-1160
Sponsors and Collaborators
Arbeitsgemeinschaft medikamentoese Tumortherapie
Amgen
Assign Data Management and Biostatistics GmbH
Investigators
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Study Director: Heinz Ludwig, MD Wilheminenspital

Additional Information:
Publications:
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Responsible Party: Arbeitsgemeinschaft medikamentoese Tumortherapie
ClinicalTrials.gov Identifier: NCT03792763     History of Changes
Other Study ID Numbers: AGMT_MM-3
First Posted: January 3, 2019    Key Record Dates
Last Update Posted: January 3, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Arbeitsgemeinschaft medikamentoese Tumortherapie:
early multiple myeloma
smoldering multiple myeloma
SLiM CRAB
denosumab
Austrian Study Group of Medical Tumour Therapy (AGMT)
high risk smoldering myeloma

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Smoldering Multiple Myeloma
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Precancerous Conditions
Hypergammaglobulinemia
Pharmaceutical Solutions
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs