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Effect of Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Disease in Patients With Multiple Myeloma Relapsed After 1-3 Prior Lines of Therapy

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ClinicalTrials.gov Identifier: NCT00972959
Recruitment Status : Completed
First Posted : September 9, 2009
Results First Posted : August 5, 2014
Last Update Posted : August 5, 2014
Sponsor:
Information provided by (Responsible Party):
Meletios A. Dimopoulos, University of Athens

Tracking Information
First Submitted Date  ICMJE September 8, 2009
First Posted Date  ICMJE September 9, 2009
Results First Submitted Date  ICMJE January 15, 2014
Results First Posted Date  ICMJE August 5, 2014
Last Update Posted Date August 5, 2014
Study Start Date  ICMJE July 2009
Actual Primary Completion Date May 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2014)
Bone Mineral Density (BMD) [ Time Frame: day 84 ]
BMD of the lumbar spine (L1-L4, anteroposterior view) and femoral neck (FN) was measured by dual energy X-ray absorptiometry (DXA) using a Hologic QDR-1000 scanner on day 21 of cycle 4 (day 84)
Original Primary Outcome Measures  ICMJE
 (submitted: September 8, 2009)
Bone Mineral Density (BMD) [ Time Frame: At the end of cycle 4 or at termination of the combination therapy ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2014)
  • Bone Mineral Density (BMD) [ Time Frame: day 168 ]
    BMD of the lumbar spine (L1-L4, anteroposterior view) and femoral neck (FN) was measured by Dual Energy X-Absorptiometry scan (DEXA-scan) using a Hologic QDR-1000 scanner on day 21 of cycle 8 (day 168)
  • Bone Remodelling [ Time Frame: day 84 ]
    Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA): i) bone resorption marker C-terminal cross-linking telopeptide of collagen type I (CTX) and ii) bone formation markers [osteocalcin (OC)].
  • Bone Remodelling [ Time Frame: day 168 ]
    Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 8 (day 168) using an enzyme-linked immunosorbent assay (ELISA): i) bone resorption marker C-terminal cross-linking telopeptide of collagen type I (CTX) and ii) bone formation marker [osteocalcin (OC)].
  • Bone Pain [ Time Frame: On the day 84 ]
    Bone pain was measured with the use of the Visual Analogue Scale on day 21 of cycle 4 (day 84). Bone pain was measured with the use of the Visual Analogue Scale. The visual analogue scale or visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured. The VAS for Bone Pain was constructed as follows: None Mild Moderate Severe Worst possible 1,2 3,4 5,6 7,8 9,10 Lower values are considered to be of a better outcome, higher values are considered to be of a worst outcome.
  • Bone Pain [ Time Frame: On the day 168 ]
    Bone pain was measured with the use of the Visual Analogue Scale on day 21 of cycle 8 (day 168). Bone pain was measured with the use of the Visual Analogue Scale. The visual analogue scale or visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured. The VAS for Bone Pain was constructed as follows: None Mild Moderate Severe Worst possible 1,2 3,4 5,6 7,8 9,10 Lower values are considered to be of a better outcome, higher values are considered to be of a worst outcome.
  • Skeletal Survey for New Osteolytic Lesions/Fractures [ Time Frame: day 168 ]
    Skeletal survey was measured using conventional radiography [imaging of the whole skeleton (skull, cervical spine, thoracic spine, lumbar spine, pelvis, humeri, femoral bones)] on day 21 of cycle 8 (day 168)
  • Skeletal Survey for New Osteolytic Lesions/Fractures [ Time Frame: 18 months ]
    Skeletal survey was measured using conventional radiography [imaging of the whole skeleton (skull, cervical spine, thoracic spine, lumbar spine, pelvis, humeri, femoral bones)] every 6 months for up to 18 months
  • New Skeletal-related Events (SRE: Pathologic Fractures, Need for Bone Radiation Therapy or Surgery) [ Time Frame: day 168 ]
    New Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) following 8 cycles (day 168) of therapy
  • New Skeletal-related Events (SRE: Pathologic Fractures, Need for Bone Radiation Therapy or Surgery) [ Time Frame: 18 months ]
    New Skeletal-related Events (SRE: Pathologic Fractures, Need for Bone Radiation Therapy or Surgery) after 18 months post VD
  • Bone Remodelling [ Time Frame: day 84 ]
    Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA) bone formation marker [bone-specific alkaline phosphatase (bALP)].
  • Bone Remodelling [ Time Frame: day 168 ]
    Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA): bone formation marker [bone-specific alkaline phosphatase (bALP) ].
Original Secondary Outcome Measures  ICMJE
 (submitted: September 8, 2009)
Bone Mineral Density (BMD), Serum values of Bone Metabolism Markers, Bone Pain, Skeletal Related Events, Osteolytic Bone Lesions [ Time Frame: At the end of cycle 8 or at termination of the combination therapy, at the end of 18 months period following discontinuation of VELCADE and dexamethasone (but not of zoledronic acid) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Disease in Patients With Multiple Myeloma Relapsed After 1-3 Prior Lines of Therapy
Official Title  ICMJE A Prospective, Multicenter, Non-comparative, Open-label, Phase II Study to Evaluate the Effects of the Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Mineral Density, Bone Metabolism, Radiographically-detected Osteolytic Bone Lesions, Skeletal-related Events and Bone Pain in Patients With Multiple Myeloma Who Have Relapsed After 1-3 Prior Lines of Therapy
Brief Summary The aim of this study is to evaluate the effect of bortezomib in combination with dexamethasone and zoledronic acid on bone mineral density (BMD) and skeletal related events (SREs) in Patients with Multiple Myeloma who Have Relapsed after 1-3 Prior Lines of Therapy
Detailed Description

Multiple Myeloma represents a malignant proliferation of plasma cells derived from a single clone. The most common symptom in myeloma, affecting more than 70% of patients at diagnosis, is bone pain. The pain usually involves the back and ribs, and is precipitated by movement. Bone fractures are commonly seen in myeloma patients and may present with persistent localized pain.

VELCADE (bortezomib) is a proteasome inhibitor used for the treatment of multiple myeloma.

VELCADE seems to be the first agent to combine significant anti-myeloma activity and beneficial effects on bone remodeling. Thus, it appears to be a very promising tool for the treatment of myeloma patients.

In this study, a regimen consisting of bortezomib/dexamethasone/zoledronic acid will be used. The rationale for using this regimen is that:

  • VELCADE (bortezomib) is indicated for the treatment of relapsed myeloma patients participating in the study and it has also a beneficial effect on biochemical markers of bone formation.
  • In phase II studies, the addition of dexamethasone in patients with a suboptimal response to bortezomib alone improved efficacy in relapsed or refractory multiple myeloma patients, without increasing adverse events. Therefore, in this study, the addition of dexamethasone aims at providing the optimal therapy for participating myeloma patients.
  • Zoledronic acid, the most potent i.v. bisphosphonate, is used because of its established effect on reducing skeletal related events in patients with multiple myeloma due to its inhibitory effect on osteoclastic bone resorption.

Dosages and timing of dosages are based on current recommendations and guidelines for the treatment of myeloma patients who Have Relapsed after 1-3 Prior Lines of Therapy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Drug: Bortezomib
    1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle for up to 8 chemotherapy cycles
    Other Name: Velcade
  • Drug: Zoledronic Acid
    4 mg, iv, at a 15 min infusion, Day 1 of every cycle for up to 8 cycles, and then every 28 days for the next 18 months
    Other Name: Zometa
  • Drug: Dexamethasone
    12 mg/m2 p.o. on days 1-2, 4-5, 8-9 and 11-12 of a 21-day cycle for up to 8 chemotherapy cycles
Study Arms  ICMJE Experimental: Bortezomib/Dexamethasone/Zoledronic Acid

For this study, Velcade will be administered at the standard dose of 1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle.

Dexamethasone will be administered at a dose of 12 mg/m2 p.o., on days 1-2, 4-5, 8-9 and 11-12 of the same cycle.

Zoledronic acid will be administered at a dose of 4 mg, iv (15-minute infusion), every 28 days for up to 8 cycles, and then every 28 days for the next 18 months

Interventions:
  • Drug: Bortezomib
  • Drug: Zoledronic Acid
  • Drug: Dexamethasone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 8, 2014)
17
Original Estimated Enrollment  ICMJE
 (submitted: September 8, 2009)
62
Actual Study Completion Date  ICMJE May 2013
Actual Primary Completion Date May 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with Multiple Myeloma who Have Relapsed after 1-3 Prior Lines of Therapy
  • Women > 50 years old
  • Κarnofsky performance status ≥ 60 (patients with lower performance status due to myeloma bone disease can also be included)
  • Measurable disease
  • Platelet count >50x10(9)/L
  • Neutrophil count >0.75x10(9)/L
  • Hemoglobin ≥7.0 g/dL (the use of recombinant human erythropoietin or red blood Hell transfusions to maintain hemoglobin levels above 7.0 g/dL is not an exclusion criterion)
  • Serum ALT and AST ≤ 3-fold of upper normal limit
  • Serum bilirubin ≤ 2-fold of upper normal limit
  • Serum Calcium ≤ 10.5 mg/dL
  • Expected survival ≥ 2 months
  • Signed informed consent

Exclusion Criteria:

  • Presence of another cancer
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study
  • Grade 2-4 peripheral neuropathy or neuropathic pain Grade 2 or higher as defined by NCI CTCAE version 3
  • Pregnant women > 50 years old or breast-feeding
  • Woman > 50 years old capable of becoming pregnant [anyone who has not undergone a hysterectomy, has not had both ovaries removed or has not been post-menopausal for more than 24 months in a row not using adequate contraception
  • Known or suspected hypersensitivity or intolerance to bortezomib, boron, mannitol, zoledronic acid, dexamethasone, or heparin (if an indwelling catheter is used)
  • Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months prior to first dose of study drug)
  • Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrolment, New York Heart Association (NYHA) Class III or IV heart failure (Attachment 4, NYHA Classification of Cardiac Disease), uncontrolled angina, pericardial disease, or cardiac amyloidosis
  • Acute diffuse infiltrative pulmonary disease
  • History of hypotension or patient has decreased blood pressure (sitting systolic blood pressure [SBP] 100 mmHg and/or sitting diastolic blood pressure [DBP] 60 mmHg)
  • Patient has received extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy within 4 weeks prior to enrolment
  • Patient has received any drugs or agents that inhibit (e.g., cimetidine, erythromycin, fluoxetine, ketoconazole, paroxetine) or induce (e.g., carbamazepine, glucocorticoids, phenobarbital, rifampin) CYP2C19 or CYP3A4 within 14 days before the first dose of VELCADE (proton pump inhibitors are allowed)
  • Need for therapy with concomitant CYP 3A4 inhibitors (e.g., itraconazole, fluconazole, clarithromycin, erythromycin, norfloxacin, fluvoxamine, cimetidine, indinavir, ritonavir) or inducers (e.g., efavirenz, barbiturates, phenytoin, rifampin, glitazones). Proton pump inhibitors are allowed.
  • Patient has received an experimental drug or has used an experimental medical device within 4 weeks prior to the planned start of treatment. Concurrent participation in non-treatment studies is allowed, provided it will not interfere with participation in this study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Greece
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00972959
Other Study ID Numbers  ICMJE 26866138MMY 2051
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Meletios A. Dimopoulos, University of Athens
Study Sponsor  ICMJE University of Athens
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Meletios- Athanasios Dimopoulos, Professor Therapeutic Clinic Department, Faculty of Medicine. University of Athens
PRS Account University of Athens
Verification Date July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP