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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2011 by University of Athens
Sponsor:
Information provided by:
University of Athens
ClinicalTrials.gov Identifier:
NCT00972959
First received: September 8, 2009
Last updated: February 1, 2013
Last verified: February 2011
  Purpose

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


Condition Intervention Phase
Multiple Myeloma
Drug: Bortezomib
Drug: Zoledronic Acid
Drug: Dexamethasone
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by University of Athens:

Primary Outcome Measures:
  • Bone Mineral Density (BMD) [ Time Frame: day 84 ] [ Designated as safety issue: No ]
    At the end of cycle 4 (day 84) from the treatment initiation


Secondary Outcome Measures:
  • Bone Mineral Density (BMD) [ Time Frame: On day 168 of treatment ] [ Designated as safety issue: No ]
    Bone mineral density (BMD)will be assessed following 8 cycles (168 days)of treatment with the VELCADE/dexamethasone/zoledronic acid

  • Bone mineral density (BMD) [ Time Frame: At the end of 18 months follow up period ] [ Designated as safety issue: No ]
    Bone mineral density (BMD)will be assessed 18 months following 8 cycles of combined treatment (only for patients with at least stable disease at the end of cycle-4)

  • Serum values of bone-specific alkaline phosphatase, osteocalcin and C-terminal cross-linking telopeptides of collagen type-I [ Time Frame: On the day 84 ] [ Designated as safety issue: No ]
    Serum values of bone-specific alkaline phosphatase, osteocalcin and C-terminal cross-linking telopeptides of collagen type-I following 4 cycles (day 84) of the combination therapy with the VELCADE/dexamethasone/zoledronic acid

  • Serum values of bone-specific alkaline phosphatase, osteocalcin and C-terminal cross-linking telopeptides of collagen type-I [ Time Frame: On the day 168 ] [ Designated as safety issue: No ]
    Serum values of bone-specific alkaline phosphatase, osteocalcin and C-terminal cross-linking telopeptides of collagen type-I following 8 cycles (day 168)of the combination therapy with the VELCADE/dexamethasone/zoledronic acid

  • Serum values of bone-specific alkaline phosphatase, osteocalcin and C-terminal cross-linking telopeptides of collagen type-I [ Time Frame: At the end of 18 months follow up period ] [ Designated as safety issue: No ]
    Serum values of bone-specific alkaline phosphatase, osteocalcin and C-terminal cross-linking telopeptides of collagen type-I eighteen (18) months following 8 cycles of combined treatment (only for patients with at least stable disease at the end of cycle-4)

  • Bone pain [ Time Frame: On the day 84 ] [ Designated as safety issue: Yes ]
    Bone pain following 4 cycles of the combination therapy with the VELCADE/dexamethasone/zoledronic acid

  • Bone pain [ Time Frame: On the day 168 ] [ Designated as safety issue: Yes ]
    Bone pain following 8 cycles of treatment of the combination therapy with the VELCADE/dexamethasone/zoledronic acid

  • Bone pain [ Time Frame: At the end of 18 months follow up period ] [ Designated as safety issue: Yes ]
    Bone pain will be assessed eighteen (18) months following 8 cycles of combined treatment (only for patients with at least stable disease at the end of cycle-4)

  • Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) [ Time Frame: On the day 84 ] [ Designated as safety issue: Yes ]
    Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) following 4 cycles of treatment of the combination therapy with the VELCADE/dexamethasone/zoledronic acid

  • Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) [ Time Frame: On the day168 ] [ Designated as safety issue: Yes ]
    Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) following 8 cycles of treatment with the VELCADE/dexamethasone/zoledronic acid

  • Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) [ Time Frame: At the end of 18 months follow up period ] [ Designated as safety issue: Yes ]
    Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) 18 months following 8 cycles of combined treatment (only for patients with at least stable disease at the end of cycle-4)

  • Improvement of osteolytic lesions [ Time Frame: On day 84 ] [ Designated as safety issue: No ]
    Improvement of osteolytic lesions, detected in Baseline Full Skeletal Radiography, following 4 cycles of treatment of the combination therapy with the VELCADE/dexamethasone/zoledronic acid combination regimen

  • Improvement of osteolytic lesions [ Time Frame: On the day 168 ] [ Designated as safety issue: No ]
    Improvement of osteolytic lesions, detected in Baseline Full Skeletal Radiography, following 8 cycles of treatment of the combination therapy with the VELCADE/dexamethasone/zoledronic acid combination regimen

  • Improvement of osteolytic lesions [ Time Frame: At the end of 18 months follow up period ] [ Designated as safety issue: No ]
    Improvement of osteolytic lesions, detected in Baseline Full Skeletal Radiography will be assessed 18 months following 8 cycles of combined treatment (only for patients with at least stable disease at the end of cycle-4)


Estimated Enrollment: 62
Study Start Date: July 2009
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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
Other Name: Dexamethasone

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00972959

Contacts
Contact: Evangelos Terpos, PhD +30-693-7437111 e.terpos@imperial.ac.uk
Contact: Dimitrios Christoulas, MD christoulasdimitrios@hotmail.com

Locations
Greece
Department of Clinical Therapeutics, University of Athens School of Medicine, "Alexandra" General Hospital Recruiting
Athens, Greece, 115 28
Principal Investigator: Meletios- Athanasios Dimopoulos, Prof.         
Department of Hematology & Medical Research, 251 General Air Force Hospital Recruiting
Athens, Greece, 11525
Principal Investigator: Konstantinos Anargyrou, MD         
Department of Hematology, "Theagenion" Cancer Center Recruiting
Thessaloniki, Greece, 540 07
Principal Investigator: Konstantinos Zervas, PhD         
Sponsors and Collaborators
University of Athens
Investigators
Study Chair: Meletios- Athanasios Dimopoulos, Professor Therapeutic Clinic Department, Faculty of Medicine. University of Athens
  More Information

No publications provided

Responsible Party: Prof. Meletios- Athanasios Dimopoulos, Department of Clinical Therapeutics, University of Athens School of Medicine
ClinicalTrials.gov Identifier: NCT00972959     History of Changes
Other Study ID Numbers: 26866138MMY 2051
Study First Received: September 8, 2009
Last Updated: February 1, 2013
Health Authority: Greece: National Organization of Medicines
Greece: Ethics Committee

Keywords provided by University of Athens:
multiple myeloma
1-3 Prior Lines of Therapy
bortezomib (Velcade)
zoledronic acid (Zometa)
Dexamethasone
bone mineral density
bone pain
bone metabolism
osteolytic lesions
DEXA-scans
X-ray radiography

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
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
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Bortezomib
BB 1101
Zoledronic acid
Diphosphonates
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents

ClinicalTrials.gov processed this record on July 22, 2014