Zoledronate With or Without Thalidomide in Treating Patients With Early Stage Multiple Myeloma

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00432458
First received: February 5, 2007
Last updated: June 4, 2012
Last verified: June 2012
  Purpose

RATIONALE: Zoledronate may prevent bone loss and stop the growth of cancer cells in bone. Thalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. It is not yet know whether giving zoledronate together with thalidomide is more effective than zoledronate alone in treating multiple myeloma.

PURPOSE: This randomized phase III trial is studying zoledronate and thalidomide see how well they work compared with zoledronate alone in treating patients with early stage multiple myeloma.


Condition Intervention Phase
Multiple Myeloma and Plasma Cell Neoplasm
Drug: Thalidomide
Drug: zoledronic acid
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Randomized Trial of Thalidomide Plus Zoledronic Acid Versus Zoledronic Acid Alone in Patients With Early Stage Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Time to Disease Progression (TTP) [ Time Frame: randomization to progression (up to 5 years) ] [ Designated as safety issue: No ]
    Time to disease progression (TTP) was defined as the time from randomization to the earliest documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method, a two-sided (stratified) log-rank test was calculated.


Secondary Outcome Measures:
  • 12-month Progression-free Survival (PFS) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    PFS at 12 months is a dichotomized outcome indicating whether or not a participant was progression free (and alive) at 12 months from the date of randomization.

  • Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    Response is defined as follows:

    • CR: Complete disappearance of M-protein from serum & urine on immunofixation, <5% plasma cells in bone marrow (BM)
    • VGPR: >=90% reduction in serum M-component; Urine M-Component <100 mg per 24 hours; <=5% plasma cells in BM
    • PR: >= 50% reduction in serum M-Component and/or Urine M-Component >= 90% reduction or <200 mg per 24 hours; or >= 50% decrease in difference between involved and uninvolved FLC levels

  • Duration of Response (Complete Response, Partial Response, and Very Good Partial Response) [ Time Frame: time from start of response to progression (up to 5 years) ] [ Designated as safety issue: No ]
    Duration of response (DOR) is defined as the time from first documentation of response (CR, VGPR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method

  • Time to Subsequent Treatment [ Time Frame: time from end of treatment to subsequent treatment (up to 5 years) ] [ Designated as safety issue: No ]
    Time to subsequent treatment (TTS) was defined as time from end of active (protocol) treatment to the start of subsequent treatment for participants with progressive disease. The median TTS with 95% CI was estimated using the Kaplan Meier method

  • Time to Treatment Failure [ Time Frame: time from randomization to treatment failure (up to 5 years) ] [ Designated as safety issue: No ]
    Time to treatment failure (TTF) was defined as the time from randomization to the date at which the patient was removed from (protocol) treatment due to disease progression, unacceptable toxicity, participant refusal or death. The median TTF with 95% CI was estimated using the Kaplan Meier method

  • Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events [ Time Frame: During treatment (up to 5 years) ] [ Designated as safety issue: Yes ]

    Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 2.

    Description of Grades:

    Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death



Enrollment: 68
Study Start Date: July 2003
Study Completion Date: April 2012
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I: Thal/ZLD
Thalidomide (Thal) + Zolendronic acid (ZLD)
Drug: Thalidomide
200 mg orally on days 1-28 of 28 day cycle
Drug: zoledronic acid
4 mg^2 by IV on day 1 every 84 days for 1 year and once per year thereafter
Experimental: Arm II: ZLD
Zoledronic acid (ZLD)
Drug: zoledronic acid
4 mg^2 by IV on day 1 every 84 days for 1 year and once per year thereafter

Detailed Description:

OBJECTIVES:

Primary

  • Compare time to progression in patients with early stage multiple myeloma treated with zoledronate with or without thalidomide.

Secondary

  • Compare the response rate, 1-year progression-free survival rate, duration of response, and time to next therapy in patients treated with these regimens.
  • Assess differences in toxicity of these regimens in these patients.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to the presence of lytic lesions on metastatic bone survey (yes vs no), beta-2 microglobulin level (high vs normal), and bone marrow labeling index (high [> 1.0%] vs low [≤ 1.0%]). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive oral thalidomide on days 1-28. Treatment with thalidomide repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive zoledronate IV over 15 minutes on day 1. Treatment with zoledronate repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive zoledronate IV over 15 minutes on day 1. Treatment repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity.

Blood samples are collected for research studies at baseline and after courses 3, 6, 9, and 12. Bone marrow aspirates are performed at baseline and after courses 6 and 12. Samples are evaluated for bone marrow angiogenesis; vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR-1), and VEGFR-2 expression; bone marrow angiogenesis-VEGF relationship; bone marrow angiogenesis/apoptosis rate relationship; bone marrow angiogenesis/plasma cell (PC) proliferation rate relationship; VEGF expression/apoptosis rate relationship; and VEGFR expression/PC proliferation rate relationship.

After completion of study treatment, patients are followed every 6 months for up to 5 years.

PROJECTED ACCRUAL: A total of 120 patients will be accrued for this study.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Diagnosis of multiple myeloma (MM)

    • Previously untreated asymptomatic disease
    • No requirement for immediate chemotherapy for active MM, such as hypercalcemia from myeloma or painful bone lesions
  • No solitary plasmacytoma
  • Measurable or evaluable disease as defined by one of the following:

    • Serum monoclonal protein ≥ 1.0 g by protein electrophoresis
    • More than 200 mg of monoclonal protein in the urine by 24-hour electrophoresis
    • Measurable soft tissue plasmacytoma by physical exam with ruler or by MRI or positron emission tomography/CT scan

      • If the only measurable lesion is the plasmacytoma, it must be ≥ 1.5 cm in 1 dimension
  • Must have ≥ 10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index
  • No amyloidosis

PATIENT CHARACTERISTICS:

  • Performance status 0-2
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Hemoglobin ≥ 8.0 g/dL
  • Creatinine ≤ 2.0 mg/dL (elevation above normal range should not be felt to be related to myeloma)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and for 4 weeks after completion of study treatment
  • No uncontrolled infection
  • No other active malignancy
  • No New York Heart Association class III or IV heart disease
  • No pre-existing neuropathy ≥ grade 2
  • No concurrent major dental work

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Prior corticosteroids (for nonmalignant disorders) allowed
  • Prior therapy with experimental agents not shown to have significant activity in MM, such as clarithromycin, dehydroepiandrosterone, and anakinra allowed
  • No prior thalidomide or corticosteroids for MM
  • No more than 3 doses of IV zoledronate or pamidronate within the past 12 months
  • At least 3 months since prior radiotherapy, including radiotherapy for solitary plasmacytoma
  • No concurrent oral bisphosphonate therapy for osteoporosis
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00432458

Locations
United States, Arizona
Mayo Clinic Scottsdale
Scottsdale, Arizona, United States, 85259-5499
United States, Florida
Mayo Clinic - Jacksonville
Jacksonville, Florida, United States, 32224
United States, Minnesota
Mayo Clinic Cancer Center
Rochester, Minnesota, United States, 55905
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Mayo Clinic
Investigators
Study Chair: Thomas E. Witzig, MD Mayo Clinic
Principal Investigator: Craig Reeder, M.D. Mayo Clinic
Principal Investigator: Vivek Roy, M.D. Mayo Clinic Florida
  More Information

Additional Information:
No publications provided by Mayo Clinic

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT00432458     History of Changes
Other Study ID Numbers: CDR0000530050, P30CA015083, MC0289, 421-03
Study First Received: February 5, 2007
Results First Received: April 11, 2012
Last Updated: June 4, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
stage I multiple myeloma

Additional relevant MeSH terms:
Neoplasms
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Thalidomide
Zoledronic acid
Diphosphonates
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on April 17, 2014