Single Dosing of Zoledronic Acid in Cancer Therapy Induced Bone Loss (CTIBL)

This study has been completed.
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Allan Lipton, Penn State University
ClinicalTrials.gov Identifier:
NCT00712985
First received: July 9, 2008
Last updated: September 13, 2012
Last verified: April 2012
  Purpose

The purpose of this research is to establish if a once a year dose of Zoledronic Acid is sufficient to suppress and maintain urine bone density markers (NTx) within normal range at 12 months post-dosing in postmenopausal early breast cancer patients receiving additional treatment with non-steroidal aromatase inhibitors.


Condition Intervention Phase
Breast Cancer
Drug: Zometa
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Single Dosing of Zoledronic Acid in Cancer Therapy Induced Bone Loss (CTIBL)

Resource links provided by NLM:


Further study details as provided by Penn State University:

Primary Outcome Measures:
  • The primary objective of this study is to establish if once a year 5mg dosing of zoledronic acid is sufficient to suppress and maintain urine NTx within normal range at 12 months post-dosing in postmenopausal early breast cancer patients. [ Time Frame: One year ] [ Designated as safety issue: No ]

Enrollment: 18
Study Start Date: September 2005
Study Completion Date: March 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: I
Zometa (Zoledronic Acid) 5 mg IV given over 15 minutes as a one time dose & 12 month follow-up of serum & urine markers of bone destruction (NTx & CTx).
Drug: Zometa
Zometa (Zoledronic Acid) 5 mg IV over 15 minutes in a one time dose
Other Name: Zoledronic Acid

Detailed Description:

Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. Skeletal complications due to metastatic disease include (severe) bone pain, spinal cord compromise, pathological fractures, and hypercalcemia.

Zoledronic acid is a member of a class of compounds known as bisphosphonates. Bisphosphonates are effective inhibitors of osteoclastic bone resorption and have demonstrated therapeutic efficacy in the treatments of hypercalcemia of malignancy, lytic bone disease associated with multiple myeloma, and mixed lytic and blastic bone metastases associated with breast cancer. The precise mechanism by which bisphosphonates inhibit osteoclast function is not fully understood, but may include a direct toxic effect on mature osteoclasts, an inhibition of osteoclast production from precursor cells, and an impairment of osteoclast chemotaxis to sites of active bone resorption. Osteoclasts are specialized bone cells which erode mineralized bone by secreting acids and lysosomal enzymes. In normal bone remodeling, osteoclastic bone resorption is coupled to and is in equilibrium with osteoblastic bone formation. The lytic bone destruction associated with malignant bone metastases develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The osteoclastic activating factors released by tumor cells include parathyroid hormone-related peptide (PTHrP), growth factors, and cytokines. The malignant activation of osteoclasts results in a disruption of normal bone remodeling wherein the equilibrium between bone resorption and bone formation is shifted toward increased bone resorption. This relative increase in osteoclastic bone resorption results in a net loss of bone. Thus, the predominant role of the osteoclast in the pathogenesis of bone destruction and the inhibitory effects of bisphosphonates on osteoclast function have formed the rationale for the use of bisphosphonates in the treatment of osteolytic bone metastases. The common role, regardless of tumor type, of the osteoclast as the mediator of bone destruction in metastatic skeletal disease is indicated by the inhibitory effects of bisphosphonates on tumor-induced osteolysis in animal models utilizing various malignant cell lines and the effectiveness of bisphosphonates in the therapy of tumor-induced hypercalcemia arising from any type of cancer. Moreover, recent studies have specifically shown that therapy with the bisphosphonate pamidronate (Aredia) combined with antineoplastic therapy significantly reduces the proportion of patients having skeletal complications due to the lytic bone disease associated with multiple myeloma and breast cancer compared to antineoplastic therapy alone.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Postmenopausal women with Stage I, II or IIIa breast cancer being treated with a non-steroidal AI.Negative bone scan (no bone metastases).
  • Calculated creatinine clearance > 40 ml/min
  • Documented T score of less than or equal to -1.5 on DXA scan at the lumbar spine or femoral neck within 3 months prior to screening.
  • Urine NTx > 50nM BCE based on second morning void.
  • Signed informed consent.
  • Ambulatory patients at least 18 years of age.
  • ECOG 0-2.
  • Ability to comply with trial requirements.

Exclusion Criteria:

  • Bone Metastases.
  • Any woman of child bearing potential.
  • Patients with fractures occurring within three months prior to randomization. - Greater than a 2+ protein on urine dipstick without evidence of contamination or bacteriuria (may be repeated one time, at least a day apart).
  • Calculated creatinine clearance less than 30 mL/min at screening.
  • Serum calcium > 2.75 mmol/L (11.0 mg/dL) or < 2.00 mmol/L (8.0 mg/dL).
  • AST or ALT > 2.0 x ULN.
  • Serum alkaline phosphatase > 1.5 x ULN. History of hypersensitivity to bisphosphonates.
  • Evidence of vitamin D deficiency (serum 25-(OH) D of less than 15 ng/ml).
  • History of uveitis or iritis, except when secondary to trauma, and must have resolved > 2 years prior to entry.
  • A history of invasive malignancy of any organ system, treated or untreated, within the past 12 months prior to screening; excluding, basal cell or squamous cell carcinoma of the skin, colonic polyps with non-invasive malignancy which have been removed, Ductal Carcinoma in-situ (DCIS) that has been surgically removed, and Carcinoma in-situ (CIS) of the uterine cervix that has been surgically removed.
  • Previous major solid organ transplant recipient or on a transplant waiting list.
  • Treatment with any investigational drug within 30 days prior to randomization.
  • History of hyperparathyroidism, hypoparathyroidism, Osteogenesis imperfecta, Paget's disease or any metabolic bone disease other than osteoporosis.
  • Any medical condition which would interfere with the action of the study drug or limit life expectancy to less than 6 months.
  • Any medical or psychiatric condition which, in the opinion of the investigator, would preclude the participant from adhering to the protocol or completing the trial.
  • Prior treatment with IV bisphosphonates within the last 2 years.
  • Previous use of oral bisphosphonates within the past 2 years (unless used for less than 8 weeks*). *NOTE: If used less than 8 weeks, the washout period is 6 months.
  • Treatment with raloxifene, calcitonin, tibolone or hormone replacement therapy. The washout period for these medications is 6 months prior to randomization.
  • Any treatment with strontium renalate, samarium, sodium fluoride or parathyroid hormone.
  • Use of systemic high dose corticosteroids at an average dose of > 7.5 mg per day of oral prednisone or equivalent for a period of three months or more prior to screening.
  • Known hypersensitivity to zoledronic acid or other bisphosphonates.
  • Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.
  • Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants).
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00712985

Locations
United States, Pennsylvania
Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
Sponsors and Collaborators
Penn State University
Novartis
Investigators
Principal Investigator: Allan Lipton, MD Milton S. Hershey Medical Center
  More Information

Publications:
BIG 1-98 Collaborative Group. Letrozole versus tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. BIG 1-98: a prospective randomized double-blind phase III study. Breast. 2005;14:Suppl 1:S3. Abstract.

Responsible Party: Allan Lipton, MD, Penn State University
ClinicalTrials.gov Identifier: NCT00712985     History of Changes
Other Study ID Numbers: CZOL446H US113
Study First Received: July 9, 2008
Last Updated: September 13, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Penn State University:
Breast cancer
aromatase inhibitors

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Zoledronic acid
Diphosphonates
Aromatase Inhibitors
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 15, 2014