Zoledronate in Treating Bone Marrow Micrometastases in Women With Stage I, Stage II, or Stage III Breast Cancer

Pilot Study to Evaluate the Effect of Zoledronic Acid (Zometa) on Occult Malignant Bone Marrow Cells in Patients With High Risk Early Stage Breast Cancer

RATIONALE: Zoledronate may delay or prevent bone marrow metastases in patients with breast cancer.

PURPOSE: This phase II trial is studying how well zoledronate works in treating bone marrow micrometastases in women with stage I, stage II, or stage III breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Zoledronic Acid

Detailed Description

OBJECTIVES:

Primary

• Determine the response of bone marrow micrometastases, as measured by immunocytochemistry/flow cytometry (IC/FC), during and after 2 years of treatment with zoledronate in women with stage I-III breast cancer.

Secondary

• Evaluate the effects of zoledronate on the bone osteoclast activation marker, n-telopeptide, in these patients.
• Evaluate the incidence of distant recurrences in high-risk women with early-stage breast cancer and bone marrow micrometastases who receive adjuvant zoledronate.

OUTLINE: This is a pilot study.

Patients receive zoledronate IV over 15 minutes once a month for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115-1710
      • University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria

1. Women > 18 years of age with histologically or cytologically confirmed stage I, II or III breast cancer.
2. If adjuvant chemotherapy is recommended, it must be completed before study start.

3. Bone marrow aspirate positive by IC/FC assay

   a. Definition of positive: > 4 MM/ml b. Timing of bone marrow aspiration to determine study eligibility: i. If patient is to receive either no adjuvant therapy or hormonal therapy alone, the aspiration may be performed at diagnosis as part of the large MM study at University of California, San Francisco, or following diagnosis if the patient received initial surgery elsewhere. This is also true for patients who have surgery following neoadjuvant therapy for breast cancer.

   ii. If the patient is to receive adjuvant chemotherapy, the aspiration will be performed at least three weeks after chemotherapy has been completed.

4. Adequate renal function as defined by:

   a. Creatinine must be < upper limit of normal

5. Normal liver function tests including total bilirubin, alkaline phosphatase, and aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT)
6. Ability to understand and sign informed consent.
7. Concomitant hormonal therapy is allowed
8. Concomitant radiation therapy is allowed
9. Patients who have had surgery following neoadjuvant chemotherapy or hormonal therapy are eligible to participate in this trial

Exclusion Criteria

1. History of allergy to bisphosphonates. Acute phase reactions occur in up to 24% of patients and disappear with subsequent dosing. An acute phase reaction does not qualify as an allergic reaction.
2. History of renal insufficiency. Renal insufficiency is defined by a serum creatinine greater than the upper limit of normal or a creatinine clearance < 50 mL/min due to any underlying cause.
3. Karnofsky Performance status < 90%.
4. Any significant medical condition that might interfere with treatment.
5. Women participating in this study are not allowed to receive other bisphosphonate therapy during the study period, either oral or intravenous.
6. Patients who are pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Zoledronic Acid; Patients women with early stage breast cancer and evidence of occult malignant cells in bone marrow aspirates following adjuvant chemotherapy will receive zoledronic acid (Zometa) 4mg, given intravenously over 15 minutes, once a month for two years.

Drug: Zoledronic Acid; Zoledronic acid is a new, highly potent, heterocyclic nitrogen-containing third generation bisphosphonate that has demonstrated 40- to 850- fold greater potency than pamidronate in preclinical models of bone resorption. The mechanism of action of nitrogen-containing bisphosphonates such as pamidronate and zoledronic acid appears to involve inhibition of the mevalonate pathway; Other Names: Zometa; Zoledronate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response of Bone Marrow Micrometastases	Median change in disseminated tumor cells (DTCs)/mL from baseline after 24 months	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in N-telopeptide Level	N-telopeptide levels in urine will be recorded to evaluate the effect of zoledronic acid on bone mineralization (nmol bone collagen equivalents/mmol creatinine) at baseline and after 24 months on study treatment	up to 2 years
Number of Patients With Incidences of Distant Recurrence	Distant breast cancer recurrence is when the cancer has spread to another organ within the body.	up to 5 years post initiation of treatment

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Novartis

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2004
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: February 23, 2006
• First Submitted That Met QC Criteria: February 23, 2006
• First Posted (Estimate): February 24, 2006

Study Record Updates

• Last Update Posted (Actual): May 12, 2020
• Last Update Submitted That Met QC Criteria: May 4, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage IIIC breast cancer; stage I breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: 037519; UCSF-H6961-24352-02 (Other Identifier: University of California, San Francisco); 10-01674 (Other Identifier: University of California, San Francisco)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No