Biomarkers in Tissue Samples From Patients With Newly Diagnosed Breast Cancer Treated With Zoledronic Acid

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01409811
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 9
• Location: 1
• Arm: 1
• Duration (Months): 28.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This pilot clinical trial studies biomarkers in tissue samples from patients with newly diagnosed breast cancer treated with zoledronic acid (ZA). Studying samples of tumor tissue in the laboratory from patients receiving ZA may help doctors learn more about the effects of ZA on cells. It may also help doctors understand how well patients respond to treatment.

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer	Drug: zoledronic acid; Other: laboratory biomarker analysis; Procedure: therapeutic conventional surgery	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate 14 tumor biomarkers of growth and metastasis (10 by microarray and 4 by RT-PCR) for change in response to ZA.

SECONDARY OBJECTIVES:

1. To evaluate 30 measures of immunologic function (by Luminex panel) for change in response to ZA a) after 48-72 hours and b) after 10-23 days.

2. To explore additional tumors biomarkers (approximately 20 by immunohistochemistry) for change in response to ZA.

OUTLINE: Patients receive zoledronic acid intravenously (IV) over 15 minutes on day 1. Patients then undergo planned definitive surgery (lumpectomy or mastectomy) on day 10-23. Tissue and blood samples from the initial biopsy and definitive surgery are collected to measure changes in biomarkers of tumor growth and metastasis, immunologic function, and the expression of genes important to breast cancer progression and metastasis.

After completion of study treatment, patients are followed up at 40-44 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of the Impact of a Single Dose of Zoledronic Acid on Biomarkers in Breast Cancer
• Study Start Date: Sep 14, 2012
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (zoledronic acid) Patients receive a single dose of zoledronic acid 4 mg IV over 15 minutes on day 1. Patients then undergo planned definitive surgery (lumpectomy or mastectomy) on day 10-23. Tissue and blood samples from the initial biopsy and definitive surgery are collected to measure changes in biomarkers of tumor growth and metastasis, immunologic function, and the expression of genes important to breast cancer progression and metastasis. zoledronic acid: Given IV laboratory biomarker analysis: Correlative studies therapeutic conventional surgery: Undergo definitive lumpectomy or mastectomy

Drug: zoledronic acid; Given IV; Other Names: CGP 42446 CGP42446A NDC-zoledronate zoledronate Zometa ; Other: laboratory biomarker analysis; Correlative studies; Procedure: therapeutic conventional surgery; Undergo definitive lumpectomy or mastectomy

Outcome Measures

Primary Outcome Measures

1. Mean (SE) Change From Pre-Treatment Baseline in (Log)pg/mL of Biomarker, by Time, Adjusted for Level at Baseline ["48-72 hrs" and "Surgery (10-23 days)"]

   After the trial's premature closure, no data were collected for the primary endpoints; however, data on 14 of 30 secondary endpoints were obtained and are summarized below. Serum level (pg/mL) per biomarker was log-transformed. Change from baseline over time was evaluated using a generalized linear mixed model where follow-up time was represented by terms for the sequence of post-baseline samples or for (log)day on study. To recognize regression to the mean across repeated samples, a term for biomarker level at baseline, with or without interaction by time, was included when it improved the model's fit to the observed data. With 14 biomarkers sampled twice after baseline, there were 28 evaluations of change in biomarker level with exposure to study drug. Therefore, to control the False Discovery Rate (FDR), only evaluations that maintained the study's FDR at no more than 5 percent were accepted as true.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Postmenopausal women

• Diagnosis of early stage, invasive ductal carcinoma (for which a lumpectomy or mastectomy is planned prior to systemic therapy)

• Estrogen receptor (ER)/progesterone receptor (PR) positive tumor (as confirmed by City of Hope Pathology Department if done on the outside) or

• Biopsy proven ER/PR positive tumor

• Ability to provide informed consent

Exclusion Criteria:

• Tumor that lacks both estrogen and progesterone receptors

• Patients who will receive neoadjuvant therapy prior to definitive surgery

• Bisphosphonate therapy currently or within the past 12 months

• Regular use of anti-inflammatory agents, with the exception of a baby aspirin regimen per principal investigator's (PI's) discretion

• Renal impairment as determined by a creatinine clearance < 60 ml/min as calculated by the Cockcroft-Gault formula using the patient's actual weight

• 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

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Joanne Mortimer, City of Hope Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT01409811
• Other Study ID Numbers: 10192; NCI-2011-02137
• First Posted: Aug 4, 2011
• Last Update Posted: May 8, 2020
• Last Verified: Apr 1, 2020

• Additional relevant MeSH terms: Breast Neoplasms; Carcinoma, Ductal, Breast; Zoledronic Acid

Study Results

Participant Flow

Arm/Group Title	Treatment (Zoledronic Acid)
Arm/Group Description	Patients receive a single dose of zoledronic acid 4 mg IV over 15 minutes on day 1. Patients then undergo planned definitive surgery (lumpectomy or mastectomy) on day 10-23. Tissue and blood samples from the initial biopsy and definitive surgery are collected to measure changes in biomarkers of tumor growth and metastasis, immunologic function, and the expression of genes important to breast cancer progression and metastasis. zoledronic acid: Given IV laboratory biomarker analysis: Correlative studies therapeutic conventional surgery: Undergo definitive lumpectomy or mastectomy
Period Title: Overall Study
STARTED	9
COMPLETED	8
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Zoledronic Acid)
Arm/Group Description	Patients receive a single dose of zoledronic acid 4 mg IV over 15 minutes on day 1. Patients then undergo planned definitive surgery (lumpectomy or mastectomy) on day 10-23. Tissue and blood samples from the initial biopsy and definitive surgery are collected to measure changes in biomarkers of tumor growth and metastasis, immunologic function, and the expression of genes important to breast cancer progression and metastasis. zoledronic acid: Given IV laboratory biomarker analysis: Correlative studies therapeutic conventional surgery: Undergo definitive lumpectomy or mastectomy
Overall Participants	9
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	9 100%
Male	0 0%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	6 66.7%
Hispanic	2 22.2%
Asian	1 11.1%
Region of Enrollment (participants) [Number]
United States	9 100%

Outcome Measures

1. Primary Outcome

Title	Mean (SE) Change From Pre-Treatment Baseline in (Log)pg/mL of Biomarker, by Time, Adjusted for Level at Baseline
Description	After the trial's premature closure, no data were collected for the primary endpoints; however, data on 14 of 30 secondary endpoints were obtained and are summarized below. Serum level (pg/mL) per biomarker was log-transformed. Change from baseline over time was evaluated using a generalized linear mixed model where follow-up time was represented by terms for the sequence of post-baseline samples or for (log)day on study. To recognize regression to the mean across repeated samples, a term for biomarker level at baseline, with or without interaction by time, was included when it improved the model's fit to the observed data. With 14 biomarkers sampled twice after baseline, there were 28 evaluations of change in biomarker level with exposure to study drug. Therefore, to control the False Discovery Rate (FDR), only evaluations that maintained the study's FDR at no more than 5 percent were accepted as true.
Time Frame	"48-72 hrs" and "Surgery (10-23 days)"

Outcome Measure Data

Analysis Population Description

The analysis included data from all evaluable subjects.

Arm/Group Title	Treatment (Zoledronic Acid)
Arm/Group Description	Patients receive a single dose of zoledronic acid 4 mg IV over 15 minutes on day 1. Patients then undergo planned definitive surgery (lumpectomy or mastectomy) on day 10-23. Tissue and blood samples from the initial biopsy and definitive surgery are collected to measure changes in biomarkers of tumor growth and metastasis, immunologic function, and the expression of genes important to breast cancer progression and metastasis. zoledronic acid: Given IV laboratory biomarker analysis: Correlative studies therapeutic conventional surgery: Undergo definitive lumpectomy or mastectomy
Measure Participants	8
MIG @ 48-72 hrs	2.31 (0.24)
MIG @ Surgery (Day 10-23)	0.62 (0.14)
IP-10 @ 48-72 hrs	1.47 (0.18)
IP-10 @ Surgery (Day 10-23)	0.16 (0.08)
IL-12 @ 48-72 hrs	0.23 (0.06)
IL-12 @ Surgery (Day 10-23)	-0.01 (0.05)
Eotaxin @ 48-72 hrs	-0.23 (0.06)
Eotaxin @ Surgery (Day 10-23)	0.02 (0.06)
IL-2R @ 48-72 hrs	0.17 (0.04)
IL-2R @ Surgery (Day 10-23)	0.10 (0.11)
IFN-gamma @ 48-72 hrs	0.04 (0.01)
IFN-gamma @ Surgery (Day 10-23)	-0.01 (0.02)
MIP1B @ 48-72 hrs	0.37 (0.17)
MIP1B @ Surgery (Day 10-23)	0.28 (0.25)
EGF @ 48-72 hrs	-0.18 (0.10)
EGF @ Surgery (Day 10-23)	0.25 (0.12)
MCP-1 @ 48-72 hrs	0.15 (0.08)
MCP-1 @ Surgery (Day 10-23)	-0.02 (0.08)
IFN-alpha per (log)Day until Surgery (Day 10-23)	-0.026 (0.000)
MIP1A per (log)Day until Surgery (Day 10-23)	0.12 (0.05)

Adverse Events

Time Frame	Adverse events collected over a period of 2 years and 3 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Treatment (Zoledronic Acid)
Arm/Group Description	Patients receive a single dose of zoledronic acid 4 mg IV over 15 minutes on day 1. Patients then undergo planned definitive surgery (lumpectomy or mastectomy) on day 10-23. Tissue and blood samples from the initial biopsy and definitive surgery are collected to measure changes in biomarkers of tumor growth and metastasis, immunologic function, and the expression of genes important to breast cancer progression and metastasis. zoledronic acid: Given IV laboratory biomarker analysis: Correlative studies therapeutic conventional surgery: Undergo definitive lumpectomy or mastectomy
All Cause Mortality
	Treatment (Zoledronic Acid)
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Serious Adverse Events
	Treatment (Zoledronic Acid)
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Zoledronic Acid)
	Affected / at Risk (%)	# Events
Total	8/9 (88.9%)
Cardiac disorders
Left ventricular systolic dysfunction	1/9 (11.1%)	1
Pulmonary valve disease	1/9 (11.1%)	1
Sinus bradycardia	2/9 (22.2%)	2
Tricuspid valve disease	1/9 (11.1%)	1
Gastrointestinal disorders
Diarrhea	1/9 (11.1%)	1
Nausea	2/9 (22.2%)	2
General disorders
Chills	2/9 (22.2%)	2
Edema limbs	1/9 (11.1%)	1
Fever	1/9 (11.1%)	1
Infusion site extravasation	1/9 (11.1%)	1
Pain	2/9 (22.2%)	2
Infections and infestations
Eye infection	1/9 (11.1%)	1
Injury, poisoning and procedural complications
Bruising	1/9 (11.1%)	1
Investigations
Alanine aminotransferase increased	1/9 (11.1%)	1
Aspartate aminotransferase increased	2/9 (22.2%)	2
Cholesterol high	3/9 (33.3%)	3
Creatinine increased	1/9 (11.1%)	1
Platelet count decreased	1/9 (11.1%)	1
White blood cell decreased	1/9 (11.1%)	2
Metabolism and nutrition disorders
Hypernatremia	1/9 (11.1%)	1
Hypertriglyceridemia	1/9 (11.1%)	1
Hypoglycemia	2/9 (22.2%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/9 (11.1%)	1
Back pain	1/9 (11.1%)	1
Bone pain	2/9 (22.2%)	2
Joint range of motion decreased	1/9 (11.1%)	1
Myalgia	1/9 (11.1%)	1
Nervous system disorders
Dizziness	1/9 (11.1%)	1
Headache	2/9 (22.2%)	2
Renal and urinary disorders
Chronic kidney disease	1/9 (11.1%)	1
Reproductive system and breast disorders
Breast pain	1/9 (11.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Pruritus	1/9 (11.1%)	1
Vascular disorders
Hematoma	2/9 (22.2%)	2
Hypertension	4/9 (44.4%)	4
Hypotension	1/9 (11.1%)	1

Limitations/Caveats

Results shown come from the 8 evaluable subjects enrolled before early closure of the trial, originally planned to include 40 subjects.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.