Metformin Hydrochloride in Treating Women With Stage I or Stage II Breast Cancer That Can Be Removed By Surgery

• Sponsor: Vanderbilt-Ingram Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00984490
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 5
• Locations: 3
• Arm: 1
• Duration (Months): 21.9
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying how well metformin hydrochloride works in treating women with stage I or stage II breast cancer that can be removed by surgery.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: metformin hydrochloride; Other: laboratory biomarker analysis	N/A

Detailed Description

OBJECTIVES:

Primary

• To determine the in situ effects of metformin hydrochloride on proliferation (Ki67) and apoptosis (caspase-3) in women with operable stage I or II breast cancer.

Secondary

• To determine the in situ biologic effect of metformin hydrochloride on the AMP kinase, MTOR/PI3K, and IGF pathways in breast cancer (tissue S6K and phospho S6K, p53, p63, and p73 levels as well as p53 [(Ser-15), if wild-type p53 is present], p63 [Ser-66/68, Ser-301, and Ser-361], and p73 [Y-99] phosphorylation, PTEN [clone 6H2.1], phospho-Akt [S473], insulin receptor substrate 1 and 2 [IRS-1 and IRS-2], and LKB1).

• To determine if molecular classification (basal-type vs luminal A vs luminal B) and the established p63 and p73 RNA microarray gene signatures correlate with the metformin hydrochloride-induced effects on proliferation (Ki67), apoptosis (caspase-3) and the selected biomarkers (listed above) in breast cancer.

• To collect and analyze pre- and post-treatment peripheral blood specimens for serum glucose and insulin levels, as well as circulating IGF-1 and IGF binding protein 3 (IGFBP3).

OUTLINE: Patients receive oral metformin hydrochloride twice daily for 7-21 days. Approximately 24-36 hours after the last dose of metformin hydrochloride, patients undergo surgical resection (total mastectomy or segmental resection with lymph node evaluation) of tumor.

Patients undergo blood and tissue sample collection periodically for biomarker analysis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pre-Surgical Trial of Metformin in Patients With Operable Breast Cancer
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin Metformin: 850 mg orally (PO) twice daily (BID) for 7-21 days, discontinued 24-36 hrs prior to surgery	Drug: metformin hydrochloride; Metformin: 850 mg orally (PO) twice daily (BID) for 7-21 days, discontinued 24-36 hrs prior to surgery; Other: laboratory biomarker analysis; Blood and tissue collection to determine the in situ biologic effect of metformin

Outcome Measures

Primary Outcome Measures

1. Change in Ki67 Levels Before and After Treatment [baseline and between 8-23 days]

   Change in Ki67 levels in pre-treatment, pre-surgery and post-treatment, surgically excised breast tissue. Measured by percentage of positive-staining nuclei with a minimum of 0% to a maximum of 100%. A mean score is determined.

Secondary Outcome Measures

1. Changes in Circulating Insulin-like Growth Factor 1 (IGF-1) and IGF Binding Protein 3 (IGFBP-3) [baseline and 23 days]

   Effect of study drug on circulating IGF-1 and IGFBP-3 as measured in ng/mL in peripheral blood samples taken pre-treatment and post-treatment with metformin

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion:

• Patients must provide informed written consent

• Eastern Cooperative Oncology Group performance status 0-1.

• Clinical stage I, II or IIIA invasive mammary carcinoma, any estrogen receptors(ER), progesterone receptors (PR), or Human Epidermal Growth Factor Receptor (HER2/NEU) status

• Patients who have measurable residual tumor at the primary site Measurable disease: a mass that can be reproducibly measured by physical examination and/or ultrasound and is at least 1 cm in size by physical examination or ultra-sound measurement

• Patients who will undergo surgical treatment with either segmental resection or total mastectomy with lymph node evaluation

• Consultations: All patients should be evaluated by a surgeon prior to study entry.

• Available core biopsies from the time of diagnosis. These may include sections paraffin-embedded material.

• Female subjects ≥18 years of age

• No prior chemotherapy for this primary breast cancer.

• Patients with a prior history of contralateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer.

• Women may have been taking tamoxifen or raloxifene as a preventive agent prior to study entry but must have discontinued the drug for at least 21 days prior to study enrollment.

• Patients must have adequate hepatic and renal function. All tests must be obtained less than 4 weeks from study entry. This includes:

• Creatinine </= to 1.5X upper limits of normal

• Bilirubin, SGOT, SGPT < or = to 1.5X upper limits of normal

• Able to swallow and retain oral medication

Exclusion:

• Patients with locally advanced disease who are candidates and wish to undergo preoperative chemotherapy at the time of initial evaluation. Patients with operable locally advanced disease (stage IIIA) are eligible for participation.

• Locally recurrent breast cancer

• Evidence of distant metastatic disease (i.e. lung, liver, bone, brain, etc.)

• History of diabetes mellitus

• Pregnant or lactating women

• Metformin treatment within 30 days of study entry

• Serious medical illness that in the judgment of the treating physician places the patient at high risk of operative mortality.

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded.

• History of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinomas are eligible

• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.

• History of a medical condition leading to chronic hypoxemia and/or ischemia (congestive heart failure, emphysema or chronic lung disease requiring supplemental oxygen)

• Chronic metabolic acidosis (serum HCO3- < or = to 20 or requiring sodium bicarbonate supplementation)

• Concurrent anti-cancer therapy (chemotherapy, radiotherapy, immunotherapy, hormonal therapy, or any other biologic therapy)

• Concurrent treatment with an investigational agent

• Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital	Atlanta	Georgia	United States	30322
2	Vanderbilt-Ingram Cancer Center - Cool Springs	Nashville	Tennessee	United States	37064
3	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6838

Sponsors and Collaborators

• Vanderbilt-Ingram Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ingrid Mayer, M.D., Vanderbilt-Ingram Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ingrid Mayer, MD, Assistant Professor of Medicine; Clinical Director, Breast Cancer Program; Medical Oncologist, Vanderbilt-Ingram Cancer Center
• ClinicalTrials.gov Identifier: NCT00984490
• Other Study ID Numbers: VICC BRE 0942; P30CA068485; VU-VICC-BRE-0942
• First Posted: Sep 25, 2009
• Last Update Posted: Jul 13, 2012
• Last Verified: Jun 1, 2012

• Keywords provided by Ingrid Mayer, MD, Assistant Professor of Medicine; Clinical Director, Breast Cancer Program; Medical Oncologist, Vanderbilt-Ingram Cancer Center: stage I breast cancer; stage II breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Metformin

Study Results

Participant Flow

Recruitment Details	This study recruited patients from September 24, 2009 through June 28, 2011.
Pre-assignment Detail	Five patients enrolled on this study during the first nine months. Accrual continued to be slow causing its premature closing.

Arm/Group Title	Metformin
Arm/Group Description	Metformin: 850 mg PO twice a day for 7-21 days (discontinued 24-36 hrs prior to surgery
Period Title: Overall Study
STARTED	5
COMPLETED	5
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Metformin
Arm/Group Description	Metformin: 850 mg PO twice a day for 7-21 days (discontinued 24-36 hrs prior to surgery
Overall Participants	5
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45 (1)
Sex: Female, Male (Count of Participants)
Female	5 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	Change in Ki67 Levels Before and After Treatment
Description	Change in Ki67 levels in pre-treatment, pre-surgery and post-treatment, surgically excised breast tissue. Measured by percentage of positive-staining nuclei with a minimum of 0% to a maximum of 100%. A mean score is determined.
Time Frame	baseline and between 8-23 days

Outcome Measure Data

Analysis Population Description

No Ki67 levels were determined. This clinical trial was closed due to slow accrual

Arm/Group Title	Metformin
Arm/Group Description	Metformin: 850 mg orally (PO) twice a day for 7-21 days, discontinued 24-36 hrs prior to surgery
Measure Participants	0

2. Secondary Outcome

Title	Changes in Circulating Insulin-like Growth Factor 1 (IGF-1) and IGF Binding Protein 3 (IGFBP-3)
Description	Effect of study drug on circulating IGF-1 and IGFBP-3 as measured in ng/mL in peripheral blood samples taken pre-treatment and post-treatment with metformin
Time Frame	baseline and 23 days

Outcome Measure Data

Analysis Population Description

No levels of IGF-1 and IGFBP-3 were determined. This clinical trial was closed due to slow accrual.

Arm/Group Title	Metformin
Arm/Group Description	Metformin: 850 mg PO twice a day for 7-21 days (discontinued 24-36 hrs prior to surgery)
Measure Participants	0

Adverse Events

Arm/Group Title	Metformin
Arm/Group Description	Metformin: 850 mg PO twice a day for 7-21 days (discontinued 24-36 hrs prior to surgery
All Cause Mortality
	Metformin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Metformin
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Other (Not Including Serious) Adverse Events
	Metformin
	Affected / at Risk (%)	# Events
Total	4/5 (80%)
Gastrointestinal disorders
diarrhea	4/5 (80%)	5
nausea	2/5 (40%)	2
Injury, poisoning and procedural complications
vomiting	1/5 (20%)	1
Investigations
weight loss	1/5 (20%)	1

Limitations/Caveats

Because this study was closed prematurely, no assay level markers or pathways were performed consequently no data are available to provide results.

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.