Pre-Surgical Trial of the Combination of Metformin and Atorvastatin in Newly Diagnosed Operable Breast Cancer

Sponsor

Columbia University (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01980823

Collaborator

(none)

Enrollment

Location

Arm

110

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effects of combining metformin and atorvastatin treatment in patients with newly diagnosed breast cancer during the interval between breast biopsy and surgery.

This study is designed to assess whether tumor proliferation, as measured by the natural log expression of Ki-67 staining of breast tumor cells, is reduced following approximately 2 weeks of treatment with the combination of metformin plus atorvastatin in patients with newly diagnosed breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Breast Tumors Cancer of Breast	Drug: Metformin Drug: Atorvastatin Procedure: Breast surgery	Early Phase 1

Detailed Description

Breast cancer cells require energy homeostasis shifts with enhanced anabolism to enable rapid growth and continued proliferation. The main energy regulatory system in eukaryotes and breast cancer cells is the AMP-activated kinase (AMPK) pathway. AMPK is triggered by changes in the AMP/Adenosine triphosphate (ATP) ratio thus impacting energy reserves and requirements. AMPK pathway closely interacts with the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, affecting the downstream function of the master regulator mammalian target of rapamycin (mTOR). Activation of AMPK has been shown in vitro to result in inhibition of proliferation of various cancer cell lines.

Utilizing a pre-surgical model, the investigator plans to conduct a pilot study of 40 women with newly diagnosed invasive breast cancer or ductal carcinoma in-situ (DCIS) who will receive oral metformin and atorvastatin daily in the interval between diagnostic breast biopsy and definitive breast surgery.

The goal is to determine if dual combination treatment with metformin plus atorvastatin significantly impacts tumor-based markers, such as proliferation, and blood-based biomarkers.

Study Design

Study Type:

Interventional

Actual Enrollment :

23 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Pre-Surgical "Window of Opportunity" Trial of the Combination of Metformin and Atorvastatin in Newly Diagnosed Operable Breast Cancer

Actual Study Start Date :

Oct 1, 2013

Actual Primary Completion Date :

May 24, 2018

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin-Atorvastatin combination Patients will receive metformin and atorvastatin for approximately 2 weeks prior to breast surgery.	Drug: Metformin Metformin is an oral diabetes medicine that helps control blood sugar levels. Dosage/Frequency: 1500 mg per day: divided 500 mg in the morning and 1000 mg in the evening Metformin is for people with type 2 diabetes. Metformin is sometimes used in combination with insulin or other medications, but it is not for treating type 1 diabetes. Other Names: Glucophage Drug: Atorvastatin Atorvastatin is in a group of drugs called "statins." Atorvastatin reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL). Dosage/Frequency: 80 mg once a day at bedtime Atorvastatin is used to treat high cholesterol, and to lower the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes, coronary heart disease, or other risk factors. Other Names: Lipitor Procedure: Breast surgery (Non-experimental) Female subjects with histologically-confirmed operable invasive breast cancer or DCIS will undergo core needle biopsy with a plan of surgical excision. Other Names: No other name

Arm

Intervention/Treatment

Experimental: Metformin-Atorvastatin combination

Patients will receive metformin and atorvastatin for approximately 2 weeks prior to breast surgery.

Drug: Metformin

Metformin is an oral diabetes medicine that helps control blood sugar levels. Dosage/Frequency: 1500 mg per day: divided 500 mg in the morning and 1000 mg in the evening Metformin is for people with type 2 diabetes. Metformin is sometimes used in combination with insulin or other medications, but it is not for treating type 1 diabetes.

Other Names:

Glucophage

Drug: Atorvastatin

Atorvastatin is in a group of drugs called "statins." Atorvastatin reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL). Dosage/Frequency: 80 mg once a day at bedtime Atorvastatin is used to treat high cholesterol, and to lower the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes, coronary heart disease, or other risk factors.

Other Names:

Lipitor

Procedure: Breast surgery

(Non-experimental) Female subjects with histologically-confirmed operable invasive breast cancer or DCIS will undergo core needle biopsy with a plan of surgical excision.

Other Names:

No other name

Outcome Measures

Primary Outcome Measures

Change in tissue levels of the proliferation marker Ki-67 [Baseline, 2 weeks after start of treatment]
Tumor proliferation, as measured by the natural log expression of Ki-67 staining of breast tumor cells.

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Female subjects with histologically-confirmed operable invasive breast cancer or DCIS, who undergo core needle biopsy followed by surgical excision at least 2 weeks after enrollment
≥ 5 mm by imaging/pathology of core to ensure enough pre- and post-treatment tissue for analysis
Age ≥ 21 years. Breast cancer is uncommon in patients less than this age.
No prior chemotherapy, radiation therapy, or breast resection within 6 months of study entry
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
Signed informed consent

Exclusion Criteria:

Currently on medication for diabetes or hypercholesterolemia
Treatment with other investigational drugs within 6 months of study entry
Strong Cytochrome P450 3A4 (abbreviated CYP3A4) (e.g., clarithromycin, HIV protease inhibitors, and itraconazole), given potential interactions with atorvastatin
Renal impairment with a creatinine > 1.4 mg/dl
Hepatic impairment: Aspartate transaminase (AST)/(SGOT), Alanine Transaminase(ALT)/(SGPT) ≥ 2.5 x upper limit of normal range (ULN), OR Total bilirubin ≥ 1.5 x ULN (subjects with Gilbert's syndrome can have bilirubin of up to 1.5 x ULN), OR Alkaline phosphatase > 2.5 x ULN