This phase II trial studies how well metformin hydrochloride works together with doxycycline in treating patients with localized breast or uterine cancer. Metformin hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Doxycycline may stop the growth of bacteria by keeping them from making proteins and minimized the toxic side effects of anti-cancer therapy. It is not yet known whether giving metformin hydrochloride together with doxycycline may be a better way in treating patients with localized breast or uterine cancer.
PRIMARY OBJECTIVES: I. To determine if treatment with a combination of metformin and doxycycline can increase the percentage of cells that express Caveolin-1 in the cancer associated fibroblasts of patients with breast, or uterine, and cervical cancers. SECONDARY OBJECTIVES: I. To determine the effect of metformin and doxycycline treatment on the percentage of cells that express monocarboxylate transporter (MCT)4 in cancer associated fibroblasts and MCT1 and transporter of outer mitochondrial membrane (TOMM)20 in the cancer cells of breast and uterine cancer patients. II. To assess safety and tolerability of metformin and doxycycline treatment in subjects with breast and uterine cancer. III. To determine the relationship of the percentage of stromal cells expressing caveolin (CAV)1 or MCT4 and tumor cells that express MCT1 and TOMM20 at baseline and after treatment with metformin and doxycycline with the percentage of cells expressing estrogen receptor (ER) and progesterone receptor (PR) for breast and uterine samples and human epidermal growth factor (HER)2 in breast cancer samples. TERTIARY OBJECTIVES: I. To assess the effect of combined metformin and doxycycline therapy on the metabolic profile of cancer cells and stroma using mass spectroscopy imaging (MSI) on paired samples, comparing metabolite profiles in the pre-metformin and post-metformin tumor sample. II. To assess, when possible, the impact of a patient's nutritional status, estimated using 3 day dietary recall versus caloric needs as calculated by the Harris-Benedict equation on the baseline and net change in CAV1 III. To assess the effect of combined metformin and doxycycline therapy on oncomiR micro ribonucleic acid (RNA) (miR-21) after intervention. IV. To assess the effect of combined metformin and doxycycline therapy on adipokines and the insulin-like growth factor (IGF)-1/insulin signaling pathways through assessment of serum triglycerides, IGF-1, IGF-binding protein (BP)3, erythrocyte sedimentation rate (ESR), adiponectin, leptin, IGF-1 receptor (R), exosome evaluation, metabolomics profile, and microRNA expression profile.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Given orally
Given orally
Thomas Jefferson University
Philadelphia, Pennsylvania, United States
Change in the percent of stromal cells expressing Caveolin-1 (CAV1) at an intensity of 1+ or greater assessed by immunohistochemistry
Within-patient change in immunohistochemistry scores will be analyzed using the Wilcoxon signed-rank test.
Time frame: Baseline to week 6
Incidence of adverse events evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time frame: At 30 days after last dose of metformin and doxycycline
Change in the percent of stromal cells expressing express Monocarboxylate Transporter 4 (MCT4) in the cancer cells
Analysis will be performed separately in breast and uterine cancer patients. Evaluated using Aperio analyses of expression intensity with previously validated algorithms. Analysis will be performed using the Wilcoxon signed-rank test.
Time frame: Baseline up to week 5
Change in the percent of tumor cells that express Monocarboxylate Transporter 1 (MCT1) and Transporter of Outer Mitochondrial Membrane 20 (TOMM20) in the cancer cells
Analysis will be performed separately in breast and uterine cancer patients. Evaluated using Aperio analyses of expression intensity with previously validated algorithms. Analysis will be performed using the Wilcoxon signed-rank test.
Time frame: Baseline up to week 5
Percentage of stromal cells expressing Caveolin-1 (CAV1) or Monocarboxylate Transporter 4 (MCT4)
Assessed in relation to the percentage of cells expressing Estrogen Receptor (ER) and Progesterone Receptor (PR) for breast and uterine samples and Human Epidermal Growth Factor Receptor 2 (HER2) in breast cancer samples.
Time frame: Baseline up to week 5
Percentage of tumor cells that express Monocarboxylate Transporter 1 (MCT1) and Transporter of Outer Mitochondrial Membrane 20 (TOMM20)
Assessed in relation to the percentage of cells expressing Estrogen Receptor (ER) and Progesterone Receptor (PR) for breast and uterine samples and Human Epidermal Growth Factor Receptor 2 (HER2) in breast cancer samples.
Time frame: Baseline up to week 5
Progress-free survival
Will be estimated using the Kaplan-Meier method.
Time frame: Up to 12 months post last dose of metformin and doxycycline
Overall survival
Will be estimated using the Kaplan-Meier method.
Time frame: Up to 12 months post last dose of metformin and doxycycline
Objective response rate
Up to 12 months
Time frame: Up to 12 months post last dose of metformin and doxycycline
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