Breast Carcinoma, Endometrial Clear Cell Adenocarcinoma, Endometrial Serous Adenocarcinoma, Uterine Corpus Cancer, Uterine Corpus Carcinosarcoma
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGMetformin Hydrochloride
Given orally
DRUGDoxycycline
Given orally
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
In order to be eligible for participation in this trial, the subject must: 1. Diagnosis of localized breast or uterine cancer that is either biopsy proven or suspected based on history, physical, and or radiographic findings, and who are planned for definitive resection of the tumor without the use of neoadjuvant chemotherapy or radiation therapy at TJUH are eligible to participate. 2. Subjects must be ≥ 18 years of age at time of consent. 3. Subjects must be newly diagnosed or suspected to have breast, uterine (endometrial cancer with histologies including endometrioid, serous, clear cell, and carcinosarcoma) or cervical cancer. 4. Patient must be able to swallow pills. 5. Patients with serum creatinine levels less than 1.5 mg/dL. 6. Women of child bearing potential must have a negative urine or blood pregnancy test within 14 days of study enrollment. 7. Informed Consent: All subjects must be able to comprehend and sign a written informed consent document. 8. ECOG Performance status \<1
Exclusion criteria
The subject must be excluded from participating in the trial if the subject: 1. Received any prior cancer therapy for the breast or uterine cancer that is being resected, including progesterone therapy for endometrial cancer patients. a. Patients may have had prior therapy for other contra-lateral breast cancer. 2. Subjects who are pregnant or breastfeeding or may become pregnant during metformin and doxycycline administration. 3. Subjects on metformin or doxycycline for any reason during the preceding 4 weeks. 4. Diabetic subjects that are managed by taking metformin or insulin. 5. Subjects who have received iodinated contrast dye must wait 12 hours prior to starting Metformin. If a CT scan with contrast is scheduled after screening and consent, the metformin cannot be taken until after the CT with contrast has been completed and they have waited 12 hours. 6. Patients with serum creatinine level greater than 1.5 mg/dL. 7. Patients with history of lactic or any other metabolic acidosis. 8. Patients with history of congestive heart failure stage III or greater. 9. Patients scheduled for definitive cancer surgical resection less than 7 days from beginning of study drug administration or greater than 6 weeks from beginning study drug administration. 10. Patients with history of hepatic dysfunction or hepatic disease and abnormal liver function tests defined as AST, ALT, Alk Phos, and or total bilirubin greater than 2.5 times the upper limit of normal. a. Patients who have a history of hepatic dysfunction or hepatic disease and normal liver function tests will be eligible to participate. 11. Patients with a current history (in the past 30 days) of heavy drinking which is defined in accordance with CDC definition as more than 8 drinks per week for women and more than 15 drinks per week for men. A standard drink contains .6 ounces of pure alcohol. Generally, this amount of pure alcohol is found in 12-ounces of beer, 8-ounces of malt liquor, 5-ounces of wine, 1.5-ounces or a "shot" of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey). While on study, patients should limit their alcohol consumption to no more than 8 drinks per week for women and no more than 15 drinks per week for men. Patients who feel they cannot comply with this recommendation are not eligible. 12. Prior allergic reaction to metformin, doxycycline, or any other tetracycline antibiotic in the past. 13. Patient is on medications that are contraindicated with metformin or doxycycline under current FDA recommendations. The following is a list of medications identified as class D (consider therapy modification) when treatment with metformin or doxycycline is considered: * Class D: * Bismuth Subsalicylate * Cimetidine * Iodinated contrast agents * Somatropin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Percentage of Stromal Cells Expressing Caveolin-1 (CAV1) at an Intensity of 1+ or Greater by Immunohistochemistry | Pre-treatment (Baseline) and Post-treatment (week 6) | Caveolin-1 (CAV1) expression in stromal cells is assessed by immunohistochemistry using a standard intensity scale of 0 to 3+, where 0 indicates no staining and 1+, 2+, and 3+ indicate increasing levels of staining intensity. For this measure, stromal cells with CAV1 staining of 1+ or higher are considered positive. Results are reported as the percentage of positive stromal cells, ranging from 0% (no positive cells) to 100% (all cells positive). Higher percentages indicate a worse outcome, as higher CAV1 expression is associated with more aggressive tumor behavior. Within-patient changes will be analyzed using the Wilcoxon signed-rank test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | 12 months | Incidence of adverse events evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 |
| Change in the Percent of Stromal Cells Expressing Express Monocarboxylate Transporter 4 (MCT4) in the Cancer Cells | at 5 weeks | 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. |
| Percent of Tumor Cells That Express Transporter of Outer Mitochondrial Membrane 20 (TOMM20) in the Cancer Cells | at 5 weeks | Analysis was performed in breast and uterine cancer patients together due to lower than expected tumor viability. |
| Percentage of Stromal Cells Expressing Caveolin-1 (CAV1) or Monocarboxylate Transporter 4 (MCT4) | 5 weeks | 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. |
| Percentage of Tumor Cells That Express Monocarboxylate Transporter 1 (MCT1) | Pre-treatment (Baseline) and Post-treatment (week 6) | Analyzed breast and uterine cancer patients together due to low tumor viability. Mean scores and full range are provided. Expression is reported as the percentage of tumor cells staining on a positive scale from 0-100%, where higher percentages indicate greater MCT1 expression. Pre-treatment and post treatment samples were compared. |
| Progression-free Survival | 1 year | The time from the start of treatment until disease progression or death from any cause, whichever occurs first. The number of participants who experienced progression or death during the follow up period is reported. |
| Overall Survival (OS) | 12 months | The time from the start of treatment until death from any cause. The number of participants who died during the 12 month follow up period. |
| Clinical Response Rate | 12 months | The number of participants with clinical improvement in disease status following treatment. Clinical response is defined as the continued eligibility for the surgical procedure as initially planned at the time of trial enrollment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJennifer Johnson, MD, PhD
Thomas Jefferson University
Participant flow
Pre-assignment details
This was a single-arm study in which all participants received the same intervention. Participants included patients with breast, uterine, and cervical cancers, which were treated as subgroups within a single analysis population. While the protocol specified enrollment targets by disease cohort, these cohorts were not intended to function as independent comparison groups, and the study was not powered for separate analyses. Accordingly, results are reported for the combined population.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 29 |
| other Total, other adverse events | 3 / 29 |
| serious Total, serious adverse events | 1 / 29 |
Outcome results
None listed