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Metformin Hydrochloride and Doxycycline in Treating Patients With Localized Breast or Uterine Cancer

This study is currently recruiting participants.
See Contacts and Locations
Verified September 2017 by Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )
ClinicalTrials.gov Identifier:
NCT02874430
First received: August 17, 2016
Last updated: September 15, 2017
Last verified: September 2017
  Purpose
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.

Condition Intervention Phase
Breast Carcinoma Endometrial Clear Cell Adenocarcinoma Endometrial Serous Adenocarcinoma Uterine Corpus Cancer Uterine Corpus Carcinosarcoma Drug: Metformin Hydrochloride Drug: Doxycycline Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Metformin in Combination With Doxycycline in Patients With Localized Breast and Uterine Cancer

Resource links provided by NLM:


Further study details as provided by Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University ):

Primary Outcome Measures:
  • Change in the percent of stromal cells expressing Caveolin-1 (CAV1) at an intensity of 1+ or greater assessed by immunohistochemistry [ Time Frame: Baseline to week 6 ]
    Within-patient change in immunohistochemistry scores will be analyzed using the Wilcoxon signed-rank test.


Secondary Outcome Measures:
  • 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 [ Time Frame: Baseline up to week 5 ]
    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.

  • 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 [ Time Frame: Baseline up to week 5 ]
    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.

  • Percentage of stromal cells expressing Caveolin-1 (CAV1) or Monocarboxylate Transporter 4 (MCT4) [ Time Frame: Baseline up to week 5 ]
    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) and Transporter of Outer Mitochondrial Membrane 20 (TOMM20) [ Time Frame: Baseline up to week 5 ]
    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.

  • Progress-free survival [ Time Frame: Up to 12 months post last dose of metformin and doxycycline ]
    Will be estimated using the Kaplan-Meier method.

  • Overall survival [ Time Frame: Up to 12 months post last dose of metformin and doxycycline ]
    Will be estimated using the Kaplan-Meier method.

  • Objective response rate [ Time Frame: Up to 12 months post last dose of metformin and doxycycline ]
    Up to 12 months


Estimated Enrollment: 74
Study Start Date: June 2016
Estimated Study Completion Date: January 2022
Estimated Primary Completion Date: February 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (metformin hydrochloride, doxycycline)
Patients receive metformin hydrochloride orally daily on days 1-3 and twice a day starting on day 4. Patients also receive doxycycline orally every 12 hours starting on day 1. Treatment repeats every 7 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
Drug: Metformin Hydrochloride
Given orally
Other Names:
  • 1,1-Dimethylbiguanide Hydrochloride
  • 1115-70-4
  • 91485
  • Cidophage
  • Dimefor
  • Glifage
  • Glucoformin
  • Glucophage
  • N,N-Dimethylimidodicarbonimidic Diamide Monohydrochloride
  • Riomet
  • Siofor
Drug: Doxycycline
Given orally
Other Names:
  • 17086-28-1
  • Doxycycline Monohydrate

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine if treatment with a combination of metformin hydrochloride (metformin) and doxycycline can increase the percentage of cells that express caveolin-1 in the cancer associated fibroblasts of patients with breast or uterine 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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 or uterine cancer (endometrial cancer with histologies including endometrioid, serous, clear cell, and carcinosarcoma).
  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. Subjects that do not have a baseline tumor specimen/biopsy prior to starting study medications.

    a. Tumor specimens do not need to be at Jefferson at time of eligibility determination. Tumor specimens held at outside institutions are not a reason for exclusion. Samples from outside institutions should be requested for analysis of pre-treatment tumor vs post-treatment tumor.

  2. 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.

  3. Subjects who are pregnant or breastfeeding or may become pregnant during metformin and doxycycline administration.
  4. Subjects on metformin or doxycycline for any reason during the preceding 4 weeks.
  5. Diabetic subjects that are managed by taking metformin or insulin.
  6. Subjects who have received iodinated contrast dye less than 48 hours prior to screening meet a temporary exclusion criteria to receive metformin. These patients cannot start investigational metformin until 48 hours have elapsed from contrast administration. Subjects who are scheduled for iodinated contrast dye administration within 48 hours of definitive surgery are excluded.
  7. Patients with serum creatinine level greater than 1.5 mg/dL.
  8. Patients with history of lactic or any other metabolic acidosis.
  9. Patients with history of congestive heart failure stage III or greater.
  10. 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.
  11. 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.

  12. Patients with a history of excessive alcohol intake which is defined in accordance with CDC definitions as more than 1 drink per day for women and more than 2 drinks per day for men. This definition is referring to the amount consumed on any single day and is not intended as an average over several days. A standard drink is equal to 13.7 grams (0.6 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).
  13. Prior allergic reaction to metformin, doxycycline, or any other tetracycline antibiotic in the past.
  14. 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02874430

Contacts
Contact: Jennifer Johnson, MD, PhD 215-955-8874

Locations
United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Jennifer Johnson, MD, PhD    215-955-8874      
Sub-Investigator: Adam Berger, MD         
Sub-Investigator: Theodore Tsangaris, MD         
Sub-Investigator: Melissa Lazar, MD         
Sub-Investigator: Christine Kim, MD         
Sub-Investigator: Norman Rosenblum, MD, PhD         
Sub-Investigator: Benjamin Leiby, PhD         
Sub-Investigator: Madalina Tuluc, MD         
Sub-Investigator: Joanna Chan, MD         
Sub-Investigator: Ubaldo Martinez Outschoorn, MD         
Sub-Investigator: Nicole Simone, MD         
Sponsors and Collaborators
Sidney Kimmel Cancer Center at Thomas Jefferson University
Investigators
Principal Investigator: Jennifer Johnson, MD, PhD Thomas Jefferson University
  More Information

Additional Information:
Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT02874430     History of Changes
Other Study ID Numbers: 16D.317
Study First Received: August 17, 2016
Last Updated: September 15, 2017

Additional relevant MeSH terms:
Adenocarcinoma
Breast Neoplasms
Uterine Neoplasms
Carcinosarcoma
Mixed Tumor, Mullerian
Cystadenocarcinoma, Serous
Adenocarcinoma, Clear Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Uterine Diseases
Genital Diseases, Female
Neoplasms, Complex and Mixed
Sarcoma
Neoplasms, Connective and Soft Tissue
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Metformin
Doxycycline
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials

ClinicalTrials.gov processed this record on September 19, 2017