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Metformin Hydrochloride and Doxycycline in Treating Patients With Head and Neck Squamous Cell Carcinoma That Can Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT03076281
Recruitment Status : Recruiting
First Posted : March 10, 2017
Last Update Posted : June 5, 2018
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )

Brief Summary:
This randomized phase II trial studies how well metformin hydrochloride and doxycycline work in treating patients with head and neck squamous cell carcinoma that can be removed by surgery. Metformin hydrochloride may reduce the metabolic activity of cancer cells and of surrounding supportive tissue. Doxycycline may minimize toxic side effects of anti-cancer therapy. Giving metformin hydrochloride and doxycycline may work better in treating patients with head and neck squamous cell carcinoma.

Condition or disease Intervention/treatment Phase
Larynx LIP Oral Cavity Pharynx Drug: Metformin Hydrochloride Drug: Doxycycline Drug: Metformin +Doxycycline Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine if treatment with metformin hydrochloride (metformin), doxycycline, or a combination of metformin and doxycycline can increase the percentage of stromal cells that express CAV1 in patients with squamous cell carcinoma of the head and neck.

SECONDARY OBJECTIVES:

I. To determine the effect of metformin, doxycycline, or metformin and doxycycline treatment on the percentage of tumor cells that are apoptotic as determined by the TdT-Mediated dUTP Nick End Labeling Assay (TUNEL) assay, and express MCT4, MCT1, BGAL, and TOMM20 in squamous carcinoma of head and neck region tumor cells.

II. To assess safety and tolerability of metformin, doxycycline, or metformin and doxycycline treatment in subjects with squamous cell carcinoma of the head and neck.

TERTIARY OBJECTIVES:

I. To assess the effect of metformin, doxycycline, or 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-treatment and post-treatment tumor samples.

II. To assess the effect of metformin, doxycycline, or metformin and doxycycline therapy on the metabolic state of the patient as characterized serologically by: erythrocyte sedimentation rate, exosome evaluation, metabolomics profile, and micro ribonucleic acid (RNA) expression profiles and physiologically by performing a nutritional assessment via a nutritionist-mediated 3-day dietary recall and comparing a patient's estimated dietary intake against their estimated caloric needs.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II Study of Metformin, Doxycycline, or a Combination of Both Agents in Head and Neck Squamous Cell Carcinoma
Actual Study Start Date : April 3, 2017
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : August 2020


Arm Intervention/treatment
Experimental: Arm A (metformin hydrochloride)
Patients receive metformin hydrochloride PO daily on days 1-3 and twice daily starting on day 4 to the day prior to surgery 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
  • Glucoformin
  • Glucophage
  • Glifage

Experimental: Arm B (doxycycline)
Patients receive doxycycline PO every 12 hours on days 1 to the day prior to surgery in the absence of disease progression or unacceptable toxicity.
Drug: Doxycycline
Given orally
Other Names:
  • 17086-28-1
  • Doxycycline Monohydrate

Experimental: Arm C (metformin hydrochloride, doxycycline)
Patients receive metformin hydrochloride PO daily on days 1-3 and twice daily starting on day 4 to the day prior to surgery and doxycycline PO every 12 hours on days 1to the day prior to surgery in the absence of disease progression or unacceptable toxicity.
Drug: Metformin +Doxycycline
Given orally




Primary Outcome Measures :
  1. Change in percent of CFS expressing CAV-1 at an intensity of 1+ or greater assessed in tumor-associated stroma cells by immunohistochemistry (IHC) [ Time Frame: Baseline to 30 days after last drug dose ]
    Within-patient change in IHC scores will be analyzed using the Wilcoxon signed-rank test. Comparisons will be made between pretreatment and post-treatment within each of the cohorts


Secondary Outcome Measures :
  1. Incidence of adverse events as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after last drug dose ]
    Safety will be provided in descriptive tables.

  2. Change in percent of tumor cells expressing MCT4, that are TUNEL positive and that express BGAL [ Time Frame: Baseline to 30 days after last drug dose ]
    Analysis will be performed using the Wilcoxon signed-rank test.

  3. Change in percent of tumor cells expressing MCT4, that are TUNEL positive and that express MCT1 [ Time Frame: Baseline to 30 days after last drug dose ]
    Analysis will be performed using the Wilcoxon signed-rank test.

  4. Change in percent of tumor cells expressing MCT4, that are TUNEL positive and that express MCT4 [ Time Frame: Baseline to 30 days after last drug dose ]
    Analysis will be performed using the Wilcoxon signed-rank test.

  5. Change in percent of tumor cells expressing MCT4, that are TUNEL positive and that express TOMM20 [ Time Frame: Baseline to 30 days after last drug dose ]
    Analysis will be performed using the Wilcoxon signed-rank test.



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

Inclusion Criteria:

  1. Diagnosis of head and neck squamous cell carcinoma 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. Patient must be able to swallow pills.
  4. Patients with serum creatinine levels less than 1.5 mg/dL
  5. Women of childbearing potential must have a negative urine or blood pregnancy test within 14 days of study enrollment.
  6. Informed Consent: All subjects must be able to comprehend and sign a written informed consent document.
  7. ECOG Performance status ≤1

Exclusion Criteria:

  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 should be requested for analysis of pre-treatment tumor vs post-treatment tumor.

  2. Subjects who are pregnant or breastfeeding, or may become pregnant during metformin and doxycycline administration.
  3. Received prior cancer therapy for the HNSCC that is being resected.
  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 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.
  7. Patients with serum creatine ≥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. 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 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.
  13. Patient with 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 cont

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03076281


Contacts
Contact: Jennifer Johnson, MD, PhD (215) 955-8874 jennifer.johnson@jefferson.edu

Locations
United States, Pennsylvania
Sidney Kimmel Cancer Center at Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Jennifer Johnson, MD, PhD    215-955-8874    jennifer.johnson@jefferson.edu   
Sponsors and Collaborators
Sidney Kimmel Cancer Center at Thomas Jefferson University
Investigators
Principal Investigator: Jennifer Johnson, MD, PhD Sidney Kimmel Cancer Center at Thomas Jefferson University

Additional Information:
Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT03076281     History of Changes
Other Study ID Numbers: 16D.703
First Posted: March 10, 2017    Key Record Dates
Last Update Posted: June 5, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Neoplasms by Site
Metformin
Doxycycline
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents