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

A Phase II Study of Metformin, Doxycycline, or a Combination of Both Agents in Head and Neck Squamous Cell Carcinoma

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Larynx; Oral Cavity; LIP; Pharynx
• Intervention / Treatment: Drug: Metformin Hydrochloride; Drug: Doxycycline; Drug: Metformin +Doxycycline

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
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Sidney Kimmel Cancer Center at Thomas Jefferson University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / 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: Glucophage; Cidophage; Glifage; Dimefor; Glucoformin; 1,1-Dimethylbiguanide Hydrochloride; 1115-70-4; 91485
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: Doxycycline Monohydrate; 17086-28-1
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in percent of CFS expressing CAV-1 at an intensity of 1+ or greater assessed in tumor-associated stroma cells by immunohistochemistry (IHC)	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	Baseline to 30 days after last drug dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0	Safety will be provided in descriptive tables.	Up to 30 days after last drug dose
Change in percent of tumor cells expressing MCT4, that are TUNEL positive and that express BGAL	Analysis will be performed using the Wilcoxon signed-rank test.	Baseline to 30 days after last drug dose
Change in percent of tumor cells expressing MCT4, that are TUNEL positive and that express MCT1	Analysis will be performed using the Wilcoxon signed-rank test.	Baseline to 30 days after last drug dose
Change in percent of tumor cells expressing MCT4, that are TUNEL positive and that express MCT4	Analysis will be performed using the Wilcoxon signed-rank test.	Baseline to 30 days after last drug dose
Change in percent of tumor cells expressing MCT4, that are TUNEL positive and that express TOMM20	Analysis will be performed using the Wilcoxon signed-rank test.	Baseline to 30 days after last drug dose

Collaborators and Investigators

• Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University

Publications and helpful links

Helpful Links

• Thomas Jefferson University Hospital
• Sidney Kimmel Cancer Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 3, 2017
• Primary Completion (ACTUAL): December 3, 2018
• Study Completion (ANTICIPATED): August 1, 2020

Study Registration Dates

• First Submitted: March 6, 2017
• First Submitted That Met QC Criteria: March 6, 2017
• First Posted (ACTUAL): March 10, 2017

Study Record Updates

• Last Update Posted (ACTUAL): December 24, 2018
• Last Update Submitted That Met QC Criteria: December 21, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Hypoglycemic Agents; Physiological Effects of Drugs; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Metformin; Doxycycline
• Other Study ID Numbers: 16D.703

Drug and device information, study documents

• 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