Metformin Hydrochloride in Affecting Cytokines and Exosomes in Patients With Head and Neck Cancer

• Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03109873
• Collaborator: (none)
• Enrollment: 9
• Location: 1
• Arms: 2
• Actual Duration (Months): 42.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This pilot clinical trial studies how well metformin hydrochloride works in affecting cytokines and exosomes in patients with head and neck cancer. Metformin hydrochloride may reduce the metabolic activity of cancer cells and of surrounding supportive tissues.

Condition or Disease	Intervention/Treatment	Phase
Larynx; Lip; Oral Cavity; Pharynx	Radiation: External Beam Radiation Therapy; Drug: Metformin Hydrochloride; Other: Placebo	Early Phase 1

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the capacity of metformin hydrochloride (metformin) to alter the cytokine and exosome profiles.

2. To assess the capacity of metformin to mitigate known side effects of external beam radiation therapy including inflammation, mucositis, dysphagia, xerostomia, and fatigue.

SECONDARY OBJECTIVES:

1. Assess safety and tolerability of metformin treatment in subjects undergoing external beam radiation treatment for head and neck cancer.

2. To determine the effect of metformin treatment on symptoms of xerostomia as assessed by the Xerostomia Questionnaire (XQ).

3. To determine the effect of metformin treatment on symptoms of mucositis as assessed by World Health Organization (WHO) classification.

4. To determine the effect of metformin treatment on symptoms of dysphagia as assessed by the MD Anderson Dysphagia Inventory.

5. To determine the effect of metformin treatment on symptoms of fatigue as assess by the Multidimensional Fatigue Inventory (MFI).

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Pilot Study of Metformin in Head and Neck Cancer and Its Effect on Proinflammatory Cytokines and Exosomes Implicated in Acute and Chronic Toxicity
• Actual Study Start Date: Jan 5, 2017
• Actual Primary Completion Date: Jul 31, 2020
• Actual Study Completion Date: Jul 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (EBRT, metformin hydrochloride) Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT.	Radiation: External Beam Radiation Therapy; Undergo External Beam Radiation Therapy; Other Names: Definitive Radiation Therapy EBRT External Beam RT ; Drug: Metformin Hydrochloride; Given orally; Other Names: 1,1-Dimethylbiguanide Hydrochloride 1115-70-4 91485 Cidophage Glucoformin Glucophage ER Dimefor
Placebo Comparator: Arm II (EBRT, placebo) Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT.	Radiation: External Beam Radiation Therapy; Undergo External Beam Radiation Therapy; Other Names: Definitive Radiation Therapy EBRT External Beam RT ; Other: Placebo; Given orally

Outcome Measures

Primary Outcome Measures

1. Cytokine/Chemokine Profile [Up to 1 year]

   Mixed effects linear regression will be used to model longitudinal measurements of each cytokine.

Secondary Outcome Measures

1. Mucositis Assessed Using WHO Classification [Up to 1 year]

   Analysis will be primarily descriptive. The distribution of swallowing function and mucositis scores will be summarized by arm using means, medians, standard deviations, and ranges.

2. Objective Response Rate [Up to 2 years]

   The objective response rate will be estimated by arm along with an exact 95% binomial confidence interval

3. Exosome Profile [Up to 1 year]

   Longitudinal measurements of exosomes will also be modeled using mixed effects linear regression. This analysis is treated as separate from the cytokine questions and the p-value will not be adjusted.

4. Incidence of Toxicities [Up to 2 years]

   Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects with a diagnosis of head and neck cancer biopsy proven, and who are candidates for radiation therapy

• All subjects must be able to comprehend and sign a written informed consent document.

Exclusion Criteria:

• Subjects who are pregnant or may become pregnant during metformin administration; pregnancy testing will be done in conjunction with preradiation protocols

• Subjects on metformin for any reason during the preceding 4 weeks

• Diabetic subjects are eligible if they are not taking metformin or insulin

• 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.

• Patients with plasma creatinine level greater than 1.3 mg/dL

• Patients with plasma bicarbonate less than 22 mEq/L or history of lactic or any other metabolic acidosis

• Patients with history of congestive heart failure

• Patients with myocardial ischemia or peripheral muscle ischemia

• Patients with sepsis or severe infection

• Patients with history of lung disease currently requiring any supplemental oxygen treatment

• Patients scheduled for radiation less than 6 days from enrollment

• Patients with history of hepatic dysfunction or hepatic disease and abnormal liver function tests; patients who have a history of hepatic dysfunction or hepatic disease and normal liver function tests will be eligible to participate

• Patients with a current history (in the past 30 days) of heaving 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".

• All medications are permitted except those that are contraindicated with metformin under current Food and Drug Administration (FDA) recommendations

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Cancer Center at Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107

Sponsors and Collaborators

• Sidney Kimmel Cancer Center at Thomas Jefferson University

Investigators

• Principal Investigator: Adam Luginbuhl, MD, Sidney Kimmel Cancer Center at Thomas Jefferson University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 20, 2019

More Information

Additional Information:

• Sidney Kimmel Cancer Center
• Thomas Jefferson University Hospital

Publications

None provided.

• Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT03109873
• Other Study ID Numbers: 16D.639
• First Posted: Apr 12, 2017
• Last Update Posted: Dec 29, 2020
• Last Verified: Dec 1, 2020

• 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: Head and Neck Neoplasms; Metformin

Study Results

Participant Flow

Arm/Group Title	Arm I (EBRT, Metformin Hydrochloride)	Arm II (EBRT, Placebo)
Arm/Group Description	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Metformin Hydrochloride: Given orally	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Placebo: Given orally
Period Title: Overall Study
STARTED	5	4
COMPLETED	5	4
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm I (EBRT, Metformin Hydrochloride)	Arm II (EBRT, Placebo)	Total
Arm/Group Description	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Metformin Hydrochloride: Given orally	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Placebo: Given orally	Total of all reporting groups
Overall Participants	5	4	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 60%	2 50%	5 55.6%
>=65 years	2 40%	2 50%	4 44.4%
Sex: Female, Male (Count of Participants)
Female	2 40%	1 25%	3 33.3%
Male	3 60%	3 75%	6 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 20%	0 0%	1 11.1%
Not Hispanic or Latino	4 80%	4 100%	8 88.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	5 100%	4 100%	9 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%	4 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	Cytokine/Chemokine Profile
Description	Mixed effects linear regression will be used to model longitudinal measurements of each cytokine.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

Due to insufficient accrual, statistical results cannot be reported.

Arm/Group Title	Arm I (EBRT, Metformin Hydrochloride)	Arm II (EBRT, Placebo)
Arm/Group Description	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Metformin Hydrochloride: Given orally	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Placebo: Given orally
Measure Participants	0	0

2. Secondary Outcome

Title	Mucositis Assessed Using WHO Classification
Description	Analysis will be primarily descriptive. The distribution of swallowing function and mucositis scores will be summarized by arm using means, medians, standard deviations, and ranges.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

Due to insufficient accrual, statistical results cannot be reported.

Arm/Group Title	Arm I (EBRT, Metformin Hydrochloride)	Arm II (EBRT, Placebo)
Arm/Group Description	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Metformin Hydrochloride: Given orally	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Placebo: Given orally
Measure Participants	0	0

3. Secondary Outcome

Title	Objective Response Rate
Description	The objective response rate will be estimated by arm along with an exact 95% binomial confidence interval
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Due to insufficient accrual, statistical results cannot be reported.

Arm/Group Title	Arm I (EBRT, Metformin Hydrochloride)	Arm II (EBRT, Placebo)
Arm/Group Description	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Metformin Hydrochloride: Given orally	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Placebo: Given orally
Measure Participants	0	0

4. Secondary Outcome

Title	Exosome Profile
Description	Longitudinal measurements of exosomes will also be modeled using mixed effects linear regression. This analysis is treated as separate from the cytokine questions and the p-value will not be adjusted.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

Due to insufficient accrual, statistical results cannot be reported.

Arm/Group Title	Arm I (EBRT, Metformin Hydrochloride)	Arm II (EBRT, Placebo)
Arm/Group Description	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Metformin Hydrochloride: Given orally	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Placebo: Given orally
Measure Participants	0	0

5. Secondary Outcome

Title	Incidence of Toxicities
Description	Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Due to insufficient accrual, statistical results cannot be reported.

Arm/Group Title	Arm I (EBRT, Metformin Hydrochloride)	Arm II (EBRT, Placebo)
Arm/Group Description	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Metformin Hydrochloride: Given orally	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Placebo: Given orally
Measure Participants	0	0

Adverse Events

Time Frame	baseline through one year after completion of treatment
Arm/Group Title	Arm I (EBRT, Metformin Hydrochloride)		Arm II (EBRT, Placebo)
Arm/Group Description	Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Metformin Hydrochloride: Given orally		Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. External Beam Radiation Therapy: Undergo External Beam Radiation Therapy Placebo: Given orally
All Cause Mortality
	Arm I (EBRT, Metformin Hydrochloride)		Arm II (EBRT, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/4 (0%)
Serious Adverse Events
	Arm I (EBRT, Metformin Hydrochloride)		Arm II (EBRT, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (EBRT, Metformin Hydrochloride)		Arm II (EBRT, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		3/4 (75%)
General disorders
Xerostomia	4/5 (80%)		2/4 (50%)
Dysphagia	4/5 (80%)		2/4 (50%)
Fatigue	4/5 (80%)		3/4 (75%)
Dysgeusia	4/5 (80%)		3/4 (75%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.