Dose-finding Study of Metformin With Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this research study is to test the safety of adding metformin to standard of care. The standard of care treatment will be cisplatin once every 3 weeks for 3 treatments and radiation for 7 weeks. Metformin is a medication that is currently used to treat diabetes. Increasing amounts of metformin will be given to groups of patients already receiving normal treatment for their cancer to see if metformin causes any good effects by killing your cancer or bad effects (side effects).

Detailed Description
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Patients were registered by contacting the University of Cincinnati Clinical Trials Office. Patients must be registered and consent obtained prior to initiation of any protocol therapy. Treatment was administered on an outpatient basis. Adverse events and potential risks for metformin and cisplatin and radiation were reported. Patients must have screening labs performed within 2 weeks of start of treatment including a complete blood count, liver function tests, metabolic renal panel including magnesium, vitamin B12 level, lactate, and C-peptide. Renal panel must be verified within 24 hours of cisplatin administration. They must fulfill inclusion criteria. The recommended starting dose of metformin in diabetic patients is 500mg orally twice a day which can be escalated by 500mg increments weekly as tolerated with the maximum recommended daily dose of 2550mg. Cisplatin was given either before or after the radiation therapy fraction that is given on the same day. If radiation is held for more than 2 days (for any reason), cisplatin may be held as well until radiation resumes. The prescribed radiotherapy dose was be 70 Gy in 2 Gy once-daily fraction size (total of 35 fractions).

Official Title
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A Phase I Dose-finding Study of Metformin in Combination With Concurrent Cisplatin and Radiation in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: Metformin
* Drug: Cisplatin
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced squamous cell cancer of the head and neck, stage III or IV disease (T1-2, N2a-3 or T3-4). Measurable disease No prior chemotherapy or radiation for head and neck squamous cell cancer Life expectancy of greater than 3 months. Adequate labs Exclusion Criteria: Known metastatic disease. Nasopharyngeal carcinoma History of allergic reactions attributed to metformin or other agents used in study. Known diagnosis of diabetes requiring insulin for control. Administration of metformin within last 4 weeks.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin with Chemoradiation<br>Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. | Drug: Metformin<br>* Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation.<br>* Other names: Riomet;Drug: Cisplatin<br>* Dosed at 100mg/m2 on days 1, 22, and 43<br>* Other names: Platinol-AQ;Radiation: Radiation Therapy<br>* 70 Gy in 2 Gy once daily fractions of 35 fractions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Metformin in Combination With Concurrent Cisplatin and Radiation | Cohorts of patients received escalating doses of metformin (2000 mg, 2550 mg, or 3000 mg divided into daily doses) with a 7-day to 14-day lead-in prior to CRT based on the modified toxicity probability interval design to allow for possible re-escalation after previous de-escalation and to maximize the ability to identify the maximum tolerated dose (MTD). Patients continued to receive metformin for the duration of CRT as tolerated. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing No-Reoccurrence at 36 Months | Patients were evaulated at 36 months to determine if there was recurrence of disease. | 36 months | 
| Number of Participants With Adverse Events | Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.Any participants with any adverse event at any grade was included. Adverse events were collected during the on study period of 21 weeks up to three months after the study for a total of 34 weeks. | 36 months | 
| Progression Free Survival | 2-year progression free survival | 24 months | 
| Overall Survival | 2 year overall survival | 24 months |