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

Phase 1

Completed

Brief Summary: 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: 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).

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Metformin with Chemoradiation	Radiation Therapy	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating.
Metformin with Chemoradiation	Metformin	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating.
Metformin with Chemoradiation	Cisplatin	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Metformin in Combination With Concurrent Cisplatin and Radiation	24 months	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Experiencing No-Reoccurrence at 36 Months	36 months	Patients were evaulated at 36 months to determine if there was recurrence of disease.
Number of Participants With Adverse Events	36 months	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.
Progression Free Survival	24 months	2-year progression free survival
Overall Survival	24 months	2 year overall survival