Head and Neck Cancer
Conditions
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).
Interventions
DRUGMetformin
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.
DRUGCisplatin
Dosed at 100mg/m2 on days 1, 22, and 43
RADIATIONRadiation Therapy
70 Gy in 2 Gy once daily fractions of 35 fractions
Sponsors
University of Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Recruitment details
Patients were 18 years or old, with newly diagnosis LAHNSCC and ECOG rating of better than or equal to 1, with adequate organ function. Individuals were excluded if they had a diagnosis of: nasopharyngeal cancer, metastatic disease, diabetes requiring insulin, or receipt of metformin with in the last 4 weeks, or history of intercurrent illness.
Participants by arm
| Arm | Count |
|---|---|
| Metformin With Chemoradiation Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating.
Metformin: 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.
Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43
Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Metformin With Chemoradiation |
|---|---|
| Age, Continuous Metformin (2000mg) With Chemoradiation | 54 Years |
| Age, Continuous Metformin (2550mg) With Chemoradiation | 55.5 Years |
| Age, Continuous Metformin (3000mg) With Chemoradiation | 53 Years |
| Ethnicity (NIH/OMB) Metformin (2000mg) With Chemoradiation Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Metformin (2000mg) With Chemoradiation Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Metformin (2000mg) With Chemoradiation Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Metformin (2550mg) With Chemoradiation Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Metformin (2550mg) With Chemoradiation Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Metformin (2550mg) With Chemoradiation Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Metformin (3000mg) With Chemoradiation Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Metformin (3000mg) With Chemoradiation Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Metformin (3000mg) With Chemoradiation Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Metformin (2000mg) With Chemoradiation American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Metformin (2000mg) With Chemoradiation Asian | 0 Participants |
| Race (NIH/OMB) Metformin (2000mg) With Chemoradiation Black or African American | 0 Participants |
| Race (NIH/OMB) Metformin (2000mg) With Chemoradiation More than one race | 0 Participants |
| Race (NIH/OMB) Metformin (2000mg) With Chemoradiation Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Metformin (2000mg) With Chemoradiation Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Metformin (2000mg) With Chemoradiation White | 6 Participants |
| Race (NIH/OMB) Metformin (2550mg) With Chemoradiation American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Metformin (2550mg) With Chemoradiation Asian | 0 Participants |
| Race (NIH/OMB) Metformin (2550mg) With Chemoradiation Black or African American | 0 Participants |
| Race (NIH/OMB) Metformin (2550mg) With Chemoradiation More than one race | 0 Participants |
| Race (NIH/OMB) Metformin (2550mg) With Chemoradiation Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Metformin (2550mg) With Chemoradiation Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Metformin (2550mg) With Chemoradiation White | 8 Participants |
| Race (NIH/OMB) Metformin (3000mg) With Chemoradiation American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Metformin (3000mg) With Chemoradiation Asian | 0 Participants |
| Race (NIH/OMB) Metformin (3000mg) With Chemoradiation Black or African American | 2 Participants |
| Race (NIH/OMB) Metformin (3000mg) With Chemoradiation More than one race | 0 Participants |
| Race (NIH/OMB) Metformin (3000mg) With Chemoradiation Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Metformin (3000mg) With Chemoradiation Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Metformin (3000mg) With Chemoradiation White | 2 Participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Metformin (2000mg) With Chemoradiation Female | 1 Participants |
| Sex: Female, Male Metformin (2000mg) With Chemoradiation Male | 5 Participants |
| Sex: Female, Male Metformin (2550mg) With Chemoradiation Female | 0 Participants |
| Sex: Female, Male Metformin (2550mg) With Chemoradiation Male | 8 Participants |
| Sex: Female, Male Metformin (3000mg) With Chemoradiation Female | 2 Participants |
| Sex: Female, Male Metformin (3000mg) With Chemoradiation Male | 2 Participants |
| Tobacco Users Metformin (2000mg) With Chemoradiation | 3 Participants |
| Tobacco Users Metformin (2550mg) With Chemoradiation | 7 Participants |
| Tobacco Users Metformin (3000mg) With Chemoradiation | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 0 / 8 | 0 / 4 |
| other Total, other adverse events | 6 / 6 | 7 / 8 | 4 / 4 |
| serious Total, serious adverse events | 6 / 6 | 1 / 8 | 1 / 4 |
Outcome results
Primary
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.
Time frame: 24 months
Population: Proportion of the study sample that were evaulable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin (2000mg) With Chemoradiation | Maximum Tolerated Dose (MTD) of Metformin in Combination With Concurrent Cisplatin and Radiation | NA mg |
| Metformin (2550mg) With Chemoradiation | Maximum Tolerated Dose (MTD) of Metformin in Combination With Concurrent Cisplatin and Radiation | NA mg |
| Metformin (3000mg) With Chemoradiation | Maximum Tolerated Dose (MTD) of Metformin in Combination With Concurrent Cisplatin and Radiation | NA mg |
Secondary
Number of Participants Experiencing No-Reoccurrence at 36 Months
Patients were evaulated at 36 months to determine if there was recurrence of disease.
Time frame: 36 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin (2000mg) With Chemoradiation | Number of Participants Experiencing No-Reoccurrence at 36 Months | 6 Participants |
| Metformin (2550mg) With Chemoradiation | Number of Participants Experiencing No-Reoccurrence at 36 Months | 8 Participants |
| Metformin (3000mg) With Chemoradiation | Number of Participants Experiencing No-Reoccurrence at 36 Months | 4 Participants |
Secondary
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.
Time frame: 36 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin (2000mg) With Chemoradiation | Number of Participants With Adverse Events | 6 Participants |
| Metformin (2550mg) With Chemoradiation | Number of Participants With Adverse Events | 7 Participants |
| Metformin (3000mg) With Chemoradiation | Number of Participants With Adverse Events | 4 Participants |
Secondary
Overall Survival
2 year overall survival
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin (2000mg) With Chemoradiation | Overall Survival | 5 participants |
| Metformin (2550mg) With Chemoradiation | Overall Survival | 8 participants |
| Metformin (3000mg) With Chemoradiation | Overall Survival | 4 participants |
Secondary
Progression Free Survival
2-year progression free survival
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin (2000mg) With Chemoradiation | Progression Free Survival | 6 Participants |
| Metformin (2550mg) With Chemoradiation | Progression Free Survival | 8 Participants |
| Metformin (3000mg) With Chemoradiation | Progression Free Survival | 4 Participants |