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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).
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin with Chemoradiation | Experimental | Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | 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. |
|
| 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 |
| 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 |
Not provided
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Trisha Wise-Draper, MD | University of Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Cincinnati Cancer Institute | Cincinnati | Ohio | 45267 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36328378 | Derived | Crist M, Yaniv B, Palackdharry S, Lehn MA, Medvedovic M, Stone T, Gulati S, Karivedu V, Borchers M, Fuhrman B, Crago A, Curry J, Martinez-Outschoorn U, Takiar V, Wise-Draper TM. Metformin increases natural killer cell functions in head and neck squamous cell carcinoma through CXCL1 inhibition. J Immunother Cancer. 2022 Nov;10(11):e005632. doi: 10.1136/jitc-2022-005632. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Metformin (2000mg) With Chemoradiation | Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. This is the 2000mg cohort. |
| FG001 | Metformin (2550mg) With Chemoradiation | Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. This is the 2550mg cohort. |
| FG002 | Metformin (3000mg) With Chemoradiation | Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. This is the 3000mg cohort. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
There is a total of 18 participants in three cohorts: Metformin (2000mg) (n = 6); Metformin (2500mg) (n = 8); Metformin (3000mg) (n = 4).
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | There is a total of 18 participants in three cohorts: Metformin (2000mg) (n = 6); Metformin (2500mg) (n = 8); Metformin (3000mg) (n = 4). |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Proportion of the study sample that were evaulable. | Posted | Number | mg | 24 months |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Metformin With Chemoradiation- 2000mg Cohort | Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg. 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lung infection | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal Pain | Gastrointestinal disorders | CTCAE | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Trisha Wise-Draper M.D., Ph.D., Associate Professor of Medicine, Medical Director of the UC Cancer C | University of Cincinnati | (513) 558-2826 | wiseth@ucmail.uc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 31, 2017 | Mar 5, 2020 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Feb 7, 2018 | Mar 6, 2020 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D006258 | Head and Neck Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| D002945 | Cisplatin |
| D011878 | Radiotherapy |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D017606 |
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|
| Cisplatin | Drug | Dosed at 100mg/m2 on days 1, 22, and 43 |
|
|
| Radiation Therapy | Radiation | 70 Gy in 2 Gy once daily fractions of 35 fractions |
|
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 |
| Median |
| Full Range |
| Years |
|
| Sex: Female, Male | There is a total of 18 participants in three cohorts: Metformin (2000mg) (n = 6); Metformin (2500mg) (n = 8); Metformin (3000mg) (n = 4). | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | There is a total of 18 participants in three cohorts: Metformin (2000mg) (n = 6); Metformin (2500mg) (n = 8); Metformin (3000mg) (n = 4). | Count of Participants | Participants |
|
| Race (NIH/OMB) | There is a total of 18 participants in three cohorts: Metformin (2000mg) (n = 6); Metformin (2500mg) (n = 8); Metformin (3000mg) (n = 4). | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Tobacco Users | There is a total of 18 participants in three cohorts: Metformin (2000mg) (n = 6); Metformin (2500mg) (n = 8); Metformin (3000mg) (n = 4). | Count of Participants | Participants |
|
| OG001 | Metformin (2550mg) 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 |
| OG002 | Metformin (3000mg) 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 |
|
|
| Secondary | Number of Participants Experiencing No-Reoccurrence at 36 Months | Patients were evaulated at 36 months to determine if there was recurrence of disease. | Posted | Count of Participants | Participants | 36 months |
|
|
|
| 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. | Posted | Count of Participants | Participants | 36 months |
|
|
|
| Secondary | Progression Free Survival | 2-year progression free survival | Posted | Count of Participants | Participants | 24 months |
|
|
|
| Secondary | Overall Survival | 2 year overall survival | Posted | Number | participants | 24 months |
|
|
|
| 1 |
| 6 |
| 6 |
| 6 |
| 6 |
| 6 |
| EG001 | Metformin With Chemoradiation- 2550mg Cohort | Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2550 mg. 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 | 0 | 8 | 1 | 8 | 7 | 8 |
| EG002 | Metformin With Chemoradiation- 3000mg Cohort | Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 3000 mg. 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 | 0 | 4 | 1 | 4 | 4 | 4 |
| Atrial fibrillation | Cardiac disorders | CTCAE | Systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment |
|
| Syncope | Nervous system disorders | CTCAE | Systematic Assessment |
|
| Febrile Neutropenia | Blood and lymphatic system disorders | CTCAE | Systematic Assessment |
|
| Mucositis Oral | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Acute Kidney Injury | Renal and urinary disorders | CTCAE | Systematic Assessment |
|
| Creatinine Increased | Blood and lymphatic system disorders | CTCAE | Systematic Assessment |
|
| Neutrophil count decreased | Blood and lymphatic system disorders | CTCAE | Systematic Assessment |
|
| Acute Kidney Disease | Renal and urinary disorders | CTCAE | Systematic Assessment |
|
| Acute Kidney Injury | Renal and urinary disorders | CTCAE | Systematic Assessment |
|
| Alanine aminotransferase increased | Hepatobiliary disorders | CTCAE | Systematic Assessment |
|
| Alkaline phosphatase increased | Hepatobiliary disorders | CTCAE | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | CTCAE | Systematic Assessment |
|
| Chills | General disorders | CTCAE | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment |
|
| Creatinine increase | Hepatobiliary disorders | CTCAE | Systematic Assessment |
|
| Depression | Psychiatric disorders | CTCAE | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Dry Mouth | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Dysgeusia | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Ear Pain | Ear and labyrinth disorders | CTCAE | Systematic Assessment |
|
| Edema Trunk | General disorders | CTCAE | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE | Systematic Assessment |
|
| Fever | General disorders | CTCAE | Systematic Assessment |
|
| Gastroesophageal reflux disease | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Headache | Nervous system disorders | CTCAE | Systematic Assessment |
|
| Hearing impaired | Ear and labyrinth disorders | CTCAE | Systematic Assessment |
|
| Hiccups | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment |
|
| Hoarseness | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | CTCAE | Systematic Assessment |
|
| Hyperkalemia | Metabolism and nutrition disorders | CTCAE | Systematic Assessment |
|
| Hypokalemia | Metabolism and nutrition disorders | CTCAE | Systematic Assessment |
|
| Hypomagnesemia | Metabolism and nutrition disorders | CTCAE | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | CTCAE | Systematic Assessment |
|
| Hypotension | Vascular disorders | CTCAE | Systematic Assessment |
|
| Hypothyroidism | Endocrine disorders | CTCAE | Systematic Assessment |
|
| Thrush | Infections and infestations | CTCAE | Systematic Assessment |
|
| Throat Swelling | Infections and infestations | CTCAE | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | CTCAE | Systematic Assessment |
|
| Odynophagia | Investigations | CTCAE | Systematic Assessment |
|
| Laryngeal mucositis | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment |
|
| Lymphedema | Vascular disorders | CTCAE | Systematic Assessment |
|
| Lymphocyte count increased | Blood and lymphatic system disorders | CTCAE | Systematic Assessment |
|
| Decreased Appetite | Metabolism and nutrition disorders | CTCAE | Systematic Assessment |
|
| VB12 deficiency | Metabolism and nutrition disorders | CTCAE | Systematic Assessment |
|
| Mucositis oral | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Nervous system disorders | Nervous system disorders | CTCAE | Systematic Assessment |
|
| Neutrophil count decreased | Investigations | CTCAE | Systematic Assessment |
|
| Pain | General disorders | CTCAE | Systematic Assessment |
|
| Paresthesia | Nervous system disorders | CTCAE | Systematic Assessment |
|
| Peripheral sensory neuropathy | Nervous system disorders | CTCAE | Systematic Assessment |
|
| Photophobia | Eye disorders | CTCAE | Systematic Assessment |
|
| Odgnophagia | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | CTCAE | Systematic Assessment |
|
| Sore throat | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment |
|
| Stomach Pain | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Thrombotic thrombocytopenic purpura | Blood and lymphatic system disorders | CTCAE | Systematic Assessment |
|
| Tinnitus | Ear and labyrinth disorders | CTCAE | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE | Systematic Assessment |
|
| Weight Loss | Investigations | CTCAE | Systematic Assessment |
|
| White blood cell decreased | Investigations | CTCAE | Systematic Assessment |
|
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| Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017672 | Nitrogen Compounds |
| D017671 | Platinum Compounds |
| D013812 | Therapeutics |
|
|
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|