Phase I/II Study OF Metformin in Combination With Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this research is to see whether metformin can improve the response rate in patients undergoing chemotherapy and radiation for squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx. The purpose of this research is also to see the effects, good and bad, of metformin therapy for this disease. Researchers will also analyze tumor and blood samples from study patients to test and understand the characteristics of tumors which respond to metformin.

Detailed Description
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Information from laboratory studies and retrospective studies of patients with this disease has shown that the addition of metformin (a commonly used medicine for treating diabetes) to chemotherapy and radiation can improve the rate at which the cancer responds to treatment. Metformin is used frequently in the treatment of patients with diabetes and other illness, but has not yet been used to treat patients with this type of cancer. In this research study, we want to see if using metformin during treatment with chemotherapy and radiation will increase the chance that the cancer will respond to treatment and not return.

Official Title
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A Phase I/II Study OF Metformin in Combination With Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Diagnosis: Patients must have histologically or cytologically confirmed squamous cell carcinoma (SCC) of the oral cavity, oropharynx, hypopharynx or larynx. Patients eligible for inclusion must have stage III-IV SCC of the above sites based on current AJCC clinical and imaging based staging (see Appendix A for staging criteria). For the phase II component, patients should present with: 1) HPV- SCC or 2) HPV+ SCC and a concomitant ≥10pack-year smoking history documented in the clinical record; HPV status will be ascertained using the currently utilized clinical standard of p16 overexpression via immunohistochemistry for all patients. Immunohistochemistry to determine p16 overexpression is only a requirement for oropharyngeal disease. Disease Status: Only patients with active, measurable disease will be included in the study. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Patients treated with chemotherapy (i.e. cisplatin) and/or EBRT for a cancer at a different, non-head and neck site, will be eligible for the trial. Patients previously treated with chemotherapy and/or EBRT for a cancer of the head and neck region, irrespective of histology will not be eligible to participate in the trial. Myelosuppressive chemotherapy: Must not have received within 4 weeks of enrollment onto this study (6 weeks if prior nitrosourea). Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. Monoclonal Antibody: At least 6 weeks must have elapsed since prior therapy that includes a monoclonal antibody. Other: For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. XRT: >/= 14days for local palliative XRT (small port); >/= 90days must have elapsed if prior TBI, craniospinal XRT or if >/= 50% radiation of pelvis; >/= 45days must have elapsed if other substantial bone marrow radiation. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and >/= 2 months must have elapsed since transplant. Age: Patients must be >/=18 years of age. Because no dosing or adverse event data are currently available on the use of metformin in cancer patients <18 years of age, children are excluded from this study but will be eligible for future pediatric single-agent trials, if applicable. Performance Status: ECOG performance status less than or equal to 3. Organ Function: Patients must have normal organ and marrow function as defined below: leukocytes >/= 3,000/mcL absolute neutrophil count >/= 1,500/mcL platelets >/= 100,000/mcL total bilirubin within normal institutional limits AST(SGOT) </= 2.5X institutional upper limit of normal creatinine < 1.5mg/dL OR creatinine clearance >/= 60 mL/min/1.73 m2 for patients with creatinine levels > institutional normal Patients must be candidates for standard of care treatment consisting of chemotherapy (cisplatin) and radiation. Willingness to Use Contraception: The effects of metformin on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Informed Consent: Ability to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Concomitant Medications: Patients may not be receiving any other investigational agents. Brain metastases: Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Prior Allergies: History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin. Patients with diabetes mellitus (DM) will be excluded from the study. Criteria for a diagnosis of diabetes mellitus are as follows: a) known diagnosis of DM, b) active treatment for DM, c) fasting glucose level ≥ 126mg/dl or d) hemoglobin A1c ≥ 6.0% obtained within 30 days prior to registration. Intercurrent Illness: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnancy: Patients may not be pregnant or breastfeeding. HIV: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with metformin. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. Patients taking metformin for any reason will not be eligible for inclusion in the study. Patients may not have been treated for another SCC of the oral cavity, oropharynx, hypopharynx or larynx in the past.

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: Single arm, treatment<br>Patients in the Phase I trial will be assigned to a single arm, experimental treatment which will test dose escalation for metformin in the context of chemo-radiation, with toxicity as the primary outcome. Patients in the Phase II trial will be assigned to a single arm, experimental treatment consisting of metformin plus chemo-radiation. | Drug: Metformin<br>* Metformin will be administered orally twice daily during treatment with chemo-radiation for head and neck squamous cell carcinoma. This will occur 7 to 11 days prior to chemotherapy and radiation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Dose-Limiting Toxicity | Dose limiting toxicities include diarrhea/gastrointestinal disturbance and hypoglycemia requiring dose reduction, and they will be measured for the time frame detailed above. Adverse Events (AE)s will be graded in accordance with the NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) http://ctep.cancer.gov/ reporting/ctc.html. If not described in the NCI-CTCAE, AEs will be graded according to their severity using the following criteria: grade 1 (mild), grade 2 (moderate), grade 3 (severe), and grade 4 (life threatening). | treatment duration plus 30 days following treatment (an average of 13 weeks) | 
| Phase II - Efficacy (Disease Response Rate) | Response and progression will be evaluated using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST1.1) Committee [Eur J Cancer. 2009 Jan; 45(2):228-47]. Changes in only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST 1.1 criteria. For the purposes of this study, patients should be reevaluated for response following completion of treatment as per current institutional protocol for this disease site: 1) spiral contrast enhanced computed tomography (CECT) at 10 weeks following completion of treatment or 2) positron emission tomography (PET) at 12 weeks following completion of treatment. Per RECIST v1.1 criteria for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Disease response rate is defined as the percentage of patients with OR. | Treatment duration plus 8-12 weeks following treatment completion (up to 21 weeks total) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II - Progression Free Survival | Measurement of time from date of study registration to date of documented radiographic recurrence/progression or death. | Date of study registration to recurrence/progression/death or up to 2 years following treatment completion, whichever comes first. | 
| Phase II - Overall Survival | Measurement of time from date of study registration to date of death. | Date of study registration to death or up to 2 years following treatment completion, whichever comes first. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metformin, head and neck cancer