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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02949700
Recruitment Status : Active, not recruiting
First Posted : October 31, 2016
Last Update Posted : February 25, 2021
Information provided by (Responsible Party):
Vlad Sandulache, Baylor College of Medicine

Tracking Information
First Submitted Date  ICMJE October 27, 2016
First Posted Date  ICMJE October 31, 2016
Last Update Posted Date February 25, 2021
Actual Study Start Date  ICMJE January 26, 2017
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 28, 2016)
  • Phase I - toxicity [ Time Frame: treatment duration plus 30 days following treatment ]
    Metformin associated toxicities include diarrhea and gastrointestinal disturbance and 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) 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).
  • Phase II - efficacy [ Time Frame: Treatment duration plus 2 years following treatment completion ]
    We will measure disease response rate for patients in the trial and compare this outcome with matched historical controls. 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Phase I/II Study OF Metformin in Combination With Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma
Official Title  ICMJE A Phase I/II Study OF Metformin in Combination With Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma
Brief Summary 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 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Head and Neck Squamous Cell Carcinoma
Intervention  ICMJE Drug: Metformin
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.
Study Arms  ICMJE Experimental: Single arm, treatment

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.

Intervention: Drug: Metformin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: October 28, 2016)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE


  1. 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.
  2. Disease Status: Only patients with active, measurable disease will be included in the study.
  3. 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.
  4. Myelosuppressive chemotherapy: Must not have received within 4 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
  5. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor.
  6. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent.
  7. 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.

  8. 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.
  9. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and >/= 2 months must have elapsed since transplant.
  10. 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.
  11. Performance Status: ECOG performance status less than or equal to 3.
  12. Organ Function: Patients must have normal organ and marrow function as defined below:

    1. leukocytes >/= 3,000/mcL
    2. absolute neutrophil count >/= 1,500/mcL
    3. platelets >/= 100,000/mcL
    4. total bilirubin within normal institutional limits
    5. AST(SGOT) </= 2.5X institutional upper limit of normal
    6. creatinine < 1.5mg/dL OR
    7. creatinine clearance >/= 60 mL/min/1.73 m2 for patients with creatinine levels > institutional normal
  13. Patients must be candidates for standard of care treatment consisting of chemotherapy (cisplatin) and radiation.
  14. 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.
  15. Informed Consent: Ability to understand and the willingness to sign a written informed consent document.


  1. Concomitant Medications: Patients may not be receiving any other investigational agents.
  2. 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.
  3. Prior Allergies: History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin.
  4. 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.
  5. 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.
  6. Pregnancy: Patients may not be pregnant or breastfeeding.
  7. 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.
  8. Patients taking metformin for any reason will not be eligible for inclusion in the study.
  9. Patients may not have been treated for another SCC of the oral cavity, oropharynx, hypopharynx or larynx in the past.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02949700
Other Study ID Numbers  ICMJE H-39773
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Vlad Sandulache, Baylor College of Medicine
Study Sponsor  ICMJE Baylor College of Medicine
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Vlad Sandulache, MD, PhD Baylor College of Medicine
PRS Account Baylor College of Medicine
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP