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

NCT ID: NCT02949700

Last Updated: 2023-06-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-26
• Study Completion Date: 2022-07-07

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.

Conditions

Head and Neck Squamous Cell Carcinoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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.

Exclusion Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Baylor College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Vlad Sandulache

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Vlad Sandulache, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Locations

Baylor College of Medicine

Houston, Texas, United States

Michael E. DeBakey Veterans Affairs Medical Center

Houston, Texas, United States

Harris Health System - Smith Clinic

Houston, Texas, United States

Countries

United States

References

Kemnade JO, Florez M, Sabichi A, Zhang J, Jhaveri P, Chen G, Chen A, Miller-Chism C, Shaun B, Hilsenbeck SG, Hernandez DJ, Skinner HD, Sandulache VC. Phase I / II trial of metformin as a chemo-radiosensitizer in a head and neck cancer patient population. Oral Oncol. 2023 Oct;145:106536. doi: 10.1016/j.oraloncology.2023.106536. Epub 2023 Aug 8.

Reference Type: DERIVED

PMID: 37562095 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

H-39773

Identifier Type: -

Identifier Source: org_study_id