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

NCT02949700 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: H-39773
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 3

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.

Conditions

Head and Neck Squamous Cell Carcinoma

Keywords

metformin; head and neck cancer

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Phase II - Progression Free Survival

  Date of study registration to recurrence/progression/death or up to 2 years following treatment completion, whichever comes first.

• Phase II - Overall Survival

  Date of study registration to death or up to 2 years following treatment completion, whichever comes first.

Study Arms (1)

Single arm, treatment

EXPERIMENTAL

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

Interventions

Metformin 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.

Single arm, treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 may not have been treated for another SCC of the oral cavity, oropharynx, hypopharynx or larynx in the past.

Sponsors & Collaborators

• Baylor College of Medicine: lead

Study Sites (3)

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Michael E. DeBakey Veterans Affairs Medical Center

Houston, Texas, 77030, United States

Location

Harris Health System - Smith Clinic

Houston, Texas, 77054, United States

Location

Related Publications (1)

• 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.

  PMID: 37562095 DERIVED

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms

Interventions

Metformin

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Dr. Vlad Sandulache
• Organization: Baylor College of Medicine

Vlad.Sandulache@bcm.edu

713-798-7218

Study Officials

• Vlad Sandulache, MD, PhD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: October 27, 2016
• First Posted: October 31, 2016
• Study Start: January 26, 2017
• Primary Completion: June 28, 2021
• Study Completion: July 7, 2022
• Last Updated: June 29, 2023
• Results First Posted: July 21, 2022

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)