A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01981525
First received: November 7, 2013
Last updated: April 30, 2015
Last verified: July 2014
  Purpose

Background:

  • Li Fraumeni Syndrome (LFS) is a highly penetrant, autosomal dominant cancer predisposition disorder. Four main cancer types including sarcoma, adrenocortical carcinoma, breast cancer, and malignant brain tumors commonly characterize LFS but the syndrome can include other cancers.
  • Metformin is an oral biguanide drug that is approved by the FDA for the treatment of type II diabetes. Metformin has been associated with reduced cancer risk in several epidemiologic studies and reduced cancer mortality in patients with type 2 diabetes.
  • Metformin decreases circulating insulin and IGF1, and promotes glucose uptake in skeletal muscle and inhibits gluconeogenesis in the liver. Elevations in circulating insulin and IGF1 levels have been associated with increased cancer risk.
  • Preclinical research in animal models shows that metformin may be more toxic in cancer cells that have lost p53 function.
  • Lifetime risk of cancer in LFS patients with germline TP53 mutations is estimated to be up to 70% by age 60, with women having excess lifetime cancer risk (up to 100%) compared to men (up to 80%). There are currently no approved chemopreventive agents for patients with LFS.
  • Metformin has been shown to be safe and tolerable in diabetic and non-diabetics, and may be an ideal candidate for chemoprevention of cancer in this population.

Objectives:

  • Determine the tolerability of oral daily metformin in patients with LFS caused by germline TP53 mutations.
  • Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3

Eligibility:

  • Must have a germline TP53 mutation and provide documentation of testing.
  • Must have adequate organ function.
  • Age greater than or equal to 18 years.

Design:

  • This is a pilot study to assess the tolerability of daily oral metformin administration in patients with LFS caused by germline TP53 mutations and to study the effect of metformin on biomarker levels in these subjects.
  • In the absence of intolerable toxicity, a minimum of 22 patients will take metformin by mouth for a total of 14 weeks and then discontinue metformin for 6 weeks. The total time on study will be 20 weeks.
  • Patients will be assessed for biomarker levels (IGF-1, insulin, IGFBP3) by blood sample at baseline, and weeks 0 and 8.

Condition Intervention Phase
Li-Fraumeni Syndrome
Drug: Metformin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Determine the tolerability of metformin in patients with LFS caused by germline TP53 mutations [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3 [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Determine if daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3 levels, two weeks after the start of metformin administration and six weeks after discontinuing metformin (week 20) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Determine if daily metformin administration has any effect on skeletalmuscle mitochondrial function using phosphorous-31 magnetic resonance spectroscopy (31P-MRS) baseline and eight weeks after the start of metformin. If there is a change bet... [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 36
Study Start Date: October 2013
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
Patients will receive metformin at level 1 dose for 2 weeks. If dose is tolerated, patient will receive level 2 dose for 2 weeks and if tolerated will escalate to level 3 dose, and if tolerated will escalate to level 4 dose.
Drug: Metformin
Treatment will be administered primarily on an outpatient basis. Patients will be instructed to take 500 mg metformin by mouth 1, 2 or 3 times a day or 1000 mg twice per day depending on dose level. Patients will receive metformin at level 1 dose for 2 weeks. If dose is tolerated, patient will receive level 2 dose for 2 weeks and if tolerated will escalate to level 3 dose, and if tolerated will escalate to level 4 dose. Metformin will be taken for 14 weeks.

Detailed Description:

Background:

  • Li Fraumeni Syndrome (LFS) is a highly penetrant, autosomal dominant cancer predisposition disorder. Four main cancer types including sarcoma, adrenocortical carcinoma, breast cancer, and malignant brain tumors commonly characterize LFS but the syndrome can include other cancers.
  • Metformin is an oral biguanide drug that is approved by the FDA for the treatment of type II diabetes. Metformin has been associated with reduced cancer risk in several epidemiologic studies and reduced cancer mortality in patients with type 2 diabetes.
  • Metformin decreases circulating insulin and IGF1, and promotes glucose uptake in skeletal muscle and inhibits gluconeogenesis in the liver. Elevations in circulating insulin and IGF1 levels have been associated with increased cancer risk.
  • Preclinical research in animal models shows that metformin may be more toxic in cancer cells that have lost p53 function.
  • Lifetime risk of cancer in LFS patients with germline TP53 mutations is estimated to be up to 70% by age 60, with women having excess lifetime cancer risk (up to 100%) compared to men (up to 80%). There are currently no approved chemopreventive agents for patients with LFS.
  • Metformin has been shown to be safe and tolerable in diabetic and non-diabetics, and may be an ideal candidate for chemoprevention of cancer in this population.

Objectives:

  • Determine the tolerability of oral daily metformin in patients with LFS caused by germline TP53 mutations.
  • Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3

Eligibility:

  • Must have a germline TP53 mutation and provide documentation of testing.
  • Must have adequate organ function.
  • Age greater than or equal to 18 years.

Design:

  • This is a pilot study to assess the tolerability of daily oral metformin administration in patients with LFS caused by germline TP53 mutations and to study the effect of metformin on biomarker levels in these subjects.
  • In the absence of intolerable toxicity, a minimum of 22 patients will take metformin by mouth for a total of 14 weeks and then discontinue metformin for 6 weeks. The total time on study will be 20 weeks.
  • Patients will be assessed for biomarker levels (IGF-1, insulin, IGFBP3) by blood sample at baseline, and weeks 0 and 8.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • All TP53 germline mutation positive adult patients will be eligible for this study. All patients must have a documented TP53 germline mutation.
  • Patients with history of cancer must be in remission, with surgery completed at least 6 months prior to enrollment and chemotherapy completed at least 1 year prior to enrollment (except for basel cell carcinoma of the skin).
  • Age greater than or equal to 18 years. The doses of metformin used in this study exceed the maximum recommended daily dose for the pediatric population.

GENERAL EXCLUSION CRITERIA:

  • Patients who have had stem-cell transplantation.
  • Current use of metformin or other anti-diabetic agents, or hypersensitivity or allergy to metformin.
  • Patients who are receiving any other investigational agents.
  • Patients with history of chronic alcohol use
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin or other agents used in study.
  • Patients with congestive heart failure requiring pharmacological management.
  • Uncontrolled inter-current 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01981525

Contacts
Contact: Farzana L Walcott, M.D. (240) 276-7661 walcottfl@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Contact: Robin Eisch    (301) 402-5958    eischar@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Antonio T Fojo, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01981525     History of Changes
Other Study ID Numbers: 140005, 14-C-0005
Study First Received: November 7, 2013
Last Updated: April 30, 2015
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
TP53 Mutation
Autosomal Dominant Hereditary Disorder
Chemoprevention

Additional relevant MeSH terms:
Li-Fraumeni Syndrome
Syndrome
DNA Repair-Deficiency Disorders
Disease
Genetic Diseases, Inborn
Metabolic Diseases
Neoplasms
Neoplastic Syndromes, Hereditary
Pathologic Processes
Metformin
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 21, 2015