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

NCT01981525 | Completed Phase 1 FDA Drug

• 2 other identifiers: 14000514-C-0005
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Li-Fraumeni Syndrome

Keywords

TP53 germline mutations

Outcome Measures

Primary Outcomes (2)

• Determine the tolerability of metformin in patients with LFS caused by germline TP53 mutations

  toxicity assessment by CTCAE ver 4.0

  2 years

• Determine if 8 weeks of daily metformin administration has any effect on circulating IGF-1, insulin, and IGFBP3

  biomarker levels (IGF-1, insulin, IGFBP3) by blood sample at baseline, and weeks 0, 8, 14 and 20

  2 years

Secondary Outcomes (2)

• 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)

  2 years

• 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.

  2 years

Study Arms (1)

Arm 1

EXPERIMENTAL

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

Interventions

Metformin DRUG

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.

Arm 1

Eligibility Criteria

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

You may qualify if:

• 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.
• ECOG performance status 0 or 1 or Karnofsky greater than or equal to 70%
• Patients must have normal organ and marrow function as defined below:
• Leukocytes\*: greater than or equal to 3,000/microL\*
• Absolute neutrophil count: greater than or equal to 1,500/ microL
• Platelets: greater than or equal to 100,000/ microL
• Total bilirubin: Within normal institutional limits
• AST(SGOT) / ALT(SGPT): less than or equal to 2.5 times institutional upper limit of normal
• Creatinine: Within normal institutional limits OR
• Creatinine clearance: greater than or equal to 60 mL/min/1.73m(2) if serum creatinine \> institutional normal
• Note: If leukopenia is idiopathic and no other significant co-morbidities exist patients will not be excluded on the basis of their WBC.
• Metformin is a category B drug and can be used to treat gestational diabetes. Levels of metformin excreted in breast milk appear to be low and not clinically significant. However, for protocol safety reasons, we will not be enrolling pregnant and/or nursing women in this study as metformin as has not been extensively evaluated in non-diabetic pregnant and nursing women. For this reason, women of child-bearing potential 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. Women who are nursing will be advised to discontinue breastfeeding if the mother is treated with metformin. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform Drs. Annunziata or Walcott, or protocol physicians/study team at NCI and her primary care provider immediately.
• Ability of subject to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• 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.
• Gastric paresis
• Short gut syndrome
• Inflammatory bowel disease\*
• Celiac sprue
• Pancreatic insufficiency or disease
• Any malabsorption disease/syndrome
• Chronic PPI use or H2 blocker use that cannot be temporarily discontinued (at least 48 hours)
• Any acetaminophen, aspirin, NSAID, or statin use within 2 days of testing (known to affect mitochondrial function)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969 Oct;71(4):747-52. doi: 10.7326/0003-4819-71-4-747. No abstract available.

  PMID: 5360287 BACKGROUND

• Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988 Sep 15;48(18):5358-62.

  PMID: 3409256 BACKGROUND

• Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, Novokmet A, Finlay J, Malkin D. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011 Jun;12(6):559-67. doi: 10.1016/S1470-2045(11)70119-X. Epub 2011 May 19.

  PMID: 21601526 BACKGROUND

• Wang PY, Li J, Walcott FL, Kang JG, Starost MF, Talagala SL, Zhuang J, Park JH, Huffstutler RD, Bryla CM, Mai PL, Pollak M, Annunziata CM, Savage SA, Fojo AT, Hwang PM. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. J Clin Invest. 2017 Jan 3;127(1):132-136. doi: 10.1172/JCI88668. Epub 2016 Nov 21.

  PMID: 27869650 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Li-Fraumeni Syndrome

Interventions

Metformin

Condition Hierarchy (Ancestors)

Neoplastic Syndromes, Hereditary; Neoplasms; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Christina M Annunziata, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 7, 2013
• First Posted: November 11, 2013
• Study Start: January 27, 2014
• Primary Completion: June 30, 2016
• Study Completion: December 11, 2020
• Last Updated: December 14, 2020

Record last verified: 2020-12

Locations

US (1)