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

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

Overview[ - collapse ][ - ]

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. - Sixty to eighty percent of classic LFS families have detectable germline TP53 mutations. - TP53 encodes p53 protein. Among many other functions p53 is involved in the regulation of mitochondrial respiration and energy homeostasis. - 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. - Metformin and p53 both have effects on the mitochondria. One effect of metformin is inhibition of mitochondrial respiratory complex I, thereby decreasing ATP production via oxidative phosphorylation. - It is proposed that in the absence of a normal functioning p53, metformin may modulate mitochondrial function by inhibiting oxidative phosphorylation in turn inducing a bioenergetic crisis in rapidly proliferating cells and cellular senescence or apoptosis. 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. - Patients will be assessed for biomarker levels (IGF-1, insulin, IGFBP3) by blood sample at baseline, and weeks 2 and 8. - Patients will also undergo optional mitochondrial studies.
Condition	Li-Fraumeni Syndrome
Intervention	Drug: Metformin
Phase	Phase 1
Sponsor	National Cancer Institute (NCI)
Responsible Party	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier	NCT01981525
First Received	November 7, 2013
Last Updated	March 14, 2014
Last verified	September 2013

Tracking Information[ + expand ][ + ]

First Received Date	November 7, 2013
Last Updated Date	March 14, 2014
Start Date	October 2013
Estimated Primary Completion Date	September 2014
Current Primary Outcome Measures	Determine the tolerability of oral daily metformin in patients with LFS caused by germline TP53 mutations. [Time Frame: 12 months] [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: 12 months] [Designated as safety issue: No]
Current Secondary Outcome Measures	Not Provided

Descriptive Information[ + expand ][ + ]

Brief Title	A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome
Official Title	A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome
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. - Sixty to eighty percent of classic LFS families have detectable germline TP53 mutations. - TP53 encodes p53 protein. Among many other functions p53 is involved in the regulation of mitochondrial respiration and energy homeostasis. - 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. - Metformin and p53 both have effects on the mitochondria. One effect of metformin is inhibition of mitochondrial respiratory complex I, thereby decreasing ATP production via oxidative phosphorylation. - It is proposed that in the absence of a normal functioning p53, metformin may modulate mitochondrial function by inhibiting oxidative phosphorylation in turn inducing a bioenergetic crisis in rapidly proliferating cells and cellular senescence or apoptosis. 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. - Patients will be assessed for biomarker levels (IGF-1, insulin, IGFBP3) by blood sample at baseline, and weeks 2 and 8. - Patients will also undergo optional mitochondrial studies.
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. - Sixty to eighty percent of classic LFS families have detectable germline TP53 mutations. - TP53 encodes p53 protein. Among many other functions p53 is involved in the regulation of mitochondrial respiration and energy homeostasis. - 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. - Metformin and p53 both have effects on the mitochondria. One effect of metformin is inhibition of mitochondrial respiratory complex I, thereby decreasing ATP production via oxidative phosphorylation. - It is proposed that in the absence of a normal functioning p53, metformin may modulate mitochondrial function by inhibiting oxidative phosphorylation in turn inducing a bioenergetic crisis in rapidly proliferating cells and cellular senescence or apoptosis. 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. - Patients will be assessed for biomarker levels (IGF-1, insulin, IGFBP3) by blood sample at baseline, and weeks 2 and 8. - Patients will also undergo optional mitochondrial studies.
Study Type	Interventional
Study Phase	Phase 1
Study Design	Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition	Li-Fraumeni Syndrome
Intervention	Drug: Metformin N/A
Study Arm (s)	Not Provided

Recruitment Information[ + expand ][ + ]

Recruitment Status	Recruiting
Estimated Enrollment	36
Estimated Completion Date	September 2014
Estimated Primary Completion Date	September 2014
Eligibility 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. - 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. Fojo 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. 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. - Current use of diuretics. - Patients who are receiving any other investigational agents. - 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.
Gender	Both
Ages	18 Years
Accepts Healthy Volunteers	No
Contacts	Contact: Farzana L Walcott, M.D. (240) 276-7661 walcottfl@mail.nih.gov
Location Countries	United States

Administrative Information[ + expand ][ + ]

NCT Number	NCT01981525
Other Study ID Numbers	140005
Has Data Monitoring Committee	Not Provided
Information Provided By	National Institutes of Health Clinical Center (CC)
Study Sponsor	National Cancer Institute (NCI)
Collaborators	Not Provided
Investigators	Principal Investigator: Antonio T Fojo, M.D. National Cancer Institute (NCI)
Verification Date	September 2013

Locations[ + expand ][ + ]

National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda, Maryland, United States, 20892 Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office \| 888-624-1937 Recruiting