Pilot Study of Metformin for Patients With Fanconi Anemia

Inclusion Criteria:

- Age > 6 years and ≤35 years

- Lansky/Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥
50% for patients <16 years of age (see Appendix A)

- Diagnosis requirement

- Participants must have a clinical diagnosis of Fanconi Anemia.

- Participants must have confirmed diepoxybutane-mitomycin C (DEB/MMC) stress
testing to document diagnosis of Fanconi Anemia.

- Patients must have at least one of the following cytopenias: Hemoglobin <10g/dL;
Platelets <100k/uL; Absolute neutrophil count <1000/uL

- Participants must have normal organ function as defined below:

- Hepatic Function : Total bilirubin ≤ 1.5 x upper limit of normal for age; alanine
aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 135 U/L

- Renal Function: A serum creatinine based on age/gender as follows:

Age Maximum Serum Creatinine (mg/dL) Male Female

1. to < 2 years 0.6 0.6

2. to < 6 years 0.8 0.8

6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

≥ 16 years 1.7 1.4

AND

• Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above
institutional normal

- Normal cardiac status as documented clinically, otherwise they will need an
echocardiogram prior to enrollment

- Serum bicarbonate must be >17.

- Participants of child-bearing or child-fathering potential must agree to use adequate
contraception (hormonal birth control; intrauterine device; double barrier method; or
total abstinence) throughout their participation, including up until 30 days after
last dose of Metformin.

- Patients must be able to swallow pills.

- Ability to understand and/or the willingness of the patient (or parent or legally
authorized representative, if minor) to provide informed consent, documented using an
institutionally approved informed consent procedure

Exclusion Criteria:

- Patients must not have undergone prior bone marrow transplantation.

- Patients must not have very severe aplastic anemia at the time of enrollment which
would require bone marrow transplantation (as defined by at least 2 out of the
following 3: Absolute Neutrophil Count (ANC) <200k/uL, platelets <20k/uL, absolute
reticulocyte count <40k/uL).

- Patients must not be taking any other concurrent medications to improve their
hematopoiesis such as androgens or growth factors such as Granulocyte
colony-stimulating factor (G-CSF), erythropoietin (EPO), or thrombopoietin (TPO)
mimetics. There is a one month wash-out period for prior therapies including
androgens.

- Pregnant participants will not be entered on this study given that the effects of
Metformin on the developing human fetus are unknown.

- Breastfeeding mothers are not eligible because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
Metformin.

- Patients must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to Metformin.

- Patients must not have 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.

- Patients must not have prior history of symptomatic hypoglycemia over the past year or
hypoglycemia with glucose <50mg/dL on screening and baseline laboratory assessments.

- Patients must not have type 1 diabetes mellitus.

- Patients must abstain from alcohol as part of this study.

- Patients must not have a diagnosis of myelodysplastic syndrome or leukemia, or other
concurrent malignancy undergoing treatment.

- Patients must not have vitamin B12 deficiency.

- Patients must not have Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency.