Eltrombopag for People With Fanconi Anemia

• INCLUSION CRITERIA:

• Confirmed diagnosis of Fanconi anemia. Diagnosis is confirmed by a biallelicmutation in a known FANC gene and/or by positive chromosome breakage analysis inlymphocytes and/or skin fibroblasts (for mosaicism).

• One or more of the following three clinically-significant cytopenias: platelet count <= 50,000/microliter or platelet-transfusion-dependence (requiring at least 4platelet transfusions in the 8 weeks prior to study entry, see definition ofplatelet transfusion units at 8.2.1); neutrophil count less than 1000/microliter;hemoglobin less than 10 g/dL or red cell transfusion- dependence (requiring at least 4 transfusions of PRBCs (adult patient 4 units PRBC, pediatric patients at least 10ml/kg/transfusion) in the eight weeks prior to study entry.

• Failed or declined treatment with androgens (danazol or oxymetholone).

• Age >= 6 years old.

• Weight >=10kg.

EXCLUSION CRITERIA:

• Known active or uncontrolled infections not adequately responding to appropriatetherapy.

• Evidence for MDS or AML as defined by WHO criteria.

• Any cytogenetic abnormality associated with poor prognosis in FA, including gains ofchromosome 3q, gains of chromosome 1q, deletions of chromosome 7, and complexcytogenetics (88-90) identified from bone marrow aspirate. Patients with knownbiallelic mutations in BRCA2 (FANCD1).

• Active malignancy or likelihood of recurrence of malignancies within 12 months

• Moribund status such that death within 7 to 10 days is likely. Comorbidities of suchseverity that in the view of the investigator it would likely preclude the patient'sability to tolerate eltrombopag.

• Treatment with androgens (danazol or oxymetholone) less than 4 weeks prior toinitiating eltrombopag.

• Creatinine > 2.5 times ULN

• Direct Bilirubin > 3.0mg/dL, indicating congenital abnormalities in the bilirubinlevel

• SGOT (AST) or SGPT (ALT) >5 times the ULN normal

• Known liver cirrhosis in severity that would preclude tolerability of eltrombopag asevidenced by albumin < 35g/L

• Known immediate or delayed hypersensitivity to EPAG or its components

• Female subjects who are nursing or pregnant (positive serum or urine Beta-humanchorionic gonadotrophin (Beta-hCG pregnancy test) at screening or pre-dose on Day 1.

• Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionduring dosing and for 30 days after the last dose of EPAG. Highly effectivecontraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy or tubal ligation at least six weeks beforetaking study treatment. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment

• Male sterilization (at least 6 months prior to screening). For female patientson the study the vasectomized male partner should be the sole partner for thatpatient.

• Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device (IUD) or intrauterine system (IUS), orother forms of hormonal contraception that have comparable efficacy (failurerate <1%), for example hormone vaginal ring or transdermal hormonecontraception.

• In case of use of oral contraception women should have been stable on the samepill for a minimum of 3 months before taking study treatment.

• Women are considered post-menopausal and not of child bearing potential if theyhave had over 12 months of natural (spontaneous) amenorrhea with an appropriateclinical profile age appropriate (e.g. generally 40-59 years), history ofvasomotor symptoms (e.g. hot flushes) in the absence of other medicaljustification or have had surgical bilateral oophorectomy (with or withouthysterectomy), total hysterectomy or tubal ligation at least six weeks ago. Inthe case of oophorectomy alone, only when the reproductive status of the womanhas been confirmed by follow up hormone level assessment is she considered notof childbearing potential.

• Sexually active males unless they use a condom during intercourse while takingthe study treatment and for 30 days after stopping study treatment and shouldnot father a child in this period. A condom is required to be used also byvasectomized men as well as during intercourse with a male partner in order toprevent delivery of the drug via seminal fluid.

• History of thromboembolic events.

• Unable to take oral medication

• History or current diagnosis of cardiac disease indicating significant risk ofsafety for patients participating in the study such as uncontrolled or significantcardiac disease, including any of the following:

• Recent myocardial infarction (within last 6 months),

• Uncontrolled congestive heart failure,

• Unstable angina (within last 6 months)

• Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustainedventricular tachycardia, and clinically significant second or third-degree AVblock without a pacemaker.)

• Long QT syndrome, family history of idiopathic sudden death, congenital long QTsyndrome or additional risk factors for cardiac repolarization abnormality, asdetermined by the investigator.

• Impaired cardiac function such as corrected QTc>450msec using Fridericiacorrection on the screening EKG, other clinically significant cardio-vasculardiseases (e.g. uncontrolled hypertension, history of labile hypertension),history of known structural abnormalities (e.g. cardiomyopathy).

• History of HIV positivity.

• History of alcohol/drug abuse.

• Concurrent participation in an investigational study within 30 days prior toenrollment or within 5-half-lives of the investigational product, whichever islonger. Note: parallel enrollment in a disease registry is permitted.