Eltrombopag for People With Fanconi Anemia

Fanconi anemia (FA) is a rare genetic disease that often presents as a bone marrow failure
(BMF) syndrome but also can affect any other organ. Etiologically, loss of function mutations
in more than 21 different gene members of the FA core complex (i.e. FANCA-FANCV) have been
associated with FA. The FA core complex is involved in interstrand cross-link DNA damage
repair during cell division. Impaired DNA repair causes genomic instability which
consequently can cause apoptosis of the cell or malignant transformation. In addition to
impaired DNA repair mechanisms, FA cells exhibit increased sensitivity to pro-inflammatory
cytokines (e.g. IFN- >=, TNF- ) and elevated levels of these cytokines have been associated
with bone marrow failure in subjects with FA and other inherited bone marrow failure
syndromes.

Patients with FA may present with congenital anomalies, such as microcephaly or short
stature. However, the failure of the hematopoietic stem cell (HSC) compartment to produce
sufficient numbers of peripheral blood cells, and progression to myelodysplastic syndrome
(MDS) and acute myelogenous leukemia are the greatest risk factors for morbidity and
mortality, particular in young patients with FA In a few reported cases, spontaneous somatic
reversion of inherited mutations has resulted in a selective growth advantage of corrected
HSCs that subsequently restored hematopoiesis. However, therapeutic options are limited in
FA. Although HSC transplantation outcomes have significantly improved over the past two
decades, donor availability, graft failure, and FA-specific transplant toxicities are still
significant hurdles towards a curative treatment of FA-associated BMF. Moreover, attempts at
genetic correction of FA are not yet ready for patient care.

The thrombopoietin (TPO) mimetic eltrombopag (EPAG) has recently been shown to be effective
in restoring tri-lineage hematopoiesis in patients with treatment refractory acquired severe
aplastic anemia (SAA). Of particular interest for patients with FA is the observation that
EPAG also improves the repair of double strand DNA breaks, a mechanism that is impaired in
patients with FA. Additionally, our pre-clinical studies indicate that EPAG evades INF- >=
blockade of signal transduction from the TPO receptor (c-MPL) resulting in improved survival
and proliferation of HSCs. Based on these clinical and pre-clinical studies, we hypothesize
that EPAG will improve peripheral blood cell counts in patients with FA and thus positively
affect morbidity and mortality.

This phase II clinical trial proposes to treat patients with FA for 6 months with EPAG to
assess safety and efficacy at improving hematological manifestations of FA. Responders at 6
months will be able to continue EPAG on the extension part of this protocol for an additional
3 years. During this time frame we anticipate further improvement of peripheral blood cells
counts that will eventually result in the discontinuation of EPAG after a tapering period.
Translational studies will explore EPAG effects on DNA repair activity, apoptosis, global
transcriptome and TPO signaling pathways in patient s hematopoietic stem and progenitor cells
(HSPCs).

- INCLUSION CRITERIA:

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

- One or more of the following three clinically-significant cytopenias: platelet count
less than or equal to 30,000/microliter or platelet-transfusion-dependence (requiring
at least 4 platelet transfusions in the 8 weeks prior to study entry, see definition
of platelet transfusion units at 8.2.1); neutrophil count less than 500/ microliter;
hemoglobin less than 9.0 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 greater than or equal to 4 years old.

- Weight >12kg.

EXCLUSION CRITERIA:

- Known active or uncontrolled infections not adequately responding to appropriate
therapy.

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

- Any cytogenetic abnormality associated with poor prognosis in FA, including gains of
chromosome 3q, deletions of chromosome 7, and complex cytogenetics (72, 73) identified
from bone marrow aspirate. Patients with known biallelic 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 such
severity that in the view of the investigator it would likely preclude the patient's
ability to tolerate eltrombopag.

- Treatment with androgens (danazol or oxymetholone) less than 4 weeks prior to
initiating eltrombopag.

- Creatinine > 2.5 times ULN

- Direct Bilirubin > 1.5 times ULN

- SGOT (AST) or SGPT (ALT) >5 3 times the ULN normal

- Known liver cirrhosis in severity that would preclude tolerability of eltrombopag as
evidenced 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-human
chorionic gonadotrophin (b-hCG) pregnancy test) at screening or pre-dose on Day 1.

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 30 days after the last dose of eltrompobag. Highly effective
contraception methods include:

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

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment

- Male sterilization (at least 6 months prior to screening). For female patients on
the study the vasectomized male partner should be the sole partner for that
patient.

- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception.

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

- Women are considered post-menopausal and not of child bearing potential if they
have had over 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile age appropriate (e.g. generally 40-59 years), history of
vasomotor symptoms (e.g. hot flushes) in the absence of other medical
justification or have had surgical bilateral oophorectomy (with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In
the case of oophorectomy alone, only when the reproductive status of the woman
has been confirmed by follow up hormone level assessment is she considered not of
child bearing potential.

- Sexually active males unless they use a condom during intercourse while taking
the study treatment and for 30 days after stopping study treatment and should not
father a child in this period. A condom is required to be used also by
vasectomized men as well as during intercourse with a male partner in order to
prevent 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 of safety
for patients participating in the study such as uncontrolled or significant cardiac
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., sustained
ventricular tachycardia, and clinically significant second or third degree AV
block without a pacemaker.)

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

- Impaired cardiac function such as corrected QTc>450msec using Fridericia
correction on the screening EKG, other clinically significant cardio-vascular
disease (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 to
enrollment or within 5-half-lives of the investigational product, whichever is longer.
Note: parallel enrollment in a disease registry is permitted.