Eltrombopag for Moderate Aplastic Anemia

Moderate aplastic anemia (MAA) is a blood disease which can be effectively treated with
immunosuppressive drug regimens. However, a significant number of patients have persistent
cytopenias. Currently, the treatment of these patients is regular transfusion, which are
expensive, inconvenient, and associated with serious side effects related to iron overload,
or cytokines such as erythropoietin or G-CSF, which are expensive, and not effective in many
patients.

Thrombopoietin (TPO) is a protein made by the body that is important for normal production of
platelets by the bone marrow. TPO may also be able to stimulate bone marrow stem cells to
produce red cells and white cells. TPO cannot be given by mouth, and as an alternative, a
drug, eltrombopag, has been designed that acts in the same way as TPO but is stable and
active when given by mouth. Eltrombopag has been shown to safely increase platelet numbers in
healthy volunteers and in patients with chronic immune thrombocytopenic purpura (ITP). It has
been recently granted accelerated approval by FDA on November 20, 2008 for the treatment of
patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient
response to standard therapies.

We have previously shown encouraging results when eltrombopag is used to treat patients with
severe aplastic anemia, with some patients responding with increases in platelets, red cells
and white cells. Given these encouraging early preliminary results in our clinical trial
using eltrombopag in SAA, and low toxicity and ease of administration of this drug, we now
propose a non-randomized pilot phase II study of eltrombopag in moderate aplastic anemia
patients with clinically significant thrombocytopenia or anemia. Patients with MAA may not
reach criteria for SAA, but none the less may be transfusion-dependent or have significant
symptoms from cytopenias. We hypothesize that patients with MAA as compared to SAA may have a
better chance of response, due to better residual marrow function in MAA patients compared to
SAA.

Eligible patients can have treated or untreated MAA, as well as counts meeting criteria for
MAA following a partial response to treatment with immunosupression for SAA. We will also
include patients with bone marrow failure and unilineage cytopenia. Treatment response for
the platelet lineage is defined as platelet count increases to 20,000/microL above baseline
at 16 to 20 weeks, or freedom from platelet transfusions for greater than or equal to 8 weeks
in transfusion-dependent patients. For patients with anemia (untransfused hemoglobin less
than or equal to 8.5 g/dL), a treatment response will be an increase in Hb by greater than or
equal to 1.5g/dl at four months, measured on at least 2 serial measurements and sustained for
1 month or more without transfusion support OR for transfusion dependent patients, reduction
of units of RCC transfused by 50 percent/8 weeks compared with the pretreatment transfusion
number in the previous 8 weeks or transfusion independence (no transfusions for greater than
or equal to 8 weeks). Subjects with evidence for a clinical response in any lineage at 16
weeks but not yet meeting full primary endpoint response criteria, and who are tolerating
investigational treatment, may receive an additional 4 weeks of eltrombopag and be reassessed
after 20 weeks. At that time, if they meet primary endpoint response criteria, they will be
eligible to enter the extended access part of the study. If they do not meet primary endpoint
response criteria, eltrombopag will be discontinued.

The primary objective is to assess the safety and efficacy of the oral thrombopoietin
receptor agonist (TPO-R agonist) eltrombopag in moderate aplastic anemia patients or patients
with bone marrow failure and unilineage cytopenia. Secondary objectives include the analysis
of the incidence and severity of bleeding, clonal evolution to PNH, clonal chromosomal
population in bone marrow, myelodysplasia by morphology, or acute leukemia and the impact on
quality of life.

- INCLUSION CRITERIA:

Current diagnosis of moderate aplastic anemia or unilineage bone marrow failure disorders.

- Moderate aplastic anemia is defined as aplastic anemia (hypocellular bone marrow for
age) with no evidence for other disease processes causing marrow failure, and
depression of at least two out of three blood counts below the normal values:

- ANC less than or equal to 1200/mm(3)

- platelet count less than or equal to 70,000/mm(3)

- anemia with hemoglobin less than or equal to 8.5 g/dL and absolute reticulocyte
count less than or equal to 60,000/mm(3) in transfusion-dependent patients but
not fulfilling the criteria for severe disease defined by depression of two of
the three peripheral counts:

- ANC less than or equal to 500/mm(3)

- platelet count less than or equal to 20,000/mm(3)

- r-eticulocyte count less than or equal to 60,000/mm(3)

- Unilineage bone marrow failure disorders are defined:

- Hemoglobin less than 8.5 g/dL and reticulocyte count less than 60,000 or red cell
transfusion dependent and hypocellular to normocellular bone marrow for age with
significantly reduced erythroid precursors.

- OR thrombocytopenia less than or equal to 30,000/uL or platelet transfussion
dependent and hypocellular to normocellular bone marrow for age with reduced
megakaryocytes.

- No evidence of viral or drug supression of the marrow, dysplasia, or underproduction
anemias secondary to B12, folate, iron or other reversible causes.

Platelet transfusion dependent is defined as the need for platelet transfusion due to
platelet counts of < 10,000/microL with no bleeding (prophylactic transfusion) or <
20,000/microL with bleeding (therapeutic transfusion). Red cell transfusion dependent is
defined as transfusion of greater than 4 units of blood in the 8 weeks prior to study
entry.

Age greater than or equal to 2 years old

Weight greater than 12 kg

EXCLUSION CRITERIA:

Known diagnosis of Fanconi anemia

Counts that meet criteria for severe aplastic anemia

Infection not adequately responding to appropriate therapy

HIV positivity

Creatinine > 2.5 mg/dL

Bilirubin > 2.0 mg/dL, including congenital abnormalities in the bilirubin count

SGOT or SGPT >5 times the upper limit of normal

Hypersensitivity to eltrombopag or its components

Female subjects who are nursing or pregnant or are unwilling to take oral contraceptives or
refrain from pregnancy if of childbearing potential

Evidence of an active malignant hematological or clonal disorder, or abnormal cytogenetic
studies of the bone marrow performed within 12 weeks of study entry.

Unable to understand the investigational nature of the study or give informed consent or
does not have a legally authorized representative or surrogate that can provide informed
consent

Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious,
or metabolic disease of such severity that it would preclude the patient's ability to
tolerate protocol therapy, or that death within 7-10 days is likely.

Treatment with horse or rabbit ATG or Campath within 6 months of study entry.

Treatment with cytokines such as G-CSF or Erythropoeitin.

Subjects with known cirrhosis in severity that would preclude tolerability of eltrombopag
as evidenced by albumin less than 35g/L.

Life expectancy of less than 3 months

Patients with an active diagnosis of cancer who have received chemotherapeutic treatment or
other specific antineoplastic drugs or radiation therapy within 6 months of study entry.

Unable to take investigational drug