Trial Information

A Pilot Study of a Thrombopoietin-Receptor Agonist (TPO-R Agonist), Eltrombopag, in Patients With Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

The myelodysplastic syndromes (MDS) are bone marrow disorders characterized by anemia,
neutropenia, and thrombocytopenia. Patients with MDS are at risk for symptomatic anemia,
infection, and bleeding, as well as a variable risk of progression to acute leukemia. With
the exception of stem cell transplant, the standard treatments for MDS are rarely curative,
and relapse rates are significant. MDS patients with cytopenias who fail standard therapies
require regular blood or platelet transfusions which are expensive and inconvenient, and are
at risk for serious bleeding complications.

Thrombopoietin (TPO) is the principal regulator of platelet production by megakaryocytes in
the bone marrow. A 2nd generation TPO-agonist, eltrombopag (Promacta(Registered Trademark))
has been shown to increase platelets in thrombocytopenic patients with chronic immune
thrombocytopenic purpura (ITP). Eltrombopag is administered orally, is well-tolerated, and
is FDA approved for the treatment of thrombocytopenia in patients with chronic ITP who
failed to respond to standard treatment.

Because the management of MDS patients with persistent cytopenias remains unsatisfactory and
novel therapeutic approaches are needed, we propose a non-randomized, pilot, phase II study
of eltrombopag in low to Int-2 risk MDS subjects with thrombocytopenia and anemia cytopenias
who are either untreated or cytopenias that persist despite treatment with standard
therapies to assess its utility in these settings.

Subjects will initiate study medication at an oral dose of 50 mg/day (25 mg/day for East
Asians), which will be adjusted as clinically indicated to the lowest dose that maintains a
stable platelet count greater than or equal to 20,000/microL above baseline while maximizing
tolerability. Treatment response will be any increase in a cytopenia, in the lineage that
fulfilled eligibility criteria for enrollment and will be defined as: (a) platelet count
increases to 20,000/microL above baseline at 16 weeks , or stable platelet counts with
transfusion independence for a minimum of 8 weeks in subjects who were previously
transfusion dependent; (b) erythroid response for subjects with a pretreatment hemoglobin of
less than 9 g/dL will be defined as an increase in hemoglobin by greater than or equal to
1.5g/dL without packed red blood cell (PRBC) transfusion support, or a reduction in the
units of transfusions by an absolute number of at least 4 PRBC transfusions for eight
consecutive weeks compared with the pretreatment transfusion number in the previous 8 weeks;
(c) neutrophil response will be defined in those with a pretreatment absolute neutrophil
count (ANC) of < 0.5 times 10(9)/L as at least a 100% increase or an absolute increase >
0.5 times 10(9)/L. Subjects meeting a response may remain on the extended access until they
meet an off study criteria or the study is closed.

Subjects with response at 16 weeks may be consented for entry into the extended access part
of the trial. In the event that a subject is transfused platelets for a count >
10,000/microL without a medical indication during the study period, the subject may continue
on study drug and the response assessment may be extended for an additional 4 weeks at the
discretion of the principal investigator.

Primary objective is to assess the efficacy of eltrombopag in patients with low to Int-2
risk MDS. Safety of eltrombopag in this subject population will be assessed concurrently.

Secondary objectives include the toxicity profile of extended treatment with eltrombopag
(treatment longer than 4 months), reduction in incidence and severity of bleeding episodes,
and response following extended access to study drug (treatment longer than 4 months).

The primary endpoint will be the portion of drug responders as defined by changes in the
platelet count and/or platelet transfusion requirements, or the proportion of subjects who
meet erythroid response, or neutrophil response criteria.. Platelet response is defined as
platelet count increases to 20,000/microL above baseline at 16 weeks, or stable platelet
counts with transfusion independence for a minimum of 8 weeks. Erythroid response for
subjects with a pretreatment hemoglobin of less than 9 g/dL will be defined as an increase
in hemoglobin by greater than or equal to 1.5g/dL without packed red blood cell (PRBC)
transfusion support, or a reduction in the units of transfusions by an absolute number of at
least 4 PRBC transfusions for eight consecutive weeks compared with the pretreatment
transfusion number in the previous 8 weeks. Neutrophil response will be defined in those
with a pretreatment absolute neutrophil count (ANC) of < 0.5 times 10(9)/L as at least a
100% increase or an absolute increase > 0.5 times 10(9)/L. Subjects with an erythroid,
and/or neutrophil response at 16 weeks may continue study medication (extended access) until
they meet an off study criteria. Subjects with erythroid, or neutrophil response at 16
weeks may continue study medication for an additional 4 weeks (to ensure eligibility) prior
to being consented for entry into the extended access part of the trial. Patients may
remain on the extended access until they met an off study criteria.

The toxicity profile will be measured using the CTCAE Version 4.0 criteria.

Secondary endpoints will include incidence of grade 2 or higher bleeding events as measured
by CTCAE v. 4.0; changes in serum thrombopoietin level, measured at 4 months; and
progression to higher risk MDS as measured by IWG criteria.