Trial of Eltrombopag During Consolidation Therapy in Adults With AML in Complete Remission

Consolidation chemotherapy with high dose cytarabine usually causes myelosuppression for 14
to 21 days after each treatment. Patients have low blood counts for days or weeks before the
bone marrow resumes function. This may result in e.g., hospitalization, treatment with
antibiotics, and transfusions with blood and/or platelets. In addition, this may cause a
delay in treatment and reduction in dose. To achieve the best outcome from treatment, dose
reductions and delays in treatment must be avoided.

The incidence and duration of decreased white blood cells (neutropenia) and neutropenic
complications have been reduced by the use of growth colony stimulating factors.
Additionally, the use of erythropoietin-stimulating factors has reduced anemia and the need
for red blood cell transfusions. Thrombocytopenia remains an important limiting factor in
administration of chemotherapy and maintaining dose intensity in some patients.
Additionally, the risk of bleeding secondary to low platelet counts may increase sickness or
even death in patients undergoing cancer treatment.

Thrombopoietin (TPO) is the principal cytokine involved in the regulation of
megakaryopoiesis and platelet production. Eltrombopag is an orally bioavailable, small
molecule, TPO-receptor agonist that stimulates platelet production by a similar, but not
identical, mechanism to endogenous TPO. Eltrombopag has been approved in the U.S. for the
treatment of chronic Idiopathic Thrombocytopenic Purpura. Eltrombopag is also under
development for other indications such as Hepatitis C Virus-associated thrombocytopenia,
Myelodysplastic Syndrome/AML, and oncology related thrombocytopenias. This agent appears to
possess many of the desirable properties for a treatment for chemotherapy induced
thrombocytopenia, including oral administration.

The Phase I portion of this study will be conducted using a dose escalation/de-escalation
strategy for patients in either the first or second complete remission. Dose escalations are
planned in the form of both acceleration of date of initiation of eltrombopag relative to
the start of consolidation chemotherapy as well as increasing daily dosing.

The Phase II portion will be conducted using the dose and schedule selected from the Phase I
portion of the study for those patients in first complete remission. Patients will be used
as their own controls, e.g., a two-period two-treatment cross-over design. Patients will be
randomly allocated 1:1 to one of two sequences. Patients randomized to Sequence A will
receive eltrombopag with their first cycle of consolidation and placebo with Cycle 2.
Patients randomized to Sequence B will receive placebo with their first cycle of
consolidation and eltrombopag with Cycle 2. The treatment assignment will be blinded to the
patient and all study/sponsor personnel.

Patients will undergo blood sample collection for Thrombopoietin(TPO)/ Erythropoietin(EPO)
and pharmacokinetic analysis of eltrombopag in Phase I and pharmacokinetic analysis of
eltrombopag in the Phase II portion of the study.

Inclusion Criteria:

• Cytomorphologically documented diagnosis of acute myeloid leukemia (AML). Acute
promyelocytic leukemia patients will be excluded (FAB M3). FAB classification,
cytogenetics and molecular markers (if applicable) must be available at registration.

Phase I Enrollment:

- Must be in first or second complete remission, e.g., no evidence of active disease in
blood, bone marrow (<5% blasts), or other tissues.

- For each remission, may have received no more than 2 cycles of induction treatment
(any type).

- May have received no more than one course of consolidation for the current remission
prior to enrollment (any type)

Phase II Enrollment:

- Must be in first complete remission, e.g., no evidence of active disease in blood,
bone marrow (<5% blasts), or other tissues.

- May have received no more than 2 cycles of induction treatment (any type).

Enrollment in Either Phase:

- Remission status must be documented by a bone marrow examination up to 28 days prior
to study registration.

- Have recovered from induction and first consolidation (if applicable) therapy side
effects (or ≤grade 1).

- ≥18 years of age and ≤70 years of age.

- ECOG performance status 0, 1, 2.

- Have not received cytotoxic drug therapy within 21 days of registration.

- Have not received hematopoietic colony stimulating growth factors within 14 days of
registration.

- Have not received packed red blood cells or platelets within 7 days of registration.

- Have not received investigational agents within 30 days of registration and will not
receive any investigational agents other than eltrombopag/placebo during study.

- Signed IRB-approved informed consent.

- Willing to provide blood samples for research purposes.

- Adequate organ function obtained within 28 days prior to registration:

- Absolute neutrophil count >1 x 10⁹/L

- Platelet count >100 x 10⁹/L

- Total direct serum bilirubin ≤1.5x upper limit of normal (ULN)

- ALT and AST ≤3x ULN

- BUN and serum creatinine <2x ULN

- Albumin ≥2.5 g/dL

- PT and PTT 80-120% of institutional normal range

- Women of childbearing potential must have a negative serum pregnancy test within 14
days of registration.

- Not pregnant nor breast feeding.

- Women of childbearing potential and sexually active males must use an accepted and
effective method of contraception.

- Patients of known East Asian ancestry (Chinese, Japanese, Taiwanese, and Korean) are
excluded from protocol participation for safety and efficacy reasons.

- Able to swallow and retain orally administered medication.

- No clinically significant gastrointestinal abnormalities such as malabsorption
syndrome or major resection of the stomach or bowels.

- No clinical evidence of hepatomegaly or splenomegaly.

- No known risk for Torsades de Pointes. (Eltrombopag use has not been shown to be
associated with Torsades de Pointes.)

- No active or unresolved infection and must be off all antibiotics for at least 7 days
prior to registration.

- No current evidence of invasive fungal infection.

- No known Hepatitis B, Hepatitis C active disease.

- No known Human Immunodeficiency Virus (HIV) seropositivity. The risk for potential
toxicities secondary to HIV (e.g., increased risk for fatal opportunistic infection)
may confound the toxicity profile of eltrombopag.

- Patients with a history of Central Nervous System (CNS) leukemia are eligible if
there is documentation of no current CNS involvement on cerebrospinal fluid (CSF)
examination (e.g., negative CSF by lumbar puncture) within 28 days of registration.

- No prior or concomitant malignancy in the past 5 years which is currently active and
likely to interfere with the patient's treatment for AML or which is likely to
increase the patient's morbidity or mortality. No prior chemotherapy or radiation
therapy allowed (unless related to AML treatment).

- No concurrent organ damage or medical problems that would prohibit therapy.