Eltrombopag Olamine in Improving Platelet Recovery in Older Patients With Acute Myeloid Leukemia Undergoing Chemotherapy

PRIMARY OBJECTIVES:

I.To determine whether eltrombopag leads to early platelet recovery in older AML patients (≥
60years) who attain morphologic remission on day 14 (range, day 14-17) bone marrow assessment
following remission induction chemotherapy (IC).

SECONDARY OBJECTIVES:

I. To determine the effect of eltrombopag on megakaryopoiesis - median time to reach platelet
count ≥50,000 /μL and ≥100,000 /μL, number of days of platelet transfusion, rates of platelet
transfusion-independence and the median time to reach platelet transfusion independence.

II. To determine the effect of eltrombopag on the rates of clinically significant bleeding
events (CSBE).

III. To determine the effect of eltrombopag on erythropoiesis the median time to red blood
cell transfusion independence.

IV. To determine the effect of eltrombopag on granulopoiesis- the time taken to reach an
absolute neutrophil count of ≥ 500 /μL. V. To determine the safety and tolerability of
eltrombopag in AML patients undergoing remission IC - incidence and severity of
eltrombopag-related adverse events. VI. To determine rates of complete remission (CR), rates
of partial complete remission (CRp), time to attain CR, and time to initiation of
postremission consolidation therapy.

OUTLINE:

Patients receive eltrombopag olamine orally (PO) once daily (QD) until platelet counts reach
≥50,000/uL or for 8 weeks, whichever comes earlier. Treatment continues in the absence of
unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years.

Inclusion Criteria:

- All categories of AML will be included except for acute promyelocytic leukemia (APL),
acute megakaryocytic leukemia, and acute leukemias of ambiguous lineage undergoing 7 +
3 remission IC with cytarabine and an anthracycline (daunorubicin or idarubicin). All
cases have to be histopathologically confirmed by a diagnostic bone marrow biopsy. Use
of granulocyte colony-stimulating factor (G-CSF) for any indication must have been
discontinued at least 7 days prior to entry into the study.

- Patients with secondary AML arising out of MDS (all subtypes under WHO
classification), chronic myelomonocytic leukemia (CMML); therapy-related AML and those
with a prior autologous hematopoietic cell transplantation are eligible.

- No morphological evidence of disease on day 14 bone marrow examination following IC

- Must be able to give voluntary informed written consent to participate in the study;
informed consent will be obtained prior to initiation of remission IC and before any
study-related procedure not part of normal medical care, with the understanding that
consent may be withdrawn by the subject at any time without prejudice to future
medical care

- Women of childbearing potential should be advised to avoid becoming pregnant and men
should be advised to not father a child while receiving treatment. All men and women
of childbearing potential must use acceptable methods of birth control throughout the
study as described below:

1. Females of childbearing potential: Recommendation is for 2 effective
contraceptive methods during the study. Adequate forms of contraception are
double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with
spermicidal jelly or foam), oral, depo provera, or injectable contraceptives,
intrauterine devices, and tubal ligation.

2. Male patients with female partners who are of childbearing potential:
Recommendation is for male and partner to use at least 2 effective contraceptive
methods, as described above, during the study or to abstain.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

Exclusion Criteria:

- Any serious medical condition, laboratory abnormality, or psychiatric illness that, in
the view of the treating physician, would place the participant at an unacceptable
risk if he or she were to participate in the study or would prevent that person from
giving informed consent

- Any active malignancy (unrelated, non-hematological malignancy) diagnosed within the
past 12 months of starting the study drug (other than curatively treated
carcinoma-in-situ of the cervix or non-melanoma skin cancer).

- Secondary AML arising out of myeloproliferative neoplasms [as per the revised 2008 WHO
classification of myeloid neoplasms and acute leukemias] and MDS/MPD neoplasms other
than CMML [as per the revised 2008 WHO classification of myeloid neoplasms and acute
leukemias]. Refractory Anemia with Ringed Sideroblasts with thrombocytosis (RARS-T)
classified as MDS/MPN neoplasm, unclassifiable will be excluded. AML patients with
presenting features suspicious of underlying unrecognized MPD such as marked
splenomegaly (> 20 cm) and thrombocytosis (>400,000 per microliter) will be excluded.
Patients with relapsed or refractory AML will be excluded.

- Radiation therapy, cytotoxic chemotherapy, and combined modality (both radiation and
chemotherapy) used to treat other cancers or medical conditions and administered
within 12 months prior to signing informed consent. Use of hydroxyurea or emergent
leukapheresis (for cytoreduction of highly elevated white blood cell counts) is
permissible. Those AML patients who initially receive treatment with all-trans
retinoic acid (ATRA) for presumptive diagnosis of APL but if APL is ruled out in final
pathology will be eligible for the study.

- Prior history of treatment with recombinant thrombopoietin (TPO) or TPO-receptor (R)
agonists

- History of arterial or venous thrombosis [excluding line-thrombosis] within the last 1
year, or those with known inherited coagulopathies. Arterial or venous thrombosis
includes pulmonary embolism, deep vein thrombosis of both upper [excluding
line-thrombosis] and lower extremities, coronary artery disease managed medically or
requiring intervention (percutaneous stent placement or coronary bypass surgery),
cerebrovascular accident (for transient ischemic attacks clinical documentation is
required), or involvement of other organs (such as hepatic, renal, spleen or other
sites).

- Evidence of fibrosis on bone marrow examination at the time of diagnosis

- Active participation in any other investigational treatment study

- Uncontrolled intercurrent illness including, but not limited to uncontrolled
infection, symptomatic congestive heart failure, cardiac arrhythmia, unstable angina
or renal insufficiency (acute or chronic) on hemodialysis

- Liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT])
can not be greater than or equal to 2.5 times the upper limits of normal (ULN)

- Total bilirubin ≥ 1.5 x ULN within 14 days of enrollment.

- Serum creatinine should be ≥ 2.5 x ULN within 14 days of enrollment

- A known immediate or delayed hypersensitivity reaction or idiosyncrasy that, in the
opinion of the Medical Monitor is due to drugs chemically related to eltrombopag or
excipients (e.g. mannitol)

- Known history of human immunodeficiency virus (HIV) or active hepatitis B or C

- No major surgery within 2 weeks prior to trial enrollment

- Female subject is pregnant or breast-feeding

- Male and female patients who are fertile who do not agree to use an effective barrier
methods of birth control (i.e. abstinence) to avoid pregnancy while receiving study
treatment.