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A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Eltrombopag in Myelodysplastic Syndrome (MDS) Patients With Thrombocytopenia Who Progressed or Are Resistant to Hypomethylating Agents

Phase 1/Phase 2
18 Years
Open (Enrolling)
Myelodysplastic Syndrome (MDS), Thrombocytopenia

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Trial Information

A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Eltrombopag in Myelodysplastic Syndrome (MDS) Patients With Thrombocytopenia Who Progressed or Are Resistant to Hypomethylating Agents

Study drug will be administered on an outpatient basis. The study is divided into two parts:
in Stage 1 the best dose of eltrombopag will be found to take forward to Stage 2. In Stage 1
of the study, small groups of participants will be enrolled in steps. The first group will
be given a dose of 50 mg per day of study drug for 8 weeks. If these participants have few
or manageable side effects, the next group of participants enrolled will receive a higher
dose of study drug (100 mg per day for 8 weeks). This increase in doses with groups of
participants will continue until the study doctor finds the highest dose of study drug that
can be given without causing severe or unmanageable side effects up to a 300 mg daily dose.
Stage 2 will include 15 participants at the best dose based on the Stage 1 part of the
study. The participant's dose may be adjusted to a lower or higher dose based upon their
platelet count, which will be determined by the study doctor. Eltrombopag will be supplied
by a company called GlaxoSmithKline as white to off-white, round film coated tablets
containing eltrombopag equivalent to 12.5mg, 25mg, 50 mg, 75 mg and 100 mg of eltrombopag.

Inclusion Criteria:

- Confirmed diagnosis of MDS using the World Health Organization (WHO) classification
or a diagnosis of WHO Myelodysplastic/ Myeloproliferative Neoplasm (MDS/MPN) or MDS
refractory anemia with excess blast in transformation (RAEB-t) by French American
British (FAB) classification (AML with 20-30% myeloblasts by WHO classification).

- All prognostic risk groups according to the International Prognostic Scoring System
(IPSS) and MD Anderson Risk Model

- At least one prior HMTA treatment with either azacitidine or decitabine and
subsequent loss of response to HMTA, progression while on HMTA, or no response to
HMTA, defined as failure to achieve at least HI after 4 cycles of treatment

- The mean of the two platelet counts taken within 1 month prior to dosing must be ≤50
x 10^9/L. Platelets counts must reflect pre-transfusion trough results or be obtained
no sooner than 1 week after platelet transfusion to assure stable baseline platelet
count. The platelet count obtained should be outside the expected nadir of prior

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >60%

- Adequate liver function, as evidenced by total serum bilirubin ≤ 1.5 times the upper
limit of normal (patients with Gilbert's disease are eligible, provided intermittent
indirect hyperbilirubinemia), aspartic transaminase (AST) or alanine transaminase
(ALT) ≤ 3 times the upper limit of normal (ULN).

- A serum creatinine concentration ≤ 2 x ULN

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately.

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- Clinically significant bleeding within 4 weeks of screening defined as any grade 3 or
grade 4 bleeding by WHO Bleeding Scale or any gastrointestinal (GI) bleeding or
intracranial hemorrhage

- Splenic enlargement extending >8 cm below the left costal margin

- Myelodysplastic syndrome with fibrosis (MF 3)

- Received Anti-Thymocyte Globulin (ATG) within 6 months of screening

- Received immunomodulating agents, histone deacetylase inhibitors, cyclosporine, or
mycophenolate within 4 weeks of screening

- History of treatment with eltrombopag, romiplostim or other thrombopoietin receptor
(TPO-R) agonists

- Concurrent use of granulocyte colony-stimulating factor (G-CSF) except for the
short-term management of neutropenic infection. Stable doses of erythropoietin
stimulating agents or corticosteroids that were being administered prior to screening
are allowed.

- Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
longer) preceding the first dose of study medication.

- Pregnant or breast feeding

- Current alcohol or drug abuse

- Known Hepatitis B or Hepatitis C infection or liver cirrhosis

- Uncontrolled current illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- At eltrombopag dose levels 200 mg and above cohorts, participants with a QT corrected
for heart rate (QTc) > 480 msec at screening, if other drugs known to cause prolonged
QT are stopped an EKG documenting QTc below 480 msec is required.

- History of metastatic malignancy in the preceding 2 years

- Known Human Immunodeficiency Virus (HIV) positive patients. These patients are
excluded because they may have morphologic dysplasia which mimics MDS but is not true
MDS Tand thrombocytopenia could be multifactorial secondary to HIV infection or to

- Receiving, or planning to receive, any of the medications listed in the Prohibited
Medications section during conduct of the study.

- East Asian patients (Chinese, Japanese, Taiwanese, and Korean ancestry) are excluded
during stage I of the study (dose escalation phase) due to the different
pharmacogenomics in this patient population.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Description:

Determine the maximum tolerated dose (MTD) of eltrombopag for the treatment of thrombocytopenia in participants with MDS who have either progressed or are resistant to Hypomethylating Agents (HMTA). The MTD is defined as the highest dose where less than 33% of participants experience a drug related predefined dose limited toxicity (DLT).

Outcome Time Frame:

24 months

Safety Issue:


Principal Investigator

Rami Komrokji, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

March 2011

Completion Date:

December 2013

Related Keywords:

  • Myelodysplastic Syndrome (MDS)
  • Thrombocytopenia
  • platelets
  • Myelodysplastic Syndromes
  • Preleukemia
  • Thrombocytopenia



H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612