Lenalidomide and Eltrombopag Olamine in Treating Patients With Symptomatic Anemia in Low or Intermediate Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. To evaluate the rate of hematologic improvement of the eltrombopag (eltrombopag
olamine)/lenalidomide combination (as per Modified International Working Group [IWG]
criteria).

II. To evaluate the safety and tolerability of the combination.

SECONDARY OBJECTIVES:

I. To compare the time to hematologic improvement. II. To evaluate the duration of
hematologic improvement III. To evaluate the effect of combination treatment on platelet
counts, platelet transfusions and bleeding events.

IV. To evaluate the frequency of bone marrow response (complete response [CR] + partial
response [PR]) and cytogenetic response.

V. To evaluate the relationship between mutations in bone marrow stem cells and response.

VI. To evaluate the relationship between various stem and progenitor alterations and
response.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM A: Patients with platelet counts >= 50,000 receive lenalidomide orally (PO) daily or
every other day (QOD) on days 1-21. If platelet counts fall below 50,000, patients
discontinue lenalidomide and receive eltrombopag olamine PO daily or QOD until platelet
count is maintained above 50,000 for 2 weeks. Patients then resume lenalidomide PO daily or
QOD. If platelets fall below 50,000 again, patients receive eltrombopag olamine as before.
When platelet counts are maintained above 50,000 for 2 weeks, patients resume lenalidomide
concurrently with eltrombopag for all subsequent courses.

ARM B: Patients with platelet counts < 50,000 receive eltrombopag olamine PO daily or QOD on
days 1-28 until platelet counts is maintained above 50,000 for 2 weeks. Patients then
receive treatment as in Arm A.

In both arms, treatment repeats every 28 days for 4 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then every 12 months for 5 years.

Inclusion Criteria:

- Patient must have a documented diagnosis of myelodysplastic syndrome (MDS) of at
least three months duration (MDS duration >= 3 months) according to World Health
Organization (WHO) criteria or non-proliferative chronic myelomonocytic leukemia
(CMML) (white blood cells [WBC] =< 12,000/L)

- Patients must have International Prognostic Scoring System (IPSS) categories of low-
or intermediate-1-risk disease

- Patients must have symptomatic anemia untransfused with hemoglobin =< 9.5 g/dL within
8 weeks of registration or with red blood cell (RBC) transfusion-dependence (i.e., >=
2 units/month) confirmed for a minimum of 8 weeks before randomization

- Patients must have IPSS score determined by cytogenetic analysis prior to
randomization; patients with cytogenetic failure and =< 10% marrow blasts will be
eligible

- Patients must be off all disease modifying therapy for MDS for 28 days prior to
initiation of study treatment; patients may receive hydrocortisone prophylactically
to prevent transfusion reactions

- Patients must not have documented iron deficiency; all patients must have documented
marrow iron stores; if marrow iron stain is not available, the transferrin saturation
must be >= 20% or a serum ferritin >= 100 ng/100 mL or soluble transferring receptor
< 5 mg/L.

- Women must not be pregnant or breastfeeding; females of childbearing potential should
have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL); the first test
should be performed within 10-14 days, and the second test within 24 hours prior to
prescribing lenalidomide

- Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS® program; able to take aspirin (81 or 325 mg) daily as
prophylactic anticoagulation (patients intolerant to acetylsalicylic acid [ASA] may
use warfarin or low molecular weight heparin)

- Women of childbearing potential and sexually active males must agree to use 2 methods
of an accepted and effective method of contraception and counseled on the potential
teratogenic effects of lenalidomide; effective contraception must be used by patients
for at least 4 weeks before beginning lenalidomide therapy, during lenalidomide
therapy, during dose interruptions and for 4 weeks following discontinuation of
lenalidomide therapy; reliable contraception is indicated even where there has been a
history of infertility, unless due to hysterectomy or because the patient has been
postmenopausal naturally for at least 24 consecutive months; two reliable forms of
contraception must be used simultaneously unless continuous abstinence from
heterosexual sexual contact is the chosen method; females of childbearing potential
should be referred to a qualified provider of contraceptive methods, if needed;
sexually mature females who have not undergone a hysterectomy or who have not been
postmenopausal naturally for at least 24 consecutive months (i.e., who have had
menses at some time in the preceding 24 consecutive months) are considered to be
females of childbearing potential; it is not known whether CC-5013 (lenalidomide) is
present in the semen of patients receiving the drug; therefore, males receiving
CC-5013 (lenalidomide) must always use a latex condom during any sexual contact with
females of childbearing potential even if they have undergone a successful vasectomy

- Patients must not have received prior therapy with lenalidomide (for more than 2
months) nor eltrombopag

- Patients must not have uncontrolled hypertension

- Patients must have absolute neutrophil count (ANC) >= 500 cells/L (0.5 x 10^9/L)

- Eastern Cooperative Oncology Group (ECOG) performance 0-3

- Subject is able to understand and comply with protocol requirements and instructions

- Patient has signed and dated informed consent

- Prothrombin time (PT/international normalized ratio [INR]) and activated partial
thromboplastin time (aPTT) must be within 80 to 120% of the normal range at baseline

Exclusion Criteria:

- Pre-existing cardiovascular disease (including congestive heart failure, New York
Heart Association [NYHA] grade III/IV), or arrhythmia known to increase the risk of
thromboembolic events (e.g. atrial fibrillation), or subjects with a corrected QT
interval (QTc) > 450 msec

- Patients determined to be at increased risk of arterial or venous thrombosis by the
investigator

- Bone marrow fibrosis that leads to a dry tap

- Female subjects who are nursing or pregnant (positive serum or urine beta-human
chorionic gonadotropin (beta-hCG) pregnancy test) at screening or pre-dose on day 1

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

- Patients with documented liver cirrhosis

- Patients with splenomegaly with a spleen size > 16 cm