Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia

PRIMARY OBJECTIVES:

I. To compare the rate of major erythroid response (MER) between lenalidomide monotherapy and
combined treatment of lenalidomide and epoetin alfa in erythropoietin non-responsive
low-/intermediate-1 (Int-1)-risk myelodysplastic syndrome (MDS) patients or erythropoietin
treatment naïve patients with low probability of erythropoietin benefit.

SECONDARY OBJECTIVES:

I. To compare the time to MER by treatment assignment. II. To evaluate the duration of MER by
treatment assignment. III. To estimate the frequency of MER to salvage combination therapy in
patients who fail to experience a MER with lenalidomide monotherapy.

IV. To evaluate and compare the frequency of minor erythroid response by treatment
assignment.

V. To investigate the mechanism and target of lenalidomide action in patients with chromosome
5q31.1 deletion.

VI. To evaluate the frequency of cytogenetic response and progression, and the relationship
between cytogenetic pattern and erythroid response.

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

VIII. To evaluate the relationship between erythroid response and laboratory correlates
outlined below: pretreatment and on study endogenous erythropoietin level (Arm A); to
evaluate the effect of CD45 isoform profile on lenalidomide enhancement of
erythropoietin-induced STAT5 phosphorylation in CD71^Hi erythroid precursors and the
relationship to erythroid response; to characterize molecular targets relevant to
lenalidomide cytotoxicity in del5q31.1 cells; to evaluate the frequency of cryptic chromosome
5q31.1 deletions in patients with non-del5q31.1 MDS by array-based genomic scan, and to
determine the relationship to hematologic response.

OUTLINE: Patients are randomized to 1 of 2 treatment arms. Patients with del 5q31.1 karyotype
are assigned to Arm A.

ARM A: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21.

ARM B: Patients receive lenalidomide PO QD on days 1-21 and epoetin alfa subcutaneously (SC)
once weekly.

In both arms, treatment repeats every 28 days for 4 courses. Patients who achieve a major
erythroid response (MER) may continue treatment beyond 4 courses in the absence of disease
progression, disease conversion to acute myeloid leukemia, or unacceptable toxicity. Patients
in Arm A who fail to achieve MER or who achieve MER but relapse after 16 weeks of treatment
with lenalidomide may crossover and receive treatment in Arm B.

After completion of study treatment, patients are followed up for 6 months.

Inclusion Criteria:

- NOTE: Results of the bone marrow biopsy and aspirate as well as cytogenetics are
mandatory to register subjects onto study, which are indispensable to determine
International Prognostic Scoring System (IPSS) category needed for eligibility; please
note that it is not necessary to wait for the week 16, week 32, or week bone marrow
and cytogenetic results prior to starting the next cycle unless deemed necessary by
the treating physician; one example of this exception can include if the subject shows
signs of progression, such as increased peripheral blood blast percentage; at that
juncture, the treating physician may prefer to await the results prior to starting a
new cycle; if a cycle is started, and based on the bone marrow results it is felt by
the treating physician that the subject should not continue on treatment, please be
sure to note this information on the case report forms at end of treatment

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

- Patient must have IPSS categories of low- or intermediate-1-risk disease; patients
must have IPSS score determined by cytogenetic analysis prior to randomization;
patients must have cytogenetic analysis done (to calculate IPSS); if the current bone
marrow biopsy is a dry tap, patients with cytogenetic failure and < 10% marrow blasts
will be eligible; subjects with cytogenetic failure must have previous cytogenetic
results (fluorescence in situ hybridization [FISH] is not a substitute) within the
last 6 months post last type of MDS treatment (in this case, not referring to growth
factors as type of MDS treatment)

- Must have symptomatic anemia untransfused with hemoglobin < 9.5 g/dL =< 8 weeks prior
to randomization or with red blood cells (RBC) transfusion dependence (i.e., >= 2
units/month) confirmed for =< 8 weeks before randomization

- NOTE: For non-transfusion dependent patients (i.e., receiving < 2 units/4 weeks x
8 weeks pre-study) who receive periodic transfusions, the mean 8 week
pre-transfusion hemoglobin should be used to determine protocol eligibility and
response reference

- For non-transfusion dependent patients, a minimum of 2 pre-transfusion or
un-transfused hemoglobin values are required

- Applies only for patients without the deletion 5q 31.1; patients must have failed
treatment with an erythropoietic growth factor, or have a low probability of response
to rhu-erythropoietin; patients with low probability of response to rhu-erythropoietin
or prior erythropoietin failures are defined as follows:

- Prior erythropoietin failure-requires a minimum trial of >= 40,000 units epoetin
alfa/week x 8 weeks or equivalent dose of darbepoetin alfa for 8 weeks with
failure to achieve transfusion independence in dependent patients or a failure to
achieve a >= 2 g rise in hemoglobin sustained for >= 4 weeks in non-transfusion
dependent patients

- Low erythropoietin response profile-rhu-erythropoietin and epoetin alfa-naïve
patients receiving >= 2U packed (p)RBC/month for a minimum of 8 weeks, and serum
erythropoietin > 500 mU/mL in the 8 weeks prior to randomization for a hemoglobin
< 9.5 g/dL

- Patients must be off all non-transfusion therapy for MDS for 28 days prior to
initiation of study treatment, including all types of growth factors; patients may
receive hydrocortisone prophylactically to prevent transfusion reactions

- Patients must have a serum erythropoietin level documented before randomization and =<
56 days before day 1 of study treatment; NOTE: hemoglobin must be < 9.5 g/dL at time
that serum erythropoietin is drawn

- 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/mL

- Women must not be pregnant or breastfeeding; females of childbearing potential must
have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL
within 10-14 days and again within 24 hours prior to starting cycle 1 of lenalidomide;
a female of childbearing potential (FCBP) is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months; FCBP must also agree to ongoing
pregnancy testing)

- Effective contraception must be used by patients participating in lenalidomide
therapy, and all patients must agree to counseling by a trained counselor every 28
days about pregnancy precautions and risks of fetal exposure; females of childbearing
potential (FCBP) must either commit to continued abstinence from heterosexual
intercourse or begin TWO acceptable methods of birth control: one highly effective
method and one additional effective method AT THE SAME TIME, at least 28 days before
starting lenalidomide, during lenalidomide therapy, during dose interruptions, and for
at least 28 days following discontinuation of lenalidomide therapy; females of
childbearing potential should be referred to a qualified provider of contraceptive
methods, if needed; males receiving lenalidomide must agree to 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 prior therapy with lenalidomide

- Patients must not have a diagnosis of uncontrolled seizure or uncontrolled
hypertension

- Patients must not have proliferative (WBC >= 12,000/mcL) chronic myelomonocytic
leukemia (CMML); WBC must be < 12,000/mcL

- Patients must not have MDS secondary to treatment with radiotherapy, chemotherapy,
and/or immunotherapy for malignant or autoimmune diseases

- Within 56 days prior to randomization: Platelet count >= 50,000/mcL (50 x 10^9/L)
without platelet transfusion

- Within 56 days prior to randomization: Absolute neutrophil count (ANC) >= 500
cells/mcL (0.5 x 10^9/L); hence ANC must be >= 500/mcL without myeloid growth factor
support

- Within 56 days prior to randomization: Serum creatinine =< 1.5 times upper limit of
normal (ULN)

- Within 56 days prior to randomization: Serum glutamic oxaloacetic transaminase
(SGOT)/aspartate aminotransferase (AST) or serum glutamate pyruvate transaminase
(SGPT)/alanine aminotransferase (ALT) =< 2.0 x ULN

- Within 56 days prior to randomization: Serum total bilirubin < 3.0 mg/dL

- Prior thalidomide is allowed, however, patients must not have prior >= grade-3
allergic reactions to thalidomide

- Patients must not have prior history of desquamating rash from thalidomide at time of
study entry

- Patients must not have clinically significant anemia resulting from iron, B12 or
folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding

- Patients must not have used cytotoxic chemotherapeutic agents or experimental agents
(agents that are not commercially available) for the treatment of MDS within 8 weeks
of randomization

- Patients must not have prior history of malignancy other than MDS (except basal cell
or squamous skin cell carcinoma or carcinoma in situ of the cervix or breast) unless
the subject has been confirmed free of disease for >= 3 years

- Patients must not have any serious medical condition or any other unstable medical
co-morbidity, or psychiatric illness that will prevent the subject from signing the
informed consent form or will place the subject at unacceptable risk if he/she
participates in the study

- Patients must not have a history of thrombo-embolic events within 3 years prior to
study randomization

- Patients must not have known human immunodeficiency virus (HIV)-1 seropositivity

- Patients must not have a known allergic reaction to epoetin alfa (Procrit) or human
serum albumin

- Eligibility for crossover registration from Arm A (lenalidomide alone) to Arm B
(lenalidomide and epoetin alfa):

- Patients must have completed 16 weeks of monotherapy with lenalidomide

- Patients must show failure to achieve MER (major erythroid response) or have achieved
MER but relapsed on Arm A

- Patients must not have a limiting unresolved grade 3 or greater toxicity from
lenalidomide monotherapy or drug intolerance preventing continuation of lenalidomide
treatment