Clofarabine Followed By Lenalidomide for High-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia

High risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute
myelogenous leukemia (AML) are hetereogeneous myeloid malignancies that are associated with a
poor prognosis. Due to advanced age and medical comorbidities, the majority of MDS, CMML, and
AML patients are not candidates for potentially curative standard treatments such as
allogeneic stem cell transplantation (SCT) or intensive chemotherapy (ICT). New therapeutic
approaches that improve response rates, have lesser toxicity, and extend survival are clearly
needed for high risk MDS and AML patients.

Clofarabine is a myelosuppressive, second generation purine nucleoside analogue which has
shown meaningful efficacy at variable dosing levels for high risk MDS and AML patients with a
favorable toxicity profile compared to intensive chemotherapy. Lenalidomide is an oral
structural analogue of thalidomide with a complex mechanism of action including
immunomodulatory, anti-angiogenic, and direct cytotoxic effects which is a well-established
treatment for MDS and has shown agent single efficacy at higher doses for AML. Lenalidomide s
therapeutic benefit in AML has been the greatest in patients with low presenting total
leukocyte and circulating blast counts. We hypothesize that the initial cytoreductive effects
of clofarabine may augment the effectiveness of subsequent lenalidomide therapy and create a
favorable immunologic milieu for patients eligible for lenalidomide maintenance therapy. This
open-label, single institution phase I trial will evaluate a sequential combination of IV
clofarabine with oral lenalidomide for the treatment of high risk MDS, CMML, and AML.
Subjects will receive a single course of IV clofarabine (5 milligrams per metered square per
day times 5) for cytoreduction. This will be followed by oral lenalidomide consolidation with
dose escalation from 25 mg daily for 21/28 days for 1 cycle in the first cohort up to 50 mg
daily for 28/28 days for 2 cycles in the fourth cohort. In the absence of dose limiting
toxicity or disease progression, Subjects will receive lenalidomide maintenance, starting at
a dose of 10 mg daily in 28 day cycles, with dose adjustments, for up to 12 cycles.

The overall objective is to determine the safety of sequential therapy with clofarabine and
lenalidomide in subjects with high risk MDS, CMML, and AML. The primary study endpoint will
be the toxicity profile of this novel treatment combination in each cohort. Secondary
endpoints will include characterization of response and duration, overall survival, and the
feasibility of maintenance lenalidomide therapy for responding subjects.

- INCLUSION CRITERIA:

- Age greater than or equal to 18 years old

- Unequivocal diagnosis of MDS (including chronic myelomonocytic leukemia- CMML)
according to WHO criteria with IPSS risk categorization for MDS subjects of
intermediate-2 to high confirmed by bone marrow evaluation within 30 days prior to
study enrollment

OR

Unequivocal diagnosis of AML according to WHO criteria to include secondary and relapsed or
refractory disease confirmed by bone marrow evaluation within 30 days prior to study
enrollment

- ECOG Performance Status less than or equal to 2

- Must have failed at least one prior therapy before study enrollment

- Ability to comprehend the investigational nature of the study and provide informed
consent

- All study participants must be registered into the mandatory RevAssistRevlimid REMS
program, and be willing and able to comply with the requirements of RevAssistRevlimid
REMS .

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 50 mIU/mL within 10 14 days and again within 24
hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled
within 7 days as required by RevAssistRevlimid REMS ) and 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 she starts taking lenalidomide. FCBP must also
agree to ongoing pregnancy testing. Females of reproductive potential must adhere to
the scheduled pregnancy testing as required in the Revlimid REMSTM program. Men must
agree to use a latex condom during sexual contact with a FCBP even if they have had a
successful vasectomy.

EXCLUSION CRITERIA:

- Prior Allogeneic Stem Cell Transplant

- Diagnosis of acute promyelocytic leukemia

- Diagnosis of atypical chronic myeloid leukemia BCR-ABL1 negative, juvenile
myelomonocytic leukemia, yelodysplastic/myeloproliferative neoplasm unclassifiable)

- Prior therapy with clofarabine at any dose

- Prior therapy with lenalidomide at doses greater than or equal to 25 milligrams daily

- Clinically significant active infection not responding adequately to therapy

- HIV Positive

- Uncontrolled concurrent hepatic, renal, cardiac, pulmonary, neurologic, infectious, or
metabolic disease of such severity, which in the opinion of the PI, would preclude the
subjects s ability to tolerate protocol therapy

- Ejection fraction less than 40% by Echocardiogram or MUGA

- Calculated creatinine clearance less 60 milliliters per minute

- Serum bilirubin greater than 1.5 times upper limit of normal

- Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) greater than 3
times upper limit normal

- Decreased oxygen saturation at rest (e.g. pulse oximeter less than 88% or PaO2 less
than or equal to 55 millimeters of mercury)

- Patients with any condition that prevents their ability to swallow and retain
lenalidomide tablets

- Severe psychiatric illness or complex social situations that would limit the patient s
ability to tolerate and/or comply with study requirements

- Current pregnancy or breastfeeding