Oral Clofarabine for Acute Myeloid Leukemia

The prognosis of acute myeloid leukemia (AML) in patients 60 and older is dismal with
traditional therapy. Several factors contribute to the poor prognosis of older individuals,
including the increased incidence of the multidrug resistance efflux pump, comorbidities and
unfavorable cytogenetics. The recently reported AML-13 and ALFA trials suggest that less
intense consolidation in this population is at least equivalent to more intense, induction
style efforts.

Clofarabine is a next generation nucleoside analogue that was designed to optimize the
favorable attributes of fludarabine and cladribine, while minimizing toxicity. The
intravenous formulation has shown considerable activity in older patients with AML who have
been considered either unfit for or unlikely to benefit from conventional therapy.
Additionally, clofarabine has an oral formulation that patients may find more acceptable for
consolidation therapy rather than multiple courses of intravenous medications, administered
over several days.

This study is designed as a traditional 3x3 phase I trial with the intention of defining the
maximum tolerated dose of oral clofarabine consolidation for older patients with AML in
remission.

Inclusion Criteria:

- Diagnosis of Acute Myeloid Leukemia according to WHO criteria

- Age ≥ 60 years at enrollment

- Patients must be in complete remission by bone marrow examination, within 30 days of
enrollment, following treatment with a cytotoxic induction chemotherapy regimen (such
as 7+3)

- Patients may have received "low-intensity" therapy (i.e. decitabine, lenalidomide,
etc) prior to traditional induction chemotherapy.

- Patients may have received 1 cycle of cytarabine-based consolidation therapy.

- Patients must have an ECOG performance status of 0-2 at the beginning of
consolidation therapy.

- Have adequate renal and hepatic functions as indicated by the following laboratory
values:

- Serum creatinine ≤ 1.0 mg/dL; if serum creatinine >1.0 mg/dL, then the estimated
glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2 as calculated by the
Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) =
186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female)
x (1.212 if patient is black)

- Serum total bilirubin ≤ 1.5 mg/dL × upper limit of normal (ULN) except for
unconjugated hyperbilirubinemia secondary Gilbert's syndrome

- Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2.5 × ULN

- Alkaline phosphatase ≤ 2.5 × ULN

- Capable of understanding the investigational nature, potential risks and benefits of
the study, and able to provide signed valid written informed consent or when
appropriate, have an appointed legally authorized representative who is capable of
understanding the investigational nature, potential risks and benefits of the study,
and able to provide signed valid written informed consent for the benefit of the
patient.

- Male and female patients who are of child bearing potential must use an effective
contraceptive method during the study and for a minimum of 6 months after study
treatment.

- Patients MAY have received prior therapy with purine analogs (such as fludarabine and
cladribine).

Exclusion Criteria:

- Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as
specified in the protocol.

- The diagnosis of AML-M3 (acute promyelocytic leukemia) characterized by
translocations involving the retinoic acid receptor-alpha (RAR-alpha) gene.

- Use of investigational agents within 2 weeks or any anticancer therapy within 2 weeks
before study entry. The patient must have recovered from all acute toxicities from
any previous therapy.

- Have any other severe concurrent disease, or have a history of serious organ
dysfunction or disease involving the heart, kidney, liver, or other organ system that
may place the patient at undue risk to undergo treatment.

- Patients with a systemic fungal, bacterial, viral, or other infection not controlled
(defined as exhibiting ongoing signs/symptoms related to the infection and without
improvement, despite appropriate antibiotics or other treatment).

- Have currently active gastrointestinal disease, or prior surgery that may affect the
ability of the patient to absorb oral clofarabine.