Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of clofarabine, and the dose-limiting toxicities
of the combination of clofarabine and cytarabine with G-CSF priming, in the treatment of
patients with relapsed or refractory AML.

SECONDARY OBJECTIVES:

I. To determine the hematological and non-hematological side effect profile of the
combination of clofarabine, cytarabine, and G-CSF.

II. To determine the efficacy of clofarabine in combination with cytarabine and G-CSF priming
in the treatment of patients with relapsed or refractory AML.

III. To determine the disease-free and overall survival after therapy with clofarabine,
cytarabine, and G-CSF for relapsed or refractory AML.

OUTLINE: This is a dose escalation study of clofarabine.

PART I:

INDUCTION THERAPY: Patients receive clofarabine IV over 1 hour and cytarabine IV over 2 hours
on days 1-5, and filgrastim (G-CSF) subcutaneously once daily beginning 24 hours prior to
chemotherapy and continuing until blood count recover. Patients with residual leukemia (>= 5%
blasts by morphology) at day 14 and if blast remain > 5% by day 21 receive a second course of
induction therapy.

CONSOLIDATION THERAPY: Patients receive clofarabine, cytarabine, and G-CSF as in induction
therapy. Patients may receive a second course of consolidation therapy depending on response
and whether additional therapy (e.g., stem cell transplant or donor lymphocyte infusion) is
planned.

PARTS II and III:

Patients receive induction therapy and consolidation therapy as in part 1.

After completion of study treatment, patients are followed every 3 months for 2 years and
then annually for 3 years.

Inclusion Criteria:

- ECOG performance status 0-2

- Capable of understanding the investigational nature, potential risks and benefits of
the study, and able to provide valid informed consent

- Female patients of childbearing potential must have a negative serum pregnancy test
within 2 weeks prior to enrollment

- Male and female patients must be willing to use an effective contraceptive method
during the study and for a minimum of 6 months after study treatment

- Serum Total or Direct bilirubin =< 1.5 times upper limit of normal (ULN)

- Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 times ULN

- Diagnosis of acute myeloid leukemia by WHO criteria, either relapsed or refractory;
acute promyelocytic leukemia [acute promyelocytic leukemia with t(15;17)(q22;q12) and
variants] would be eligible only after failure of a regimen containing arsenic
trioxide

- 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 m^2

- Alkaline phosphatase =< 2.5 times ULN

Exclusion Criteria:

- Use of investigational agents within 30 days or initiation of any other anticancer
therapy within 2 weeks before study entry with the exception of hydroxyurea, and
intrathecal therapy for leukemic meningitis

- 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)

- Pregnant or lactating patients

- Any significant concurrent disease, illness, or psychiatric disorder that would
compromise patient safety or compliance, interfere with consent, study participation,
follow up, or interpretation of study results

- Have any other severe concurrent disease, history of serious organ dysfunction, or
disease involving the heart, kidney, liver (including symptomatic hepatitis,
veno-occlusive disease, or hepatic graft-versus-host disease [for acute >= grade 2]),
or other organ system dysfunction

- No concomitant cytotoxic therapy or investigational therapy is allowed during the
study with the exception of intrathecal therapy for leukemic meningitis; intrathecal
therapy must not be given during or within 24 hours of any 5 day
Clofarabine/Cytarabine treatment period

- To the extent possible, use of nephrotoxic (e.g., vancomycin, amphotericin B, etc) and
hepatotoxic (e.g., voriconazole, cyclosporine, etc) agents is to be avoided during
clofarabine; use of alternative medications (e.g., herbal or botanical for anticancer
purposes) is not permitted during the entire study period

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

- More than two failed induction attempts for initial diagnosis or current relapse; for
patients enrolled under part III of the protocol, patients must be at first salvage
after relapse less than one year from complete remission, or salvage after initial
induction chemotherapy

- Allogeneic transplant recipients on immunosuppression or on treatment for GVHD