Clofarabine and Cytarabine in Treating Young Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

OBJECTIVES:

Primary

- To define the overall response rate (complete remission or remission without platelet
recovery) in young patients with relapsed or refractory acute myeloid leukemia (AML) or
acute lymphoblastic leukemia (ALL) treated with clofarabine in combination with
cytarabine.

Secondary

- To determine the safety profile and tolerability of clofarabine when given in
combination with cytarabine in patients with and without prior stem cell
transplantation.

- To identify apoptosis specific genes that are important in mediating response to
clofarabine and cytarabine.

- To quantitate the level of human equilibrative nucleoside transporter proteins (hENT1
and hENT2) and human concentrative nucleoside transporter proteins (hCNT2 and hCNT3) in
blasts of these patients.

- To determine gene expression profiles at study entry and at time of relapse in order to
isolate profiles that may predict response and also to complement apoptosis specific
protein arrays.

- To perform serial measurements of minimal residual disease (MRD) to provide an
objective determination of the effectiveness of this treatment regimen and to correlate
with post remission events (relapse, death).

- To perform FLT3/ITD analysis to help determine the prevalence and clinical significance
of this somatic mutation in patients with relapsed AML.

OUTLINE: This is a multicenter, phase I, dose-escalation study of clofarabine followed by a
phase II study. Patients are stratified according to disease (acute lymphoblastic leukemia
[ALL] vs acute myeloid leukemia [AML]). (Phase I closed to accrual as of 09/16/09)

- Intrathecal CNS prophylaxis (all patients with ALL and at physician's discretion for
patients with AML or acute leukemia of ambiguous lineage): Patients receive intrathecal
(IT) cytarabine on day 0 of the first course of induction therapy. Patients also
receive IT methotrexate on day 1 of the second course of induction therapy and on day 1
of all courses of maintenance therapy.

- Induction therapy:

- Course 1: Patients receive cytarabine IV over 2 hours and clofarabine IV over 2
hours on days 1-5. Patients with ≥ 5% blasts (i.e., M2 or M3 bone marrow) at days
14-21 proceed immediately to course 2 of induction therapy. Patients with < 5%
blasts (i.e., M1 bone marrow) may proceed to course 2 of induction therapy at
blood count recovery or at day 42.

- Course 2: Patients receive clofarabine IV over 2 hours followed by cytarabine IV
over 2 hours on days 1-5. After the second course of induction therapy, patients
with M2 or M3 bone marrow at days 14-21 are removed from the study. Patients with
M1 bone marrow proceed to maintenance therapy 14-42 days after the initiation of
course 2.

- Maintenance therapy: Patients receive clofarabine and cytarabine as in induction
therapy. Treatment repeats every 14-42 days for up to 10 courses in the absence of
disease progression or unacceptable toxicity.

Patients may undergo blood and bone marrow sample collection periodically for correlative
laboratory studies.

After completion of study therapy, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 87 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically confirmed diagnosis of 1 of the following:

- Acute myeloid leukemia (AML) with ≥ 5% blasts in the bone marrow (M2/M3 bone
marrow) with or without extramedullary disease

- Acute lymphoblastic leukemia (ALL) with > 25% blasts in the bone marrow (M3 bone
marrow) with or without extramedullary disease

- Acute leukemia of ambiguous lineage with ≥ 5% blasts in the bone marrow (M2/M3
bone marrow) with or without extramedullary disease

- Disease must have relapsed after or be refractory to prior induction therapy

- Patients with AML or acute leukemia of ambiguous lineage must be in first
relapse OR refractory to first induction therapy with ≤ 1 attempt at remission
induction

- Patients with AML who enroll on the phase I portion of the study must have
received prior mitoxantrone hydrochloride and cytarabine for newly
diagnosed AML (phase I closed to accrual as of 09/16/09)

- Patients with ALL must be in second or third relapse (≤ 3 prior induction
regimens) OR refractory to reinduction in first relapse

- Patients with ALL refractory to first induction therapy are not eligible

- No acute promyelocytic leukemia

- No CNS 3 involvement (i.e., WBC ≥ 5/μL in the cerebrospinal fluid with blasts present
on cytospin)

PATIENT CHARACTERISTICS:

- Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤
16 years of age) OR ECOG PS 0-2

- Life expectancy ≥ 8 weeks

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min

- Direct bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT < 2.5 times ULN (unless it is related to leukemic involvement)

- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 45% by gated
radionuclide study

- No evidence of dyspnea at rest or exercise intolerance

- Pulse oximetry > 94% at room air

- Amylase ≤ 1.5 times ULN

- Lipase < 1.5 times ULN

- No active, uncontrolled grade 3 or 4 infection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 3 months after
completion of study treatment

- No known hepatitis B or C infection or history of cirrhosis

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from all prior therapy*

- At least 14 days since prior cytotoxic therapy (except hydroxyurea and intrathecal
chemotherapy)*

- At least 7 days since prior biologic agent*

- At least 14 days since prior monoclonal antibody therapy*

- No more than 1 prior autologous or allogeneic hematopoietic stem cell transplantation

- No evidence of active graft-vs-host disease

- At least 4 months since transplantation

- No other concurrent chemotherapy or immunomodulating agents

- No other concurrent investigational therapy NOTE: *Patients who relapse during ALL
maintenance therapy do not require a waiting period.