Trial Information

A Phase I/II Study of CLOLAR® (Clofarabine, IND# 73, 789) in Combination With Cytarabine in Pediatric Patients With Refractory/Relapsed 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.