Phase 1-2 Safety and Efficacy Study of DACOGEN in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia.

DACOGEN® is a DNA hypomethylating agent approved for the treatment of older
patients with acute myeloid leukemia (AML). This protocol extends the
evaluation of DACOGEN to the treatment of relapsed/ refractory pediatric
patients with AML from 1 month to less than 18 years old.

Primary Objectives
Phase 1 portion:
• to determine the maximum tolerable dose (MTD) of cytarabine (up to 2 g/m2/day
x 5) that can be administered on Days 8-12 following treatment with DACOGEN 20
mg/m2/day on Days 1-5 of a 28 day cycle.
• to determine decitabine PK parameters from blood sampling on Day 5 of Cycle
1. (PK parameter determinations are also a secondary endpoint in the Phase 2
portion of the study)
Phase 2 portion:
• response rate (complete remission [CR] + complete remission with incomplete
blood count recovery [CRi]) with DACOGEN followed by cytarabine at the
determined MTD for up to 4 cycles of treatment.
Secondary Objectives
- Safety
- duration of CR + CRi,
- overall response rate (CR + CRi + partial response [PR])
- event-free survival (EFS) and overall survival (OS)
- pharmacodynamic effects of DACOGEN with respect to DNA hypomethylation
status and gene expression, and to explore predictive biomarkers for response
to DACOGEN and cytarabine sequential treatment.
- Plasma PK profile. Additionally, levels of decitabine in the cerebrospinal
fluid (CSF) will be evaluated if samples are collected as part of other
required medical care.

For the Phase 1 portion of the study, a *rolling 6* design (Skolnik 2008) is
used to determine the MTD of cytarabine following DACOGEN. The Phase 2 portion
of the study will be an open-label, single arm study of the sequential
administration of DACOGEN and cytarabine in at least 15 evaluable children with
relapsed or refractory AML.
After completing up to 4 cycles of sequential DACOGEN - cytarabine treatment in
either Phase 1 or Phase 2 of this study, subjects who, in the opinion of the
treating physician, may benefit, can receive single agent DACOGEN at 20 mg/m2
IV infusion over 1 hour on Days 1-5 every 28 days in the study Continuation
Phase.

At fase one: DACOGEN will be administered as a 1-hour IV infusion of 20 mg/m2
once daily for 5 consecutive days on Days 1 to 5 of each 28 day cycle.
Cytarabine will be administered as an IV infusion over 4 hours daily for 5
consecutive days (Day 8 to Day 12). A maximum of 3 dose levels (1 g/m2, 2 g/m2,
and 1.5 g/m2) will be evaluated, with a maximum of 18 evaluable subjects.

At the continuation phafse, subjects who, in the opinion of the treating
physician, may benefit, can receive single agent DACOGEN at 20 mg/m2 IV
infusion over 1 hour on Days 1-5 every 28 days in the study Continuation Phase.

Efficacy assessments include blood and bone marrow examination at baseline,
cycles 1, 2 and end of treatment. PK sampling will be performed on Day 5 of
Cycle 1 only and will include regular sampling from pre-infusion until 2 hours
post DACOGEN infusion; each sample requires 0.5ml whole blood. Safety
assessments include hematology, chemistry, physical examination and
echocardiogram at baseline and end of treatment. Pharmacodynamic and biomarker
sampling requires 2ml and 2.5ml whole blood, respectively, to be taken at
baseline, Day 8 and end of cycle 1.
After treatment patients will be followed-up for any late occurring advsrse
events, subsequent treatments and survival.

Through its novel epigenetic mechanism, DACOGEN may enhance the anti-neoplastic
activity of cytarabine; a key component of AML-directed therapy in children.
The potential benefits of DACOGEN given sequentially with cytarabine for these
patients may include induction of a CR or CRi that could enable the patient to
receive a potentially-curative stem cell transplant. The principal risks for
subjects in this study include myelosuppression and consequences of
myelosuppression which are manifestations of AML and have been previously
identified as
toxicities of both agents in clinical studies. These risks are minimized
through repeated physician visits, laboratory assessments, and clinical
management of affected subjects with transfusions, prophylactic antibiotics, or
other supportive measures. Unanticipated risks associated with
administration of this regimen may also emerge. Treatment cycle delays,
cytarabine dose reduction, and specific requirements for treatment
discontinuation have been included in the protocol for the clinical management
of subjects with toxicities during the study.