Epigenetic Reprogramming in Relapse AML

Phase 1 Study Number of Patients: 12 to 24 evaluable subjects will be required to enroll
subjects in all 4 dose levels.

Study Objectives:

Primary Objectives

- To determine the maximum tolerated dose (MTD) of decitabine when used in this
combination with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG) for
children and young adults with relapsed or refractory AML.

- To evaluate the ability to safely deliver the combination of decitabine and vorinostat
followed by fludarabine, high dose cytarabine and G-CSF (FLAG) in pediatric and young
adult patients with relapsed or refractory AML.

Secondary Objectives o To establish the extent of hypomethylation of peripheral blood (PB)
and bone marrow (BM) pre- and post- decitabine and vorinostat treatment by: LINE-1
methylation assay as a surrogate marker of global DNA methylation. Direct Comprehensive DNA
methylation analysis Gene expression profiling to assess genetic changes

- To analyze the correlation between DNA methylation and gene expression pre- and
post-treatment with decitabine and vorinostat.

- To analyze the correlation between biological changes and clinical response

Selection of Study Patients:

• Study entry is open to patients regardless of gender or ethnic background. While there will
be every effort to seek out and include females and minority patients, the patient population
is expected to be no different than that of other acute leukemia studies at the Medical
College of Wisconsin.

Inclusion Criteria:

The eligibility criteria listed below are interpreted literally and cannot be waived.

• Age: Patients must be ≥ 1 and ≤ 25 years of age when originally diagnosed with AML.

- Diagnosis:

o Patients must have a diagnosis of AML with > 5% blast in the bone marrow and fall
into one of the categories listed below:

- Any patient in 1st or greater relapse OR Patients failed to go into remission after
first or greater relapse OR Patients failed to go into remission from original
diagnosis after two or more induction attempts.

o Patients with CNS 1 or CNS 2 leukemia are eligible

- Performance Level: (See Appendix 2 for Performance Scales)

o Karnofsky Performance Status ≥ 50% for patients 16 years and older

o Lansky Play Score ≥ 50 for patients under 16 years of age

- Life Expectancy:

o Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling
investigator.

- Prior Therapy:

o Cytotoxic Therapy: At least 7 days must have elapsed from prior chemotherapy with
the exception of hydroxyurea which can be used up to 24 hours of starting this
protocol therapy.

o Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their
relapse after a HSCT are eligible, provided they have no evidence of active
Graft-versus-Host Disease (GVHD).

o Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior
DNMTi (e.g. decitabine) and/or HDACi (e.g. vorinostat) are eligible to participate in
this Phase 1 study.

o Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic
agent. For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur. The duration of this interval must be discussed with the
study chair

o Monoclonal Antibodies: At least 3 half-lives of the antibody must have elapsed after
the last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)

- Immunotherapy: At least 42 days after the completion of any type of
immunotherapy, e.g. tumor vaccines.

- XRT: > 14 days for local palliative XRT for CNS chloromas; No washout period is
necessary for other chloromas; > 30 days must have elapsed if prior TBI,
craniospinal XRT.

- Organ Function:

- Patients must have acceptable organ function as defined within 7 days of study
registration

- Renal: creatinine clearance ≥ 60 mL/min/1.73 m2 or serum creatinine based on age
and gender as follows:

Maximum Serum Creatinine (mg/dL) Age Male Female 1 month to < 6 months 0.4 0.4 6 months to
< 1 year 0.5 0.5

1. year to < 2 years 0.6 0.6

2. years to < 6 years 0.8 0.8

6 years to < 10 years 1.0 1.0 10 years to < 13 years 1.2 1.2 13 years to < 16 years 1.5 1.4

- 16 years 1.7 1.4

- Hepatic: ALT < 5 × upper limit of normal (ULN) and total bilirubin ≤ 1.5 × upper
limit of normal (ULN) for age. The hepatic requirements are waived for patients
with known or suspected leukemia liver involvement who would otherwise be
eligible after consultation with the Study Chair or Vice Chair.

- Cardiac: left ventricular shortening fraction > 27% by ECHO/MUGA or an ejection
fraction ≥ 40% by ECHO/MUGA

- Reproductive Function:

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed prior to enrollment.

- Female patients with infants must agree not to breastfeed their infants while on
this study.

- Male and female patients of child-bearing potential must agree to use an
effective method of contraception approved by the investigator during the study.

• Sexually active females of child bearing potential must agree to use adequate
contraception (diaphragm, birth control pills, injections, intrauterine device
[IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for
the duration of treatment and for 2 months after the last dose of chemotherapy.
Sexually active men must agree to use barrier contraceptive for the duration of
treatment and for 2 months after the last dose of chemotherapy.

- Voluntary written consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be
withdrawn by the subject at any time without prejudice to future medical
care.

Exclusion Criteria:

Patients will be excluded if they meet any of the following criteria

- They are unable to swallow Vorinostat capsules or take oral solution.

- They are currently receiving other investigational drugs.

- There is a plan to administer non-protocol chemotherapy, radiation therapy, or
immunotherapy during the study period.

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

- They have a known allergy to any of the drugs used in the study.

- Patients with Down syndrome are excluded.

- They are receiving Valproic Acid (VPA) therapy.

- Patients with Acute Promyelocytic Leukemia (APL, APML) are excluded

- Patients with documented active and uncontrolled infection at the time of study entry
are not eligible.