Epigenetic Reprogramming in Relapse/Refractory AML

Decitabine is a demethylating agent and vorinostat is a HDAC inhibitor. The use of
demethylating agents and HDAC inhibitors in combination have been previously shown to have
synergistic effects in altering neoplastic pathways of cancer cells and be well tolerated in
human clinical studies. With the ability of decitabine and vorinostat to alter the abnormal
cellular pathways of leukemic blasts and essentially turn off anti-apoptotic proteins, the
leukemia cells have become primed for cytotoxic cell kill via chemotherapeutic agents. This
study will ask the question as to whether or not the combination of decitabine and vorinostat
followed by chemotherapy is feasible and whether it can positively impact outcome in patients
with relapsed or refractory acute myelogenous leukemia.

Inclusion Criteria:

- Patients must be ≥ 1 and ≤25 years of age.

Diagnosis:

- Patients with AML must have ≥ 5% blasts (by morphology) in the bone marrow

- Patients may have CNS or other sites of extramedullary disease. No cranial irradiation
is allowed during the protocol therapy.

- Patients with secondary AML are eligible

- Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom
syndrome) are excluded.

Performance Level:

- Karnofsky >50% for patients >16 years of age and Lansky > 50% for patients ≤ 16 years of
age (See Appendix II for Performance Scales)

Prior therapy

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

1. Phase 1

- Any patient with AML in 1st or greater relapse, OR

- Patients with AML failed to go into remission after first or greater relapse, OR

- Patients with AML failed to go into remission from original diagnosis after two or
more induction attempts.

2. Cytoreduction with hydroxyurea - Hydroxyurea can be initiated and continued for up to
24 hours prior to the start of decitabine/vorinostat. It is recommended to use
hydroxyurea in patients with significant leukocytosis (WBC >50,000/L) to control blast
count before initiation of systemic protocol therapy.

3. Patients who relapsed while they are receiving cytotoxic therapy

- At least 14 days must have elapsed since the completion of the cytotoxic
therapy,except Intrathecal chemotherapy.

Hematopoietic stem cell transplant (HSCT):

- Patients who have experienced their relapse after a HSCT are eligible, provided they
have no evidence of acute or chronic Graft-versus-Host Disease (GVHD).

Hematopoietic growth factors:

- It must have been at least 7 days since the completion of therapy with GCSF or other
growth factors at the time of enrollment. It must have been at least 14 days since the
completion of therapy with pegfilgrastim (Neulasta ®)

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.

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 time of immunotherapy,
e.g. tumor vaccines or CAR T-cell therapy.

XRT: Cranio or craniospinal XRT is prohibited during protocol therapy. No washout
period is necessary for radiation given to non-CNS chloromas; >90 days must have
elapsed if prior TBI, cranio or craniospinal XRT.

Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior
DNMTi (e.g. decitabine) and/or HDACi (e.g. vorinostat) therapy are eligible to
participate in this Phase 1 study. At least 7 days must have passed from prior DNMTi
or HDACi as a washout period.

Renal and hepatic function: Patients must have adequate renal and hepatic functions as
indicated by the following laboratory values:

A. Adequate renal function defined as: Patient must have a calculated creatinine
clearance or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on
age/gender.

B. Adequate Liver Function Defined as: Direct bilirubin < 1.5 x upper limit of normal
(ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age. The hepatic
requirements are waived for patients with known or suspected liver involvement by
leukemia. This must be reviewed by and approved by the study chair or vice chair.

Adequate Cardiac Function Defined as: Shortening fraction of ≥ 27% by echocardiogram,
OR ejection fraction of ≥ 50% by radionuclide angiogram (MUGA).

Reproductive Function A. Female patients of childbearing potential must have a
negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.

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

C. Male and female patients of child-bearing potential must agree to use an effective
method of contraception approved by the investigator during the study and for a
minimum of 6 months after study treatment.

Exclusion Criteria:

-No NG or G-Tube administration of Vorinostat is allowed. Capsule must be swallowed
whole or given as oral suspension.

-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.

- Patients with DNA fragility syndromes are excluded (e.g. Fanconi Anemia, Bloom
Syndrome)

- 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