Panobinostat With Fludarabine and Cytarabine for Treatment of Children With Acute Myeloid Leukemia or Myelodysplastic Syndrome

STUDY PART 1: Dose Escalation Cohort

During the dose escalation phase (Part 1), participants will receive one course of
panobinostat plus fludarabine and cytarabine. The starting dose of panobinostat will be 10
mg/m^2/dose, with 2 additional dose levels of 15 and 20, depending on tolerability. Each
course is 12 days

STUDY PART 2: Dose Expansion Cohort

The recommended phase 2 dose (RP2D) will be chosen based on the maximum tolerated dose (MTD)
and the totality of data obtained from study Part 1. Additional patients will be enrolled, if
needed, so that at least 6 patients are treated with the recommended RP2D to confirm the MTD
of panobinostat to be given in study Part 2.

After final MTD determination, 12 additional participants will be treated at this dose level
for further evaluation of tolerability and response, including more complete toxicity data
and estimation of the response rate to the combination of panobinostat, fludarabine, and
cytarabine.

Inclusion Criteria:

- Participants must have a diagnosis of AML or MDS and must have disease that has
relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic
stem cell transplantation (HSCT).

- Refractory disease is defined as persistent disease after at least two courses of
induction chemotherapy.

- Patients with AML must have ≥ 5% leukemic blasts in the bone marrow or increasing
levels of minimal residual disease (MRD) in the bone marrow as assessed by flow
cytometry. If an adequate bone marrow sample cannot be obtained, patients may be
enrolled if there is unequivocal evidence of leukemia in the peripheral blood.

- Adequate organ function defined as the following:

- Direct bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)

- AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN

- Creatinine ≤ 1.5 x ULN for age

- Serum albumin > 3.0 g/dl

- Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%.

- Age ≤ 24 years

- Patients must be able to swallow capsules

- Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥
50% for patients who are > 16 years old.

- Patients must have fully recovered from the acute effects of all prior therapy and
must meet the following criteria:

- At least 14 days must have elapsed since the completion of myelosuppressive
therapy

- At least 24 hours must have elapsed since the completion of low-dose
chemotherapy, such as hydroxyurea or low-dose cytarabine (up to 200 mg/m^2/day).

- For patients who have received prior HSCT, there can be no evidence of GVHD and
greater than 60 days must have elapsed since the HSCT. Patients cannot be
receiving therapy, including steroids, for the treatment or prevention of GVHD.
All such medications must be discontinued at least 24 hours prior to enrollment.

- Body Surface Area: Because the smallest capsule size available for the panobinostat is
10 mg, the minimum BSA allowed for enrollment at Dose Level 1 to 0.85 m^2. The minimum
for Dose Level 2 is BSA=0.6 m^2 and the minimum for Dose Level 3 is BSA=0.42 m^2.

Exclusion Criteria:

- Must not be pregnant or breastfeeding. Female patients who are sexually active and of
child-bearing potential must agree to use dual methods of contraception and have a
negative serum pregnancy test at screening, and male patients who are sexually active
must use an effective barrier method of contraception if sexually active with a female
of child-bearing potential. For both male and female patients who are sexually active,
effective methods of contraception must be used throughout the study and for three
months following the last dose. Abstinence is an acceptable form of contraception.

- Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic
leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other bone marrow
failure syndromes are not eligible.

- Use of investigational agents within 30 days.

- Any significant concurrent disease, illness, or psychiatric disorder that would
compromise patient safety or compliance, study participation, follow up, or
interpretation of study research.

- Uncontrolled infection within one week of the first dose. Infections controlled on
concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per
institutional guidelines are acceptable.

- Known human immunodeficiency virus infection (pre-study testing not required).

- Patient with diarrhea > CTCAE grade 2. (CTCAE version 4.0)

- Impaired cardiac function or clinically significant cardiac diseases, history of
arrhythmia (including ventricular fibrillation or torsade de pointes), bradycardia <50
bpm, screening ECG with prolonged QTc (> 450 msec), uncontrolled hypertension or any
history or presence of sustained ventricular tachyarrhythmia.

- Impairment of GI function or GI disease that may significantly alter the absorption of
panobinostat.

- Patients using medications that have a relative risk of prolonging the QT interval or
inducing torsade de pointes if treatment cannot be discontinued or switched to a
different medication prior to starting treatment. Granisetron may be administered, but
antiemetics associated with QT prolongation (e.g., ondansetron) are not allowed.