LBH589 Plus Decitabine for Myelodysplastic Syndromes or Acute Myeloid Leukemia

To address the need for less toxic, more effective treatments for older patients with
advanced MDS and AML, the purpose of this Phase 1-2 single institution study is to evaluate
the safety and efficacy of LBH 589 and decitabine administered in combination.

Decitabine is an epigenetic modifier of gene expression that has been shown to be
well-tolerated in this population at the dose schedule proposed in this study, with
reasonable efficacy. Although its precise mechanism of action is incompletely understood, it
is postulated to work by reactivating the expression of key tumor suppressor genes silenced
in tumor cells by reversing a pattern of hypermethylation of promotor elements.

LBH389 is likewise an epigenetic modifier that inhibits the deacetylation of both histones
and non-histone proteins, including HSP90 and p53. Although clinical experience with LBH589
in AML is limited, aberrant histone deacetylase activity has been previously shown to play a
significant role in the pathogenesis of AML. The addition of LBH589 to a decitabine regimen
of previously established efficacy and tolerability will allow us to evaluate the hypothesis
that two epigenetic modifiers that are believed to work through distinct mechanisms of
action may act together to improve the responses of patients treated with decitabine alone,
without significant additional toxicity.

Inclusion Criteria:

- AML (except t(15;17), inv(16) or t(8;21) and variants) or high risk MDS (IPSS Int-2
or High) diagnosed according to WHO criteria (see Appendix 1)

- Age ≥ 60 years old

- Not a candidate for allogeneic stem cell transplantation within next 12 weeks

- Ability to provide written informed consent, obtained prior to participation in the
study and any related procedures being performed

- Patients must meet the following laboratory criteria: Serum albumin > 3 g/dL,
AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) ) or ≤ 5.0 x ULN if the
transaminase elevation is due to leukemic involvement, Serum bilirubin ≤ 1.5 x ULN,
Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min, Serum
potassium ≥ LLN, Serum phosphorus ≥ LLN, Serum total calcium (corrected for serum
albumin) or serum ionized calcium ≥ LLN, Serum magnesium ≥ LLN, TSH and free T4
within normal limits (WNL) (patients may be on thyroid hormone replacement)

- Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional
normal.

- ECOG Performance Status of ≤ 2

Exclusion Criteria:

- Prior treatment for MDS / AML with HDAC inhibitor or hypomethylating agent (e.g.,
Decitabine, azacitadine etc.)

- Active CNS involvement with MDS/AML

- Impaired cardiac function including any one of the following:

- Screening ECG with a QTc > 450 msec confirmed by central laboratory prior to
enrollment to the study

- Patients with congenital long QT syndrome

- History of sustained ventricular tachycardia

- Any history of ventricular fibrillation or torsades de pointes

- Bradycardia defined as heart rate < 50 beats per minute. Patients with a pacemaker
and heart rate ≥ 50 beats per minute are eligible.

- Patients with a myocardial infarction or unstable angina within 6 months of study
entry

- Congestive heart failure (NY Heart Association class III or IV)

- Right bundle branch block and left anterior hemiblock (bifasicular block)

- Uncontrolled hypertension

- Concomitant use of drugs with a risk of causing torsades de pointes (See Appendix
2-1)

- Patients with unresolved diarrhea > CTCAE grade 1

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral LBH589

- Other concurrent severe and/or uncontrolled medical conditions

- Patients who have received chemotherapy or any investigational drug < 2 weeks or
hydroxyurea < 48 hours prior to starting study drug or who have not recovered from
side effects of such therapy.

- Concomitant use of any anti-cancer therapy or radiation therapy

- Male patients whose sexual partners are WOCBP not using effective birth control

- Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis
C; baseline testing for HIV and hepatitis C is not required

- Patients with any significant history of non-compliance to medical regimens or with
inability to grant a reliable informed consent