Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients With Acute Graft Versus Host Disease (GVHD)
Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients With Acute Graft Versus Host Disease (GVHD)
To test a new agent, LBH589, in combination with glucocorticoids as initial therapy of acute
 graft versus host disease (GVHD).
Dose escalation study to test the safety (Phase I), pharmacology and preliminary clinical
 activity (Phase II) of a Novel histone deacetylase (HDAC) inhibitor, LBH589, in the treatment
 of the following GVHD presentations: Classic, Late-onset acute GVHD, Recurrent acute GVHD,
 Overlap syndrome.
Inclusion Criteria:

 1. Patients receiving allogeneic hematopoietic cell transplantation (HCT) with peripheral
 blood, bone marrow or cord blood stem cells regardless of initial diagnosis who
 develop a clinical diagnosis of acute GVHD as defined in Section 2 diagnosed and
 treated with systemic glucocorticoids within 72 hours prior to enrollment. Biopsy of
 involved skin and gastrointestinal tract is strongly encouraged, but not required for
 study entry. For patients with aspartic transaminase (AST) or alanine transaminase
 (ALT) or Alkaline phosphatase with gamma-glutamyltransferase (GGT) elevations without
 bilirubin elevation must have a liver biopsy to document GVHD diagnosis. Patients
 should meet one of the following criteria:

 If GVHD is present in an isolated organ:

 1. Skin rash involvement of a minimum of 50% of body surface area in absence of
 documented drug allergy or infectious etiology.

 2. Diarrhea with a minimum stool volume of 500 mL/day and/or a minimum of 2 stools
 above baseline/day in absence of enterocolitis from C. difficile or other
 documented pathogens.

 3. Increase in bilirubin above upper limit of normal (ULN) in absence of clinically
 defined veno-occlusive disease.

 4. Isolated increased AST and/or ALT and/or increased alkaline phosphatase above ULN
 with GGT elevation above ULN with documented liver GVHD biopsy.

 If GVHD presentation involves >/= 2 organs: GVHD Grade >/= II as defined in Table D of
 protocol.

 2. Male or female patients aged 18 or older at time of enrollment

 3. Signed informed consent

 4. Absolute neutrophil count (ANC) greater than 500/μL, platelets >/= 20 x 10^9/L
 supported by platelet transfusion and hemoglobin >/= 8 g/dl supported by red cell
 transfusion.

 5. Calculated creatinine clearance (CrCl) >/= 30 mL/min (MDRD Formula)

 6. Serum potassium >/= lower limit of normal (LLN), Total serum calcium [corrected for
 serum albumin] or ionized calcium >/= LLN, Serum magnesium >/= LLN and Serum
 phosphorus >/= LLN on the day of LBH589 administration

 7. Thyroid-stimulating hormone (TSH) </= ULN and free T4 within normal limits at the time
 of patient enrollment within baseline laboratories. Patients are permitted to receive
 thyroid hormone replacement to treat underlying hypothyroidism

 8. Baseline multiple gated acquisition scan (MUGA) or echocardiogram (ECHO) must
 demonstrate left ventricular ejection fraction (LVEF) >/= the lower limit of the
 institutional normal before transplantation.

 Exclusion Criteria:

 1. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)
 not using an effective method of birth control. WOCBP are defined as sexually mature
 women who have not undergone a hysterectomy or who have not been naturally
 postmenopausal for at least 12 consecutive months (i.e., who has had menses any time
 in the preceding 12 consecutive months). Women of childbearing potential must have a
 negative serum pregnancy test within 24 hrs of receiving the first dose of study
 medication if a pregnancy test was not done pre-transplant. Male patients whose sexual
 partners are WOCBP not using effective birth control

 2. Patients requiring mechanical ventilation support.

 3. Active, uncontrolled life threatening viral or fungal disease, such as cytomegalovirus
 (CMV) pneumonia or gastroenteritis, Aspergillus pneumonia or brain abscess. For
 bacterial or viral infections, patients must be receiving therapy and have no signs of
 progression for 48 hours prior to enrollment. For fungal infection patients must be
 receiving systemic anti-fungal therapy and have no signs of progression for 1 week
 prior to enrollment. Progressing infection is defined as hemo-dynamic instability
 attributable to sepsis or new symptoms, worsening physical signs or radiographic
 findings attributable to infections. Persisting fever without other signs of symptoms
 will not be interpreted as progressing infections.

 4. Receipt of other investigational new drugs for GVHD including agents used for GVHD
 prophylaxis within 30 days. The following agents are not considered experimental and
 therefore are not excluded: cyclosporine, tacrolimus, sirolimus, glucocorticoids,
 antithymocyte globulin, replacement corticosteroid therapy for hypoadrenalism and
 methotrexate.

 5. HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer within 30
 days.

 6. Patients who will need valproic acid for any medical condition during the study or
 within 5 days prior to first LBH589 treatment.

 7. Impaired cardiac function or clinically significant cardiac diseases, including any
 one of the following:

 1. Patients with congenital long QT syndrome.

 2. History or presence of sustained ventricular tachyarrhythmia. (Patients with a
 history of a controlled atrial arrhythmia are eligible).

 3. Any history of ventricular fibrillation or torsade de pointes.

 4. Bradycardia defined as heart rate (HR)< 50 bpm. Patients with pacemakers are
 eligible if HR >/= 50 bpm.

 5. Patients are excluded if the average of the QT Corrected by the Fridericia
 Formula (QTcF) is > 470 msec on the screening EKGs.

 6. Right bundle branch block + left anterior hemiblock (bifascicular block).

 7. Patients with myocardial infarction or unstable angina </= 6 months prior to
 starting study drug.

 8. Other clinically significant heart disease (e.g., congestive heart failure (CHF)
 New York Heart Association class III or IV, or uncontrolled hypertension.

 8. 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 study drug.

 9. Concomitant use of CYP3A4 inhibitors with the exception of tacrolimus, voriconazole
 (or posaconazole), cyclosporine that are required for all GVHD patients to control
 GVHD and prevent mould infections (Appendix A of protocol).

 10. Patients with known positivity for human immunodeficiency virus (HIV) before
 transplant.

 11. Patients with any significant history of non-compliance to medical regimens or
 unwilling or unable to comply with the instructions given to him/her by the study
 staff.