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A Phase I/II Trial Evaluating the Use of Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients With Acute Graft Versus Host Disease

Phase 1/Phase 2
18 Years
Open (Enrolling)
Graft-Versus-Host Disease

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Trial Information

A Phase I/II Trial Evaluating the Use of Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients With Acute Graft Versus Host Disease

Dose escalation study to test the safety (Phase I), pharmacology and preliminary clinical
activity (Phase II) of a Novel 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 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 AST
or ALT or Alkaline phosphatase with 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 500mL/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. ANC greater than 500/μL, platelets >/= 20 x 109/L supported by platelet transfusion
and hemoglobin >/= 8 g/dl supported by red cell transfusion.

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

6. Serum potassium >/= 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. TSH baseline laboratories. Patients are permitted to receive thyroid hormone replacement
to treat underlying hypothyroidism

8. Baseline MUGA or ECHO must demonstrate 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 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

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

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 HR< 50 bpm. Patients with pacemakers are eligible if HR
>/= 50 bpm.

5. Screening EKG with a QTc > 450 msec

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

7. Patients with myocardial infarction or unstable angina starting study drug.

8. Other clinically significant heart disease (e.g., CHF NY 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

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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety of LBH589 (Phase I)

Outcome Description:

LBH589 treatment safety will be determined by the proportion of study patients who develop adverse events ≥ grade 3 severity as graded by Common Terminology Criteria for Adverse Events (CTCAE Version 4.0)

Outcome Time Frame:

36 +/- 3 days from initiation of LBH589

Safety Issue:


Principal Investigator

Lia Perez, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:

MCC 15618



Start Date:

April 2010

Completion Date:

April 2013

Related Keywords:

  • Graft-Versus-Host Disease
  • Graft versus host disease
  • GVHD
  • allogeneic transplant
  • acute GVHD
  • chronic GVHD
  • Graft vs Host Disease



H Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612