Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients With Acute Graft Versus Host Disease (GVHD)

Study Overview
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Brief Summary
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To test a new agent, LBH589, in combination with glucocorticoids as initial therapy of acute graft versus host disease (GVHD).

Detailed Description
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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.

Official Title
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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

Conditions
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Graft-Versus-Host Disease

Intervention / Treatment
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* Drug: Panobinostat (LBH589)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: Skin rash involvement of a minimum of 50% of body surface area in absence of documented drug allergy or infectious etiology. 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. Increase in bilirubin above upper limit of normal (ULN) in absence of clinically defined veno-occlusive disease. 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. Male or female patients aged 18 or older at time of enrollment Signed informed consent 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. Calculated creatinine clearance (CrCl) >/= 30 mL/min (MDRD Formula) 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 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 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: 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 Patients requiring mechanical ventilation support. 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. 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. HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer within 30 days. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first LBH589 treatment. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: Patients with congenital long QT syndrome. History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of a controlled atrial arrhythmia are eligible). Any history of ventricular fibrillation or torsade de pointes. Bradycardia defined as heart rate (HR)< 50 bpm. Patients with pacemakers are eligible if HR >/= 50 bpm. Patients are excluded if the average of the QT Corrected by the Fridericia Formula (QTcF) is > 470 msec on the screening EKGs. Right bundle branch block + left anterior hemiblock (bifascicular block). Patients with myocardial infarction or unstable angina </= 6 months prior to starting study drug. Other clinically significant heart disease (e.g., congestive heart failure (CHF) New York Heart Association class III or IV, or uncontrolled hypertension. 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. 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). Patients with known positivity for human immunodeficiency virus (HIV) before transplant. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LBH589, in Addition to Glucocorticoids<br>Phase I Dose Escalation, Followed by Phase II Treatment at Maximum Tolerated Dose (MTD) of LBH589, in Addition to Glucocorticoids. | Drug: Panobinostat (LBH589)<br>* Phase I Initial Treatment Plan - Intravenous (IV) Formulation: Up to 4 dose levels (DL) of LBH589 IV formulation to establish LBH589 Maximum Tolerated Dose (MTD) in acute GVHD treatment. The first 4 participants began this treatment plan, before the IV Formulation became unavailable. DL -1: 1.25 mg/m^2 IV; DL 1: 2.5 mg/m^2 IV; DL 2: 5 mg/m^2 IV; DL 3: 7.5 mg/m^2 IV; DL 4: 10 mg/m^2 IV. Phase I Revised Treatment Plan - Oral Formulation (to replace IV Formulation): Dose escalation levels for LBH589; participants treated with LBH589 by mouth (PO) 3 times a week (48 hours apart) every week for 4 weeks. DL -1: 5 mg PO; DL 1: 10 mg PO (starting dose level); DL 2: 15 mg PO; DL 3: 20 mg PO; DL 4: 25 mg PO. Phase II Treatment Plan: LBH589 PO at MTD, 3 times a week (48 hours apart) every week for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) in Milligrams | MTD of LBH589 in addition to glucocorticoids as treatment for Graft Versus Host Disease (GVHD) manifestations. MTD in Milligrams (mg), taken by mouth (PO), 3 times per week, for 4 weeks. The oral formulation replaced the IV formulation (which became unavailable) after the first 4 participants were treated. Dose limiting toxicity (DLT) is defined by the occurrence of Common Toxicity Criteria (CTC) grade 3 or greater toxicity that is unexpected with transplantation, except for hematological toxicity, where DLT is defined as absolute neutrophil count (ANC) <750, and for those participants who were platelet transfusion independent is defined as platelets <10 K. | 2 years, 8 months | 
| Phase II: Overall Rate of Response (ORR) | Rate of Complete Response (CR), Partial Response (PR), Progressive Disease (PD) and Stable Disease (SD). Assessment of GVHD will include the skin, liver and gut. Other possible etiologies of organ disease such as C difficile enterocolitis, viral infection, drug reaction, veno-occlusive disease of the liver, etc., will be excluded by appropriate tests. CR is defined as resolution of GVHD in all evaluable organs with no subsequent additional treatment given for acute GVHD. PR is defined as improvement in ≥ one evaluable organ without deterioration in at least one other. PD is defined as deterioration in at least on evaluable organ. SD is defined as the absence of any difference sufficient to meet minimal criteria for improvement or deterioration in any evaluable organs. | 1 year, 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of GVHD Flares Requiring Increasing Immune Suppressive Therapy | Number of participants with GVHD flares requiring increasing immune suppressive therapy within 36 days of study initiation. Cumulative incidence of GVHD flares requiring increasing immune suppressive therapy will be analyzed using the competing risk method by Gray (1988). GVHD flares (progressive disease (PD)) may result in discontinuation from Panobinostat. | Up to 36 days per participant | 
| Overall Survival (OS) | Overall Survival (OS) at one year post initiation of therapy. | 1 year | 
| Occurrence of Discontinuation of All Immune Suppression | Number of participants discontinuing all immune suppression without subsequent flare by 1 year post initiation of therapy. | 1 year | 
| Chronic GVHD Onset | Chronic GVHD onset in participants without overlap syndrome at initiation of study therapy. Number of participants with overlap syndrome at MTD. | Up to 1 year | 
| Chronic GVHD Severity at MTD | Chronic GVHD maximum severity grade at MTD, in participants without overlap syndrome at initiation of study therapy. Maximum c-GVHD severity: Mild, Moderate, Severe. | Up to 1 year | 
| Stable or Improved Chronic GVHD Severity Score | Stable or improved Chronic GVHD score: Improved Mild to None; Improved Severe to Moderate; Improved Moderate to None, Remained Stable at Mild. | 1 year | 
| Occurrence of Possibly Related Adverse Events | Number of participants with adverse events possibly related to study treatment, per event category. | 5 years, 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft versus host disease, GVHD, allogeneic transplant, acute GVHD, chronic GVHD