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

NCT01111526 | Completed Phase 1 Results DMC

• 2 other identifiers: MCC-15618CLBH589BUS20T
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Graft-Versus-Host Disease

Keywords

Graft versus host disease; GVHD; allogeneic transplant; acute GVHD; chronic GVHD

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• Incidence of GVHD Flares Requiring Increasing Immune Suppressive Therapy

  Up to 36 days per participant

• Overall Survival (OS)

  1 year

• Occurrence of Discontinuation of All Immune Suppression

  1 year

• Chronic GVHD Onset

  Up to 1 year

• Chronic GVHD Severity at MTD

  Up to 1 year

Study Arms (1)

LBH589, in Addition to Glucocorticoids

EXPERIMENTAL

Phase I Dose Escalation, Followed by Phase II Treatment at Maximum Tolerated Dose (MTD) of LBH589, in Addition to Glucocorticoids.

Drug: Panobinostat (LBH589)

Interventions

Panobinostat (LBH589) DRUG

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.

LBH589, in Addition to Glucocorticoids

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead
• Novartis: collaborator

Study Sites (1)

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Related Links

• H. Lee Moffitt Cancer Center \& Research Institute

MeSH Terms

Conditions

Graft vs Host Disease; Bronchiolitis Obliterans Syndrome

Interventions

Panobinostat

Condition Hierarchy (Ancestors)

Immune System Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

The discontinuation of the IV Formulation of LBH589 required a treatment plan change to Oral Formulation LBH589, after the first 4 participants were treated. The study accrued fewer participants than investigators had planned to evaluate.

Results Point of Contact

• Title: Dr. Lia Perez
• Organization: H. Lee Moffitt Cancer Center and Research Institute

lia.perez@moffitt.org

813-745-3665

Study Officials

• Lia Perez, MD

  H. Lee Moffitt Cancer Center and Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2010
• First Posted: April 27, 2010
• Study Start: April 1, 2010
• Primary Completion: October 1, 2015
• Study Completion: June 1, 2016
• Last Updated: May 15, 2018
• Results First Posted: December 22, 2016

Record last verified: 2016-08

Locations

US (1)