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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by H. Lee Moffitt Cancer Center and Research Institute
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT01111526
First received: April 16, 2010
Last updated: June 11, 2014
Last verified: June 2014
  Purpose

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


Condition Intervention Phase
Graft-Versus-Host Disease
Drug: Panobinostat (LBH589)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Safety of LBH589 (Phase I) [ Time Frame: 36 +/- 3 days from initiation of LBH589 ] [ Designated as safety issue: Yes ]
    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)

  • Efficacy of LBH589 (Phase II) [ Time Frame: 36 +/- 3 days from initiation of LBH589 ] [ Designated as safety issue: Yes ]
    Efficacy endpoint will be carried out based on patient response rate of complete remission. 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.


Estimated Enrollment: 70
Study Start Date: April 2010
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LBH589, in Addition to Glucocorticoids
Phase I Dose Escalation, Followed by Phase II Treatment at Maximum Tolerated Dose (MTD) of LBH589, in Addition to Glucocorticoids.
Drug: Panobinostat (LBH589)

Phase I, dose escalation levels for LBH589; patients treated with LBH589 PO three times a week (48 hours apart) every week for four 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 ;

*DL -1, represents a potential treatment dose for patients requiring a dose reduction from a higher dose level. In addition, dose level -1 may be used as a contingency dose level if the starting dose level of LBH589 is not tolerated in the initial cohort.

Phase II, patients treated with LBH589 PO (MTD to be determined) three times a week (48 hours apart) every week for four weeks


Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01111526

Contacts
Contact: Lia Perez, MD 813-745-7208 lia.perez@moffitt.org
Contact: Erika Elmer, CCRP 813-745-2721 erika.elmer@moffitt.org

Locations
United States, Florida
H Lee Moffitt Cancer Center and Research Institute Recruiting
Tampa, Florida, United States, 33612
Contact: Lia Perez, MD    813-745-7208    Lia.Perez@moffitt.org   
Contact: Erika Elmer, CCRP    813-745-2721    erika.elmer@moffitt.org   
Principal Investigator: Lia Perez, MD         
Sub-Investigator: Claudio Anasetti, MD         
Sub-Investigator: Melissa Alsina, MD         
Sub-Investigator: Ernesto Ayala, MD         
Sub-Investigator: Teresa Field, MD, PhD         
Sub-Investigator: Hugo Fernandez, MD         
Sub-Investigator: William Janssen, PhD         
Sub-Investigator: Leonel Ochoa-Bayona, MD         
Sub-Investigator: Daniel Sullivan, MD         
Sub-Investigator: Marcie Riches, MD, MS         
Sub-Investigator: Taiga Nishihori, MD         
Sub-Investigator: Joseph Pidala, MD         
Sub-Investigator: Brian Betts, MD         
Sub-Investigator: Fred Locke, MD         
Sub-Investigator: Mohamed Kharfan-Dabaja, MD         
Sub-Investigator: Asmita Mishra, MD         
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Novartis
Investigators
Principal Investigator: Lia Perez, MD H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01111526     History of Changes
Other Study ID Numbers: MCC-15618, CLBH589BUS20T
Study First Received: April 16, 2010
Last Updated: June 11, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
Graft versus host disease
GVHD
allogeneic transplant
acute GVHD
chronic GVHD

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Glucocorticoids
Histone Deacetylase Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 24, 2014