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A Study of Panobinostat (LBH589) as Second-Line Therapy in Patients With Chronic Graft-Versus-Host Disease

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ClinicalTrials.gov Identifier: NCT01028313
Recruitment Status : Withdrawn (A decision was made to not move forward with the study. No participants were enrolled or treated.)
First Posted : December 9, 2009
Last Update Posted : February 13, 2013
Sponsor:
Collaborator:
Information provided by:

Study Description
Brief Summary:

There is a clear need for effective, steroid-sparing agents for the management of chronic graft-versus-host disease (GVHD). Thus, agents like Histone deacetylase (HDAC) inhibitors, with the potential of decreasing pro-inflammatory events leading to GVHD without affecting graft-versus-leukemia (GVL), may have a central role in the prevention and treatment of GVHD.

This study will look at the efficacy of panobinostat (LBH589), an HDAC inhibitor, in the treatment of patients with chronic GVHD who have failed corticosteroids. In this group of patients, effective steroid-sparing options are limited and are usually associated with profound immunosuppression and decreased GVL effect.


Condition or disease Intervention/treatment Phase
Chronic Graft-Versus-Host Disease Drug: LBH589 Drug: Methylprednisolone Phase 2

Detailed Description:

Chronic GVHD is an autoimmune, inflammatory disorder that occurs in the majority of patients who experience acute GVHD. Long-term corticosteroids are still standard therapy for chronic GVHD. Corticosteroids are associated with high morbidity and non-relapse mortality. In addition, corticosteroids are broadly immunosuppressive and can also decrease the GVL effect and increase the incidence of relapse. There is a clear need for effective, steroid-sparing agents for the management of chronic GVHD. Thus, agents like HDAC inhibitors, with the potential of decreasing pro-inflammatory events leading to GVHD without affecting GVL, may have a central role in the prevention and treatment of GVHD.

This study will look at the efficacy of panobinostat (LBH589), an HDAC inhibitor, in the treatment of patients with chronic GVHD who have failed corticosteroids. In this group of patients, effective steroid-sparing options are limited and are usually associated with profound immunosuppression and decreased GVL effect.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Panobinostat (LBH589) as Second-Line Therapy in Patients With Chronic Graft-Versus-Host Disease


Arms and Interventions

Arm Intervention/treatment
Experimental: 1
Systemic Therapy
Drug: LBH589
20 mg PO three times weekly
Other Name: Panobinostat
Drug: Methylprednisolone
1 mg/kg/day PO continuously
Other Name: Medrol, Depo-Medrol


Outcome Measures

Primary Outcome Measures :
  1. To assess the response rate to panobinostat of patients with cGvHD inadequately treated with steroids and calcineurin inhibitors. [ Time Frame: 30 months ]

Secondary Outcome Measures :
  1. To evaluate the safety and tolerability of panobinostat in patients with cGvHD. [ Time Frame: 30 months ]
  2. To assess the steroid-sparing capacity of panobinostat (as proportion of patients able to discontinue steroids while receiving, or following therapy with, panobinostat). [ Time Frame: 30 months ]
  3. To assess changes in quality of life (QOL) after treatment with panobinostat. [ Time Frame: 30 months ]
  4. To analyze survival at 6 and 12 months after initiation of panobinostat. [ Time Frame: 30 months ]
  5. To evaluate the relapse rate of the underlying malignancy as well as the occurrence of second malignancies at 6 and 12 months after initiation of panobinostat. [ Time Frame: 30 months ]

Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Chronic GvHD following allogeneic HSCT of any source (bone marrow, peripheral blood, or cord blood stem cells), from any donor type (related, unrelated, or mismatched) and with any type of malignancy. Chronic GvHD will be defined according to NIH Consensus Criteria.
  2. Patients must have had inadequate response to treatment with steroids and calcineurin inhibitors. Patients must have been treated with an initial dose of at least 1 mg/kg/day of methylprednisolone (MP) or equivalent in combination with tacrolimus or cyclosporine and must fulfill the definition of steroid refractoriness or resistance. Steroid refractoriness or resistance will be defined as:

    1. Lack of any response after 1 month of treatment with MP, including 15 days of at least 0.5 mg/kg/day.
    2. Worsening of existing GvHD or new organ involvement at any time following one week of initiation of MP at 1 mg/kg/day.
    3. Reflare or worsening of GvHD at any time during steroid taper.
    4. Patients should not have received any drug or treatment for chronic GvHD other than steroids and calcineurin inhibitors (i.e., cyclosporine or tacrolimus).
  3. Patient must not have evidence of primary disease relapse.
  4. An ECOG (Eastern Cooperative Oncology Group) performance status of ≤2
  5. Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥40%.
  6. No uncontrolled arrhythmias or symptoms of heart disease.
  7. FEV1, FVC, and DLCO ≥40%.
  8. Laboratory values as follows:

    • white blood cell ≥2500/mm³;
    • absolute neutrophil count (ANC) ≥1,000/mm³;
    • hemoglobin ≥9.5 g%;
    • platelets ≥50,000/mm³;
    • total bilirubin <3 x upper limits of normal;
    • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × the institutional upper limit of normal (ULN);
    • creatinine <1.5 × ULN or creatinine clearance ≥ 50 ml/min;
    • serum potassium ≥ LLN;
    • serum sodium ≥ LLN;
    • serum calcium WNL;
    • serum phosphorus WNL;
    • serum magnesium WNL;
  9. Patients with elevated alkaline phosphatase due to bone metastasis may be enrolled.
  10. TSH and free T4 within normal limits (clinically euthyroid patients are permitted to receive thyroid supplements to treat underlying hypothyroidism).
  11. Age ≥ 18 years, male or female.
  12. Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

  1. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer.
  2. Patients who will need valproic acid for any medical condition during the study or ≤5 days prior to first panobinostat treatment.
  3. Use of prior immunosuppressants other than steroids and calcineurin inhibitors(i.e. cyclosporine or tacrolimus).
  4. Chronic active hepatitis or cirrhosis.
  5. Impaired cardiac function including any of the following:

    • Patients with congenital long QT syndrome;
    • Patients with history or presence of sustained ventricular tachyarrhythmias;
    • Patients with any history of ventricular fibrillation or Torsades de Pointes;
    • Patients with bradycardia defined as HR <50 bpm. Patients with pacemakers are eligible if HR ≥50 bpm.
    • Patients with myocardial infarction or unstable angina ≤6 months prior to starting study drug;
    • Right bundle branch block plus left anterior hemiblock (bifasicular block);
    • Screening ECG with QTc >450 msec;
    • Congestive heart failure (CHF) > New York Heart Association (NYHA) Class II (see Appendix D).
  6. Concomitant use of drugs with a risk of causing Torsades de Pointes (see Appendix A).
  7. Other concurrent severe and/or uncontrolled medical conditions.
  8. Any condition that impairs patient's ability to swallow whole pills or gastrointestinal (GI) tract disease that involves an inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV)
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01028313


Locations
United States, Tennessee
Tennessee Oncology, PLLC
Nashville, Tennessee, United States, 37023
Sponsors and Collaborators
SCRI Development Innovations, LLC
Novartis
Investigators
Study Chair: Daniel R Couriel, M.D. SCRI Development Innovations, LLC
More Information

Responsible Party: Daniel Couriel, MD, SCRI Oncology Research Consortium
ClinicalTrials.gov Identifier: NCT01028313     History of Changes
Other Study ID Numbers: SCRI BMT 02
First Posted: December 9, 2009    Key Record Dates
Last Update Posted: February 13, 2013
Last Verified: February 2013

Keywords provided by SCRI Development Innovations, LLC:
Chronic Graft-Versus-Host Disease
GVHD
LBH589
Panobinostat

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Panobinostat
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action