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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.
Full 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.
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Inclusion criteria
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.
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:
Patient must not have evidence of primary disease relapse.
An ECOG (Eastern Cooperative Oncology Group) performance status of ≤2
Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥40%.
No uncontrolled arrhythmias or symptoms of heart disease.
FEV1, FVC, and DLCO ≥40%.
Laboratory values as follows:
Patients with elevated alkaline phosphatase due to bone metastasis may be enrolled.
TSH and free T4 within normal limits (clinically euthyroid patients are permitted to receive thyroid supplements to treat underlying hypothyroidism).
Age ≥ 18 years, male or female.
Ability to understand and willingness to sign a written informed consent document.
Exclusion criteria
Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer.
Patients who will need valproic acid for any medical condition during the study or ≤5 days prior to first panobinostat treatment.
Use of prior immunosuppressants other than steroids and calcineurin inhibitors(i.e. cyclosporine or tacrolimus).
Chronic active hepatitis or cirrhosis.
Impaired cardiac function including any of the following:
Concomitant use of drugs with a risk of causing Torsades de Pointes (see Appendix A).
Other concurrent severe and/or uncontrolled medical conditions.
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)
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Data sourced from clinicaltrials.gov
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