Panobinostat (LBH589): Acute Graft Versus Host Disease (aGVHD) Prevention

Status: Active

Description

This phase II trial studies how well panobinostat works in preventing graft-versus-host disease (GVHD) in patients with hematologic disorders (begins in blood-forming tissue, such as the bone marrow, or in cells of the immune system) undergoing donor stem cell transplant. GVHD is a disease caused when cells from a donated stem cell graft attack the normal tissue of the transplant patient. Panobinostat may help suppress the immune system (cells in the body that can cause GVHD), reduce the release of proteins (cytokines) that may contribute to inflammation in GVHD and increase production of cells (T regulatory cells) that can help to protect against GVHD.

Eligibility Criteria

Inclusion Criteria

  • Signed informed consent
  • Hematologic disorder requiring allogeneic hematopoietic cell transplantation
  • Left ventricular ejection fraction (LVEF) >= 45% by multigated acquisition (MUGA) scan or echocardiogram
  • Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusion capacity of the lung for carbon monoxide (DLCO) adjusted >= 50% of predicted values on pulmonary function tests
  • Aspartate aminotransferase < 3 times upper limit of normal value
  • Alanine aminotransferase < 3 times upper limit of normal value
  • Creatinine clearance calculated >= 50 mL/min
  • Karnofsky performance status score >= 60%
  • Human leukocyte antigen (HLA) matched 8/8 (A, B, C, DRB1) related or unrelated donor

Exclusion Criteria

  • Active infection not controlled with appropriate antimicrobial therapy
  • Human immunodeficiency virus (HIV), hepatitis B (hepatitis B core antibody [HBcAb] positive but hepatitis B surface antigen [HBsAg] negative with undetectable viral load are eligible), or hepatitis C infection
  • Sorror’s co-morbidity factors with total score >= 4 * Important modification to co-morbidity index calculation: DLCO adjusted will not be included in assessment of pulmonary risk, except those patients with DLCO adjusted < 50% who are excluded from the trial
  • Anti-thymocyte globulin as part of the conditioning regimen
  • Cyclophosphamide as part of the conditioning regimen or for GVHD prophylaxis
  • Pregnancy
  • Histone deacetylase (HDAC), deacetylase (DAC), heat shock protein (HSP)90 inhibitors or valproic acid for the treatment of cancer within 30 days; only Food and Drug Administration (FDA) approved drug are vorinostat and romidepsin the rest are considered investigational and are not allowed
  • Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first PANO treatment
  • Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: * Any history of ventricular fibrillation or torsade de pointes * Bradycardia defined as heart rate (HR) < 45 beats per minute (bpm); patients with pacemakers are eligible if HR >= 45 bpm * Screening electrocardiogram with a QT corrected for Fridericia's formula (QTcF) >= 480 msec * Right bundle branch block + left anterior hemiblock (bifascicular block) * Patients with myocardial infarction or unstable angina =< 12 months prior to starting study drug * Other clinically significant heart disease (e.g., Classification of Heart failure [CHF] New York Heart Association class III or IV, uncontrolled hypertension) as per discretion of principal investigator and/or treating physician * 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 with the exception of drugs that are required for hematopoietic cell transplantation (HCT) patients

Locations & Contacts

Florida

Tampa
Moffitt Cancer Center
Status: Active
Contact: Lia Elena Perez
Phone: 813-745-7208
Email: lia.perez@moffitt.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To prospectively determine the cumulative incidence of acute GVHD grades II-IV by day 100 when combining PANO (panobinostat) with standard combination of TAC (tacrolimus)/SIR (sirolimus) for GVHD prevention.

SECONDARY OBJECTIVES:

I. Cumulative incidence of chronic GVHD. (Clinical Objectives)

II. Engraftment, relapse, non-relapse mortality, overall and relapse-free survival at one year. (Clinical Objectives)

III. Immune reconstitution determined by flow cytometry; histone acetylation of T cells and dendritic cell (DC) subsets by western blot and flow cytometry; regulatory T cell (T reg) immune-reconstitution, Foxp3+ expression and acetylation by flow cytometry; inflammatory cytokine and biomarker expression profiling; signal transducer and activator of transcription 3 (stat-3) activation and acetylation; panobinostat pharmacokinetics. (Biological studies to test the pharmacodynamics of TAC/SIR/PANO combination for GVHD prevention)

OUTLINE:

CONDITIONING REGIMEN: Patients receive either myeloablative busulfan and fludarabine phosphate; reduced-intensity (RIC) busulfan and fludarabine phosphate; or RIC fludarabine phosphate and melphalan per physician discretion.

GVHD PROPHYLAXIS: Patients receive panobinostat orally (PO) 3 times a week (TIW) on days -5 and continuing for 26 weeks. Patients then receive tacrolimus PO or intravenously (IV) on days -3 to 50 with suggested taper and sirolimus PO daily on days -1 to 365 with suggested taper per institutional standards.

After completion of study treatment, patients are followed up weekly for 100 days for acute GVHD and on days +90 +/- 14, 120 +/- 14, 150 +/- 14, 180+/- 14, 270+/- 30, and 360 +/- 30 for chronic-GVHD assessment and adverse events toxicity assessment.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Prevention

Lead Organization

Lead Organization
Moffitt Cancer Center

Principal Investigator
Lia Elena Perez

Trial IDs

Primary ID MCC-18374
Secondary IDs NCI-2016-00054, Novartis CLBH589BUS100T
Clinicaltrials.gov ID NCT02588339