Back to resultsPanobinostat (LBH589): Acute Graft Versus Host Disease (aGVHD) Prevention
Primary Purpose
Graft Versus Host Disease, GVHD
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Panobinostat
Sirolimus
Tacrolimus
Sponsored by
About this trial
This is an interventional prevention trial for Graft Versus Host Disease focused on measuring Hematologic disorder, allogeneic hematopoietic cell transplantation
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 18 years or older at time of enrollment
- Signed informed consent
- Hematologic disorder requiring allogeneic hematopoietic cell transplantation
- Left ventricular ejection fraction (LVEF) ≥ 45% by multiple uptake gated acquisition (MUGA) scan or echocardiogram
- Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and diffusing lung capacity oxygenation (DLCO) adjusted ≥ 50% of predicted values on pulmonary function tests
- Transaminases (AST, ALT) < 3 times upper limit of normal (ULN) values
- 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
- HIV, hepatitis B (HBcAb positive but 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 (ATG) as part of the conditioning regimen
- Cyclophosphamide as part of the conditioning regimen or for GVHD prophylaxis
- Pregnancy
- Histone deacetylase (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 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 bpm (Patients with pacemakers are eligible if HR ≥ 45 bpm); Screening electrocardiogram (ECG) with a 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., New York Heart Association (NYHA) 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 listed on Appendix B of study documents that are required for hematopoietic cell transplantation (HCT) patients.
Sites / Locations
- H. Lee Moffitt Cancer Center and Research Institute
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Panobinostat (PANO) Therapy
Arm Description
Participants will be treated with standard of care chemotherapy agents prior to their allogeneic hematopoietic cell transplant. For Graft Versus Host Disease (GVHD) prevention, participants will receive PANO, Sirolimus and Tacrolimus.
Outcomes
Primary Outcome Measures
Number of Participants Stratified by Acute Graft Versus Host Disease GVHD Stage
Cumulative incidence of acute GVHD grades II-IV by day 100. Investigators will consider ≥43% incidence of grade II-IV aGVHD not acceptable. Investigators will use 23% incidence rate of GVHD as target. GVHD severity stage and grading and distribution will be measured weekly from day of transplant to day 90 +/- 14 using standard scoring system. Stage of GVHD will be given for each site of involvement (e.g. skin, liver, and gut), as well as a composite score for overall acute GVHD grade. Pathologic confirmation of aGVHD will be dictated by usual clinical practice, and not mandated by this protocol.
Secondary Outcome Measures
Number of Participants Stratified by Chronic Graft Versus Host Disease (GVHD) Stage
GVHD with onset after 100 days post-HCT with presence of at least one diagnostic manifestation of chronic c-GVHD or distinct manifestation confirmed by biopsy or other relevant tests (e.g., PFT). Classified as: 1- Classic chronic GVHD - meets criteria for chronic GVHD and has no features consistent with aGVHD or 2-Overlap syndrome - features of acute and chronic GVHD exist together. C-GVHD will be measured prospectively in all participants on days 90+/-14 , 120 +/- 14, 150 +/- 14, 180+/- 14, 270+/- 30, and 365 +/- 30 as per standardized scoring system.
Time to Stable Engraftment
Stable engraftment for white blood count (WBC) is defined as a sustained absolute neutrophil count > 500 over 3 days without cytokine support. Stable platelet engraftments is defined as count of > 20,000 over 7 days without transfusion support. Time to engraftment is defined as time from day 0 to day of sustained engraftment per above criteria for both platelets and WBC.
Number of Participants With Primary Disease Relapse
Incidence of primary disease relapse and non-relapse related death will be reported per standard definitions. These will be treated as competing risk events.
Number of Participants With Non-relapse Mortality
Incidence of primary disease relapse and non-relapse related death will be reported per standard definitions. These will be treated as competing risk events. Non-relapse death is defined as death in continuous remission from primary disease requiring transplantation.
Percentage of Participants With Overall Survival (OS)
Overall survival: Time from transplant date to death from any cause. Time-to-event data such as overall survival is measured from the date of transplantation. OS will be analyzed using the Kaplan-Meier method.
Percentage of Participants With Relapse-free Survival (RFS)
Relapse-free survival: Time from transplant date to death or primary disease relapse. Time-to-event data such as relapse-free survival is measured from the date of transplantation. RFS will be analyzed using the Kaplan-Meier method.
Full Information
NCT ID
NCT02588339
First Posted
October 26, 2015
Last Updated
July 19, 2021
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Novartis
1. Study Identification
Unique Protocol Identification Number
NCT02588339
Brief Title
Panobinostat (LBH589): Acute Graft Versus Host Disease (aGVHD) Prevention
Official Title
A Phase II Trial Evaluating the Use of a Histone Deacetylase Inhibitor Panobinostat for Graft Versus Host Disease (GVHD) Prevention
Study Type
Interventional
2. Study Status
Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
March 4, 2016 (Actual)
Primary Completion Date
December 7, 2018 (Actual)
Study Completion Date
July 13, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Novartis
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This study will test PANO in combination with tacrolimus/sirolimus (TAC/SIR) for acute GVHD prevention. The purpose of this study is to determine if Panobinostat (PANO) when used in combination with sirolimus and tacrolimus will help reduce the incidence of Graft-vs-host disease (GVHD).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease, GVHD
Keywords
Hematologic disorder, allogeneic hematopoietic cell transplantation
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
42 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Panobinostat (PANO) Therapy
Arm Type
Experimental
Arm Description
Participants will be treated with standard of care chemotherapy agents prior to their allogeneic hematopoietic cell transplant. For Graft Versus Host Disease (GVHD) prevention, participants will receive PANO, Sirolimus and Tacrolimus.
Intervention Type
Drug
Intervention Name(s)
Panobinostat
Other Intervention Name(s)
PANO, Farydak, LBH-589
Intervention Description
Panobinostat (PANO) will begin 5 days (Day -5) before transplant day (Day 0). All participants will take PANO by mouth once a day, three times a week (48 hours apart), every week for 26 weeks (approximately 6 months). PANO will be provided by Novartis as 5-mg pink gelatin capsules.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
SIR, Rapamune
Intervention Description
Sirolimus will be given the day before transplant and continued daily for at least one year. SIR will be administered starting on day -1 and thereafter. Dosing will be adjusted to maintain therapeutic targets per Moffitt institutional standards.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
TAC, Prograf
Intervention Description
Tacrolimus as an infusion or as a pill will begin 3 days before transplant (day -3) and following Moffitt institutional guidelines for dosing. Tacrolimus will be given for at least 50 days and participants will remain on Tacrolimus for as long as it is necessary per standard of care.
Primary Outcome Measure Information:
Title
Number of Participants Stratified by Acute Graft Versus Host Disease GVHD Stage
Description
Cumulative incidence of acute GVHD grades II-IV by day 100. Investigators will consider ≥43% incidence of grade II-IV aGVHD not acceptable. Investigators will use 23% incidence rate of GVHD as target. GVHD severity stage and grading and distribution will be measured weekly from day of transplant to day 90 +/- 14 using standard scoring system. Stage of GVHD will be given for each site of involvement (e.g. skin, liver, and gut), as well as a composite score for overall acute GVHD grade. Pathologic confirmation of aGVHD will be dictated by usual clinical practice, and not mandated by this protocol.
Time Frame
100 days post transplant
Secondary Outcome Measure Information:
Title
Number of Participants Stratified by Chronic Graft Versus Host Disease (GVHD) Stage
Description
GVHD with onset after 100 days post-HCT with presence of at least one diagnostic manifestation of chronic c-GVHD or distinct manifestation confirmed by biopsy or other relevant tests (e.g., PFT). Classified as: 1- Classic chronic GVHD - meets criteria for chronic GVHD and has no features consistent with aGVHD or 2-Overlap syndrome - features of acute and chronic GVHD exist together. C-GVHD will be measured prospectively in all participants on days 90+/-14 , 120 +/- 14, 150 +/- 14, 180+/- 14, 270+/- 30, and 365 +/- 30 as per standardized scoring system.
Time Frame
100 days post transplant
Title
Time to Stable Engraftment
Description
Stable engraftment for white blood count (WBC) is defined as a sustained absolute neutrophil count > 500 over 3 days without cytokine support. Stable platelet engraftments is defined as count of > 20,000 over 7 days without transfusion support. Time to engraftment is defined as time from day 0 to day of sustained engraftment per above criteria for both platelets and WBC.
Time Frame
100 days post transplant
Title
Number of Participants With Primary Disease Relapse
Description
Incidence of primary disease relapse and non-relapse related death will be reported per standard definitions. These will be treated as competing risk events.
Time Frame
1 year
Title
Number of Participants With Non-relapse Mortality
Description
Incidence of primary disease relapse and non-relapse related death will be reported per standard definitions. These will be treated as competing risk events. Non-relapse death is defined as death in continuous remission from primary disease requiring transplantation.
Time Frame
1 year
Title
Percentage of Participants With Overall Survival (OS)
Description
Overall survival: Time from transplant date to death from any cause. Time-to-event data such as overall survival is measured from the date of transplantation. OS will be analyzed using the Kaplan-Meier method.
Time Frame
1 year
Title
Percentage of Participants With Relapse-free Survival (RFS)
Description
Relapse-free survival: Time from transplant date to death or primary disease relapse. Time-to-event data such as relapse-free survival is measured from the date of transplantation. RFS will be analyzed using the Kaplan-Meier method.
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age ≥ 18 years or older at time of enrollment
Signed informed consent
Hematologic disorder requiring allogeneic hematopoietic cell transplantation
Left ventricular ejection fraction (LVEF) ≥ 45% by multiple uptake gated acquisition (MUGA) scan or echocardiogram
Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and diffusing lung capacity oxygenation (DLCO) adjusted ≥ 50% of predicted values on pulmonary function tests
Transaminases (AST, ALT) < 3 times upper limit of normal (ULN) values
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
HIV, hepatitis B (HBcAb positive but 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 (ATG) as part of the conditioning regimen
Cyclophosphamide as part of the conditioning regimen or for GVHD prophylaxis
Pregnancy
Histone deacetylase (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 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 bpm (Patients with pacemakers are eligible if HR ≥ 45 bpm); Screening electrocardiogram (ECG) with a 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., New York Heart Association (NYHA) 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 listed on Appendix B of study documents that are required for hematopoietic cell transplantation (HCT) patients.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lia Perez, M.D.
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
H. Lee Moffitt Cancer Center and Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
34242388
Citation
Perez L, Fernandez H, Kharfan-Dabaja M, Khimani F, Betts B, Mishra A, Ayala E, Locke FL, Ochoa-Bayona L, Nieder M, Pidala J, Achille A, Powers J, Sahakian E, Thapa R, Wang X, Anasetti C. A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention. Blood Adv. 2021 Jul 13;5(13):2740-2750. doi: 10.1182/bloodadvances.2021004225.
Results Reference
derived
Links:
URL
https://moffitt.org/clinical-trials-research/
Description
Moffitt Cancer Center Clinical Trials website
Learn more about this trial
Panobinostat (LBH589): Acute Graft Versus Host Disease (aGVHD) Prevention
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