Graft Versus Host Disease, GVHD
Conditions
Keywords
Hematologic disorder, allogeneic hematopoietic cell transplantation
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).
Interventions
DRUGPanobinostat
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.
DRUGSirolimus
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.
DRUGTacrolimus
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.
Sponsors
Novartis
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Stratified by Acute Graft Versus Host Disease GVHD Stage | 100 days post transplant | 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
| Measure | Time frame | Description |
|---|---|---|
| Time to Stable Engraftment | 100 days post transplant | 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 | 1 year | 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 Stratified by Chronic Graft Versus Host Disease (GVHD) Stage | 100 days post transplant | 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. |
| Percentage of Participants With Overall Survival (OS) | 1 year | 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) | 1 year | 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. |
| Number of Participants With Non-relapse Mortality | 1 year | 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. |
Countries
United States
Participant flow
Recruitment details
Participants recruited between March 2016 and August 2018
Participants by arm
| Arm | Count |
|---|---|
| Panobinostat (PANO) Therapy 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. | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | GVHD Progression prior to treatment | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Panobinostat (PANO) Therapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Age, Continuous | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 36 Participants |
| Region of Enrollment United States | 42 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 39 |
| other Total, other adverse events | 32 / 39 |
| serious Total, serious adverse events | 12 / 39 |
Outcome results
Primary
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.
Time frame: 100 days post transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Panobinostat (PANO) Therapy | Number of Participants Stratified by Acute Graft Versus Host Disease GVHD Stage | Grade II GVHD | 6 Participants |
| Panobinostat (PANO) Therapy | Number of Participants Stratified by Acute Graft Versus Host Disease GVHD Stage | Grade III GVHD | 1 Participants |
Secondary
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 frame: 100 days post transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Panobinostat (PANO) Therapy | Number of Participants Stratified by Chronic Graft Versus Host Disease (GVHD) Stage | Mild GVHD | 10 Participants |
| Panobinostat (PANO) Therapy | Number of Participants Stratified by Chronic Graft Versus Host Disease (GVHD) Stage | Moderate GVHD | 2 Participants |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Panobinostat (PANO) Therapy | Number of Participants With Non-relapse Mortality | 1 Participants |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Panobinostat (PANO) Therapy | Number of Participants With Primary Disease Relapse | 7 Participants |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panobinostat (PANO) Therapy | Percentage of Participants With Overall Survival (OS) | 87 percentage of participants |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panobinostat (PANO) Therapy | Percentage of Participants With Relapse-free Survival (RFS) | 77 percentage of participants |
Secondary
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.
Time frame: 100 days post transplant
Population: Participants with stable engraftment were analyzed
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Panobinostat (PANO) Therapy | Time to Stable Engraftment | ANC engraftment | 15 days |
| Panobinostat (PANO) Therapy | Time to Stable Engraftment | Platelet engraftment | 16 days |