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

Phase 2

Completed

Conditions: Graft Versus Host Disease
GVHD

Interventions: Drug: Panobinostat
Drug: Sirolimus
Drug: Tacrolimus

Registration Number: NCT02588339

Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 42

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Panobinostat (PANO) Therapy	Sirolimus	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.
Panobinostat (PANO) Therapy	Tacrolimus	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.
Panobinostat (PANO) Therapy	Panobinostat	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	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.
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.
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.
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 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.