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

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02588339
• Collaborator: Novartis (Industry)
• Enrollment: 42
• Location: 1
• Arm: 1
• Actual Duration (Months): 64.3
• Patients Per Site Per Month: 0.7

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease; GVHD	Drug: Panobinostat; Drug: Sirolimus; Drug: Tacrolimus	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase II Trial Evaluating the Use of a Histone Deacetylase Inhibitor Panobinostat for Graft Versus Host Disease (GVHD) Prevention
• Actual Study Start Date: Mar 4, 2016
• Actual Primary Completion Date: Dec 7, 2018
• Actual Study Completion Date: Jul 13, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 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.

Drug: Panobinostat; 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.; Other Names: PANO Farydak LBH-589 ; Drug: Sirolimus; 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.; Other Names: SIR Rapamune ; Drug: Tacrolimus; 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.; Other Names: TAC Prograf

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Novartis

Investigators

• Principal Investigator: Lia Perez, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 12, 2018

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT02588339
• Other Study ID Numbers: MCC-18374; CLBH589US100T
• First Posted: Oct 27, 2015
• Last Update Posted: Jul 21, 2021
• Last Verified: Jul 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Hematologic disorder; allogeneic hematopoietic cell transplantation
• Additional relevant MeSH terms: Graft vs Host Disease; Sirolimus; Panobinostat; Tacrolimus

Study Results

Participant Flow

Recruitment Details	Participants recruited between March 2016 and August 2018

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group Description	Participants treated with standard of care chemotherapy agents prior to their allogeneic hematopoietic cell transplant. For Graft Versus Host Disease (GVHD) prevention, participants received PANO, Sirolimus and Tacrolimus. GVHD graded using NIH criteria, scores of 0-3 per area of involvement (e.g; skin, liver and gut) 0 being no symptoms and 3 being symptomatic, over 50% of waking hours in bed, ECOG 3-4.
Period Title: Overall Study
STARTED	42
COMPLETED	39
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
Overall Participants	42
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	29 69%
>=65 years	13 31%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	17 40.5%
Male	25 59.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 16.7%
Not Hispanic or Latino	35 83.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2.4%
White	36 85.7%
More than one race	0 0%
Unknown or Not Reported	4 9.5%
Region of Enrollment (participants) [Number]
United States	42 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
Measure Participants	7
Grade II GVHD	6 14.3%
Grade III GVHD	1 2.4%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
Measure Participants	12
Mild GVHD	10 23.8%
Moderate GVHD	2 4.8%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants with stable engraftment were analyzed

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
Measure Participants	38
ANC engraftment	15
Platelet engraftment	16

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
Measure Participants	39
Count of Participants [Participants]	7 16.7%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
Measure Participants	39
Count of Participants [Participants]	1 2.4%

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
Measure Participants	39
Number [percentage of participants]	87 207.1%

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
Measure Participants	39
Number [percentage of participants]	77 183.3%

Adverse Events

Time Frame	3 years, 6 months
Arm/Group Title	Panobinostat (PANO) Therapy
Arm/Group 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.
All Cause Mortality
	Panobinostat (PANO) Therapy
	Affected / at Risk (%)	# Events
Total	2/39 (5.1%)
Serious Adverse Events
	Panobinostat (PANO) Therapy
	Affected / at Risk (%)	# Events
Total	12/39 (30.8%)
Cardiac disorders
Chest pain - cardiac	1/39 (2.6%)	1
Atrial fibrillation	1/39 (2.6%)	2
Gastrointestinal disorders
Enterocolitis	3/39 (7.7%)	3
Nausea	2/39 (5.1%)	2
General disorders
Edema limbs	2/39 (5.1%)	2
Hepatobiliary disorders
Portal hypertension	1/39 (2.6%)	2
Hepatobiliary disorders - other	2/39 (5.1%)	3
Immune system disorders
Immune system disorders -Other	1/39 (2.6%)	1
Allergic reaction	1/39 (2.6%)	1
Infections and infestations
Upper respiratory infection	1/39 (2.6%)	1
Sepsis	2/39 (5.1%)	2
Sinusitis	2/39 (5.1%)	2
Appendicitis	1/39 (2.6%)	1
Investigations
Aspartate aminotransferase increased -Transiminitis	1/39 (2.6%)	2
Metabolism and nutrition disorders
Anorexia	1/39 (2.6%)	2
Nervous system disorders
Akathisia	1/39 (2.6%)	1
Psychiatric disorders
Confusion	2/39 (5.1%)	2
Renal and urinary disorders
Urinary frequency	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Sinus disorder	1/39 (2.6%)	1
Lung infection	2/39 (5.1%)	2
Pneumonitis	1/39 (2.6%)	1
Pulmonary edema	1/39 (2.6%)	1
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders -Other	1/39 (2.6%)	1
Rash maculo-papular	5/39 (12.8%)	5
Vascular disorders
Hypertension	1/39 (2.6%)	1
Other (Not Including Serious) Adverse Events
	Panobinostat (PANO) Therapy
	Affected / at Risk (%)	# Events
Total	32/39 (82.1%)
Blood and lymphatic system disorders
Leukocytosis	1/39 (2.6%)	1
Cardiac disorders
Atrial fibrillation	2/39 (5.1%)	2
Eye disorders
Floaters	1/39 (2.6%)	1
Gastrointestinal disorders
Nausea	1/39 (2.6%)	1
Diarrhea	2/39 (5.1%)	2
General disorders
Non-cardiac chest pain	1/39 (2.6%)	1
Fever	1/39 (2.6%)	1
Edema limbs	1/39 (2.6%)	1
Immune system disorders
Immune system disorders -Other	1/39 (2.6%)	1
Infections and infestations
Lung Infection	2/39 (5.1%)	2
Sinusitis	2/39 (5.1%)	2
Encephalitis infection	1/39 (2.6%)	1
Sepsis	1/39 (2.6%)	1
Papulopustular rash	1/39 (2.6%)	1
Appendicitis	1/39 (2.6%)	1
Investigations
Neutrophil count decreased	10/39 (25.6%)	12
Platelet count decreased	7/39 (17.9%)	9
Weight loss	1/39 (2.6%)	1
Metabolism and nutrition disorders
Hypocalcemia	4/39 (10.3%)	4
Anorexia	1/39 (2.6%)	1
Nervous system disorders
Headache	1/39 (2.6%)	1
Syncope	1/39 (2.6%)	1
Myelitis	2/39 (5.1%)	2
Akathisia	2/39 (5.1%)	2
Psychiatric disorders
Confusion	1/39 (2.6%)	1
Hallucinations	1/39 (2.6%)	1
Renal and urinary disorders
Acute kidney injury	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/39 (2.6%)	1
Pulmonary edema	1/39 (2.6%)	1
Pleural effusion	1/39 (2.6%)	1
Cough	1/39 (2.6%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	4/39 (10.3%)	5
Bullous dermatitis	1/39 (2.6%)	1
Periorbital edema	2/39 (5.1%)	2
Palmar-plantar erythrodysesthesia syndrome	1/39 (2.6%)	1
Vascular disorders
Hypertension	1/39 (2.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.