Conditions: Graft Versus Host Disease GVHD
Keywords: Hematologic disorder allogeneic hematopoietic cell transplantation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 42
Healthy volunteers: no

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:

Arms:
arm 1: 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.

Interventions: intervention 1: Panobinostat intervention 2: Sirolimus intervention 3: Tacrolimus
Intervention descriptions: intervention 1: 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 2: 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 3: 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.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 A Phase II Trial Evaluating the use of a Histone Deacetylase Inhibitor Panobinostat for graft versus 
host disease (GVHD) prevention 
 
NCT02588339 
 
Version 9 
April 12, 2018 


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A Phase II Trial Evaluating the use of a Histone Deacetylase Inhibitor Panobinostat for graft 
versus host disease (GVHD) prevention 
 
 
Novartis Protocol No.= CLBH589BUS100T 
 
 
Author(s): 
Principal Investigator:    Lia Elena Perez, MD 
 
Sub-Investigators: 
 
Melissa Alsina, MD 
Brian Betts, MD 
Marco Davila, MD, PhD 
Hugo F. Fernandez, MD 
Linda Kelley, Ph.D. 
Farhad Khimani, MD 
Fred Locke, MD 
Asmita Mishra, MD 
Taiga Nishihori, MD 
Leonel Ochoa, MD 
Joseph Pidala, MD 
 
 
Biostatistician: Xuefeng Wang 
 
H. Lee Moffitt Cancer Center & Research Institute 
Blood and Marrow Transplant Program 
12902 Magnolia Drive 
Tampa, FL 33612 
Telephone:  (813) 745-2557 / Fax: (813) 745-8468 
 
 
 
 
 


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Table of contents 
List of abbreviations ................................................................................................. 5 
1. 
Background and Rationale ....................................................................................... 7 
1.1.  Overview of Allogeneic hematopoietic cell transplantation (HCT) and 
Graft Versus Host Disease (GVHD) prevention ............................................ 7 
1.2.  Overview of Histone deacetylase inhibitors immunomodulation and their 
role in a-GVHD .............................................................................................. 8 
1.3.  HDACi immune-modulatory properties and GVHD role: ............................... 9 
1.4.  Panobinostat use in allogeneic HCT setting: ................................................. 10 
1.5.  Panobinostat Clinical experience ................................................................... 12 
1.6.  Cardiac Safety ................................................................................................ 19 
1.7.  Relationship between panobinostat plasma concentrations and QTcF .......... 20 
1.8.  Human pharmacokinetics............................................................................... 21 
1.9.  Dose proportionality ...................................................................................... 23 
1.10. Food Effect..................................................................................................... 23 
1.11. Study rationale/purpose ................................................................................. 23 
2. 
Study objective ....................................................................................................... 24 
2.1.  Primary Objective .......................................................................................... 24 
2.2.  Secondary Objectives ..................................................................................... 24 
3. 
Overall study design............................................................................................... 26 
3.1.  This study will test PANO in combination with TAC/SIR for acute GVHD 
prevention ..................................................................................................... 27 
3.2.  Site(s): ............................................................................................................ 27 
3.3.  Sample Size and accrual rate ......................................................................... 27 
3.4.  Patient Follow up ........................................................................................... 27 
3.5.  Withdrawal. .................................................................................................... 27 
4. 
Patient Population: Inclusion and Exclusion criteria ............................................. 27 
4.1.  Inclusion Criteria: .......................................................................................... 27 
4.2.  Exclusion Criteria .......................................................................................... 28 
5. 
Intervention/Treatments ......................................................................................... 29 
5.1.  Stem cell mobilization and collection of Donor ............................................ 29 
5.2.  Conditioning regimen: ................................................................................... 29 
5.3.  Supportive Care ............................................................................................. 29 
5.4.  Antifungal Prophylactic Medications ............................................................ 29 
5.5.  Other medications .......................................................................................... 30 
5.6.  EKG monitoring............................................................................................. 31 
5.7.  GVHD prophylaxis ........................................................................................ 34 


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5.7.1.  Standard GVHD prophylaxis regimen: ........................................................ 34 
5.7.1.1 Tacrolimus(TAC) ........................................................................................ 35 
5.7.1.2 Sirolimus (SIR) ........................................................................................... 35 
5.7.1.3 Investigational therapy: Panobinostat (PANO) .......................................... 35 
6. 
GVHD .................................................................................................................... 36 
7. 
Safety assessment ................................................................................................... 37 
7.1.  Anticipated adverse events of the transplant protocol and recommended 
management .................................................................................................. 38 
7.2.  Anticipated events for PANO and recommended .......................................... 39 
8. 
Reasons to hold/discontinue treatment .................................................................. 40 
9. 
Adverse events ....................................................................................................... 43 
9.1.  AE definition .................................................................................................. 44 
9.2.  AE reporting................................................................................................... 46 
9.3.  SAE is an undesirable sign ............................................................................ 47 
9.4.  Special considerations for AE attribution ...................................................... 47 
10. 
Required Evaluations ............................................................................................. 48 
10.1. Demographics ................................................................................................ 48 
10.2. Physical examination ..................................................................................... 48 
10.3. Vital signs ...................................................................................................... 48 
10.4. Laboratory evaluations................................................................................... 48 
10.5. Hematology .................................................................................................... 48 
10.6. Biochemistry .................................................................................................. 49 
10.7. Viral studies ................................................................................................... 49 
10.8. Standard urinalysis ......................................................................................... 49 
10.9. Thyroid function test ...................................................................................... 49 
10.10. Serum pregnancy test ................................................................................... 49 
10.11. Electrocardiogram (ECG) ............................................................................. 49 
10.12. Follow up ...................................................................................................... 49 
10.13. Correlative studies. ....................................................................................... 49 
11. 
Data and Safety monitoring ................................................................................... 50 
11.1. Initial and Ongoing Monitoring and Review ................................................. 50 
11.2. The Scientific Review Committee (SRC) ...................................................... 50 
11.3. The Protocol Review and Monitoring Committee (PRMC) .......................... 51 
11.4. The Cancer Center’s Compliance Office (RCD) ........................................... 51 
11.5. Protocol amendments, or changes in study ................................................ 5152 
11.6. Institutional Review Board/Independent Ethics ............................................ 52 


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11.7. Instructions for data ....................................................................................... 52 
11.8. Data review and management ........................................................................ 54 
12. 
Statistical methods ................................................................................................. 54 
12.1. Sample Size Determination ............................................................................ 54 
12.2. Stopping criteria for toxicity .......................................................................... 55 
12.3. Population for Primary and Secondary Endpoints ......................................... 55 
12.4. Analysis Plan for Primary Endpoint .......................................................... 5556 
12.5. Analysis Plan for Secondary Endpoints ......................................................... 56 
13. 
Procedures and instructions ................................................................................... 56 
13.1. Publication of results.................................................................................. 5657 
13.2. Disclosure and confidentiality ....................................................................... 57 
13.3. Discontinuation of study ................................................................................ 57 
13.4. Ethics and Good Clinical Practice ................................................................. 57 
13.5. Institutional Review Board/Independent Ethics Committee.......................... 57 
13.6. Informed consent ........................................................................................... 58 
14. 
REFERENCES....................................................................................................... 58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of abbreviations 
 
AE 
adverse event 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
Cmax 
maximum concentration of drug 
CNS 
central nervous system 
CR 
complete response/remission 
CS&E 
clinical safety and epidemiology 
CTCAE 
NCI common terminology criteria for adverse events (version 4.0) 
CV 
coefficient of variation 
DLT 
dose-limiting toxicity 
DNA 
deoxyribose nucleic acid 
EKG 
12 lead electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eRT 
eResearchTechnology 
FDA 
food and drug administration 
G-CSF 
granulocyte colony-stimulating factor (e.g. filgrastim) 
GM-CSF 
granulocyte-macrophage colony-stimulating factor (e.g. sargramostim) 
H3, H4 
histones H3, H4 
HAT 
histone acetyltransferase 
HDAC 
histone deacetylase 
HDACi 
histone deacetylase inhibitor 
i.v. 
intravenous(ly) 
IEC 
independent ethics committee 
IRB 
institutional review board 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
mg/m2 
milligrams per square meter 
MTD 
maximum tolerated dose 
MUGA 
multiple uptake gated acquisition scan 
MWF 
monday, wednesday, friday 
NIH 
PANO 
national institutes of health 
panobinostat 
PD 
pharmacodynamic 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic 
PLT 
Platelet 
PR 
partial response 
REB 
research ethics board 


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SAE 
serious adverse event 
SAHA 
suberoylanilide hydroxamic acid 
SOP 
standard operating procedure 
T4 
Thyroxine 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
WNL 
within normal limits 
WOCBP 
women of childbearing potential 
a-GVHD 
Acute Graft versus Host Disease 
SR/D-GVHD steroid-refractory/dependent GVHD  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. Background and Rationale 
1.1. Overview of Allogeneic hematopoietic cell transplantation (HCT) and Graft 
Versus Host Disease (GVHD) prevention 
 
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment 
modality for many patients with hematological malignancies, solid tumors and acquired or 
congenital non-malignant disorders. Despite recent advances in the understanding of 
transplantation immune tolerance, graft versus host disease (GVHD) remains a principal 
obstacle to achieve successful outcomes. Serious infections and impairment of generalized 
immune dysfunction are responsible for GVHD-associated mortality.  GVHD incidence 
and severity depends primarily on donor and recipient matching for human leukocyte 
antigens (HLA) and the regimen used for post-grafting immune suppression.  The NIH 
consensus development project working group recognized 2 main categories of GVHD, 
each with 2 subcategories. The acute GVHD (aGVHD) category is defined in the absence 
of diagnostic or distinctive features of chronic GVHD and includes (1) classic acute 
GVHD occurring within 100 days after transplantation and (2) persistent, recurrent, or late 
acute GVHD (features of acute GVHD occurring beyond 100 days, often during 
withdrawal of immune suppression). The broad category of chronic GVHD (c-GVHD) 
includes (1) classic chronic GVHD (without features or characteristics of acute GVHD) 
and (2) an overlap syndrome in which diagnostic or distinctive features of chronic GVHD 
and acute GVHD appear together.1  
 
Identification of novel agents that can prevent GVHD without compromising graft versus 
tumor (GVT) effect is essential. Ideal GVHD prevention requires a strategy that will 
generate donor immune tolerance to recipient allo-antigens while preserving host immune 
reconstitution and reactivity against tumor and infectious agents. GVHD prevention has 
largely been based on the use of pharmacological agents, and to a lesser degree on 
depletion of T cells from the bone marrow (BM) or blood (PBSC) hematopoietic stem cell 
graft. Randomized phase III clinical studies have shown that the combination of 
tacrolimus (TAC) and methotrexate (MTX) is more effective in preventing GVHD 
compared to cyclosporine (CsA) and MTX following  matched related donor (MRD) 
transplant 2.  A Phase III, multicenter, controlled trial comparing MTX and TAC with 
MTX and CsA for acute GVHD prophylaxis after marrow transplantation from matched 
unrelated donors (MUD), showed that there was a significant trend toward decreased 
severity of acute GVHD with TAC/MTX and established this regimen as state-of the-art 
for GVHD prophylaxis for MUD transplants 3. 
 
Sirolimus (SIR), or rapamycin, is an immunosuppressive medication with potential for 
improving outcomes in allogeneic HCT with dual benefit of both immune suppression and 
anti-malignancy effect. SIR produces at least partial blockade of CD28 mediated co-
stimulatory signaling and is permissive for CD4+CD25+ regulatory T cell (Treg) 
expansion, proliferation, and survival. SIR has also been shown to inhibit differentiation 


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of naïve CD4 T cells to Th17 cells, cells involved in GVHD pathophysiology creating an 
immune tolerant environment. We completed a randomized Phase II trial of TAC and SIR 
vs. TAC and MTX as GVHD prophylaxis after allogeneic transplantation.4 The 100-day 
cumulative incidence of grade 2-4 acute GVHD for SIR was 43% (95% CI 30-63%), and 
89% (95% CI 80-100%) for MTX, p<0.0001. Grade 3-4 acute GVHD for SIR was 16% 
(95% CI 7-36%) and 13% (95% CI 5-33%) for MTX, p=0.16. The incidence of any grade 
chronic GVHD for SIR was 51% (95% CI 34-78%) and 67% (95% CI 52-85%) for MTX, 
p=0.56. The cumulative incidence of moderate to severe chronic GVHD was 20% (95% 
CI 9-43%) following SIR, and 63% (95% CI 47-83%) for MTX, p=0.013. Median percent 
Tregs among blood CD4 T cells at day 30 was 16.3 (range 12.5-17.9) for SIR versus 9.9 
(8.6-13.5) for MTX, p < 0.0001, and 14.6 (10.8-18.1) for SIR and 9.7 (7.5-11.6) for MTX 
at day 90 post-HCT, p = 0.0009. SIR-treated patients had increased absolute numbers of 
Treg, and decreased absolute numbers of non-Treg CD4+ cells on days 30 and 90 after 
HCT supporting the hypothesis 4. 
 
A Phase III, randomized, multicenter, open label clinical trial recently published compared 
TAC/SIR versus TAC/MTX as GVHD prophylaxis using peripheral blood stem cells 
(PBSC) in MRD transplants only. The primary objective was comparison of day+114 
grade II-IV acute GVHD free survival between patients in the two arms from the time of 
randomization using intent-to treat analysis (NCT00406393). The cumulative incidence of 
grade II-IV acute GVHD at 114 days was 34% in the TAC/MTX group and 26 % in the 
TAC/SIR group. Grade III-IV acute GVHD was 15% in TAC/MTX group, and 8 % in 
TAC/SIR group with a rate of chronic GVHD of 43% (TAC/MTX) compared to 54% 
(TAC/SIR). Overall survival did not differ (60% vs. 61%, p NS).5  
 
New immunosuppressive agents and strategies are required for GVHD prevention as 
it might improve survival after allogeneic HCT. In this protocol we will build upon 
prior experience using full intensity conditioning regimen by adding panobinostat 
(PANO) to TAC/SIR GVHD prevention backbone in order to investigate whether we 
can achieve further reductions in the incidence and severity of acute GVHD while 
maintaining a graft versus tumor effect. 
 
1.2. Overview of Histone deacetylase inhibitors immunomodulation and their 
role in a-GVHD 
 
Histones are part of the core proteins of nucleosomes, and acetylation and deacetylation of 
these proteins play a role in the regulation of gene expression. Highly charged 
deacetylated histones bind tightly to the phosphate backbone of DNA, inhibiting 
transcription, presumably, by limiting access of transcription factors and RNA 
polymerases to DNA. Acetylation neutralizes the charge of histones and generates a more 
open DNA conformation. This conformation allows transcription factors and associated 
transcription apparatuses access to the DNA, promoting expression of the corresponding 
genes. The opposing activities of two groups of enzymes, histone acetyltransferases 
(HATs) and Histone protein deacetylases (HDACs) control the amount of acetylation. 
HDACs regulate chromatin remodeling and gene expression as well as the functions of 


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more than 50 transcriptions factors and non-histone proteins such as P53. HATs acetylate 
and HDACs deacetylate, ε-acetylcystein residues of the histone tails. HATs generally 
increase accessibility and gene transcription, whereas HDACs dampen histone-DNA and 
histone/non-histone interactions. In normal cells a balance exists between HAT and 
HDAC activity that leads to cell specific patterns of gene expression. Interruption of this 
balance produces changes in gene expression. Several lines of evidence suggest that 
aberrant recruitment of HDAC and the resulting modification of chromatin structure may 
play a role in changes in gene expression seen in cancer cells suggesting that HDAC 
inhibitors (HDACi) may provide a novel approach to treat malignancies. 6  Silencing of 
tumor suppressor genes at the level of chromatin is common in human tumors7,8 9 10 11 12 
and HDAC complexes have been shown to be crucial to the activity of the AML-specific 
fusion proteins PLZF-RAR-α, PML-RAR-α, and AML1/ETO.13 14 15 16  HDACi have been 
shown to induce differentiation, cell cycle arrest or apoptosis in cultured tumor cells, and 
to inhibit the growth of tumors in animal models.17,18 19 20 21 22 23Tumor growth inhibition 
and apoptosis in response to HDACi treatment may also be mediated through changes in 
acetylation of non-histone proteins (e.g. HSP90, p53, HIF-1α, α-tubulin).24 25 26 Antitumor 
activity has been reported in preclinical studies with valproic acid, PXD101 and 
MGCD0103 and in clinical studies with other HDACi, including intravenous (IV) 
depsipeptide and oral MS-275.27 HDACi suberoylanilide hydroxamic acid (SAHA) has 
been shown to have activity in cutaneous T cell lymphoma (CTCL), diffuse large cell 
lymphoma, and head and neck cancer.   
 
HDACi are very attractive molecules in the allogeneic transplant setting since they have a 
dual effect, anti-tumor activity and immune modulatory effects. PANO is one of most 
potent HDACi known to date in clinical development by Novartis.  PANO effects are 
nonselective, targeting HDACs classes I (HDAC1, 2, 3, 8), class IIA (HDAC4,5,7,9), 
class IIb (HDAC6,10), class III (SIRT1-7), and class IV (HDAC11). The clinical 
development program for PANO includes Phase III clinical trial in multiple myeloma28, 
early-stage trials in acute myeloid leukemia and myelodysplastic syndromes and for 
advanced Hodgkin lymphoma or as maintenance therapy following autologous stem cell 
transplant in this disease.  
 
1.3. HDACi immune-modulatory properties and GVHD role: 
 
A preclinical study demonstrates that PANO significantly impairs the phenotype and 
function of dendritic cells (DCs) to stimulate antigen-specific immune responses and 
represses the production of pro-inflamatory cytokines (IL-6, IL-10, IL-12p70, IL-23 and 
TNF-α).6,29-31  Deacetylase inhibition promotes the generation and function of regulatory 
T cells 32. Preclinical studies in mice have shown that vorinonstat resulted in protection of 
GVHD with moderate efficacy without impairing GVL activity 29,30. Furthermore, Choi et 
al studied the safety and activity of vorinostat, in combination with standard 
immunoprophylaxis, for prevention of GVHD in patients undergoing related-donor 
reduced-intensity conditioning HCT (NCT00810602). All patients (n=50) received a 
conditioning regimen of fludarabine (40 mg/m2 daily for 4 days) and busulfan (3·2 mg/kg 
daily for 2 days) and GVHD immunoprophylaxis of mycophenolate mofetil (1 g three 


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times a day, days 0—28) and tacrolimus (0·03 mg/kg a day, titrated to a goal level of 8—
12 ng/mL, starting day −3 until day 180). Vorinostat (either100 mg or 200 mg, twice a 
day) was initiated 10 days before HCT until day 100. The cumulative incidence of grade 
2-4 acute GVHD by day 100 was 22% (95% CI 13—36). The most common non-
hematological adverse events included electrolyte disturbances (n=15), hyperglycemia 
(n=11), infections (n=6), mucositis (n=4), and increased activity of liver enzymes (n=3). 
Non-symptomatic thrombocytopenia after engraftment was the most common 
hematological grade 3-4 adverse event (n=9) but was transient and all cases resolved 
swiftly. Acetylation of H3 and H4 was increased in PBMC in association with decreased 
TNF-alpha by intracellular staining. Total number of T cells, CD4+ and CD8+ cells were 
not increased although the number of regulatory T cells was increased in association to 
enhanced FOX-P3 and IDO expression by RT-PCR. In summary, administration of 
vorinostat proved safe and was associated with a lower than expected incidence of severe 
acute GVHD establishing HDACi role in GVHD prevention in patients undergoing 
related-donor reduced-intensity conditioning HCT 33 which is a less stringent setting 
compared to the one that we proposed in this study  (full intensity conditioning and 
matched unrelated donors).  
 
1.4. Panobinostat use in allogeneic HCT setting: 
 
Pan-HDACi in allogeneic BMT may have different effects and encourages investigations 
to study the function of individual HDAC members which are not elucidated to date. 
PANO tested in murine models accelerated GVHD compared to vorinostat which was 
unexpected but has not translated in humans in 2 ongoing clinical trials discussed herein. 
Pathological changes in mice showed increased liver damage without significant changes 
in colon or small intestine. Changes were associated with increased systemic Th1 
cytokines, enhanced CXCR3 expression on donor CD4+ and CD8+ T cells, and T cell 
infiltration in the liver 34. 
 
In parallel to the development of murine models, we have tested the safety of PANO 
administered to patients with acute GVHD within 72 hours of initiation of glucocorticoid 
therapy (methylprednisolone 0.8 mg/Kg/day IV or equivalent for at least 14 days) as first 
line therapy. As of November 2014, We have enrolled 20 subjects, median age 53 years (range, 
34-76), male (n=13)/female (n=7), white(n=15)/hispanic(n=5); with diagnosis of CLL (n=2), MDS 
(n=2), Myeloma (n=1),  Follicular NHL (n=1), CML(n=1), Myelofibrois (n=3), AML (n=6), 
MDS/CMML 
(n=3) 
or 
ALL(n=1). 
Conditioning 
regimens 
included 
Busulfan(BU)/fludarabine(FLU)  AUC 5300 (n=10) or AUC 3500 (n=3), FLU/Melphalan (n=5) or 
Pentostatin/BU (n=2); and GVHD prophylaxis for MUD 8/8 (n=11) or MRD (n=5) HCT with 
TAC/MTX (n=7), TAC/rapamycin(n=7)(sirolimus-SIR), TAC/MMF(n=3) and for mismatched 
transplants with either TAC/SIR/ATG (n=2) or TAC/MTX/ATG (n=1). Median day of acute 
GVHD (n=19) onset was day + 37 post HCT (26 -100 days) with overall grade GVHD II (n=) or 
III (n=6); and median day of acute symptoms in overlap GVHD patients (n=5) was day + 528 
(109-981). All Patients were treated with voriconazole (n=14) or micafungin (n=5) for fungal 
prophylaxis. For the first four patients Panobinostat was administered intravenously (IV) weekly x 
4 at 2.5MG/M2 (n=3) or 5MG/M2 IV (n=1) with all 4 achieving either CR (n=3) or PR (n=1) 
GVHD responses by day +15 of Panobinostat. Due to manufacturer discontinuation of IV 


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formulation, the protocol was amended to use PO Panobinostat. Using 10mg PO TIW 3 doses q 
week x 4 weeks, we treated 2 subjects which were both discontinued from study drug due to 
presumed GHVD progression within 7 days of Panobinostat (after 3-4 doses). First subject had 
grade II GVHD (skin stage 3, gut stage 1 and liver stage 0) that progress in gut and skin; second 
subject with grade II GVHD (skin stage 3, gut stage 1, liver stage 1) with LFTs worsening 
ultimately evolving into VOD. Due to safety concerns next subjects were treated with 5 mg PO 
TIW 3 doses q week x 4 weeks, dose that was determined to be the maximal tolerated dose (MTD) 
after 6 patients completed therapy in phase I. Currently we are enrolling in phase II portion (n=8). 
GVHD response rate among MTD treated was complete in 86% (n=12), partial in 7.6% (n=1) or 
progressive in 7.6% (n=1) by day +36 after Panobinostat with majority achieving responses by day 
+21. Chronic GVHD at day +365 in evaluable patients (n=6) was none (n=3) or mild (n=3) and 
steroid was discontinued at a median of 3 months (3-6). Hematological toxicities in evaluable 
patients (n=14) were mild with worsening of prior thrombocytopenia (n=8/10), anemia (n=3/10) 
and leukopenia (n=3/10) and returned to baseline within 1-2 weeks; LFTs deterioration (n=1) 
within 1 week of Panobinostat in a GVHD stage 3 liver/3 skin patient; pericarditis/cardiogenic 
shock CTCAE(v4) 5 of unclear etiology (n=1); worsening thyroid function (n=1) and 
hypercholesterolemia (n=1). Preliminary correlative studies in MTD treated patients showed that 
CD4 and CD8 numbers remained stable during treatment. T regulatory cells numbers decreased at 
day +8 after Panobinostat and recovered by days +15 and +29 of treatment. Level of T regs 
inducing cytokines (TGFB and IL-10) increased, possibly contributing to an immune-modulatory 
environment.  There is evidence of an increased in acetylation of histone 3 in CD4, CD8 and 
monocytes subsets over time. We are encouraged with tolerability of level -1 Panobinostat dose 
and the high GVHD response rate of 86% which may compare favorably to the historical GVHD 
response rate. These results suggest a potential role for Panobinostat as a tool to improve success 
of glucocorticoids for acute GVHD treatment35. 
 
Phase I/II Study with oral PANO maintenance therapy following allogeneic HCT in 
patients with MDS or AML (PANOBEST) (NCT01451268) has been reported by Dr. Bug 
et al 36. PANO was started at a median of 73 days (range, 60-126) after HCT, for patients 
with active disease (n=11) or in CR2 (n=1) in 12 patients (11 AML, 1 MDS), median age 
of 52 years (range, 21-62). The MTD was determined to be 20 mg TIW based on one DLT 
(fatigue grade 3) at 20 mg and two DLTs (nausea/emesis and colitis grade 3 each) at 30 
mg. Grade 2-4 adverse events (AEs) were reported in 83%. Grade 3/4 AEs included 
hematologic toxicity (50%), laboratory alterations (33%), gastrointestinal symptoms 
(25%), fatigue, pulmonary infection (17% each), sepsis, herpes stomatitis, diabetes, 
syncope, deep vein thrombosis and pulmonary embolism (8% each). Toxicity was 
reversible and required at least one PANO dose reduction in 3 patients. As of ASH 2013, 
acute GVHD was reported in few patients (grade 2 (n=1) and 3 (n=2) responsive to 
steroids (n=2) or salvage therapy (n=1). Four patients developed mild (n=3) or moderate 
(n=1) chronic GVHD. With a median follow up of 579 days (range, 129-911), 11/12 
patients are alive and 10/12 in continuous CR after HCT. Immunophenotyping revealed 
no impact of PANO on absolute T reg numbers (n=9), but a significantly reduced 
proportion of CD4+CD25++CD127dim/- T reg to CD3+CD4+ T helper (Th) cells by day 8 
after 3 doses of PANO (mean±SEM: 14.6±2.6 vs. 9.6±1.2%, p value of t test =0.03). 
PANO was well tolerated with low relapse rate in this high risk population in association 
with modulation of the T reg/Th proportion. A Phase II Study using PANO as Second-
Line Therapy in Patients with Chronic GVHD is reported at clinicaltrial.gov 


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(NCT01028313). To date, two clinical protocols reporting the use of PANO in the 
allogeneic HCT patients have proven to be safe and may provide GVHD control with 
additive function to target MRD.  
 
Summary of trial rationale: The burden of acute GVHD that remains despite current 
preventive strategies makes clear the rationale for novel approaches. Our clinical 
results demonstrate reduction in acute GVHD, suppression of non-Treg CD4 cells, 
and significantly improved Treg reconstitution with SIR/TAC over MTX/TAC acute 
GVHD prophylaxis. However, prevention is not complete. PANO is a potent and 
versatile inhibitor that targets various proteins in the cells and has been shown to be 
active in vorinostat resistant cancers which is an advantage. This protocol will test 
the hypothesis that addition of PANO to TAC/SIR may abolish GVHD in matched 
related or unrelated HCT while sparing GVL effect. Accordingly, the combination of 
SIR-based immune suppression and PANO may more effectively facilitate Treg 
differentiation, may inhibit the differentiation of pathogenic Th1 and Th17 cells, and 
more effectively prevent acute GVHD based on known biological activity and role in 
GVHD treatment while potentially targeting minimal residual disease. 
We will test this hypothesis in a single arm phase II clinical trial testing potential 
reduction of acute GVHD incidence, from 50% to 30%, with screening intent to 
discern biologic and potential clinical activity of PANO worthy of a larger 
randomized trial. HDACs are a diverse family of enzymes acting on various 
substrates and HDACi mechanism in GVHD remains unknown to date. We 
hypothesize that PANO has a higher efficacy in preventing GVHD while sparing 
GVL effect. The findings of this study should indicate whether the effect noted with 
vorinostat is shared by additional non-selective HDACi and/or if have a superior 
efficacy or fewer toxic effects and/or adverse effects in patients receiving a full-
intensity conditioning regimen using matched unrelated/related donors.37 
1.5.Panobinostat Clinical experience 
Clinical development of PANO focuses on the oral formulation. The clinical program for 
the i.v. formulation is completed with no further company-sponsored studies currently 
planned. As of 31 December 2013, 36 clinical studies, including clinical pharmacology 
(CP), Phase I and Phase II trials, as well as two randomized Phase III studies have either 
been completed or are ongoing. A total of 2428 patients were enrolled, 235 for i.v. and 
2193 for oral, who received at least one dose of PANO either as a single agent or in 
combination with other agents.  
Patients were treated with PANO either TIW QW (666 patients) or TIW QOW (96 
patients) in single agent oral PANO clinical trials. These patients comprise the pooled 
safety population experiencing AEs during study treatment. The most frequent non-
hematologic toxicity included GI events (diarrhea, nausea, vomiting), mostly of Grade 1-
2, in both groups. Blood and lymphatic system disorders were the second most often 
reported specific system organ class, with dose-related thrombocytopenia being the most 
frequent AE. Fatigue, mostly Grade 1-2, was also common among patients treated for 
TIW QW and TIW QOW. 


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Thyroid function, as monitored by the measurement of TSH and free T4, did not reveal 
overt hyper- or hypo- thyroidism, with fluctuations in TSH values being within normal 
limits. 
 
Table 1            All grade adverse events regardless of causality in patients receiving oral 
panobinostat three-times-a-week every-week (TIW QW) 
Primary system 
organ class 
Preferred term 
20 mg 
(N=309 
n      % 
30 mg 
(N=81) 
n      % 
40 mg 
(N=163) 
n      % 
60 mg 
(N=113) 
n      % 
TOTAL 
(N=666) 
n      % 
-Any primary system organ class 
-Total 
307 (99.4) 
81 
(100.0) 
163(100.0) 
113(100.0) 
664 (99.7) 
Blood and lymphatic system disorders 
-Total 
193 (62.5) 
50 (61.7) 
145 (89.0) 
87 (77.0) 
475 (71.3) 
Anaemia 
63 (20.4) 
32 (39.5) 
65 (39.9) 
35 (31.0) 
195 (29.3) 
Febrile neutropenia 
9 (2.9) 
0 (0.0) 
7 (4.3) 
33 (29.2) 
49 (7.4) 
Leukopenia 
19 (6.1) 
1(1.2) 
18 (11.0) 
4 (3.5) 
42 (6.3) 
Neutropenia 
53 (17.2) 
4 (4.9) 
48 (29.4) 
29 (25.7) 
134 (20.1) 
Thrombocytopenia 
133 
( 43.0) 
31(38.3) 
137(84.0) 
58 (51.3) 
359 (53.9) 
Endocrine disorders 
-Total 
21 (6.8) 
7 (8.6) 
27 (16.6) 
9 (8.0) 
64 (9.6) 
Hypothyroidism 
15 (4.9) 
3 (3.7) 
21 (12.9) 
4 (3.5) 
43 (6.5) 
Gastrointestinal disorders 
-Total 
246 (79.6) 
76 (93.8) 
152 (93.3) 
107(94.7) 
581(87.2) 
Abdominal pain 
33 (10.7) 
11 (13.6) 
30 (18.4) 
23 (20.4) 
97 (14.6) 
Abdominal pain 
upper 
26 (8.4) 
5 (6.2) 
24 (14.7) 
9(  8.0) 
64(  9.6) 
Constipation 
46 (14.9) 
15 (18.5) 
32 (19.6) 
24 (21.2) 
117( 17.6) 
Diarrhoea 
158 (51.1) 
46 (56.8) 
117 (71.8) 
85 (75.2) 
406 (61.0) 
Dry mouth 
17 (5.5) 
6 (7.4) 
22 (13.5) 
9 (8.0) 
54 (8.1) 
Nausea 
142( 46.0) 
51( 63.0) 
112( 68.7) 
67( 59.3) 
372( 55.9) 
Vomiting 
68( 22.0) 
33( 40.7) 
73( 44.8) 
47( 41.6) 
221( 33.2) 
General disorders and administration site conditions 
-Total 
229( 74.1) 
70( 86.4) 
137( 84.0) 
98( 86.7) 
534( 80.2) 
Asthenia 
52( 16.8) 
6(  7.4) 
29( 17.8) 
21( 18.6) 
108( 16.2) 
Chills 
19(  6.1) 
4(  4.9) 
13(  8.0) 
17( 15.0) 
53(  8.0) 
Fatigue 
126( 40.8) 
56( 69.1) 
85( 52.1) 
59( 52.2) 
326( 48.9) 
Oedema peripheral 
62( 20.1) 
21( 25.9) 
30( 18.4) 
24( 21.2) 
137( 20.6) 
Pyrexia 
61( 19.7) 
18( 22.2) 
67( 41.1) 
47( 41.6) 
193( 29.0) 


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Primary system 
organ class 
Preferred term 
20 mg 
(N=309 
n      % 
30 mg 
(N=81) 
n      % 
40 mg 
(N=163) 
n      % 
60 mg 
(N=113) 
n      % 
TOTAL 
(N=666) 
n      % 
Infections and infestations 
-Total 
152( 49.2) 
40( 49.4) 
101( 62.0) 
76( 67.3) 
369( 55.4) 
Sepsis 
6(  1.9) 
3(  3.7) 
4(  2.5) 
13( 11.5) 
26(  3.9) 
Upper respiratory 
tract infection 
12(  3.9) 
5(  6.2) 
24( 14.7) 
4(  3.5) 
45(  6.8) 
Urinary tract 
infection 
23(  7.4) 
11( 13.6) 
10(  6.1) 
7(  6.2) 
51(  7.7) 
Investigations 
-Total 
143( 46.3) 
40( 49.4) 
71( 43.6) 
57( 50.4) 
311( 46.7) 
Blood creatinine 
increased 
37( 12.0) 
7(  8.6) 
13(  8.0) 
13( 11.5) 
70( 10.5) 
Platelet count 
decreased 
13(  4.2) 
14( 17.3) 
4(  2.5) 
7(  6.2) 
38(  5.7) 
Weight decreased 
44( 14.2) 
12( 14.8) 
30( 18.4) 
22( 19.5) 
108( 16.2) 
Metabolism and nutrition disorders 
-Total 
179( 57.9) 
56( 69.1) 
92( 56.4) 
83( 73.5) 
410( 61.6) 
Anorexia 
45( 14.6) 
10( 12.3) 
16(  9.8) 
24( 21.2) 
95( 14.3) 
Decreased appetite 
49( 15.9) 
30( 37.0) 
49( 30.1) 
31( 27.4) 
159( 23.9) 
Dehydration 
12(  3.9) 
12( 14.8) 
13(  8.0) 
19( 16.8) 
56(  8.4) 
Hypocalcaemia 
22(  7.1) 
3(  3.7) 
8(  4.9) 
21( 18.6) 
54(  8.1) 
Hypokalaemia 
33( 10.7) 
11( 13.6) 
28( 17.2) 
35( 31.0) 
107( 16.1) 
Hypophosphataemia 
25(  8.1) 
1(  1.2) 
9(  5.5) 
14( 12.4) 
49(  7.4) 
Musculoskeletal and connective tissue disorders 
-Total 
114( 36.9) 
29( 35.8) 
90( 55.2) 
43( 38.1) 
276( 41.4) 
Back pain 
35( 11.3) 
8(  9.9) 
30( 18.4) 
13( 11.5) 
86( 12.9) 
Muscle spasms 
19(  6.1) 
6(  7.4) 
32( 19.6) 
2(  1.8) 
59(  8.9) 
Myalgia 
16(  5.2) 
1(  1.2) 
17( 10.4) 
2(  1.8) 
36(  5.4) 
Nervous system disorders 
-Total 
147( 47.6) 
36( 44.4) 
86( 52.8) 
52( 46.0) 
321( 48.2) 
Dizziness 
42( 13.6) 
14( 17.3) 
15(  9.2) 
10(  8.8) 
81( 12.2) 
Dysgeusia 
44( 14.2) 
13( 16.0) 
28( 17.2) 
22( 19.5) 
107( 16.1) 
Headache 
49( 15.9) 
14( 17.3) 
34( 20.9) 
16( 14.2) 
113( 17.0) 
Psychiatric disorders 
-Total 
65( 21.0) 
17( 21.0) 
43( 26.4) 
38( 33.6) 
163( 24.5) 
Anxiety 
12(  3.9) 
3(  3.7) 
18( 11.0) 
9(  8.0) 
42(  6.3) 
Insomnia 
20(  6.5) 
10( 12.3) 
14(  8.6) 
19( 16.8) 
63(  9.5) 
Respiratory, thoracic and mediastinal disorders 
-Total 
117( 37.9) 
42( 51.9) 
97( 59.5) 
53( 46.9) 
309( 46.4) 


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Primary system 
organ class 
Preferred term 
20 mg 
(N=309 
n      % 
30 mg 
(N=81) 
n      % 
40 mg 
(N=163) 
n      % 
60 mg 
(N=113) 
n      % 
TOTAL 
(N=666) 
n      % 
Cough 
30(  9.7) 
11( 13.6) 
48( 29.4) 
19( 16.8) 
108( 16.2) 
Dyspnoea 
49( 15.9) 
28( 34.6) 
32( 19.6) 
20( 17.7) 
129( 19.4) 
Epistaxis 
16(  5.2) 
3(  3.7) 
22( 13.5) 
20( 17.7) 
61(  9.2) 
Skin and subcutaneous tissue disorders 
-Total 
147( 47.6) 
21( 25.9) 
73( 44.8) 
38( 33.6) 
279( 41.9) 
Pruritus 
56( 18.1) 
3(  3.7) 
22( 13.5) 
3(  2.7) 
84( 12.6) 
Vascular disorders 
-Total 
61( 19.7) 
17( 21.0) 
26( 16.0) 
33( 29.2) 
137( 20.6) 
Hypotension 
18(  5.8) 
4(  4.9) 
10(  6.1) 
18( 15.9) 
50(  7.5) 
Includes only events occurring in ≥10% of patients 
A patient with multiple occurrences of an AE is counted only once in that AE category. 
A patient with multiple adverse events within a primary system organ class is counted only once in the total row. 
If an AE frequency matches the criteria in one dose category, the frequency of that event is shown for all doses. 
Primary system organ classes are presented alphabetically; preferred terms are sorted within primary system organ class 
alphabetically. 
 
As shown in Table 1 above, AEs regardless of causality for TIW QW dosing were 
reported in 664 patients, 99.7% of the safety population for this dosing schedule. The most 
commonly reported AEs across doses were gastrointestinal (GI), i.e., diarrhea in 406 
patients (61.0%) and nausea in 372 patients (55.9%). Thrombocytopenia was the third 
most frequent AE in 359 patients (53.9%) with the highest frequency in the 40 mg dose 
level (137 patients; 84%). Fatigue also was commonly seen across dose levels in 326 
patients (48.9%) overall. Of note hypothyroidism was reported in 12.9% of patients 
treated at the dose level of 40 mg, mostly deriving from study [CLBH589E2214] in HL 
patients who are known to have an increased risk for hypothyroidism. 


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Table 2 Grade 3-4 adverse events regardless of causality in patients receiving oral 
panobinostat three-times-a-week every-week (TIW QW) 
 
Primary system organ 
class 
20 mg 
30 mg 
40 mg 
60 mg 
Total 
Preferred term 
N=309 
N=81 
N=163 
N=113 
N=666 
n  (%) 
n  (%) 
n  (%) 
n  (%) 
n  (%) 
-Any primary system organ class 
-Total 
209( 
67.6) 
70( 
86.4) 
150(92.0) 
105(92.9) 
534( 
80.2) 
Blood and lymphatic system disorders 
-Total 
120( 
38.8) 
26( 
32.1) 
138(84.7) 
84( 74.3) 
368( 
55.3) 
Anaemia 
29( 9.4) 
8( 9.9) 
35( 21.5) 
31( 27.4) 
103( 
15.5) 
Febrile neutropenia 
9( 2.9) 
0( 0.0) 
6( 3.7) 
31( 27.4) 
46(  6.9) 
Leukocytosis 
4( 1.3) 
2( 2.5) 
0( 0.0) 
3(2.7) 
9( 1.4) 
Leukopenia 
2( 0.6) 
0( 0.0) 
11(  6.7) 
4(  3.5) 
17(  2.6) 
Neutropenia 
42( 
13.6) 
4( 4.9) 
39( 23.9) 
26( 23.0) 
111( 
16.7) 
Thrombocytopenia 
66( 
21.4) 
21( 
25.9) 
129( 
79.1) 
56( 49.6) 
272( 
40.8) 
Gastrointestinal disorders 
-Total 
24( 7.8) 
20( 
24.7) 
24( 14.7) 
31( 27.4) 
99( 
14.9) 
Abdominal pain 
5(  1.6) 
3(  3.7) 
7(  4.3) 
2(  1.8) 
17(  2.6) 
Ascites 
0(  0.0) 
4(  4.9) 
0(  0.0) 
0(  0.0) 
4(  0.6) 
Diarrhoea 
10(  3.2) 
6(  7.4) 
6(  3.7) 
18( 15.9) 
40(  6.0) 
Nausea 
6(  1.9) 
6(  7.4) 
2(  1.2) 
7(  6.2) 
21(  3.2) 
Vomiting 
4(  1.3) 
3(  3.7) 
4(  2.5) 
3(  2.7) 
14(  2.1) 
General disorders and administration site conditions 
-Total 
35( 
11.3) 
25( 
30.9) 
38( 23.3) 
41( 36.3) 
139( 
20.9) 
Asthenia 
8(2.6) 
2(2.5) 
7(4.3) 
10(8.8) 
27( 4.1) 
Fatigue 
13(4.2) 
19( 
23.5) 
26( 16.0) 
24( 21.2) 
82( 
12.3) 
General physical 
health deterioration 
6(1.9) 
2(2.5) 
0(0.0) 
1(0.9) 
9(1.4) 
Pain 
3(1.0) 
0(0.0) 
0(0.0) 
3(2.7) 
6(0.9) 
Pyrexia 
4(1.3) 
1(1.2) 
4(2.5) 
2(1.8) 
11(1.7) 
Hepatobiliary disorders 
-Total 
3(1.0) 
3( 3.7) 
6(3.7) 
3(2.7) 
15(2.3) 
Hyperbilirubinaemia 
2(0.6) 
0(0.0) 
4(2.5) 
2(1.8) 
8(1.2) 
Infections and infestations 
-Total 
37( 
12.0) 
12( 
14.8) 
27( 16.6) 
49( 43.4) 
125( 
18.8) 


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Bacterial infection 
0(0.0) 
0(0.0) 
1(0.6) 
5(4.4) 
6(0.9) 
Infection 
1(0.3) 
2(2.5) 
1( 0.6) 
1(0.9) 
5(0.8) 
Pneumonia 
7( 2.3) 
2(2.5) 
6(3.7) 
6 ( 5.3) 
21(3.2) 
Sepsis 
5(1.6) 
3( 3.7) 
4( 2.5) 
9( 8.0) 
21(3.2) 
Septic shock 
2(0.6) 
1(1.2) 
1(0.6) 
3(2.7) 
7(1.1) 
Urinary tract 
infection 
1( 0.3) 
3(3.7) 
0( 0.0) 
3( 2.7) 
7(1.1) 
Investigations 
-Total 
39( 
12.6) 
14( 
17.3) 
22( 13.5) 
26( 23.0) 
101( 
15.2) 
Alanine 
aminotransferase 
increased 
1(0.3) 
1(1.2) 
4(2.5) 
1(0.9) 
7(1.1) 
Aspartate 
aminotransferase 
increased 
1(0.3) 
0(0.0) 
5(3.1) 
1(0.9) 
7(1.1) 
Electrocardiogram 
qt prolonged 
6(1.9) 
1(1.2) 
0(0.0) 
4(3.5) 
11(1.7) 
Platelet count 
decreased 
8(2.6) 
7(8.6) 
3(1.8) 
6(5.3) 
24(3.6) 
Weight decreased 
2(0.6) 
1(1.2) 
4(2.5) 
1(0.9) 
8(1.2) 
Metabolism and nutrition disorders 
-Total 
42( 
13.6) 
16( 
19.8) 
27( 16.6) 
38( 33.6) 
123( 
18.5) 
Anorexia 
3(1.0) 
1(1.2) 
2(1.2) 
5(4.4) 
11(1.7) 
Decreased appetite 
2(0.6) 
0( 0.0) 
5(3.1) 
3( 2.7) 
10(1.5) 
Dehydration 
2(0.6) 
4(4.9) 
2(1.2) 
5( 4.4) 
13( 2.0) 
Failure to thrive 
1(0.3) 
2(2.5) 
0(0.0) 
0( 0.0) 
3( 0.5) 
Hyperglycaemia 
6(1.9) 
1(1.2) 
3(1.8) 
5(4.4) 
15(2.3) 
Hypoalbuminaemia 
1(0.3) 
2(2.5) 
1(0.6) 
0( 0.0) 
4(0.6) 
Hypocalcaemia 
4(1.3) 
0(0.0) 
1( 0.6) 
5(4.4) 
10(1.5) 
Hypokalaemia 
10(3.2) 
3(3.7) 
9(5.5) 
15( 13.3) 
37(5.6) 
Hyponatraemia 
7(2.3) 
3(3.7) 
2(1.2) 
2(1.8) 
14(2.1) 
Hypophosphataemia 
7(2.3) 
1(1.2) 
5(3.1) 
10(8.8) 
23(3.5) 


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Musculoskeletal and connective tissue disorders 
-Total 
18(  5.8) 
2(  2.5) 
12(  7.4) 
7(  6.2) 
39(  5.9) 
Back pain 
5(  1.6) 
1(  1.2) 
4(  2.5) 
2(  1.8) 
12(  1.8) 
Nervous system 
disorders 
 
 
 
 
 
-Total 
24(  7.8) 
4(  4.9) 
16(  9.8) 
14( 12.4) 
58(  8.7) 
Lethargy 
1(  0.3) 
0(  0.0) 
5(  3.1) 
4(  3.5) 
10(  1.5) 
Respiratory, thoracic and mediastinal disorders 
-Total 
17(  5.5) 
14( 
17.3) 
18( 11.0) 
10(  8.8) 
59(  8.9) 
Dyspnoea 
10(  3.2) 
8(  9.9) 
8(  4.9) 
1(  0.9) 
27(  4.1) 
Hypoxia 
0(  0.0) 
2(  2.5) 
2(  1.2) 
3(  2.7) 
7(  1.1) 
Pleural effusion 
3(  1.0) 
2(  2.5) 
1(  0.6) 
0(  0.0) 
6(  0.9) 
Pulmonary embolism 
1(  0.3) 
2(  2.5) 
3(  1.8) 
0(  0.0) 
6(  0.9) 
Skin and subcutaneous tissue disorders 
-Total 
20(  6.5) 
1(  1.2) 
6(  3.7) 
4(  3.5) 
31(  4.7) 
Pruritus 
9(  2.9) 
0(  0.0) 
3(  1.8) 
1(  0.9) 
13(  2.0) 
Vascular disorders 
-Total 
8(  2.6) 
5(  6.2) 
9(  5.5) 
8(  7.1) 
30(  4.5) 
Hypertension 
1(  0.3) 
2(  2.5) 
1(  0.6) 
1(  0.9) 
5(  0.8) 
Hypotension 
3(  1.0) 
1(  1.2) 
4(  2.5) 
5(  4.4) 
13(  2.0) 
Includes only events occurring ≥ 2% of patients in any dose group. 
A patient with multiple occurrences of an AE is counted only once in that AE category. 
A patient with multiple adverse events within a primary system organ class is counted only once in the total row. 
Primary system organ classes are presented alphabetically; preferred terms are sorted 
within primary system organ class alphabetically. 
If an AE frequency matches the criteria in one dose category, the frequency of that event is shown for all doses. 
 
 
As shown in Table 2 above, Grade 3-4 AEs regardless of causality were reported in 534 
patients, 80.2% of the safety population for the QW schedule. The most commonly 
reported Grade 3-4 AEs across doses were thrombocytopenia in 272 patients (40.8%), 
neutropenia in111 patients (16.7%), anemia in 103 patients (15.5%), fatigue in 82 
patients (12.3%) and febrile neutropenia in 46 patients (6.9%). There were more Grade 
3-4 hematologic AEs at higher dose levels, with the highest incidences at 40 and 60 
mg. The highest incidence of febrile neutropenia was seen at the dose level of 60 mg 
(27.4%) compared to the other dose levels where the incidence was ≤ 3.7%. This could 
be 
because 
this 
dose 
level 
was 
only 
tested 
in  leukemia   patients,   in   whom   febrile   neutropenia   is   a   common 
AE.   Grade   3-4 thrombocytopenia,  grade  3-4  neutropenia  and  grade  3-
4  anemia  accounted  for  75.7% (272/359), 82.8% (111/134) and 52.8% (103/195) of 
their respective all grade events. Grade3-4 diarrhea, Grade 3-4 vomiting and Grade 3-4 
nausea accounted for less than 10% of their respective all grades events (see also Table 


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1).For the TIW QOW dosing schedule, AEs regardless of causality were reported in 96 
patients, which is 100% of the safety population. The most commonly reported AEs (all 
grades) across doses were diarrhea in 65 patients (67.7%), nausea in 60 patients 
(62.5%), fatigue in 54 patients (56.3%), vomiting in 42 patients (43.8%), 
thrombocytopenia in 41 patients (42.7%), pyrexia in 35 patients (36.5%) and anorexia in 
33 patients (34.4%). 
 
In the TIWQOW schedule, Grade 3-4 AEs regardless of causality were reported in 81 
patients, 84.4% of the safety population. The most commonly reported Grade 3-4 AEs 
across doses were thrombocytopenia in 35 patients (36.5%), neutropenia in 25 patients 
(26.0%), fatigue in 14 patients (14.6%), diarrhea in 11 patients (11.5%), anemia in 10 
patients (10.4%), and febrile neutropenia in 8 patients each (8.3%). 
 
Overall, the most frequent Grade 3-4 AEs regardless of causality for both schedules 
(TIWQW and TIWQOW) were ascribed to the same SOC, namely blood and 
lymphatic system disorders. 
1.6. Cardiac Safety 
 
As of 31 December 2013, cardiac safety data for 666 patients treated with oral PANO 
TIW QW are presented in Table 3. All patients underwent intensive pre- and post-dose 
ECG monitoring intended to measure the occurrence of QTcF (Fridericia Correction 
Formula) and to capture other ECG abnormalities as well. The most common finding 
continues to be a post-baseline QTcF increase of >30 and ≤60 msec with both dosing 
schedules (approximately 22%). No cases of torsades de pointes have been observed with 
either oral dosing schedule. 
QTcF abnormalities are shown in Table 1-3, for the QW schedule. 
 
Table 3.  QTcF changes in patients receiving oral panobinostat three-times-a-week 
every-week (TIW QW) 
QTcF 
variable 
20 mg 
(N=309 
Total  n  % 
30 mg 
(N=81) 
Total  n  % 
40 mg 
(N=163) 
Total  n  % 
60 mg 
(N=113) 
Total  n  % 
TOTAL 
(N=666) 
Total  n  % 
QTcF 
increase 
from 
baseline 
> 30 and 
<= 60 
ms 
309  47 
(15.2) 
81  12 
(14.8) 
163  46 
(28.2) 
113  38 
(33.6) 
666 143 
(21.5) 
QTcF 
increase 
from 
baseline 
> 60 ms 
309   7 
( 2.3) 
81   1 
( 1.2) 
163   6 
( 3.7) 
113  13 
(11.5) 
666  27 
( 4.1) 


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Absolute 
QTcF > 
450 and 
<= 480 
ms 
305  38 
(12.5) 
81  10 
(12.3) 
162  13 
( 8.0) 
110  27 
(24.5) 
658  88 
(13.4) 
Absolute 
QTcF > 
480 ms 
and <= 
500 ms 
309   5 
( 1.6) 
81   1 
( 1.2) 
163   4 
( 2.5) 
113   7 
( 6.2) 
666  17 
( 2.6) 
Absolute 
QTcF > 
500 ms 
309   1 
( 0.3) 
81   0 
( 0.0) 
163   0 
( 0.0) 
113   5 
( 4.4) 
666   6 
( 0.9) 
N= Number of patients in the group. 
n= Number of patients at risk for a designated change with both non-missing baseline and post-baseline values. 
Patients are counted only for the worst grade observed post-baseline. 
As shown in Table 3 above, post-baseline increase of >30 and ≤60 msec (Grade 1) was 
frequently reported (143 patients, 21.5%). A post-baseline increase of >60 msec was less 
frequent (27 patients, 4.1%). QTcF prolongation translating into an absolute value of 450 
to 480 msec and of > 480 - 500 msec was measured in 88 patients (13.4%) and in 17 
patients (2.6%), respectively. Absolute QTcF prolongation > 500 msec was uncommon (6 
patients, 0.9%), mostly referred to 5 patients treated at 60 mg weekly dose level. For the 
QOW schedule, post-baseline increased values of >30 and ≤60 msec were observed in 16 
(16.7%) patients. Post-baseline increase of >60 msec was less frequent (4 patients, 4.2%). 
Absolute QTcF prolongation values of 450 msec to 480 and of >480 to 500 msec were 
reported in 9 patients (9.6%) and in 1 patient (1.0%), respectively. Absolute QTcF 
prolongation above 500 msec was not observed. 
 
 
1.7.  Relationship between panobinostat plasma concentrations and QTcF 
 
As presented in Figure 2 (po) below, the maximum change of QTcF from baseline does 
not coincide with the peak plasma concentration-time course of PANO suggesting a 
possible delayed effect.   
 
Figure 2  QTcF change from baseline over time vs. PANO conc-time course following 
the first oral PANO doses of a MWF schedule 


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All data points with n>3, all dose levels
QTcF change
PK conc
-10
0
10
20
Time from dose (hr)
0
10
20
30
40
50
0
10
20
30
40
 
 
1.8. Human pharmacokinetics 
 
After oral administration, PANO is rapidly absorbed with no observed lag phase. 
Maximum plasma concentrations were generally reached within 1 hour after oral dosing. 
The absolute bioavailability was 30% (data on file) and the mean (SD) half-life of PANO 
was comparable following i.v. and oral dosing ~15.0 (5) hours (Figure 3). Moderate drug 
accumulation was observed with oral three-times-a-week schedule but not with the weekly 
i.v. schedule (1.4-fold drug accumulation with oral three-times-a-week dosing), consistent 
with 
the 
terminal 
half-life 
of 
15 
hours 
and 
dosing 
interval. 
Different  degrees  of  renal  impairment  (mild,  moderate  and  severe)  did  not  alter 
PANO plasma exposure, whereas, mild hepatic dysfunction increased PANO plasma 
exposure by 43% and moderate hepatic impairment marginally increased PANO plasma 
exposure by 105% in cancer patients. 
 
Figure 3           Mean panobinostat plasma concentration versus time profiles 
following single oral or intravenous administration 


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Table 4            Pharmacokinetic parameters of panobinostat in three phase I 
studies         
Route 
of 
administration 
& Dose (No. of 
patients 
following single 
dose) 
Mean (CV%) 
Single 
dose 
Cmax(ng/mL) 
Mean (CV%) 
Single dose 
AUC0-inf 
(ng*hr/mL) 
Mean (CV%) 
Multiple dose 
AUC0-48 
(ng*hr/mL) 
i.v. 20 mg/m2 
(n=31) 
784 (45) 
1041 (38) 
n/a 
p.o. 
20 
mg 
(n=45) 
22.8 (58) 
194 (58) 
258 (65) 
p.o. 
30 
mg 
(n=49) 
36.2 (62) 
267 (54) 
279 (54) 
p.o. 
40 
mg 
(n=24) 
58.0 (59) 
329 (77) 
270 (59) 
p.o. 
60 
mg 
(n=57) 
66.1 (68) 
362 (62) 
306 (50) 
p.o. 
80 
mg 
(n=18) 
63.5 (58) 
397 (49) 
369 (52) 
n/a: 
not 
applicable with 
weekly 
i.v. 
administration 
  
 
In vitro experiments suggested that the hepatic oxidative metabolism of PANO is 
mediated primarily by cytochrome P450 (CYP)3A4, and to a lesser extent by CYP2D6 
and CYP2C19. In addition to monooxygenation, hydrolysis of the hydroxamic sid chain 


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(M43.5) were also found to be mediated (at least in-part) by the CYPs. These same 
metabolic pathways, were also observed in the recent human ADME and mass balance 
study [CLBH589B218]. 
1.9. Dose proportionality 
A positive and linear dose-exposure relationship was found following single i.v. 
administration (1.2 to 20 mg/m2, Rs = 0.83; p<0.0001).  After oral dosing with 15 mg to 
80 mg of PANO, dose-proportionality analysis indicated that systemic exposure increased 
nearly dose-proportionally at doses below 60 mg and there is less than proportional 
increase in AUC after 60 mg and 80 mg doses of panobinostat.  It appears that absorption 
may become limiting at doses ≥ 60 mg of PANO.   
1.10. Food Effect 
Influence of food on PANO PK was evaluated in patients with advanced cancer who 
received 20 mg panobinostat twice a week and were randomized to receive PANO under 
fasting, high fat, and normal breakfast conditions [CLBH589B2111]. The overall 
exposure and inter-patient variability (CV 59%) in 34 patients remained unchanged with 
or without food, whereas Cmax was transiently reduced by <45% and Tmax prolonged by 
food (i.e., both normal and high fat breakfast).  Since food did not alter the overall extent 
of absorption, food is unlikely to significantly impact PANO’s systemic exposure in 
cancer patients. The findings from this formal food effect are consistent with the results 
from an earlier pilot food effect [CLBH589B2101] arm 1. Therefore, panobinostat can be 
administered without regard to food in future studies.   
 
1.11. 
Study rationale/purpose 
For patients with hematological malignancies that cannot be cured by standard 
chemotherapy/immune-modulators/radiation alone, allogeneic HCT represents the only 
curative option. Treatment failure occurs most commonly due to GVHD, toxicity from the 
preparative regimen and/or disease relapse. GVHD continues to be a major cause of 
morbidity and mortality to date. The reported rate of acute GVHD by day 100 in a Phase 
III, randomized, multicenter, trial comparing the use of PBSC versus bone marrow in 
MUD transplants showed a rate of acute GVHD II-IV by day 100 was 47% (40%-53%) 
with grade III-IV 16% (12%-21%) using PBSC (16). In our randomized Phase II trial of 
TAC and SIR vs. TAC and MTX as GVHD prophylaxis after allogeneic transplantation 
we observed an acute GVHD incidence of 50% with TAC/SIR 4.  
 
Allogeneic HCT patients could benefit from PANO given its putative immunosuppressive 
activity in order to improve the success rate of allogeneic HCT. HDACi have several 
unique properties such as pro-inflammatory cytokines reduction38,39 that translate into 
decreased GHVD mortality without affecting GVL in murine transplantation models.29,30  
HDACi increases production and suppressive function of regulatory T-Regs,32 exhibit 
immunomodulatory properties in human dendritic cells,40 and have antitumor activity.41  
These properties make them an attractive class of agents to explore for GVHD prevention 
and potentially to target minimal residual disease to reduce relapse rate after allogeneic 
HCT.  


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In this Phase II trial we will test the preliminary clinical activity of a PANO in addition to 
TAC/SIR for GVHD prevention. Patients will be evaluated for parameters that measure 
the safety, efficacy and pharmacodynamics of these agents combination.  
2. Study objective 
2.1. Primary Objective 
 
To prospectively determine the cumulative incidence of acute GVHD grades II-IV by day 
100 when combining PANO with standard combination of TAC/SIR for GVHD 
prevention. It is anticipated that the combination will decrease of acute GVHD risk to 
30% compared to our historical control of 50% with TAC/SIR alone. 
 
2.2. Secondary Objectives 
 
2.2.1. Clinical objectives: 
2.2.1.1. Cumulative incidence of chronic GVHD 
2.2.1.2. Engraftment, relapse, non-relapse mortality, overall and 
relapse-free survival at one year. 
2.2.2. Biological studies to test the pharmacodynamics of TAC/SIR/PANO 
combination for GVHD prevention:  
2.2.2.1. Immune Reconstitution determined by flow cytometry 
2.2.2.2. Histone acetylation of T cells and DC subsets by Western 
Blot and flow cytometry 
2.2.2.3. T reg immune-reconstitution, Foxp3+ expression and 
acetylation by flow cytometry 
2.2.2.4. Inflammatory cytokine and Biomarker expression profiling 
2.2.2.5. Stat-3 activation and acetylation 
2.2.2.6. Panobinostat pharmacokinetics 
 
 
Objective 
Endpoint 
Primary 
Clinical 
Objectives 
 
Prospectively 
determine 
the cumulative incidence 
of acute GVHD grades 2-4 
using TAC and SIR in 
addition to PANO for 
GVHD prevention. Study 
parameters: 
We 
will 
consider ≥43% incidence 
of grade II-IV aGVHD not 
acceptable. We 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 +/- 
14using 
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 


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mandated by this protocol. 
Treatment of GVHD will not 
be mandated. 
Secondary  
Clinical 
Objectives 
 
Cumulative incidence of 
chronic GVHD  
 
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 
(eg 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 patients on days  90+/-14 , 
120 +/- 14, 150 +/- 14, 180+/-
14, 270+/- 30, and 365 +/- 30 
as per standardized scoring 
system.  
Engraftment 
 
 
Stable engraftment for 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.  
Cumulative incidence of 
relapse/progression and 
non-relapse mortality at 
one year. 
 
Overall Survival and 
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-


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Relapse-free Survival at 
one year. 
 
 
 
 
relapse death is defined as 
death in continuous remission 
from 
primary 
disease 
requiring transplantation.  
Survival outcomes: 
Overall survival: Time from 
transplant date to death from 
any cause.  
Relapse-free survival: Time 
from transplant date to death 
or primary disease relapse.  
Secondary  
Exploratory 
Objectives 
 
Biologic studies ( 
appendix F)to test 
thepharmacodynamics of 
TAC/SIR/PANO 
combination for GVHD 
prevention. Results will be 
compared with compared 
to data from similar 
external control patients 
treated with an identical 
protocol except for PANO  
 
 
T Cells, especially T regs, 
immune-reconstitution, will 
be measured to assess 
whether PANO increased 
amounts of Treg cells post 
HCT.  
 
Histone acetylation of T cells, 
T regs and DC subsets will be 
measured to test the activity 
of PANO as an inhibitor of 
histone deacetylases on 
targeted specific cell subsets. 
 
Inflammatory cytokine will be 
measure to assess whether 
PANO contribute to generate 
an immune-modulatory 
cytokine micro-enviroment 
decreasing the production of 
pro-inflammatory cytokines . 
 
 Biomarker expression 
profiling will be measured to 
assess correlation with GVHD 
clinical outcome.  
 
Stat-3 activation and 
acetylation will be measured 
in cells subsets to test the 
activity of PANO as an 
inhibitor of histone 
deacetylases   
 
 
3. Overall study design 
 


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3.1. 
This study will test PANO in combination with TAC/SIR for acute GVHD 
prevention. This is a Phase II, single arm, non-randomized study and does not 
contain a treatment control group.  This Phase II study will assess whether 
TAC/SIR/PANO provides potential efficacy for GVHD prevention, and 
whether results hold sufficient promise for definitive testing of PANO in 
subsequent randomized clinical trials and/or TAC de-escalation studies. 
Correlative studies results ONLY will be compared to an “external control” 
patient subset that will be treated with TAC/SIR with same inclusion and 
exclusion criteria as this protocol except that they will not be treated with 
PANO. 
 
3.2. 
Site(s): Protocol will be performed at Moffitt Cancer Center. 
 
3.3. 
Sample Size and accrual rate. It is estimated that 2 patients will be entered 
into the treatment study each month, therefore, we anticipate 24 months for 
completion of the study that will require n=44 total patients for the treatment 
arm.  We are planning to enroll n=20 patients for “external control patients”. 
We anticipate 0.5 patients/month for “external control” subjects and accrual 
will happen concomitant to treatment arm patients. Therefore a total of 64 
subjects will be accrued in total including treatment arm and external control.  
 
3.4. 
Patient Follow up. Patients will be evaluated weekly from day of transplant 
until day 100 to measure acute GVHD using standard scoring system (defined 
in Appendix A). Stage of GVHD will be assessed for each site of involvement 
(e.g. skin, liver, and gut), as well as a composite score for overall acute GVHD 
grade determined. Pathologic confirmation of aGVHD will be dictated by 
usual clinical practice. Patient will be followed on days +90 +/-14, 120 +/- 14, 
150 +/- 14, 180+/- 14, 270+/-30, and 360 +/- 30 for chronic-GVHD assessment 
and adverse events toxicity assessment.  Taper of immunosuppression is 
suggested- not mandatory and treatment of GVHD is not mandated (section 
6.2-6.3). 
 
3.5. 
Withdrawal. from the study will take place under the following 
circumstances: those patients who sign consent for the study, but fail to initiate 
treatment due to: 
3.5.1. denial of coverage from insurance provider 
3.5.2. disease progression prior to initiation of treatment 
3.5.3. death prior to initiation of treatment 
3.5.4. withdrawal of patient consent at any time after therapy 
 
                            
4. Patient Population: Inclusion and Exclusion criteria 
4.1. 
Inclusion Criteria: 
4.1.1. 
Male or female 


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4.1.2. 
Age ≥ 18 years or older at time of enrollment 
4.1.3. 
Signed informed consent 
4.1.4. 
Hematologic disorder requiring allogeneic hematopoietic cell 
transplantation  
4.1.5. 
LVEF ≥ 45% by MUGA scan or echocardiogram 
4.1.6. 
FEV1, FVC, and DLCO adjusted ≥ 50% of predicted values on 
pulmonary function tests 
4.1.7. 
Transaminases (AST, ALT) < 3 times upper limit of normal values 
4.1.8. 
Creatinine clearance calculated ≥ 50mL/min 
4.1.9. 
Karnofsky Performance Status Score ≥ 60%. 
4.1.10. HLA matched 8/8 (A, B, C, DRB1) related or unrelated donor 
 
4.2. 
Exclusion Criteria: 
4.2.1. 
Active infection not controlled with appropriate antimicrobial therapy 
4.2.2. 
HIV, hepatitis B (HBcAb positive but HBsAg negative with 
undetectable viral load are eligible), or hepatitis C infection 
4.2.3. 
Sorror’s co-morbidity factors with total score > 4  
4.2.3.1. 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. 
4.2.4. 
Anti-thymocyte globulin (ATG) as part of the conditioning regimen 
4.2.5. 
Cyclophosphamide as part of the conditioning regimen or for GVHD 
prophylaxis. 
4.2.6. 
Pregnancy  
4.2.7. 
HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of 
cancer within 30 days. Only FDA approved drug are Vorinostat and 
Romidepsin the rest are considered investigational and are not 
allowed.  
4.2.8. 
Patients who will need valproic acid for any medical condition during 
the study or within 5 days prior to first PANO treatment 
4.2.9. 
Impaired cardiac function or clinically significant cardiac diseases, 
including any one of the following: 
4.2.9.1. Any history of ventricular fibrillation or torsade de pointes 
4.2.9.2. Bradycardia defined as HR< 45 bpm. Patients with 
pacemakers are eligible if HR ≥ 45 bpm. 
4.2.9.3. Screening ECG with a QTcF ≥ 480 msec  
4.2.9.4. Right bundle branch block + left anterior hemiblock 
(bifascicular block) 
4.2.9.5. Patients with myocardial infarction or unstable angina ≤ 12 
months prior to starting study drug 
4.2.9.6. Other clinically significant heart disease (e.g., CHF NY 
Heart Association class III or IV , uncontrolled 
hypertension) as per discretion of principal investigator 
and/or treating physician 


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4.2.9.7. 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 that are required for HCT 
patients. 
 
5. Intervention/Treatments 
 
5.1. 
Stem cell mobilization and collection of Donor: 
5.1.1. 
Peripheral blood stem cells: the stem cell product will be mobilized 
and collected as per institutional (Moffitt) or NMDP standards for 
related and unrelated donors respectively.  The target graft will have a 
CD34 count of 5-10 x 106 cells/kg; however, a cell dose ≥ 2 x 106 
CD34/kg is the minimal dose permitted. 
5.1.2. 
Umbilical cord blood and bone marrow stem cells are not an accepted 
stem cell source per this protocol. 
5.2. 
Conditioning regimen: The conditioning regimen is per physician discretion 
and can include either 1) myeloablative (MAC) busulfan targeted at an AUC of 
4800 μM/L*min/day and fludarabine; 2) reduced-intensity (RIC) busulfan 
(6.4mg/kg total over 2 days or targeted at an AUC or 3500 μM/L*min/day) and 
Fludarabine; or 3) RIC fludarabine and melphalan (140mg/m2). Busulfan 
targeted to an AUC of greater than 5,300µM/L*min/day will not be allowed, 
given the concurrent administration of SIR, as this combination (escalated 
AUC of busulfan and sirolimus) was associated with increased risk for veno-
occlusive disease (VOD) of the liver and non-relapse mortality in prior Moffitt 
trial (MCC 15372). Conditioning regimens/GVHD prophylaxis utilizing 
cyclophosphamide and/or anti-thymocyte globulin (ATG) as part of the 
conditioning regimen are not eligible. 
 
5.3. 
Supportive Care: Transfusion as per institutional practice. Anti-infective 
prophylaxis or preemptive therapy as per institutional guidelines. 
  
5.4. 
Antifungal Prophylactic Medications:  
5.4.1. 
Micafungin is the preferred primary antifungal prophylaxis treatment 
given its minimal interaction with TAC and SIR metabolism.  
5.4.2. 
Voriconazole or Posaconazole is allowed as per treating physician 
discretion.  
5.4.3. 
Patients with presumed or proven pre-transplant infection treated with 
Voriconazole or Posaconazole will be allowed to continue with this 
treatment as it has been shown that for primary treatment of invasive 
aspergillosis, azoles like voriconazole have shown better responses 
and improved survival when compared to amphotericin B.42   


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5.4.4. 
If patients develop GVHD (see section 6) on trial it is our standard 
practice to use voriconazole or posaconazole in patients receiving 
prednisone at a dose higher than 0.5mg/kg/day.  In a randomized trial 
for prophylaxis against fungal infections among patients with GVHD, 
posaconazole was similar to fluconazole for prophylaxis against 
fungal infections among patients with GVHD; and posaconazole was 
superior in preventing invasive aspergillosis and reducing the rate of 
deaths related to fungal infections. 43 .  
 
5.5. 
Other 
medications: 
In 
general, 
the 
use 
of 
any 
concomitant 
medication/therapies deemed necessary for the care of the patient are allowed, 
including drugs given prophylactically (e.g. antiemetics) with the following 
precautions: 
5.5.1. 
Any medications listed in Appendix B: 
5.5.1.1. 
Which may cause QTcF prolongation or inducing 
torsades de pointes should not be used. Concomitant use 
of CYP3A4 inhibitors with PANO should be avoided to 
prevent potential increase in PANO exposure during 
concomitant treatment with these drugs.   
5.5.1.2. 
 Medications known to be substrates of the isoenzyme 
CYP2D6 should be avoided in use with PANO as this 
drug can inhibit isoenzyme CYP2D6 at low micromolar 
ranges. Please refer to Appendix B for the list of 
CYP2D6 substrates.  
 
5.5.2. 
Patients receiving any medications that have the potential to alter 
serum electrolytes (e.g., diuretics) should be monitored very closely 
for electrolyte abnormalities as these can contribute to the risk of 
QT prolongation and ventricular arrhythmias.  
 
5.5.3. 
No other investigational therapy should be given to patients during 
PANO administration or until toxicity related to PANO has not 
resolved. 
 
5.5.4. 
Leukocyte growth factors (e.g.G-CSF and GM-CSF) are not to be 
administered systematically but may be prescribed for ANC < 750 
per microliter if this is thought to be appropriate.  
 
5.5.5. 
Ursodiol is allowed as per institutional guidelines at any time 
during this trial. 
  
5.5.6. 
 Budesonide and beclomethasone. For patients with gastrointestinal 
GVHD, budesonide and/or beclomethasone, with or without 
systemic corticosteroids are allowed.    
  


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5.6. EKG monitoring: 
 
5.6.1. 
Screening. One 12-lead EKGs will be performed to assess study 
eligibility at time of enrollment to  accurately estimate Fridericia 
correction for QTC (QTcF) calculation as listed in Table 4 which is 
available in MUSE system. If  EKG QTcF is above 480msec a 
minimum of 3 sequential 12 lead EKGs, separated by at least 2 
minutes, must be performed. The QTcF , or average of 3, ( at 
baseline must be ≤ 480 msec for the patient to be eligible for 
participation in the trial). The EKG will be analyzed by the treating 
physician or principal investigator or designee to assess eligibility 
of the patient.  
 
5.6.2. 
Additional 12-lead EKGs will be performed at a minimum at 
scheduled time points as indicated in Table 4 as follows:  
5.6.2.1. With 1st dose: Pre-dose EKG and post dose EKG 
5.6.2.2. With 3rd dose: Pre-dose EKG  
5.6.2.3. If  EKG QTcF prior to 1st dose, or any EKG performed 
then after, is above 480msec a minimum of 3 sequential 
12 lead EKGs, separated by at least 2 minutes, must be 
performed.  
5.6.3. 
For the multiple EKGs which are obtained, the average of the QTcF 
intervals must be ≤ 480 msec before the patient is dosed.  Dosing 
management based on QTc interval it is described in table 5. 
 
5.6.4. 
If EKG average is ≥ 480 msec patient must have an assessment of 
serum potassium, magnesium, and calcium (total corrected for 
albumin, or ionized calcium) in order to rule out correctable 
electrolytes abnormalities that could potentially correct prolonged 
QTcF. On any day and time in which electrolytes are assessed, if 
the value is < LLN, then the patient’s potassium, calcium, 
phosphorous or magnesium should be supplemented as per standard 
Moffitt procedure. After electrolytes replacement 3 sequential 12 
lead EKGs, separated by at least 2 minutes, must be performed to 
ensure it is ≤ 480 msec to proceed. 
 
5.6.5. 
Treatment decision to administered PANO will be made by the 
treating provider at Moffitt Cancer Center and will be based on 
QTcF as determined by the automated machine reading at the 
investigational site which is available in the MUSE system. All 
cardiac events should be treated as per the local standard of care 
and referred to a cardiologist if clinically indicated. Any final 
decisions 
concerning 
dose 
modifications 
or 
permanently 


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discontinuing the patient from study drug due to QTcF prolongation 
will be based on the Investigator’s clinical assessment.  
 
 If ANY EKG performed while patient is on trial shows a QTcF ≥ 
480, a minimum of 3 sequential 12 lead EKGs separated by at least 
2 minutes, should be performed. QTcF from single EKG or average 
of 3 EKG must be ≤ 480 msec for the patient to be treated with 
PANO. Electrolyte replacement and/or avoiding drug(s) that could 
potentially prolonged QTcF should be attempted when indicated.  
PANO could be resumed once QTcF is ≤ 480 as per clinical 
judgement of the treating physician at Moffitt Cancer Center or PI 
or designee. If Muse system is malfunctioning, EKG machine 
should provide EKG printout which provides QT correction based 
on Bazett's formula. In these circumstances, QTcB is allowed to be 
used to decide eligibility and/or PANO dosing if heart rate is equal 
or above 60. QTcF can also be calculated with QT and heart rate 
provided in printout. QTcF is obtained based on the following 
formula: QT/RR^0.33. RR= 60000/Heart rate. Can use web based  
link 
http://www.thecalculator.co/health/QTc-Calculator-385.html. 
or similar to avoid calculation errors. 
 
Table 4 
Cardiac assessment monitoring schedule 
Day of 
Treatment 
EKG monitoring 
Screening 
1 EKG 
If QtcF ≥ 480 msec a total of 3 sequential EKGs separated by at 
least 2-5 minutes will be performed and the average QTcF should 
be less than 480 msec to be eligible. 
First  dose 
of PANO 
PRE DOSE: 1 EKG.   
 
If QtcF ≥ 480 msec a total of 3 sequential EKGs separated by at 
least 2-5 minutes will be performed and the average QTcF should 
be less than 480 msec to proceed. Check correctable electrolytes 
abnormalities (section 5.6.4), replace and repeat 3EKG to ensure 
Qtc≤  479 to proceed. 
 
 
POST DOSE:  should be performed at 3 hours ± 0.5 
hour. Perform 1 EKG. If QtcF ≥ 480 msec then 
performed 3 EKGs at least 2-5 minutes.  If 
average QTcF ≥  480 msec or 60 msec above 
baseline, dosing should be held including follow-
up triplicate ECGs and correction of electrolyte 
abnormalities should be performed to proceed 
with dose number 2 of PANO.   
 


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Day of 
Treatment 
EKG monitoring 
 
 
 
Third dose 
of PANO 
PRE DOSE: 1 EKG.  If QtcF ≥ 480 msec a total of 3 sequential 
EKGs separated by at least 2-5 minutes will be performed and the 
average QTcF should be less than 480 msec to proceed. Check 
correctable electrolytes abnormalities (section 5.6.4), replace and 
repeat 3EKG to ensure bellow QtcF ≤ 479 to proceed. 
 
 
 
Table 5:  Treatment decision based on EKGs findings: 
Time Point 
Average QTcF* 
Action 
Pre-dose 
before first 
dose 
≥ 480 msec (if 1 EKG 
more than 480 obtain 
a total of 3 sequential 
EKGs separated by at 
least 2-5 minutes to 
calculate the average) 
Delay treatment andcorrect any 
electrolyte abnormal values ** 
and repeat 3 EKG. If after 
electrolyte replacement QTcF 
remains ≥ 480 msec, do not 
dose and patient is  not eligible 
Above 500 msec 
Patient is not eligible 
Pre-dose 
before third 
dose 
 
≥ 480 msec or above 
60 
msec 
from 
baseline (last EKG 
average at time of 
first dose)   
Delay treatment 
Correct any electrolyte 
abnormal values ** and repeat 3 
EKG. If after electrolyte 
replacement QTcF remains ≥ 
480 msec, do not dose patient. 
PANO could be resume if QTcF 
is ≤480  as per clinical 
judgement of the treating 
physician at Moffitt Cancer 
Center or PI or designee 
before subsequent doses. 
Above 500 msec 
 
Do NOT dose patient. Correct 
any 
electrolyte 
abnormal 
values** and repeat 3 EKGs. 
PANO could be resume if 
QTcF is ≤480  as per clinical 
judgement of the treating 
physician at Moffitt Cancer 
Center or PI or designee 
before subsequent doses. 


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*QTcF: Heart rate corrected QT interval using the Fredericia formula: 
QTc=QT/RR0.33 as per automated machine available in MUSE system or 
calculated manually (see 5.6.7). 
**: serum potassium, magnesium, calcium 
 
 
5.7. GVHD prophylaxis 
 
We will test the combination of TAC and SIR, a combination that has proven to 
be safe and effective for GVHD prevention in matched allogeneic transplants 
(related or unrelated) in addition to PANO. We propose to test the hypothesis that 
this combination not only enhances T regulatory development but may modulate 
host-donor antigen presentation to allow an immune-tolerant microenvironment to 
prevent GVHD. Therefore, PANO will be initiated prior to stem cell infusion (see 
Appendix G)and continued for 26 weeks as shown in Figure 4:  
 
Figure 4. GVHD prophylaxis plan. 
 
 
 
 
                                                                                                                                                                                 
 
5.7.1. Standard GVHD prophylaxis regimen: 
 


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5.7.1.1 Tacrolimus(TAC) 
5.7.1.1.1. Tacrolimus will be administered starting on day -3 and 
following our institutional guidelines for dosing.  
 
5.7.1.1.2. Micafungin will be used for primary fungal 
prophylaxis, given its minimal interaction with TAC 
and SIR metabolism; there will be no dose adjustment 
made of TAC or SIR with Micafungin as fungal 
prophylaxis. In those patients with active fungal 
infection, anti-fungal treatment will be changed to 
Voriconazole or Posaconazole. Additionally, those 
patients on corticosteroid treatment (cumulative dose 
of greater than or equal to 0.5 mg/kg/day) will be 
treated with Voriconazole or Posaconazole. In those 
patients on Voriconazole or Posaconazole, TAC dose 
will be decreased by 50-67% of its original dose and 
further adjusted based on serum levels.  
 
5.7.1.1.3. Thrombotic microangiopathy (TMA) will be graded 
for severity according to CTC version 4. No changes 
in TAC dose will be made for TMA of grades 1 or 2. 
For grade 3 TMA, TAC dose will be reduced by 50%. 
For grade 4 TMA, TAC will be discontinued. 
 
5.7.1.2. Sirolimus (SIR) 
 
SIR will be administered starting on day -1 and thereafter, dosing 
will be adjusted to maintain therapeutic targets per our 
institutional standards.  
SIR levels should be monitored on days 0, 2, and at least once 
weekly thereafter until on stable oral dose and schedule. Dose 
adjustments should be made according to drug levels per standard 
practice guidelines.  
 
5.7.1.3   Investigational therapy: Panobinostat (PANO) 
 
5.7.3.1      Patients will be treated with PANO 5 MG PO TIW (3 
doses about 48 hours apart in a 7 day period) QW for 26 
weeks starting prior to stem cell infusion (see Appendix 
G) Patient follow up will be for a total of 365 ± 30 days 
from initiation of the drug. During the study, PANO will 
be administered orally as once daily dose. Patients 
should receive their once-a-day oral dose of PANO 
approximately at the same time each day in AM or PM 


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(preferable PM). Each dose of PANO should be taken 
with about 8 oz / 240 ml glass of water. Patients should 
be instructed to swallow the capsules whole and not 
chew them. Patients must avoid grapefruit or grapefruit 
juice and seville (sour) oranges during the entire study. 
 
5.7.3.2      PANO will be provided by Novartis. Oral PANO will be 
supplied as 5-mg pink gelatin capsules. Medication 
labels will comply with US legal requirements and be 
printed in English. They will supply no information 
about the patient. The storage conditions for study drug 
will be described on the medication label. 
 
5.7.3.3    If the patient cannot take Panobinostat due to mucositis 
and/or 
HCT 
related 
GI 
toxicities 
(nausea/vomit/diarrhea), then he/she should take PANO 
on that same day within 16 hours after the missed dose if 
possible. After more than 16 hours, that day’s dose 
should be withheld, and the patient should wait to take 
PANO until the next scheduled treatment day (i.e., 
patients should be instructed not to try to make-up the 
missed dose after 16 hours). (In our prior experience 
majority 
of 
patients 
with 
mucositis 
and/or 
GI 
toxicitieswere able to complete SIR PO as specified in 
protocol4). 
 
  
 
5.7.3.4        The investigator should instruct the patient to take the 
study drug exactly as prescribed (promote compliance). 
Pill diary to help adhere with compliance is highly 
recommended to record actual drug compliance and will 
be provided to patients. All dosages prescribed and 
dispensed to the patient and all dose changes during the 
study should be recorded in pharmacy chart.  
5.7.3.5       Patients will receive the planned treatment with PO 
PANO until they experience unacceptable toxicity that 
precludes further treatment (as specified in section 9).  
5.7.3.6 
 If they develop GVHD and requires treatment with high 
dose corticosteroids (1-2MG/Kg) as defined in section 6 
they should stop PANO as determined in section 6.3.   
 
6. GVHD 
Acute GVHD manifests clinically as involvement of the skin, gastrointestinal tract, 
and liver, either as an isolated site of involvement or in combination. The traditional 
grading scheme for GVHD was developed by Glucksberg, et al, in 1974. This grading 


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scheme was updated in 1995 with the publication of new consensus guidelines.44 A 
major addition was the incorporation of persistent nausea with pathologic evidence of 
acute GVHD as grade 1 gastrointestinal GVHD. This established grading scheme will 
be utilized for the grading of this endpoint in the trial. (see Appendix A) 
6.1. Evaluation procedures: Incidence of acute GVHD will be characterized by 
weekly clinical evaluations from day of transplant to day 90±10 using the 
above described objective standard scoring system. Organ stage of GVHD 
will be given for each site of involvement (e.g. skin, liver, and gut), as well 
as a composite grade for overall acute GVHD (see Appendix A). Pathologic 
confirmation of aGVHD will be dictated by usual clinical practice and it is 
highly encouraged, but not mandated by this protocol. If patients develop 
diarrhea while receiving PANO see recommended management in section 
7.2. If patients develop isolated upper GI symptoms, pathology confirmation 
of GVHD is needed to score as GVHD.  
6.2. Taper of immunosuppression is suggested- not mandatory- on days 50±3 for 
TAC or 365±30 for SIR in the absence of GVHD.   
6.3. Therapy for established acute GVHD: Upon recognition of acute GVHD, 
standard treatment may involve high dose (1-2mg/kg) corticosteroids. The 
primary therapy of acute GVHD is not mandated by this protocol. Interval 
progress will be assessed on a routine basis by the treating physician. 
Without anticipated resolution, additional immunosuppression may be added 
per the treating physicians’ discretion. The agents used, time of initiation, 
duration of exposure, interval response, and any specific toxicities will be 
recorded. 
If GVHD develops and requires treatment with high dose corticosteroids (1-
2mg/kg) while on planned PANO dosing schedule PANO should be stopped 
as failed primary endpoint. 
 
 
7. Safety assessment: 
 
Safety assessments will consist of monitoring and recording focused toxicities/adverse 
events (AE) and serious adverse events (SAE) unexpected to HCT (table 8), the 
regular monitoring of hematology, blood chemistry and urine values, vital signs, 
ECOG/Karnosfsky performance status, and the regular physical examinations and 
EKG assessments as specified in the protocol. 


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7.1. Anticipated adverse events of the transplant protocol and recommended 
management 
7.1.1. 
Mucositis: The advent of mucositis will be anticipated, objectively 
characterized and scored per CTCAE (v 4.0) criteria, and recorded. It is 
suggested that patients with inadequate oral nutrition will have 
Nutrition evaluation and consideration for TPN. Pain control is at the 
discretion of the treating physician 
 
7.1.2. 
Cytopenias: Transfusion support will be provided as needed per 
standard of care. Hematopoietic growth factors will not be routinely 
employed to hasten recovery. 
 
7.1.3. 
Thrombotic microangiopathy (TMA): The BMT Clinical Trial Network 
has developed a consensus statement regarding both a uniform 
diagnostic scheme for post-transplant thrombotic microangiopathy, as 
well as recommendations for its management. The authors provide a 
definition for TMA which includes the following: RBC fragmentation 
and > 2 schistocytes per high-power filed on peripheral blood smear; 
concurrent increased serum LDH above baseline; concurrent renal 
(defined as doubling of baseline serum creatinine or decrement of > 
50% of baseline creatinine clearance) and/or neurologic dysfunction 
without an alternate explanation; and negative direct and indirect 
Coombs test results. The primary management strategy should be the 
dose reduction or discontinuation of calcineurin-inhibitors upon the 
recognition of post-transplant TMA. Consideration of calcineurin 
inhibitor replacement by non-calcineurin inhibitor immune suppressant 
agents is at the discretion of the treating physician.45 In those who meet 
criteria, changes to the immunosuppression regimen will be dictated by 
the following strategy: No change for CTCAE(v.4)  grade 1-2; For 
CTCAE(v.4) grade 3 dose reduction by 50% of original dose of TAC; 
For CTCAE(v.4)  grade 4 TAC will be discontinued. Plasma exchange 
upon recognition of TMA is not indicated. 
 
7.1.4. 
Hepatic veno-occlusive disease (VOD)/ sinusoidal obstruction 
syndrome (SOS): Hepatic VOD/SOS, is clinically characterized by 
painful hepatomegaly, jaundice, abnormal liver function tests, and 
volume overload. This syndrome is seen in association with several 
precipitants, notably including high dose therapy with hematopoietic 
cell transplantation. Several risk factors have been identified by 
multivariable analysis including pre-transplantation abnormalities of 
liver 
transaminases, 
chronic 
hepatitis 
C 
and 
B, 
certain 
chemotherapeutic agents used in conditioning regimens primarily 
cyclophosphamide, mismatched or unrelated donor graft source, prior 
irradiation therapy to the abdomen, other medications including 
acyclovir and vancomycin administered at the time of pre-transplant 


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conditioning, and prior exposure to gemtuzumab ozogamycin. 
McDonald, et al. examined liver toxicity in the setting of 
cyclophosphamide/TBI conditioning prior to HCT. These authors 
monitored plasma levels of cyclophosphamide metabolites and 
demonstrated that its metabolism widely varied among subjects. 
Exposure to elevated levels of a metabolite, o-carboxyethyl-
phosphoramide mustard, was significantly related to development of 
hepaticVOD/SOS, non-relapse mortality, and survival. Those in the 
highest quartile for exposure to this metabolite had a 5.9-fold increased 
risk of non-relapse mortality46. Accordingly, we will exclude those 
conditioning regimens employing cyclophosphamide. 
 
The reported rate of VOD/SOS complicating HCT varies from 0 to 70% due to 
differences in diagnostic criteria, recognition, sample populations, and distribution 
of risk factors. More current reports, including a large multicenter prospective trial 
from the EBMT, describe hepatic VOD/SOS rates of 8-9%47.  While mild hepatic 
VOD/SOS produces minimal morbidity and mortality, severe hepatic VOD/SOS 
related mortality reaches 90% which is rare in our experience 4.  
 
Evaluation and management: Surveillance for development of this condition will 
take place in all patients. Criteria for diagnosis include painful hepatomegaly, 
abnormal liver function tests, fluid overload, and the absence of alternate etiology 
to explain these abnormalities. Management of VOD/SOS consists of supportive 
care, and is not mandated by this protocol.  
 
7.2.Anticipated events for PANO and recommended management: 
 
To date the main adverse events reported are similar among all the studies performed with 
oral PANO formulations. Information about common side effects already known about the 
investigational drug can be found in the Investigators’ Brochure (IB) or will be 
communicated between IB updates in the form of Investigator Notifications. This 
information will be included in the patient informed consent and should be discussed with 
the patient during the study as needed. 
 
7.2.1. The most common non-hematological events (Table 1) reported were:  
7.2.1.1. GI events (nausea/vomiting/ diarrhea);  
7.2.1.2. Fatigue and electrolytes abnormalities are less common. 
7.2.2. The most common hematological toxicity reported was thrombocytopenia 
and to a lesser extent mild anemia and leukopenia.  
 
These potential adverse effects will be monitored, and their occurrence recorded as 
specified in section 9.2. No specific diagnostic or therapeutic measures are prescribed by 
this protocol for majority of toxicities unless specified. GI toxicity is a common side effect 
of HCT especially in the immediate transplant period (see expected HCT complications 
section 9). Etiology of GI symptoms could be multifactorial including conditioning 


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regimen, medications, GVHD and/or infections. For patients with diarrhea, evaluations for 
other etiologies including infection are highly recommended.  Endoscopy with biopsies 
should be considered for evaluation of GVHD if the patient is beyond day +22, but is left 
to the discretion of the treating physician.  
 
 
8. Reasons to hold/discontinue treatment:   
8.1. 
Investigator(s) decision to withdraw patient from the study in the event of 
inter-recurrent illness, adverse events, or other reason that he deems necessary 
to discontinue study drug. Patients who discontinue from the study for AE or 
SAE will all be evaluable. Date of and reason for study discontinuation will be 
noted. Patients whose treatment is interrupted or permanently discontinued due 
to an AE must be followed until resolution or stabilization of the event, 
whichever comes first.  
 
8.2. 
Abnormal laboratory result unable to be corrected to levels acceptable for 
treatment with the study drug. 
 
8.3. 
 Patient non-compliance 
  
8.4. 
Subject withdrew consent from study at any time for any reason. 
 
8.5. 
Death. 
 
8.6. 
Prolongation of QTcF (see section 5.6). 
 
8.7. 
For patients that PANO is discontinued due to GVHD they are allowed to continue 
to be ON study. All assessment, procedures, CRF forms, correlative studies 
(appendix F) will be performed identically to patients that continue to take 
PANO and we will not deviate from what is stipulated in the protocol for 
patients that are receiving study drug on study. 
 
8.8. 
Special considerations for toxicity observed up to day +7 post transplant: Due to 
unknown interactions between conditioning regimen and PANO, guidance is 
provided between PANO 1st dose to day +7 HCT as follows: 
8.8.1. 
PANO will be stopped for any non-hematological CTCAE (v4) grade 
3 or higher toxicities unexpected for HCT (see table 8) seen between 
first dose of study drug and day +7 post-HCT. If there is complete 
reversal of toxicity, PANO can be resumed after 7 days and a 
minimum of one week off study drug and continued until completion 
of protocol-specified dosing schedule. In the absence of complete 
reversal of toxicity within 7 days, the study drug will be discontinued 
and the patient removed from the study. All such patients will remain 
evaluable for analysis and not replaced.  


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8.9. For gastrointestinal (GI) symptoms (diarrhea or nausea/vomiting) thought to be 
related to PANO from day -5/-6 to day +7 and/or after recovery from acute GI 
toxicity due to chemotherapy: The PANO dose may be modified according to the 
severity of the GI side effects as suggested and described in Table 6 and 7. 
Depending on the patients’ clinical status, dose adjustments may be made within 1 
week from when the lab work is completed. Patients who require PANO 
adjustment will have their dose HOLD for 3 doses and may resume 100% dosing 
thereafter at physician discretion. A trial of anti-emetics and anti-motility agents 
should be considered (institutional Clinical Practice Guidelines) before modifying 
the dose of PANO. In case patient regurgitate PANO pill will be allowed to re-
dose after anti-emetics trial.  PANO should continue for patients who develop GI 
symptoms related to infection.  
 
 
Table 6. Management guidance for Diarrhea. 
 
 
Diarrhea Grade 
PANO dose 
reduction 
Mild 
Grade 1: 
<4 stools/day 
over baseline 
0% 
Moderate 
Grade 2: 
Increase 4-6 stools/day 
over baseline 
 
0%  
Severe 
Grade 3: 
Increase >7 stools/day 
over baseline 
 
No GI GVHD: hold 
only after failure of 
antimotility agents. 
Resume once the GI 
toxicity has resolved 
to grade 0-2 and 
continued until 
completion of 
protocol-specified 
dosing schedule 
 
If GI GVHD* 
Life Threatening 
Grade 4: 
Life-threatening 
consequences 
No GI GVHD: 
Discontinue 
permanently. 
 
If GI GVHD* 
*If acute GI GVHD develops and requires treatment with high dose corticosteroids (1-2MG/Kg) 
PANO should be discontinued if still taking protocol specified dosing as failed primary endpoint 
 


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Table 7. Management guidance for Nausea/Vomiting* 
 
 
Nausea/vomiting Grade 
PANO dose 
reduction 
Mild 
Grade 1: 
Loss of appetite 
without alteration 
in eating habits; 
1 episode of 
vomiting w/i 24 hrs. 
0% 
Moderate 
Grade 2: 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs; 
2-5 episodes of vomiting in 
24 hrs. 
0%  
Severe 
Grade 3: 
Inadequate oral 
caloric or fluid 
intake; IV fluids, 
tube feedings, or 
TPN indicated ≥24 
hrs; ≥6 episodes of 
vomiting in 24 hrs. 
No GI GVHD: HOLD 
ONLY after failure 
antiemetics. 
Resume once the GI 
toxicity has resolved 
to grade 0-2. 
 
 
 
Life Threatening 
Grade 4: vomiting with life-
threatening consequences 
No GI GVHD: 
Discontinue 
permanently. 
 
If GI GVHD* 
* If acute GI GVHD develops and requires treatment with high dose corticosteroids (1-2MG/Kg) 
PANO should be discontinued if still taking protocol specified dosing as failed primary endpoint 
 
* Patients receiving high dose chemotherapy may develop mucositis which inhibits oral 
intake and may require total parental nutrition (TPN).  Use of TPN does not necessarily 
constitute Grade 3 nausea/vomiting and patient must be assessed for the indication of 
TPN. 
 
8.10. 
Definition of engraftment and delayed engraftment: 
8.10.1. 
Engraftment: Engraftment for neutrophils is defined as the first of 
three consecutive days in which the absolute neutrophil count (ANC) 
is > 500/uL. Engraftment for platelets is defined as the first of three 


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consecutive days in which the platelet count is > 20,000/uL, without 
platelet transfusion in the prior 7 days. 
8.10.2. 
Delayed engraftment: In preceding HCT trials we observed 
engraftment of WBC (defined as ANC >500 for 3 days) by median 
day 16 (range 11-30), while engraftment of platelets occurred by 
median day 14 (range 0-71) after HCT. In the current trial, delayed 
engraftment will be defined as either ongoing ANC <500/uL on or 
after day 23; or ongoing dependence of platelet transfusions on or 
after day 21. Patients who engraft prior to day 21 or 23, for platelets 
or ANC respectively,  and later have low ANC or platelet transfusion 
requirements, as occasionally occurs in HCT patients due to infection 
and other complications will NOT be considered to have delayed 
engraftment.  
 
8.11. Dosing modifications during pre-engraftment period: If ANC <500/uL on day 
23: HOLD PANO  until ANC > 1000, then resume at 100% dose. If platelets 
<20,000/uL on day 21: HOLD PANO  until platelet count > 30,000/ul 
(without platelet transfusion support x 3 consecutive days), then resume at 
100% dosing. 
 
8.12. Dosing modifications after primary engraftment: 
8.12.1. 
If ANC decreases to 500–1000/uL, CONTINUE PANO at 100% 
dosing. Begin growth factor support.  
8.12.2. 
If the ANC decreases to <500/uL, HOLD PANO until ANC 
recovers to >1000/uL, then RESTART PANO at 100% dosing.  
8.12.3. 
If ANC decreases to < 500/uL again, HOLD PANO until the ANC 
recovers to >1000/uL, then RESTART  PANO at every other week 
regime(TIW QOW). May resume 100% dosing of PANO (weekly 
dosing)  when G-CSF is discontinued, provided the ANC remains 
>1000/uL.  
8.12.4. 
If the platelet count decreases to < 20,000/uL, HOLD PANO until 
platelet count recovers to >20,000/uL (without platelet transfusion 
support x 3 consecutive days) then RESTART at 100% dosing.  
8.12.5. 
If platelet count decreases to <20,000 /uL again, HOLD the PANO 
until the platelet count recovers to >20,000/uL (without platelet 
transfusion support x 3 consecutive days), then RESTART PANO 
every other week. May resume 100% dosing provided the platelet 
count remains >20,000/uL (without platelet transfusion support).  
 
 
9. Adverse events (AE):  
  


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9.1. AE definition: An adverse event (AE) is the appearance or worsening of any 
undesirable sign, symptom, or medical condition occurring after starting PANO 
that is unexpected with HCT. Table 8 describes criteria for “expected” toxicities 
for HCT/GVHD-related symptoms that are commonly observed in transplant 
patients. Certain Grade 4 toxicities under particular categories in the NCI 
CTCAE are common in the HCT transplant setting, and patients with Grade III 
or IV GVHD are likely to experience additional serious symptoms.  These listed 
toxicities are likely related either to the HCT or preparatory and treatment 
regimens, however, the investigator must use best medical judgment in making 
an assessment as whether or not the study drug (PANO) may have had a 
contributory role. 
 


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Table 8. Expected Transplant/GVHD-Related Toxicities in HSC Transplant Patients. 
 
Category 
Symptoms/Event 
Category 
Symptom/Eve
nt 
Dermatological 
Pruritus 
Rash/dermatitis 
associated with high-
dose chemotherapy or 
GVHD 
 
Renal/Genitourinary 
 Bladder 
spasms/cystitis 
 Creatinine 
elevation/renal 
failure 
 Dysuria 
frequency-
urgency 
 Urinary 
retention 
Constitutiona
l 
Fever, Rigors, Chills 
Headache 
Tremors 
Weight lost and gain 
Confusion due to 
medications 
Peripheral edema 
 
Reproductive 
Persistent 
amenorrhea 
Gastrointestin
al 
Gastritis 
GERD 
Colitis 
Dehydration 
Diarrhea  
Nausea/vomiting 
Dysphagia 
Stomatitis/pharyngitis 
Hematocheza/melena 
Abdominal pain or 
cramping 
Metabolic/Laborato
ry 
Acidosis/alkalo
sis 
Amylase/lipase 
elevation 
Hypo-
/Hyperglycemi
a 
Hypo-
/Hyperkalemia 
Hypo-
/hypercalcemia 
Hypo-
/Hypermagnese
mia, 
Hypophosphate
mia 
Hypo-
/Hypernatremia 
Hypertriglyceri
demia/Hyperlip
idemia/hyperch
olesterolemia 
Hyperuricemia 
Increased LDH 


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Category 
Symptoms/Event 
Category 
Symptom/Eve
nt 
Hepatic 
LFT elevation 
Bilirubin elevation 
Hypoalbuminemia 
Hepatomegaly 
BMTComplex/ 
Multicomponent 
Events 
GVHD* 
Stem-cell 
infusion 
complications 
Venoocclusive 
Disease/ascites 
Cardio-
vascular 
Edema 
Hypertension/Hypotens
ion 
Sinus tachycardia 
Arrythmia (Atrial 
fibrillation/flutter; 
Sinus ventricular 
tachycardia and others) 
Vascular access 
complication- deep 
vein thrombosis 
requiring 
anticoagulation 
Thomboembolic event 
Hematologic 
Cytopenias 
Catheter 
associated 
venous 
thrombosis 
Infections* 
Bacterial, fungal and/or 
viral infections 
Sepsis/confusion 
 
 
 
*Infection and GVHD: These toxicities will not be considered AEs but data will be 
captured on eCRFs. Other toxicities will NOT be captured as expected HCT 
complications.  
 
Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse 
Events, 
version(CTCAE) 
version 
4.0 
(v.4) 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
).  
 
 
9.2. 
AE reporting:  
9.2.1. 
 All  non-hematological toxicities unexpected with HCT will be 
reported from the first day PANO is administered until day 180±7 
days unless specified otherwise in the protocol. After day 180±7 post 
HCT subjects will only be followed only for GVHD, relapse and 
survival until day 365±30.    
9.2.2. 
Information about relevant AE unexpected to HCT, whether 
volunteered by the subject, discovered by investigator questioning, or 
detected through physical examination, laboratory test or other 
means, will be collected and recorded.  AE should be followed as 


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appropriate for at least 14 days following the last dose of PANO. All 
AE should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or 
discontinuation, starting or stopping concomitant treatments, changes 
in the frequency or nature of assessments, hospitalization, or any 
other medically required intervention.      
9.2.3. 
As far as “possible or definitive” related AE unexpected to HCT, 
each adverse event should be evaluated  to determine: 
9.2.3.1. the severity grade (mild, moderate, severe) or (grade 1-4) 
9.2.3.2. its relationship to the study drug(s) (suspected/not 
suspected) 
9.2.3.3. its duration (start and end dates or if continuing at final 
exam) 
9.2.3.4. action taken (no action taken; study drug dosage 
adjusted/temporarily interrupted; study drug permanently 
discontinued due to this adverse event; concomitant 
medication 
taken; 
non-drug 
therapy 
given; 
hospitalization/prolonged hospitalization) 
9.2.3.5. whether it constitutes a serious adverse event (SAE). 
 
 
9.3. 
SAE is an undesirable sign, symptom or medical condition which: 
9.3.1. 
Is fatal or life-threatening 
9.3.2. 
Results in persistent or significant disability/incapacity 
9.3.3. 
Constitutes a congenital anomaly/birth defect 
9.3.4. 
Is medically significant, i.e., defined as an event that jeopardizes the 
patient or may require medical or surgical intervention to prevent one 
of the outcomes listed above 
9.3.5. 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
9.3.6. 
Note that hospitalizations for the following reasons should not be 
reported as serious adverse events: 
9.3.6.1. Routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition  
9.3.6.2. Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since 
signing the informed consent 
9.3.6.3. Social reasons and respite care in the absence of any deterioration in 
the patient’s general condition 
9.3.6.4. Note that treatment on an emergency outpatient basis that does not 
result in hospital admission and involves an event not fulfilling any of 
the definitions of a SAE given above is not a serious adverse event 
9.3.7. 
Reporting: See section 11.7. 
 
9.4. Special considerations for AE attribution: 


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9.4.1. 
Diarrhea: 
9.4.1.1. From  PANO first dose to day +21 post-HCT attribution to 
study drug  is difficult as majority of patients develop 
diarrhea as part of the conditioning regimen and/or rarely 
due to GVHD.  
9.4.1.2. After day + 22 post HCT,  if a patient develops diarrhea 
grade 3 (increase more than 7 stools above baseline) or 
grade 4 (life threatening), excluding infection and/or 
GVHD, the AE is considered “probable” or “definitive” 
related to PANO. Protocol specific stopping rules have 
been formulated for excess GI toxicity (section 12.2). 
9.4.2. 
Vomiting: 
9.4.2.1. From PANO first dose to day +21 post-HCT attribution to 
study drug is difficult as vomiting is a possible 
complication of the conditioning regimen and/or rarely 
due to GVHD. 
9.4.2.2. After day + 22 post HCT if a patient develops vomiting 
grade 3 (increase more than 6 episodes in 24 hours) or 
grade 4 (life threatening), excluding infection and/or 
GVHD, it is considered “probable” or “definitive” related 
to PANO. Protocol specific stopping rules have been 
formulated for excess GI toxicity (section 12.2). 
 
10. Required Evaluations: Evaluations and study visits are listed in Appendix C. 
 
10.1. 
Demographics: Ethnic origin, date of birth, gender, primary diagnosis 
necessitating HCT, HLA-A, B, C, DRB1  matching of donor and recipient, 
stem cell product (peripheral blood stem cells are only allowed), Date of 
HCT. 
10.2. 
Physical examination: A directed examination will be performed as per 
treating physician discretion and based upon patient symptoms. Performance 
status will be specified by Karnofsky (Appendix D). Comorbidity score 
(Appendix E). 
10.3. 
Vital signs: body surface area of recipient (at enrollment), height (at 
enrollment), pulse, blood pressure, respiration rate, temperature and weight.  
10.4. 
Laboratory evaluations: should be done at baseline (within ≤ 72 hours prior 
to to the first administration of oral PANO), during the course of the study 
and at the time of the study treatment completion visit as specified in 
calendar (Appendix C). Results must be reviewed prior to administering 
PANO. More frequent examinations may be performed if medically 
indicated.  
10.5. 
Hematology: include hemoglobin, hematocrit, platelets, total white blood 
cell count (WBC) and differential. The coagulation profile includes a 


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prothrombin time or International Normalized Ratio (INR), activated partial 
thromboplastin time and fibrinogen. 
10.6. 
Biochemistry: includes the following parameters: BUN, creatinine, sodium, 
potassium, chloride, CO2 (HCO3), glucose, calcium, albumin, total protein, 
total bilirubin, alkaline phosphatase, LDH, AST/SGOT, ALT/SGPT, 
phosphorous and magnesium,.  If total bilirubin is greater than the upper 
limit of normal, direct and indirect bilirubin should be performed. 
Biochemistry tests should be obtained after patient has fasted, if possible. 
Cholesterol, LDL, HDL, triglycerides, and uric acid should be performed at 
baseline only.   
10.7. 
Viral studies: Plasma CMV PCR as per institutional guidelines.  
10.8. 
Standard urinalysis: dipstick assessment (pH, protein, glucose, blood, 
ketones, and leukocytes) should be performed. This must be supplemented 
with laboratory quantification of any potentially relevant abnormalities. 
10.9. 
Thyroid function test: Thyroid Stimulating Hormone (TSH) and free T4 
(thyroxine) will be measured at screening, and at study treatment completion. 
10.10. 
Serum pregnancy test: All females of childbearing potential should 
complete a pregnancy test (serum or urine) prior to transplant. 
Postmenopausal women must have been amenorrheic for ≥ 12 months in 
order to be considered “of non-childbearing potential”. 
10.11. 
Electrocardiogram (ECG): as specified in section 5.6 
 
10.12. 
Follow up:  
10.12.1. GVHD: 
Date 
of 
onset 
of 
acute 
GVHD, 
names 
of 
immunosuppressive drugs received and dates, Date of onset of 
chronic GVHD, Organ staging will be assessed prior to therapeutic 
intervention, according to the consensus grading44  (Appendix A). 
The diagnosis of Grades II-IV GVHD should be confirmed by 
histo-pathological examination whenever possible but is not 
mandatory. Pathology will be reviewed by H. Lee Moffitt Cancer 
Center pathologists. 
10.12.2. Study medications: Records of study medication used, dosages 
administered, and intervals between visits will be recorded during 
the study. Drug accountability will be noted by research pharmacy. 
10.12.3. AE: Significant findings made after the start of study drug which 
meet the definition of an AE and SAE must be recorded.  
10.12.4. Infections and relapse will be captured but they are not considered 
AE 
 
10.13. 
Correlative studies. See appendix F 
 
 
 


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11.  Data and Safety monitoring: 
The Data Safety & Monitoring Plan (DSMP) will ensure that this trial is well 
designed, responsibly managed, appropriately reported, and that it protects the rights 
and welfare of patients. The following internal and external review and monitoring 
processes provide oversight and active monitoring of this trial: 
 The Principal Investigators (PI) 
 The Scientific Review Committee (SRC) 
 The Protocol Review and Monitoring Committee (PRMC); 
 The Research Compliance Division (RCD) of the Cancer Center's Compliance 
Office; 
 The Institutional Review Board. 
 We will follow the Moffitt Cancer Center policy for monitoring of Investigator 
Initiated Trials ( MRI-P.PSO.03) 
 
 The protocol includes a section that specifies the following with respect to 
Adverse Event (AE) reporting: what constitutes an AE (versus what is a serious 
adverse event), the entities to which AE should be reported, the timing of this 
reporting, and the person or persons responsible for reporting. This includes 
prompt (within one day of knowledge of the event) reporting to the IRB for 
unanticipated risks to subjects and reporting in writing within five working days 
to the IRB. It is required reporting of SAE to Novartis but not AEs as indicated in 
section 9. If necessary, corrective action and/or educational programs will occur 
to ensure subject safety and data integrity. Reports to the SRC, PMC, and IRB 
will be submitted as required. 
11.1. Initial and Ongoing Monitoring and Review: The principal investigator will 
have the primary responsibility for data safety and monitoring. Input will be 
sought from sub-investigators and other members of the BMT Program 
concerning data and safety issues.  The PI of the study will have primary 
responsibility for ensuring that the protocol is conducted as approved by the 
SRC and IRB.  The PI will ensure that the monitoring plan is followed, that all 
data required for oversight of monitoring are accurately reported to a DSMB 
and/or to the PMC and IRB as required, that all adverse events are reported 
according to protocol guidelines, and that any adverse actions reflecting patient 
safety concerns are appropriately reported. The investigators and members of 
the BMT Research Staff will meet at least monthly. The following data will be 
reviewed: rate of accrual, adverse events and protocol deviations and/or 
violations.  
11.2. The Scientific Review Committee (SRC): The Cancer Center's internal 
Scientific Review Committee (SRC) provides for a formal internal peer review 
of all protocols and general scientific oversight of interventional clinical 
research. The Committee has a defined membership representing all of the 


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major research divisions of the Cancer Center, including biostatisticians. All 
new protocol submissions must contain the required elements of the protocol, 
and must include a DSMP prior to approval by the Committee. The plan has to 
be appropriate for the phase and risk of the proposed study.  
11.3. The Protocol Review and Monitoring Committee (PRMC): The Protocol 
Review and Monitoring Committee (PRMC) will monitor this trial for safety, 
progress, protocol compliance, accrual, adverse event reporting, and data 
integrity. The membership of the PRMC includes physician representation 
from each program area and a biostatistician. In addition to the existing 
stopping rules, the PRMC is authorized to suspend a trial for non-compliance 
with a DSMP or as a result of audit findings deemed unacceptable. The PRMC 
will report significant findings to the IRB and the applicable regulatory body. 
Interim meetings are scheduled to address specific issues that require 
immediate attention to ensure safety of research participants. 
11.4. The Cancer Center’s Compliance Office:  Corporate Compliance conducts 
internal audits of selected clinical trials conducted at the Cancer Center and its 
affiliates.  The purpose of the internal audit program is to: 
11.4.1. Assure patient safety by monitoring compliance 
11.4.2. Assure regulatory compliance by reviewing consent and adverse 
event reporting 
11.4.3. Assure scientific value by monitoring accuracy and completeness of 
data collection 
11.4.4. Monitor and coordinate research compliance activities associated 
with institutional and individual conflict of interest 
11.4.5. Make recommendations for modification of research practices as 
necessary and provide education on issues that are critical to good 
research practices 
Audits are conducted by Corporate Compliance in accordance with applicable 
regulatory standards. Investigator initiated trials, such as the one proposed here, 
receive the highest priority for audit. Corporate Compliance will conduct and 
report the findings of audits to the PMC in accordance with a protocol's annual 
review. The PRMC will determine the findings to be acceptable with minor 
deviations, acceptable with corrective action, or unacceptable with suspension or 
closure. The PRMC Chairperson will notify the IRB of the audit findings. The 
PRMC will be informed of all significant open follow-up items. For those 
observations where no action has been taken, Corporate Compliance will inform 
the PRMC and may conduct a focused audit. 
 
11.5. 
Protocol amendments, or changes in study conduct 


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Any change or addition (excluding administrative) to this protocol requires a 
written protocol amendment that must be reviewed by Novartis and the 
investigator before implementation and submission for IRB review.  A copy of 
the written approval of the IRB must be provided to Novartis. Examples of 
amendments requiring such approval are: 
11.5.1. increases in drug dose or duration of exposure of subjects, 
11.5.2. significant changes in the study design (e.g. addition or deletion of 
a control group), 
11.5.3. increases in the number of invasive procedures, 
11.5.4. addition or deletions of a test procedure required for monitoring of 
safety. 
These requirements for approval should in no way prevent any immediate action 
from being taken by the investigator or by Novartis in the interests of preserving 
the safety of all patients included in the trial.  If an immediate change to the 
protocol is felt to be necessary by the investigator and is implemented for safety 
reasons Novartis must be notified and the IRB at the center must be informed 
immediately.   Amendments affecting only administrative aspects of the study do 
not require formal protocol amendments or IRB approval but the IRB must be 
kept informed of such administrative changes. Examples of administrative 
changes not requiring formal protocol amendments and IRB approval include 
either 
changes 
in 
the 
staff 
used 
to 
monitor 
trials  
or minor changes in the packaging or labeling of study drug. 
 
11.6. 
Institutional Review Board/Independent Ethics Committee 
 
Before implementing this study, the protocol, the proposed informed consent 
form and other information to subjects, must be reviewed by a properly 
constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB). A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Any amendments to the protocol, other than 
administrative ones, must be reviewed by Novartis approved by this committee. 
 
11.7. 
Instructions for data reporting 
11.7.1.         To ensure patient safety, every SAE, regardless of suspected 
causality, occurring after the patient has provided informed 
consent and until at least 14 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours 
of learning of its occurrence. 
Any SAEs experienced after this 14 days period should only 
be reported to Novartis if the investigator suspects a causal 
relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be 


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reported as follow-up to the original episode within 24 hours 
of the investigator receiving the follow-up information. An 
SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one 
should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the 
Serious Adverse Event Report Form as outlined per 
contractual agreement; all applicable sections of the form 
must be completed in order to provide a clinically thorough 
report. The investigator must assess and record the 
relationship of each SAE to each specific study treatment (if 
there is more than one study treatment), complete the SAE 
Report Form in English, and send the completed, signed form 
by fax within 24 hours to the oncology Novartis Drug Safety 
and Epidemiology (DS&E) department. 
The telephone and telefax number of the contact persons in 
the local department of Drug Safety and Epidemiology 
(DS&E) are included in the contractual agreement. The 
original copy of the SAE Report Form and the fax 
confirmation sheet should be kept with the case report form 
documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom 
the original SAE Report Form was sent, using a new SAE 
Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each 
re-occurrence, complication, or progression of the original 
event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, 
if and how it was treated, whether the blind was broken or not, 
and whether the patient continued or withdrew from study 
participation. 
If the SAE is not previously documented in the Investigator’s 
Brochure or Package Insert (new occurrence) and is thought to 
be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department 
associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may 
need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that 
this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported 
to the competent authorities and relevant ethics committees in 


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accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 
11.7.2. Pregnancies: To ensure patient safety, each pregnancy 
occurring while the patient is on study treatment must be 
reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy 
Form and reported by the investigator to the oncology 
Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form 
and should include an assessment of the possible relationship 
to the panobinostat any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE 
Report Form. 
Pregnancy outcomes must be collected for the female partners 
of any males who took study treatment in this study. Consent 
to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
11.8. 
Data review and management: The Principal Investigator and the Clinical 
Trial Coordinator(s) assigned to the case will be primarily responsible for 
maintaining all study related documents including clinical research forms, as 
applicable. The Principal Investigator has the ultimate responsibility. 
Investigators must enter the information required by the protocol onto Case 
Report Forms (CRFs). ONCORE is the database of record for all CRF entries 
and will be verified with source documentation.  The review of medical 
records within PowerChart will be done in a manner to assure that patient 
confidentiality is maintained. Data collected will be stored in a secure BMT 
program database and Moffitt Cancer Center’s database system, ONCORE.  
Identifying patient information will be kept confidential.  Representatives of 
the USF IRB and the FDA will have access to patient information as it 
pertains to the study.  Privacy and confidentiality of the information will be 
protected to the extent provided by law. 
 
12. Statistical methods 
12.1. Sample Size Determination 
            In our randomized Phase II trial of TAC and SIR vs. TAC and MTX as GVHD 
prophylaxis after allogeneic transplantation we observed an acute GVHD 
incidence of 43% (95% CI 30-63%)  with TAC/SIR 4. Simon’s minimax two-
stage design with 10% one-sided type I error and 10% type II error rate is used 
for study design as follows. We will consider 43% incidence of grade II-IV 


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acute GVHD (aGVHD) not warranting further study. We will use 23% 
incidence rate as a promising result to pursue further study. With these study 
parameters, 15 evaluable patients will be investigated in the first stage. If 7 or 
more of 15 evaluable patients experience the grade II-IV acute GVHD, the 
treatment will be stopped. Otherwise, once 9 or more of 15 patients completed 
the +90 (+/-14) days follow up without experiencing the grade II-IV acute 
GVHD 23 additional evaluable patients (a total of 38 evaluable patients) will 
be enrolled. If the number of patients experiencing the grade II-IV aGVHD is 
12 or less, (≤31.6% incidence rate at day 100), the null hypothesis will be 
rejected and the regimen will be considered promising. An evaluable patient 
for primary endpoint is defined as patients who receive at least one dose of 
PANO per protocol and who neither relapse nor die of any reasons without 
experiencing grade II-IV aGVHD until day 100. A non-evaluable patient will 
be replaced and we anticipate a total of 44 patients will be accrued in order to 
account for 10% of competing risks (relapse or death without GVHD) at day 
100. 
 
12.2. Stopping criteria for toxicity 
            A patient who receives at least one dose of the study drug (PANO) per protocol 
is evaluable for toxicity. As shown in Table 9, the accrual will be suspended if 
c or more of n patients experience CTCAE (v.4) grade 3 or higher toxicity 
unexpected with transplant, where n is the number of evaluable patients and c 
is the number of patients who experience CTCAE (v.4) grade 3 unexpected 
toxicity or higher. Assuming true toxicity rate is 20% and the type I error rate 
is 5%, the stopping boundary was computed by Ivanova et al49. If true toxicity 
rate is 20%, 40% and 50%, then the probability of early stopping is 4.9%, 79% 
and 98%, respectively.  
 
 
Table 9. Boundary for early stopping rule for toxicity  
n 
3 
4 
5 
6 
7 
8 
9 
10 
11 
1
c 
3 
4 
4 
5 
5 
5 
6 
6 
6 
n 
21 
22 
23 
24 
25 
26 
27 
28 
29 
3
c 
9 
10 
10 
10 
11 
11 
11 
11 
12 
1
Note: 1. n = # of patients who receive at least one dose of study drug 
         2. c = # of patients who experience CTCAE (v4) Grade 3 or higher toxicity unexpected to HCT 
 
12.3 
Population for Primary and Secondary Endpoints  
 
Patients who receive at least one dose of the study drug (PANO) per protocol 
will be eligible for primary and secondary endpoints.  
 
12.4 
Analysis Plan for Primary Endpoint 
 
The cumulative incidence rate of grade II-IV acute GVHD at day 100 is the 
primary endpoint of the study and will be estimated along with one-sided 90% 


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confidence interval using the approach proposed by Gray50. The log-log 
transformation will be used to compute the point-wise confidence intervals. 
The death and relapse will be considered as competing risks of acute GVHD.  
 
12.5 
Analysis Plan for Secondary Endpoints 
The demographic and clinical characteristics of subjects will be summarized 
using descriptive statistics; mean, median, standard deviation and range for 
continuous measures and counts and frequencies for categorical measures. 
Adverse events will be recorded, including the details of the duration and the 
severity. Time-to-event data such as overall survival (OS) and relapse-free 
survival (RFS) is measured from the date of transplantation. OS and RFS will 
be analyzed using the Kaplan-Meier method51. The cumulative incidence of 
relapse and non-relapse mortality will be computed by Gray method. Death 
and relapse will be considered as the competing risks of chronic GVHD and 
the cumulative incidence of chronic GVHD will be measured by Gray method. 
The association of time-to-event data with and without competing risks will be 
explored by the method by Fine and Gray52 and the Cox proportional hazards 
regression model53, respectively. 
                
For correlative studies (appendix F) results will be compared to an external 
control patient subset that will be treated with TAC/SIR with same inclusion 
and exclusion criteria as this protocol except that they will not be treated with 
PANO. For the regulatory T-cell repopulation, the profiles of regulatory T cell 
counts will be analyzed using generalized linear models for repeated measures 
based on generalized estimating equations. The comparisons of profiles of T-
cells and DC cells with external control will be made using the Satterthwaite 
t-test.  
 
The analysis of the secondary endpoints is considered exploratory and no 
multiplicity adjustment is planned for it. A two-sided p-value of <0.05 is 
considered statistically significant. 
 
If we compare a total of 30 patients (15 in treatment group and 15 in 
external control) that will achieve 83% power to detect an effect size (mean 
difference divided by standard deviation) of 1.1 between two groups. 
 
If we compare a total of 40 patients (20 in PANO group and 20 in external 
control) will achieve 87% power to detect an effect size (mean difference 
divided by standard deviation) of 1 between two groups. 
 
13 Procedures and instructions 
 
13.1 Publication of results: Any formal presentation or publication of data from 
this trial may be published after review and comment by Novartis and prior to 
any outside submission.  Novartis must receive copies of any intended 


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communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts).   
These requirements acknowledge Novartis’ responsibility to provide peer input 
regarding the scientific content and conclusions of such publications or 
presentations.  Principal Investigation/Institution shall have the final authority 
to determine the scope and content of its publications, provided such authority 
shall be exercised with reasonable regard for the interests of Novartis and, in 
accord with the trial contract and shall not permit disclosure of Novartis 
confidential or proprietary information. 
 
13.2 
Disclosure and confidentiality: The investigator agrees to keep all 
information provided by Novartis in strict confidence and to request similar 
confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be 
stored appropriately to ensure their confidentiality. The information provided 
by Novartis to the investigator may not be disclosed to others without direct 
written authorization from Novartis, except to the extent necessary to obtain 
informed consent from patients who wish to participate in the trial. 
 
13.3 
Discontinuation of study: Novartis reserves the right to discontinue any 
study support under the conditions specified in the clinical trial agreement. 
 
13.4 
Ethics and Good Clinical Practice: This study must be carried out in 
compliance with the protocol and the principles of Good Clinical Practice, as 
described in Novartis standard operating procedures and: (1) ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. (2) US 21 Code of Federal Regulations dealing with clinical 
studies (including parts 50 and 56 concerning informed consent and IRB 
regulations); and (3)Declaration of Helsinki and amendments, concerning 
medical research in humans (Recommendations Guiding Physicians in 
Biomedical Research Involving Human Subjects).The investigator agrees to 
adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
 
13.5 
Institutional Review Board/Independent Ethics Committee. Before 
implementing this study, the protocol, the proposed informed consent form 
and other information to subjects, must be reviewed by a properly constituted 
Institutional Review Board/Independent Ethics Committee/Research Ethics 
Board (IRB/IEC/REB). A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Any amendments to the protocol, other than 
administrative ones, must be reviewed by Novartis approved by this 
committee. 
 


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13.6 
Informed consent. The investigator must explain to each subject (or legally 
authorized representative) the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved and 
any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the 
study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
 
              This informed consent should be given by means of a standard written 
statement, written in non-technical language. The subject should read and 
consider the statement before signing and dating it, and should be given a 
copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the 
subject’s legally appointed representative, if witnessed by a person not 
involved in the study, mentioning that the patient could not read or sign the 
documents. No patient can enter the study before his/her informed consent 
has been obtained. 
                
               The informed consent form is considered to be part of the protocol, and must 
be submitted by the investigator with it for IRB/IEC/REB approval. 
 
14  REFERENCES 
 
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31. Marks PA. Discovery and development of SAHA as an anticancer agent. Oncogene. 
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32. Tao R, de Zoeten EF, Ozkaynak E, et al. Deacetylase inhibition promotes the 
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47. Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive 
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APPENDIX  A:  
1. Acute GVHD organ staging 
 
 
 
 


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2. Grading of Chronic GVHD (NIH Criteria) 
 
 
 
 


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3. Categories of Acute and Chronic GVHD 
 
 
 
Categories of Acute and Chronic GVHD 
Category 
Time of 
Symptoms 
after HCT  
Presence 
of Acute 
GVHD 
Features 
Presence 
of 
Chronic 
GVHD 
Features* 
Acute GVHD 
Classic acute GVHD 
≤100 d 
Yes 
No 
Late-onset acute GVHD 
>100 d 
Yes 
No 
Chronic GVHD 
Classic chronic GVHD 
No time 
limit 
No 
Yes 
Overlap syndrome 
No time 
limit 
Yes 
Yes 
 
*as described herein: 
 
Signs and Symptoms of Chronic GVHD 
 
Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctive 
(Seen in 
Chronic 
GVHD, but 
Insufficient 
Alone to 
Establish a 
Diagnosis of 
Chronic 
GVHD) 
Other Features* 
Common 
(Seen 
with Both 
Acute 
and 
Chronic 
GVHD) 
Skin 
Poikiloderma 
Depigmentati
on 
Sweat impairment 
Erythema 
 
Lichen 
planus-like 
features 
 
Ichthyosis 
Maculopa
pular rash 


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Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctive 
(Seen in 
Chronic 
GVHD, but 
Insufficient 
Alone to 
Establish a 
Diagnosis of 
Chronic 
GVHD) 
Other Features* 
Common 
(Seen 
with Both 
Acute 
and 
Chronic 
GVHD) 
 
Sclerotic 
features 
 
Keratosis pilaris 
Pruritus 
 
Morphea-like 
features 
 
Hypopigmentation 
 
 
Lichen 
sclerosis-like 
features 
 
Hyperpigmentation 
 
Nails 
 
Dystrophy 
 
 
 
 
Longitudinal 
ridging, 
splitting, or 
brittle features 
 
 
 
 
Onycholysis 
 
 
 
 
Pterygium 
unguis 
 
 
 
 
Nail loss 
(usually 
symmetric; 
affects most 
nails)† 
 
 


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Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctive 
(Seen in 
Chronic 
GVHD, but 
Insufficient 
Alone to 
Establish a 
Diagnosis of 
Chronic 
GVHD) 
Other Features* 
Common 
(Seen 
with Both 
Acute 
and 
Chronic 
GVHD) 
Scalp and 
body hair 
 
New onset of 
scarring or 
nonscarring 
scalp alopecia 
(after 
recovery from 
chemoradioth
erapy) 
Scaling, 
papulosquamo
us lesions 
Thinning scalp hair, 
typically patchy, 
coarse, or dull (not 
explained by 
endocrine or other 
causes) 
 
 
 
 
Premature gray hair 
 
Mouth 
Lichen-type 
features 
Xerostomia 
 
Gingivitis 
 
Hyperkeratoti
c plaques 
Mucocele 
 
Mucositis 
 
Restriction of 
mouth 
opening from 
sclerosis 
Mucosal 
atrophy 
Pseudomembr
anes† 
Ulcers† 
 
Erythema 
Pain 
Eyes 
 
New onset 
dry, gritty, or 
painful eyes‡ 
Photophobia 
 
 
 
Cicatricial 
conjunctivitis 
Keratoconjun
ctivitis sicca‡ 
Confluent 
areas of 
punctate 
keratopathy 
Periorbital 
hyperpigmentation 
 


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Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctive 
(Seen in 
Chronic 
GVHD, but 
Insufficient 
Alone to 
Establish a 
Diagnosis of 
Chronic 
GVHD) 
Other Features* 
Common 
(Seen 
with Both 
Acute 
and 
Chronic 
GVHD) 
 
 
 
Blepharitis 
(erythema of the 
eyelids with 
edema) 
 
Genitalia 
Lichen 
planus-like 
features 
Erosions† 
 
 
 
Vaginal 
scarring or 
stenosis 
Fissures† 
 
 
 
 
Ulcers† 
 
 
GI tract 
Esophageal 
web 
Strictures or 
stenosis in 
the upper to 
mid third of 
the 
esophagus† 
 
Exocrine 
pancreatic 
insufficiency 
Anorexia 
Nausea 
Vomiting 
Diarrhea 
 
 
 
 
Weight 
loss 
 
 
 
 
Failure 
to thrive 
(infants 
and 
children) 


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Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctive 
(Seen in 
Chronic 
GVHD, but 
Insufficient 
Alone to 
Establish a 
Diagnosis of 
Chronic 
GVHD) 
Other Features* 
Common 
(Seen 
with Both 
Acute 
and 
Chronic 
GVHD) 
Liver 
 
 
 
Total 
bilirubin, 
alkaline 
phosphat
ase >2 × 
upper 
limit of 
normal† 
 
 
 
 
ALT or 
AST >2 
× upper 
limit of 
normal† 
Lung 
Bronchiolitis 
obliterans 
diagnosed 
with lung 
biopsy 
Bronchiolitis 
obliterans 
diagnosed 
with PFTs 
and 
radiology‡ 
 
BOOP 
Muscle
s, 
fascia, 
joints 
Fasciitis 
Joint 
stiffness or 
contractur
es 
secondary 
to 
sclerosis 
Myositis 
or 
polymyosi
tis‡ 
Edema 
Muscle cramps 
Arthralgia or 
arthritis 
 
Hemato
poietic 
and 
immun
e 
 
 
Thrombocytope
nia 
 
 
 
 
Eosinophilia 
 


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Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctive 
(Seen in 
Chronic 
GVHD, but 
Insufficient 
Alone to 
Establish a 
Diagnosis of 
Chronic 
GVHD) 
Other Features* 
Common 
(Seen 
with Both 
Acute 
and 
Chronic 
GVHD) 
 
 
 
Lymphopenia 
 
 
 
 
Hypo- or 
hypergammagl
obulinemia 
 
 
 
 
Autoantibodies 
(AIHA and 
ITP) 
 
Other 
 
 
Pericardial or 
pleural 
effusions 
 
 
 
 
Ascites 
 
 
 
 
Peripheral 
neuropathy 
 
 
 
 
Nephrotic syndrome 
 
 
 
 
Myasthenia gravis 
 


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Organ or 
Site 
Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctive 
(Seen in 
Chronic 
GVHD, but 
Insufficient 
Alone to 
Establish a 
Diagnosis of 
Chronic 
GVHD) 
Other Features* 
Common 
(Seen 
with Both 
Acute 
and 
Chronic 
GVHD) 
 
 
 
Cardiac conduction 
abnormality or 
cardiomyopathy 
 
GVHD 
indicates 
graft-versus-host 
disease; 
ALT, 
alanine 
aminotransferase; 
AST, 
aspartate 
aminotransferase; BOOP, bronchiolitis obliterans-organizing pneumonia; PFTs, pulmonary function tests; 
AIHA, autoimmune hemolytic anemia; ITP, idiopathic thrombocytopenic purpura. 
* Can be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed. 
† In all cases, infection, drug effects, malignancy, or other causes must be excluded. 
‡ Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes). 
 
 


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Appendix B 
General Guidance:  
 In generally, medications listed in Table 1 should be avoided while medications 
listed in Tables 2 and 3 are to be used with caution when co-administered with 
PANO.  
 
 It is of great importance to avoid combining drugs listed below in Table 1 and 
Table 2 (CYP3A inhibitors) especially in the presence of electrolyte abnormalities, 
notably decreased potassium or magnesium levels commonly associated with 
diuretic usage. 
1 
Medications which have a risk of causing Torsades de pointes ventricular 
arrhythmia should be avoided 
Patients who are currently receiving treatment of the medications in Table 1 and cannot 
either discontinue from this treatment or switch to an alternative medication prior to 
enrollment, will be excluded from the study.  Patients may not begin PANO treatment 
with any of the medications listed in Table 1 unless this is discussed with and approval is 
granted by Novartis. It may be agreed to temporarily discontinue PANO treatment (e.g., 
for 72 hours) during administration with these drugs or withheld medications in Table 1 
for at least 72 hours when PANO is to be administered and missed dose(s) should be 
administered until completion of the trial specified PANO schedule.   
This is not a comprehensive list of medications which may prolong the QT interval or 
have a risk of causing Torsades de pointes. This list of medications was developed in 
collaboration with an external cardiology consultant, and represents those medications 
which are deemed to have an unacceptable risk of co-administration with PANO. 
The following website may be referenced as a supplemental guide for drugs which have 
been associated with Torsades de pointes or prolonging the QT interval but at this point 
lack substantial evidence for causing Torsades de pointes: 
http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm#. 
Medications listed on the website which do not appear in Table 1 may be used with 
caution at the discretion of the investigators.  
The serotonin (5HT3) antagonists, often used as antiemetics, such as ondansetron 
dolasetron, (also are known CYP2D6 substrates, see Table 3), or granisetron have been 
associated with Torsades de points and QT prolongation but have not been shown to cause 
Torsades de pointes. Therefore, 5HT3 antagonists are not per se prohibited but close 
monitoring for signs and symptoms of QT prolongation is recommended.  Caution is to be 
exercised when using these or other agents that may prolong QT intervals in combination 
with PANO.  
 
 


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Table 1.  Medications which have a risk of causing Torsades de pointes to be avoided 
All Class IA antiarrhythmics  
 quinidine 
 procainamide 
 disopyramide 
 any other class IA antiarrhythmic drug 
All Class III antiarrhythmics  
 
 
amiodarone* 
 
sotalol 
 
bretylium 
 
disopryramide 
 
dofetilide 
 
ibutilide 
 
any other class III antiarrhythmic drug 
Antibiotics 
Macrolide antibiotics* 
 erythromycin 
 clarithromycin 
 telithromycin 
Quinolone antibiotics* 
 
sparfloxacin 
Antipsychotics 
 
thioridazine 
 
mesoridazine 
 
chlorpromazine 
 
pimozide 
Antimalarials 
 halofantrine 
 chloroquine 
Miscellaneous drugs 
 arsenic trioxide 
 astemizole 
 bepridil 
 domperidone 


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 levomethadyl 
 methadone 
 pentamidine IV* 
 droperidol 
 
*Note: azithromycin, ciprofloxacin, levofloxacin, pefloxacin, ofloxacin, 
tosufloxacin, difloxacin, temafloxacin, fleroxacin, acrosoxacin, nalidixic 
acidand enoxacin are allowed. Inhaled pentamidine can be used for PCP 
prophylaxis (less likely to induce QTc prolongation). If amiodarone is 
used to the discretion of the treating physician, close monitoring of QTcF 
is recommended as clinically indicated. 
2 
Medications which are known strong CYP3A4/5 inhibitors to be used with 
caution Table 2.  
Table 2   
Medications which are known strong CYP3A4/5 inhibitors to be used 
with caution 
Macrolide antibiotics* 
 clarithromycin 
 telithromycin 
 troleandomycin  
 erythromycin 
Antifungals (azoles)* 
 ketoconazole 
 itraconazole  
 fluconazole  
Antidepressants 
 nefazodone 
Calcium channel blockers* 
 diltiazem 
 verapamil 
HIV protease inhibitors: 
 indinavir 
 nelfinavir 
 ritonavir 
 saquinavir  
 Miscellaneous drugs or products 
 aprepitant 


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 grapefruit product or juice or grapefruit 
* azithromycin, voriconazole, ketoconazole, regular orange juice and 
dihydropyridine calcium channel blockers (e.g. amlodipine, felodipine, 
nicardipine, nifedipine) are allowed.  
This is not a comprehensive list of medications which may inhibit CYP3A4/5.  Additional 
updated versions with moderate and weak CYP3A inhibitors, which are meant to be used 
as 
a 
guide, 
may 
be 
found 
at 
the 
following 
website: 
http://medicine.iupui.edu/clinpharm/DDIs 
3 
Medications which are known CYP2D6 substrates to be used with caution 
Panobinostat was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) in vitro.  Thus, 
clinical drug-drug interaction study with panobinostat as CYP2D6 inhibitor and 
dextromethorpan as CYP2D6 substrate was recently conducted in study CLBH589B2109. 
Multiple panobinostat doses increased Cmax and AUC of dextromethorphan by a mean of 
1.8- and 1.6-fold respectively, but with no change in Tmax in 17 cancer patients.  An 
approximately 2-fold increase in dextromethorphan AUC upon co-administration with 
panobinostat indicated that in vivo CYP2D6 inhibition of panobinostat is weak.  
As the study was conducted using a sensitive CYP2D6 substrate which resulted in a weak 
inhibition, drugs with a large therapeutic index such as anti-emetics, anti-hypertensives, 
and anti-depressants are generally safe to be co-administered with panobinostat.  
Patients should be carefully monitored for potential signs and symptoms of toxicity and 
may require dose titration or dose reduction of a sensitive CYP2D6 substrate which also 
have a narrow therapeutic window (e.g., the ratio of toxicity exposure is ≤ 2-fold higher 
than the efficacious or therapeutic exposure).  
Table 3-1   
Medications which are known CYP2D6 substrates to be used with 
caution 
Beta blockers (listed below): 
Antipsychotics (listed below): 
carvedilol 
aripiprazole 
metoprolol 
haloperidol 
propafenone 
perphenazine 
timolol 
risperidone 
Antidepressants (listed below): 
thioridazine 
amitriptyline 
zuclopenthixol 
chlormipramine 
amphetamine  
desipramine 
alprenolol 
imipramine 
bufuralol 


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fluoxetine 
chloropheniramine 
paroxetine 
Antiarrhythmics (listed below): 
venlafaxine 
quinidine 
bupropion 
lidocaine 
duloxetine  
mexiletine 
Antiemetics (listed below): 
propafenone 
 
Others: 
 
oxycodone 
metoclopramide 
codeine 
 
hydrocodone 
 
terbinafine 
 
promethazine 
 
tamoxifen 
 
Tramadol 
Use of antiemetics ondansetron and 
dolasetron 
is 
contraindicated 
(granisetron use as an antiemetic is 
permitted). 
 
This is not a comprehensive list of CYP2D6 substrates.  Additional updated versions of 
this list, which are meant to be used as a guide, may be found at the following website: 
http://medicine.iupui.edu/clinpharm/DDIs 1 Synold TW, Takimoto CH, Doroshow JH, 
Gandara D, Mani S, Remick SC, Mulkerin DL, Hamilton A, Sharma S, Ramanathan RK, 
Lenz HJ, Graham M, Longmate J, Kaufman BM, Ivy SP. Dose-Escalating and 
Pharmacological Study of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic 
Function: A National Cancer Institute Organ Dysfunction Working Group Study, Clin 
Cancer Res. 2007 13; 3660  


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APPENDIX C. Study calendar for patients treated with TAC+SIR+PANOor with TAC+SIR (PANO has been discontinued due to GVHD)
Test and Procedures 
Screening 
-6/-57 
-1 
+28 
+60 
+90 
+120 
+150 
+180 
+270 
+365 
 
 
 
 
+/- 
3days 
+/- 14 days 
+/- 30 days 
Medical history, complete physical exam, weight, 
vital signs, performance status by Karnofsky. 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Transplant Vital organ testing.1 
X 
 
 
 
 
 
 
 
 
 
 
BSA- Height. 
X 
 
 
 
 
 
 
 
 
 
 
Consent signing 
X 
 
 
 
 
 
 
 
 
 
 
TSH4, free T44 
X 
 
 
 
 
 
 
 
 
 
X 
Coagulation Profile (PT, PTT, Fibrinogen4) 
X 
 
 
 
 
 
 
 
 
 
 
PANO (PO) administration5 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiograms (EKGs)2 
X 
X 
X 
 
 
 
 
 
 
 
 
Biochemistries3 
X 
 
 
 
 
 
 
 
 
 
 
Cholesterol, LDL, HDL, triglycerides, and uric 
acid4 
X 
 
 
 
 
 
 
 
 
 
 
GVHD organ assessments 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Record immune suppression 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE and SAE 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Research Studies6 (see Appendix F) 
 
 
 
 
 
 
 
 
 
 
 
1  LVEF by MUGA  and/or echocardiogram, PFT, CT chest, CT sinus, bone marrow,  liver function tests, creatinine clearance, 
serum pregnancy test, infectious disease panel as per SOP. All must meet inclusion criteria detailed in body of protocol. 
Exclusionary factors must be confirmed as negative upon screening evaluation, as detailed in the protocol.  
2  Electrocardiograms (EKGs): see section 5.6. 
3 Biochemistry:: BUN, creatinine, sodium, potassium, chloride, CO2 (HCO3), glucose, calcium, albumin, total protein, total 
bilirubin, alkaline phosphatase, LDH, AST/SGOT, ALT/SGPT, phosphorous and magnesium, and uric acid.  If total bilirubin is 
greater than the upper limit of normal, direct and indirect bilirubin should be performed. Biochemistry tests should be obtained 
after patient has fasted if possible. 
4 test specific to study- cost covered by study budget  
5PANO administration:  Patients will be treated with PANO 5 MG PO TIW (3 doses about 48 hours apart in a 7 day period) QW 
for 26 weeks starting prior to stem cell infusion. See section 5.7.1.3 and Appendix G for further details. 
TAC will be administered starting on day -3 and SIR on day -1 following our institutional guidelines for dosing. See section 
5.7.1.1 and 5.7.1.2. 
 6Research samples will be obtained on days-30 to -5,15±3, 28±3, 90±14 and 365±45 
7See Appendix G with details of PANO administration depending on conditioning regimen 


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APPENDIX D 
Karnofsky Performance Status Criteria 
Able to carry on normal activity; no special care is needed 
 
100 
Normal; no complaints; no evidence of disease         
(ECOG  0) 
90 
Able to carry on normal activity 
 
 
 
(ECOG  0) 
80  
Normal activity with effort 
 
 
 
 
(ECOG  1) 
 
Unable to work; able to live at home, cares for most personal needs; a varying amount of 
assistance is needed 
 
70  
Cares for self; unable to carry on normal activity 
 
(ECOG  1) 
  
or to do active work 
60 
Requires occasional assistance 
 
 
 
(ECOG  2) 
  
but is able to care for most needs 
50 
Requires considerable assistance 
 
 
 
(ECOG  2) 
 
and frequent medical care 
 
Unable to care for self; requires equivalent of institutional or hospital care; disease may be 
progressing rapidly 
 
40 
Disabled; requires special care and assistance 
 
(ECOG  3) 
30 
Severely disabled; hospitalization indicated,  
 
(ECOG  3) 
 
although death not imminent 
20  
Very sick; hospitalization necessary  
 
 
(ECOG  4) 
10  
Moribund; fatal process progressing rapidly  
 
(ECOG  4) 
 
 
 
APPENDIX E. Comorbid Conditions 
Comorbidity score per Sorror, et al.  


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*composite score obtained by summing total points 
*modification made to “pulmonary” co-morbidity: given marked discrepancy in frequency 
distribution of reduced DLCO in analysis of 59 contemporary patients from our center 
compared to published standards, decrement in DLCO alone will not factor into 
calculation of “pulmonary” comorbidity. Only those with DLCO < 50% will be considered 
to have “severe pulmonary” comorbidity and be excluded from the trial. 
*psychiatric disturbance: only those with psychiatric disturbance (such as depression 
and/or anxiety) requiring therapy or treatment will be assigned a point on this measure. 
 Non-relapse mortality per Sorror, et al 
 
 
 
 
 
 
 


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APPENDIX F 
 
Translational research Introduction: 
The goals of correlative studies are to test the pharmacodynamics of PANO administered 
in for GVHD prevention.  We will determine whether PANO abrogates HCT induced 
cytokine storm, if there is a correlation between HDAC enzymatic activity inhibition and 
clinical GVHD prevention; we will establish whether there is enhanced proteins/histones 
acetylation in T-cell subsets that may be responsible for GVHD prevention and effects on 
immune reconstitution.  Samples will be collected with the AM blood draw whenever 
possible.  Samples will be labeled with the patient's name and Moffitt unique patient 
number (UPN), date and time of draw, and transported immediately by courier to the 
Moffitt Cancer Center Research laboratory no. 22324, in the Stabile Building at the 
Moffitt Cancer Center and/or to Novartis pharmaceutical (If PK performed.  Samples 
acquisition, results and statistics will be recorded into a Microsoft Excel database.  
 
Data for each correlative study performed from the whole study population (patients 
receiving TAC+SIR +PANO) will be presented over time and compared to data from 
similar “external control” patients treated TAC/SIR with identical inclusion and exclusion 
criteria except that will not be treated with PANO. We are going to accrue n=20 subjects 
as “external control”. These patients will be consented with an specific “external control” 
consent.  
 
Immune Reconstitution after TAC/SIR/PANO: 
 
To describe the kinetics of total T cells, CD4+ (T helper) and CD8+ (T cytotoxic), Th1, 
Th2, Th17, regulatory T-cells (Tregs), CD19+ (B cells), CD56 (NK cells) and DCs cell 
subsets recovery following TAC/MTX/PANO treatment FACS analysis will be performed 
on lysed whole blood samples with previously established multicolor antibodies panels.  
FACS Calibur flow cytometer will be used for acquisition and analysis will be performed 
with FlowJo software. All appropriate compensation tubes, including fluorescence minus 
1, will be prepared from normal donor blood cells. The absolute lymphocyte subset counts 
will be determined using the formula: (absolute subset count) x (percentage of events 
positive for the TEST). To test circulating monocytes and/or DCs we will establish a 
lineage negative (Lin-) panel consisting of CD3, CD19, CD16, 14 and CD56 antibodies. 
Monocytes will be characterized by CD14+, 16+ (or CD16-), CD11c-, CD86- and CD123 
low/neg cells. Dentritic cells subsets will be gated on the Lin- and HLA-DR+ gate.  
Monocytes derived DCs (CD11c+, CD86+, CD123-), plasmocytoid DC ( CD11c-, CD86+, 
CD123++) and 6-sulfoLacNac DC (slanDC) (M-DC8+/1c-/11c+14- 16+ 45RA+ 5aR+).  


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In addition we will test for type-2 myeloid dendritic cells by BDCA-3 (CD141) 
expression. Absolute cell counts will be enumerated using the Becton Dickinson 
TruCOUNT tubes with MultiSET software. Flow cytometry and absolute cell counts will 
be enumerated before PANO administration (days -30 to -5, 15(+/-3), 28(+/-3), 90(+/-14) 
and 365(+/-45)  in order to determine changes in the absolute cell numbers over time. In a 
group of patients we will correlate the flow cytometry findings with Western blot 
acetylation analysis of PBMC at the same time points. Data for each cell subset from the 
whole study population will be presented over time and compared to data from similar 
external control patients treated TAC/SIR with identical inclusion and exclusion criteria 
except that will not be treated with PANO. 
 
- 
Histone acetylation of T cells and DC subsets with TAC/SIR/PANO 
To determine the level of protein acetylation and more specifically of hyper-acetylated 
histones (H3 and/or H4) in total T cells, T-regs, CD4/CD8 and DC subsets in peripheral 
blood we will use multi parameter flow cytometry assay. In a group of patients we will 
correlate the flow cytometry results by histone acetylation measured by Western blot 
analysis of PBMC. We speculate that TAC/SIR/PANO will lead to an overall increase in 
the number of acetylated proteins. It remains to be determined which T-cell subsets will be 
more susceptible to HDACi with PANO at this point. In summary, whole blood will be 
collected and separated in 100μL aliquot and/or PBMC (5-10x106) will be obtained after 
Ficoll-Paque or Buffy coat/RBC lysis separation. For multiparameter flow staining, an 
aliquot containing at least 1 x 106 cells will be used per tube if possible.  Cells will be 
washed in PBS and fixed with 0.4% paraformaldehyde in PBS for 5-10 minutes at 37ºC 
and washed with buffer. The fixed cells will be re-suspended in permeabilization buffer for 
5 minutes (0.4% Triton X-100 in wash buffer) and then washed. After fixation and 
permeabilization, cells will be stained with anti-acetylated-lysine or anti-acetylated histone 
antibodies as well as with a variety of lymphocytes markers (CD4, CD8, CD3, CD25 
and/or CD117) and apoptosis detection markers including annexin, 7-AAD and/or caspase 
3. Some antibodies may be directly labeled with fluorochrome prior to their use to 
minimize secondary antibody staining background. All compensation tubes, including 
fluorescence minus 1, will be prepared from normal donor blood cells. Test will be done 
before PANO administration on day -5, and on days 30 to -5, 15(+/-3), 28(+/-3), 90(+/-14) 
and 365(+/-45).  Data for histone acetylation and DC subset from the whole study 
population will be presented over time and compared to data from similar external control 
patients treated TAC/SIR with identical inclusion and exclusion criteria except that will 
not be treated with PANO. 
 
 
 


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T reg immune-reconstitution, Foxp3+ expression and acetylation with 
TAC/SIR/PANO 
 
T-regs will be measured with the 259D Biosciences Biolegend Foxp3 kit antibody that 
identifies CD4+CD25+ Tregs and/or by FACS as determined by the lack of CD127 
expression. Since Foxp3 requires cell membrane permeabilization, standard viable dyes 
are not applicable. The Live/Dead Fixable Dead Cell Violet Stain (L/D) from Molecular 
Probes will be used for exclusion of dead cells. We propose that one of the benefit 
conferred by TAC/SIR/PANO-based immune suppression results from apoptosis of 
alloreactive donor non-Treg CD4+ cells while sparing T regulatory cells that mitigate 
GVHD risk and promote immune tolerance. Accordingly, we will study the proportion of 
Treg/total CD4+ cells. We will also measure the expression of FOXP3 and IDO mRNA in 
PBMC by RT-PCR. Test will be done before PANO administration on day -30 to -5, and 
on days 30 to -5, 15(+/-3), 28(+/-3), 90(+/-14) and 365(+/-45).  Data for T-reg immune 
reconstitution and acetlylation from the whole study population will be presented over 
time and compared to data from similar external control patients treated TAC/SIR with 
identical inclusion and exclusion criteria except that will not be treated with PANO. 
 
 
Inflammatory cytokine expression profiling with TAC/SIR/PANO 
 
In order to rapidly and accurately measure the expression levels of up to 40 
cytokines/chemokines and other relevant proteins in GVHD inflammation (cytokine 
storm) we will use a human inflammation antibody array assay. The technology is 
designed based on the sandwich immunoassay principle. A panel of antibodies (capture) is 
immobilized in the specific spot locations on the surface of membrane. Incubation of array 
membranes with biological samples results in capturing cytokines by corresponding 
antibodies. The bound cytokines are detected with a cocktail of biotinylated antibodies. 
Signals are then visualized using chemiluminescence. We hypothesize that HDACi will 
reduce the level of expression of pro-inflammatory cytokines like TNF/IFN and increase 
level of tolerogenic cytokines (TGFb-b /IL-10). We will use a Raybiotech’s Human 
inflammation antibody array (catalog #, AAH-INF -3-8) to detect the following cytokines 
IL-1, 2, 3, 4, , 6, 7, 8, 10, 11, 12, 13, 15, 16, 17 , IFN, TNF-α, TNF-β, TNF RI, s TNF RII,  
MCP1-2, M-CSF, MIP, GM-CSF, G-CSF among others proteins.  
We will also measure serum levels of soluble IL-2 receptor α using a commercially 
available ELISA kit. Test will be done before PANO administration on day 30 to -5, 
15(+/-3) and 28(+/-3). Data for inflammatory cytokines from the whole study population 
will be presented over time and compared to data from similar external control patients 


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treated TAC/SIR with identical inclusion and exclusion criteria except that will not be 
treated with PANO. 
 
 
GVHD Biomarkers 
ELISA-based analysis will be used to determine whether a marker panel comprised of IL-
2Rα , TNFR1, HGF, IL-8, Elafin, REG-3α and ST2 levels tested prospectively at 30 to -5, 
and 15(+/-3) after allogeneic HCT is able to predict for the development of acute GVHD. 
Test will be done before PANO administration on day –30 to 5, and on days 15+/-1. Data 
for GVHD biomarkers from the whole study population will be presented over time and 
compared to data from similar external control patients treated TAC/SIR with identical 
inclusion and exclusion criteria except that will not be treated with PANO. 
 
 
Stat-3 activation and acetylation, STAT-5 and S6 phosphorylation 
 
To determine the functional impact of HDACi on PBMCs we will measure total STAT-3, 
phosphorylated STAT3 and acetylated STAT-3 by WB and flow cytometry in PBMC and 
gated T/DCs cells populations in patients and external controls  on day 30 to -5, 15(+/-3), 
28(+/-3), 90(+/-14) and 365(+/-45).  T-cell STAT5 and S6 phosphorylation will also be 
measured among the external controls on day +30+/-3 and day +90+/314. Data for stat -
3/stat-5and S6 phosphorylation and/or acetylation subset from the whole study population 
will be presented over time and compared to data from similar external control patients 
treated TAC/SIR with identical inclusion and exclusion criteria except that will not be 
treated with PANO. 
 
 
Note: The data gathered on these results will be used for future analysis not considered in 
the context of this proposal. Thus, after identifying changes in phenotype and the 
expression pattern of immune-related genes upon PANO/TAC/SIR treatment, we will 
expand our research to investigate the role of PANO in their regulation. 
 
 
 
 


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List of Test to be performed in patients treated with TAC+SIR+PANO and “external 
control patients” treated with TAC+SIR only: 
TEST 
-30 to -5 
15(+/-3) 
 28(+/-3) 
90(+/-14) 
365(+/-45) 
ImmuneReconsti
tution  
(T, DCs and 
Tregs) 
x 
x 
x 
x 
x 
Histone 
Acetylation      
(T and DCs) 
x 
x 
x 
x 
x 
STAT-3 
activation and 
acetylation 
x 
x 
x 
x 
x 
Cytokine 
profiling 
x 
x 
x 
  
  
Biomarker  
profiling 
x 
x 
  
  
  
 
*Note:  T-cell STAT5 and S6 phosphorylation will also be measured among the external controls on day +28 
(+/- 3) and day +90(+/-10). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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Appendix G.  
Panobinostat administration as per conditioning regimen. Patients will be treated with 
PANO 5 MG PO TIW (3 doses about 48 hours apart in a 7 day period) QW for 26 weeks 
starting prior to stem cell infusion. During the study, PANO will be administered orally as 
once daily dose. Patients should receive their once-a-day oral dose of PANO 
approximately at the same time each day in AM. Each dose of PANO should be taken with 
about 8 oz / 240 ml glass of water. Patients should be instructed to swallow the capsules 
whole and not chew them. Patients must avoid grapefruit or grapefruit juice and seville 
(sour) oranges during the entire study. If the patient forgets to take his/her dose on 
scheduled treatment day or cannot take it due to mucositis and/or HCT related GI toxicities 
(nausea/vomit), then he/she should take PANO on that same day within 16 hours after the 
missed dose if possible. After more than 16 hours, that day’s dose should be withheld, and 
the patient should wait to take PANO until the next scheduled treatment day (i.e., patients 
should be instructed not to try to make-up the missed dose after 16 hours). If mucositis 
and/or GI toxicity preclude PANO oral intake, patient are allowed to hold up to 3 doses 
and administration should be resumed once mucositis and/or toxicity resolves. Patient 
should complete missed doses and then continue treatment as planned per protocol 
extending PANO administration period.  
 
 


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