Clinical trial NCT01693601
Conditions: Myelofibrosis
Keywords: Myelofibrosis Panobinostat Ruxolitinib
Sponsor: John Mascarenhas
Start date: 2013-01-01; Completion date: 2018-05-18
Enrollment: 15 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a single-center, single arm, dose finding study to assess safety and tolerability of the oral combination of Panobinostat and Ruxolitinib in patients with myelofibrosis (MF) in chronic and accelerated phase.

Detailed description:
Phase I/II open label, single institution, combination therapy trial of induction Ruxolitinib followed by combination with Panobinostat in dose escalation cohorts with a primary endpoint of determining the safety and tolerability of combination therapy in patients with myelofibrosis (MF) in chronic and accelerated phase. A 3+3standard dose escalation scheme will be employed and the occurrence of dose limiting toxicities (DLTs) will be captured and the occurrence of such events will determine dose cohort escalation by predetermined and established rules. In addition to establishing the DLTs, maximally tolerated dose (MTD), and recommended phase II dose (RPTD) in the phase I portion of this trial, exploratory biomarkers will be evaluated within phase I as well. Pharmacodynamics and exploratory genetic and epigenetic biomarkers will be explored as predictors of response to therapy. The RPTD cohort will be expanded to incorporate a total of 22 patients, including 6 from phase I, in order to assess clinical response as assessed by International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) as a primary endpoint for the phase II portion of this trial.

Arms: arm 1: Combination of Panobinostat and Ruxolitinib
Interventions: intervention 1: Panobinostat intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: PO TIW QOW or PO TIW QW intervention 2: PO BID x 28 days

Protocol documents:
Prot_SAP_000.pdf: 
PANOBINOSTAT and RUXOLITINIB In MyElofibrosis 
PRIME STUDY 
Phase I/II Study of Combination oral JAK2 tyrosine kinase inhibitor (JAK2-TKI) and Histone 
Deacetylase Inhibitor (HDACI) therapy in patients with Myelofibrosis 
PI: John Mascarenhas, MD 
NCT01693601 
Document Date: May 19, 2015 


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Mount Sinai School of Medicine 
PANOBINOSTAT and RUXOLITINIB In MyElofibrosis  
PRIME STUDY 
 
 
Phase I/II Study of Combination oral JAK2 tyrosine kinase inhibitor (JAK2-TKI) and Histone Deacetylase 
Inhibitor (HDACI) therapy in patients with Myelofibrosis 
 
Principal Investigator: 
John Mascarenhas, MD 
Mount Sinai School of Medicine 
Tisch Cancer Institute 
One Gustave L. Levy Place,  
Box #1079 
New York, NY 10029 
Phone: (212) 241-1948 
Fax: (212) 876-5276 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co-Investigator/Statistician: 
James Godbold, PhD 
 
One Gustave L. Levy Place, 
Box 1057 
New York, NY 10029 
Phone: (212) 824-7114 
Fax: (212)  
 
Co-Investigator 
Ronald Hoffman, MD 
Mount Sinai School of Medicine 
Tisch Cancer Institute 
One Gustave L Levy Place,  
Box #1079 
New York, NY 10029 
Phone: (212) 241-2296 
Fax: (212) 876-5276 
Co-Investigator 
Marina Kremyanskaya, MD 
Mount Sinai School of Medicine 
Tisch Cancer Institute 
One Gustave L Levy Place, Box 
#1079 
New York, NY 10029 
Phone: (212) 241-3356 
Fax: (212) 876-5276 
 


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Summary  
This is a single-center, single arm, dose finding study to assess safety and tolerability of the 
oral combination of PANOBINOSTAT and RUXOLITINIB in patients with myelofibrosis 
(MF) in chronic and accelerated phase. 
Study phase: I/II 
Study objectives: 
• Primary 
o Assess the safety and tolerability of RUXOLITINIB in combination with 
PANOBINOSTAT in patients with MF  
o Identify a recommended phase II dose of each agent in combination 
o Assess treatment response as defined by the International Working Group 
for Myelofibrosis Research and Treatment (IWG-MRT)  
 
• Secondary 
o Assess changes in spleen size with combination therapy  
o Assess symptom response with a validated MPN tool 
• Exploratory 
o Evaluate changes in biomarkers in relation to response to combination 
treatment with RUXOLITINIB and PANOBINOSTAT  
 Bone marrow histopathology 
 Cytogenetics 
 Acetylation of H2B and H3 histones 
 JAK2V617F peripheral blood mononuclear cell mutational load 
 Peripheral blood CD34+ hematopoietic cell load  
 Peripheral blood CD34+ hematopoietic cells expression of CXCR4 
 Peripheral blood cytokine profile  
o Evaluate a panel of biomarkers as predictors of response and prognosis 
 ASXL1, EZH2, TET2, and others to be determined 
Study population: 
Adult male or female patients ages 18 or older, who have been diagnosed with intermediate-2 
or higher (IWG risk group) chronic and accelerated phase PMF, Post PV MF, or Post ET MF 
as defined by the World Health Organization.  Only patients seen in the Mount Sinai 
Myeloproliferative Disease Program (MPD) clinic will be enrolled in this protocol. These 
patients will either be primary patients of this clinic or patients referred by outside 
hematologists or oncologists. Written informed consent must be obtained prior to any 
screening procedures. Patients may have received prior therapy for MF, however they must be 


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willing and able to discontinue all drugs used to treat underlying MF disease, at least 28 days 
or 5 half-lives (whichever is longer) prior to starting study drug. This trial will allow patients 
who were treated with either HDACis or JAK2is, as long as these agents were not 
discontinued due to clinically relevant toxicities as per the investigator’s assessment. 
Number of patients:   33 to 58  
Overview of study design: 
Phase I/II open label, single institution, combination therapy trial of induction 
RUXOLITINIB followed by combination with PANOBINOSTAT in dose escalation cohorts 
with a primary endpoint of determining the safety and tolerability of combination therapy in 
patients with myelofibrosis (MF) in chronic and accelerated phase. A 3+3standard dose 
escalation scheme will be employed and the occurrence of dose limiting toxicities (DLTs) will 
be captured and the occurrence of such events will determine dose cohort escalation by 
predetermined and established rules. In addition to establishing the DLTs, maximally 
tolerated dose (MTD), and recommended phase II dose (RPTD) in the phase I portion of this 
trial, exploratory biomarkers will be evaluated within phase I as well. Pharmacodynamics and 
exploratory genetic and epigenetic biomarkers will be explored as predictors of response to 
therapy. The RPTD cohort will be expanded to incorporate   a total of 22 patients, including 6 
from phase I, in order to assess clinical response as assessed by International Working Group 
for Myelofibrosis Research and Treatment (IWG-MRT) as a primary endpoint for the phase II 
portion of this trial. 
Screening for this study will have a window of 56 days and start on day -84 with signing of 
informed consent.  See Figure  4-1 A and B. Eligible patients will begin induction phase 
therapy on day -28, receiving single agent RUXOLITINIB PO BID daily for 28 days. Patients 
who maintain a platelet count ≥ 50,000/ul at Day 1
 will then receive concomitant 
PANOBINOSTAT PO TIW QOW or PO TIW QW depending on the cohort assignment.  
The first 28 days of combination therapy will be the evaluable phase I portion of the study. 
Patients who do not experience a defined DLT in the evaluable phase I period can remain on 
study receiving combination drug therapy for a total of 6 cycles (cycles 2-6). See Figure 4-1 
A. AEs will continue to be recorded on all patients (phase I and II) receiving combination 
therapy beyond the first cycle of the study. Dose escalation rules are based on the standard 
3+3 design as shown in Figure 4-2.  
Phase I patients who complete a total of 6 cycles of combination therapy will be assessed for 
clinical response by IWG-MRT criteria. Patients who achieve at least Stable Disease (SD) by 
IWG-MRT (Table 4-2) can remain on therapy indefinitely or until disease progression or drug 
toxicity as assessed by the investigators. At the discretion of the investigator, phase I patients 
who have completed 6 cycles of therapy with a minimum of SD can also be dose 
escalated/deescalated at that time to the RPTD once it is determined. These patients will not 
be considered for evaluation of response in Phase II.  
Once a RPTD is determined from the dose escalation phase I part of this trial, the dose 
expansion phase-II part of this trial will commence with additional patients added to the 
original RPTD cohort from phase I to a sample size of 22. See Figure 4-1 B. IWG-MRT 
response criteria will be applied at the end of cycle 6 and this will include spleen volume 


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measurement by MRI and bone marrow biopsy to appreciate changes in morphology, degree 
of reticulin/collagen fibrosis, cytogenetics and molecular markers. Patients who have obtained 
at least SD by IWG-MRT can remain on study receiving combination therapy in the dose 
extension stage of Phase II.  
In this part of phase II, patients have obtained at least SD by IWG-MRT after 6 cycles of 
combination therapy and will continue to be treated with dose modifications and stopping 
rules that are the same as the expansion stage of Phase II. Patients will continue to be 
followed for signs of response on each monthly visit. After 24 cycles, stable patients may be 
seen every other month at the discretion of the investigator. Repeat imaging of the spleen and 
bone marrow biopsy with repeat cytogenetic and molecular testing when appropriate can be 
performed at the discretion of the investigator for the purpose of assessment of response or 
disease progression. Additional biomarker assessments can also be made at intervals 
determined by the clinical course and at the discretion of the investigator. 
 


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Table of contents 
 
Bone marrow histopathology ................................................................................... 2 
 
Cytogenetics ............................................................................................................ 2 
 
Acetylation of H2B and H3 histones ....................................................................... 2 
 
JAK2V617F peripheral blood mononuclear cell mutational load ........................... 2 
 
Peripheral blood CD34+ hematopoietic cell load .................................................... 2 
 
Peripheral blood CD34+ hematopoietic cells expression of CXCR4 ...................... 2 
 
Peripheral blood cytokine profile ............................................................................ 2 
o 
Evaluate a panel of biomarkers as predictors of response and prognosis................ 2 
Table of contents ................................................................................................................. 5 
List of figures .................................................................................................................... 10 
List of tables ...................................................................................................................... 10 
List of abbreviated terms ................................................................................................... 11 
Glossary of terms ............................................................................................................... 14 
1 
Background ........................................................................................................................ 15 
1.1 
Overview of Myelofibrosis .................................................................................... 15 
1.2 
Introduction to PANOBINOSTAT (LBH589) ...................................................... 16 
1.2.1 
Overview of PANOBINOSTAT in MF ................................................ 16 
1.2.2 
PANOBINOSTAT non-clinical experience .......................................... 17 
1.2.3 
PANOBINOSTAT clinical experience ................................................. 17 
1.2.4 
PANOBINOSTAT clinical pharmacokinetics ...................................... 20 
1.3 
Introduction to RUXOLITINIB (INC424) ............................................................ 20 
1.3.1 
Overview of RUXOLITINIB ................................................................ 20 
1.3.2 
RUXOLITINIB non-clinical experience ............................................... 21 
1.3.3 
RUXOLITINIB clinical experience ...................................................... 21 
1.3.4 
RUXOLITINIB clinical pharmacokinetics ........................................... 25 
1.4 
Risk assessment of the combination of PANOBINOSTAT and 
RUXOLITINIB ...................................................................................................... 26 
1.4.1 
Assessment of drug-interaction potential between 
PANOBINOSTAT and RUXOLITINIB ............................................... 26 
1.4.2 
Integrative toxicological assessment of PANOBINOSTAT and 
RUXOLITINIB in combination ............................................................ 26 
2 
Rationale ............................................................................................................................ 28 
2.1 
Study rationale and purpose ................................................................................... 28 
2.2 
Rationale for the study design ............................................................................... 30 
2.3 
Rationale for dose and regimen selection .............................................................. 30 


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2.4 
Rationale for choice of combination drugs ............................................................ 31 
3 
Objectives and endpoints ................................................................................................... 32 
4 
Study design ...................................................................................................................... 33 
4.1 
Description of study design ................................................................................... 33 
4.2 
Definition of end of the study ................................................................................ 39 
4.3 
Timing of interim analyses and design adaptations ............................................... 39 
4.4 
Early study termination .......................................................................................... 39 
5 
Population .......................................................................................................................... 39 
5.1 
Patient population .................................................................................................. 39 
5.2 
Inclusion criteria .................................................................................................... 40 
6 
Treatment ........................................................................................................................... 42 
6.1 
Investigational treatment ....................................................................................... 42 
6.1.1 
Dosing administration ........................................................................... 42 
6.1.2 
Ancillary treatments .............................................................................. 43 
6.1.3 
Rescue medication ................................................................................ 43 
6.1.4 
Guidelines for continuation of treatment .............................................. 43 
6.1.5 
Study duration ....................................................................................... 43 
6.2 
Dose escalation guidelines ..................................................................................... 44 
6.2.1 
Starting dose rationale ........................................................................... 44 
6.2.2 
Provisional dose levels .......................................................................... 44 
6.2.3 
Criteria for dose escalation and determination of MTD and/or 
RPTD..................................................................................................... 45 
6.2.4 
Dose cohort modification ...................................................................... 47 
6.2.5 
Definitions of dose limiting toxicities (DLTs) ...................................... 47 
6.2.6 
Follow-up for toxicities ......................................................................... 48 
6.2.7 
Dose modification and dose delay ........................................................ 49 
#
53
Management of anemia ........................................................................................ 
 
6.2.8 
Dose modifications for prolonged QTc interval ................................... 54 
6.2.9 
Dose escalation ...................................................................................... 55 
6.2.10 
Optional dose tapering strategy for RUXOLITINIB in the event of 
discontinuation ...................................................................................... 56 
6.2.11 
Management of diarrhea ....................................................................... 57 
6.3 
Concomitant medications ...................................................................................... 57 
6.3.1 
Permitted concomitant therapy ............................................................. 57 
6.3.2 
Permitted concomitant therapy requiring caution and/or action ........... 57 
6.3.3 
Prohibited concomitant therapy ............................................................ 58 


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6.3.4 
Dose reduction of RUXOLITINIB for concomitant strong CYP3A 
inhibitor usage ....................................................................................... 59 
6.4 
Patient numbering, treatment assignment and randomization ............................... 59 
6.4.1 
Patient numbering ................................................................................. 59 
6.4.2 
Treatment assignment and randomization ............................................ 59 
6.4.3 
Treatment blinding and Randomization ................................................ 59 
6.5 
Study drug supply .................................................................................................. 60 
6.5.1 
Study drug preparation and dispensation .............................................. 60 
6.5.2 
Study drug packaging and labeling ....................................................... 60 
6.5.3 
Drug supply and storage ........................................................................ 60 
6.5.4 
Study drug compliance and accountability ........................................... 61 
6.5.5 
Disposal and destruction ....................................................................... 61 
7 
Visit schedule and assessments ......................................................................................... 61 
7.1 
Visit schedule ......................................................................................................... 61 
7.1.1 
Pre-screening assessments .................................................................... 62 
7.1.2 
Screening ............................................................................................... 62 
7.1.3 
Run-in period ........................................................................................ 64 
7.1.4 
Treatment period ................................................................................... 64 
7.1.5 
End of treatment visit, including premature withdrawal and study 
discontinuation visit .............................................................................. 64 
7.1.6 
Follow up period ................................................................................... 65 
7.2 
Assessment types ................................................................................................... 66 
7.2.1 
Disease progression ............................................................................... 66 
7.2.2 
Efficacy assessments ............................................................................. 66 
7.2.3 
Safety assessments ................................................................................ 67 
7.2.4 
Physical examination ............................................................................ 67 
7.2.5 
Laboratory evaluations .......................................................................... 68 
7.2.6 
Radiological examinations .................................................................... 70 
7.2.7 
Cardiac assessments .............................................................................. 70 
7.2.8 
Tolerability ............................................................................................ 71 
7.2.9 
Biomarkers ............................................................................................ 71 
7.2.10 
Transfusion dependence ........................................................................ 72 
8 
Safety monitoring and reporting ........................................................................................ 73 
8.1 
Adverse events ....................................................................................................... 73 
8.1.1 
Definitions and reporting ...................................................................... 73 
8.1.2 
Laboratory test abnormalities ................................................................ 74 


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8.1.3 
Adverse events of special interest ......................................................... 75 
8.2 
Serious adverse events ........................................................................................... 75 
8.2.1 
Definitions ............................................................................................. 75 
8.2.2 
Reporting ............................................................................................... 75 
8.3 
Emergency unblinding of treatment assignment ................................................... 76 
8.4 
Pregnancies ............................................................................................................ 76 
8.5 
Warnings and precautions ...................................................................................... 77 
8.6 
Data Monitoring Committee .................................................................................. 77 
8.7 
Steering Committee ............................................................................................... 77 
9 
Data collection and management ....................................................................................... 77 
9.1 
Site monitoring ...................................................................................................... 77 
9.2 
Data collection ....................................................................................................... 77 
9.2.1 
Biomarker data collection ..................................................................... 77 
9.3 
Database management and quality control ............................................................ 77 
10 Statistical methods and data analysis ................................................................................ 78 
10.1 
Analysis sets .......................................................................................................... 78 
10.1.1 
Full Analysis Set ................................................................................... 78 
10.1.2 
Safety Set .............................................................................................. 78 
10.1.3 
Per-Protocol Set .................................................................................... 78 
10.1.4 
Dose-determining set ............................................................................ 78 
10.2 
Patient demographics/other baseline characteristics ............................................. 78 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 78 
10.4 
Primary objective ................................................................................................... 79 
10.4.1 
Variable ................................................................................................. 79 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 79 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 80 
10.4.4 
Supportive analyses ............................................................................... 81 
10.5 
Secondary objectives ............................................................................................. 81 
10.5.1 
To evaluate the safety of the oral co-administration of 
RUXOLITINIB and PANOBINOSTAT to patients with MF .............. 81 
10.5.2 
Safety objectives ................................................................................... 81 
10.5.3 
Biomarkers ............................................................................................ 82 
10.5.4 
Resource utilization ............................................................................... 82 
10.5.5 
Patient-reported outcomes ..................................................................... 83 
10.6 
Exploratory objectives ........................................................................................... 83 


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10.6.1 
To assess preliminary efficacy of the combination of 
RUXOLITINIB and PANOBINOSTAT by physician palpation in 
all dosing cohorts .................................................................................. 83 
10.6.2 
To assess the preliminary efficacy at the MTD and/or RPTD by the 
use of MRI/CT ...................................................................................... 83 
10.6.3 
To assess (preliminary) efficacy of the combination of 
RUXOLITINIB and PANOBINOSTAT by bone marrow biopsy in 
all dosing cohorts .................................................................................. 83 
10.6.4 
To explore biomarkers at the MTD and/or RPTD (including but not 
limited to: JAK2V617F allele burden, genetic mutations impacting 
the molecular  pathogenesis of MF other than JAK2V617F , and 
cytokine measures) ................................................................................ 84 
10.6.5 
To evaluate changes in packed red blood cell transfusion 
dependence ............................................................................................ 84 
10.7 
Interim analysis ...................................................................................................... 84 
10.8 
Sample size calculation .......................................................................................... 84 
11 Ethical considerations and administrative procedures ...................................................... 85 
11.1 
Regulatory and ethical compliance ........................................................................ 85 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 85 
11.3 
Informed consent procedures ................................................................................. 86 
11.4 
Discontinuation of the study .................................................................................. 86 
11.5 
Publication of study protocol and results............................................................... 86 
11.6 
Study documentation, record keeping and retention of documents ....................... 86 
11.7 
Confidentiality of study documents and patient records ....................................... 87 
11.8 
Audits and inspections ........................................................................................... 87 
11.9 
Financial disclosures .............................................................................................. 87 
12 Protocol adherence ............................................................................................................ 87 
12.1 
Amendments to the protocol .................................................................................. 88 
13 References (available upon request) .................................................................................. 89 
14 Appendices ........................................................................................................................ 92 
Appendix 1 Co-medications which are known to prolong the QT interval and/or 
induce Torsades de Pointes, are strong CYP3A4/5 inhibitors and inducers, 
moderate CYP3A4 inducers, CYP2D6 substrates, or otherwise prohibited for 
use .......................................................................................................................... 93 
Appendix 2 Study Schedules ........................................................................................... 101 
Appendix 3 MPN-SAF .................................................................................................... 104 
Appendix 4 DIPPS .......................................................................................................... 106 
Appendix 5 Subject Study Pill Diaries ............................................................................ 107 


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List of figures 
Figure 4-1 
Study Design ......................................................................................... 35 
 
List of tables 
Table 1-1 
CLBH589B2102 MF patients by dosing cohort ................................... 18 
Table 1-2 
CLBH589B2102 AE and SAE for patients with hematologic 
malignancies and myelodysplastic syndrome treated across dosing 
range (30-80mg TIW) on the QOW schedule ....................................... 19 
Table 1-3 
CLBH589BUS58 most common (>15%) AEs in patients with MF, 
treated with PANOBINOSTAT at 40mg TIW QW (N=35) ................. 19 
Table 1-4 
Integrative toxicological assessment of PANOBINOSTAT 
(LBH589) / RUXOLITINIB (INC424) combination ............................ 28 
Table 2-1 
Comparison of dose reductions, duration of exposure, relative dose 
intensity and thrombocytopenia between QW and QOW schedule 
with oral PANOBINOSTAT in patients with HL in study 
CLBH589B2102 ................................................................................... 31 
Table 6-1 
Dose and treatment schedule ................................................................. 42 
Table 6-2    Dose escalation cohorts for combination therapy evaluable phase I study ........... 45 
Table 6-3 
Criteria for Defining Dose Limiting Toxicity (DLT) ........................... 48 
Table 6.2.3 
Criteria for dose modifications of RUXOLITINIB and 
PANOBINOSTAT due to study drug-related toxicity from Day 29 
and beyond in Phase I or anytime in Phase II (see Table 6-6 for QT 
prolongation dose management) ........................................................... 51 
Table 6-4 
Criteria for dose delays, dose reductions, and re-initiation of 
treatment due to study drug related QTc abnormalities* ...................... 55 
Table 7-3 
ECOG performance status ..................................................................... 68 
Table 7-1 
12-Lead ECG schedule time points: ..................................................... 70 
 


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List of abbreviated terms 
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 concentration time curve 
BFU-E 
Burst forming unit erythroid 
BLRM 
Bayesian logistic regression dose-escalation model 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of federal regulations 
Cmax 
Maximal plasma concentration 
eCRF 
Electronic Case Report/Record Form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computer tomography 
CV 
Coefficient of variation 
DACi 
Pan-deacetylase inhibitor 
DS&E 
Drug safety and epidemiology 
DLT 
Dose limiting toxicity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EPO 
Erythropoietin 
ET 
Essential thrombocythemia 
EWOC 
Escalation with Overdose Control 
FDA 
Food and Drug Administration 
FT4 
Free thyroxine 
G-CSF 
Granulocyte colony stimulating factor 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
H3/4 
Histone 3 or 4 
HDAC 
Histone deacetylase 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HL 
Hodgkin’s Lymphoma 
HPLC 
High-performance liquid chromatography 
HSCT 
Hematopoietic stem cell transplant 
HSP90 
Heat shock protein 90 
Hr 
Hour 


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IB 
Investigator’s brochure 
i.v. 
intravenous(ly) 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWG 
International Working Guidelines 
JAK1/JAK2 
Janus kinase 1 or 2 
LC-MS/MS 
liquid chromatography-tandem mass spectrometry method 
LFTs 
Liver function tests 
LLOQ 
lower limit of quantification 
LMWH 
Low molecular weight heparin 
LVEF 
Left ventricular ejection fraction 
LPFV 
Last patient first visit 
MAP 
Master Analysis Plan documents project standards in the statistical methods which 
will be used within the individual clinical trial RAP documentation 
MedDRA 
Medical dictionary for regulatory activities 
MDS 
Myelodysplastic syndromes 
MF 
Myelofibrosis 
MFSAF 
Modified Myelofibrosis Symptom Assessment Form 
MPD 
Myeloproliferative disorder 
MM 
Multiple myeloma 
MMSAF 
Modified Myelofibrosis Symptom Assessment Form 
MPL 
Myeloproliferative leukemia 
MPN 
Myeloproliferative neoplasms 
MRI 
Magnetic resonance imaging 
MRM 
Multiple reaction monitoring 
MTBE 
methyl-t-butyl ether 
MTD 
Maximum tolerated dose 
MUGA 
Multi Gated Acquisition Scan 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s Lymphoma 
NIH 
National Institute of Health 
NYHA 
New York Heart Association 
o.d. 
omnia die/once a day 
p.o. 
per os/by mouth/orally 
pan 
PANOBINOSTAT 
PD 
Progressive disease 
PD 
Pharmcodynamics 
PET-MF 
Post essential thrombocythemia-myelofibrosis 
Ph 
Philadelphia chromosome 


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PHI 
Protected health information 
PK 
Pharmacokinetic 
PK-PD 
Pharmacokinetic – pharmacodynamic 
PMF 
Primary myelofibrosis 
PPV-MF 
Post polycythemia vera-myelofibrosis 
PP-MF 
post-polycythemia vera-myelofibrosis 
PRBC 
Packed red blood cells 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PV 
Polycythemia vera 
q 
Every 
QD 
Once daily 
QOW 
Every other week 
QW 
Every week 
pSTAT3/5 
Phosphorylated signal-transducer and activator of transcription 3 or 5 
RA - need 
subscript A 
Accumulation ratio 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses 
RBC/HPF 
Red blood cells/high power field 
REB 
Research Ethics Board 
RPTD 
Recommended Phase 2 Dose 
rux 
RUXOLITINIB 
SAE 
Serious Adverse Event 
SD 
Standard deviation 
SEC 
Safety event categories 
STAT 
Signal transducers and activators of transcription 
T1/2 
Half life 
Tmax 
Maximum plasma concentration time 
TEAE 
Treatment emergent adverse event 
TIW 
Three times a week 
TK 
Tyrosine kinase 
tlast 
time zero to the last measurable concentration sampling time 
TNF 
Tumor necrosis factor 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell count 
WBC/HPF 
White blood cells/high power field 
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (eg: q28 days) 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being testing in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Patient Number (Patient No.) 
A unique identifying number assigned to each patient who enrolls in the 
study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression and/or survival 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered 
to the patient (subject) as part of the required study procedures. = 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient 
withdrawal 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 


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1 
Background 
 
1.1 
Overview of Myelofibrosis 
Polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), 
belong to a group of Philadelphia chromosome  negative (Ph-) myeloproliferative neoplasms 
(MPNs) involving a malignant clonal hematopoetic stem cell population leading to the 
expansion of myeloid lineage derived cells. (Tefferi 2005) The estimated incidence of PMF is 
between 0.5-1.5 per 100,000 population with a median age at diagnosis of 65 years (Mesa 
1999, Dupriez 1996). PV and ET both have a propensity to transform to a myelofibrotic state, 
designated Post– PV/ET MF. The three disorders (PMF, Post-PV/ET, collectively termed MF) 
are related in that progressive bone marrow collagen fibrosis, peripheral cytopenias, 
extramedullary hematopoesis, and splenomegaly result in debilitating constitutional 
symptoms, increased risk of infections, thrombotic tendencies, and heightened risk of 
transformation to acute leukemia (Tefferi 2000).  
 
MF can be risk stratified for survival by multiple scoring systems. The Lille score is based on 
two prognostic factors: white blood count >30 X 109/ul or < 4 X 109 /ul and hemoglobin <10 
g/dL and stratified as low, intermediate or high risk (Dupriez 1996) .  Median survival for low 
risk (0 adverse factors), intermediate risk (1 adverse factor) and high risk disease (2 adverse 
factors) is 93, 26, 13 months, respectively. Cervantes et al identified age > 65 years, presence 
of constitutional symptoms, hemoglobin < 10 g/dL, white blood cell count > 25 x 109/ul, and 
a circulating blast >1% as significant risk factors in multivariate analysis (Cervantes 2009). 
Patients with no risk factors fell into a low-risk group with a median survival of 135 months, 
patients with one risk factor fell into an intermediate-1 group with a median survival of 95 
months, patients with two risk factors fell within an intermediate-2 group with a median 
survival of 48 months, and patients with 3 or more risk factors formed a high-risk group with 
a median survival of 27 months. A dynamic international prognostic scoring system (DIPSS) 
has recently been developed to predict survival real time (Passamonti 2010). DIPSS predicts a 
median survival for the low-risk patients (score=0) that has not yet been reached; 14.2 years in 
intermediate-1 (score=1 or 2) patients; 4 years in the intermediate-2 (score 3 or 4) patients; 
and 1.5 years in the high-risk (score 5 or 6) patients. Thrombocytopenia is a common 
hematologic abnormality in MF and holds prognostic significance. The DIPSS Plus 
incorporates thrombocytopenia into this model to predict survival in a dynamic fashion 
(Gangat 2011).  With this scoring system the median survival for the low-risk patients is 180 
months; 80 months for intermediate-1 risk patients; 35 months for intermediate-2 risk 
patients, and 16 months for the high-risk patients. The most common causes of death in MF 
are infectious bleeding as a result of bone marrow failure, complications of portal 
hypertension and transformation to acute myelogenous leukemia (AML) designated MF in 
blast phase (MF-BP) by the WHO 2008. MF-BP holds a dismal prognosis with a median 
survival of 3-5 months 1
 
.  
 


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Allogeneic stem cell transplantation (ASCT) is the only treatment modality that offers the 
potential of cure at a significant risk of morbidity and mortality (Rondelli 2005, Kroger 2005). 
For many patients due to advanced age and/or concurrent medical illness, stem cell transplant 
is not a valid option, and they must rely on treatments aimed at palliation of symptoms. These 
treatments include splenic irradiation, splenectomy, melphalan, interferon, corticosteroids, 
thalidomide, lenalidomide, hydroxyurea, busulfan, danazol, and erythropoietic stimulating 
agents.  Although collectively these therapies have response rates (reduction in splenomegaly 
and improvement in anemia) of approximately 20-50%, none have definitively been shown to 
improve survival in MF patients (Mascarenhas 2010). 
 
Activating mutations of the Janus Kinase 2 receptor tyrosine kinase (JAKV617F ) and/or the 
thrombopoetin receptor (MPL W515L/K) have been identified in patients with MPNs in 50-
65% of patients with MF carry the JAK2V617F mutation (Baxter 2005; James 2005, 
Kralovics 2005; Levine 2005,Tefferi 2005). The JAK/STAT signal transduction pathway is 
believed to be hyperactive in MF patients regardless of the JAK2 mutation status leading to 
inappropriate cytokine release, and plays a role in the diminished apoptosis of the 
hematopoietic progenitor cells (Wang 2009). Small molecule inhibitors of JAK2 are currently 
being evaluated in phase I/II/III trials to treat patients with MF and although there use is 
associated with dramatic resolution of splenomegaly and constitutional symptoms, these 
agents as a class do not result in correction of cytopenias or alteration in the JAK2V617F 
allele burden.  
 
Ruxolitinib (Jakafi; Incyte) is the first FDA-approved (12/2011) therapy for the treatment of 
patients with intermediate/high risk MF based on the results of 2 pivotal studies (COMFORT 
1 and COMFORT 2). These multicenter randomized (placebo controlled in COMFORT1 and 
versus best available therapy in COMFORT 2) trials achieved their primary endpoint of 
spleen reduction (>35% of spleen volume by radiographic measurement) as well as significant 
amelioration of MF related symptoms. The comfort 1 study also was able to show a very 
modest improvement, but statistically significant difference, in overall survival compared to 
placebo (Verstovsek et al., NEJM 2012). Although single agent Ruxolitinib appears to 
improve spleen size and symptoms in patients with MF, it has not been shown to affect the 
abnormal bone marrow morphology, eliminate JAK2V617F mutation burden, or eliminate 
karyotypic abnormalities.  
 
1.2 
Introduction to PANOBINOSTAT (LBH589) 
1.2.1 
Overview of PANOBINOSTAT in MF 
HDACi’s are a class of agents regulating the acetylation of core histones responsible for the 
epigenetic control of tumor suppressor gene expression, and other genes responsible for cell 
differentiation and apoptosis in a cell-specific manner (Grozinger 2002). HDACi’s also 
promote the acetylation of other non-histone proteins including heat shock protein 90 
(HSP90), a chaperone for various proteins offering protection from ubiquitin directed 
proteasomal degradation (Bali 2005). Data suggest that malignantly transformed cells are 


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more sensitive to HDACi induced apoptosis than are normal cells (Zhang 2005). In vitro 
studies investigating the use of DACi in the JAK2V617F mutant HEL cell line and JAK2V617F+ 
cells from PV and ET patients have shown preferential reduction in the mutant JAK2 clone 
with preservation of the wild type cells (Guerini 2008). In a preclinical experiment by Wang 
et al, DACis play an important role in the control of cell cycle progression and apoptosis, and 
have been shown to have increased cytotoxicity in cells bearing mutated JAK2V617F while 
having relatively minimal effect on normal CD34+ cells (Wang 2009). Also shown in this 
experiment was a PANOBINOSTAT mediated reduction in JAK2 mRNA by 40%, and 
hyperacetylation of HSP90 causing a partial disruption of the binding to JAK2. This inhibition 
of chaperone/client binding resulted in proteasomal degradation of the JAK2 protein. In a 
separate pre-clinical experiment by Gupta et al (Gupta 2009, poster #925), PANOBINOSTAT 
was shown to inhibit the STAT proteins by causing STAT3 acetylation in DLBCL cells. 
Wang et al also reported p-STAT3 and p-STAT5 inhibition following PANOBINOSTAT 
treatment in HEL cells, with greater reduction being seen in STAT3 levels (Wang 2009). PMF 
is also characterized by an increased proportion of circulating peripheral blood CD34+ 
hematopoietic stem cells. Ex vivo exposure of PMF CD34+ cells to sequential DNA 
methyltransferase (DNMT) inhibitor and DACi has been shown to dramatically reduce the 
burden of malignant progenitor cells as detected by a reduction in JAK2V617F allele burden 
(Shi 2007). 
1.2.2 
PANOBINOSTAT non-clinical experience 
PANOBINOSTAT (LBH589) is a novel cinnamic hydroxamic pan-DACi that specifically 
enhances the acetylation of H3, H4, and HSP90 (Glaser 2007). Targeted inhibition of 
HDAC6, a member of the class IIB HDACs, by PANOBINOSTAT has been shown to 
enhance acetylation of HSP90 and disrupt its chaperone function leading to the degradation of 
various client proteins such as BCR-ABL, AKT, c-RAF, FLT-3 (Bali 2005; George 2005). 
JAK2 is also a client protein of HSP90, and inhibition of this chaperone protein results in the 
degradation of JAK2 and impairment in cytokine signaling (Shang 2006; Wang 2009). 
Importantly for patients with MF, DACI’s have been shown to down-modulate several soluble 
cytokines including IL-6, and VEGF (Carta 2006). In a mouse bone marrow 
transduction/transplantation 
model 
of 
JAK2V617F-driven 
MPN-like 
disease, 
PANOBINOSTAT treatment was found to suppress splenomegaly, reticulocyte count, HCT 
and WBC count. PANOBINOSTAT treatment also reduced circulating GFP-(JAK2V617F
1.2.3 
PANOBINOSTAT clinical experience 
)-
positive cells in the blood and the mutant allele burden in bone marrow and spleen, as 
assessed by FACS and qPCR on genomic DNA, respectively (unpublished, data: Novartis). 
PANOBINOSTAT was tested in a Phase IA/II study [CLH589B2102] in advanced 
hematologic malignancies including acute myelogenous leukemia, myelodysplasia, multiple 
myeloma, Hodgkin’s lymphoma, Non-Hodgkin’s Lymphoma, and myelofibrosis. A total of 
176 patients with advanced hematologic malignancies were enrolled in this study, and treated 
at escalating doses of oral PANOBINOSTAT from 20mg up to 80mg three times a week 
(TIW). There were two dosing schedules administered: every week (QW) or every other week 
(QOW). Of these 176 patients, 86 patients received PANOBINOSTAT TIW QW, and 33 


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patients received PANOBINOSTAT TIW QOW. The remaining 57 patients had indications, 
including MM, HL, and NHL. A total of 13 MF patients were treated with 
PANOBINOSTAT, and 4 of these patients saw a clinical improvement lasting ≥8 weeks with 
reduction in palpable spleen size up to 86% (data on file: Novartis). Refer to Table 1-3 for 
specifics of the treatment schedule for these patients with MF. 
The most commonly reported adverse events (AEs) both regardless of causality and suspected 
to be related to PANOBINOSTAT, were nausea, diarrhea and fatigue. Thrombocytopenia was 
the most common grade 3 and 4 AE, regardless of causality across doses and indications. 
Refer to Table 1-4 for further details of AE’s, serious adverse events (SAE’s) and Grade 3/4 
AE’s for the patients with hematologic malignancies and MDS across all QOW dosing 
cohorts. There were no Grade 3 or 4 bleeding events reported in any of the patients with MF 
treated on this study. In total there were 4 bleeding events seen across the dosing spectrum 
and diagnostic categories, two of which were suspected to be treatment related. One patient 
with AML who was treated at 60 mg TIW QW developed Grade 4 pulmonary hemorrhage on 
Cycle1 Day16 along with a diagnosis of bronchopulmonary aspergillosis. A patient with CML 
who was treated at 60mg TIW QW developed a Grade 4 cerebral hemorrhage 8 days after the 
last dose of study medication. 
In a Phase I study by Mascarenhas et al, [CLBH589BUS32T], 18 patients with PMF or Post-
PV/ET MF were treated with escalating doses of PANOBINOSTAT starting at 20mg TIW 
QW. Four patients showed clinical improvement as defined by resolution of a palpable spleen 
and a 2 g/dL increase in hemoglobin, 5 patients had stable disease, and 1 patient had 
progressive disease. The MTD (maximum tolerated dose) for this trial was 25mg TIW QW, 
and thrombocytopenia was the main DLT. In a Phase II trial by DeAngelo et al, 
[CLBH589BUS58], 35 patients with MF were enrolled, and treated with 40mg TIW, QW 
with dose reductions allowed for toxicities. Thrombocytopenia was the most common Grade 3 
or 4 AE occurring in 57% of the patients, however, 45.2% of the patients had a ≥25% 
reduction in spleen size. See Table 1-5 for more information on the remainder of the AE’s for 
this trial. From this study, the JAK2V617F mutation allele burden was measured pre- and post-
treatment from 10 patients. The median percent of mutant JAK2 pre-treatment was 27%, and 
the median percent post-treatment was 10% indicating a significant median decline in the 
JAK2V617F allelic burden (DeAngelo 2010). 
Table 1-1 
CLBH589B2102 MF patients by dosing cohort 
Schedule 
TIW QW 
TIW QOW 
Total # of MF patients 
12 
1 
30mg 
1 
 
60mg 
11 
 
80mg 
 
1 


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Table 1-2 
CLBH589B2102 AE and SAE for patients with hematologic 
malignancies and myelodysplastic syndrome treated across dosing 
range (30-80mg TIW) on the QOW schedule 
Adverse Event 
AE 
SAE 
Grade 3-4 
 
N = 33 
N = 33 
N = 33 
Nausea 
63.6% 
0% 
0% 
Diarrhea 
54.5% 
3.0% 
9.1% 
Fatigue 
54.5% 
6.1% 
30.3 
Pyrexia 
51.5% 
21.2% 
0% 
Thrombocytopenia 
42.4% 
6.1% 
39.4% 
Neutropenia 
39.4% 
6.1% 
39.4% 
Febrile Neutropenia 
27.3% 
27.3% 
27.3% 
Sepsis 
12.1% 
9.1% 
12.1% 
Tumor lysis syndrome 
9.0% 
6.1% 
9.1% 
Atrial fibrillation 
6.1% 
3.0% 
3.0% 
Tachycardia 
4.0% 
3.0% 
0% 
Table 1-3 
CLBH589BUS58 most common (>15%) AEs in patients with MF, 
treated with PANOBINOSTAT at 40mg TIW QW (N=35) 
 
Any Grade 
N (%) 
Grade 3/4 
N (%) 
Thrombocytopenia 
23 (65.7%) 
20 (57.1%) 
Diarrhea 
23 (65.7%) 
3 (8.6%) 
Nausea 
17 (48.5%) 
2 (5.7%) 
Fatigue 
16 (45.7%) 
8 (22.9%) 
Decreased appetite 
15 (42.9%) 
1 (2.9%) 
Vomiting 
12 (34.3%) 
1 (2.9%) 
Anemia 
10 (28.6%) 
10 (28.6%) 
Dyspnea 
8 (22.9%) 
4 (11.4%) 
Constipation 
7 (20.0%) 
1 (2.9%) 
Abdominal pain 
6 (17.4 %) 
1 (2.9%) 
1.2.3.1 
Electrocardiographic experience with PANOBINOSTAT as single agent 
In the initial Phase I study utilizing the IV formulation, and where PANOBINOSTAT was 
dosed on a consecutive day schedule, ECG abnormalities were noted, with one patient 
experiencing Torsade de pointes. Since then, extensive ECG monitoring has been conducted 
for patients who are enrolled in clinical studies of PANOBINOSTAT. 
As of 31 December 2009, cardiac safety data were available for 532 patients in the TIW QW 
dose schedule and 70 patients in the TIW QOW dose schedule. All of these patients 
underwent intensive pre- and post-dose ECG recording to monitor the occurrence of QTc 
changes as well as to capture other ECG abnormalities. There are mounting evidences that the 
most common finding is a QTc increase of ≤ 60 msec (CTCAE grade 1) from baseline in both 


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schedules. The absolute maximal QTc values remain limited to ≤ 480 msec (grade ½). Higher 
absolute values are infrequent. Of note a QTc increase > 480 msec has been mostly observed 
at the highest oral dose of 60 mg given TIW QW. There were no cases of torsade de pointes 
with either schedule for oral PANOBINOSTAT. 
1.2.4 
PANOBINOSTAT clinical pharmacokinetics 
Clinical development of PANOBINOSTAT focuses on the oral administration where 
PANOBINOSTAT was given TIW (i.e. on days 1, 3, 5), QW or QOW, of a 28-day cycle. To 
date, the pharmacokinetics (PK) of PANOBINOSTAT have been characterized in over 600 
patients with cancer, of which, over 400 patients have used the TIW dosing schedule. 
PANOBINOSTAT is rapidly absorbed with a median Tmax reached within 2 hours after oral 
administration. PANOBINOSTAT can be administered with or without food as the overall 
bioavailability and variability in systemic exposure remained unchanged in patients with or 
without food (Lewis 2009). 
The metabolism of PANOBINOSTAT is extensive and several metabolic pathways are 
involved including reduction, hydrolysis, oxidation, and glucuronidation processes. Oxidation 
by Cytochrome P450 (CYP) is a minor pathway (fmcyp = 0.4), in comparison to the above non-
CYP pathways) where CYP3A4 is the main metabolizing enzyme with minor involvement of 
CYP2D6 and 2C19. PANOBINOSTAT is an inhibitor of CYP2D6 in vitro. It is not an 
inducer of CYP, UGT1A1, Pgp, MRP2 in vitro. 
Clinical drug interaction studies showed that a strong CYP3A inhibitor, ketoconazole 
increased PANOBINOSTAT systemic exposure by 80% in patients (deJonge 2009) which 
indicated the interaction was weak. PANOBINOSTAT (as a CYP2D6 inhibitor) increased the 
systemic exposure of a sensitive CYP2D6 substrate, dextromethorphan, by 60% in patients. 
These two drug interaction studies indicated that PANOBINOSTAT is a weak CYP2D6 
inhibitor clinically and is not a sensitive CYP3A substrate. 
Based on in vitro and in silico data, it is also estimated that PANOBINOSTAT may increase a 
sensitive CYP3A substrate, midazolam, exposure by < 20% and has a low drug interaction 
risk with a non-sensitive CYP3A substrate. 
PANOBINOSTAT and its metabolites are almost equally excreted in the kidney and liver. 
The median plasma elimination terminal half-life was 15-18 hours. Steady state was achieved 
by the 3rd
1.3 
Introduction to RUXOLITINIB (INC424) 
 dose following days 1, 3, and 5 dosing. On day 5, AUC accumulation ratio (RA) was 
~1.14 times over the single-dose AUC which is consistent with the estimated RA based on a 
linear pharmacokinetic process. Doses increased linearly and nearly proportionally with AUC 
up to 60mg. The inter-individual variability (CV%) in systemic exposure is 60%. 
1.3.1 
Overview of RUXOLITINIB 
RUXOLITINIB is a potent, dual JAK1 and JAK2 inhibitor with excellent selectivity over 
other kinases (Quintás-Cardama 2010), has been developed to target the constitutive 
activation of the JAK-STAT pathway for the treatment of MPNs and other hematologic 
malignancies. It is an important agent in controlling the symptomatology of this disease in 


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that it is able to inhibit multiple dysregulated JAK pathways; JAK1 plays a major role in the 
signaling of a number of pro-inflammatory cytokines in MF (Plo 2008) and JAK2 mutations 
may account for the majority of deregulated oncogenic signaling used primarily by receptors 
for hematopoietic growth factors (e.g. erythropoietin and thrombopoietin) in MPN patients 
(Quintás-Cardama 
2010). 
Toxicity 
(primarily 
decreased 
erythropoiesis 
and 
thrombocytopoiesis) has been managed by close control of dosing. Based on efficacy and 
safety data from INC424-251, RUXOLITINIB is a drug that is individually titrated for each 
patient based on hematologic safety parameters, and that some opportunity for individual 
titration of dose might offer the best balance of safety and efficacy for any single agent. The 
dose range of 10-25mg BID for individual dose titration, depending on patient platelet count, 
is supported by the data from INC424-251.  
This study, designed to determine a maximum tolerated dose (MTD) / recommended phase II 
dose (RPTD) of the combination within a 28 day dose limiting toxicity observation window, 
will not explore pharmacokinetics. 
1.3.2 
RUXOLITINIB non-clinical experience 
RUXOLITINIB demonstrated potent and selective inhibition of JAK1 and JAK2 (IC50 values 
of 3.3 and 2.8 nM, respectively) in vitro. In whole blood assays, RUXOLITINIB inhibited 
both IL-6- and thrombopoietin-mediated STAT3 phosphorylation, reflecting selective 
inhibition of JAK1 and JAK2, respectively, in this model system. RUXOLITINIB inhibited 
JAK2V617F-dependent Ba/F3 and IL-6 driven INA-6 cell proliferation with an IC50 value of 
127 nM and 141 nM, respectively. In Ba/F3 JAK2V617F cells RUXOLITINIB induced 
apoptosis with an IC50 value of 126 nM. Exogenous RUXOLITINIB blocked IL-6-mediated 
or thrombopoietin-induced STAT3 phosphorylation in human whole blood, with an IC50 value 
of 282 nM or 281 nM, respectively. RUXOLITINIB preferentially suppressed erythroid 
progenitor colony formation in primary cultures of cells from patients with JAK2V617F-
positive PV (BFU-E IC50 of 223 nM) vs. cells from healthy donors (BFU-E IC50 of 407 nM). 
In a mouse mechanistic model of JAK2V617F-positive MPN, oral administration of 
RUXOLITINIB reduced splenomegaly, tumor burden and circulating levels of inflammatory 
cytokines (IL-6 and TNF-α), resulting in prolonged survival without causing anemia or 
lymphopenia (Quintás-Cardama 2010). 
1.3.3 
RUXOLITINIB clinical experience 
In a Phase I/II study [INC424-251] for patients with MF, a total of 154 patients were treated 
with increasing doses of RUXOLITINIB. 57% of patients treated sustained at least a 50% 
reduction in palpable splenomegaly below the left costal margin (corresponding to an 
approximate 35% reduction in volumetric spleen size), and were treated at doses up to 50mg 
BID, with activity seen at multiple dose levels from 10mg BID (n=30), 15mg BID (n=35), 
25mg BID (n=47), and 50mg BID (n=5). This reduction in splenomegaly occurred regardless 
of presence or absence of the JAK2V617F mutation and independent of the MF disease subtype 
(PMF, PPV-MF, or PET-MF). The responses seen regardless of the presence or absence of the 
JAK2V617F mutation are consistent with dysregulated JAK signaling in MF patients. Within 1 
month of initiating treatment, levels of pro-inflammatory cytokines and angiogenic growth 
factors, including CRP, IL-1ra, MIP 1ß, TNF α, and IL -6 were reduced, and patients noted 


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improvement in night sweats, pruritus, and abdominal pain (Verstovsek 2010). This 
improvement in symptoms was even seen at the lowest end of the dosing spectrum (10mg 
BID) even when there was not a clinically noticeable reduction in splenic size. In 34 evaluable 
patients, treatment with RUXOLITINIB suppressed allelic burden by 13% after 12 cycles 
(Verstovsek 2010). 
The Modified Myelofibrosis Symptom Assessment Form (MMSAF) developed by Mesa et al, 
and based on an international internet-based survey of over 1000 patients with 
myeloproliferative diseases (Mesa 2007), was used to probe a range of constitutional 
symptoms that are related to splenomegaly (including impaired ability to ambulate, abdominal 
pain and discomfort and early satiety) and elevated cytokines (including fatigue, night sweats 
and pruritus). Between 45% and 94% of patients report a given symptom at baseline. After 2 
or more weeks of RUXOLITINIB therapy, 28% to 61% of patients showed a reduction in 
individual symptom scores of at least 50% after 6 cycles of therapy when all doses were 
combined and assessed together. 
RUXOLITINIB has been well tolerated by this aged population with advanced disease. Most 
adverse events were mild to moderate in severity, considered unrelated to study drug 
administration and not dose dependent. Related adverse events occurring in at least 8 patients 
(5%) included in the safety database through December 31, 2009 were restricted to 
thrombocytopenia (66 patients, 43%), anemia (45 patients, 29%), weight increased (11 
patients, 7%), diarrhea (10 patients, 6.5%) and fatigue (8 patients, 5%). Both anemia and 
thrombocytopenia represent JAK2-inhibitor myelosuppression, and are therefore not 
unexpected for a JAK2 inhibitor. Thrombocytopenia represents the DLT in the population of 
the [INCB18424-251] study. Forty (40) subjects (26% of study population) had a Grade 3 or 
Grade 4 decline in platelet count during the study (31 Grade 3 events, 9 Grade 4 events). 
Subjects with Grade 3 or 4 thrombocytopenia entered the study, in general, with platelet 
counts less than 200K/µL, although there are exceptions to this trend. Thrombocytopenia 
occurred rapidly: 20% of Grade 3 and 4 events occurred in the first 4 weeks of dosing, just 
under half (48%) of Grade 3 and 4 events occurred in the first 16 weeks of dosing. For most 
subjects, regardless of dose level, thrombocytopenia was rapidly reversible and manageable 
with RUXOLITINIB dose interruption and/or dose reduction. 
The 25mg BID dose group was the largest dose group examined. This dose group included 
subjects with mean baseline platelet counts of 345 x109/L and had an overall incidence of 
Grade 3 + 4 thrombocytopenia of 36% (17 of 47 subjects); 12 subjects had Grade 3 events 
(26%), and 5 subjects had Grade 4 events (11%). Subjects enrolled in a subsequent cohort 
were assigned to an initial dose of 15mg BID provided their baseline platelet count was >200 
x109/L; the incidence of Grade 3 thrombocytopenia was markedly reduced (1 of 35 subjects) 
and there were no Grade 4 events. At a starting dose of 10mg BID, there were 6 of 30 subjects 
(20%) with Grade 3 thrombocytopenia; there were no Grade 4 events. Importantly, 8 of the 30 
subjects at a starting dose of 10mg BID enrolled into the study under a protocol amendment 
specifying this dose for a baseline platelet count between 100 x 109/L to 200 x 109/L, 
inclusive. This is reflected in a lower mean platelet count at baseline for this dose group. 
Three of these subjects (38%) had baseline platelet counts ranging from 119 x109/L to 156 x 
109/L and subsequently developed Grade 3 thrombocytopenia. This accounts, in part, for the 
higher incidence of Grade 3 and 4 thrombocytopenia in this dose group compared to 15mg 


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BID. Subjects initially assigned to the 50mg BID dose group had an incidence of Grade 3 
thrombocytopenia of 60% (3 of 5 subjects) and of Grade 4 thrombocytopenia of 20% (1 of 5 
subjects). From the combined safety and efficacy data of INC424-251, 15mg BID was 
determined to be the most effective and safe starting dose. 
 
On November 16, 2011, Ruxolitinib was approved by the U.S. Food and Drug Administration 
(FDA) for the treatment of intermediate/high-risk MF based upon the combined results of the 
COMFORT-I and COMFORT-II Trials. The COntrolled MyeloFibrosis Study with ORal 
JAK2 inhibitor Treatment (COMFORT-1) study was a randomized (1:1), double-blinded 
phase III study sponsored by Incyte comparing Ruxolitinib to placebo in patients with 
intermediate-2 or high risk MF and a baseline platelet count of at least 100 x 109/L (25). Oral 
ruxolitinib was dosed at 15mg BID for patients with platelet counts between 100-200 x 109/L 
and 20mg BID for patients with >200 x109
 
/L. A total of 309 patients were randomized 
(ruxolitinib 155, placebo 154), with a median age of 68 years. The primary endpoint of this 
study was a reduction in spleen volume of at least 35% by either MRI/CT. The 35% reduction 
in spleen volume was chosen based on previous studies that established a correlation of 35% 
reduction in volume by imaging to approximately 50% reduction by manual palpation on 
physical exam. Secondary endpoints included assessment of duration of spleen reduction and 
improvement in disease related symptoms as assessed by the MFSAF (myelofibrosis 
symptom assessment form) (26). Patients were allowed to crossover from placebo if they had 
a greater than 25% increase in spleen volume by imaging from baseline and all patients were 
un-blinded and could crossover when every patient had completed week 24 or discontinued 
the treatment and 50% of remaining patients had completed week 36.  
Grade 3/4 anemia was the most frequent hematologic AE observed in 45% vs 19.2%, in the 
ruxolitinib vs placebo arm, respectively. Grade 3/4 thrombocytopenia was observed in 12.9% 
vs 1.3% in patients treated with ruxolitinib vs placebo, respectively. Neutropenia that was 
grade 3/4 was observed in 7.1% vs 2% in the ruxolitinib vs placebo arm, respectively. The 
most common non-hematologic adverse event seen of any grade in the ruxolitinib treated 
group was diarrhea 23.2% (compared to 21.2% in placebo group).  All in all, this was a well- 
tolerated drug.  
 
At 24 weeks, 41.9% of patients treated with ruxolitinib experienced a 35% or greater 
reduction in spleen volume compared to 0.7% of patients receiving placebo (P
Survival analysis on extended ruxolitinib therapy with a mean follow up of 52 weeks showed 
a statistically significant reduction in death with a hazard ratio of 0.499 (0.254, 0.98) and a 
probability of survival compared to placebo of 0.98 vs 0.90 and 0.84 vs 0.77 in patients with a 
baseline hemoglobin >10g/dL and <10g/dL, respectively (27). In further subset analysis, 
patient age ≤ 65 years appeared to have a survival benefit over > 65 years of age with a HR 
0.22 (0.06,0.84) with ruxolitinib therapy.  
 < 0.0001). 
45.9% of ruxolitinib treated patients regardless of their JAK2 mutational status experienced a 
≥50% improvement in constitutional symptoms as compared to 0.7% in the placebo group.  
 
The drug therapy was uniformly ineffective in reversing histopathological abnormalities in the 
peripheral blood or marrow, eliminating marker cytogenetic abnormalities or reducing the 


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JAK2V617F allele burden to a degree associated with tyrosine kinase inhibitor therapy of 
BCR/ABL1 for chronic myeloid leukemia. The other limitation of the agent that has been the 
rapid return of splenomegaly following discontinuation of the drug and the occasional 
occurrence of life threatening syndromes attributed to the rapid elevation of cytokines. This 
“ruxolitinib withdrawal syndrome” has been described in 5 of the 47 MF patients treated at 
Mayo Clinic that had rapid discontinuation and the authors advise tapering the drug when 
possible in addition to upfront discussion with the patient regarding this potential drug 
associated serious adverse event (28).  
 
The COntrolled MyeloFibrosis Study with ORal JAK2 inhibitor Treatment COMFORT-2 
study was a randomized (2:1), Novartis sponsored, open-label phase III clinical trial 
conducted in nine European countries comparing ruxolitinib to best available therapy (BAT) 
(29). Hydroxyurea (46.6%), steroids (16.4%) and supportive therapy (32.9%) comprised the 
BAT arm. At a median age of 66 years, 219 patients with intermediate-2 or high risk MF were 
randomized (146 ruxolitinib, 73 BAT).  
 
The primary endpoint was met at 48 weeks, when 28.5% of patients treated with ruxolitinib 
achieved a 35% or greater reduction in spleen volume, compared to 0% of patients in the BAT 
arm (P < 0.0001). The secondary endpoint of spleen reduction at 24 weeks was 31.9% vs 0%, 
ruxolitinib arm vs BAT, respectively.  
 
As was seen in the COMFORT-1 study, hematologic toxicity of all grades was frequent with 
ruxolitinib (44.5% and 40.4%, thrombocytopenia and anemia, respectively)  and was grade 
3/4 thrombocytopenia (7.5% vs 4.1%), and anemia (11% vs 4.1%) in ruxolitinib vs BAT 
arms, respectively.  Diarrhea of all grades was the most frequent non-hematologic adverse 
event seen in 23% of ruxolitinib treated patients and was grade 3/4 in 1%.  
 
Progression-free survival, leukemia-free survival and overall survival were not statistically 
significant between the two treatment arms.  
 
1.3.3.1 
Electrocardiographic experience with RUXOLITINIB 
A thorough QT study [INC18424-138] was performed to assess the heart rate corrected QT 
interval in healthy subjects dosed with a single dose of 25 mg and 200 mg of RUXOLITINIB, 
compared to placebo and moxifloxacin. The pharmacokinetic parameters observed in this 
study were consistent with those reported from previous clinical studies conducted in healthy 
volunteers. Based on the ICH E14 this study met the requirements for a negative QT study. 
For RUXOLITINIB dosing, at no time did the upper bound of the 2-sided 90% confidence 
interval exceed 10 msec. The largest mean change was seen following the 200 mg dose, 
which was 3.7 beats per minute at 1.5 hours post-dose. This was not considered clinically 
significant by the expert cardiologist at the central ECG laboratory. There was also no 
evidence that increasing plasma concentrations of RUXOLITINIB was associated with 
increases in the change of QTc. 


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1.3.4 
RUXOLITINIB clinical pharmacokinetics 
In clinical studies, RUXOLITINIB is completely and rapidly absorbed after oral 
administration with maximal plasma concentration (Cmax) achieved approximately 1.5 hours 
post-dose. Administration with a high-fat meal decreased RUXOLITINIB mean Cmax by 24% 
and increased RUXOLITINIB mean AUC by 4%. A linear dose-exposure relationship was 
observed over a dose range of 5 to 200 mg (single dose). There was minimal accumulation 
(12%) with multiple dose administration (q12h x 10 days) compared single dose 
administration. The steady state dose-exposure was linear over the dose range of 15 to 50 mg 
q12hours. In vitro studies indicate that CYP3A4 is the major enzyme responsible for 
metabolism of RUXOLITINIB. At clinically relevant concentrations, RUXOLITINIB is not 
expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 
and is not a potent inducer of CYP1A2, CYP2B6 or CYP3A4. RUXOLITINIB is eliminated 
almost completely by oxidative metabolism with a terminal elimination half-life of 
approximately 3 h. Following a single oral dose of [14
The pharmacodynamic activity of RUXOLITINIB was characterized by an ex vivo whole 
blood assay that involves quantitation of pSTAT3 following IL-6 stimulation. Following oral, 
single or multiple dose administration in healthy subjects, RUXOLITINIB demonstrated dose 
dependent inhibition of ex vivo cytokine-induced pSTAT3 with maximal inhibition occurring 
at 1-2 hours after administration for all doses, coincident with maximal RUXOLITINIB 
levels. The oxidative metabolites of RUXOLITINIB retain pharmacologic activity to varying 
degrees albeit with 2-5-fold greater IC50 compared to the parent compound and represent 
approximately 20% of overall activity (inhibition of IL-6 stimulated STAT3 phosphorylation 
in whole blood) observed after a RUXOLITINIB dose. 
C]-labeled RUXOLITINIB in healthy 
adult volunteers, 74% of radioactivity excreted in urine and 22% excretion via feces. 
Unchanged RUXOLITINIB accounted for less than 1% of the excreted total radioactivity. 
In vitro metabolism studies strongly suggest that CYP3A4 is the predominant human CYP 
isozyme responsible for the metabolism of RUXOLITINIB. Co-administration of 
RUXOLITINIB with ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximate 
doubling of plasma AUC, whereas co-administration with erythromycin, a moderate CYP3A4 
inhibitor, caused approximately 27% increase in exposure. In the presence of rifampin, a 
potent inducer of CYP3A4, an approximate 70% decrease in plasma AUC of RUXOLITINIB 
was observed. 
In patients with varying degrees of renal impairment, the pharmacokinetics and 
pharmacodynamics of RUXOLITINIB was similar to the healthy subjects, except in patients 
with end stage renal disease on hemodialysis who exhibited modestly higher response in the 
pSTAT3 assay when dosed following dialysis. The recovery of RUXOLITINIB in dialysate 
was negligible, consistent with the high serum protein binding (97%) of RUXOLITINIB. 
There was little effect on the plasma Cmax values of RUXOLITINIB metabolites, whereas the 
AUC values of RUXOLITINIB metabolites tended to increase with increasing severity of 
renal impairment, and most markedly in the subjects with end stage renal disease requiring 
hemodialysis. The metabolites appeared to be dialyzable to varying degrees in a 4-hour 
hemodialysis procedure. 


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In patients with hepatic impairment there was no rank order correlation between exposure and 
degree of hepatic impairment assessed by Child-Pugh scores. RUXOLITINIB AUC increased 
88% in mild, 29% in moderate, and 66% in severe disease. The terminal elimination half-life 
ranged from 4.6 hours in mild, 4.1 hours in moderate and 5.1 hours in severe hepatic 
impairment compared to 2.8 hours in healthy subjects. No significant differences in 
pharmacodynamics were observed among subjects with mild or moderate hepatic impairment 
compared to healthy subjects. In subjects with severe hepatic impairment, the inhibition of IL-
6 stimulated pSTAT3 levels appeared to be prolonged. Hepatic impairment, in general, 
decreased the plasma Cmax but not the AUC values of RUXOLITINIB metabolites, and no 
correlation was observed between the change in pharmacokinetic parameters of the 
metabolites and the degree of hepatic impairment. 
Additional details as to the clinical pharmacology of RUXOLITINIB may be found in the IB. 
1.4 
Risk assessment of the combination of PANOBINOSTAT and 
RUXOLITINIB 
1.4.1 
Assessment of drug-interaction potential between PANOBINOSTAT 
and RUXOLITINIB 
Based on in vitro metabolic profiling and results from clinical PANOBINOSTAT drug 
interaction studies ([CLBH589B2110] and [CLBH589B2109]), PANOBINOSTAT was 
shown to be a non-sensitive CYP3A substrate and a weak CYP2D6 inhibitor in patients. It has 
also been predicted to have minimal clinical drug interaction risk with a non-sensitive CYP3A 
substrate. 
RUXOLITINIB was also shown to be a non-sensitive CYP3A substrate based on the results 
from Study [INCB18424-133] (ketoconazole inhibition study) and is not known to be a CYP 
inhibitor or inducer in vitro. 
Since CYP3A is the most abundant CYP enzyme in the liver, drugs with shared elimination 
pathway via CYP3A had not been shown to have compromised elimination. Drug-interaction 
between PANOBINOSTAT and RUXOLITINIB is therefore not expected by being CYP3A 
substrates. Based on available in vitro and clinical data, clinical drug interaction between 
PANOBINOSTAT and RUXOLITINIB is therefore not expected. 
PANOBINOSTAT is a weak time-dependent CYP3A inhibitor and predicted to have no 
clinically relevant consequence on a non-sensitive CYP3A substrate, such as RUXOLITINIB. 
As PANOBINOSTAT is also administered intermittently, its clinical impact on the chronic 
RUXOLITINIB administration is deemed even more remote.  
1.4.2 
Integrative toxicological assessment of PANOBINOSTAT and 
RUXOLITINIB in combination 
When combining both compounds the potential for overlapping toxicities needs to be 
considered. For PANOBINOSTAT the predominant toxicities seen preclinically consisted of: 
myelosuppression, lymphoid depletion, degeneration of the intestinal epithelium, variable 
effects on the thyroid epithelium and thyroid hormones, anabolic effects on bone (manifested 


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as hyperstosis), atrophy/degeneration of testes, prostate and ovarian follicles and embryo-
lethality and fetotoxicity (manifested as decreased fetal body weight). For RUXOLITINIB the 
predominant toxicities seen preclinically consisted of: myelosuppression, lymphoid depletion 
resulting in decreased erythropoiesis and lymphopoiesis, immunosuppression resulting in 
secondary infections in dogs, and embryo-lethality and fetotoxicity (manifested as decreased 
fetal body weight). For both compounds most of the findings were reversible or showed 
trends toward reversibility and can be readily monitored in the clinical setting. Preliminary 
clinical data available from ongoing trials in myelofibrosis with PANOBINOSTAT or 
RUXOLITINIB as single agents indicate thrombocytopenia as the principal overlapping dose-
limiting toxicity. Fatigue, neutropenia and diarrhea are also listed as toxicities for 
PANOBINOSTAT. Although no combination PANOBINOSTAT and RUXOLITINIB 
toxicity studies have been conducted, based on clinical data with each. it appears likely that 
thrombocytopenia will be dose limiting when these agents are combined in the clinical setting. 
In addition to identifying common target organ toxicities understanding the metabolism and 
elimination of each compound and how the presence of one compound might impact systemic 
drug concentrations of the other can further inform the potential for additive or synergistic 
toxicities. Based on in vitro metabolic profiling and results from clinical PANOBINOSTAT 
drug interaction studies, PANOBINOSTAT has shown to be a non-sensitive CYP3A substrate 
and a weak CYP2D6 inhibitor in patients. It has also been predicted to have minimal clinical 
risk with a non sensitive CYP3A substrate. RUXOLITINIB is also a non-sensitive CYP3A 
substrate and is not known to be a CYP inhibitor or inducer. Since CYP3A is the most 
abundant CYP enzyme, drugs with shared elimination pathway via CYP3A have not been 
shown 
to 
have 
compromised 
elimination. 
Therefore 
drug-interaction 
between 
PANOBINOSTAT and RUXOLITINIB is not expected by being CYP3A substrates. 
PANOBINOSTAT is a weak time-dependent CYP3A inhibitor and predicted to have no 
consequence on a non-sensitive CYP3A substrate, such as RUXOLITINIB. Since 
PANOBINOSTAT is also administered intermittently, its clinical impact on the chronic 
RUXOLITINIB administration is deemed even more remote. Based on available in vitro and 
clinical data, clinical drug interaction between PANOBINOSTAT and RUXOLITINIB is not 
expected. Based on preclinical data a summary of the integrative assessment for potential for 
additive and/or synergistic toxicity of combining PANOBINOSTAT with RUXOLITINIB is 
presented below. 


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Table 1-4 
Integrative toxicological assessment of PANOBINOSTAT (LBH589) / 
RUXOLITINIB (INC424) combination 
Target Organ 
LBH589 
INC424 
Potential Impact of 
Combination 
Genotoxicity 
Positive in Ames and 
Chromosomal Aberration 
Assays 
Not genotoxic 
None predicted 
Cardiovascular 
QT prolongation (dog, 
human) 
↓ in blood pressure, ↑ heart 
rate (dog), ↓ respiratory 
minute volume (rat) 
minimal heart fibrosis (rat) 
None predicteda 
Hematopoietic 
Myelosuppression, lymphoid 
atrophy and/or depletion 
(↓ erythrocytes, granulocytes 
and platelets). Rat, dog) 
Thrombocytopenia, most 
common adverse event 
seen in patients 
Myelosuppression, 
lymphoid atrophy, ↓ 
erythropoiesis and 
lymphopoiesis (rat, mouse, 
dog). Infections/infestations 
due to immunosuppression 
(dog) 
Thrombocytopenia, most 
common adverse event 
seen in patients, not 
observed in non clinical 
studies 
Potential for additive or 
synergistic 
hematopoietic toxicity 
(thrombocytopenia most 
likely in patients) 
Gastrointestinal 
Degeneration/necrosis - 
epithelium of the small 
intestine, diarrhea (dog), 
atrophy of parotid gland (rat) 
Inflammation and/or erosion 
of the small intestine (dog), 
Hyperplasia of non-
glandular stomach (mouse) 
Potential for additive 
gastrointestinal toxicity 
Thyroid 
Follicular epithelial 
hypertrophy, cytoplasmic 
vacuolation, reduced 
follicular colloid, variable 
changes in T3, T4 and TSH 
(rat, dog) 
No change 
None predicted 
Reproductive 
♂ Atrophy/degeneration of 
prostate and testes 
(oligospermia), ♀ atretic 
ovarian follicles and uterine 
atrophy (rat, dog), Embryo-
lethal and fetotoxic, but not 
teratogenic (rat, rabbit) 
Embryo-lethal and fetotoxic, 
but not teratogenic (rat, 
rabbit) 
Embryo-fetal warning 
and highly effective birth 
control required clinically 
Bone 
Endosteal Hyperstosis (rat) 
No change 
None predicted 
a INC424 cardiovascular effects in dogs and rats were seen at maximal plasma concentrations (Cmax) and 
exposures (AUC) that were 10 -50-fold greater than those seen in patients at the MTD of 25 mg bid. 
2 
Rationale 
2.1 
Study rationale and purpose 
Histone deacetylase inhibitors (HDACi) are a class of agents regulating the acetylation of core 
histones responsible for the epigenetic control of tumor suppressor gene expression and other 
genes responsible for cell differentiation and apoptosis (Schreiber 2002). Acetylated histones 
remain in a relaxed state allowing for the transcription of genes. HDACi block the action of 


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histone deacetylases (HDAC) from removing these moieties and repressing transcription. 
HDACi also promote the acetylation of other non-histone proteins including heat shock 
protein, HSP90, a chaperone for various proteins offering protection from ubiquitin directed 
proteasomal degradation (Bali 2005). HDACi promote cell cycle growth arrest and 
accumulation in G1 or G2-M and apoptosis involving both mitochondrial and receptor ligand-
mediated pathways. Previous in vitro studies investigating the use of HDACi in the HEL cell 
line and JAK2V617F+ cells from PV and ET patients have shown selective reduction in the 
mutant JAK2 clone with preservation of the wild type cells (Guerini 2007). These studies also 
make the point that not only are direct targets of the mutated JA2 pathway such as signal 
transducers and activators 3 and 5 (STAT3/5) down-modulated, but so are downstream target 
genes such as PRV-1.  JAK2V617F specific attenuation was only seen at the protein level as 
JAK2 mRNA levels remained unaffected and may reflect either preferential mutant directed 
proteosomal degradation, selective acetylation of the mutant form or acetylation of other 
stabilizing proteins. PMF is also characterized by an increased proportion of circulating 
peripheral blood CD34+ hematopoietic stem cells and ex vivo exposure of PMF CD34+ cells 
to sequential DNA methyltransferase (DNMT) inhibitor and HDACi has been shown 
previously to dramatically reduce the burden of malignant progenitor cells as detected by a 
reduction in JAK2V617F allele burden (Shi 2007). 
 
PANOBINOSTAT is a novel cinnamic hydroxamic HDACi and a very potent pan-HDAC 
inhibitor specifically enhancing acetylation on H3 and H4 and HSP90 (Glaser 2007). Targeted 
inhibiton of HDAC6, a member of the class IIB HDACs, by PANOBINOSTAT has been 
shown to enhance acetylation of HSP90 and disrupt its chaperone function leading to the 
degradation of various client proteins such as BCR/ABL, AKT, c-RAF, and FLT-3(Bali 2005; 
George 2005). JAK2 is also a client protein of HSP90 and inhibition of this chaperone protein 
results in the degradation of JAK2 and impairment in cytokine signaling (Shang 2006). The 
use of PANOBINOSTAT in MF patients would be an additional or alternative mechanism of 
down-regulating the JAK2V617F mutant clone by direct inhibition of JAK2V617F and 
suppression of the various downstream targets and effectors responsible for cell growth, 
differentiation and survival with the ultimate goal of modifying the disease phenotype. 
PANOBINOSTAT has shown activity in patients with MF as described in the previous 
section.  PANOBINOSTAT will be provided in the oral formulation for ease of administration 
in the outpatient setting and due to the fact that PK/PD studies have already been completed in 
previous studies using oral PANOBINOSTAT [CPANOBINOSTATB 2101] and both 
bioavailability and histone acetylation data as mentioned previously favor oral dosing on a 
TIW schedule in this patient population.   
 
Due to the encouraging, but limited results of RUXOLITINIB alone in patients with MF, we 
propose a phase I/II study of PANOBINOSTAT in combination with RUXOLITINIB in 
patients with MF. A standard 3+3 dose escalation schema with RUXOLITINIB at a starting 
dose of 10mg PO BID given continuously will be combined with PANOBINOSTAT given 
QOW on 28 day cycle with continuous RUXOLITINIB at 10mg PO BID. This schedule will 
allow for determination of both the dose limiting toxicity (DLT) and maximum tolerated dose 
(MTD) of both drugs as well as evidence of clinical response as defined by the International 
Working Group (IWG) criteria. Based on our previous work with PANOBINOSTAT (not yet 


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published), we hypothesize that prolonged administration at low doses is required to effect 
changes in the peripheral blood and ultimately in the bone marrow that reflect disease 
modification and potential improvement in outcome.    
 
At this time there still exists no standard medical treatment for myelofibrosis and of the many 
drugs that have been used in the past (hydroxyurea, melphalan, danazol, interferon-alfa, 
thalidomide, lenalidomide) and presently being investigated (JAK2-TKI, HDACI, mTORi 
pomalidomide) have not been shown to affect the natural history and progression of disease. 
These drugs have individually shown the ability to induce response rates as measured in 
spleen reduction, amelioration of constitutional symptoms and to some degree modulation of 
hematologic profile and reduction in JAK2V617F allele burden. We believe that the 
combination of the RUXOLITINIB and PANOBINOSTAT is a novel and rational approach 
to the treatment of MF based on both pre-clinical science and clinical data as single agents in 
MF. 
To further the benefit seen with RUXOLITINIB in patients with MF, PANOBINOSTAT will 
be added to the treatment regimen to act synergistically in the blockade of the dysregulated 
pathway driving this disease. See Section 2.4 for more information on the preclinical study 
demonstrating the synergistic activity exerted by the combination of PANOBINOSTAT and 
the JAK inhibitor TG101209 against CD34+
2.2 
Rationale for the study design 
 primary MPN cells and JAK2V617F-expressing 
cell lines. This synergy will hopefully provide enhanced anti-proliferative activity in patients 
and reduce overall treatment related toxicity by using lower than single agent maximum 
tolerated dose levels. This clinical trial will be a single arm, safety and dose-finding phase I/II 
study, with a primary endpoint within the phase II portion of IWG-MRT treatment response 
and secondary endpoints of spleen volume response and changes in exploratory biomarkers 
This is a Phase I/II single arm, dose escalation study with expansion at the RPTD to assess 
efficacy and exploratory endpoints and further define safety and toxicity.  This dose escalation 
process will be based on the toxicity profile. Following the determination of the MTD and/or 
potential RPTD, a dose expansion phase will be conducted at that dose to further define the 
safety and tolerability of the combination. See Section 10.4.2.1 for further details of the dose 
expansion cohort. Also during the dose expansion phase, biomarker data will be collected. 
2.3 
Rationale for dose and regimen selection 
Since thrombocytopenia has been established as the DLT of PANOBINOSTAT, a dosing 
schedule of QOW will first be attempted in the early dose escalation cohorts since data from 
[CLBH589B2102] suggests QOW dosing decreased the incidence and time to severe 
treatment related thrombocytopenia as well as the duration of thrombocytopenia. Refer to 
Table 2-1 for more detailed information.  


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Table 2-1 
Comparison of dose reductions, duration of exposure, relative dose 
intensity and thrombocytopenia between QW and QOW schedule with 
oral PANOBINOSTAT in patients with HL in study CLBH589B2102 
 
Every Week Schedule (QW) 
Every Other Week 
Schedule (QOW) 
Parameters Analyzed 
30 
mg 
TIW 
40 mg 
TIW 
60 mg 
TIW 
All 
45 mg 
TIW 
60 mg 
TIW 
All 
N=2 
N=15 
N=5 
N=22 
N=3 
N=7 
N=10 
Dose Reductions (%) 
 
 
 
 
 
 
 
 
None 
100 
40 
60 
50 
100 
71 
80 
 
1 dose reduction 
0 
27 
40 
27 
0 
29 
20 
 
≥2 dose reductions 
0 
33 
0 
23 
0 
0 
0 
Thrombocytopenia 
 
 
 
 
 
 
 
Time to grade 3/4 (median, 
days) 
86.5 
12 
8 
12 
N/A 
(>376) 
64 
N/A 
(>208) 
Duration (median, days) 
4.5 
8 
5 
7 
N/A 
7 
7 
Maximum duration (days) 
6 
26 
29 
29 
N/A 
8 
8 
Exposure (median, days) 
392.5 
115 
176 
136 
348 
131 
260 
Relative dose intensity 
91.0
% 
62.1% 
47.3% 
57.3% 
92.9% 
96.7% 
94.5% 
Abbreviation: N/A = not applicable (median not reached because Grade 3/4 thrombocytopenia has 
not yet occurred) 
From study [INC424-251], anemia and thrombocytopenia were the most frequently reported 
grade 3 or 4 events. While thrombocytopenia was the most frequently reported treatment 
emergent adverse event (TEAE) leading to study drug interruption (18.8%), only 3.2% of the 
patients required discontinuation of study medication. The only other TEAEs leading to 
discontinuation that occurred in more than one patient were anemia (2.6%), multi-organ 
failure (1.3%), and acute myeloid leukemia (1.3%). Analysis of grade 3 and 4 
thrombocytopenia by initial treatment group also showed a clear dose response. Patients who 
began therapy at lower doses (10-15mg BID) were less likely to have grade 3 
thrombocytopenia, and no patient receiving these doses had grade 4 thrombocytopenia or 
worsening anemia (data on file: Novartis). Refer to Section 1.3.3 for more detailed 
information on these events. 
2.4 
Rationale for choice of combination drugs 
In a preclinical study (Wang 2009), it was demonstrated that compared with either agent 
alone, combined treatment with PANOBINOSTAT and TG101209 (a JAK2 TK inhibitor) is 
more effective in attenuating not only p-STAT3 and p-STAT5, but also the mutant 
JAK2V617F. This effect was more pronounced when PANOBINOSTAT was combined with 
lower concentrations of TG101209. Preclinically this combination also showed a synergistic 
increase in cytotoxicity for cells expressing the JAK mutation (Wang 2009). HEL cells treated 
with PANOBINOSTAT showed an approximately 40% depletion of the mRNA expression of 
JAK2 (Wang 2009). PANOBINOSTAT has also been shown to induce hyperacetylation and 


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inhibition of the chaperone function of HSP90, resulting in proteasomal degradation of 
HSP90 client proteins which includes JAK2. The distinct mechanisms of action of 
PANOBINOSTAT in addition to the blockade of the JAK/STAT pathway provided by 
RUXOLITINIB, may allow for greater disease control at lower doses of each of these agents 
to avoid toxicities. There is no predicted pharmacokinetic interaction between these two 
drugs, and synergistic toxicities are not anticipated. See Section 1.4.1 and Section 1.4.2 for 
further details. 
From this study, the JAK2V617F mutation allele burden was measured pre- and post-
treatment from 10 patients. The median percent of mutant JAK2 pre-treatment was 27%, and 
the median percent post-treatment was 10% indicating a significant median decline in the 
JAK2V617F allelic burden (DeAngelo 2010). 
From study INC424-251, in the 34 patients for whom data were available the mean maximal 
suppression of 13% from baseline was seen after 12 cycles of therapy (Verstovsek 2010). 
As both of these agents modify the overall JAK2V617F allele burden, given sufficient follow 
up this may prove to have meaningful clinical benefit. 
3 
Objectives and endpoints 
Objectives:   
• Evaluate the tolerability and safety of combination RUXOLITINIB and 
PANOBINOSTAT in patients with MF in chronic and accelerated phase.   
• Assess clinicopathologic response of MF patients treated with RUXOLITINIB and 
PANOBINOSTAT. 
• Assess changes in biomarkers of disease in relation to response to combination 
treatment with oral PANOBINOSTAT and RUXOLITINIB.  
• Explore genetic and epigenetic predictors of disease response to combination therapy in 
MF. 
Endpoints:   
• Determine the Dose Limiting Toxicities (DLTs) of each agent in combination. 
• Characterize the adverse events (AEs) and serious adverse events (SAEs) of 
combination therapy.  
• Establish the Maximally Tolerated Doses (MTDs) and the Recommended Phase Two 
Doses (RPTDs) for each agent in combination.  
• Assessing clinical response by International Working Group for Myelofibrosis 
Research and Treatment (IWG-MRT) consensus criteria. 
o Spleen reduction by palpation on exam. 
o Peripheral blood count and morphology normalization. 
o Bone marrow histopathology and fibrosis.  
• Evaluate reduction in spleen volume by MRI/CT. 
• Evaluation bone marrow response in terms of cellularity, histopathology and fibrosis 
in patients treated with RUXOLITINIB and PANOBINOSTAT. 


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• Evaluation of  histone H3/H4 acetylation, JAK2V617F mononuclear allele burden, 
degree of circulating CD34+ hematopoietic cells in the peripheral blood; CXCR4 
expression in CD34+ hematopoietic cells;  changes in cytokine and other plasma 
protein levels from baseline.  
• Assess if the presence of JAK2V617F, TET2, ASXL1, EZH2 and other MPN markers 
can predict clinical response to combination therapy 
4 
Study design 
4.1 
Description of study design 
 
Phase I/II open label, single institution, study of induction RUXOLITINIB followed by 
concurrent administration of RUXOLITINIB and PANOBINOSTAT in a 3+3 cohort dose 
escalation schema in eligible patients with MF (see Figure 4-2).  Screening for this study will 
have a window of 56 days and start on day -84 with signing of informed consent.  See Figure  
4-1 A and B. Eligible patients will begin induction phase therapy on day -28, receiving single 
agent RUXOLITINIB PO BID daily for 28 days. The dose of RUXOLITINIB in the induction 
cycle days -28 to 0 will be the same dose that the patient will receive in the assigned 
combination cycles. Patients who maintain a platelet count ≥ 50,000/ul at Day 1 will then 
receive concomitant PANOBINOSTAT PO TIW QOW or PO TIW QW depending on the 
cohort assignment. The induction phase of the Phase I study is not the evaluable phase I 
component and AEs that are noted in the induction phase will not constitute a dose limiting 
toxicity (DLT) and patients who do not maintain a platelet count >50 x 109
Phase I 
/L will be removed 
and will not be able to continue onto the combination drug evaluable phase I period of 28 
days and will not be counted in the evaluable phase I cohort for the purposes of dose 
escalation.  
The first 28 days of combination therapy will be the evaluable phase I portion of the study. 
Patients who do not experience a defined DLT in the dose evaluation stage of phase I can 
remain on study receiving combination drug therapy for a total of 6 cycles (cycles 2-6). See 
Figure 4-1 A. AEs will continue to be recorded on all patients (phase I and II) receiving 
combination therapy beyond the first cycle of the study. Dose escalation rules are based on the 
standard 3+3 design as shown in Figure 4-2.  
Note that in this Phase I study, the initial cohort(s) will fix the dose of RUXOLITINIB and 
escalate the dose of PANOBINOSTAT. Thus, the first endpoint will be to find the MTD of 
PANOBINOSTAT associated with a fixed dose of 10 mg of RUXOLITINIB.  At that point, 
the dose of PANOBINOSTAT will be fixed at the MTD just mentioned, and RUXOLITINIB 
will be escalated to 15 mg.  The rules of the 3+3 design will govern whether 15 mg is an 
acceptable dose for RUXOLITINIB in combination with the MTD of PANOBINOSTAT.  
The rules of the 3+3 design will again be employed to decide on the frequency of 
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Phase I patients who complete a total of 6 cycles of combination therapy will be assessed for 
clinical response by IWG-MRT criteria. Patients who achieve at least Stable Disease (SD) by 
IWG-MRT (Table 4-1) can remain on therapy indefinitely or until disease progression or drug 
toxicity as assessed by the investigators in the Phase I extension stage. After 24 cycles, stable 
patients may be seen every other month at the discretion of the investigator. At the discretion 
of the investigator, phase I patients who have completed 6 cycles of therapy with a minimum 
of SD can also be dose escalated at that time to the RPTD once it is determined. These 
patients will not be considered for evaluation of response in Phase II.  
Myelosuppression is expected and anticipated given the known toxicity profiles of these drugs 
in single agent therapy for MF. During the dose evaluation stage, Days 1-28, while both drugs 
are administered in combination, platelet transfusions will not be allowed to avoid the 
predetermined DLT of platelet count <10 x 109/L or any platelet count with grade 3 bleeding.  
If a platelet transfusion is indicated by best clinical practice guidelines and the PI feels it is 
necessary to transfuse a patient in these 28 days of the phase I study even at a platelet count 
>10 x 109
Phase II 
/L, then the patient will be transfused and will come off study and this will be 
considered a DLT. Platelet transfusions are allowed and should be given when clinically 
indicated and at the discretion of the investigator in Phase I continuation stage and extension 
stage. This would not necessarily require discontinuation from the study. 
Expansion stage [Cycles 1-6] 
Once a RPTD is determined from the dose escalation phase I part of this trial, the dose 
expansion of the phase-II part of this trial will commence with 16 additional patients added to 
the 6 original RPTD cohort from phase I to total 22 patients. See Figure 4-1 B. IWG-MRT 
response criteria will be applied at the end of cycle 6 and this will include spleen volume 
measurement by MRI/CT and bone marrow biopsy to appreciate changes in morphology, 
degree of reticulin/collagen fibrosis, cytogenetics and molecular markers. Patients who have 
obtained at least SD by IWG-MRT can remain on study receiving combination therapy in the 
phase II extension stage. 
Extension stage [Cycles 7+] 
In this part of phase II, patients have obtained at least SD by IWG-MRT after 6 cycles of 
combination therapy and will continue to be treated with dose modifications and stopping 
rules that are the same as the expansion stage. Patients will continue to be followed for signs 
of response on each monthly visit. After 24 cycles, stable patients may be seen every other 
month at the discretion of the investigator. Repeat imaging of the spleen and bone marrow 
biopsy with repeat cytogenetic and molecular testing when appropriate can be performed at 
the discretion of the investigator for the purpose of assessment of response or disease 
progression. Additional biomarker assessments can also be made at intervals determined by 
the clinical course and at the discretion of the investigator. 
Platelet transfusions are allowed in the Phase II portion of this trial and should be given when 
clinically indicated. Specific instructions are provided for dose modifications and holding of 
study drugs as outlined in Table 6.2.3. Red blood cell transfusion are allowed and anemia 
does not require dose holding or modification until after cycle 6 if the PI believes the study 


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drugs are primarily the cause of worsening anemia and in these cases the instructions for dose 
holding and modification can be followed as outlined in Table 6.2.3.  
 
 
 
 
Figure 4-1 
Study Design 
A. Phase I Study design 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet  ≥ 75,000/ul 
Platelet ≥ 50,000/ul 
 
Extension stage 
Days 
169+ 
 


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B.  Phase II study design 
 
 
 
*Phase II expansion stage is Days 1 to 168 (end of cycle 6)  
**Phase II extension stage is days 169 and beyond (cycle 7+) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet  ≥ 75,000/ul 
Platelet ≥ 50,000/ul 


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Figure 4-2 Dose escalation rules for 3+3 phase I study design 
 
 
 
 
 


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TABLE 4-1 International Working Group (IWG) consensus criteria for treatment response in 
myelofibrosis with myeloid metaplasia 
 
 
 
 
 
 
 
 
 
 


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4.2 
Definition of end of the study 
Patients may continue treatment until they progress, withdraw consent, experience 
unacceptable toxicity, start new MF therapy, and/or it is believed by the investigator to be in 
the best interest of the patient to discontinue. The study will continue until the last patient 
completes all required safety evaluations per extension phase of protocol. Data on patients 
will continue to be collected on all patients who remain on study. 
4.3 
Timing of interim analyses and design adaptations 
No interim analyses are planned for this study.  
4.4 
Early study termination 
The sponsor/investigator has the right to terminate the study at any time. Should this be 
necessary, the patient should be informed, and seen as soon as possible to perform a final 
visit. At this visit, the same assessments should be performed as End of Treatment, see 
Appendix A. The investigator will be responsible for informing the patients and the IRBs 
and/or ECs and FDA, as well as other relevant committees at MSSM of the early termination 
of the trial. 
 
5 
Population 
5.1 
Patient population 
Adult male or female patients ages 18 or older, who have been diagnosed with Primary 
myelofibrosis (PMF), Post-polycythemia vera related myelofibrosis (Post PV MF) or Post 
Essential Thrombocythemia related Myelofibrosis (Post ET MF) as defined by the World 
Health Organization (WHO 2008), will be included in this study. These patients will be seen 
at the Mount Sinai School of Medicine Myeloproliferative Disorders Program. 
Patients must be classified by the International Working Group for Myelofibrosis Research 
and Treatment (IWG-MRT) (Passamonti, 2010) and be either Intermediate-2: 3-4 points; or 
High Risk: 5 or more points. Patients can have either chronic phase (MF-CP), or accelerated 
phase (MF-AP) disease.  
Patients may have received prior therapy for MF, but must discontinue chemotherapy for 3 
weeks (except for hydroxyurea which can be discontinued 24 hours before starting 
RUXOLITINIB), and targeted therapy for 2 weeks prior to screening. Anagrelide can be 
continued up until 24 hours of starting the RUXOLITINIB. An exception are patients 
currently on at least 10mg BID of RUXOLITINIB for greater than 3 months and who have 
not shown an optimal response (i.e. without 50% reduction in palpable splenomegaly or 50% 
reduction in symptom burden). With a reduction of RUXOLITINIB to 10mg BID these 
patients may enter onto the study without stopping RUXOLITINIB. This trial will allow 


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patients who were treated with either HDACi’s or JAK2 inhibitors, as long as these agents 
were not discontinued due to clinically relevant toxicities per the investigator. 
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies.  
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are allowed to enter study treatment in this study. 
Written informed consent must be obtained prior to any screening procedures. 
5.2 
Inclusion criteria 
 
1 Male or female patients aged ≥ 18 years old 
2 Ability to provide written informed consent obtained prior to participation in the study 
and any related procedures being performed 
3 Intermediate-2 and higher by IWG-MRT Post PV/ET MF and PMF patients either in 
a. Chronic Phase (MF-CP) 
b. Accelerated Phase (MF-AP)  
4 Patients must meet the following laboratory criteria: 
a. ANC ≥ .750 x 109
b. Platelets ≥ 75 x 10
/L   
9
c. Creatinine ≤ 1.5 x ULN, 
/L  
d. AST and ALT ≤ 2.5 x ULN  
e. Serum bilirubin ≤ 1.5 x ULN (unless Gilbert’s syndrome and evidence of 
hemolysis) 
f. Serum potassium ≥ LLN 
g. Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN, 
h. Serum magnesium ≥ LLN 
i. Serum phosphorus ≥ LLN 
j. Free T4 within normal limits   
5 ECOG Performance Status of ≤ 3 
6 Any prior therapy with JAK2-TKI, hypomethylating agents, HDACI, mTORi, or 
iMiDs is allowed as long as it is greater than 3 weeks since last dose of administration 
and in the case of a JAK2-TKI or HDACI that discontinuation was not due to non-
hematologic drug toxicity. An exception to this criteria are patients currently on at 
least 10mg BID of ruxolitinib for greater than 3 months and who have not shown an 
optimal response (i.e. without 50% reduction in palpable splenomegaly or 50% 
reduction in symptom burden). With a reduction of ruxolitinib to 10mg BID these 
patients may enter onto the study without stopping ruxolitinib. 
 
Exclusion criteria 
1. Patients who will need valproic acid for any medical condition during the study or 
within 5 days prior to first PANOBINOSTAT treatment. 
2. Impaired cardiac function or clinically significant cardiac diseases, including any one 
of the following: 
a. With permanent cardiac pacemaker 


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b. Resting bradycardia defined as <50 beats per minute 
c. QTcF >480 msec on screening ECG 
d. Complete Left bundle branch block, bifascicular block 
e. Any clinically significant ST segment and/or T-wave abnormalities 
f. Presence of unstable atrial fibrillation (ventricular response rate >100 bpm).  
Patients with stable atrial fibrillation can be enrolled provided they do not meet 
other cardiac exclusion criteria. 
g. Symptomatic congestive heart failure (NYHA class III-IV) 
3. Impairment of GI function or GI disease that may significantly alter the absorption of  
PANOBINOSTAT or RUXOLITINIB  
4. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled 
diabetes or active or uncontrolled infection) including abnormal laboratory values, that 
could cause unacceptable safety risks or compromise compliance with the protocol 
5. 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    
6. Concomitant use of strong CYP3A4 inhibitors  
7. Patients who have received targeted agents within 2 weeks or within 5 half-lives of the 
agent and active metabolites (whichever is longer) and who have not recovered from 
side effects of those therapies. 
8. Chemotherapy witihin 3 weeks prior to screening are excluded (other than 
hydroxyurea at stable doses and will be discontinued 24 hours prior to starting study 
drug).  
9. Patients with an active bleeding tendency or are receiving any treatment with 
therapeutic doses of sodium warfarin (Coumadin®
10. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or 
who have not recovered from side effects of such therapy 
) or coumadin derivatives. Patients 
will be allowed to enter study on aspirin at doses of 81mg/d. 
11. Women who are pregnant or breast-feeding or women of childbearing potential 
(WOCBP) not using an effective method of birth control. WOCBP are defined as 
sexually mature women who have not undergone a hysterectomy or who have not 
been naturally postmenopausal for at least 12 consecutive months (i.e., who has had 
menses any time in the preceding 12 consecutive months). Women of childbearing 
potential must have a negative serum pregnancy test within 24hrs of receiving the first 
dose of study medication.   
12. Male patients whose sexual partners are WOCBP not using effective birth control 
13. Patients with a prior malignancy within the last 5 years (except for basal  or squamous 
cell carcinoma, or in situ cancer of the cervix) 
14. Disease associated with secondary MF such as metastatic carcinoma, lymphoma, 
myelodysplasia, hairy cell leukemia, mast cell disease or acute leukemia (including 
M7 disease or acute panmyelosis with MF) 
 


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6 
Treatment 
6.1 
Investigational treatment 
The terms “investigational study drug(s)” or “study drug(s)” will refer to oral RUXOLITINIB 
(also known as INCB18424) tablets and oral PANOBINOSTAT (also known as LBH589) 
capsules and both drugs will be supplied by Incyte and Novartis, respectively, at no cost to the 
subjects.  
6.1.1 
Dosing administration 
RUXOLITINIB is administered orally BID everyday in a 28-day treatment cycle (Q4wk). 
Induction phase dose is 10 mg PO BID.  In the combination phase, the starting dose of 
RUXOLITINIB is 10 mg and may be increased to 15mg PO BID. See Table 6-1, Table 6-2 
for dose and treatment schedules. 
PANOBINOSTAT is administered orally TIW, QOW, or QW in a 28-day cycle depending on 
the assigned cohort. Starting dose of PANOBINOSTAT is 10mg TIW QOW and may be 
increased to 20mg TIW QW depending on the assigned cohort. See Table 6-1 for dose and 
treatment schedules. 
Patients may take RUXOLITINIB and PANOBINOSTAT without regard to food. However, 
once the patient has made a choice (e.g., take drug after breakfast or at fasting), it is 
recommended that patient will follow the election choice consistently throughout the protocol. 
On Day -28, the first dose of RUXOLITINIB only will be administered at the clinical site. 
First dose of PANOBINOSTAT will start on Cycle 1 Day 1 administered with the 
RUXOLITINIB morning dose at the clinical site. See Table 6-2 for provisional escalating 
dose levels. 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form 
and route of 
administration 
Escalating Doses 
Frequency and/or Regimen 
RUXOLITINIB 
Oral 
10,15 mg 
Twice daily, 28-day cycles 
PANOBINOSTAT 
Oral 
10, 15 mg 
Three times a week, every other 
week, 28-day cycles OR 
Three times a week, every week, 
28 day cycle 
To be taken with the AM dose of 
RUXOLITINIB 
Patients will self-administer RUXOLITINIB and PANOBINOSTAT as instructed as follows: 
• RUXOLITINIB will be orally administered BID (approximately 12 hours apart: morning 
and evening) 
• PANOBINOSTAT should be taken orally TIW (e.g. day 1, 3, and 5) at the same time on 
each day with the AM dose of RUXOLITINIB. Doses should be separated by a minimum 
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• Dose may be taken with or without food 
• Each dose of study drug should be taken with a glass of non-carbonated water 
(approximately 8 ounces/240ml). Patients should be instructed to swallow the 
capsules/tablets whole and not chew them. 
• Patients must avoid grapefruits, grapefruit juice, pomegranate, starfruit, starfruit juice, 
Seville oranges and Seville orange juice during the entire study treatment period 
• The timing of the clinic visit for ECG monitoring (7-1) should be considered when 
determining the initial time of dosing, as the dose time on the day of ECG performance 
should be consistent, as much as possible, throughout the study. 
• If the patient forgets to take a dose of RUXOLITINIB, then he/she should take study drug 
within 3 hours after the missed dose. If more than 3 hours have passed, then that missed 
dose should be omitted and the patients should continue treatment with the next scheduled 
dose.  
• If the patient forgets to take a dose of PANOBINOSTAT, then he/she should take study 
drug within 12 hours after the missed dose. If more than 12 hours have passed, then that 
missed dose should be omitted and the patients should continue treatment with the next 
scheduled dose.  
• If a patient vomits study drug within one hour of study drug administration, the dose will 
not be re-administered. The patient will resume therapy at the next schedule dose. On all 
other days corresponding to study visits, the patients may take the morning dose of study 
drug prior to their scheduled clinic visit. 
• If vomiting occurs on non-study visit days, re-dosing of the patient is not allowed before 
the next scheduled dose, and the event should be noted in the appropriate eCRFs. 
6.1.2 
Ancillary treatments 
Not applicable 
6.1.3 
Rescue medication 
Not applicable 
6.1.4 
Guidelines for continuation of treatment 
Patients may continue treatment until they progress, withdraw consent, experience 
unacceptable toxicity, start new MF therapy, and/or it is believed by the investigator to be in 
the best interest of the patient to discontinue (in consultation between the sponsor and 
investigator).  
6.1.5 
Study duration 
The study will continue until the last patient completes all required safety evaluations per 
protocol per extension stage of Phase II protocol.  


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6.2 
Dose escalation guidelines 
6.2.1 
Starting dose rationale 
In [CLBH589BUS32T], the established MTD of PANOBINOSTAT in patients with MF, was 
25mg PO TIW QW. PANOBINOSTAT has been tolerated up to a dose of 80mg TIW QW, 
but the majority of these patients will dose reduce due to toxicities [CLBH589B2102]. 
RUXOLITINIB has been tolerated up to doses of 50mg BID, but a minimum of 25% 
reduction in splenomegaly was seen in the majority of patients treated at 10mg BID, 15mg 
BID, and 25mg BID (Verstovsek 2010). From [INCB018424-251], 15mg BID was 
established as the most effective and safest starting dose, followed by individualized dose 
titration (Verstovsek 2010). 
As described in Section 2.4, there was synergistic anti-proliferative activity seen in a 
preclinical in vitro experiment (Wang 2009) when combining the JAK2 inhibitor TG101209 
and PANOBINOSTAT. This combination of agents was effective in attenuating mutant 
JAK2V617F, p-STAT3 and p-STAT5, especially when PANOBINOSTAT was combined 
with lower concentrations of TG101209. 
In the interest of patient safety, both of these compounds will start at dose levels below 50% 
of the respective maximum tolerated doses due to the potential overlapping toxicity with 
respect to thrombocytopenia, anemia and neutropenia. This was also determined to be an 
appropriate way to assess if a more biologically effective dose could be found prior to 
determining the MTD for this combination. As such the provisional doses are shown in 
Table 6-2. 
6.2.2 
Provisional dose levels 
The provisional dose escalation levels for RUXOLITINIB and PANOBINOSTAT are 
described in Table 6-2. Deviation from this provisional dose escalation plan is allowed if 
emerging data on toxicities and signals for activity are observed and are felt to be important to 
warrant modification of the provisional dose levels by the Investigators. It will be the 
responsibility of the Investigators to provide appropriate rationale and study data to justify 
deviation. Any planned deviation from the provisional dose escalation levels shown in Table 
6.2 will have to first be approved by the local IRB, FDA and Novartis. 


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Table 6-2    Dose escalation cohorts for combination therapy evaluable phase I study 
 
Cohorts 
1 
2 
3 
4a 
4b 
5 
6 
7 
RUXOLITINIB 
10mg 
PO  
BID 
10mg 
PO 
BID 
10mg 
PO 
BID 
15mg 
PO 
BID 
15mg 
PO 
BID 
15mg 
PO  
BID 
15mg 
PO  
BID 
15mg 
PO  
BID 
 
PANOBINOSTAT 
 
 
 
Cumulative 
dose/cycle 
10mg 
PO  
TIW 
QOW 
15mg 
PO 
 TIW 
QOW 
20mg 
PO  
TIW 
QOW 
15mg* 
PO 
TIW 
QOW 
20 
mg 
PO 
TIW 
QOW 
10mg 
PO 
 TIW 
QW 
15mg 
PO 
 TIW 
QW 
20mg 
PO  
TIW 
QW 
60mg 
90mg 
120mg 
90mg* 
120mg 
120mg 
180mg 
240mg 
*
6.2.3 
Criteria for dose escalation and determination of MTD and/or RPTD 
DOSE WILL DEPEND ON PREVIOUS COHORT AND WILL EITHER BE PANOBINOSTAT 10MG, 
15MG OR 20MG PO TIW QOW FOR A CUMULATIVE DOSE/CYCLE OF EITHER 60MG, 90MG, OR 
120MG 
A patient will be considered evaluable for the dose-determining set if he or she experiences a 
DLT during the combination phase days 1 to 28, or is observed for at least 28 days in the 
combination phase and is fully evaluated for any toxicities and has completed all study 
required tests. Patients who do not experience a DLT in the 28 days of the combination phase 
are considered evaluable if they have taken at least 50% of the RUXOLITINIB doses and not 
missed more than 1 dose of PANOBINOSTAT in the QOW dosing cohorts and no more than 
2 doses in the QW dosing cohorts.  
All available safety information (including DLTs, adverse events that are not DLTs, vital 
signs, and ECGs will be reviewed by the investigators in each cohort to decide if the next dose 
cohort will begin. Drug administration at the next dose level may not proceed until the 
investigators have documented it is safe to proceed to a higher dose level. Dose escalation will 
continue until identification of the MTD and/or RPTD is made.  


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The initial 3 cohorts will have RUXOLITINIB administered at a fixed dose of 10mg PO BID 
and cohort 1 will combine PANOBINOSTAT at a dose of 10mg PO TIW QOW, cohort 2 will 
be PANOBINOSTAT 15mg PO TIW QOW and cohort 3 will be PANOBINOSTAT 20mg 
PO TIW QOW for cumulative cycle doses of 60mg, 90mg and 120mg, respectively. If an 
MTD of PANOBINOSTAT is not established by cohort 3, then cohort 4a will test 
RUXOLITINIB at 15mg PO BID in combination with PANOBINOSTAT 15mg PO TIW 
QOW and 20mg PO TIW QOW in 4b. If an MTD of PANOBINOSTAT is established in the 
first 3 cohorts, then the cohort 4a will test RUXOLITINIB at 15mg PO BID in combination 
with PANOBINOSTAT at the dose level preceding the MTD dose level of 
PANOBINOSTAT. 
If the dose escalation of RUXOLITINIB continues to cohort 4b and this cohort does not 
define the MTD of RUXOLITINIB, then cohort 5 will allow patients to be treated at a dose of 
PANOBINOSTAT of 10mg PO TIW QW for a cumulative dose/cycle of 120mg. Cohorts 6 
and 7 will be pursued if the previous cohorts don’t reach MTD and will include 15mg PO BID 
of RUXOLITINIB and 15mg PO TIW QW and 20mg PO TIW QW, respectively.  
The RPTD of each agent will be determined by the MTD and the dose limiting toxicities 
observed in Phase I. The RPTD will not necessarily be the MTD doses reached in the Phase I 
dose escalation part of this study.  However, the RPTD will not exceed the estimated MTD 
dose of either drug as determined from the drugs given in combination in Phase I.  The 
decision to define the RPTD will ultimately be made by the PI and will be based on the 
toxicity profiles and in part any and all data on tolerability and efficacy of the combination 
therapy in the Phase I patients who remain on study drugs beyond the first cycle. 
6.2.3.1 
Definition of MTD 
The MTD is defined as the highest drug dosage not causing in the first cycle of treatment 
medically unacceptable, dose-limiting toxicity in more than 33% of the treated patients.  
6.2.3.2 Definition of RPTD 
If the evolving safety profile (long term or overall) along with other assessments suggest that 
further increases in dose will result in excessive toxicity, without substantial benefit in 
exposure/activity, the dose escalation phase of the study will be halted. The potential RPTD 
will be determined by a combination of the MTD determination in the Phase I and the 
tolerability and efficacy of PANOBINOSTAT and RUXOLITINIB in combination over 
multiple cycles in patients who remain receiving therapy beyond cycle 1. The rationale for 
this approach is based on the fact that although higher doses of PANOBINOSTAT may be 
tolerated, lower doses (or alterations in the treatment schedule) may be equally effective or 
even more effective in inducing chromatin modifying effects in the malignant cells while 
limiting both heme and non-heme toxicities. It is the hypothesis of the investigators based on 
the previous studies of PANOBINOSTAT in MF that lower doses of drug delivered over 
extended periods of time are most effective and most well tolerated.  


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6.2.4 
Dose cohort modification 
Provisional dose level cohorts are listed in Table 6-2. Possible changes in dose administration 
include but are not limited to: 
• Expansion of the current dose group to further assess safety 
• Administration of an intermediate dose between the current and preceding dose 
• Administration of an intermediate dose between the current and the next planned dose 
• Termination of any further escalation of study drug 
If there is less than the required number of evaluable patients, then additional patients will be 
enrolled until at least the minimum number of evaluable patients is available for assessment. 
6.2.5 
Definitions of dose limiting toxicities (DLTs) 
DLTs are listed in Table 6-3, and will be defined as all AEs of the specified grade occurring 
within Days 1-28 of the combination phase, unless clearly and incontrovertibly due to 
extraneous causes.. Table 6-3 was created using Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03. 
For the purpose of dose-escalation decisions, only DLTs occurring during the first 28 days of 
treatment with RUXOLITINIB and PANOBINOSTAT will considered and included in dose 
escalation decisions. However, all safety information including adverse events, ECG 
monitoring data, and vital sign abnormalities, will be included in the final decision for dose 
escalation and determination of how many patients should be evaluated at a given dose level.  
Thrombocytopenia will only be considered a DLT in the combination phase (Day 1-28) if the 
platelet count is recorded below 10,000/ul by manual count or ≥10,000/ul and associated with 
a grade 3 bleed. Phase I patients who require platelet transfusions within Days 1-28 will have 
to be removed from study. Patients are allowed to receive platelet transfusions after day 28 if 
clinically warranted, and this does not necessitate removal from study.  Transfusional support 
of red blood cells (RBC) is permissible at any point in the study and is not considered a DLT.  
In the event that an AE begins during the first 28 days of combination therapy, but does not 
qualify for the definition of a DLT at the time of the dose-escalation decision, due to a 
specific length requirement until Cycle 2; it will be provisionally considered a DLT during the 
decision-making process. Adverse events occurring after treatment day 28 will not be 
considered DLTs, however, they will guide the decision of dose escalation and how many 
patients will be evaluated at a given dose level. All AE’s, vital signs, and ECG data will be 
included in the final analysis to determine the MTD and/or RPTD. 


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Table 6-3 
Criteria for Defining Dose Limiting Toxicity (DLT) 
TOXICITY 
Any of the following criteria: 
Hematologic 
 Febrile Neutropenia 
≥Grade 3 (ANC < 1.0 x 109/L + Fever single reading >38.3°C or ≥38°C sustained 
>1 hr) 
 Thrombocytopenia 
<10 x 106/ul or ≥10 x106/ul associated with grade 3 bleeding 
Non-Hematologic 
Gastrointestinal 
 Vomiting 
≥Grade 3  
 Nausea 
≥Grade 3 nausea uncontrolled despite use of standard anti-emetics 
 Diarrhea 
≥Grade 3 Diarrhea  
Constitutional symptoms 
 Fatigue 
Grade 4 Fatigue 
Hepatobiliary 
 Bilirubin 
≥Grade 3, Coincident Direct Bilirubin ≥0.5mg/dl 
 AST/SGOT and/or 
 ALT/SGPT 
≥ Grade 3  
≥Grade 4 
Other 
Any Grade 3 non-hematologic toxicity : 
With the exception of: 
≥Grade 3 QTc prolongation (QTc > 500 ms), which is a DLT at any incidence 
 
Any Grade 4 non-hematologic toxicity 
Any of the following AEs, which when assessed as treatment related, will require patients to 
be permanently discontinued from study: 
• any grade ≥ 3 hemorrhagic event 
• 2nd
• grade 3 renal toxicity  
 episode of grade ≥3 febrile neutropenia 
• grade ≥ 3 QTc prolongation (QTc > 500 ms) 
• grade 4 renal toxicity 
• grade 4 serum bilirubin with direct bilirubin ≥ 0.5 mg/dL 
• grade 4 non-hematologic toxicity 
6.2.6 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed at least once a week for 4 weeks up to day 28. 
Patients whose treatment is interrupted or permanently discontinued due to an SAE, must be 
followed at least once a week for 4 weeks up to day 28, and subsequently at 4-week intervals, 
until resolution or stabilization of the event, whichever comes first. If a patient requires a dose 
delay for either drug for longer than 90 days from the intended day of the next scheduled 
dose, then the patient must be discontinued from the study. Hematology labs (CBC) and 
pertinent non-hematology labs will be part of the follow up procedures. ECG will also be part 
of the follow up procedures if the AE/SAE was cardiac related. 
All patients will be followed for AE’s and SAE’s for 30 days following the last dose of study 
treatment, with the exception of prolonged QTc.  


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6.2.7 
Dose modification and dose delay 
Transfusional support as clinically indicated is also permissible at the discretion of the 
investigators. 
 
Dose modification rules in Phase I cycles 2-6 (Day 29 - 168) and beyond cycle 7 (Day 169+) 
or any time in phase II are shown in Table 6.2.3 below. These are to be followed for patients 
in Phase I as well as Phase II expansion and extension stages.  Dose reductions (for 
PANOBINOSTAT) based on platelet count will be allowed and the dose of 
PANOBINOSTAT will not go below 5mg PO TIW QOW. See Table 6.2.1/6.2.2 for 
PANOBINOSTAT and RUXOLITINIB dose levels. The dose of RUXOLITINIB will not be 
reduced below 5mg PO BID. 
 
Based on the expected occurrence of thrombocytopenia in this patient population with the 
combination of these agents, we intend to submit a request for agency feedback form to 
update the safety data in terms of thrombocytopenia after 10 patients have been enrolled on 
this study. If the safety profile with the combination of PANOBINOSTAT and 
RUXOLITINIB is acceptable in terms of incidence of platelet count below 20 x 109/L and 
grade 3 or higher bleeding events, then we will continue the study with a threshold of 20 x 
109/L for dose holding/modification. If there is a single incidence of grade 3 or higher 
bleeding in association with a platelet count of <35 x 109
 
/L, then this threshold will be 
modified accordingly. This determination will be made after review by the FDA.  
Table 6.2.1  RUXOLITINIB dose levels for dose modifications in Cycles 2+ (day 29+) 
Dose level 
RUXOLITINIB 
Comment 
-1 
5mg PO BID 
Lowest dose allowed in the 
study 
0 
10mg PO BID 
Starting dose in induction phase 
for all patients on study 
1 
15mg PO BID 
Starting dose for cohort 4a, 4b 
 
 
 
 
 
 
 


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Table 6.2.2 PANOBINOSTAT dose levels for dose modifications in Cycles 2+ (day 29+) 
Dose level 
PANOBINOSTAT 
Cumulative dose 
(per cycle) 
Comment 
-1 
5mg PO TIW 
QOW 
30mg 
Lowest allowable dose 
on the study 
0 
10mg PO TIW 
QOW 
60mg 
Starting dose of cohort 1 
1 
15mg PO TIW 
QOW  
90mg 
Starting dose for cohort 
2, 4a 
2 
20mg PO TIW 
QOW 
120mg 
Starting dose for cohort 
3, 4b 
3 
10mg PO TIW 
QW 
120mg 
Starting dose for cohort 
5 
4 
15mg PO TIW 
QW 
180mg 
Starting dose for cohort 
6 
5 
20mg PO TIW 
QW 
240mg 
Maximum dose allowed 
in study 
 
Dose modifications or interruptions for adverse events occurring during the DLT-definition 
period (Cycle 1 Day 1 through Cycle 1 Day 28 of Phase I), and considered as treatment-
related will not be allowed. This would require removal of a patient with a DLT within Day 1-
28 of Phase I.  
Beginning in cycle 2 (day 29), patients who do not tolerate the protocol-specified dosing 
schedule are permitted to dose adjust in order to allow the patient to continue the study 
treatment. Tables 6.2.1 and 6.2.2 outline the possible dose level reductions permitted 
depending on the current dose of each drug at the time of the AE. Patients who experience 
toxicity at either a dose of RUXOLOTINIB at 5mg PO BID or PANOBINOSTAT at 5mg PO 
TIW QOW cannot be dose reduced further and will be removed from study. Table 6.2.3 and 
Table 6-4 provide instruction on management per toxicity. All dose modifications should be 
based on the worst preceding toxicity (CTCAE version 4.0). Patients who require dose hold of 
RUXOLITINIB are allowed to receive steroids (prednisone, dexamthesone, etc) as per the 
Investigators discretion to avoid or blunt potential RUXOLITINIB-withdrawal syndrome.  
All adverse events should be treated as per the local standard of care and referred to a 
specialist if clinically indicated. Investigators can use their discretion when making dose-
reduction decisions unless otherwise specified in the guidelines below.  


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If at any time during the study period the use of a strong CYP3A4 inhibitor becomes 
necessary to treat the patient, a dose modification for RUXOLITINIB is necessary. See 
Section 6.3 for permitted or prohibited concomitant medications for this study. Also see 
Section 6.3.4 for dose modification schema for RUXOLITINIB. 
Table 6.2.3 
Criteria for dose modifications of RUXOLITINIB and PANOBINOSTAT due 
to study drug-related toxicity from Day 29 and beyond in Phase I or anytime 
in Phase II (see Table 6-6 for QT prolongation dose management) 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
HEMATOLOGICAL TOXICITIES 
Thrombocytopenia 
< 20 x 109
Interrupt study treatment dosing until 
resolved to ≥ 20 x 10
/L 
9/L, then restart 
study treatment at reduced level as per 
Table 6.2.1/6.2.2. 
> 20 x 109
Interrupt study treatment dosing until 
bleeding is resolved and platelet count 
is at level before bleed was noted, then 
resume study treatment at reduced 
level as per Table 6.2.1/6.2.2 
/L + grade 3 bleed 
Neutropenia (ANC) 
Grade 4 (ANC < 0.5 x 109
Interrupt study treatment dosing until 
resolved to ≤ grade 2, or baseline, 
then: 
/L) 
• 
If resolved within 7 days restart 
study treatment at an unchanged 
dose level 
• 
If resolved in more than 7 days 
then restart study treatment at 
reduced level as per Table 
6.2.1/6.2.2. 
Febrile neutropenia 
(ANC < 1.0 x 109
Interrupt study treatment dosing until 
fever resolved and ANC ≤ grade 2, 
then restart study treatment at reduced 
level as per Table 6.2.1/6.2.2 
/L, fever ≥ 
38.5°C) 
Anemia#
only requires dose 
reductions after cycle 6 
(day 169+) 
  
Doubling of transfusion 
frequency from baseline or 
hemoglobin 2g/dL below 
baseline (screening period) 
Hold PANOBONISTAT only and 
continue RUXOLITINIB, if hemoglobin 
(or transfusion frequency) returns to 
baseline within 28 days restart 
PANOBINOSTAT at same dose, if this 
recurs again then reduce dose as pre 
TABLE 6.2.1/6.2.2 
NON-HEMATOLOGICAL TOXICITIES 
CARDIAC 
Cardiac - Prolonged QT interval** 
Please refer to Table 6-6, Section 6.2.8 
and Section 7.2.7. 


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Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
GASTROINTESTINAL 
Diarrhea 
Grade 2 (4-6 stools/day over 
baseline, etc) despite the use 
of optimal anti-diarrheal 
medications 
Hold PANOBINOSTAT dosing until 
resolved to ≤ grade 1, or baseline, then 
restart at unchanged dose level 
Grade 3 (≥ 7 stools/day over 
baseline, etc) despite the use 
of optimal antidiarrheal 
medications 
Hold PANOBINOSTAT dosing until 
resolved to ≤ grade 1, or baseline, then 
restart study treatment at reduced level 
as per Table 6.2.2 
Grade 4 (life-threatening 
consequences, hemodynamic 
collapse, etc) despite the use 
of optimal antidiarrheal 
medications 
Permanently discontinue study 
treatment dosing 
Vomiting/Nausea*** 
Grade 1 & 2 not requiring 
treatment or controlled using 
standard anti-emetics 
Maintain dose level 
Grade 3 or 4 vomiting or Grade 
3 nausea that cannot be 
controlled despite the use of 
standard anti-emetics 
Interrupt study treatment dosing until 
resolved to ≤ grade 1, or baseline, then 
restart study treatment at reduced level 
as per Table 6.2.1/6.2.2 
Fatigue 
Fatigue 
Grade 3 
Hold PANOBINOSTAT dosing until 
resolved to ≤ grade 2, or baseline, 
then: 
• 
If resolved within 7 days after 
suspending study treatment, then 
restart at unchanged dose level 
• 
If resolved in more than 7 days 
after suspending study treatment, 
then restart study treatment at 
reduced level as per Table 
6.2.1/6.2.2 
HEPATIC 
Total Bilirubin 
Grade 3 or 4 
Interrupt study treatment dosing until 
resolved to ≤ grade 2, or baseline, then 
restart study treatment at reduced level 
as per Table 6.2.1/6.2.2 
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to the indirect component only, and hemolysis 
as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood 
smear and haptoglobin determination), then reduction of one dose level and continuation of treatment 
is at the discretion of the Investigator. 


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Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
AST/SGOT, ALT/SGPT 
> 5-10 x ULN 
Interrupt study treatment dosing until 
resolved to ≤ grade 1 (or ≤ grade 2 if 
liver infiltration with tumor is present), 
or baseline, then: 
• 
If resolved within 7 days, then: 
• 
restart study treatment at 
unchanged dose level 
• 
If resolved in more than 7 days, 
then restart study treatment at 
reduced level as per Table 
6.2.1/6.2.2. 
> 10 x ULN 
Interrupt study treatment dosing until 
resolved to ≤ grade 1, or baseline, 
then: 
• 
restart study treatment at reduced 
level as per Table 6.2.1/6.2.2. 
All dose modifications should be based on the worst preceding toxicity. 
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.0) 
** It is critical that electrolyte abnormalities be followed closely and corrected prior to dosing 
*** See also concomitant medication Section 6.3. 
#Management of anemia 
Prior experience with RUXOLITINIB and PANOBINOSTAT as single agents in patients with 
myelofibrosis suggest that worsening anemia can be treated with PRBC transfusions, and will 
eventually resolve within 4-6 months without other interventions (LBH589BUS58, LBH589BUS32T). 
Interestingly, the decrease in spleen size observed in the PANOBINOSTAT responders was 
accompanied by increases in hemoglobin by at least 2 g/dL (LBH589BUS58). 
Dose modifications specifically for anemia should be implemented after cycle 6 if the rate of 
transfusion has significantly increased, and continues without improvement as compared to baseline. 
Following day 168, patients can be placed in dose hold of the PANOBINOSTAT (up to 28 days) to 
allow for hemoglobin to return to baseline, after which the study treatment should then be resumed at 
the same level. If after resumption of PANOBINOSTAT, worsening anemia recurs, then dose 
modifications according to Table 6.2.1/6.2.2 will be followed. 
If after holding PANOBINOSTAT for 28 days the patient’s hemoglobin has not returned to baseline, 
but attained a clinically acceptable hemoglobin level, dose modifications according to Tables 
6.2.1/6.2.2 can be followed. If after a dose hold of study treatment for 28 days a clinically acceptable 
hemoglobin value has not been reached the patient must be discontinued from study treatment.  
 
 
If a patient experiences new (or treatment emergent) grade 2 non-hematologic adverse 
event(s) considered at least possibly related to study treatment, and which the patient finds 
intolerable or in the Investigator’s judgment is/are not acceptable, treatment should be held 


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until the adverse event(s) resolves to 
≤ CTCAE g rad e 1 .  Stu dy treatmen t may then  be 
restarted at the same dose and schedule. If the same intolerable grade 2 adverse event(s) 
occurs again, study treatment should again be temporarily discontinued until the toxicity 
resolves to ≤ CTCAE grade 1. Study treatment should then be restarted at a reduced dose level 
as per Tables 6.2.1/6.2.2. At the discretion of the Investigator, patients with grade ≥ 2 adverse 
events of major organs (e.g., heart, lungs, CNS) may be discontinued from further study 
therapy without being retreated with a dose reduction. 
6.2.7.1 
Dose modifications for Grade 3 or 4 non-hematologic toxicity 
Patients experiencing new (or treatment emergent) CTCAE grade 3 or 4 non-hematologic AEs 
not listed in Table 6.2.3, should have their treatment temporarily discontinued until the 
adverse event resolves to ≤ CTCAE grade 1 or baseline. If the AE was considered related to 
study treatment, the drug should then be restarted at reduced level according to Table 
6.2.1/.2.2. If the AE was considered not related to study treatment, then therapy may be 
restarted (when the AE resolves to ≤ grade 1 or baseline) at the current dose. 
6.2.8 
Dose modifications for prolonged QTc interval 
All cardiac events should be treated as per the local standard of care and referred to a 
specialist if clinically indicated. Any final decision concerning dose modifications or 
permanent discontinuation of the patient from study drug due to QTc prolongation will be 
based on the assessment of the Investigator. If a patient cannot be dosed due to prolonged 
QTc for more than 7 days since last dose, the patient should be discontinued from study. See 
Table 6-4 for further details on criteria for dose delays, dose reductions, and re-initiation of 
study treatment for drug related QTc abnormalities. 


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Table 6-4 
Criteria for dose delays, dose reductions, and re-initiation of treatment 
due to study drug related QTc abnormalities* 
ECGs to be 
performed at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy (including 
intended day of dosing) 
Pre-Dose Combination phase day 1 (triplicate ECGs only) 
Pre-dose in cycle 1, 
Day 1 : 
3 ECGs separated 
by 5-10 minutes, 
obtained prior to  
dosing 
One of the three ECGs 
obtained shows QTc > 
500 msec 
 
Check and correct the patient’s serum potassium, 
magnesium and calcium immediately, as well as 
evaluate con-meds.. 
Delay PANOBINOSTAT dose at least 3 days and 
repeat ECGs in triplicate. 
If the 3 ECGs: 
QTc > 500 msec, discontinue patient from study. 
 
Post-Dose Combination phase day 1 and Subsequent Cycles (triplicate ECG only) 
3 hr Post-Dose: 
triplicate ECGs 
Cycle 1, Day 1, 5, 8, 
15, 22 
 
Cycle 2  Day 1 (Day 
29) and beyond 
One of the three ECGs 
obtained shows QTc > 
500 msec 
OR 
QTc increased > 60 
msec compared to 
baseline. 
Check and correct the patient’s serum potassium, 
magnesium and calcium immediately, as well as 
evaluate con-meds. 
Monitor ECG hourly or by telemetry until at least 2 
consecutive hourly ECGs performed at least 3 hours 
post dose are <500. 
If any ECG has QTc > 500 msec. discontinue patient 
from study. 
* If there are no additional procedures to be carried out on the day, arrangements may be made such 
that the ECGs may be performed at their local physician’s office near the patient’s home and 
transmitted to the site investigator or responsible delegate in a timely manner. ECGs done outside the 
MSSM MPD clinic are only permitted day 29 and beyond. 
6.2.9 
Dose escalation 
 
Dose escalation post-toxicity after cycle 2 (Day 29) 
Patients who have experienced treatment-related ≥ grade 3 toxicity of any nature aside from 
thrombocytopenia, or grade 4 thrombocytopenia may not dose re-escalate nor return to the 
dose level for which this toxicity was encountered. 
At the discretion of the Investigator, a patient may undergo dose re-escalation if it is felt to be 
in the best interest of the patient, and they have met the criteria as outlined in Section 6.2.6, 
6.2.7, or 6.2.8 depending on the toxicity.  For patients who undergo dose re-escalation, 
platelet counts must be obtained at least weekly for 4 weeks, and then at least every second 
week for the next 4 weeks. Thereafter, they may resume monthly evaluations.  
Patients may continue treatment with RUXOLITINIB and PANOBINOSTAT until they 
experience unacceptable toxicity that precludes any further treatment, disease progression, 
and/or at the discretion of the Investigator. Patients will be discontinued from the study if they 
withdraw consent, or if the treating physician judges that further therapy with RUXOLITINIB 
and PANOBINOSTAT is no longer in the patient’s best interest. 


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6.2.9.1 
Intra-patient dose escalation Post MTD and/or RPTD determination 
(non-toxicity related) 
Intra-patient dose escalation may be permitted by the Investigator following 13 patients 
treated for at least 2 cycles at the RPTD. During the course of study treatment, patients can be 
dose-escalated to the next higher dose level only once every two cycles, provided that ALL of 
the following criteria are met: 
• Inadequate efficacy is seen with the current dose level, as defined by the observation of 
one or both of the following: 
• Not achieving at least a 50% reduction in palpable spleen length compared to baseline 
• Lack of meaningful improvement in disease symptoms based on the Investigator’s 
expert judgment 
• No treatment related toxicity has occurred with the current dose level, resulting in 
treatment reduction or interruption or discontinuation in the previous 56 days 
• The higher dose with which the patient is to be treated does not exceed the MTD and/or 
RPTD 
• Platelet counts must be obtained at least weekly for 4 weeks, and then at least every 
second week for the next 4 weeks after escalation. Thereafter, they may resume monthly 
evaluations. 
There is no limit to the number of times the study drug may be increased for each patient, 
provided the above rules are followed for each subsequent dose escalation. The same rules for 
dose reductions as outlined in Section 6.2.7 apply to these patients. 
The rules for intra-patient dose escalation described above apply only to those patients who 
have undergone one and only one dose reduction. Once a patient undergoes a dose reduction 
due to treatment-related toxicity, the patient may not have a dose increase unless they have 
been on a stable dose for at least 28 days with no dose interruptions. 
 
6.2.10 
Optional dose tapering strategy for RUXOLITINIB in the event of 
discontinuation 
When RUXOLITINIB therapy is stopped, the return of constitutional symptoms associated 
with elevated cytokines (e.g. night sweats, fever, fatigue) that had been suppressed while on 
therapy is expected. When a decision is made to permanently discontinue RUXOLITINIB 
therapy for reasons other than hematologic safety, a dose tapering strategy may be considered, 
based on evaluation of the condition of the patient, current dosing regimen and the clinical 
judgment of the Investigator, so that symptoms may return to pre-treatment condition more 
slowly. If considered to be medically necessary, the Investigator may use any treatment to 
manage withdrawal from RUXOLITINIB including gradual tapering of the study drug dosage 
or use of other medications to manage events occurring after discontinuation. Short-term 
course of corticosteroids at doses > 10mg/day have been used in patients with MF and may be 
considered as part of a tapering strategy. Corticosteroids may be started prior to, or concurrent 
with, RUXOLITINIB tapering. When a decision has been made to discontinue the patient 
utilizing a tapering strategy, regardless of the use of concomitant medications, safety data will 


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continue to be assessed in accordance with the protocol for a period of times at least through 
the continued administration of RUXOLITINIB and 30 days after for AEs. 
6.2.11 
Management of diarrhea 
Patients should be instructed to contact their physician at the onset of diarrhea. Each patient 
should be instructed to have loperamide readily available and to begin treatment for diarrhea 
at the first episode of poorly formed or loose stools or the earliest onset of bowel movements 
more frequent than normally expected for the patient. 
Loperamide 4 mg should be taken at the first loose stool or more frequent than usual bowel 
movements, followed by 2 mg as needed, no more frequently than every 4 hours, not to 
exceed a total of 16 mg in 24 hours. Patients with diarrhea ≥ grade 2 despite this l operamide 
regimen should interrupt study treatment as described in Table 6.2.3. If the above regimen is 
inadequate then additional evaluation and treatment should be pursued as medically indicated. 
Replacement i.v. fluids and electrolytes may be used as appropriate. Additional treatment 
should be provided in accordance with institutional standard of care and/or local guidelines. 
Premedication with loperamide is not recommended. 
The use of drugs with laxative properties should be avoided because of the potential for 
exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any 
laxative use. 
6.3 
Concomitant medications 
6.3.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy and blood transfusions) administered during 
the study must be recorded in source documents and eCRFs.  
6.3.2 
Permitted concomitant therapy requiring caution and/or action 
The following medications have restrictions on use or doses or required changes to the way in 
which RUXOLITINIB and/or PANOBINOSTAT is administered during the study: 
• Systemic corticosteroid doses greater than the equivalent of 10 mg of prednisolone per day 
are not permitted, unless use is part of a RUXOLITINIB dose tapering strategy (Section 
6.2.10) as this may impact splenic size and cytokine reduction and interfere with the 
ability to assess the clinical activity of this combination of agents in this patient 
population. 
• In patients for whom low molecular weight heparin use will be initiated, the degree of 
thrombocytopenia should be considered, coagulation parameters monitored, and dose of 
anti-coagulant adjusted accordingly. 
• During the study, concomitant use of strong CYP3A4/5 inhibitors is strongly discouraged. 
However, when such a concomitant administration of a strong systemic CYP3A4 inhibitor 
(see Appendix 1 for a listing of these medications) is required for patient management, the 


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dose of RUXOLITINIB must be adjusted as described in Section 6.3.4. However, there is 
no dose adjustment of PANOBINOSTAT proposed. 
• During the study, the use of moderate CYP3A4 inducers (e.g. bosentan, efavirenz, 
etravirine, modafinil, nafcillin, ritonavir, talviraline, tipranavir) is discouraged, and 
investigators should seek alternatives where possible. No dose adjustments are needed 
when moderate CYP3A4 inducers are co-administered with study treatment. However, 
any concomitant use of moderate CYP3A4 inducers must be documented. See Appendix 1 
for a listing of these medications. 
• During the study, concomitant use of medications which are known CYP2D6 substrates 
are to be used with caution. See Appendix 1 for a list of these medications. 
• Granulocyte growth factors (G-CSF) are not allowed while study medication is being 
administered but may be used for severe neutropenia at the Investigator’s discretion while 
study medication is being withheld. 
6.3.3 
Prohibited concomitant therapy 
The following medications are prohibited during the study: 
• Any investigational medication (other than PANOBINOSTAT) that is not approved for 
any indication. Use of such medications within 30 days, prior to the first dose of study 
drug and during the study through the Safety Follow-up Visit is prohibited. 
• Use of strong inducers of CYP3A4 (e.g. avasimibe, carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, St. John's wort) is not permitted at any time during the 
study. (See Appendix 1 for further details) 
• Patients who are currently receiving treatment with any of the medications which have a 
relative risk of prolonging the QT interval or inducing Torsades de Pointes and cannot 
either discontinue this treatment or switch to a different medication prior to study 
enrollment, will be excluded from the study. Patients may not begin treatment with any of 
the medications while receiving study treatment unless approval is given by the 
Investigators to temporarily discontinue study treatment during administration with these 
drugs. Should a patient already enrolled on this study require short-term (i.e. 
approximately ≤ 2 weeks) treatment with these drugs, study treatment must be interrupted 
for at least 72 hours prior to starting these drugs and should not resume until at least 72 
hours after the last dose of such a drug or longer (i.e. 5 half-lives) as listed. 
• Any use of drugs that interferes with coagulation or inhibits platelet function (including 
non-steroidal anti-inflammatory drugs), with the exception of: 
• Aspirin ≤ 81 mg/day 
• LMWH, direct thrombin inhibitors, anti-10a inhibitors as long as INR remains less 
than 1.5 
• Any other medication for the treatment of myelofibrosis, including but not limited to: 
• Hydroxyurea 
• Busulfan 
• Interferon 
• Lenalidomide 


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• Thalidomide 
• Anagrelide 
• Any hematopoietic growth factor receptor agonists (including but not limited to: 
erythropoietin, romiplostim, or eltrombopag). The use of G-CSF can be used as discussed 
in Section 6.3.2. 
6.3.4 
Dose reduction of RUXOLITINIB for concomitant strong CYP3A 
inhibitor usage 
RUXOLITINIB is metabolized in the liver by the cytochrome (CYP) P450 metabolizing 
enzyme system, predominantly by the 3A4 isozyme. With concomitant dosing of strong 
CYP3A4 inhibitors such as systemic ketoconazole clarithromycin, itraconazole, nefazodone 
and telithromycin (Appendix 1), plasma exposure of RUXOLITINIB increases approximately 
2-fold. Patients under therapy with a strong CYP3A4 inhibitor cannot be enrolled in the study. 
Use of strong CYP3A4 inhibitors during Cycle 1 of the study is prohibited. Use of strong 
CYP3A4 inhibitors after Cycle 1 Day 28 is strongly discouraged, and investigators should 
consider alternative therapies wherever possible. However, if the use of a strong CYP3A4 
inhibitor is necessary for the sake of patient’s safety, then a dose reduction of ~ 50% for 
RUXOLITINIB is mandatory. The following dose-reduction rules must be followed: 
• If dose is 5 mg bid., change dose to 5 mg qday 
• If dose is 10 mg bid., change dose to 10 mg qday 
• If dose is 15 mg bid., change dose to 15 mg qday 
NOTE: once the course of therapy using a CYP3A4 inhibitor has been completed, the patient 
may resume his/her prior dose level of RUXOLITINIB beginning the next day. 
6.4 
Patient numbering, treatment assignment and randomization 
6.4.1 
Patient numbering 
Each patient is uniquely identified in the study by a unique patient number (001, 002, etc), 
that is assigned when the patient is first enrolled for screening and is retained as the primary 
identifier for the patient throughout his/her entire participation in the trial. Upon signing the 
informed consent form, the patient is assigned to the next available sequential patient number. 
Once a number is assigned, it cannot be reused for any other patient and the patient number 
for that individual must not be changed, even if the patient is re-screened. 
If patient signed informed consent but fails to start the study treatment, the reason will be 
entered into the Screening Log eCRF page. 
6.4.2 
Treatment assignment and randomization 
The assignment of a patient to a particular cohort will be coordinated by the investigator. 
6.4.3 
Treatment blinding and Randomization 
Not applicable 


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6.5 
Study drug supply 
6.5.1 
Study drug preparation and dispensation 
Both 
RUXOLITINIB 
and PANOBINOSTAT 
capsules 
including 
instructions for 
administration, will be dispensed by site study personnel on an outpatient basis. Patients will 
be provided with adequate supply of study drug for self-administration at home until at least 
their next scheduled study visit. 
6.5.2 
Study drug packaging and labeling 
The investigators at MSSM will be supplied with oral PANOBINOSTAT and oral 
RUXOLITINIB by Novartis. The packaging will contain a 2-part label. Immediately before 
dispensing study drug to the patient, authorized clinical site staff member will detach the outer 
part of the label from the packaging and affix it to the source document (Drug Label Form) 
containing the patient’s unique patient number. Medication labels will comply with the legal 
requirements of the United States. The storage conditions for study drug will be described on 
the medication label. 
As with all anti-cancer drugs, their preparation and administration should be closely 
supervised by a qualified physician (Study Investigator) experienced in the use of cancer 
chemotherapeutic agents. 
RUXOLITINIB 
RUXOLITINIB tablets will be provided in bottles. Medication labels will be in the local 
language and comply with the legal requirements of each country. They will also include 
storage conditions for the drug. 
PANOBINOSTAT 
Oral PANOBINOSTAT will be supplied as 5-mg, 10-mg (when available), or 20-mg hard 
gelatin capsules and will be given on a flat scale of mg on a given day. The capsules are 
packaged in HDPE bottles with plastic child resistant closures. 
Store in very tight packaging (water permeation <0-5ng/day/L) at 15⁰C to 30⁰C (room 
temperature) and protect from light. 
6.5.3 
Drug supply and storage 
Study treatments must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels. 


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6.5.4 
Study drug compliance and accountability 
6.5.4.1 
Study drug compliance 
Dosing frequency and compliance will be assessed by the investigator and/or study personnel 
at each patient visit and information provided by the patient and/or caregiver will be captured 
in the Drug Accountability Form. This information must be captured in the source document 
at each patient visit. 
6.5.4.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability ledger. Drug accountability will be noted by the 
field monitor during site visits and at the completion of the study. Patients will be asked to 
return all unused study treatment and packaging on a regular basis, at the end of the study or 
at the time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability ledger to the the Pharmacy at MSSM. 
6.5.5 
Disposal and destruction 
The drug supply can be destroyed at the local Novartis facility, Drug Supply group or third 
party, as appropriate. 
7 
Visit schedule and assessments 
7.1 
Visit schedule 
Appendix 2 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation and data will be captured in the e-CRF.  


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7.1.1 
Pre-screening assessments 
Not applicable 
7.1.2 
Screening 
Below is a brief description of the screening tests/procedures for this protocol. The screening 
window is 56 days. The informed consent must be signed prior to any screening procedure. 
For details of assessments, refer to Appendix 2. 
• Inclusion/Exclusion 
• Demographics 
• Relevant medical history / Current Medical Conditions 
• Myelofibrosis (MF) disease history 
• Diagnosis of PMF, PPV MF and PET-MF 
• Prior and current concomitant medications and Significant non-drug therapies 
• Transfusion history 
• Physical Examination 
• Vital signs, Weight and Height 
• ECOG 
• 12-Lead ECG 
• ECHO or MUGA 
• Chest X Ray PA/Lat 
• Biomarkers (blood for genomic, epigenomic and cellular studies) 
• Buccal swab 
• Cytokine profile 
• Measurement of spleen by palpation in craniocaudal length 
• MRI/CT of spleen  
• Laboratory Safety Tests including the following: Hematology, Biochemistry, Coagulation, 
Thyroid, Urinalysis and serum Pregnancy, quantitative JAK2V617F and/or MPL, 
cytogenetics 
• Bone Marrow biopsy/aspirate  (should be done at screening but if a specimen is available 
within 3 months of screening and the patient has not had any MF-directed therapy during 
this period, a biopsy during the screening period can be omitted) 
• MPN-SAF 
7.1.2.1 
Eligibility screening 
Patients must meet all inclusion and exclusion criteria at Screening in order to be eligible for 
the study. Patient eligibility will be confirmed by the investigative staff and captured within 
the source documents maintained at the site. Only when eligibility is confirmed will the 
patient be assigned to a dose level. The Primary Investigator/co-investigators must approve 
eligibility and will assign the patient to the appropriate dose level.  


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7.1.2.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on 
the Screening Log. The demographic information must also be completed for Screen Failure 
patients. No other data will be entered into the clinical database for patients who are screen 
failures. If a patient experiences a Serious Adverse Event during the Screening Phase it will 
be captured in the source documents and eCRF but the patient will not be considered as 
evaluable within the dose cohort level and this data will not contribute to dose escalation 
decisions. 
7.1.2.3 
Patient demographics and other baseline characteristics 
At the screening visit, the following data should be collected/evaluated and recorded on the 
appropriate eCRF: 
• Complete demographic information (age, gender, race, body weight, and height) 
• Complete medical (including MF) history 
• Medication history (prior and concomitant, including those used to treat MF) 
• Prior JAK2V617F mutational status (if available before the signature of the Informed 
Consent Form) or any other MPN molecular marker  
• Review of Packed Red Blood Cells (PRBC) transfusion history (for the last 12 weeks 
prior to Screening). 
• Adverse Events 
• Eastern Cooperative Oncology Group (ECOG) status 
• Pregnancy test performed and prevention methods will be discussed 
• Spleen length below the left costal margin by palpation 
• Vital signs (blood pressure, pulse, respiratory rate and body temperature) 
• 12-lead electrocardiogram (ECG) 
• Complete physical examination 
• Buccal swab for germline DNA banking  
• Clinical laboratory tests (Biochemistry panel, hematology, and coagulation tests, 
urinalysis, TSH and fT4) 
• Cytokine profile sample 
• Chest X ray 
• MPN-SAF 
All medications and significant non-drug therapies (e.g. herbs) taken within 14 days before 
the first dose is administered must be recorded updated on a continual basis if there are any 
new changes to the medications. Medications include physician prescribed and over-the-
counter medications, as well as vitamins and herbal and alternative therapies. Information to 
be collected on concomitant medications/significant non-drug therapies will include the 
following: 
• Medication/Non-drug therapy trade name 


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• Reason for medication 
• Start date and end date or continuing at time of exam 
In addition to the general demographic and relevant medical history information, study 
specific information will be collected during the screening period as indicated in the 
assessment schedule (Appendix 2) in order to determine eligibility of the patient. 
7.1.3 
Run-in period 
Not applicable 
7.1.4 
Treatment period 
7.1.4.1 
Cycles 1-6 [core study period] 
Patients may continue study treatment through the first 6 cycles, unless they progress, 
withdraw consent, experience intolerable toxicity, start new MF therapy, and/or based on 
investigator discretion, it is believed to be in the best interest of the patient to discontinue. 
Cycle 1 will be the dose evaluation period for those patients enrolled in the phase I portion of 
the study and can continue on to complete the 6 cycles of therapy if they did not experience a 
DLT.  
7.1.4.2 
Cycle 7+ (Day 169+) [extension phase] 
Following the completion of the first 6 cycles, the patient may continue study onto if they are 
continuing to receive clinical benefit and the investigator believes it is in the best interest of 
the patient. After 24 cycles, stable patients may be seen every other month at the discretion of 
the investigator. Assessment by IWG-MRT response criteria will be applied to determine the 
patient has achieved at least Stable Disease (SD) and therefore is eligible for continued 
therapy. Refer to Table 4-1. 
7.1.5 
End of treatment visit, including premature withdrawal and study 
discontinuation visit 
Patients who discontinue study treatment should be scheduled for an end of treatment visit, at 
least 30 days post-last dose of treatment. 30 day post last dose, end of study visit will include: 
history, physical exam, Hematology, Biochemistry, and ECG. An End of Treatment Phase 
Disposition eCRF page should be completed, giving the date and reason for stopping the 
study treatment. At a minimum, all patients who discontinue study treatment, including those 
who refuse to return for a final visit, will be contacted for safety evaluations during the 30 
days following the last dose of study treatment. 
For criteria for premature withdrawal refer to Section 7.1.5.1. 
7.1.5.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be removed at the discretion of the 
investigator at any time. If such withdrawal occurs, or if the patient fails to return for visits, 
the investigator must determine the primary reason for a patient’s premature withdrawal from 


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the study and record this information on the appropriate eCRF. Patients may be withdrawn 
from the study prematurely for one of the following reasons: 
• Adverse event(s) 
• Abnormal laboratory value(s) 
• Abnormal test procedure result(s) 
• Protocol deviation 
• Subject withdrew consent 
• Lost to follow-up 
• Administrative problems 
• Death 
• Initiation of new cancer therapy 
• Disease progression 
• The investigator determines that further therapy is not in the patient’s best interest (e.g., 
due to non-compliance, toxicity etc.). 
Patients who experience disease progression, start of new anti-cancer therapy, or withdraw 
consent, must be permanently discontinued from the study. 
For patients who are lost to follow-up, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g., dates of 
telephone calls, registered letters, etc. 
Patients must be followed for 30-days post-last treatment of study drug. 
7.1.5.2 
Replacement policy 
Patients prematurely withdrawn from the study will not be replaced, however in the phase I 
portion of this study, from Cycle 1 Day 1 through Day 28, a patient misses more than 11 oral 
administrations of RUXOLITINIB or more than 1 dose of PANOBINOSTAT in QOW dosing 
or 2 doses in the QW dosing, the patient can continue in the study without being evaluable for 
DLTs. Consequently an additional patient may be added to the same dose level in order to 
reach the required number of patients in the cohort. See Section 10.4.3 for specific details. 
7.1.6 
Follow up period 
All patients must have safety evaluations for 30 days after the last dose of study treatment. In 
addition, all patients must be followed for the occurrence of Adverse Events and Serious 
Adverse Events for 30 days after the last dose of study drug. Once an Adverse Event or a 
Serious Adverse Event is detected, it should be followed until its resolution or until it is 
judged to be permanent.  
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the Investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 


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7.2 
Assessment types 
7.2.1 
Disease progression 
Disease progression will be documented by a > 25% increase in spleen length by palpation 
compared to the on-study nadir or by disease symptoms progression based on the 
Investigator’s expert judgment or by a significant increase in blood or bone marrow blasts 
consistently for at least 2 weeks that in the expert opinion of the Investigators indicates 
progression of disease. Bone marrow biopsies are not required to document progression, 
however may be performed as clinically indicated and at the discretion of the investigator. If 
performed, findings should be documented in the eCRF. 
7.2.2 
Efficacy assessments 
Efficacy, beyond clinical response assessment by IWG-MRT, is an exploratory endpoint in 
this study. 
7.2.2.1 
Splenic palpation 
This assessment will consist of measurement of the spleen length by manual palpation at the 
end of Cycle 6 (Study Day 169) in comparison to the Cycle1 Day 1 measurement or by 
change in volume by MRI/CT (see section 7.2.2.3). Patients who have a ≥ 50% reduction in 
spleen length by palpation compared to the initial measurement at Cycle 1 Day 1 will be 
considered as responders, otherwise they will be considered non-responders by IWG-MRT 
criteria. Spleen length measurements will be conducted at the start of every cycle in order to 
exclude disease progression, which is a criterion for premature patient withdrawal (see 
Section 7.1.5.1). 
The edge of the spleen shall be determined by palpation, and measured in centimeters, from 
the costal margin to the point of greatest splenic protrusion. 
7.2.2.2 
Disease symptom assessments/MPN-SAF 
Evaluation of constitutional symptoms (weight loss >10% of the baseline value in the year 
preceding C1D1, unexplained fever, or excessive night sweats persisting for more than 1 
month) should be performed at baseline, and the start of every cycle. The MPN-SAF validated 
symptom assessment tool questionnaire will be used to gauge baseline MF symptoms and 
changes in symptoms with treatment. See Appendix 3.  
7.2.2.3 
MRI/CT 
MRI or CT will be performed for the purpose of measuring spleen volume. This will be 
performed at baseline (screening), C4D1 +/- 1 week, and C6D29/C7D1 +/- 1 week, or when 
possible when the patient permanently discontinues study treatment, whichever comes first. 
Patients achieving a 35% reduction in splenic volume will be considered responders, 
otherwise they will be considered non-responders. These patients will also continue to be 
assessed by physician palpation of splenic length at the start of each cycle. MRI is the 
preferred method for obtaining spleen volume data, however, CT scans may be performed at 
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is unavailable. The imaging modality used at baseline (MRI or CT) to assess spleen volume 
should be kept constant throughout the trial period for a given patient, unless a new 
contraindication to the use of MRI occurs.  
7.2.2.4 
Bone marrow biopsy  
The bone marrow biopsy and aspirate should be collected, processed, stained, and assessed by 
an experienced hematopathologist using his/her Institutional standards. Bone marrow fibrosis 
should be graded using the European consensus grading system (Tefferi 2006). 
The bone marrow biopsy and/or aspirate will be collected at screening and C6D29 (+/- 1 
week). The screening bone marrow biopsy and/or aspirate can be omitted if a sample was 
collected within the previous 3 months from study treatment, and the subject has not been on 
any therapy for MF during the intervening period, and all data from this collection can be 
entered into the eCRF for this study, with explanation as to the origin of the data.  In the 
extension phase of the study the bone marrow biopsy and aspiration will be performed when 
clinically indicated and not more frequent than every 6 months.  
7.2.3 
Safety assessments 
Safety will be monitored by assessing and collecting the adverse events at every visit. For 
details on AE collection and reporting, refer to Section 8. 
7.2.4 
Physical examination 
A complete physical examination will be performed, as noted in Appendix 2 (+/- 3 days up 
until the end of cycle 6 and then +/- 7 days for C7 and beyond), and must include at a 
minimum measurement of spleen length, assessed by palpation and measured in centimeters 
using a soft ruler, from the costal margin to the point of greatest splenic protrusion at every 
visit. 
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent is signed must be 
recorded on the Adverse Event within the eCRF. 
7.2.4.1 
Vital signs 
Vital signs (blood pressure, pulse, respiratory rate and body temperature) will be collected at 
every visit (+/- 3 days up until the end of cycle 6 and then +/- 7 days for C7 and beyond). 
Vital signs should be taken with the patient in the sitting position after 5 minutes of rest. Body 
temperature may be measured orally or via ear. 
7.2.4.2 
Height and weight 
Height in centimeters (cm) should be measured at screening only. Body weight in kilograms 
(to the nearest 0.1 kilogram [kg], without shoes) should be measured at every visit (+/- 3 days 
up until the end of cycle 6 and then +/- 7 days for C7 and beyond). 


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7.2.4.3 
Performance status 
The performance status will be assessed according to the ECOG performance status scale 
(Table 7-3), at time points specified in Appendix 2 (+/- 3 days up until the end of cycle 6 and 
then +/- 7 days for C7 and beyond). 
Table 7-3 
ECOG performance status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
7.2.5 
Laboratory evaluations 
The laboratory evaluations will be performed by a local lab according to the visit schedule in 
Appendix 2 (+/- 3 days up until the end of cycle 6 and then +/- 7 days for C7 and beyond). 
Abnormal laboratory values or test results constitute as an AE only if they induce clinical 
signs or symptoms, and are considered clinically significant (i.e., require dose modification 
and/or interruption of study drug, lead to clinical symptoms, cause study discontinuation or 
constitute in and of itself an SAE) or require therapy. These events should be recorded on the 
eCRF. If the administration of PANOBINOSTAT and/or RUXOLITINIB is delayed/modified 
due to unacceptable toxicities (see Section 6.2.7), re-evaluation should be performed prior to 
the next study treatment at a minimum. 
All available labs should be performed and results of Hematology reviewed prior to 
administration of study drug. More frequent examinations may be performed at the 
Investigator’s discretion if medically indicated; results should be recorded on the 
Unscheduled Visit eCRF. 
Baseline labs may be repeated, if needed, to obtain acceptable values before the patient would 
screen fail. Laboratory tests should be collected and analyzed on the scheduled day appendix 
2, or +/- 3 days up until the end of cycle 6 and then +/- 7 days for C7 and beyond. 
7.2.5.1 
Hematology 
Hematology tests include the following parameters: 
• Complete blood count (CBC) consisting of total white blood cell count (WBC) with 
differential (total neutrophil including bands, lymphocyte, monocyte, eosinophil, 
basophils counts, and blasts) 
• Hemoglobin 
• Hematocrit 


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• Platelet count 
7.2.5.2 
Biochemistry 
Biochemistry includes the following parameters: 
• Urea or blood urea nitrogen (BUN), creatinine, sodium, potassium, glucose, total calcium 
(corrected for serum albumin) or ionized calcium, albumin, total protein, total bilirubin 
(direct and indirect if total bilirubin is > ULN), lactate dehydrogenase (LDH), alkaline 
phosphatase, AST/SGOT, ALT/SGPT, phosphorous, magnesium, and uric acid. 
Potassium, calcium, magnesium, and/or sodium supplements may be given to correct values 
that are <LLN. Post-correction values must not be deemed to be a clinically significant 
abnormality prior to patients being dosed. 
7.2.5.3 
Coagulation 
The coagulation profile includes a prothrombin time (PT)/International Normalized Ratio 
(INR), and partial thromboplastin time (PTT). 
The coagulation profile should be repeated as clinically indicated and these results should be 
recorded on the Unscheduled Visit eCRF.  
7.2.5.4 
Thyroid function tests 
TSH and free thyroxine (FT4) will be evaluated at time points specified in Appendix 2. 
7.2.5.5 
Urinalysis 
Urinalysis tests include a macroscopic exam, including assessment of protein, glucose, blood, 
and specific gravity at timepoints specified in Appendix 2. Should an abnormality be noted in 
the macroscopic exam, a microscopic examination should also be performed, including 
assessment of WBC/HPF, RBC/HPF, and documentation of any additional findings. 
If the administration of oral PANOBINOSTAT is delayed/modified due to unacceptable renal 
toxicities, re-evaluation should be performed prior to the next study treatment at a minimum. 
7.2.5.6 
Pregnancy test 
All WOCBP should complete a serum pregnancy test within 7 days prior to the first dose of 
study drug on Cycle 1 Day 1. The serum pregnancy test is only required to be repeated on 
Cycle 1 Day 1 if the baseline test was performed > 7 days prior to the first dose of 
PANOBINOSTAT. A urine pregnancy test will be repeated on day 1 of each 28-day cycle 
that a patient continues to receive study therapy, and at end of treatment. Evaluations may be 
repeated while the patient is on study, where clinically indicated. 
Post-menopausal women must have been amenorrheic for ≥ 12 months in order to be 
considered “of non-childbearing potential.” 


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7.2.6 
Radiological examinations 
Once the MTD/RPTD has been established, patients who are ongoing active study treatment 
and enrolled in this dosing level will have MRIs/CT performed at scheduled time points. See 
Section 7.2.2.3 for further details. 
7.2.7 
Cardiac assessments 
7.2.7.1 
Electrocradiogram (ECG) 
12-Lead ECG evaluation will be performed per Table 7-1 and Appendix 2. For phase I 
patients only, cycle 1 day 1 ECG tracings will be done in triplicates to obtain the mean, and 
should be separated by 5-10 minutes each. On treatment days when ECGs are to be 
performed, the patient should take their study medication in the clinic.  
The mean of the 3 ECGs obtained pre-dose on cycle 1 day 1 will be calculated by the 
Investigators and will be used as the baseline value to compare to throughout the study. If a 
prolonged QTc interval is noted at any time, additional days of QTc monitoring may be 
required (see Table 6.4). 
Treatment decisions should be based on the real-time assessment of QTc values at the clinical 
center, as determined by the automated machine reading or as measured and calculated by 
trained personnel at the site. All cardiac events should be treated as per the local standard of 
care and referred to a specialist, if clinically indicated (see Section 6.2.8 for required dose 
modifications for prolonged QTc). Any final decisions concerning dose modifications or 
permanently discontinuing the patient from study drug due to QTc prolongation will be based 
on the assessment performed by the Investigator. 
Table 7-1 
12-Lead ECG schedule time points: 
Screen/Cycle 
DAY 
Pre-dose 
Post dose 
 
 
0-hour 
3-hour 
Screening 
Baseline 
x 
 
Cycle 1 
1 
x 
x 
 
4, 8, 15, 22 
x 
 
Cycle 2 
1, 8, 15, 22 
x 
 
Cycle 3+subsequent cycles 
1, 15 
x 
 
Cycle 6 
29 
x 
 
Cycle 6-12 
1 
x 
 
Cycle 12+ 
1* 
 
 
• After cycle 12 ECG is no longer required prior to dosing and can be performed at any time 
during the visit  
 
ECGs will be performed at the scheduled time points, at a minimum, as indicated above as 
well as in Appendix 2. If there are no additional procedures to be carried out on that day, 
arrangements may be made such that the ECGs may be performed at a local office of a 


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physician near the patient’s home and transmitted to the site investigator or responsible 
delegate in a timely manner. ECGs should be performed on the day of dose administration 
and, therefore, should there be a delay in dose administration, the corresponding pre-and/or 
post-dose ECGs should be delayed accordingly. 
7.2.7.2 
Holter monitoing 
There will be no holter monitor used in this study. 
7.2.7.3 
Cardiac imaging -- MUGA (multiple gated acquisition) scan or 
echocardiogram 
A baseline MUGA scan or ECHO to assess left ventricular ejection fraction (LVEF) will be 
performed within the screening period prior to the first administration of study drug treatment 
and may be repeated at the Investigator’s discretion if there are signs or symptoms of 
cardiotoxicity. 
7.2.8 
Tolerability 
Not applicable 
7.2.9 
Biomarkers  
All biomarker sample collection and analysis will be done as per Appendix 2 study schedule . 
Biomarker analysis will be done to assess changes in JAK2V617F allele burden, plasma 
cytokine level, and genetic and epigenetic mutations impacting the molecular pathogenesis of 
MF other than JAK2V617F upon treatment with the combination of drugs. 
 
Peripheral blood (PB) and bone marrow (BM) aspirate samples when obtained as indicated in 
the protocol or when indicated for standard of care, will also be processed and stored in a 
secure freezer in the laboratory of Dr Ronald Hoffman at Mount Sinai School of Medicine. 
The samples will be stored in freezer vials that are labeled with the study patient identification 
number only in a box that will only be used for samples obtained from this study. These 
samples will be stored for no longer than 10 years from time of initial storage. Only the study 
investigators and those individuals under the assurance of the study will have access to the 
linked study identification numbers. The de-identified samples will be available to other 
research collaborators for the purpose of analyzing samples. The samples will be used for 
research purposes only and results will not be provided to the individual nor will they 
influence the direct care of that individual. At any time, a patient's stored BM or PB research 
sample can be destroyed if the patient requests that these samples no longer be used in the 
context of this research study. The samples will be batched and at a later date may be 
analyzed for cytokine profile, histone acetylation, DNA methylation status, and the mutational 
status of genes that have been implicated in the pathogenesis of MPNs (e.g. EZH2, ASXL1, 
TET2, IDH1/2 and others that may not yet be identified). Due to the rapidly evolving 
understanding of this disease process, additional tests may be performed on these stored 
samples that cannot yet be determined.  


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7.2.9.1 
Blood sample for allele burden analysis  
JAK2V617F allele burden analysis in the subset of subjects with evidence of a JAK2V617F 
mutation will be monitored. Subsequent samples need only to be collected from patients with 
the mutant allele present. 
Approximately 5.0 mL of blood for JAK2V617F allele burden quantitation will be collected 
at as indicated in the study schedule. 
7.2.9.2 
Blood sample for plasma cytokine assays  
A panel of cytokine and other plasma protein markers, including but not limited to, IL-1 beta, 
IL-6, and IL-8 will be analyzed and correlated with response and symptom measures. 
Approximately 5.0 mL of blood for cytokine and other plasma protein markers will be 
collected at the following time points as shown in the study schedule. 
7.2.9.3 
Genetic mutations impacting the molecular pathogenesis of MF other 
than JAK2V617F  
Genotyping of subjects will be performed on Cycle 1 Day 1 pre-dose to assess the mutational 
status at diagnosis. This assessment will require approximately 5mLs of blood and analysis 
will be performed by a collaborating laboratory. Samples will be collected at specified time 
points as shown in the study schedule and the specimens will be de-identified and processed 
in the research laboratory of Dr Ronald Hoffman. Blood will be centrifuged with ficoll and 
mononuclear cells will be separated from polymorphonuclear cells and aliqouted into 
microtubes and stored at -80’C freezer. The serum/plasma will also be collected and 
aliqouted. The samples will be analyzed for genetic and epigenetic markers by a collaborating 
laboratory at a time to be determined in the future when the investigators believe an adequate 
number of samples and time points have been obtained. The exact mutational studies will be 
determined at a later time as emerging understanding of the pathogenetic mechanisms of MF 
are elucidated.  
7.2.9.4 
Other biomarker assessments/ Buccal swab 
Buccal swab will be performed at screening for germline DNA reference. This will only be 
done at screening. 
Remaining blood samples may be used for additional biomarker assessments related to drug 
action and effect and/or cancer. 
7.2.10 
Transfusion dependence 
During the Screening Visit the patients will provide a review of PRBC transfusion history for 
the last 12 weeks prior to screening. During the Study Visits on D1 of each cycle the patients 
will provide updates on PRBC transfusion history status. 


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8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occurs after patient’s signed 
informed consent has been obtained. Abnormal laboratory values or test results occurring 
after informed consent constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy (e.g., hematologic 
abnormality that requires transfusion or hematological stem cell support), or require changes 
in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History eCRF. Adverse event monitoring should be continued for at 
least 30 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
or 
Its relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 


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All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution, it is judged as no 
longer clinically significant by the investigator, stable or until it is judged to be permanent. 
Assessment should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study treatment, the interventions required to treat it, 
and the outcome. 
Progression of disease (including fatal outcomes), if documented by use of appropriate 
method should not be reported as a serious adverse event. 
Adverse events separate from the progression of disease (example, deep vein thrombosis at 
the time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities constitute an Adverse event if they are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes 
in study treatment, and should be recorded on the Adverse Events eCRF. Whenever possible, 
a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event or laboratory abnormality (severe) as per 
CTCAE does not automatically indicate a SAE unless it meets the definition of serious as 
defined below and/or as per investigator’s discretion. A dose hold or medication for the lab 
abnormality may be required by the protocol and is still, by definition, an adverse event. 
 
Laboratory abnormalities will only be captured as adverse events if they are considered 
clinically significant by the investigator.  Laboratory abnormalities are considered clinically 
significant if they: 
 
• Require clinical intervention (medication and/or procedure) 
• Trigger additional investigation 
• Require study drug dose medication 
• Cause discontinuation of study treatment 
• Require more frequent follow-up assessments 
• Result in the alteration of the patient’s well-being 


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• Are life-threatening 
• Are considered clinically significant according to the investigator’s judgment  
8.1.3 
Adverse events of special interest 
Due to the overlapping toxicity for both study drugs, special attention should be given to the 
occurrence of hematologic adverse events, especially thrombocytopenia, hemorrhagic events 
as well as anemia and leukopenia and their clinical consequences (i.e. infections and increased 
blood transfusion requirements as well as worsening of ischemic heart disease in the presence 
of new onset anemia and/or cardiac failure/edema after blood transfusion). Thromboembolic 
events, infection, syncope with prolonged QTc, syncope without QTc, TIA, LVEF 
abnormalities, Pneumonia, Colitis, fatigue are also AEs of special interest. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• 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 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• 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 
• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Protocol exempt SAEs: Progression of disease (including fatal outcomes), if documented 
by use of appropriate method (for example, as per IWG criteria for treatment response in 
myelofibrosis with myeloid metaplasia (Tefferi 2006)), should not be reported as a serious 
adverse event. However, other adverse events associated with disease progression (PD) 
but not a typical component of PD such as thrombosis, must be reported as appropriate, 
per AE/SAE criteria. 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 working hours of learning of its 


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occurrence. Any SAEs experienced after this 30 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 reported as follow-up to the 
original episode within 24 working 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. The investigator must assess and record the relationship of each SAE to each specific 
study treatment, complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 working hours to FDA as well as fulfill the appropriate reporting 
requirements for the PPHS at MSSM. 
8.3 
Emergency unblinding of treatment assignment 
Not Applicable, as this study is open label. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
the PPHS of MSSM and the FDA. 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. 
Instances of pregnancies and positive pregnancy tests should be collected for all patients who 
have conceived after receiving study medication. Pregnancies that are noted prior to 
administration of study medication but after signing informed consent may require reporting if 
they are considered to be associated to the conduct of the study by the investigator. Pregnancy 
data should be submitted to the Local Safety Helpdesk at the CPO via the clinical trial 
pregnancy form within 24 hours of the site becoming aware of the information. If the 
pregnancy has resulted in a Serious Adverse Event (SAE), a SAE form should be completed 
irrespective of whether or not the patient has received the study medication. 
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. 
Since PANOBINOSTAT is associated with potential genotoxicity per the current labeling 
information (current Investigator’s Brochure), as such this protocol includes highly effective 
contraception per the Novartis pregnancy prevention guidelines document. Where applicable 
and able the female pregnant partner of the male study participant may also be informed of 
this information as appropriate and feasible. 
Principal Investigator Responsibilities for pregnancy reporting: 
• Report all pregnancies for all female trial participants, including outcome, and adverse 
events during pregnancy. 


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• Report all pregnancies for pregnant partners of male clinical trial participants. 
• Report all outcomes and any adverse events experienced by the pregnant partner during 
pregnancy 
• Obtain follow-up for outcome and other data as requested by CTSO/CPO. 
• Adhere to general SAE reporting timelines and guidelines. 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided 
Investigator’s Brochure (IB). Additional safety information collected between IB updates will 
be communicated 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. 
8.6 
Data Monitoring Committee 
A Data Monitoring Committee will not be used in this study. 
8.7 
Steering Committee 
A steering committee will not be used in this study. 
9 
Data collection and management 
9.1 
Site monitoring 
There is no site monitoring for this investigator-initiated study. However, the Investigators 
can choose to have internal audits performed.  
9.2 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eRAP 
system at MSSM will be used for this study. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
9.2.1 
Biomarker data collection 
Designated investigator staff must enter the information required by the protocol onto the 
biomarker sample collection eCRFs. 
9.3 
Database management and quality control 
This will be maintained by the investigators and the research staff in accordance with all the 
rules of MSSM. 


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10 
Statistical methods and data analysis 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
Patients who took at least one dose of study medication will define the full analysis set which 
will be the primary analysis set for the safety and efficacy assessments 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication. For 
this study, the safety set and the full analysis set are identical. 
10.1.3 
Per-Protocol Set 
Since the sample size for this study is relatively small, no per-protocol set will be defined, 
although protocol compliance will be reported by listing and summarizing protocol 
deviations. 
10.1.4 
Dose-determining set 
The dose escalation analysis and the determination of the MTD and/or RPTD will be based on 
the set of evaluable patients in every dose cohort where evaluability is defined in 
Section 6.2.3. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data will be listed by patient and/or summarized 
descriptively by initial doses of study treatment and by study phase for the safety set. 
Categorical data will be presented as frequencies and percentages. For continuous data, 
summary statistics such as mean, standard deviation, median, 25th and 75th percentiles, 
minimum, and maximum will be presented. This will include baseline JAK2V617F 
mutational status and review of Packed Red Blood Cell (PRBC) transfusion history for the 
last 12 weeks prior to screening; this information will be recorded in the appropriate eCRF. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
The dose and duration in days of PANOBINOSTAT and RUXOLITINIB will be listed and 
summarized by dose level using descriptive statistics. Data may be presented by cycle in 
addition to over the entire study duration. The daily dose will be summarized using 
descriptive statistics by dose level and will be listed by patient. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized for the safety set. 
Compliance to the study protocol will be assessed by reporting the number and type of 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized. 


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In this trial, the days of each cycle will continue to be counted even if study drugs are being 
held. It will be the responsibility of the investigators to monitor the actual cumulative doses 
each patient is receiving per cycle.  
10.4 
Primary objective 
The primary objective of the phase I trial is to establish safety and tolerability of the 
combination of PANOBINOSTAT and RUXOLITINIB as we’ll as the MTD and/or RPTD in 
patients with MF. The primary objective of phase II is to determine the proportion of patients 
that achieve at least SD by IWG-MRT treatment response. The target IWG-MRT treatment 
response rate of >40% in the phase II part of this study will signify a positive result.  
10.4.1 
Variable 
The quantities of primary interest are rates of dose limiting toxicities (DLTs) at the different 
dose levels, and the MTD and/or RPTD for the desired patient population. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
10.4.2.1 Dose escalation 
The initial 3 cohorts will have RUXOLITINIB administered at a fixed dose of 10mg PO BID 
and cohort 1 will combine PANOBINOSTAT at a dose of 10mg PO TIW QOW, cohort 2 will 
be PANOBINOSTAT 15mg PO TIW QOW and cohort 3 will be PANOBINOSTAT 20mg 
PO TIW for cumulative cycle doses of 60mg, 90mg and 120mg, respectively. If an MTD of 
Panobinostat is not established by cohort 3, then cohort 4a will test RUXOLITINIB at 15mg 
PO BID in combination with PANOBINOSTAT 15mg PO TIW QOW. Cohort 4b will test 
RUXOLITINIB at 15mg PO BID in combination with PANOBINOSTAT 20mg PO TIW 
QOW. If an MTD of Panobinostat is established in the first 3 cohorts, then the cohort 4a will 
test RUXOLITINIB at 15mg PO BID in combination with PANOBINOSTAT at the dose 
level preceding the MTD dose level of PANOBINOSTAT.  
If the dose escalation of Ruxolitinib continues to cohort 4b and this cohort does not define the 
MTD of Ruxolitinib, then cohort 5 will allow patients to be treated at a dose of 
PANOBINOSTAT of 10mg PO TIW QW for a cumulative dose/cycle of 120mg. Cohorts 6 
and 7 will be pursued if the previous cohorts don’t reach MTD and will include 15mg PO BID 
of RUXOLITINIB and PANOBINOSTAT at 15mg PO TIW QW and 20mg PO TIW QW, 
respectively.  
The RPTD of each agent will be determined by the MTD and the dose limiting toxicities 
observed in Phase I. Subjects can start single agent ruxolitinib as long as the dose evaluation 
period of the previous cohort is complete before combination therapy begins. The RPTD will 
not necessarily be the MTD doses reached in the Phase I dose escalation part of this study.  
However, the RPTD will not exceed the estimated MTD dose of either drug as determined 
from the drugs given in combination in Phase I.   
Initially, 3 subjects will be entered into a cohort with a specified dose level for each drug. 
• 
If 2 or more of the initial subjects experience DLT, then the Maximally Tolerated Dose 
(MTD) of the drug being escalated has been exceeded. 


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• 
If none of the 3 subjects initially enrolled into this cohort experiences DLT, then subsequent 
subjects will be enrolled into the next higher dose level of the drug being escalated. 
• 
If 1 of the initial subjects experiences DLT, then 3 additional subjects (to a total of 6 subjects) 
will be enrolled into the cohort. 
o If it is found that 1 of the 6 subjects in the cohort encounters DLT, then subsequent 
subjects will be enrolled into the next cohort. 
o If it is found that 2 or more of the 6 subjects in a cohort encounter DLT, then the MTD 
of the drug being escalated has been exceeded and the next lower dose level for that 
drug (or frequency at which the drug is administered, as in Cohorts 5, 6, and 7) will be 
evaluated with a maximum of 6 patients. 
• 
The MTD for the drug being escalated will be defined as the dose level of that drug 
immediately below that at which 2 or more patients out of 6 experience a DLT. 
• 
If the final cohort under consideration in the escalation of either drug in Phase I has enrolled 
only 3 patients and none of these 3 patients experiences a DLT, then the cohort will be 
expanded to 6 patients before deciding on a MTD for that drug (or frequency of drug 
administration). 
10.4.2.2 Dose expansion 
The cohort of 6 patients at the MTD and/or RPTD will be expanded by an additional 
16 patients in order to further assess safety and tolerability. Thus the number of 
patients treated at the MTD and/or RPTD will be 22, which ensures that there is a 
90% chance to detect any AE with a 10% incidence rate among patients treated at 
the MTD and/or RPTD. During this phase of the study, further defining of the 
biological activity of this combination will be explored. The primary endpoint of this 
portion of the trial is response rate by IWG-MRT criteria. We hypothesize a response 
rate of >40% in treated patients at C6D28 will constitute a positive primary endpoint.  
A positive response by IWG-MRT criteria includes SD, CI, PR, or CR. Since 
preclinical studies suggest a synergistic effect of the two agents in combination, we 
would expect a spleen response rate (>35% reduction in spleen volume by MRI or 
>50% reduction in palpable spleen) of >30% as was assumed in the COMFORT 
study. Since the proportion of patients obtaining this efficacy endpoint was 42%, we 
will have a target response for this secondary endpoint of >50%, and this will be 
reported in a descriptive manner. 
10.4.3 
Handling of missing values/censoring/discontinuations 
During the dose-finding part of the trial, one additional patient may be enrolled in each 
cohort, for each patient who does not meet the criteria necessary for inclusion in the dose-
determining set. During the dose expansion part of the trial, one additional patient may be 
enrolled for each patient who does not meet the criteria necessary for inclusion in the safety 
set. At the time of the writing of the study report, patients will have continuing events (e.g., 
adverse events) summarized using the data cut-off date as the date of completion, with an 
indication within the listings that the event is continuing. 


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10.4.4 
Supportive analyses 
Additional supportive analyses may be conducted if appropriate. 
10.5 
Secondary objectives 
The secondary objectives of this study are: 
10.5.1 
To evaluate the safety of the oral co-administration of RUXOLITINIB 
and PANOBINOSTAT to patients with MF 
All adverse events recorded during the study will be listed and summarized. All serious 
adverse events will be listed by patients and tabulated by type of adverse event and initial 
dose level. Any other safety information will be listed and tabulated as appropriate. This 
includes analysis of all AE, SAE, labs, vital signs, and ECG data to include dose level and 
cycle. 
10.5.2 
Safety objectives 
10.5.2.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used, except for summaries of DLTs, for which 
the dose determining set will be used in addition to the safety set. All listings will be 
presented by dose levels and all tables will be presented by dose level or groups of dose 
levels, as appropriate, based on the number of dose levels used and number of patients treated. 
The overall observation period will be divided into three mutually exclusive segments: 
• Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
• On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
• Post-treatment period: starting at day 31 after last dose of study medication. 
10.5.2.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period will be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class, preferred term, severity (based on CTCAE grades), type 
of adverse event, relation to study treatment, and dose level. Deaths reportable as SAEs and 
non-fatal serious adverse events will be listed by patient and tabulated by type of adverse 
event and dose level. 
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 


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clinical interest in connection with the study treatment(s). For each specified SEC, number 
and percentage of patients with at least one event part of the SEC will be reported. 
DLTs will be listed and their incidence summarized by primary system organ class, worst 
grade, type, and dose level. The dose determining set will be used for these summaries. 
10.5.2.3 Laboratory abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 (NCI 2009), the study’s biostatistical and reporting team will grade 
laboratory data accordingly. For laboratory tests covered by CTCAE, a grade 0 will be 
assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. For 
laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. The following by-
treatment summaries will be generated separately for hematology and biochemistry laboratory 
tests: 
• frequency table for newly occurring on-treatment grades 3 or 4 (see below for details) 
• shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value. 
• listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. Time to onset of 
grade 3 or higher SECs will be summarized by dose level. 
10.5.2.4 Other safety data 
Data from other tests (e.g., electrocardiogram or vital signs) will be listed, notable values will 
be flagged, and any other information collected will be listed as appropriate by study phase. 
Any statistical tests performed to explore the data will be used only to highlight any 
interesting comparisons that may warrant further consideration.  
10.5.2.5 Supportive analyses for secondary objectives 
No supportive analyses for secondary objectives are planned. 
10.5.2.6 Tolerability 
Not applicable 
10.5.3 
Biomarkers 
See Section 7.2.10. 
10.5.4 
Resource utilization 
Not applicable 


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10.5.5 
Patient-reported outcomes 
Not applicable 
10.6 
Exploratory objectives 
The following exploratory efficacy objectives will be included on the study: 
10.6.1 
To assess preliminary efficacy of the combination of RUXOLITINIB 
and PANOBINOSTAT by physician palpation in all dosing cohorts 
Spleen measurements by palpation will be obtained with a primary emphasis on the change in 
measurements from baseline to Week 12. Descriptive statistics will be provided for the spleen 
length and percent change from baseline over time. The proportions of patients with at least a 
50% reduction in palpable spleen length at any time point, at week 12 and at week 24 will be 
summarized. This analysis will be done separately on patients in every dosing cohort, as well 
as, on the pooled patients, in the escalation phase.  
 
10.6.2 
To assess the preliminary efficacy at the MTD and/or RPTD by the use 
of MRI/CT 
The endpoint for this objective will be the volumetric reduction in spleen size from baseline to 
Week 12 (or end of study, whichever comes early), as assessed by MRI/CT. The analysis will 
be restricted to patients in the expansion phase, who are dosed at the MTD and/or RPTD. 
Responders (defined as those achieving at least 35% reduction in splenic volume (compared 
to baseline), at week 12 or end of study, whichever comes first), will be summarized in terms 
of percentage rates of response, along with 95% confidence intervals. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement for 
one-way tables) will be calculated (Clopper 1934). Descriptive statistics for the volumetric 
reduction in spleen size and percent change (from baseline) at the end of week 24 will also be 
provided. Since preclinical studies suggest a synergistic effect of the two agents in 
combination, we would expect a spleen response rate (>35% reduction in spleen volume by 
MRI) of >30% as was assumed in the COMFORT study. Since the proportion of patients 
obtaining this efficacy endpoint was 42% in COMFORT-1, we will have a target response for 
this secondary endpoint of >50%, and this will be reported in a descriptive manner. 
 
10.6.3 
To assess (preliminary) efficacy of the combination of RUXOLITINIB 
and PANOBINOSTAT by bone marrow biopsy in all dosing cohorts 
The endpoint for this objective will be the change in bone marrow histomorphology from 
aspirate and/or biopsy samples collected at baseline as compared to Cycle 6 (+/- 1 week), and 
any subsequent biopsies. The change in fibrosis will be assessed, and graded according to the 
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10.6.4 
To explore biomarkers at the MTD and/or RPTD (including but not 
limited to: JAK2V617F allele burden, genetic mutations impacting the 
molecular  pathogenesis of MF other than JAK2V617F , and cytokine 
measures) 
Exploratory biomarker analysis include (but are not limited to) the following, JAK2V617F 
allele burden, genetic mutations impacting the molecular pathogenesis of MF other than 
JAK2V617F, and cytokine measurement (all done pre and post treatment). 
Unless otherwise specified, all statistical analyses of biomarker data will be performed on the 
FAS with the related measures. Data transformations, such as base 2 logarithms, may be used 
prior to summarizing and analyzing the data. 
Although analyses are described herein, data synergies may be realized through correlation of 
biomarker data with other biomarker and/or clinical response variables. In addition, other 
post-hoc exploratory assessments are expected and may be performed. 
Summary statistics in absolute values at each visit and absolute and percentage change from 
baseline at each visit will be provided for JAK2V617F allele burden, and cytokine 
measurement. 
Exploratory correlation of the biomarker levels at baseline or their post-treatment changes 
with clinical response variables will be performed depending on trial outcome. 
10.6.5 
To evaluate changes in packed red blood cell transfusion dependence 
The proportion of patients who are transfusion dependent, as well as, the proportion of 
patients whose transfusion status (dependent or independent) changed (from dependent to 
independent or vice versa - (Gale 2011)) at each cycle will be tabulated with summary 
statistics. 
• A patient will be defined as transfusion dependent at baseline if he or she received 2 or 
more units of red blood cell products during the 12 weeks prior to first study treatment 
administration 
• New onset of transfusion dependence will be defined as the use of 2 or more units of red 
blood cell products during the last 12 weeks prior to end of study for patients who were 
not transfusion dependent at Baseline 
• New transfusion independence will be defined as no use of red blood cell products during 
the last 12 weeks prior to the end of study for patients who met the definition of 
transfusion dependence at baseline. 
10.7 
Interim analysis 
There is no plan for an interim analysis.  
10.8 
Sample size calculation 
For a cohort size of 3-6 patients, and assuming that escalation happens all the way up to and 
including cohort 7, and all patients are evaluable, the maximum total sample size will be 58  
patients.  The minimum sample size will be 33, which will occur if DLT is observed in the 


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first 2 patients in cohort 4a.  In such a case, cohort 3 would add another 3 patients to bring its 
total to 6.  An additional 16 patients for Phase II would bring the total to 12 + 2 + 3 + 16 = 33. 
If MTD and/or RPTD is achieved earlier, the sample size will be smaller. This is a Phase I 
study with a 3 + 3 dose-escalation scheme, first escalating Panobinostat followed by 
escalation of Ruxolitinib and finally an escalation of the frequency of administration of 
Panobinostat, as described above.  In each escalation, the probabilities of escalating to the 
next dose after only 3 patients, and of escalating to the next dose after 3 or 6 patients, as a 
function of the probability of a Dose Limiting Toxicity (DLT) for a given dose, are shown in 
the table below [Rubinstein and Simon, 2003] : 
 
Probability of DLT for given dose level 
.05 .10 .20 .30 .40 .50 .60 
Probability of continuing escalation after only 3 pts .86 .73 .51 .34 .22 .13 .06 
Probability of continuing escalation after 3 or 6 pts 
.97 .91 .71 .49 .31 .17 .08 
 
Since this is an adaptive design, it is not know exactly how many patients will be required in 
the trial.  If all proposed doses of both drugs, as well as both proposed frequencies of 
administration for Panobinostat, are such that the trial does not terminate due to DLTs, it is 
possible that a maximum of  42 patients will be enrolled in Phase I, given the history of 
enrollment up through cohort 3.  Since only 12 patients have been enrolled up through cohort 
3, if 6 patients are required for each cohort up through cohort 7, a total of 42 patients will 
have contributed to Phase I.  An additional 16 patients for Phase II would bring the maximum 
number of patients to 42 + 16 = 58. 
In the Phase II expansion study, 22 patients treated at the MTD and/or RPTD, ensuring that 
there is a 90% power, at an alpha level of 5%, to detect any AE with a 10% incidence rate 
among patients treated at the MTD and/or RPTD.  However few or many patients are enrolled 
in Phase I, the 6 patients at the RPTD will be carried forward as the initial 6 patients in the 
Phase II study (Messer et al., 2010). 
All inferential statistical analyses for secondary variables will be based on an estimation 
approach. There will be no formal testing of hypotheses for these variables, and no power 
analysis has been done. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 


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Ethics Board (IRB/IEC/REB) before study start. 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. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. Informed consent 
must be obtained before conducting any study-specific procedures (i.e. all of the procedures 
described in the protocol). The process of obtaining informed consent should be documented 
in the patient source documents. The date when a subject’s Informed Consent was actually 
obtained will be captured in their eCRFs. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4. 
11.5 
Publication of study protocol and results 
The investigators assure that the key design elements of this protocol will be posted in a 
publicly accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of 
documents 
The investigators will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects.  
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 


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complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study eCRF is the primary data collection instrument for 
the study. The investigator should ensure the accuracy, completeness, legibility, and 
timeliness of the data reported in the eCRFs and all other required reports. Data reported on 
the eCRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF must be 
recorded. Any missing data must be explained. Any change or correction to an eCRF should 
be explained (if necessary) and should not obscure the original entry. An audit trail will be 
maintained by the system. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Health Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who is directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon and 
approved by the IRB/IEC/REB it cannot be implemented. All significant protocol deviations 
will be recorded and reported in the CSR. 


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12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the IRB/IEC/REB. Only amendments that are required for patient safety 
may be implemented prior to IRB/IEC/REB approval. Notwithstanding the need for approval 
of formal protocol amendments, the investigator is expected to take any immediate action 
required for the safety of any patient included in this study, even if this action represents a 
deviation from the protocol. In such cases, Novartis should be notified of this action and the 
IRB/IEC/REB at the study site should be informed within 10 working days. 


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13 
References (available upon request) 
Babb J, Rogatko A, Zacks S (1998). Cancer Phase I clinical trials: efficient dose escalation 
with overdose control. Stat Med; 17: 1103-1120. 
Bali P, Pranpat M, Bradner J, et al (2005). Inhibition of histone deacetylase 6 acetylates and 
disrupts the chaperone function of Heat Shock Protein 90. J Biological Chemistry; 280:26729-
26734. 
Barbui T, Barosi G, Birgegard G, et al (2009). Philadelphia-negative classical 
myeloproliferative neoplasms: critical concepts and management recommendations from 
European LeukemiaNet. J Clin Oncol; 29:761-770. 
Carta S, Tassi S, Semino C, et al (2006). Histone deacetylase inhibitors prevent exocytosis of 
interleukin-1beta-containing secretory lysosomes: role of microtubules. Blood; 108:1618-
1626. 
Cervantes F, Dupriez B, Pereira A, et al (2009). New prognostic scoring system for primary 
myelofibrosis based on a study of the International Working Group for Myelofibrosis 
Research and Treatment. Blood; 113:2895-2901. 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika; 26:404-413. 
de Jonge M, Woo MM, van der Biessen D, et al (2009). A drug interaction study between 
ketoconazole and PANOBINOSTAT (LBH589), an orally active histone deacetylase 
inhibitor, in patients with advanced cancer. J Clin Oncol; 27; 15s:2501. 
DeAngelo, Tefferi A, Fiskus W, et al (2010). A Phase II Trial of PANOBINOSTAT, an 
Orally Available Deacetylase Inhibitor (DACi), in Patients with Primary Myelofibrosis 
(PMF), Post Essential Thrombocythemia (ET), and Post Polycythemia Vera (PV). Blood 
(ASH Annual Meeting Abstracts); 116: Abstract 630. 
Gangat N, Caramazza D, Vaidya R, et al (2011). DIPSS Plus: A refined dynamic international 
prognostic scoring system for primary myelofibrosis that incorporates prognostic information 
from karyotype, platelet count, and transfusion status. J Clin Oncol; 29:392-397. 
George P, Bali P, Annavarapu S, et al (2004). Combination of the histone deacetylase 
inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC 
cells and AML cells with activating mutation of FLT-3. Blood; 105:1768-1776. 
Glaser KG (2007). HDAC inhibitors: clinical update and mechanism-based potential. 
Biochem Pharmacol; 74:659-671. 
Grozinger C, Schreiber S (2002). Deacetylase Enzymes: Biological functions review and the 
use of small-molecule inhibitors. Chemistry and Biology; 9: 3-16. 
Guerini V, Barbui V, Spinelli O, et al (2008). The histone deacetylase inhibitor ITF2357 
selectively targets cells bearing mutated JAKV617F. Leukemia; 22:740-747. 
Guglielmelli P, Barosi G, Specchia G, et al (2009). Identification of patients with poorer 
survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood; 
114:1477-1483. 


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Version #8 – 5/19/15 
 
Gupta M, Stenson M, Lasho T, et al (2009). Interplay between histone deacetylases (HDACs) 
and STAT3: mechanism of activated JAK/STAT3 oncogenic pathway in ABC (Activated B-
cell Type diffuse large B cell lymphoma. Blood (ASH meeting abstracts); 114: abstract 925. 
Kroger N, Zabelina T, Schieder H, et al (2005). Pilot study of reduced-intensity conditioning 
followed by allogeneic stem cell transplantation from related and unrelated donors in patients 
with myelofibrosis. Br J Haematol; 128:690-697. 
Lewis L, Frank R, Dandamudi UB, et al (2009). Influence of food on the pharmacokinetics 
(PK) of PANOBINOSTAT (LBH589), an orally active histone deacetylase inhibitor, in 
patients with advanced cancer. J Clin Oncol; 27: 15s: 2550. 
Mesa RA, Niblack J, Wadleigh M, et al (2007). The burden of fatigue and quality of life in 
myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD 
patients. Cancer; 109:68-76. 
Mesa RA, Silverstein MN, Jacobsen SJ, et al (1999). Population-based incidence and survival 
figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmstead County 
study, 1976-1995. Am J Hematol; 61:10-15. 
Messer K, Natarajan L, Ball ED, Lane TA (2010). Toxicity-evaluation designs for phase I/II 
cancer immunotherapy trials. Statist. Med.; 29:712-720. 
Passamonti F, Cervantes F, Vannucchi AM, et al (2010). Dynamic International Prognostic 
Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary 
myelofibrosis. Blood; 116:2857-2858. 
Plo I, Vainchenker W (2009). Molecular and genetic bases of myeloproliferative disorders: 
questions and perspectives. Clinical Lymphoma & Myeloma; 9:329-339. 
Quintas-Cardama A, Vaddi K, Liu P, et al (2010). Dynamic international prognostic scoring 
system (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. 
Blood; 116:2857-2858. 
Rollison DE, Howlader N, Smith MT, et al (2008). Epidemiology of myelodysplastic 
syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using 
data from the NAACCR and SEER programs. Blood; 112:45-52. 
Rondelli D, Barosi G, Bacigalupo A, et al (2005). Allogeneic hematopoietic stem-cell 
transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with 
myelofibrosis with myeloid metaplasia. Blood; 105:4115-4119. 
Rubinstein LV and Simon RM (2003). Phase I clinical trial design. In Handbook of 
Anticancer Drug Development.  Lippincott, Williams & Wilkins. Philadelphia. 
Shang L, Tomasi T (2006). The Heat Shock Protein 90-CDC37 chaperone complex is 
required for signaling by types I and II interferons. J Biol Chem; 281:1876-1884. 
Shi J, Zhao Y, Ishii, et al (2007). Effects of chromatin-modifying agents on CD34+ cells from 
patients with idiopathic myelofibrosis. Cancer Res; 67:6417-6424. 
Tefferi A (2005). Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol; 
23:8520-8530. 


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Tefferi A (2010). Novel mutations and their functional and clinical relevance in 
myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, IDH, and IKZF1. Leukemia; 
24:1128-1138. 
Tefferi A, Barosi G, Mesa RA, et al (2006). International Working Group (IWG) consensus 
criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for 
Myelofibrosis Research and Treatment (IWG-MRT). Blood; 108:1497-1503. 
Tefferi A, Vardiman JW (2009). Classification and diagnosis of myeloproliferative 
neoplasms: the 2009 World Health Organization and point-of-care diagnostic algorithms. 
Leukemia; 22:14-22. 
Thall PF, Millikan RE, Muller P, et al (2003). Dose finding with two agents in Phase I 
Oncology trials. Biometrics; 59:487-96. 
Vardiman JW, Thiele J, Arber DA, et al (2009). The 2008 revision of the World Health 
Organization (WHO) class. Blood; 114:937-951. 
Verstovsek S, Kantarjian H, Mesa RA, et al (2010). Safety and efficacy of INCB018424, a 
JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med; 363:1117-1127. 
Wang Y, Fiskus W, Chong DG, et al (2009). Cotreatment with PANOBINOSTAT and JAK2 
inhibitor TG1011209 attenuates JAK2V617F levels and signaling and exerts synergistic 
cytotoxic effects against human myeloproliferative neoplastic cells. Blood; 114:5024-5033. 
Zhang C, Richon V, Ni X, et al (2005). Selective induction of apoptosis by histone 
deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of 
therapeutic action. J Invest Dermatol; 125:1045-1052. 


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14 
Appendices 
Appendix 1: Co-medications which are known to prolong the QT interval and/or 
induce Torsades de Pointes, are strong CYP3A4/5 inhibitors and inducers, 
moderate CYP3A4 inducers, CYP2D6 substrates, or otherwise prohibited for 
use 
 
Appendix 2: Study Schedules (Phase 1 and Phase 2) 
 
Appendix 3: MPN-SAF 
 
Appendix 4: Dynamic International Prognostic Scoring System (DIPSS) 
 
Appendix 5: Subject Study Pill Diaries 


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Appendix 1 Co-medications which are known to prolong the QT interval 
and/or induce Torsades de Pointes, are strong CYP3A4/5 inhibitors and 
inducers, moderate CYP3A4 inducers, CYP2D6 substrates, or otherwise 
prohibited for use 
Table of Contents 
A. 
Medication prohibited during the treatment period and 30 day follow-up for 
Study CLBH589x2106 
B. 
Medications which are known to prolong the QT interval and/or induce 
Torsades de pointes ventricular arrhythmia should be avoided 
C. 
Medications which are known strong CYP3A4/5 inhibitors to be used with 
caution 
D. 
Medications which are known CYP2D6 substrates to be used with caution 
E. 
Medications which are known to be moderate inducers of CYP3A4 are to be 
used with caution 


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A. 
Medication prohibited during the treatment period and 30 day follow-up 
for Study CLBH589x2106 
The following medications are prohibited during this study: 
1. Systemic steroids greater than 10 mg daily, unless use is part of a RUXOLITINIB dose 
tapering strategy (Section 6.2.10) 
2. Systemic anticoagulation, or drugs that inhibit platelet function, with the exception of: 
• Aspirin ≤ 150 mg/day 
• Low molecular weight heparin (LMWH) 
3. Any other investigational medication 
4. Any other medication used for the treatment of myelofibrosis, including but not limited to 
the following: 
• Anagrelide 
• Busulfan 
• Hydroxyurea 
• Interferon 
• Lenalidomide 
• Thalidomide 
5. Any medication which is known to be a strong CYP3A4 inducer* (e.g. avasimibe, 
carbamazepine, Phenobarbital, phenytoin, rifabutin, or St. John’s wort) 
*This list of strong CYP3A4 inducers was compiled from the FDA’s “Guidance for Industry, 
Drug Interaction Studies;” from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; from the University of Washington’s Drug Interaction Database; and from 
Pursche et al (2008). 
6. Any use of hematopoietic growth factor receptor agonists (including but not limited 
to:erythropoietin, romiplostim, or eltrombopag).   The use of G-CSF may be used after 
consultation with the sponsor. See Section 6.3.2 for further details. 


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B. 
Medications which are known to prolong the QT interval and/or induce 
Torsades de pointes ventricular arrhythmia should be avoided 
Patients, who are currently receiving treatment of the medications listed in Table 2-1 and 
cannot either discontinue from this treatment or switch to an alternative medication prior to 
enrollment in a PANOBINOSTAT clinical study, will be excluded from the study. Patients 
enrolled in a PANOBINOSTAT clinical study may not begin treatment with any of the 
medications listed in Table 2-1 unless discussed with the Sponsor and approval is granted by 
the Sponsor. The Sponsor may agree to temporarily discontinue PANOBINOSTAT treatment 
(e.g., for 72 hours) during administration with these drugs or withheld medications in Table 2-
1 for at least 72 hours when PANOBINOSTAT is to be administered. 
NOTE: It is of great importance to avoid combining drugs listed below in Table 2-1 and 
Table 3-1 (CYP3A inhibitors) in combination with PANOBINOSTAT especially in the 
presence of electrolyte abnormalities, notably decreased potassium or magnesium levels 
commonly associated with diuretic usage. 
In general, medications listed in Table 2-1 should be avoided. Medications listed in Table 3-1 
and Table 4-1 are to be used with caution when co-administered with PANOBINOSTAT. The 
use of any of the drugs in Table 2-1, Table 3-1, and Table 4-1 in combination with 
PANOBINOSTAT must be discussed with the Sponsor. 
Table 2-1 
Medications which are known to prolong the QT interval and/or 
induce 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 
• 
dofetilide 
• 
ibutilide 
• 
any other class III antiarrhythmic drug 


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Anti-infectives 
Macrolide antibiotics* 
• 
erythromycin 
• 
clarithromycin 
Quinolone antibiotics* 
• 
sparfloxacin 
Antifungals 
• 
pentamidine 
Antimalarials 
• 
halofantrine 
• 
chloroquine 
Antihistamines 
• 
astemizole 
• 
terfenadine 
Antinausea 
• 
chlorpromazine 
• 
domperidone 
• 
droperidol 
• 
dolasetron (intravenous and oral)^ 
Antipsychotics 
• 
thioridazine 
• 
mesoridazine 
• 
chlorpromazine 
• 
pimozide 
Miscellaneous drugs 
• 
arsenic trioxide 
• 
bepridil 
• 
cisapride 
• 
levomethadyl 
• 
methadone 
*Note: azithromycin, ciprofloxacin, levofloxacin, pefloxacin, ofloxacin, tosufloxacin, difloxacin, 
temafloxacin, fleroxacin, acrosoxacin, nalidixic acid and enoxacin are allowed. 
^Intravenous dolasetron is contraindicated for preventing nausea and vomiting associated with 
chemotherapy based on FDA drug safety communication dated December 17, 2010. Based on 
this finding, both intravenous and oral dolasetron are prohibited to be taken with PANOBINOSTAT. 
This is not a comprehensive list of medications which may prolong the QT interval and/or 
induce 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 PANOBINOSTAT. 
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.azcert.org/medical-pros/drug-lists/drug-lists.cfm (Version 3/25/2008). 


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Medications listed on the website which do not appear in Table 2-1 above may be used with 
caution at the discretion of the investigators. 
Ondansetron (a known CYP2D6 substrate, see Table 4-1) has been associated with Torsades 
de points and QT prolongation but has not been shown to cause Torsades de pointes. 
Therefore, ondansetron is not per se prohibited to be combined with PANOBINOSTAT but 
caution is to be exercised and close monitoring for signs and symptoms of QT prolongation is 
recommended. 


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C. 
Medications which are known strong CYP3A4/5 inhibitors to be used 
with caution 
The use of these drugs is prohibited during the first cycle of study treatment 
PANOBINOSTAT is a substrate of CYP3A4 with minor involvement of CYP2D6, and 
CYP2C19 in in vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study 
was conducted using ketoconazole, a strong CYP3A inhibitor, in combination with 
PANOBINOSTAT in study [CLBH589B2110]. 
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of PANOBINOSTAT by 
1.6- and 1.8-fold, respectively, but with no change in Tmax or half-lives in 14 cancer patients. 
The less than 2-fold increase in PANOBINOSTAT AUC upon co-administration of a strong 
CYP3A inhibitor is considered a weak drug inhibition and not clinically relevant, as 
PANOBINOSTAT doses at least 2-fold greater than the evaluated 20 mg dose (i.e., 40 mg and 
60 mg) have been safely administered in patients. Thus, co-administration of 
PANOBINOSTAT with a moderate or weak CYP3A inhibitor is allowed. However, clinical 
monitoring of signs and symptoms of PANOBINOSTAT treatment related adverse events is 
recommended when long-term (≥ 1 week) concomitant administration of any strong CYP3A 
inhibitors and PANOBINOSTAT is medically indicated or investigated in a clinical study. 
RUXOLITINIB is metabolized in the liver predominantly by the CYP3A4 isozyme. With 
concomitant dosing of potent CYP3A4 inhibitors such as those medications listed in 
Table 3-1, plasma exposure of RUXOLITINIB increases approximately 2-fold. Use of those 
medications listed in Table 3-1 is strongly discouraged, and investigators should consider 
alternative therapies wherever possible. However, if the use of a potent CYP3A4 inhibitor is 
necessary for the sake of the patient’s safety, then a dose reduction of ~50% of 
RUXOLITINIB is mandatory. See Section 6.3.4 for further details of this dose reduction 
schema. 
Based on the low overall bioavailability of topical ketoconazole, with very low systemic 
levels seen following topical administration, no dose adjustment of RUXOLITINIB is needed 
for use with topical ketoconazole. No dose adjustments are necessary when RUXOLITINIB is 
co-administered with erythromycin, or by extension, with other moderate or weak inhibitors 
of CYP3A4, including grapefruit juice. 
Patients with impaired liver function (as defined by NCI CTEP criteria)1 are recommended 
not to receive PANOBINOSTAT concomitantly with strong CYP3A inhibitors because 
potential interaction has not been established in this population. 


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Table 3-1 
Medications which are known strong CYP3A4/5 inhibitors to be 
used with caution 
Macrolide antibiotics* 
• 
telithromycin 
• 
troleandomycin 
Antifungals (azoles) 
• 
ketoconazole 
• 
itraconazole 
• 
posaconazole 
• 
voriconazole 
Antidepressants 
• 
nefazodone 
HIV protease inhibitors: 
• 
indinavir 
• 
nelfinavir 
• 
ritonavir 
• 
saquinavir 
• 
lopinavir 
 Miscellaneous drugs or products 
• 
2Star fruit and pomegranate product and juice 
• 
conivaptan 
* azithromycin and regular orange juice are allowed. 
Although clarithromycin is a known strong CYP3A inhibitor, it is also known to prolong QT intervals 
which is listed in Table 2-1 and is prohibited to be taken with PANOBINOSTAT. This drug is thus 
not listed again in Table 4-1. 
This is not a comprehensive list of medications which may inhibit CYP3A4/5. The above list 
was compiled by using information listed under “draft guidance for industry, drug interaction 
studies, CDER 2006”, Indiana University School of Medicine drug interaction tables at 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp, and “drug interaction database” 
from University of Washington. 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/ClinicalTable.asp. 


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D. 
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 
dextromethorphan 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 4-1 
Medications which are known CYP2D6 substrates to be used with 
caution 
Beta blockers (listed below): 
Antipsychotics (listed below): 
S-metoprolol 
aripiprazole 
propafenone 
haloperidol 
timolol 
risperidone 
Antidepressants (listed below): 
thioridazine 
amitriptyline 
Antiarrhythmics (listed below): 
clomipramine 
mexilletine 
desipramine 
flecainide 
imipramine 
Others (listed below): 
fluoxetine 
codeine 
paroxetine 
dextromethorphan 
venlafaxine 
tamoxifen 
duloxetine 
tramadol 
Antiemetics (listed below): 
 
ondansetron^ 
 
^Intravenous dolasetron is a CYP2D6 substrate and contraindicated for preventing nausea and 
vomiting associated with chemotherapy based on FDA drug safety communication dated December 
17, 2010. Please see Table 2-1. 
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/ClinicalTable.asp 


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E. 
Medications which are known to be moderate inducers of CYP3A4 are to 
be used with caution 
During the study, the use of moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, 
modafinil, nafcillin, ritonavir, talviraline, tipranavir) is discouraged, and investigators should 
seek alternatives where possible. No dose adjustment will be used when moderate CYP3A4 
inducers are co-administered with RUXOLITINIB. However, any concomitant use of 
moderate CYP3A4 inducers must be documented. 
This is not a comprehensive list of medications which may induce CYP3A4/5. The above list 
was compiled by using information listed under “draft guidance for industry, drug interaction 
studies, CDER 2006”, Indiana University School of Medicine drug interaction tables at 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp, and “drug interaction database” 
from University of Washington. 
References (available upon request) 
Hidaka M, Fujita K, Ogikubo T, et al (2004). Potent inhibition by star fruit of human 
cytochrome P450 3A (CYP3A) activity, Drug Metab Dispos 2004; 32: 581. 
Pursche S, Schleyer E, von Bonin M, et al (2008). Influence of enzyme-inducing antiepileptic 
drugs on trough level of imatinib in glioblastoma patients, Curr Clin Pharmacol, Sep 2008. 
Synold TW, Takimoto CH, Doroshow JH et al (2007). 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; 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Study Schedules (Phase 1 and Phase 
2)


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Appendix 3 MPN-SAF Symptom Assessment PAckage 
Myeloproliferative Neoplasm Symptom Assessment Form  
(MPN-SAF) 
 
Instructions: Please fill out all questions, as best able, reflecting how these symptoms 
affected you over the LAST WEEK unless directed otherwise. Complete forms until the 
STOP instruction toward the end of the packet.  
 
Symptom  
1 to 10  (0 if absent) ranking* 
1 is most favorable and 10 least favorable 
 
Please rate your fatigue (weariness, tiredness) by 
circling the one number that best describes your 
fatigue  right NOW 
 
 
(No Fatigue)  0   1  2  3  4  5  6  7  8  9  10 (Worst Imaginable) 
 
Please rate your fatigue (weariness, tiredness) by 
circling the one number that best describes your 
USUAL Level of fatigue  during past 24 hours 
 
 
 (No Fatigue)  0   1  2  3  4  5  6  7  8  9  10 (Worst Imaginable) 
 
Please rate your fatigue (weariness, tiredness) by 
circling the one number that best describes your 
WORST level of fatigue  during past 24 hours 
 
 
 (No Fatigue)   0  1  2  3  4  5  6  7  8  9  10 (Worst Imaginable) 
 
Circle the one number that describes how, during the past 24 hours, fatigue has interfered 
with your 
 
 
• 
General Activity 
 
 
 (Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
 
• 
Mood 
 
 
 (Does not Interfere)  0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
 
• 
Walking ability 
 
 
 (Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
 
• 
Normal Work (includes work both 
outside the home and daily chores) 
 
 
 (Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
 
• 
Relations with other people 
 
 
(Does not Interfere)  0 1 2 3 4 5 6 7 8 9  10 (Completely Interferes) 
 
• 
Enjoyment of life 
 
 
(Does not Interfere)  0 1 2 3 4 5 6 7 8 9  10 (Completely Interferes) 
 
 
 
 
 
 


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Circle the one number that describes how, during the past Week how much difficulty you 
have had with each of the following symptoms 
 
Filling up quickly when you eat 
(Early Satiety) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Abdominal pain  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal discomfort 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Inactivity 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Problems with Headaches  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Problems with Concentration - 
Compared to prior to my MPD 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Dizziness/ Vertigo/ 
Lightheadedness 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Numbness/ Tingling (in my hands 
and feet) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Difficulty sleeping 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Depression or sad mood 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Problems with Sexual Desire or 
Function  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Cough 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Night Sweats 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Itching (pruritus) 
 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Bone Pain (diffuse not joint pain 
or arthritis) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
Fever (>100 F) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Daily)         
Unintentional weight loss last 6 
months 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)         
What is your Overall Quality of 
Life?  
(As good as it can be) 0   1  2  3  4  5  6  7  8  9 10 (As Bad as it can be) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4: Dynamic International Prognostic Scoring System (DIPSS) 
 
The DIPSS is calculated as follows: 
 
Age >65 years: 1 point 
 
Leukocyte count >25,000/microL: 1 point 
 
Hemoglobin <10 g/dL: 2 points 
 
Circulating blast cells ≥1 percent: 1 point 
 
Presence of constitutional symptoms: 1 point 
Subjects with zero, one to two, three to four, or 5 to 6 points were considered low, intermediate-1, 
intermediate-2, or high risk, respectively 
 
Prognostic Variable 
Value 
  
0 Points 
1 Point 
2 Points 
Hemoglobin 
≥ 10 g/dL 
  
< 10 
g/dL 
Age, years 
< 65 
≥ 65 
  
White blood cell count 
≤ 25 x 103/uL 
> 25 x 103/uL 
  
Peripheral blood blasts 
< 1% 
≥ 1% 
  
Constitutional symptoms 
No 
Yes 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5: Subject Study Pill Diaries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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