Conditions: Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Acute Myeloid Leukemia
Keywords: Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Acute Myeloid Leukemia hypomethylating therapy deacetylase inhibitor MDS CMML AML
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 113
Healthy volunteers: no

Brief summary:
The purpose of this randomized, two-arm, open-label expansion phase study was to collect preliminary efficacy data of panobinostat at the recommended phase II dose (RPIID) level in combination with azacytidine (5-Aza) versus an active control arm 5-Aza alone. This randomized phase II part also allowed collecting safety data of panobinostat in combination with 5-Aza in comparison to single-agent 5-aza.

Detailed description:
The primary objective of the phase lb portion of this study was to determine the maximum tolerated dose (MTD )and/or recommended phase ll dose (RPIID) of oral panobinostat in combination with a fixed dose of 5-Aza in adult patients with International Prognostic Scoring System intermediate-2 (IPSS INT-2) or high risk myelodysplastic syndrome (MDS), Chronic myelomonocytic leukemia (CMML), or Acute myelogenous leukemia (AML).

The primary objective of the phase llb portion of this study was to assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at the RPIID relative to treatment with single agent 5-Aza through the assessment of composite CR (complete response (CR) or CRi or bone marrow CR).

In the phase lb phase of the study, the patients received escalating oral doses of panobinostat commencing in Cycle 1. The starting dose for panobinostat was 20 mg/day administered orally commencing on Day 3. Each treatment cycle consisted of 28 days (4 weeks). In each cycle, panobinostat was administered twice in Week 1 (Day 3, Day 5), thrice in Week 2 (Day 8, Day 10, and Day 12) and once in Week 3 (Day 15), with no dosing in Week 4. Successive cohorts of patients received escalating doses of panobinostat until the MTD/RPIID was determined. The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle.

After the MTD/RPIID was determined, enrollment in the Phase Ib part was closed and the Phase IIb part of the study commenced. Ongoing patients from the Phase Ib part continued their treatment at the assigned dose level according to the regimen and schedule for the Phase Ib part.

Once the RPIID was defined in Phase Ib, additional 80 patients were to be enrolled into the Phase IIb part of the study and randomly assigned in a 1:1 ratio receiving the RPIID of panobinostat plus 5-Aza (investigational arm) or single agent 5-Aza (active control arm). The treatment schedule for the investigational arm was the same as that for the Phase Ib. Single agent 5-Aza (active control arm) was administered according to the locally approved label (75mg/m2 daily for 7 days). Patients continued treatment until disease progression, unacceptable toxicity or consent withdrawal, whichever came first.

Arms:
arm 1: In phase I: Panobinostat : Escalating doses starting with 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15.

In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15.

In both phases, dose of 5-Azacytidine was 75 mg/m\^2, subcutaneously Daily for Day 1 to Day 7. arm 2: The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis.

Dose of 5-Azacytidine : 75 mg/m\^2 subcutaneously daily from Day 1 to Day 7.

Interventions: intervention 1: Panobinostat (LBH589) intervention 2: 5-Azacytidine
Intervention descriptions: intervention 1: Panobinostat was supplied by Novartis as immediate-release hard gelatin capsules in strengths of 5 mg, 10 mg, and 20 mg packaged in high density polyethylene bottles. intervention 2: None

Protocol document:
Prot_001.pdf: 
Clinical Development & Medical Affairs
LBH589
Clinical Trial Protocol CLBH589H2101 / NCT00946647
A phase Ib/IIb, open-label, multi-center study of oral 
Panobinostat (LBH589) administered with 5-Azacitidine 
(Vidaza®) in adult patients with myelodysplastic syndromes 
(MDS), chronic myelomonocytic leukemia (CMML) or acute 
myeloid leukemia (AML)
Authors
Document type
Amended Protocol Version
EUDRACT number
2009-010548-32
Version number
05
Development phase
Phase Ib/IIb
Document status
Final
Release date
18-Nov-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
Amendment 5 (18-Nov-2016)...........................................................................................12
Amendment 4 ....................................................................................................................16
Amendment 3 ....................................................................................................................17
Amendment 2 (released on 24 October 2011)...................................................................20
Amendment 1 (released on 21 April 2010) .......................................................................26
Oncology clinical study protocol synopsis........................................................................27
1
Background........................................................................................................................37
1.1
Overview of myelodysplastic syndromes (MDS)..................................................37
1.1.1
Classification of MDS...........................................................................37
1.1.2
Treatment options in intermediate-2 (INT-2) and high risk MDS........38
1.1.3
Overview of safety profile obtained with 5-Aza...................................39
1.2
Overview of panobinostat (LBH589) ....................................................................41
1.3
Combination of DNA methyltransferase inhibitors with deacetylase inhibitors...42
1.3.1
Clinical experience combining 5-Aza and DAC inhibitors ..................43
1.3.2
Update of clinical experience with combining panobinostat with 
Vidaza from the phase Ib part of this study ..........................................44
1.4
History of Amendments.........................................................................................45
2
Rationale for the investigation of the combination treatment of 5-Aza and 
panobinostat.......................................................................................................................46
2.1
Preclinical and clinical rationale supporting the combination of 5-Aza and 
panobinostat...........................................................................................................46
2.2
5-Aza dose and schedule .......................................................................................48
2.3
Panobinostat starting dose and schedule................................................................48
2.3.1
Drug-drug interaction between panobinostat and 5-Aza ......................50
2.4
Target population...................................................................................................51
3
Objectives..........................................................................................................................51
3.1
Phase Ib part ..........................................................................................................51
3.1.1
Primary objective ..................................................................................51
3.1.2
Secondary objectives.............................................................................51
52
3.2
Phase IIb part .........................................................................................................52
3.2.1
Primary objective ..................................................................................52
3.2.2
Secondary objectives.............................................................................52


Novartis
Confidential
Page 3
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
53
4
Study design ......................................................................................................................53
5
Population..........................................................................................................................54
5.1
Inclusion criteria ....................................................................................................55
5.2
Exclusion criteria...................................................................................................55
6
Treatment...........................................................................................................................56
6.1
Investigational and combination drugs..................................................................56
6.1.1
How supplied ........................................................................................57
6.1.2
Preparation and storage.........................................................................58
6.2
Treatment Arms.....................................................................................................58
6.2.1
Phase Ib part..........................................................................................58
6.2.2
Phase IIb part.........................................................................................58
6.3
Patient numbering..................................................................................................59
6.4
Treatment assignment............................................................................................60
6.4.1
IRT procedures......................................................................................60
6.5
Treatment blinding.................................................................................................60
6.6
Treating the patient................................................................................................60
6.6.1
Study treatment administration .............................................................60
6.6.2
Other concomitant medications.............................................................69
6.6.3
Study treatment discontinuation............................................................70
6.6.4
End of treatment....................................................................................70
6.6.5
Withdrawal of consent ..........................................................................71
6.6.6
Follow-up for safety evaluation ............................................................71
6.6.7
Lost to follow-up...................................................................................71
6.6.8
End of study (study evaluation completion) .........................................72
6.6.9
Emergency unblinding of treatment assignment...................................72
7
Visit schedule and assessments .........................................................................................73
7.1
Disease classification/qualification at baseline .....................................................82
7.2
Information to be collected on screening failures..................................................82
7.3
Patient demographics/other baseline characteristics .............................................82
7.4
Treatments .............................................................................................................82
7.5
Efficacy..................................................................................................................82
7.5.1
Efficacy assessments.............................................................................82
7.6
Safety.....................................................................................................................83
7.6.1
Performance status ................................................................................83
7.6.2
Cardiac assessments..............................................................................83
7.6.3
Laboratory evaluations..........................................................................84


Novartis
Confidential
Page 4
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
7.7
Tolerability ............................................................................................................86
7.8
Resource utilization ...............................................................................................86
7.9
Patient-reported outcomes .....................................................................................86
7.10
Pharmacokinetic assessment..................................................................................87
87
89
8
Safety monitoring and reporting........................................................................................90
8.1
Adverse events.......................................................................................................90
8.1.1
Definitions and reporting ......................................................................90
8.1.2
Laboratory test abnormalities................................................................91
8.1.3
Adverse events of special interest.........................................................91
8.2
Serious adverse events...........................................................................................92
8.2.1
Definitions.............................................................................................92
8.2.2
Reporting...............................................................................................92
8.3
Emergency unblinding of treatment assignment ...................................................93
8.4
Pregnancies............................................................................................................93
8.5
Warning and precautions.......................................................................................94
8.6
Data monitoring committee...................................................................................94
8.7
Steering committee................................................................................................94
9
Data collection and management.......................................................................................94
9.1
Data confidentiality ...............................................................................................94
9.2
Site monitoring ......................................................................................................95
9.3
Data collection.......................................................................................................95
9.3.1
Electrocardiogram.................................................................................95
95
9.4
Database management and quality control............................................................96
10 Statistical methods and data analysis ................................................................................96
10.1
Phase Ib part ..........................................................................................................97
10.1.1
Populations for analysis ........................................................................97
10.1.2
Patient demographics/other baseline characteristics.............................97
10.1.3
Treatments (study drug, concomitant therapies, compliance) ..............97
10.1.4
Primary objective ..................................................................................97
10.1.5
Secondary objectives.............................................................................99
10.1.6
Population and grouping for the analyses .............................................99
10.1.7
Resource utilization.............................................................................101
10.1.8
Patient-reported outcomes...................................................................101
10.1.9
Pharmacokinetics ................................................................................101


Novartis
Confidential
Page 5
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
101
101
10.1.12
Interim analysis ...................................................................................101
10.1.13
Sample size calculation.......................................................................101
10.1.14
Power for analysis of critical secondary variables..............................102
10.2
Phase IIb part .......................................................................................................102
10.2.1
Population for analysis........................................................................102
10.2.2
Population and grouping for the analyses ...........................................102
10.2.3
Patient demographics/other baseline characteristics...........................102
10.2.4
Treatments (study drug, concomitant therapies, compliance) ............102
10.2.5
Primary objective ................................................................................102
10.2.6
Secondary objectives...........................................................................102
102
10.2.8
Efficacy variables and analysis ...........................................................103
10.2.9
Safety variables and analysis ..............................................................103
10.2.10
Sample size calculation.......................................................................104
10.2.11
Interim analysis ...................................................................................104
10.2.12
Power for analysis of critical secondary variables..............................105
10.2.13
Handling of missing values/censoring/discontinuations.....................105
11 Ethical considerations and administrative procedures ....................................................105
11.1
Regulatory and ethical compliance......................................................................105
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................105
11.3
Informed consent procedures...............................................................................105
11.4
Discontinuation of the study................................................................................106
11.5
Publication of study protocol and results.............................................................106
11.6
Study documentation, record keeping and retention of documents.....................106
11.7
Confidentiality of study documents and patient records .....................................107
11.8
Audits and inspections.........................................................................................107
11.9
Financial disclosures............................................................................................107
12 Protocol adherence ..........................................................................................................108
12.1
Amendments to the protocol................................................................................108
13 References (available upon request)................................................................................109


Novartis
Confidential
Page 6
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
List of figures
Figure 2-1
Dose-dependent induction of apoptosis by in vitro combination of 
5-Aza and LBH589 ...............................................................................46
Figure 2-2
Expression of cell cycle and apoptotic markers in U937 cell line 
due to exposure to LBH589 and 5-Aza.................................................47
Figure 6-1
Treatment schedule (Phase Ib part).......................................................58
Figure 6-2
Treatment schedule (Phase IIb part) .....................................................59
Figure 6-3
Cycle 1 DLT decision algorithm for patients not experiencing 
grade 3 or 4 non-hematological toxicities.............................................64
List of tables
Table 1-1
International Prognostic Scoring System and prognosis.......................38
Table 1-2
Hematological response and hematological improvement based on 
IWG criteria for MDS ...........................................................................39
Table 1-3
Summary of major toxic effects of 5-Aza.............................................40
Table 1-4
Study CLBH589B2102 dose escalation summary - Arm 1 (three-
times-a-week every week).....................................................................41
Table 1-5
Study CLBH589B2102 dose escalation summary - Arm 2 (three-
times-a-week every other week) ...........................................................42
Table 1-6
Clinical trials of combination regimens with DNMTi and DACi.........44
Table 6-1
Treatment doses and regimens (Phase Ib part) .....................................58
Table 6-2
Treatment doses and regimens (Phase IIb part) ....................................59
Table 6-3
Dose escalation levels ...........................................................................61
Table 6-4
Phase IIb only: Panobinostat and Vidaza dose discontinuations/ 
interruptions/reductions for Grade 4 neutropenia and Grade 4 
thrombocytopenia (NCI CTCAEv3.0)..................................................67
Table 6-5
Phase Ib and Phase IIb: Panobinostat and Vidaza dose 
discontinuations/interruptions/reductions for febrile neutropenia 
(NCI CTCAEv3.0)................................................................................68
Table 6-6
Phase Ib only: Panobinostat dose interruptions/reductions for 
treatment-emergent/new non-hematological toxicities attributable 
to study treatment (except for prolonged QT interval) .........................68
Table 6-7
Phase IIb only: Panobinostat dose interruptions/reductions for 
treatment emergent/new non-hematological toxicities attributable 
to study treatment (except for prolonged QT interval) .........................68
Table 7-1
Visit evaluation schedule for Phase Ib and Phase IIb part....................74
Table 7-2
Visit evaluation schedule after CSR data cut off date (for the phase 
Ib and IIb part) ......................................................................................78
Table 7-3
Visit evaluation schedule as of protocol amendment 5 (for the 
phase Ib and IIb part) ............................................................................80


Novartis
Confidential
Page 7
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 7-4
ECOG Performance Status....................................................................83
Table 7-5
Cardiac assessment monitoring schedule..............................................84
Table 7-6
PK blood sampling................................................................................87
87
Table 10-1
Minimum exposure criteria (Cycle 1)...................................................97
Table 10-2
Probability of detecting at least one adverse event in cohort as a 
function of the cohort size...................................................................100
Table 10-3
Probability of observing clinically relevant improvement based on 
an assessment of composite CR (CR or CRi or bone marrow CR) ....104


Novartis
Confidential
Page 8
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
List of abbreviations
5-Aza
5-azacytidine, Vidaza®
ADME
Absorption, distribution, metabolism, and elimination
AE
Adverse event
Akt
V-akt murine thymoma viral oncogene homolog
ALL
Acute lymphocytic leukemia
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT
AML
Acute myelogenous leukemia
ANC
Absolute neutrophil count
APD
Action potential duration
APL
Acute promyelocytic leukemia
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT
ATC
Acute toxic class
ATD
Accelerated titration design
ATRA
All trans-retinoic acid
AUC
Area under the curve
b.i.d.
Bis in diem/twice a day
BAPK
Bioanalytics and Pharmacokinetics
BM
Bone marrow
BrdU
5-bromo-2-deoxyuridine
BSA
Body surface area
BUN
Blood urea nitrogen
CBC
Complete blood count
CEA
Carcino-embryonic antigen
CFR
Code of Federal Regulations
CHF
Congestive heart failure
CK-MB
MB isoenzyme of creatine phosphokinase
Cmax
Maximum (peak) concentration of drug
CMML
Chronic myelomonocytic leukemia
CNS
Central nervous system
CR
Complete response
CRO
Contract research organization
CRu
Unconfirmed complete response
CSF
Cerebrospinal fluid
CT
Computed tomography
CTC
NCI common toxicity criteria (version 2.0)
CTCAE
NCI common terminology criteria for adverse events (version 3.0)
CTCL
Cutaneous T-cell lymphoma
CV
Coefficient of variation
CYP450
Cytochrome P450
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid


Novartis
Confidential
Page 9
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
DNMT
DNA methyl transferase
DSM
Drug supply management
DTIC
Dacarbazine
ECG
Electrocardiogram
CRF
Electronic case record form
ECHO
Echocardiogram
EDC
Electronic data capture
EDM
Electronic data management
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
EOS
End of study
FACS
Fluorescent-activated cell sorter
FDA
Food and Drug Administration
FPFV
First patient first visit
FPG
Fasting plasma glucose
G-CSF
Granulocyte colony-stimulating factor
GI
Gastrointestinal
GLP
Good laboratory practice
GM-CSF
Granulocyte-macrophage colony-stimulating factor
H3, H4
Histones H3, H4
HAT
Histone acetyltransferase
HbA
Adult hemoglobin
HbF
Fetal hemoglobin
HDAC
Histone deacetylase
HDACi
Histone deacetylase inhibitor
hERG
Human ether-a-go-go related gene
Hgb
Hemoglobin
HI
Hematologic Improvement
HIV
Human immunodeficiency virus
HPF
High-power field
HPLC
High pressure (performance) liquid chromatography
HSP90
Heat shock protein 90
IEC
Independent ethics committee
IEP
Immunoelectrophoresis
IMS
Integrated Medical Safety
INR
International normalized ratio
IRB
Institutional review board
ITT
Intent to treat
IRT
Interactive Response Technology
IV
Intravenous(ly)
LC-MS/MS
Liquid chromatography-mass spectrometry/mass spectrometry
LDH
Lactic dehydrogenase
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
LMWH
Low molecular weight heparin


Novartis
Confidential
Page 10
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
LOH
Loss of heterozygosity
LPLV
Last patient last visit
LVEF
Left ventricular ejection fraction
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCRM
Modified continual reassessment method
MCV
Mean corpuscular volume
MDS
Myelodysplastic syndromes
MDS-U
Myelodysplastic syndrome, unclassified
MedDRA
Medical Dictionary for Regulatory Activities
mg/m2
Milligrams per square meter
MI
Myocardial infarction
MTD
Maximum tolerated dose
MUGA
Multiple uptake gated acquisition scan
MWF
Monday, Wednesday, Friday
NCI
National cancer institute
NIH
National Institutes of Health
NPGN
Novartis pharmacogenetic network
N/V
Nausea/vomiting
OBD
Optimum biologic dose
p.o.
Per os/by mouth/orally
PBMC
Peripheral blood mononuclear cells
PD
Pharmacodynamic
PD
Progressive disease
PE
Physical examination
PG
Pharmacogenetic
P-gp
P-glycoprotein
PK
Pharmacokinetic
PLT
Platelet
PR
Partial response
PS
Performance status
PT
Prothrombin time
PTT
Partial thromboplastin time
q.d.
Once a day
Q-RT-PCR
Quantitative reverse transcription polymerase chain reaction
QT
QT interval - portion of an electrocardiogram between the onset of the Q wave and the 
end of the T wave
QTc
ECG QT interval - corrected
QTcF
QR corrected with Fridericia’s formula
RA
Retinoic acid
RA
Refractory anemia
RAEB
Refractory anemia with excess blasts
RAEB-T
Refractory anemia with excess blasts in transformation
RARS
Refractory anemia with ringed sideroblasts


Novartis
Confidential
Page 11
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
RBC
Red blood cell
RAMD
Refractory anemia with multilineage dysplasia
RAMD-RS
Refractory anemia with multilineage dysplasia and ring sideroblasts
REB
Research ethics board
Right BBB
Right bundle branch block
RNA
Ribonucleic acid
RR
Response rate
RT-PCR
Reverse transcription polymerase chain reaction
SAE
Serious adverse event
SAHA
Suberoylanilide hydroxamic acid
SD
Stable disease
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SPEP
Serum protein electrophoresis
STS
Sample tracking system
SUV
Standardized uptake value
T/C
Tumor/control
T3
Triiodothyronine
FT4
Free Thyroxin
TDL
Toxic dose low
TIW
Three times a week
Tmax
Time to peak concentration
TNF
Tumor necrosis factor
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
UNK
Unknown
UPEP
Urine protein electrophoresis
VEGF
Vascular endothelial growth factor
Vidaza®
5-azacytidine, 5-Aza
VS
Vital signs
WBC
White blood cell
WOCBP
Women of childbearing potential
WHO
World health organization
WNL
Within normal limits


Novartis
Confidential
Page 12
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Amendment 5 (18-Nov-2016)
Amendment rationale
The CLBH589H2101 study started in December 2009 as a phase Ib dose escalation study of 
oral panobinostat in combination with 5-Azacitidine (5-Aza). The study was amended to a 
phase Ib/IIb with a randomized, two-arm, open-label design, adding an active control arm 
with single agent 5-Aza, with the first patient randomized on 19-March-2012. An interim 
Clinical Study Report (CSR) was planned, using a cut-off date corresponding to the time 
when the last patient enrolled in the phase IIb part had completed 12 months of treatment. The 
corresponding cut-off date was reached on 30-Apr-2014, an interim database lock took place 
on 30-Oct-2014, and an interim CSR was released on 7-May-2015. At the time of the cut-off 
date (30-Apr-2014), 17 patients were still on treatment, 4 in the phase Ib and 13 in the phase 
IIb. As of 01-May-2014, the schedule assessment was changed (as pre-specified in the 
protocol), leaving the efficacy-related assessments involving aspirate and biopsy samples at 
the discretion of the investigators.
The results described in the interim CSR suggested an unfavorable benefit/risk profile of the 
dose and schedule of panobinostat in combination with 5-Aza in this patient population.
However, some patients appear to derive benefit from their treatment, based on investigators 
assessment, and seven of them are still on treatment. The rationale of this amendment 5 is to 
ensure treatment access for these patients with a limited data collection. Therefore, for the 
patients ongoing treatment the study will focus on collecting continuously Adverse Events, 
Serious Adverse Events, Concomitant Medications, and Dose Administration Records 
information. In addition, information (date and reason) related to End of Treatment and Study 
Evaluation Completion, date of disease progression as well as Survival information must be 
provided. All other assessments will be performed at the discretion of the investigators. 
To align with the most up-to-date protocol template, the sections 6, 8, 9, 11, and 12 of the 
protocol have been updated. The Inform Consent was also updated according to the updated 
template. Furthermore, and in order to align with program level standard language, the 
pregnancy prevention information will be implemented at the same time as this protocol 
amendment 5, by means of update of the Informed Consent.
As of this amendment 5 there are 7 patients on treatment, one in the phase Ib and 6 in the 
phase IIb part of the study. 
The detailed changes to the protocol are listed below.
Changes to the protocol
The changes that are made to the protocol are listed below and integrated directly in the 
protocol with track changes using strike-through red font for deletions, red underlined for 
insertions. 

Section 6.6.1: paragraph “Study drug supply and resupply, storage, and tracking/drug 
accountability” has been moved to this section from Section 11.4

Section 6.6.1.8: reference to Table 7-5 has been updated 


Novartis
Confidential
Page 13
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

Section 6.6.3: text has been aligned with the visit evaluation schedule described in Table 
7-3

Section 6.6.5: new section added as per DOCE (Discontinuation of Clinical Trial Protocol 
Elements) guidelines

Section 6.6.6: section number has been updated and text has been aligned to DOCE 
guidelines

Section 6.6.7: new section added as per DOCE guidelines

Section 6.6.8: section number has been updated and text has been aligned with the visit 
evaluation schedule described in Table 7-3

Section 6.6.9: section number has been updated

Table 7-1: references to Table 7-5 and to Table 7-6 have been updated

Table 7-2: reference to Table 7-5 has been updated

Table 7-3: new table added to describe the visit evaluation schedule for patients ongoing 
treatment at the time of protocol amendment 5

Section 7.5.1: text has been aligned with the visit evaluation schedule described in Table 
7-3

Section 7.6: former Section 7.6.1 (Adverse Events) has been moved to Section 8.1

Section 7.6.1: section number has been updated

Table 7-4: table number has been updated

Section 7.6.2: table number has been updated and reference to Table 7-5 has been updated 

Table 7-5: table number has been updated and one footnote has been added to align the 
table with the visit evaluation schedule described in Table 7-3

Section 7.6.3: section number has been updated and references to Table 7-2 and to table 7-
3 have been added

Section 7.6.3.1: section number has been updated and text has been aligned with the visit 
evaluation schedule described in Table 7-3

Section 7.6.3.2: section number has been updated and text has been aligned with the visit 
evaluation schedule described in Table 7-3

Section 7.6.3.3: section number has been updated and text has been aligned with the visit 
evaluation schedule described in Table 7-3

Section 7.6.3.4: section number has been updated and text has been aligned with the visit 
evaluation schedule described in Table 7-3

Section 7.6.3.5: section number has been updated and text has been aligned with the visit 
evaluation schedule described in Table 7-3

Section 7.6.3.6: section number has been updated and text has been aligned with the 
current pregnancy program standard language and updated based on the status of ongoing 
patients 

Section 7.10: reference to Table 7-6 has been updated 

Table 7-6: table number has been updated


Novartis
Confidential
Page 14
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

Section 7.11: reference to Table 7-7 has been updated and text has been aligned with the 
visit evaluation schedule described in Table 7-3

Table 7-7: table number has been updated 

Section 7.11.1: text has been aligned with the visit evaluation schedule described in Table 
7-3

Section 8: header has been aligned with the latest Clinical Trial Protocol Template 

Section 8.1: Adverse Events section has been moved here from Section 7.6 and has been 
updated to be aligned with the current Clinical Trial Protocol template

Section 8.2: Serious Adverse Events section has been updated to be aligned with the 
current Clinical Trial Protocol template

Section 8.3: section has been added to be aligned with the current Clinical Trial Protocol 
template

Section 8.4: section number has been updated and text has been aligned with the current 
Clinical Trial Protocol template

Section 8.5: section has been added to be aligned with the current Clinical Trial Protocol 
template

Section 8.6: section number has been updated

Section 8.7: section number has been updated and header has been aligned with the latest 
Clinical Trial Protocol Template

Section 9: header has been aligned with the latest Clinical Trial Protocol Template 

Section 9.1: section has been added to be aligned with the current Clinical Trial Protocol 
template

Section 9.2: section number has been updated and text has been aligned with the current 
Clinical Trial Protocol template

Section 9.3: section number has been updated and text has been aligned with the current 
Clinical Trial Protocol template

Section 9.3.1: section number has been updated

Section 9.3.2: section number has been updated

Section 9.4: section number has been updated and text has been aligned with the current 
Clinical Trial Protocol template

Section 11: header has been aligned with the latest Clinical Trial Protocol Template 

Section 11.1: text has been aligned with the current Clinical Trial Protocol template

Section 11.2: text has been aligned with the current Clinical Trial Protocol template

Section 11.3: text has been aligned with the current Clinical Trial Protocol template. The 
paragraph “Amendments to the protocol” has been moved to section 12.1

Section 11.4: text has been aligned with the current Clinical Trial Protocol template. The 
paragraph “Study drug supply and resupply, storage, and tracking/drug accountability” has 
been moved to section 6.6.1

Section 11.5: section added to be aligned with the current Clinical Trial Protocol template


Novartis
Confidential
Page 15
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

Section 11.6: section added to be aligned with the current Clinical Trial Protocol template

Section 11.7: section added to be aligned with the current Clinical Trial Protocol template

Section 11.8: section added to be aligned with the current Clinical Trial Protocol template

Section 11.9: section added to be aligned with the current Clinical Trial Protocol template

Section 12.1: paragraph “Amendments to the protocol”  has been moved here from 
Section 11.3

The synopsis has been updated according to the changes described above
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


Novartis
Confidential
Page 16
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Amendment 4
Amendment rationale
This amendment is a country-specific, non-substantial amendment for the Republic of Korea 
to clarify in the Header of Table 6-4 and Table 6-5 that the therein provided dose adjustment 
recommendations are for panobinostat and Vidaza. The Korean Health Authority has given 
full approval for amendment 3, however requesting to make the above mentioned changes 
prior to start enrollment in Korea.
The CLBH589H2101 study started in December 2009 as a phase Ib dose escalation study of 
oral panobinostat in combination with 5-Aza and was amended to a phase Ib/IIb study with a 
randomized, two-arm, open-label design, adding an active control arm with single agent 5-
Aza in October 2011. LPFV of the phase I portion was in June 2011. The first patient was 
randomized onto the phase II portion in March 2012. As of this amendment, 20 of the planned 
80 patients have been enrolled globally. 
Changes to the protocol
The changes that are made to the protocol are listed below and integrated directly in the 
protocol with track changes using strike-through red font for deletions, red underlined for 
insertions. 
Section 6.6.1.8:

Table 6-4; Header title changes made to provide clarification around dose adjustment 
recommendations for Panobinostat and Vidaza.

Table 6-5; Header title changes made to provide clarification around dose adjustment 
recommendations for Panobinostat and Vidaza.


Novartis
Confidential
Page 17
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Amendment 3
The CLBH589H2101 study started in December 2009 as a phase Ib dose escalation study of 
oral panobinostat in combination with 5-Aza. In October 2011, after the determination of the 
recommended phase II dose (RPIID) at 30 mg, the study was recently amended to a phase 
Ib/IIb study with a randomized, two-arm, open-label design, adding an active control arm with 
single agent 5-Aza. As of this amendment 5 patients are ongoing from the phase Ib part and 
the first patient was randomized into the phase IIb part on 19 March 2012. It is planned to 
enroll a total of 80 patients into the phase IIb part.
Amendment rationale
This amendment 3 is a global amendment to provide guidance on dose adjustments for 
panobinostat and/or 5-Aza in the event of hematological toxicity, in particular 
thrombocytopenia and neutropenia as well as in the event of non-hematological toxicity for 
patients enrolled in the phase IIb part. 
In the Phase I portion of this study dose modifications were guided by DLT definitions 
(Section 6.6.1.6).  In the Phase II portion, these toxicities are no longer captured as DLTs. A 
global amendment was necessary to ensure optimal risk management for patients with 
toxicities and keeping the dose adjustments consistent across sites, avoiding any ambiguity at 
the end of the study with overall patient drug exposure.
For hematological toxicities, managing grade 3-4 cytopenias with optimal hematological 
support is necessary to maximize patient exposure to 5-aza and panobinostat.  Following 
optimal hematological support, dose modifications may become necessary to help patients 
tolerate study treatment.  For the non-hematological toxicities the approach was to manage 
these patients as per the 5-aza label and in keeping with current clinical practice.  This helps 
to maintain patient exposure to 5-aza which has been shown to improve outcomes.
Rationale for other changes in the protocol and the Informed Consent Form for 
phase IIb part:
Additional editorial corrections were needed in order to provide clarifications, to increase 
consistency within the protocol as well as with the Case Report Form (CRF), to harmonize 
with the Novartis Guidance on the Prevention of Pregnancies in Participants in Clinical Trials
and to rectify typographical errors throughout.
 
To harmonize eligibility of patients with current LBH protocols, Inclusion criteria #6 
which defines eligibility of euthyroid patients’ will be clarified by removing any mention 
of supplementation to avoid previous ambiguity. 
To provide clarification around IRT procedures.
To provide clarification on dose adjustments in Phase II. In particular, this clarification 
was necessary where a reference was given to the dose escalation levels as described in 


Novartis
Confidential
Page 18
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 6-3 (e.g. Dose adjustments due to prolonged QT interval) as this table is only 
applicable in the Phase Ib part. 
To provide clarification around bone marrow aspiration and/or core biopsy at screening. 
This clarification specifies time windows and gives an option not to repeat bone marrow 
aspiration and/or core biopsy at screening, however is limited to patients where the 
original bone marrow aspiration and/or core biopsy was performed within 14 days of 
starting study drug, and the original marrow (or marrow report) has sufficient information 
to assess diagnosis or eligibility of the patient and perform assessment of response when 
comparing to the next bone marrow assessment.  In addition, the time window for bone 
marrow collection and peripheral blood collection throughout the study were clarified.
To provide consistency with the CRF, in particular the visit numbering 
To provide consistency throughout the document that the reduced visit evaluation 
schedule described in Table 7-2 will have to be followed only for patients who have 
completed 12 cycles after the data cut-off date for the CSR has been reached.
To provide clarification around cardiac monitoring for patients in the control arm by 
adding an introduction to Table 7-4 and removing a footnote.
To provide consistency between the cardiac monitoring schedules described in Table 7-4 
and footnote 13 of Table 7-1, the number of ECGs at screening will be corrected to be 
“single” in the latter. 
To provide clarification on “seriousness” of Grade 4 events a note was added to section 
7.6.1  
To provide clarification in Section 8.2 that pregnancy outcome must be collected also 
female patients that took study treatment.
The protocol and the relevant sections of the Informed Consent Form (Phase IIb part) have 
been updated 

To align with the Novartis Guidance on the Prevention of Pregnancies in Participants 
in Clinical Trials, in particular the definition of WOCBP, urinary pregnancy testing 
during the duration of the study was added and the length of contraception clarified. 
 

Study title was corrected on the IC Signature Page
Informed Consent Form for Female Partners was updated to align the time window for 
contraception with the 5-Aza label.

[Post-text supplement 3] has been updated to rectify a corrupted sentence 

For consistency with the International Prognostic Scoring System (Greenberg et al, 1997), 
the score value for category ‘poor’ and ‘intermediate’ will be corrected in [Post-text 
supplement 1 Table 2-3].
Changes to the protocol
The major changes that are made to the protocol are listed below and incorporated directly in 
the protocol with track changes using strike-through red font for deletions, red underlined for 
insertions. Where appropriate, changes to the protocol body will be made to corresponding 


Novartis
Confidential
Page 19
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
sections for consistency.  Additional minor changes (e.g., correction of typographical errors) 
and re-phrasing of existing sentences to be more precise in wording are only incorporated 
directly in the protocol with track changes. 
The major changes to the protocol, and the 
sections affected, are detailed below.
Section 
Changes made
Protocol synopsis
All relevant sections of the protocol synopsis were 
updated to be consistent with the changes in the 
protocol body described hereafter.
 
Section 5.1 Inclusion Criteria 
IC #6 was updated to clarify eligibility of patients and 
empty IC #4 was clarified
Section 6.4.1
IRT procedures were clarified
Section 6.6.1.8 Dose modification, delay and 
discontinuation
Specific guidance was proposed for the Phase IIb 
portion in subsections Dose adjustment due to 
hematologic toxicity and Dose adjustment due to non-
hematologic toxicity, including Table 6-4 and Table 6-7. 
Section 6.6.1.8 Sub-section on Dose adjustments due 
to QT prolongations 
Reference to Table 6-3 Dose escalation level for dose 
reduction was replaced.
Table 7-1 
Visit numbers in the protocol were aligned with the 
Case Report Form (CRF) and urinary pregnancy tests  
were added on Day 1 of each subsequent cycle during 
study duration
Section 7.1
A new section was added to clarify the use of historical 
bone marrow collection for disease characterization 
Table 7-1 footnote 15  and Section 10
Updated to clarify start of reduced visit schedule 
Table 7-1 footnote 13
Typo corrected for number of ECGs at screening
Table 7-4
Editorial changes made to provide clarification around 
cardiac monitoring for patients in control arm 
Section 7.5.1 Efficacy Assessment and Table 7-1 
Footnote #14
Time windows for bone marrow aspiration/biopsy and 
peripheral blood collection were clarified 
Section 7.6.1
Note was added
Section 7.6.4.6
Urinary pregnancy testing at monthly intervals during 
study duration was added and aligned with the 
definition of WOCBP
Section 8.2
Female patients added
Informed Consent Form for Phase II and 
Informed Consent Form for Female Partners
Urinary pregnancy tests were added to the tests to be 
performed during the study treatment and the length of 
contraception was clarified. 
 
Post-text 3 supplement (1st section, first sentence)
Corrupted sentence was corrected
Post-text 1 supplement – Table 2-3
The score value for category ‘poor’ and ‘intermediate’ 
has been corrected


Novartis
Confidential
Page 20
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Summary of previous amendments 
Amendment 2 (released on 24 October 2011)
The purpose of Amendment 2 is to:

Collect preliminary efficacy data of panobinostat at the recommended phase II dose 
(RPIID) level in conjunction with azacytidine (5-Aza/Vidaza®) by introducing a 
randomized, two-arm, open-label expansion phase, which determines the phase IIb part of 
the study. 

Revise the eligibility criteria based on new safety information and current clinical practice.

Update the ECG safety monitoring schedule according to the current LBH589 cardiac 
safety profile.

Align the protocol with the current LBH589 guidance on the use of concomitant 
medications (as specified in the post-text supplement 3).
As of this amendment, the phase Ib part of this study is completed and the recommended 
phase II dose (RPIID) was established at 30 mg of oral panobinostat once daily on day 3, 5, 8, 
10, 12, and 15 in combination with azacytidine (5-Aza/Vidaza®). In total, 31 patients were 
enrolled in the phase lb part. Eighteen patients were treated at the dose level of 30 mg of 
panobinostat, 16 of which were evaluable for the MTD determining set. Dose escalation was 
not continued up to the MTD because of long term tolerability considerations.
Rationale for the phase IIb part

This amendment introduces a randomized phase IIb part with an active control arm so that 
the preliminary efficacy of panobinostat at the RPIID level in combination with 5-Aza 
versus 5-Aza alone can be rigorously studied. The most important advantage of proper 
randomization is that it minimizes allocation bias and the use of an active treatment 
comparator overcomes several limitations of a historical comparator, e.g., treatment arms 
can be balanced adequately with respect to both known and unknown prognostic factors 
and the confounding effect of imbalances in prior treatment can be controlled. 

Based on the Phase III AZA-001 study data (Fenaux et al 2009a), low response rates have 
been shown with 5-Aza alone. Assuming an increase in CR response rates can be achieved 
with the combination over the low rates seen with single-agent 5-Aza, CR including CRi 
for AML patients and bone marrow CR for MDS/CMML patients have been selected as 
primary efficacy endpoints in the phase IIb part.


Novartis
Confidential
Page 21
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

This randomized phase II part allows collecting safety data of panobinostat in combination 
with 5-Aza in comparison to single-agent 5-aza. In addition, it allows to better understand 
the degree of tolerability wherefore safety and tolerability have been selected as secondary 
endpoints in the phase IIb part. 
 

Data from the phase III AZA-001 study shows that 90% of the study population achieved 
a best response by Cycle 9 (Fenaux 2009b).  The core clinical study report (encompassing 
both, the phase Ib and the phase IIb part of the study) will be based on a data cut-off 
corresponding to the time point where all patients have either completed 12 cycles of 
study treatment or discontinued study treatment for any other reason, whichever comes 
first. An addendum to the core clinical study report will be provided at the completion of 
the study to summarize and/or list the additional safety and efficacy data as appropriate. 
Patients who have completed 12 cycles of study treatment and are assessed by the 
Investigator to have the potential to benefit from ongoing treatment will continue their 
assigned treatment allowing the collection and assessment of safety, efficacy and survival 
data. After the data-cut off point for the CSR a reduced assessment schedule will be 
applied.

Clinical response, the primary efficacy endpoint in the phase IIb part, is assessed by 
changes in bone marrow and peripheral blood blast percentages based on standardized 
response criteria proposed by Cheson et al. 2003 and 2006 (as specified in the post-text 
supplement 1). The proposed open label study design is not likely to impact the objective 
determination of response based on the Cheson criteria.
Rationale for protocol adjustments related to eligibility criteria, cardiac 
assessments, ECG monitoring schedule and the current LBH589 guidance on 
the use of concomitant medications 

Inclusion criterion #4 which defines patients’ eligibility according to INR and PTT 
laboratory parameter has been replaced with a criterion based on evidence of clinically 
significant mucosal or internal bleeding. The new criterion reflects more closely clinical 
practice and is aligned with newer AML protocols.

Due to limited data about the effect of myelosuppression caused by panobinostat, in 
particular thrombocytopenia, the eligibility criterion based on INR/PTT laboratory values 
was defined at the time of the original protocol. New safety information with regards to 
thrombocytopenia showed that irrespective of new or worsening grade 3/4 
thrombocytopenia, the incidence of grade 3/4 bleeding events (regardless of causality) was 
low and may be associated with baseline thrombocyte levels and other risk factors (tumor 
types, metastases). We recommend that patients who require chronic anticoagulation 
therapy at study entry or while on panobinostat therapy use low molecular weight heparin 
(LMWH).  However, if the use of LMWH is not feasible, such patients may continue on 
sodium warfarin while on panobinostat, but a close monitoring of common coagulation 
parameters, including a PTT/INR should be conducted.  Coagulation parameters at study 


Novartis
Confidential
Page 22
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
entry and during the course of the study should be maintained within a therapeutic range 
as appropriate for the indication.

During the course of this trial four grade 3 bleeding events of hemoptysis and recurrent 
bleeding in the oral cavity, intracerebral bleeding, and acute GI bleeding were reported in 
three patients (30 mg dose cohorts). Hemoptysis and recurrent bleeding in the oral cavity 
as well as intracerebral bleeding were not suspected to be related to panobinostat. For the 
acute GI bleeding event a possible relation with the study treatment was reported. 
However, confounding factors were confirmed by the investigator as the GI bleed was 
identified to originate from internal hemorrhoids and deemed to be secondary to Grade 4 
thrombocytopenia. All patients entered the trial with grade 3 thrombocyte counts which 
worsened to grade 4 on day 8 of the first cycle but were manageable with platelet 
transfusions. All events resolved within 3 days and none of the events were considered life 
threatening or required study drug adjustments.

MUGA has been added as another validated method to assess cardiac function.  Both, 
ECHO (echocardiogram) and MUGA (multiple gated acquisitions) scan are widely 
applied methods, used to monitor cardiac function in clinical practice and therapy-induced 
cardio-toxicity in clinical trials (e.g., with anthracyclines).

The ECG safety monitoring schedule has been updated according to the current LBH589 
cardiac safety profile. This is based on an integrated analysis of completed and ongoing 
studies using oral panobinostat showing minimal risk of QT prolongation with no 
clinically significant QTc interval changes. It also showed that the risk of QTc 
prolongations does not increase over time when oral panobinostat is dosed up to 40 mg 
three times a week (TIW) every week or 45 mg TIW every other week.  An integrated 
analysis was performed on the pooled centrally reviewed ECG data collected from three 
Phase I and six Phase II studies of single-agent oral panobinostat in 559 patients with 
advanced hematologic malignancies or solid tumors (Weber et al 2009).  A total of 554 
patients had both a baseline and at least one post-baseline ECG measurement (a total of 
23.017 ECG assessments).  This analysis has shown that oral panobinostat monotherapy at 
doses up to 40 mg TIW weekly and 45 mg TIW every other week was safe and well 
tolerated with no clinically significant QTc interval changes observed.  Major outliers 
(QTcF >500 ms) were observed in two patients (less than 1 % of patients) up to doses of 
45 mg, and these sporadic cases were generally associated with significant comorbidities 
(e.g., underlying heart disease, hypertension, and severe electrolyte disturbances).  
Baseline QTcF and age, but not dosing schedule, were identified as predictive factors for 
QT prolongation.  Significant mean and maximum QTcF interval changes were observed 
in Cycle 1 on Days 1 and 5 after the first and the third consecutive dose of panobinostat. 
Beyond Day 5, mean QTcF values showed a trend towards normalization compared with 
baseline up to the completion of Cycle 2.

With a dosing interval of 48 hours and the specific dosing schedule in this protocol 
(panobinostat intake on days 3, 5, 8, 10, 12, and 15), the ECG monitoring schedule was 
adjusted as follows: Cycle 1 Day 3 (first panobinostat dose), Days 8 and 12 (third and fifth 
consecutive dose of panobinostat) as well as on Day 3 of Cycle 2 and all subsequent 
cycles. ECGs time points at screening and EOS visit did not change

No study-drug related prolonged QTcF has been observed in this study. Two grade 3 
QTcF prolongation events have been reported, each one in the 30 mg or 40 mg 


Novartis
Confidential
Page 23
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
panobinostat dose cohort; none of which was suspected to be related to the study treatment. 
One occurred at C2D18 and the other at C1D26. The individual events resolved from 
several hours to approximately 2-3 days after their onset and required no actions with 
regards to the study treatment.

With this adjusted ECG monitoring schedule, patient safety will remain uncompromised 
while eliminating excessive tests that are inconvenient for patients.

To align with the current LBH589 guidance, the use of concomitant medications (as 
specified in the post-text supplement 3) has been updated. The current LBH589 guidance 
provides new information for the management of co-medications that prolong the QT 
interval, are strong CYP3A4/5 inhibitors or are CYP2D6 substrates. It also includes an 
updated list of medications which was developed in collaboration with an external 
cardiology consultant and is based on the ARIZONA CERT website on drugs that prolong 
the QT interval and/or induce Torsades de Pointes or ventricular arrhythmia 
(...azert.org/medical-pros/drug-lists/drug-lists.cfm). Additional information from the two 
drug-drug interaction studies [CLBH589B2110] and [CLBH589B2109] were incorporated. 

To date, none of the patients enrolled in this trial were concomitantly treated with 
dolasetron mesylate which should no longer be used to prevent nausea and vomiting 
associated with cancer chemotherapy in conjunction with panobinostat (LBH589). With 
regards to the medications (which have since been removed from the list of prohibited 
concomitant medications), three protocol deviations with respect to the concomitant use of 
aprepitant have been reported. 
Rationale for other changes in this amendment: 
Editorial corrections were needed in order to provide clarifications, increase the consistency 
of the document and rectify typographical errors throughout.

The primary objective of the original protocol (specified as the primary objective of the 
phase Ib part in the proposed amendment) was clarified to indicate that the dose being 
selected to go forward with, in the phase IIb part, will be based on considerations of the 
MTD estimation process using the BLRM, and on an overall assessment of safety taking 
into consideration long term tolerability data from subsequent cycles. The selected dose 
which would be referred to as the recommended phase II dose (RPIID) could be the same 
as the MTD but will not exceed it under any circumstance. This specification of the 
primary objective is consistent with the description of the dose escalation procedure and 
the statistical principles guiding it, in sections 6.7.1.4 and 10.1.4.2 of the protocol.
 

To provide clarifications on study procedures, time points, study visit terminology 

Section 7.1.8 including table 6-4 header has been rephrased to clarify that only QT 
interval prolongation is excluded from the general guidance on dose adjustments for 
non-hematological toxicities.  To date, two treatment-related cardiac toxicities 
(electrocardiogram T-wave inversion and atrial fibrillation and syncope) have been 
reported. With regards to the T-wave inversion, the study drug was interrupted for one 
dose (C1D15) and the patient continued the study without any dose adjustments after 
exclusion of a myocardial infarction and normalization of the electrocardiogram after 


Novartis
Confidential
Page 24
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
two days. Due to the suspected study drug relationship both cases were considered a 
DLT.

The first visit (days -14 to -1) where screening activities are to be performed is 
indicated as ‘baseline’ visit. The term ‘baseline visit’ has been replaced with the term 
‘screening visit’. 

Clarifications for Study Treatment Discontinuation, End of Treatment and End of 
Study have been provided in sections 6.7.3, 6.7.4 and 6.7.6

The narrow time window for laboratory evaluations on Day 1 of each cycle, in 
particular hematology and biochemistry has been extended from 48 hours to 72 hours.
 
 
 

In section 7.5.1 it has been clarified, that if additional non-study response assessments 
are being performed the number of units for red blood cells and/or platelets 
transfusions should be collected in the additional assessments transfusion CRF pages. 
This optional data recording only applies for the additional response assessment.

Red blood cell count (RBC) has been added in Section 7.5.4.1 (hematology) to 
provide details on hematology tests to be performed, in particular complete blood 
count.

To align with current standard CRF pages

Abnormal laboratory value(s) and Abnormal test procedure result(s) are no longer 
part of the standard EOT CRF page as they are considered AE(s) wherefore they have 
been removed from the list of End of Study reasons in section 6.7.4.

To implement the most recent pregnancy protocol language based on the Novartis 
Guideline on Prevention of Pregnancy

To align with the working instructions for Eligibility Check prior to Randomization
Changes to the protocol
The major changes that are made to the protocol are listed below and incorporated directly in 
the protocol with track changes using strike-through red font for deletions, red underlined for 
insertions. Where appropriate, changes to the protocol body will be made to corresponding 
sections for consistency. Additional minor changes (e.g., correction of typographical errors) 
and re-phrase of existing sentences to be more precise in wording are only incorporated 
directly in the protocol with track changes. 
Changes introduced for the phase IIb part 

Study Title has been modified and the phase IIb information added.


Novartis
Confidential
Page 25
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

Section 1.3.2 has been added to describe the current data from the phase Ib part of the 
study

Section 3: Objectives have been specified to describe the endpoints of the phase IIb part 

Section 4: The Study Design has been modified to introduce the randomized, two-arm 
phase IIb part. 

Section 6.1 and subsections have been revised with regards to the terminology used for 
investigational, combination and control drugs.

Section 6.1.1.2 has been revised to describe how the combination and/or control drug will 
be supplied in the phase IIb part

Section 6.3 describes the treatment schedule in the phase IIb part of the study including 
the addition of Figure 6-2.

Section 6.5 describes the treatment assignment in the phase IIb part including the addition 
of subsection 6.5.1 for IVRS procedures.

Section 6.4.7 has been amended to describe collection and capturing of survival data after 
End of Study.

Section 7 and Table 7-1 describes the modifications to patient visit assessments including 
pharmacokinetic (PK), 
 collection timepoints.

Table 7-2 has been added to describe the treatment visit schedule after 12 cycles
 

Section 8.3 has been amended to introduce a steering committee for the phase IIb part of 
the study.

Section 10 has been updated to reflect the statistical details for the phase I/IIb study.

The synopsis was updated according to the changes described above.
Changes introduced to adjust with new safety information, the programs 
updated ECG schedule and post-text supplement on concomitant medications 

Section 5.1 and 5.2 have been amended removing inclusion criteria #4 and adding 
exclusion criteria #19 and providing clarification on baseline cardiac assessment tests 
(exclusion criteria #9).

Section 7.5.3 including Table 7-3 has been adjusted according to the programs updated 
ECG monitoring schedule and to provide clarification on methods for cardiac assessments 

Table 7-1 (Visit evaluation schedule) including footnotes was revised according to the 
protocol amendment and the existing protocol

Post-text supplement 3 has been adjusted to align with the current LBH589 guidance on 
the use of concomitant medications


Novartis
Confidential
Page 26
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Other Changes in this amendment

The primary objective of the original protocol (specified as the primary objective of the 
phase Ib part in the proposed amendment) was clarified in all relevant sections of the 
protocol.

Section 1.2 was aligned with data on file with regards to response rates for AML patients 
treated in the B2102 study (manuscript for publication under preparation).

Clarifications for Study Treatment Discontinuation, End of Treatment, Follow up and End 
of Study have been incorporated in  6.7.3, 6.7.4, 6.7.5, and 6.7.6

The list of EOT reasons provided in Section 6.7.4 has been aligned according to the 
current standard EOT CRF page. 

Clarification on eligibility checks prior to randomization were provided in section 6.5.1 
and section 7 of the proposed amendment. 

Clarifications for Screening visit has been incorporated in all relevant sections in the 
proposed amendment including Table 7-1

Section 7.1.8 including the header of Table 6-4 has been changed to provide clarification 
on dose adjustment for cardiac toxicity. 
 
 

Clarification on time-window and study procedures have been incorporated in Section 
7.5.4.1 Hematology and 7.5.4.3 Biochemistry.

Section 8.2 has been aligned with the current pregnancy language

2008 has been removed from the reference on the Investigator Brochure in all relevant 
sections of the protocol.

Reference to EMA and FDA with regards to the Vidaza product label has been removed in 
sections 6.1.2.2, 6.7.1.2 and the reference section

To amend the List of Abbreviations

Editorial corrections were made in order to provide clarifications, increase the consistency 
of the document and rectify typographical errors throughout including tables
IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval prior to implementation. In addition, if the changes herein affect the Informed 
Consent, sites are required to update and submit for approval a revised Informed Consent that 
takes into account the changes described in this amended protocol.
Amendment 1 (released on 21 April 2010)
Please refer to Section 1.4 History of amendments


Novartis
Confidential
Page 27
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Oncology clinical study protocol synopsis
Investigational drug
LBH589
Protocol no.
LBH589H2101
Study phase
Ib/IIb
Study title
A phase Ib/IIb, open-label, multi-center, study of oral Panobinostat (LBH589) 
administered 
with 
5-Azacitidine 
(Vidaza®) 
in 
adult 
patients 
with 
Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia 
(CMML) or Acute Myeloid Leukemia (AML).
Background
Tumor cells inactivate transcription of growth control and pro-apoptotic genes 
in order to sustain proliferation and survival. Methods of gene inactivation 
include transcriptional silencing by hypermethylation of CpG islands in gene 
promoter regions and by hypoacetylation of chromatin preventing access of 
DNA-binding transcriptional regulators to promoter regions of genes. Reversal 
of these epigenetic processes results in up-regulation of genes that can 
reverse the malignant phenotype by a number of means including the 
induction of apoptosis and differentiation. Since these two processes are 
independent, but mechanistically related, the reversal of both processes can 
lead to greater gene transcription than the reversal of either one alone.
5-Azacitidine (5-Aza) is a demethylating agent and has been approved by 
FDA for the treatment of patients with all FAB subtypes MDS and by EMEA 
for the treatment of patients with high-risk MDS, CMML and AML, not eligible 
for hematopoietic stem cell transplantation. Panobinostat is a deacetylase 
inhibitor (DACi) that has been investigated in patients with lymphoid and 
myeloid malignancies as well as solid tumors. It has shown single-agent 
activity in cutaneous T-cell lymphoma (CTCL), and hematological disorders 
including HL, AML, MDS and chronic idiopathic myelofibrosis (CIM).
Pre-clinical studies have demonstrated that the administration of a 
demethylator followed by a deacetylase inhibitor (DACi) leads to greater gene 
re-expression and apoptosis induction than either alone. Consequently, a 
number of clinical trials have been conducted by several groups using 5-Aza 
in combination with DACi agents such as phenylbutyrate, valproic acid, 
belinostat and vorinostat.
Overall, this type of combined therapy appears to be not only safe, but has 
also shown a superior response rate compared to single agent epigenetic 
therapy, although this observation needs be confirmed in prospective 
randomized clinical trials. Of note is that slow onset of response, seen for 
single agent 5-Aza therapy in MDS, CMML and AML patients, appears to be 
accelerated by combining 5-Aza with DACi, with a median time to response of 
1 course (range, 1 to 3 courses) in contrast with the 4 to 6 courses for single-
agent 5-Aza. (Silverman et al 2008)
The strong preclinical rationale, encouraging clinical activity of single agent 
panobinostat, as well as published data showing enhanced clinical activity by 
combining two epigenetic-modifying agents suggest that panobinostat and 5-
Aza can be combined safely and be a therapeutic option of benefit for the 
patient.


Novartis
Confidential
Page 28
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Purpose/rationale
The primary purpose of the phase Ib part of this study is to determine the 
maximum-tolerated dose (MTD) and/or recommended phase II dose (RPIID) 
for the panobinostat / 5-Aza drug combination in patients with MDS, CMML or 
AML.
In vitro, the combination of a hypomethylating agent and a DAC inhibitor have 
been shown to have a synergistic effect both in terms of leukemia cell killing, 
and also in terms of gene reactivation. Based on this concept, a number of 
early clinical trials have been conducted by several groups using either 5-Aza 
in combination with agents such as phenylbutyrate (Gore 2006, Maslak 2006), 
MS-275, or valproic acid (Soriano et al 2007). All these studies have shown 
promising results compared to hypomethylating therapy alone and support a 
combined epigenetic therapeutic approach.
It is expected that the combination of these two agents can be safely 
administered and result in clinical benefit for the patients. As per registered 
label, 5-Aza is given subcutaneously (sc) for 1 week (Day 1-7). Panobinostat 
will be administered intermittently (Day 3, 5, 8, 10, 12, and 15) over 2 weeks 
in a 28-day cycle. 
In the two-arm, randomized phase IIb part of the study patients will be treated 
with panobinostat at the RPIID in combination with 5-Aza versus 5-Aza alone. 
The schedule of the phase Ib part will be followed. The primary purpose is to 
assess preliminary efficacy of this new regimen and to further characterize 
safety and tolerability.
Objectives
Phase Ib part
Primary objectives

To determine the MTD and/or RPIID of oral panobinostat in combination 
with a fixed dose of 5-Aza in adult patients with MDS, CMML, or AML.
Secondary objectives

To characterize the safety and tolerability of panobinostat in combination 
with 5-Aza in the target patient populations
As of amendment 2, the primary objective of the phase Ib part has been met  
and the recommended phase II dose (RPIID) has been determined to be 
30 mg of oral panobinostat once daily on day 3, 5, 8, 10, 12, and 15 in 
combination with 5-Aza as per the registered label (75mg/m2 on day 1-7). 
Dose escalation was not continued up to the MTD because of long term 
tolerability considerations.
Phase IIb part
Primary objective

To assess preliminary efficacy of treatment with the panobinostat and 5-
Aza combination at RPIID relative to treatment with single agent 5-Aza 
through the assessment of composite CR (CR or CRi or bone marrow 
CR).
Secondary objectives

To assess preliminary efficacy of treatment with the panobinostat and 5-


Novartis
Confidential
Page 29
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Aza combination at RPIID relative to treatment with single agent 5-Aza 
through the assessment of clinical response other than the composite CR 
specified in the primary objective, 1-year survival, and time to progression 
(TTP). 

To characterize the safety and tolerability of panobinostat at RPIID in 
combination with 5-AZA, as well as, 5-AZA alone in the target patient 
population.
 
 
Endpoints (efficacy, 
safety)
Phase Ib part
Primary Endpoint:

Incidence of dose limiting toxicity (DLT)
Secondary Endpoints:

Type, duration, frequency and relatedness of Adverse Events (AE). AE 
severity will also be assessed according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0)

Laboratory (biochemistry, hematology)

ECG monitoring (central review by eRT)
Phase IIb part
Primary Endpoint:

Composite CR (CR or CRi or bone marrow CR) 
Secondary Endpoints:

Clinical response for AML: PR; for MDS/CMML: PR and Hematologic 
Improvement (HI)

Overall response (CR or CRi or bone marrow CR or PR)

1-year survival

Time to progression (TTP) based on the Guidelines for Implementation of 
IWG response criteria in AML, MDS and CMML according to Cheson 
2003 and 2006 [Post-text supplement 1]

Type, duration, frequency and relatedness of Adverse Events (AE). AE 
severity will be assessed according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0)

Laboratory (biochemistry, hematology)

ECG monitoring (central review by eRT)


Novartis
Confidential
Page 30
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Study design
This is an open-label, multi-center phase Ib/IIb trial.
The primary objective of the phase Ib part is to determine the maximum 
tolerated dose (MTD) and/or recommended phase II dose (RPIID) of oral 
panobinostat in conjunction with a fixed dose of 5-Aza in adult patients with 
MDS, CMML or AML. The phase IIb part, that will commence once MTD 
and/or RPIID is established, has a randomized, two arm design and is 
designed to assess preliminary efficacy of panobinostat (in combination with 
5-Aza) at RPIID relative to 5-Aza alone, the current standard of care,
In the phase Ib part, escalating doses of oral panobinostat will be 
administered in combination with the registered schedule of subcutaneous 
(sc) of 5-Aza (75 mg/m2 daily for 7 days). A minimum of three patients 
constitutes a cohort for each dose level. During this iterative process the dose 
limiting toxicity (DLT) will be assessed after each cohort has completed Cycle 
1. In each subsequent cohort, patients will receive a dose of panobinostat 
guided by the Bayesian logistic regression model with overdose control 
(EWOC) together with a standard dose of 5-Aza until the MTD and/or RPIID is 
determined.
Starting dose of panobinostat will be 20 mg. At least 9 evaluable patients 
need to be treated at a certain dose level before this dose can be declared to 
be the MTD and/or RPIID. 
As of August 2011, the recommended phase II dose (RPIID) was determined 
to be 30 mg of oral panobinostat once daily on day 3, 5, 8, 10, 12, and 15 in 
combination with azacytidine (5-Aza/Vidaza®).
Additional 80 patients will be randomly assigned in a 1:1 ratio into the phase 
IIb part of the study receiving 30 mg of panobinostat plus 5-Aza 
(investigational arm) or single agent 5-Aza (active control arm). Single agent 
5-Aza will be administered according to the registered label (75mg/m2 daily for 
7 days), 
Patients will continue treatment until disease progression, unacceptable 
toxicity or consent withdrawal, whichever comes first The core clinical study 
report will be based on a data cut-off corresponding to the time point where all 
patients have either completed 12 cycles of study treatment or discontinued 
study treatment for any other reason whichever comes first. An addendum to 
the core clinical study report (encompassing both phase Ib and phase IIb 
parts) will be provided at the completion of the study to summarize and/or list 
the additional safety and efficacy data as appropriate. 
Patients who have completed 12 cycles of study treatment and are assessed 
by the Investigator to have the potential to benefit from ongoing treatment will 
continue their assigned treatment allowing collecting and reviewing safety, 
efficacy and survival data. After the data-cut off point for the CSR, a reduced 
visit and assessment schedule will be applied.
Population
Adult patients with IPSS INT-2 or high risk MDS, CMML or AML not eligible 
for HSCT
Inclusion/exclusion 
criteria
Inclusion
1.
Adult patients (age ≥ 18 years) who are candidates for treatment with 5-
Aza and present with one of the following:

intermediate-2 or high-risk myelodysplastic syndromes according to 
the International Prognostic Scoring System (IPSS). OR

AML with multilineage dysplasia and maximum of 30% blasts (former 
RAEB-T according to FAB) OR

chronic myelomonocytic leukemia (CMML)


Novartis
Confidential
Page 31
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
2.
ECOG performance status ≤ 2
3.
Patients must have the following laboratory values unless elevations are 
considered due to MDS or leukemia: AST/SGOT and/or ALT/SGPT ≤ 2.5 
x ULN; serum creatinine ≤ 1.5 x ULN; serum bilirubin (total and direct) ≤ 2 
x ULN; serum electrolytes (e.g. Calcium, Magnesium and Potassium) are 
within normal ranges for the institution
4.
- Not applicable-
5.
Negative pregnancy test
6.
Patients who are clinically euthyroid
7.
Written informed consent obtained prior to any screening procedures
Exclusion
1.
Planned hematopoietic stem-cell transplantation (HSCT)
2.
Patients with therapy-related MDS
3.
Patients with therapy-related AML and/or relapsed/refractory AML
4.
Clinical symptoms suggesting CNS leukemia
5.
Concurrent therapy with any other investigational agent
6.
Prior treatment with deacetylase inhibitor(s)
7.
Prior treatment with 5-Azacytidine or 5-aza-2'-deoxycytidine
8.
Time windows for prior therapies: Last dose of therapy, including 
cytokines and/or retinoids, immunotherapy, low-dose ara-C, 
investigational agent less than 28 days with the exception of hydroxyurea 
(24 hours) prior to receipt of study medication or AEs that have not 
recovered at least to NCI CTCAE Grade 1.
9.
Patients with impaired cardiac function including any of the following:

Complete left bundle branch block or use of a permanent cardiac 
pacemaker, congenital long QT syndrome, history or presence of 
ventricular tachyarrhythmia, clinically significant resting bradycardia 
(<50 beats per minute), QTcF > 460 ms on screening ECG, or right 
bundle branch block + left anterior hemiblock (bifascicular block)

Presence of unstable atrial fibrillation (ventricular response rate >100 
bpm). Patients with stable atrial fibrillation are eligible provided they 
do not meet the other cardiac exclusion criteria

Previous history of angina pectoris or acute MI within 6 months

Screening LVEF <45% by echocardiography or MUGA

Other clinically significant heart disease (e.g. uncontrolled 
hypertension or history of poor compliance with an antihypertensive 
regimen).
10. Drugs which may cause QT prolongation and the treatment cannot be 
discontinued or switched to a different medication prior to starting study 
drug.
11. Any of concurrent severe and/or uncontrolled medical conditions which 
could compromise participation in the study. For example:

Uncontrolled diabetes

Active or uncontrolled infection

Uncontrolled hypothyroidism

Acute or chronic liver or renal disease
12. Impairment of gastrointestinal (GI) function or GI disease that may 


Novartis
Confidential
Page 32
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
significantly alter the absorption of oral panobinostat (e.g., ulcerative 
diseases, diarrhea, malabsorption syndrome, or small bowel resection).
13. HIV, Hepatitis B/C infection according to the medical history (testing will 
not be performed).
14. Female patients who are pregnant or breast feeding or patients of 
childbearing potential (WOCBP) not willing to use a double barrier method 
of contraception during the study and for 3 months following the last dose 
of study drug.
15. Male patients whose sexual partner(s) are WOCBP who are not willing to 
use a double barrier method of contraception, one of which includes a 
condom, during the study and for 3 months after the end of treatment.
16. Suspected hypersensitivity to 5-Aza or Mannitol
17. Inability to swallow capsules
18. Unwilling or unable to comply with the protocol
19. Patient has evidence of clinically significant mucosal or internal bleeding
Patient numbering
Upon signing the informed consent, each patient in the study will be uniquely 
identified by a 9 digit patient number, which is a combination of his/her 4-digit 
center number and 5-digit subject number.
In the phase IIb part, a separate numbering scheme, different from the one 
used in the phase Ib part, will be applied for the 5-digit subject number. The 
first patient, at each site, in the phase IIb part will be assigned the subject 
number 10001, and subsequent patients at the site, will then be assigned 
consecutive numbers (i.e., the second patient is assigned patient number 
10002, the third patient is assigned patient number 10003 etc).
Investigational and 
control drugs
Terminology used:
Study drug = panobinostat
Combination drug = 5-Aza
Control drug = 5-Aza (only in phase IIb part) 
Study treatment = panobinostat + 5-Aza
Dose, regimen, 
treatment cycle
A study treatment cycle lasts 28 days. 5-Aza will be administered by sc 
injection of 75 mg/m2 on Days 1 to 7. The study drug panobinostat will be 
administered orally on Days 3 and 5 in week 1, on Days 8, 10, 12 in week 2, 
and on Day 15 in week 3 of the treatment cycle (= total of 6 oral panobinostat 
doses)..
In the phase IIb part, the planned dose of panobinostat is 30 mg, which is the 
RPIID, determined in the phase Ib part of the study 
Supply, preparation, 
and administration
Oral panobinostat is available as 5-mg,10-mg (when available) or 20-mg 
capsules and will be dosed orally on a flat scale of mg/day. In the phase Ib 
part, 5-Aza will be supplied by the Sponsor (Novartis); For the phase IIb part, 
5-Aza will be purchased commercially as part of standard care. 5-Aza will be 
supplied by Novartis only for patients from those countries where 5-Aza is not 
available as standard care, or where no alternative method of obtaining or 
paying for 5-Azabased on the patient’s local regulation can be identified. 5-
Aza is administered sc Day 1-7 of the treatment cycle according to 
manufacturer’s instructions.
Visit schedule and 
assessments
See Table 7-1, Table 7-2 and Table 7-3
Efficacy 
assessment(s)
The IWG criteria for response in MDS, CMML (Cheson et al 2006) and AML 
(Cheson et al 2003) will apply to evaluate disease response as implemented 
in [Post-text supplement 1].


Novartis
Confidential
Page 33
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Special safety 
assessment(s)
Serial ECGs will be taken for cardiac safety.
Patient reported 
outcomes
There are no Quality of Life assessments in this protocol
Pharmacokinetics
Pharmacokinetic samples of panobinostat will be collected at pre-dose on 
Cycle 1 Days 4, 5, and 8 in all patients participating in the phase Ib part of the 
study. 
Whole blood (3 mL per sample) will be collected and stored frozen at < -60C 
before shipping to Novartis for analysis. Panobinostat plasma concentrations 
will be measured using a validated LC/MS/MS method with a LLOQ of 
0.5 ng/mL or lower.
Plasma panobinostat trough levels (Cmin in ng/mL) will be summarized by 
study day.
No pharmacokinetic samples of panobinostat will be collected and analyzed in 
the phase IIb part of the study.
 


Novartis
Confidential
Page 34
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Exploratory 
Biomarker 
pharmacodynamic 
studies involving 
tumor samples
Not applicable.
Optional Biomarker 
studies on additional 
or remaining samples
Not applicable
Data Monitoring 
Committee
A Data Monitoring Committee will not be in place for this trial. Instead, in the 
phase Ib part of the study, Novartis and the study investigators agree to 
convene once each treatment cohort has completed (or earlier in case of 
DLT) to make decision on whether to escalate the dose any further, or 
whether to de-escalate and/or expand recruitment into particular cohort/s. 
This group will also decide when the MTD and/or RPIID for panobinostat in 
combination with 5-Aza has been reached. In the phase IIb part a steering 
committee will be established.
Statistical methods 
and data analysis
Phase Ib part
An adaptive Bayesian logistic regression model (BLRM) for combination 
therapy, including the escalation with overdose control (EWOC) principle will 
be used to guide the dose escalation to determine the MTD of panobinostat in 
combination with a fixed dose of 5-Aza. MTD will be assessed during the first 
treatment cycle. Historical data of 5-Aza regimens as well as data from study 
[CLBH589B2102, arm X] for panobinostat were used to derive informative 
priors for the model parameters.
Each cohort will consist of a minimum of 3 patients fully evaluable for therapy-
related toxicities over the first cycle of treatment.
A dose limiting toxicity (DLT) is defined as an adverse event or abnormal 
laboratory value occurring at any time and assessed as clinically relevant and 
is considered to be related to the study treatment, unrelated to disease, 
disease progression, inter-current illness, or concomitant medications. 
Toxicities will be assessed using the NCI CTCAE, version 3.0.
After each cohort of patients has completed the first cycle of treatment, the 
posterior distribution for the model parameters will be obtained by simulation. 
Based on the posterior distribution of all model parameters, the corresponding 
posterior distributions for probabilities of a DLT are obtained. Dose 
recommendation within each part of the dose escalation will be based on 
posterior summaries for each dose combination including the mean, median, 
standard deviation, 95%-credibility interval, and the interval probabilities for 
under-dosing, targeted, excessive, and unacceptable toxicity.
Once updated, the distribution summarizes the probability that the true 
probability of a DLT for each dose combination lies in one of the following 
categories:
[0%, 20%)
under-dosing


Novartis
Confidential
Page 35
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
[20%, 35%)
targeted toxicity
[35%, 60%)
excessive toxicity
[60%, 100%]
unacceptable toxicity.
Following the principle of escalation with overdose control, after each cohort 
of patients the recommended dose combination is the one with the highest 
posterior probability of DLT in the target interval [20%, 35%) among the doses 
fulfilling the overdose criteria: there is less than 25% chance of either 
excessive or unacceptable toxicity.
The dose of panobinostat recommended by the adaptive BLRM may be 
regarded as information to be integrated with a clinical assessment of the 
toxicity profiles observed thus far in determining the next dose to be 
investigated.
At least 9 evaluable patients are to be treated at a dose level to declare the 
dose as MTD and/or RPIID.
The recommended phase II dose (RPIID)  of panobinostat in combination with 
a fixed dose of 5-Aza will be based on considerations of the  MTD estimation 
process  using  the BLRM, and on an overall assessment of safety taking into 
consideration tolerability data from subsequent cycles.
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.
Phase IIb part
The planned sample size is 40 per arm, or in other words, 80 in total.  It is 
deemed that an observed improvement of 50% in composite CR rate is 
clinically relevant in the phase llb part of the study.  Under the assumption that 
the composite CR rate in the active control arm is 17% (estimate based on 
Fenaux et al 2009a), the chance of observing a clinically relevant 
improvement when there is actually no difference in the true composite CR 
rates between the arms is estimated to be 23% while the chance of not 
observing a clinically relevant improvement when there is indeed a substantial 
difference in the true composite CR rates (true composite response rate in 
experimental arm is 35%) is estimated to be 19%.
For all safety analyses, the safety set will be used. For efficacy analyses, the 
full analysis set (FAS) will be used. All listings and tables will be presented by 
treatment arm (‘as treated’ for the safety analyses, and ‘as randomized’ for 
the efficacy analyses). 
Efficacy variables and endpoints
The primary efficacy endpoint will be the composite CR (CR or CRi or bone 
marrow CR) among all patients in the FAS.
The following other efficacy endpoints will be considered as part of the 


Novartis
Confidential
Page 36
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
secondary efficacy analysis: 

Clinical response for AML: PR; 

Clinical response for MDS/CMML:PR and Hematologic Improvement (HI)

Overall response (CR or CRi or bone marrow CR or PR)

1-year survival rate

Time to progression
Clinical responses will be summarized by treatment arm, overall and within 
disease type (i.e. AML or MDS/CMML). Percentage rates for composite CR 
(CR or CRi or bone marrow CR) will be reported along with 95% confidence 
intervals for both arms. Exact binomial confidence interval (implemented using 
SAS procedure FREQ with EXACT statement for one-way tables) will be 
calculated (Clopper and Pearson 1934). Point estimates and confidence 
intervals for the difference in rates between the treatment arms will also be
reported. The 1-year survival rate will be obtained from the Kaplan-Meier 
curve and its variance will be estimated by Greenwood’s formula. Time to 
progression will also be analyzed through Kaplan-Meier curves.
Safety variables and analysis
All adverse events recorded during the study will be summarized by treatment 
arm. The incidence of treatment-emergent adverse events (new or worsening 
from baseline) will be summarized by body system, severity (based on 
CTCAE grades), type of adverse event, and relation to the study treatment. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed 
by patient, type of adverse event, and treatment arm.
The assessment of safety will be based mainly on the frequency of adverse 
events, on the number of laboratory values that fall outside of pre-determined 
ranges, and other safety data. 


Novartis
Confidential
Page 37
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
1
Background
1.1
Overview of myelodysplastic syndromes (MDS)
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid disorders 
characterized by ineffective hematopoiesis, dysmorphic hematopoietic cells and low blood 
cell count. The worldwide incidence is approximately five per 100.000 individuals in the 
general population and rises with increasing age: 4.9 for people aged 50 to 70 years vs. 22.8 
for people older than 70 years (Aul et al 2002). Clinical characteristics are variable and 
diagnosis is typically made on the basis of abnormalities in bone marrow and peripheral blood 
appearance. As a result, patients with MDS are at risk for symptomatic anemia, infection and 
bleeding. MDS can arise de novo (primary MDS) or following treatment with chemotherapy, 
radiation therapy or chemical injury (secondary MDS). Depending on the subtype of 
myelodysplasia, there is a risk of approximately 50% for development of acute myeloid 
leukemia (AML), which is often refractory to standard treatment.
MDS are characterized by chromosomal numerical alterations or, more rarely, by 
chromosomal translocations, involving genes critical in controlling hematopoiesis. Epigenetic 
alterations may also be influential in disease progression. Epigenetic alterations significantly 
contribute to neoplastic transformation and have prognostic significance in MDS. Alterations 
may affect the pattern of histone acetylation, histone methylation and DNA methylation and 
are extremely common in high-risk MDS. Reversal of abnormalities in DNA methylation may 
restore expression of genes with tumor-suppressive function and provide a novel approach to 
therapy of MDS (see Section 1.1.2).
Patients with MDS are generally elderly and the presence of co-morbidities does not allow the 
use of aggressive chemotherapy or bone marrow transplantation.
Different MDS subtypes have been identified based on shared cellular morphology, and two 
main classification systems have been developed based on these subtypes.
1.1.1
Classification of MDS
The diagnosis and classification of MDS can be based on the French-American-British (FAB) 
classification system and the more recent updated WHO classification system. (Tefferi and 
Vardiman 2008). The World Health Organization (WHO) classification of myeloid neoplasms 
provides an extension and improvement of the FAB classification. New categories consisting 
of refractory cytopenia with multilineage dysplasia (RCMD), with (RCMD-RS) or without 
ring sideroblasts, the 5q-minus syndrome, refractory anemia with excess blast-I (RAEB-I) and 
RAEB-II, and “MDS unclassified” were added to the classification (Muller-Berndorff et al 
2006). Chronic myelomonocytic leukemia (CMML) became part of the new group of 
MPD/MDS overlap disorders. RAEB in transformation (RAEB-t) was eliminated by lowering 
the blast requirement in the bone marrow for a diagnosis of AML from 30% to 20%, taking 
into consideration the fact that patients with 20% to 30% blasts (previously called refractory 
anemia with excess blasts in transformation [RAEB-T]) might have AML. In addition to 
similarities in the natural history of RAEB-T and AML, RAEB-T responds to combination 
chemotherapy in a fashion similar to that of AML. (Albitar et al 2002)


Novartis
Confidential
Page 38
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
The International Prognostic Scoring System (IPSS) issued in 1997 provides a method for 
prediciting clinical outcome for patients with MDS [Post-text supplement 1]. Critical factors 
include risk-based cytogenetic subgroups (good, intermediate, and poor), bone marrow blast 
percentage and cytopenias. Patients are grouped into 4 risk categories based on total scores 
from these prognostic factors (Greenberg et al 1997)
Table 1-1
International Prognostic Scoring System and prognosis
Risk group
Score
Median survival 
(years)
Time to AML 
transformation 
(years)
Low risk
0
5.7
9.4
INT-1
0.5-1.0
3.5
3.3
INT-2
1.5-2.0
1.2
1.1
High risk
>2.5
0.4
0.2
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that is 
characterized by both myeloproliferative neoplasm and myelodysplastic syndrome. It is 
characterized by 1) persistent monocytosis > 1x 109/L in the peripheral blood (PB); 2) absence 
of Philadelphia chromosome and BCR-ABL 1 fusion gene; 3) no rearrangement of PDGFRA 
or PDGFRB; 4) fewer than 20% blasts in the PB and bone marrow; and 5) dysplasia involving 
one or more myeloid lineages. Reported median survival time is 20 to 40 months and 
progression to AML occurs in approximately 15-30%. (WHO 2008)
1.1.2
Treatment options in intermediate-2 (INT-2) and high risk MDS
New agents effective in the treatment of MDS have been identified. Earliest among these 
agents was azacytidine (5-Aza / Vidaza®), the first drug approved specifically for the 
treatment of MDS.
The first milestone study for 5-Aza was the Phase III trial conducted by the Cancer and 
Leukemia Group B (CALGB9221) in 191 MDS patients of all FAB subtypes randomized to 
receive sc 5-Aza (75 mg/m2/day for 7 days q 28 days) or best supportive care (BSC). While 
therapy-related mortality was negligible, overall response reached 60%, compared with 5% in 
the control arm. Recent re-evaluation of the results of all 5-Aza trials, applying IWG criteria 
of response to treatment in MDS, has confirmed the efficacy of the drug (Cheson et al 2006), 
indicating a 10-17% complete remission (CR) rate and validating an overall response of 44-
47%. In all studies, achievement of response was obtained after at least four cycles of therapy 
in 75% of MDS-responding patients, but in some cases there were late in time responders. 
Mean response duration was 15 months. (Silverman 2002, Silverman 2006) (Table 1-2)


Novartis
Confidential
Page 39
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 1-2
Hematological response and hematological improvement based on 
IWG criteria for MDS
Trial
Response (%)
Overall
CR
PR
HI
AZA-001 sc (n=179)
51
17
12
49
CALGB9221 (5-Aza sc 
arm [n=99])
47
10
1
36
CALGB9221 (5-Aza 
after cross-over 
[n=51])
35
6
4
18
CALGB8921 sc (n=72)
40
17
0
23
CALGB8421 (5-Aza iv; 
n=48)
44
15
2
27
Data from (Cheson et al 2000)
The CALGB trial did not succeed in assessing the clinical benefit of 5-Aza on overall survival 
(OS) because of the cross-over allowed to non-responding patients. Therefore, a prospective, 
randomized, Phase III, trial was conducted to assess 5-Aza’s effect on overall survival in 
patients with higher risk MDS compared with routinely used MDS treatment regimens. 
(Fenaux et al 2009a)
In the second milestone trial, the AZA-001 study, 358 patients were randomly assigned to 5-
Aza (sc 75 mg/m2/day for 7 days q 28 days) or conventional care regimens (CCR), consisting 
of BSC, low-dose ara-C or intensive chemotherapy. Patients with IPSS INT-2 and high-risk 
MDS, refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in 
transformation (RAEB-T) and modified CMML were enrolled. A total of 113 patients 
originally classified as MDS according to the FAB classification met the criteria for AML 
according to the more recent WHO classification (i.e. with >20% bone marrow blasts). The 
primary endpoint of the study was overall survival. In the ITT analysis, 5-Aza treatment was 
associated with statistically significant improvement in overall survival (OS), thereby 
suggesting that 5-Aza, acting as demethylating agent at doses lower than those of initial US-
NCI studies as cytotoxic agent, may alter the natural history of MDS. After a median follow-
up of 21.1 months, median overall survival was 24.5 months for the 5-Aza group versus 15.0 
months for CCR group (HR 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). A 
subgroup analysis indicated that prolongation of OS with 5-Aza included also patients with 
unfavorable cytogenetics, in particular a 53.6% hematological improvement (HI) in 5-Aza 
treated -7/del(7q) patients vs. 18.5% HI in -7/del(7q) patients treated with a CCR (Mufti et al 
2008).
1.1.3
Overview of safety profile obtained with 5-Aza
The safety profile emerging from the initial phase I, II and III studies in various tumor types is 
summarized in Table 1-3 and represents data on file in the US-NCI Investigational Drug 
Branch for 636 patients receiving 5-Aza alone at various continuous dose levels.


Novartis
Confidential
Page 40
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 1-3
Summary of major toxic effects of 5-Aza
Percentage of patients with toxic effects
Dose 
schedule
Dose 
range
(mg/m2)
Evaluable 
patients
(n)
Nausea
Vomiting
Diarrhea
WBC 
(<1500/ 
mm3)
PLTs
(<105/mm3)
Daily x 5, iv
Daily x 10, iv
Daily x 10, sc
5-Day cciv
50-400
0.5-2.4a
27-85
50-200
376
206
18
36
71
76
44
58
70
93
22
58
40
60
16
bOcc.
24
27
22
76
9
29
16
25
aExpressed in mg/kg; bOccasional; c Continuous intravenous infusion
Several of the initial Phase I studies showed leucopenia as a dose-limiting toxicity and a dose-
related phenomenon. The mean nadir occurred at 25-40 days with a range of 18-56 days. 
Recovery took place in 1 to 3 weeks. Thrombocytopenia (< 100 x 109/L) was reported in 17% 
of patients receiving the drug. The mean nadir occurred at 18 days with a range of 13 to 21 
days.
Two Phase 2 studies of single agent 5-Aza in high-risk MDS (RAEB and RAEB-T) conducted 
by CALGB showed myelosuppression as the most common toxicity. On the basis of standard 
CALGB criteria, grade 3 or 4 leucopenia occurred in 59%, granulocytopenia in 81%, and 
thrombocytopenia in 70% of patients. When hematological toxicity was reassessed centrally 
using relative changes in peripheral blood counts compared with those at study entry, a 
decrease of 50% to 74% was defined as grade 3 and 75% or greater was defined as grade 4. 
Based on these criteria, grade 3 or 4 leucopenia occurred in 43%, granulocytopenia in 58%,
and thrombocytopenia in 52% of patients. Toxicity was transient, and patients usually 
recovered in time for the next treatment cycle. Infection may have been related to treatment in 
20% of patients. Nausea or vomiting occurred in 4%. There was one (< 1%) treatment-related 
death.
In the Phase III AZA-001 study peripheral cytopenias were the most common grade 3-4 
adverse events for all treatments with 91% of patients in the 5-Aza group experiencing 
neutropenia, 85% thrombocytopenia and 57% anemia. Baseline grade 0-2 cytopenia 
progressed to grade 3 or 4 during treatment in 74% of patients treated with 5-Aza as compared 
to 72% of patients on CCRs. Discontinuation because of hematological adverse events was 
higher (5%) in the 5-Aza arm vs. 2% in the CCR arm. However, 5-Aza could be delivered full 
dose in 86% of patients, who remained on 75 mg/m2/day throughout the study with no dose 
adjustments. The median 5-Aza cycle-length was 28 days (range 28-35); 862 (54%) of the 
1611 cycle-lengths were 28 days, 413 (26%) 29-35 days, and 336 (21%) longer than 35 days.
In 2004, 5-Aza (Vidaza®) was granted Marketing Authorization by the FDA for treatment of 
patients with all FAB subtypes of MDS (Vidaza® PI 2004 and 2008). In 2008 EMEA/CHMP 
has granted Marketing Authorization in EU for 5-Aza treatment of patients who are not 
eligible for hematopoietic stem cell transplantation with (a) intermediate-2 and high-risk MDS 
according to the IPSS; (b) CMML (10%-29% marrow blasts without proliferative disorder); 
(c) AML with 20%-30% blasts and multi-lineage dysplasia, according to the WHO 
classification (Vidaza® SPC 2008). For more details on the safety profile please refer to the 
corresponding Prescribing Information (PI).


Novartis
Confidential
Page 41
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
1.2
Overview of panobinostat (LBH589)
Panobinostat (LBH589) is a potent class I/II pan-DAC inhibitor (pan-DACi) that has shown 
anti-tumor activity in pre-clinical models and cancer patients. Deacetylases (DAC) target 
lysine groups on chromatin and transcription factors and various non-histone proteins such as 
p53, tubulin, heat shock protein 90 (HSP90) and retinoblastoma protein (Rb). Panobinostat is 
formulated as an oral capsule and a solution for intravenous (i.v.) injection. A summary of key 
clinical data on panobinostat is herewith reported, for details please refer to the Investigator 
Brochure.
In patients oral panobinostat is rapidly absorbed and maximal plasma concentrations are 
reached within one hour. Its bioavailability is approximately 40% and the elimination half-life 
is ~ 16 hours. Using intermittent, i.e. three-times-a-week weekly, administration schedule, the 
time to reach steady-state panobinostat plasma level is approximately seven days.
Oral panobinostat as a single agent has been tested in hematological malignancies in a large 
Phase I study [CLBH589B2102] (Spencer 2007, Ottmann 2008). This study was planned to 
evaluate 2 schedules:

Arm 1 - three-times-a-week every week

Arm 2 - three-times-a-week every other week
Within each schedule (arm) patients were assigned to one of two subgroups, based upon the 
type of their hematological malignancy. Patients with leukemia, MDS and other 
hematological malignancies characterized by impaired bone marrow were included in 
subgroup X, while patients with lymphoma or myeloma were included in subgroup Y. The 
subgroups differed with respect to the definition of hematological dose limiting toxicity 
(DLT); neutropenia and thrombocytopenia were considered DLT only in the subgroup Y.
Enrollment into study [CLBH589B2102] has been completed to 152 patients. In the study 
database, clinical data are available for 146 patients (Arm 1: 90 total [64 subgroup X, 26 
subgroup Y]; Arm 2: 56 total [33 subgroup X, 23 subgroup Y]). A summary of the dose 
escalation in Arm 1 and Arm 2 is presented in Table 1-4 and Table 1-5, respectively. Only 
data on subgroup X are presented since MDS patients were assigned to this subgroup in study 
[CLBH589B2102]. Information on subgroup Y can be retrieved from the Investigator 
Brochure.
Table 1-4
Study CLBH589B2102 dose escalation summary - Arm 1 (three-times-
a-week every week)
Subgroup
Dose Level (mg)
N. Patients 
Evaluable/Treated
Cycle 1 DLTs
X
(Leukemias, MDS, 
Myelofibrosis)
20,30
12/16
None
40
8/10
G3 fatigue-2 pts
60 (MTD)
12/16
G3 fatigue-1pt
80
7/11
G3 QTcF prolongation +G3 
fatigue-1pt
G3 QTcF prolongation-1pt
G3 cardiac insufficiency-1pt
G3 fatigue-1pt


Novartis
Confidential
Page 42
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 1-5
Study CLBH589B2102 dose escalation summary - Arm 2 (three-times-
a-week every other week)
Subgroup
Dose Level (mg)
N. Patients 
Evaluable/Treated
Cycle 1 DLTs
X
(Leukemias, MDS, 
Myelofibrosis)
30,45,60
20/24
None
801
8/9
G3 QTcF prolongation-1pt
G3 atrial fibrillation-1pt
G3 fatigue-1pt
G3 bilirubin-1pt
1 MTD was not determined for the every other week schedule as this schedule did not show signals of 
clinical activity of single agent panobinostat in the study population.
2 Dose escalation above 60 mg was not permitted due to DLTs observed at 80 mg in Group X.
The MTD with the three-times-a-week weekly schedule of single agent panobinostat in 
patients with leukemias/MDS was declared to be 60 mg.
Across Arm 1 and 2, a total of 4,834 post-dose ECGs were performed in 146 enrolled patients. 
No dose dependent increase in mean change from baseline QTcF was noted. Five patients 
(3%) experienced QTcF >500 ms. However, all five patients were among the 76 patients (7%) 
treated at dose levels ≥60 mg.
A preliminary evaluation of clinical data from 71 patients with AML indicated that:

no antileukemic activity was observed in patients treated in Arm 2 (three-times-a-week 
every other week),

no antileukemic activity was noted as the dose level of ≤40 mg/day, even with the three-
times-a-week weekly regimen.
Thirty-six AML patients were treated in Arm 1 (three-times-a-week every week) at dose 
levels ≥40 mg. According to data on file, CR was reported in 2 (6%) and PR in 1 (3%) AML 
patients with prior MDS treated at 60 mg. Prolonged SD was reported in additional 2 (6%) 
AML patients with prior MDS, lasting for more than 14 months. Another patient treated at the 
60 mg dose level had no evidence of anti-leukemic effect during treatment, lasting 3 months. 
CR was reported 1 month after end of treatment. A patient treated at 40 mg had stable disease 
during study treatment which lasted for 2 months (Ottmann et al 2008). Stabilization of 
disease for 20 cycles with decrease in bone marrow blasts was observed in one MDS (RAEB-
1) patient out of 7 treated with the three-times-a-week every week schedule. A second patient 
with therapy related MDS and CD4+/56+ hematodermic neoplasm responded with SD and PR 
for 6 cycles, respectively. The patient went off study due to NHL progression.
1.3
Combination of DNA methyltransferase inhibitors with 
deacetylase inhibitors
Widespread epigenetic modifications affecting gene expression are well documented in MDS 
and AML, and hypermethylation of promoter regions of numerous genes have been shown to 
play an important role in tumorogenesis. The physiologic relevance is that silencing of some 
genes enables malignant cells to gain a selective advantage, leading eventually to immortality, 
invasion, and the development of a neoplastic phenotype. DNA methylation and histone 
acetylation are independent and modulate gene expression. In fact, chromatin status is 


Novartis
Confidential
Page 43
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
determined by chemical modifications occurring directly on DNA. Methylation recruits 
methyl-binding proteins locally and the latter bind protein complexes containing corepressors, 
DNA methyltransferases (DNMTs) and histone deacetylases. In cancer, repression of gene 
expression is maintained by corepressor complexes of proteins recruited by regionally 
hypermethylated DNA.
Whereas aberrant DNA methylation patterns, changes in chromatin structure and in gene 
expression are common in different tumor types, studies in leukemias have provided 
paradigmatic examples for the functional implications of genetic and epigentic alterations in 
cancer development (Leone et al 2008). In hematological malignancies, methylation turns off 
tumor suppressor genes to achieve an effect similar to (or complementary to) gene mutations.
Perturbation of the balance of transcriptional regulators may lead to aberrant recruitment of 
histone deacetylase (HDAC) and silencing of tumor suppressor genes (Moe-Behrens and 
Pandolfi 2003). Complexes involving DNA methyltransferase and HDACs work in 
coordination to remove acetyl groups from histone tails and add methyl groups to CpG 
dinucleotides within gene promoter regions, thereby suppressing gene transcription. Inhibiting 
each of these enzyme complexes may synergistically remove this aberrant silencing, thus 
contributing to re-expression of essential tumor-suppressor genes. Therefore the concept of 
combining demethylating agents with DAC inhibitors - both epigenetic modifiers - provides a 
sound rational strategy. On this biological background, combination therapy with 
hypomethylating agents and DAC inhibitors has been attempted.
Combination strategies involving either drug sequencing or co-administration of these agents 
in vitro have shown improved activity with greater expression of previously silenced genes 
(Cameron 1999, Zhu 2003). In addition clinical studies in hematologic malignancies 
published to date demonstrate feasibility of the association of the two types of agents in these 
disease settings.
1.3.1
Clinical experience combining 5-Aza and DAC inhibitors
Promising results have been obtained combining treatment of 5-Aza with different DACi 
(Table 1-6). Nevertheless, the most interesting results up to now have been obtained with 
vorinostat in MDS and AML patients, with more than 80% early responses. In this trial, oral 
vorinostat was combined with the 5-Aza approved sc regimen (d1-7 q 28 days) starting on day 
3 of the 5-Aza regimen. This combination was well tolerated in repetitive cycles and was 
active in lower and higher risk MDS, as well as in AML patients. Median time to response 
was 2 cycles. Among 18 evaluable patients with high risk MDS and AML 83% responded. 
Responses including CR occurred, but in 57% of patients the abnormal MDS/AML clone 
persisted, suggesting a modulating effect of the combination therapy on the clone. (Silverman 
et al 2008)


Novartis
Confidential
Page 44
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 1-6
Clinical trials of combination regimens with DNMTi and DACi
Schedule
Diagnosis
(Pts n.)
Responses
Toxicity
Reference
5-Aza 75 mg/m2 d1-7 + 
valproic acid orally 50, 
62.5, 75 mg/kg (d1-7) + 
ATRA 45 mg/m2/d (d1-7)
MDS (n= 4)
AML (n= 49)
12 CR (22%), 3 
CRp (5%), 7 
BM response 
(13%)
CNS toxicity
(Soriano et al 
2007)
5-Aza 75 mg/m2 d 1-7 + 
phenylbutyrate 200 mg/kg 
for 5 d after 5-Aza
MDS (n= 2)
AML (n= 8)
3 PR (30%)
CNS toxicity, fever, 
nausea, fatigue
(Maslak et al 
2006)
5-Aza 50 mg/m2 d 1-14, 1-
10 or 1-5, 75 mg/m2 d1-5; 
25 mg/m2 d 1-14 + 
phenylbutyrate 375 
mg/kg/d for 7d after 5-Aza
MDS (n= 13)
AML (n=18)
CMML (n=1)
4 CR (14%), 1 
PR (3%), 6 HI 
(21%)
CNS toxicity, mild 
nausea, injection side 
reactions, asthenia, 
myelosuppression
(Gore et al 2006)
5-Aza 75 mg/m2 d SC d 1-
5 + escalating doses 150-
1000 mg/m2 30 min IV 
belinostat after 5-Aza
MDS(n=10)
AML (n=12)
Myelofibrosis 
(n=1)
2 CR (10%), 1 
PR (5%), 4 HI 
(19%)
Fatigue, N/V, diarrhea, 
phlebitis
(Odenike et al 
2008)
5-Aza 50 mg/m2 d SC d1-
7 escalating to 75 mg/m2 d 
1-7 + escalating doses of 
Vorinostat 400 mg/d PO x 
7d or 14 d to 600 mg/d PO 
x 3 d or 7 d, starting on d3 
of 5-Aza
MDS(n=20)
AML (n= 8)
Ongoing
9 CR, 2CRi 
(CR+CRi 53%), 
7 HI (39%),
2 SD (11%)
Fatigue, anorexia, N/V
(Silverman et al 
2008)
Overall, the clinical experience on the use of epigenetic therapy in hematological disorders, 
although limited to phase I studies, suggests that this therapeutic approach is safe, well 
tolerated, and induces higher response rates compared to the single agent. Of note, the slow 
onset of response consistently seen with single agent 5-Aza appears to be accelerated by 
combining 5-Aza with a DACi. (Soriano 2007, Silverman 2008)
1.3.2
Update of clinical experience with combining panobinostat with 
Vidaza from the phase Ib part of this study
A total of 31 patients, with a median age of 70 years (range 34-81), in 3 dose cohorts were 
enrolled onto the phase Ib part of the CLBH589H2101 study.  Of these patients, 6 were 
treated at a dose level of 20 mg, 18 at 30 mg, and 7 at 40 mg of panobinostat; 28 patients were 
evaluable for MTD and used in the Bayesian modeling of the dose-DLT relationship. 
One DLT of febrile neutropenia was observed at 20 mg and 4 DLTs of dehydration/fatigue, 
colitis, a 1-day echocardiogram T-wave inversion, and an atrial fibrillation/syncope were seen 
at 30 mg. Of the 7 patients treated at the 40 mg dose level, 2 DLTs of hyperbilirubinaemia and 
nausea/vomiting and one withdrawal of consent most likely related to fatigue (grade 3, not 
study drug related) were reported.  As a result, dose levels at 40 mg and above were not 
further explored. 
Based on safety data of 29 patients, the most frequent AEs suspected to be related to the study 
treatment were gastrointestinal issues and fatigue. Grade 3/4 treatment-related AEs included 
thrombocytopenia (8 [28%]), neutropenia (5 [17%]), and febrile neutropenia (6 [21%]). Other 
frequent AEs of all grades, regardless of study drug relationship, included nausea (19 [67%]), 


Novartis
Confidential
Page 45
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
fatigue (18 [62%]), diarrhea (16 [55%]), vomiting (15 [52%]), thrombocytopenia (13 [45%]), 
and decreased appetite (12 [41%]). The most common serious AEs (SAEs), regardless of 
study drug relationship, were febrile neutropenia (8 [28%]) and asthenia (5 [17%]). 
At the time of amendment 2, 7 patients are ongoing, 6 of which are enrolled into the 30 mg 
cohort and have completed currently a median of 6 treatment cycles (range 2-16, 
28days/cycle). One patient from the 40 mg cohort is in Cycle 10 and no patient is ongoing 
from the initial 20 mg dose cohort.  Reasons for treatment discontinuations other than DLT 
were new antineoplastic therapy (n=1), adverse event (n=4); disease progression (n=1), and 
death (n=1) due to disease progression.   The treatment duration is exceeding 5 cycles (range 
6-16) in 7 patients treated at 30 mg of panobinostat including 2 patients who were initially 
enrolled at 40 mg but dose-reduced in cycles 4 and 5, respectively. 
Based on the DLTs observed in cycle 1 and taking long-term tolerability data into 
consideration, oral panobinostat at 30 mg/day on days 3, 5, 8, 10, 12 and 15 of a 28-day cycle 
can be safely combined with 5-aza at the registered label (75mg/m2 on day 1-7) in patients 
with intermediate-2 or high-risk MDS, CMML, or AML and was determined to be the 
recommended phase IIb dose (RPIID). 
1.4
History of Amendments
Amendment 2 
Refer to section Summary of Previous Amendments 
Amendment 1
The rationale for this amendment is to correct inconsistencies within the protocol and to 
provide clarifications on timing of study procedures. Moreover, the amendment is intended to 
clarify an exclusion criterion and to provide further details on study procedures. Amendment1 
include the following changes to the protocol:

To be more precise in wording, exclusion criterion #8 was rephrased in order to express 
the exclusion criteria according to the excluding condition. 

Timing of study procedures in case of a prolonged cycle: weekly laboratory assessments 
are required in case of a prolonged cycle. These time points have been set to Day 29 
which corresponds to the first day of the first week of the cycle prolongation.

Clarification on time points for assessment of bone marrow: It was clarified to perform 
bone marrow assessments at the end of each even-numbered cycle. 

Clarification on study visit terminology: The time point for the last assessments including 
response variables (hematology, 
 bone marrow) was defined at the end of 
treatment. The term ‘end of study visit’ was replaced with the term ‘end of treatment visit’.

Cleaning of study visit numbers: The visit numbers have been corrected.

The assessment of extramedullary disease is part of the response assessment procedure as 
described in [Post-text supplement 1]. In order to provide clear instructions, the 
description of assessments of extramedullary disease was added to the study protocol. 


Novartis
Confidential
Page 46
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

The assessment of transfusion dependency is part of the response assessment procedure. 
In order to harmonize the assessment of transfusion dependency with the response 
assessment schedule, it was clarified by adding an end of treatment visit for assessment of 
transfusion dependency. 
2
Rationale for the investigation of the combination treatment 
of 5-Aza and panobinostat
2.1
Preclinical and clinical rationale supporting the combination of 
5-Aza and panobinostat
Several preclinical studies support the view that pharmacologic targeting of both DNMT and 
DACi may result in synergistic anticancer activity including data showing synergism for the 
combination of 5-Aza and panobinostat.
In vitro studies have been conducted to test the effects of combining 5-Aza with panobinostat 
in leukemic cells. In the first preclinical experiment U937 cells were co-treated with 5-Aza 
and panobinostat and a dose-dependent apoptosis was measured at 48 hours by Annexin V/PI 
staining (Figure 2-1). The second experiment indicated synergism of the combination of 5-
Aza and panobinostat by inducing the downstream cell cycle regulators p21, acetyl tubulin 
and Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by DNA breaks, 
suggesting that the combination potentiates apoptosis, triggers progressive induction of DNA 
breaks and cell death (Figure 2-2, data unpublished, on file).
Figure 2-1
Dose-dependent induction of apoptosis by in vitro combination of 5-
Aza and LBH589


Novartis
Confidential
Page 47
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Figure 2-2
Expression of cell cycle and apoptotic markers in U937 cell line due to 
exposure to LBH589 and 5-Aza
These preclinical data support the investigation of this combination in the clinical setting. 5-
Aza is already an integral part of treatment especially in higher risk MDS. Although 5-Aza 
therapy represents a major step forward for patients with higher risk MDS, including 
significant prolongation of overall survival, all patients will ultimately progress clearly 
indicating the medical need for new treatment options.
In addition, overall response rate is still quite low and time to response with 5-Aza therapy 
can last up to 4-5 cycles. Several phase I-II studies combining DNMT and DAC inhibitors 
have reported encouraging results, the most compelling being the study conducted by 
Silverman et al. confirming the feasibility of sequential administration of several schedules 
and doses of 5-Aza and Vorinostat. Median time to response was 2 cycles. Among patients 
with high risk MDS and AML 10/12 (83%) responded (5CR, 1CRi, 4 HI) but in 57% of 
patients the abnormal MDS/AML clone persisted, suggesting a modulating effect of the 
combination on the clone. Being panobinostat is a more potent in vitro DACi than Vorinostat 
(Atadja 2009), it might be reasonable to assume that the combination of 5-Aza and 
panobinostat, as planned to be investigated in the present protocol, could be able to eradicate 
abnormal clones.
Oral panobinostat given as single agent has shown clinical activity including CRs in patients 
with AML (besides patients with relapsed/refractory Hodgkin’s disease and CIMF) and 
stabilization of disease in patients with MDS. (Ottmann et al 2008)
Not all AML or MDS patients respond to DNMT inhibitors such as 5-Aza and most responses 
are not complete. Responses seen with single agent DAC inhibitors were not impressive. 
Therefore, there is a need for better therapies to treat this heterogeneous group of 


Novartis
Confidential
Page 48
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
hematological disorders and it is a rational strategy to combine the two epigenetic modifiers 
5-Aza and panobinostat in the clinical setting.
2.2
5-Aza dose and schedule
In the present study, the approved dose is 75 mg/m2 sc on a treatment schedule 7-day q 28 
days. In the phase Ib part, 5-Aza will be investigated in combination with escalating doses of 
panobinostat. In the phase IIb part in combination with panobinostat at RPIID. As per the 
locally registered product label, a treatment cycle is 28 days, but 14 additional days (up to 42 
days) are allowed in order to recover from hematologic toxicity. The approved regimen is the 
one recommended for the target patient population. Using this regimen will facilitate 
comparison with results from other trials combining 5-Aza selected regimen with other DACi.
2.3
Panobinostat starting dose and schedule
In the phase Ib part of the study, the oral dose of 20 mg/day represents the proposed starting 
dose of panobinostat and has been selected based on the following considerations:

Clinical studies of single agent oral panobinostat in more than 350 patients consistently 
report a clinical safety characterized by the occurrence of adverse events (AE) of the 
gastrointestinal tract (nausea, diarrhea) and the hematopoietic system (thrombocytopenia 
and neutropenia). Additional common toxicities have included fatigue and vomiting. This 
is expected and in line with preclinical investigations. In 103 patients with primary bone 
marrow malignancies treated with single agent oral panobinostat 20 mg/day three-times 
per week every week, the most common AEs were nausea (41%), diarrhea (37%), 
thrombocytopenia (36%), fatigue (40%), vomiting (26%), pyrexia (27%), and anemia 
(31%). Grade 3 and 4 thrombocytopenia occurred in 27% of patients, while Grade 3 and 4 
fatigue was reported in 7% of patients. Serious Adverse Events (SAEs) with suspected 
causality to study drug included neutropenia and thrombocytopenia (1.9% each), nausea 
(1.9%), vomiting and fatigue (1.0% each) and QTcF prolongation (1%). No unexpected 
toxicities have so far emerged.

The safety and tolerability of 20 mg oral dosing three-times-a-week in a weekly schedule 
is being investigated in ongoing phase Ib dose-escalation studies, combining panobinostat 
with other standard of care compounds in hematologic malignancies. Notably, study 
[CLBH589B2207] has provided information when combining panobinostat with 
bortezomib in patients with relapsed or refractory multiple myeloma. Initial analysis of 
safety data suggests that a dose up to 20 mg/day in combination with standard 
dose/schedule of bortezomib is safe and well tolerated without occurrence of dose-limiting 
toxicities (DLTs) in a total of 8 evaluable patients (Sezer et al 2008). In an ongoing 
investigator-initiated study [CLBH589BUS07T], testing the combination of panobinostat 
with decitabine in elderly patients with higher risk MDS or AML, the dose of 20 mg three 
times-a-week has been tolerated without DLTs.

The probability of excessive or unacceptable toxicity based on the combination Bayesian 
logistic regression model [Post-text supplement 2] is considered to be less than 1%. Based 
on prior assumptions derived from historical data of 5-Aza single agent studies and study 
[CLBH589B2102], the estimate for the probability of excessive or unacceptable toxicity is 


Novartis
Confidential
Page 49
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
12.4% when panobinostat is given together with 75 mg/m2 of 5-Aza which is far below 
the overdosing criterion of a probability less than 25%.

Consequently, the starting dose of 20 mg of oral panobinostat when given for two weeks 
in a 28 days cycle in combination with 5-Aza is considered to be a clinically acceptable 
and safe starting dose to be combined with the established doses of 5-Aza.
The recommended phase II dose (RPIID) has been determined to be 30 mg of oral 
panobinostat once daily on Day 3, 5, 8, 10, 12, and 15 and is proposed as the dose for the 
phase IIb part of the study.
In the phase Ib as well as in the phase IIb part of the study oral panobinostat will be 
administered over 2 weeks in a 28-day cycle. 5-Aza and panobinostat will be delivered in a 
sequential scheme of treatment as follows:

5-Aza on Day 1-7 in week 1 of the treatment cycle

Panobinostat on Day 3 and 5 of week 1 of the treatment cycle

Panobinostat on Day 8, 10, and 12 of week 2 and on Day 15 of week 3.
Overall 7 doses of 5-Aza (1 week treatment) and 6 doses of panobinostat (2 weeks treatment) 
will be delivered in a 28 day treatment cycle. The same regimen will be repeated in 
subsequent cycles. As previously mentioned, the treatment cycle might be extended to 42 
days to allow for recovery from toxicity (Section 6.6.1.6)
According to 5-Aza label, treatment should be continued as long as the patient continues to 
benefit or until disease progression. It is also recommended that patients be treated for a 
minimum of 6 cycles. Accordingly, the present study stipulates that at least 3 or 4 cycles of 
the combination 5-Aza and panobinostat should be given unless disease progression or 
unacceptable toxicity or patient’s consent withdrawal are encountered. The rationale for this 
schedule and its duration is based on the following considerations:

There are preclinical evidences suggesting that sequential addition of DACi to cells 
preincubated with DNMTi synergistically reactivates the expression of genes silenced 
through promoter methylation (Cameron 1999, Zhu 2001).

Based on this concept, a number of clinical trials have been conducted by several groups 
using a sequential administration of 5-Aza followed by a DACi such as phenylbutyrate, 
valproic acid, belinostat and vorinostat (Table 1-6). In all these studies, the DACi inhibitor 
was delivered following 5-Aza. Two weeks of rest was part of the treatment cycle of 28 
days. With this therapeutic approach, evidences of clinical activity and a manageable 
safety profile were consistently reported, being the most promising results observed with 
the combination of 5-Aza with vorinostat (Silverman et al 2008). A similar therapeutic 
approach has been proposed in the present study.

Although the approved dose and schedule of 5-Aza cause marrow hypoplasia in a limited 
number of patients (10%), 5-Aza remains a myelosuppressive agent and patients should be 
monitored for fever, neutropenia, and thrombocytopenia. There is a greater risk of these 
events occurring during the first two cycles with single agent 5-Aza, after which their 
frequency is reduced in patients with restoration of hematological function. Mean times to 
nadir values (across all cycles) for hematological parameters, including absolute 
neutrophils and platelets, were between 15 and 16 days in the pivotal CALGB 9221 study 


Novartis
Confidential
Page 50
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
of 5-Aza (Silverman et al 2006). On the other hand, preliminary data from the single agent 
panobinostat Phase I study [CLBH589B2102] suggests that the nadir of treatment-
associated thrombocytopenia in patients with reduced blood counts at baseline may occur 
in the second week of therapy. It is worth noting that clinical experience dictates that 
continued 5-Aza treatment without dose reduction is critical to improve bone marrow 
function. In case of the proposed combination of 5-Aza and panobinostat, both agents 
present overlapping toxicities and thus continued treatment with panobinostat might not 
allow recovery from toxicity and prompt retreatment in next cycle. Therefore a treatment-
free window from day 16 to 28 of the cycle has been preserved in order to allow the 
patient to recover from toxicities and avoid premature dose reductions or early 
discontinuations due to overlapping or protracted toxicities. Similar “on/off” dosing 
schedules have been used with other DAC inhibitors in combination with DNMT 
inhibitors (see Section 1.3.1).

Clinical response to 5-Aza in MDS patients follows a typical pattern starting with an 
increase in platelet counts as first sign of response, followed by an increase in hemoglobin 
levels. Responses are usually accompanied by a reduction in bone marrow (BM) blasts to 
less than 5%. Patients can also achieve blast reduction to less than 5% even if this is not 
accompanied by an improvement in blood counts (Raj and Mufti 2006). Most responding 
patients demonstrate response at the beginning of the third or fourth month of therapy. 
Incorporation of 5-Aza into DNA inhibits DNA methyltransferase and induces DNA 
hypomethylation. This effect is S-phase dependent, and two or more cycles of DNA 
synthesis are required to alter gene transcription and expression. Thus, three to four cycles 
of therapy are usually required before an effect becomes clinically apparent.
2.3.1
Drug-drug interaction between panobinostat and 5-Aza
As the oxidative metabolism of panobinostat in human liver is primarily mediated by 
CYP3A4, with minor contributions by CYP2D6 and CYP2C19, the potential of 5-Aza to 
inhibit human cytochrome P450 (CYP) enzyme activity was assessed using pooled human 
liver microsomes. Very little or no inhibition of CYP2D6, or CYP3A4/5 activity was
observed at 5-Aza concentrations up to 100 µM, much higher than the concentrations 
measured in patients with cancer (Rudek et al 2005). In these patients with refractory solid 
tumors or hematological malignancies, Cmax values of 5-Aza following 75 mg/m2/day dosing 
were 4870.6 ± 1398.1 nM (mean ± standard deviation), which is below the concentration 
tested for CYP inhibition in vitro (Rudek et al 2005). Based on these findings, it is unlikely 
that 5-Aza would affect the oxidative metabolic clearance of panobinostat in vivo.
Conversely, the stability of 5-Aza in human plasma was not affected by the presence of 
panobinostat (0.5 or 5 µM), indicating that panobinostat is unlikely to inhibit cytidine 
deaminase, the main catabolic pathway of 5-Aza and other cytidine analogues (e.g. 
gemcitabine, cytarabine).
In conclusion, a drug-drug PK interaction between panobinostat and 5-Aza is not expected 
based on this data.


Novartis
Confidential
Page 51
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
2.4
Target population
The target population for this study is the population of patients with IPSS higher risk MDS, 
CMML or AML who are candidates for therapy with 5-Aza and who were previously not 
exposed to therapy with another DNMT inhibitor or DAC inhibitor. All eligible patients will 
receive 5-Aza approved treatment regimen, which is considered the standard of care for this 
patient population. The rationale for selecting this patient population is three-fold:

Patients with IPSS INT-2 or high risk MDS or AML (defined as per WHO as 20-30% 
blasts in bone marrow) treated with 5-Aza will ultimately progress despite of the overall 
survival benefit seen with the introduction of 5-Aza. In addition, most seen responses are 
not complete, the overall response rate is quite low, and responses tend to occur late (after 
3 - 4 cycles of therapy). Therefore, there is a need for better therapies to treat this 
heterogeneous group of hematological disorders providing increased rates of responses 
earlier.

In preclinical experiments of 5-Aza plus panobinostat, no evidence for antagonistic 
activity but the opposite was seen (Section 1.3.1). Adding panobinostat to 5-Aza in vivo
might translate in a better therapeutic option for patients who are candidates for 5-Aza 
therapy. The in vitro synergistic antileukemic activity of 5-Aza with DACi has been 
confirmed in vivo for other DACi, as well.

To mitigate the potential risk of increased hematological toxicity, and considering that 
expected bone marrow toxicity from 5-Aza and panobinostat is clinically manageable, the 
safety profile of patients will be regularly monitored (peripheral blood cell counts) in 
order not to expose patients to an unduly high risk of thrombocytopenia, neutropenia 
and/or infection. In contrast to the continuous 3 times weekly dosing regimen of single 
agent panobinostat, a treatment break will be introduced from D16 to D28 of each cycle to 
allow bone marrow recovery, if required.
3
Objectives
3.1
Phase Ib part
3.1.1
Primary objective

To determine the MTD and/or RPIID of oral panobinostat in combination with a fixed 
dose of 5-Aza in adult patients with IPSS INT-2 or high risk MDS, CMML, or AML.
3.1.1.1
End-point for primary objective

Incidence of DLT
3.1.2
Secondary objectives

To characterize the safety and tolerability of panobinostat in combination with 5-Aza in 
the target patient population.


Novartis
Confidential
Page 52
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
3.1.2.1
End-points for secondary objectives

Type, duration, frequency and relatedness of Adverse Events (AE). AE severity will also 
be assessed according to NCI Common Terminology Criteria for Adverse Events 
(CTCAE), version 3.0

Laboratory (biochemistry, hematology)

ECG monitoring (central review by eRT)
As of amendment 2, the primary objective of the phase Ib part has been met and the 
recommended phase II dose (RPIID) has been determined to be 30 mg of oral panobinostat 
once daily on day 3, 5, 8, 10, 12, and 15 in combination with 5-Aza as per the registered label 
(75mg/m2 on day 1-7). Dose escalation was not continued up to the MTD because of long 
term tolerability considerations.
3.2
Phase IIb part
3.2.1
Primary objective

To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination 
at the RPIID relative to treatment with single agent 5-Aza through the assessment of 
composite CR (CR or CRi or bone marrow CR). 
3.2.1.1
End-point for primary objective

Composite CR (CR or CRi or bone marrow CR)
3.2.2
Secondary objectives

To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination 
at the RPIID relative to treatment with single agent 5-Aza through the assessment of 
clinical responses other than the composite CR specified in the primary objective, 1 year 
survival, and time to progression (TTP). 

To characterize the safety and tolerability of panobinostat at the  RPIID in combination 
with 5-Aza, as well as, 5-Aza alone in the target patient population.


Novartis
Confidential
Page 53
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
3.2.2.1
End-points for secondary objectives

Clinical response for AML: PR; for MDS/CMML: PR, Hematologic Improvement (HI)

Overall response (CR or CRi or bone marrow CR or PR)

1-year survival rate

Time to progression (TTP) based on the Guidelines for Implementation of IWG response 
criteria in AML, MDS and CMML according to Cheson 2003 and 2006 and specified in 
[Post-text supplement 1].

Type, duration, frequency and relatedness of Adverse Events (AE). AE severity will be 
assessed according to NCI Common Terminology Criteria for Adverse Events (CTCAE), 
version 3.0

Laboratory (biochemistry, hematology)

ECG monitoring (central review by eRT)
4
Study design
This is an open-label, multi-center, phase Ib/IIb study. The phase Ib part of the study is 
designed to determine the maximum tolerated dose (MTD) and/or the recommended phase II 
dose (RPIID) of panobinostat administered in a fixed combination of 5-Aza in adult patients 
with IPSS INT-2 or high-risk MDS, CMML or AML not eligible for HSCT.  The phase IIb 
part, that will commence once MTD and/or RPIID is established, has a randomized, two arm 
design and is designed to assess preliminary efficacy of panobinostat (in combination with 5-
Aza) at RPIID relative to 5-Aza alone, the current standard of care,
In the phase Ib part, patients will receive escalating oral doses of the study drug panobinostat 
commencing in cycle 1 for a period of two weeks. The dose of 5-Aza will be 75 mg/m2/day 
for 7 days.
A treatment cycle is defined as 28 Days in duration. Patients should be treated for a minimum 
of 6 cycles. Study treatment should be continued as long as the patient continues to benefit or 
until disease progression or unacceptable toxicity is encountered or consent withdrawal 
whatever comes first.
At least 3 patients per cohort must be enrolled. During the phase Ib part, patients will be 
evaluated for DLT (Section 6.6.1.6) using an adaptive Bayesian logistic regression model 
with overdose control (EWOC) to guide the dose escalation process. Starting dose of 
panobinostat will be 20 mg.  Prior to declaring a dose to be MTD, at least 9 evaluable patients 
need to be treated at that dose level.


Novartis
Confidential
Page 54
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
After completion of a given dose cohort, the decision on the dose chosen for the next cohort 
will depend on the risk assessment using the Bayesian logistic regression method and a 
medical review of available clinical and laboratory data. Dose-limiting toxicity will be 
assessed from the safety data of Cycle 1 for each dose level.
The MTD is defined to be the highest daily dose of panobinostat given together with 5-Aza in 
the first treatment cycle in which the probability to produce medically unacceptable, dose-
limiting toxicity (DLT) in more than 35% of the patients is less or equal to 25%. The  
recommended phase II dose (RPIID) will be based on considerations of the MTD estimation 
process by the adaptive Bayesian logistic regression model, and on an overall assessment of 
safety taking into consideration tolerability data from subsequent cycles at all the different 
dose levels tested.
As of August 2011, the recommended phase II dose (RPIID) has been determined to be 30 mg 
of oral panobinostat once daily on day 3, 5, 8, 10, 12, and 15 in combination with azacytidine 
(5-Aza/Vidaza®).
Additional 80 patients will be randomly assigned in a 1:1 ratio into the phase IIb part of the 
study receiving 30 mg of panobinostat plus 5-Aza (investigational arm) or single agent 5-Aza 
(active control arm). Single agent 5-Aza will be administered according to the locally 
approved label (75mg/m2 daily for 7 days), 
Patients will continue treatment until disease progression, unacceptable toxicity or consent 
withdrawal, whichever comes first. The core clinical study report (encompassing both, the 
phase Ib and the phase IIb part of the study) will be based on a data cut-off corresponding to 
the time point where all patients have either completed 12 cycles of study treatment or 
discontinued study treatment for any other reason whichever comes first. An addendum to the 
core clinical study report will be provided at the completion of the study to summarize and/or 
list the additional safety and efficacy data as appropriate. 
Patients who have completed 12 cycles of study treatment and are assessed by the Investigator 
to have the potential to benefit from ongoing treatment will continue their assigned treatment 
allowing collecting and reviewing safety, efficacy and survival data. After the data-cut off 
point for the CSR, a reduced visit evaluation schedule will be applied
5
Population
Adult patients with intermediate-2 or high-risk MDS, AML with multilineage dysplasia and 
maximum of 30% bone marrow blasts (former RAEB-T according to FAB, currently AML 
according to WHO definition), or Chronic Myelomonocytic Leukemia (CMML) who are 
candidates for the treatment with 5-Aza will be enrolled onto the study.
Inclusion/exclusion criteria
The investigator or his/her designee must ensure that all patients who meet the following 
inclusion criteria are offered enrollment in the study.


Novartis
Confidential
Page 55
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
5.1
Inclusion criteria
1. Adult patients (age ≥ 18 years) who are candidates for treatment with 5-Aza and present 
with one of the following:

intermediate-2 or high-risk MDS according to the International Prognostic Scoring 
System (IPSS) OR

AML with multilineage dysplasia and maximum of 30% bone marrow blasts (former 
RAEB-T according to FAB, currently AML according to WHO definition) OR

Chronic Myelomonocytic Leukemia (CMML)
2. ECOG performance status ≤ 2
3. Patients must have the following laboratory values unless elevations are considered due to 
underlying disease:

AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN

Serum creatinine ≤ 1.5 x ULN

Serum bilirubin (total and direct) ≤ 2 x ULN

Serum electrolytes (i.e., Calcium, Magnesium and Potassium) within normal ranges 
for the institution
4. - Not applicable -
5. Negative pregnancy test
6. Patients who are not clinically euthyroid. 
7. Written informed consent obtained prior to any screening procedures
5.2
Exclusion criteria
1. Planned hematopoietic stem-cell transplantation (HSCT)
2. Patients with therapy- related MDS
3. Patients with therapy-related AML and/or relapsed/refractory AML
4. Clinical symptoms suggesting CNS leukemia
5. Concurrent therapy with any other investigational agent
6. Prior treatment with deacetylase inhibitor(s)
7. Prior treatment with 5-Aza or 5-aza-2'-deoxycytidine (decitabine)
8. Time windows for prior therapies: Last dose of therapy, including cytokines and/or 
retinoids, immunotherapy, low-dose ara-C, investigational agent less than 28 days with the 
exception of hydroxyurea (24 hours) prior to receipt of study medication or AEs that have 
not recovered at least to NCI CTCAE Grade 1.
9. Patients with impaired cardiac function including any of the following:

Complete left bundle branch block or use of a permanent cardiac pacemaker, 
congenital long QT syndrome, history or presence of ventricular tachyarrhythmia, 
clinically significant resting bradycardia (<50 beats per minute), QTcF > 460 ms on 
screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular 
block)


Novartis
Confidential
Page 56
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients 
with stable atrial fibrillation are eligible provided they do not meet the other cardiac 
exclusion criteria

Previous history of angina pectoris or acute MI within 6 months

ScreeningLVEF <45% by echocardiography or MUGA

Other clinically significant heart disease (e.g. uncontrolled hypertension or history of 
poor compliance with an antihypertensive regimen).
10. Drugs which may cause QT prolongation and the treatment cannot be discontinued or 
switched to a different medication prior to starting study drug
11. Any of concurrent severe and/or uncontrolled medical conditions which could 
compromise participation in the study. For example:

Uncontrolled diabetes

Active or uncontrolled infection

Uncontrolled hypothyroidism

Acute or chronic liver or renal disease
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral panobinostat (e.g., ulcerative diseases, diarrhea, malabsorption 
syndrome, or small bowel resection).
13. HIV, Hepatitis B/C infection according to the medical history (testing will not be 
performed).
14. Female patients who are pregnant or breast feeding or patients of childbearing potential 
(WOCBP) not willing to use a double barrier method of contraception during the study 
and for 3 months following the last dose of study drug.
15. Male patients whose sexual partner(s) are WOCBP who are not willing to use a double 
barrier method of contraception, one of which includes a condom, during the study and for 
3 months after the end of treatment.
16. Suspected hypersensitivity to 5-Aza or Mannitol
17. Inability to swallow capsules
18. Unwilling or unable to comply with the protocol
19. Patient has evidence of clinically significant mucosal or internal bleeding
6
Treatment
6.1
Investigational and combination drugs
Study drug refers to any Novartis investigational drug(s). For this study, study drug refers to 
oral panobinostat. Combination drug refers to 5-Aza. For the phase Ib part and in the 
investigational arm of the phase IIb part of this study, study treatment refers to combination 
treatment with oral panobinostat and 5-Aza. In the active control arm of the phase IIb part, 
single agent 5-Aza will be used as control drug 


Novartis
Confidential
Page 57
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
6.1.1
How supplied
Each study site will be supplied by Novartis with open-label oral panobinostat. Immediately 
before dispensing study drug to the patient, investigator staff will detach the outer part of the 
label from the packaging and affix it to the source document (Drug Label Form) containing 
that patient’s unique patient number. One component of the packaging has a 2-part label.
Study drug supply and resupply, storage, and tracking/drug accountability
Study drugs 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 panobinostat should be stored according 
to the instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug but no information about the 
patient.
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Drug accountability will be noted by the field monitor 
during site visits and at the completion of the trial. Patients will be asked to return all unused 
study drug and packaging at the end of the study or at the time of study drug discontinuation.
At the conclusion of the study, and, as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.
6.1.1.1
Study drug
Novartis will provide each site with open-label oral panobinostat until it is commercially 
available. It will be supplied as immediate-release hard gelatin capsules in strengths of 5 mg, 
10 mg (when available) and 20 mg which will be given on a flat scale of mg per given day. 
The capsules are packaged in HDPE bottles with plastic child resistant closures. Following 
bottle sizes are available for panobinostat (i) 5 mg - 45 capsules per bottle, (ii) 10 mg - 30 
capsules per bottle, (iii) 20 mg - 15 capsules per bottle.
6.1.1.2
Combination drug and control drug control
For the phase Ib part, 5-Azacitidine (Vidaza®) will be supplied by Novartis.  For the phase IIb 
part, 5-Azacitidine will be purchased commercially as part of standard care. 5-Azacitidine will 
be supplied by Novartis only for patients from those countries where 5-Azacytidine is not 
available as standard care, or where no alternative method of obtaining or paying for 5-
Azacytidine based on the patient’s local regulation can be identified. 


Novartis
Confidential
Page 58
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
6.1.2
Preparation and storage
6.1.2.1
Study drug
Medication labels will comply with the legal requirements of each country and be printed in 
the local language. They will supply no information about the patient. The storage conditions 
for study drug will be described on the medication label.
6.1.2.2
Combination drug and control drug
5-Aza (Vidaza®); should be prepared and stored in accordance with the manufacturer’s 
instructions.
6.2
Treatment Arms
6.2.1
Phase Ib part
Panobinostat will be dosed on a flat scale of mg/day. In the first week of treatment cycle oral 
panobinostat dosing starts on Day 3 and is given twice (Day 3 and Day 5), in the second week 
of treatment panobinostat is given thrice on Day 8, Day 10 and Day 12. In week 3 of the 
treatment panobinostat is given once (Day 15) (Figure 6-1). Up to a total of six doses of 
panobinostat will be given per cycle. 
Once the MTD and/or RPIID is established, enrollment in the phase Ib part is closed and the 
phase IIb part of the study will commence. Ongoing patients from the phase Ib part will 
continue their treatment at the assigned dose level according to the regimen and schedule for 
the phase Ib part. 
Table 6-1
Treatment doses and regimens (Phase Ib part)
Drug
Panobinostat
5-Aza (Vidaza®)
Dose
Escalating doses starting with 20 
mg delivered orally
75 mg/m2 subcutaneously
Regimen
Once daily
Day 3, 5 (week 1)
Day 8, 10, 12 (week 2)
Day 15 (week 3)
Daily for seven days
Day 1 to 7 (week 1)
Treatment Cycle
28 Days
Figure 6-1
Treatment schedule (Phase Ib part)
6.2.2
Phase IIb part
As of this amendment 2, the recommended phase II dose (RPIID) has been determined to be 
30 mg of oral panobinostat once daily on day 3, 5, 8, 10, 12, and 15 in combination with 
azacytidine (5-Aza/Vidaza®); Patients will be randomly assigned in a 1:1 ratio to the phase IIb 
part of the study receiving 30 mg of panobinostat plus 5-Aza (investigational arm) or single 


Novartis
Confidential
Page 59
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
agent 5-Aza (active control arm). Single agent 5-Aza is the current standard of care and will 
be administered according to the registered label (75mg/m2 daily for 7 days).
Panobinostat will be dosed on a flat scale of mg/day. In the first week of treatment cycle oral 
panobinostat dosing starts on Day 3 and is given twice (Day 3 and Day 5), in the second week 
of treatment panobinostat is given thrice on Day 8, Day 10 and Day 12. In week 3 of the 
treatment panobinostat is given once (Day 15) (Figure 6-2). Up to a total of six doses of 
panobinostat will be given per cycle.
Table 6-2
Treatment doses and regimens (Phase IIb part)
Drug
Panobinostat
5-Aza (Vidaza®)
Dose
30mg (RPIID)
75 mg/m2 subcutaneously
Regimen
Once daily
Day 3, 5 (week 1)
Day 8, 10, 12 (week 2)
Day 15 (week 3)
Daily for seven days
Day 1 to 7 (week 1)
Treatment Cycle
28 Days
Figure 6-2
Treatment schedule (Phase IIb part)
Investigational arm:
Active control arm: 
6.3
Patient numbering
Upon signing the informed consent, each patient in the study will be uniquely identified by a 
9 digit patient number, which is a combination of a 4-digit center number and 5-digit subject 
number. The center number is assigned by Novartis to the investigative site. 
For the phase Ib part, at each site, the first patient is assigned subject number 00001, and 
subsequent patients are assigned consecutive numbers (e.g., the second patient is assigned 
patient number 00002, the third patient is assigned patient number 00003). 
In the phase IIb part, a separate numbering scheme, different from the one used in the phase 
Ib part, will be applied for the 5-digit subject number. The first patient, at each site, in the 
phase IIb part will be assigned the subject number 10001, and subsequent patients at the site, 
will then be assigned consecutive numbers (i.e., the second patient is assigned patient number 
10002, the third patient is assigned patient number 10003 etc.).
Only the assigned subject number should be entered in the field labeled "Subject ID" on the 
CRF. Once assigned to a patient, the patient number will not be reused.


Novartis
Confidential
Page 60
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
6.4
Treatment assignment
As this trial includes a dose-escalation component, the assignment of a patient to a particular 
dose level cohort will be coordinated by the Sponsor. For treatment assignment in the phase 
IIb part of the study IRT procedures will be followed.
6.4.1
IRT procedures
Interactive Response Technology (IRT) will provide contact information and detailed 
instructions on registration and randomization procedures to each study site.

At visit 1 the investigator or his/her designee will call to register the patient with IRT.

Screening procedures may not begin until AFTER the patient has been registered with IRT. 

On Cycle 1, Day 1 (Visit 2) the investigator or his/her designee will again call IRT to 
randomize an eligible patient to one of the two treatment arms. During this process, 
eligibility questions must be answered as part of the eligibility check implemented into the 
system. This process should only occur once the investigator has completed all screening 
procedures, and considers the patient eligible for participation in this study.

Study drug kit numbers will be provided to the investigator following successful 
randomization. This number will be used to provide the randomized patient with the 
correct study treatment. The investigator or his/her designee must make sure that no study 
treatment is initiated without calling IRT and that a patient does not start study treatment 
prior to randomization.

If the screened and eligible patient fails to be randomized, the IRT must be notified as 
soon as possible. 

The investigator or his/her designee will notify IRT immediately of patient 
discontinuation from study. 

Re-supply of panobinostat will occur at 2-month (28 days/month) intervals.

Medication will be assigned for scheduled visits via the IRT

Reporting of any emergency code breaks occurrences is not applicable in this trial, since 
this is an open-label study.
6.5
Treatment blinding
The study is open label.
6.6
Treating the patient
6.6.1
Study treatment administration
The investigator should instruct the patient to take the study treatment exactly as prescribed. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
6.6.1.1
Study drug administration

Each dose of panobinostat should be taken with 240 mL of water. Patients should be 
instructed to swallow the capsules whole and not chew them.


Novartis
Confidential
Page 61
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

Panobinostat can be taken with or without food.

If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose.

Patients must avoid grapefruits, grapefruit juice, Seville (sour) oranges and Seville orange 
juice during the entire study.

If the patient forgets to take his/her dose during the morning on a scheduled treatment day 
then the missed dose should be taken on that same day within 12 hours. After more than 
12 hours, that day’s dose should be withheld, and the patient should wait to take 
panobinostat until the next scheduled treatment day. The patient should then continue 
treatment with the original dosing schedule.
The days when panobinostat and 5-Aza are scheduled together (Day 3 and Day 5 of a 
treatment cycle), panobinostat should be administered approximately 30 min prior to 5-Aza.
6.6.1.2
Combination Drug and /or Control Drug administration
The dose of 5-Aza will be 75 mg/m2. 5-Aza should be administered subcutaneously according 
to the manufacturer’s instructions provided in the Vidaza® product information.
6.6.1.3
Dose escalation levels (Phase Ib part)
Starting dose of panobinostat is 20 mg. At all dose levels, the adaptive Bayesian logistic 
model permits alterations in the dose increments based on the observed toxicities.
Table 6-3
Dose escalation levels
Dose level
Panobinostat oral dose
5-Aza SC
-1
10 mg
75 mg/m2
1
20 mg
75 mg/m2
2
30 mg
75 mg/m2
3
40 mg
75 mg/m2
4
50 mg
75 mg/m2
5
60 mg
75 mg/m2
Panobinostat will be dispensed as follows for the different dose levels:

Dose Level 1 (20 mg) - one 20 mg capsule to be dispensed

Dose Level 2 (30 mg) - two 5 mg capsules and one 20 mg capsule to be dispensed

Dose Level 3 (40 mg) - two 20 mg capsules to be dispensed

Dose Level 4 (50 mg) - two 20 mg capsules and two 5 mg capsule to be dispensed

Dose Level 5 (60 mg) - three 20 mg capsules to be dispensed

If dose level -1 (10 mg) is used - two 5 mg capsules to be dispensed.
The maximum inter-cohort dose escalation permitted is 100%.
6.6.1.4
Criteria for dose escalation and determination of MTD
The primary objective of the trial is to determine the highest safe dose of oral panobinostat 
that can be given to a patient for a duration of 1 treatment cycle together with a fixed dose of 


Novartis
Confidential
Page 62
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
5-Aza without causing serious, hence dose-limiting side effects/toxicities (DLT) given in a 7-
days schedule of 5-Aza.
The MTD is defined to be the highest dose of panobinostat given with 5-Aza in the first 
treatment cycle. The applied adaptive Bayesian logistic regression model (BLRM) provides a 
recommendation for the highest dose level of panobinostat in combination with 5-Aza by the 
dose with maximum probability of targeted toxicity (probability of DLT between 20%-35%). 
The use of escalation with overdose control (EWOC) principle limits the risk of excessive or 
unacceptable toxicity (probability of DLT ≥ 35%) to less than 25% (for further details see 
Section 10.1.4.2 and [Post-text supplement 2]).
In order to be evaluable for the MTD determining set, patients of the safety set need to have 
received sufficient study treatment as defined in the minimum exposure criteria in cycle 1 
(Table 10-1) and had sufficient safety evaluations or discontinued due to DLT in Cycle 1. 
Patients not experiencing DLT during Cycle 1 must have completed all safety assessments as 
requested in the protocol during this treatment cycle and meet the minimum exposure criteria
to be included in the MTD determining set. Patients who meet the minimum exposure criteria 
but discontinue early (e.g., for disease progression) will be asked to have all scheduled safety 
evaluations performed as delineated in the protocol in order to remain evaluable for the MTD 
determining population. Patients who do not meet these minimum safety evaluation 
requirements will be regarded as ineligible for the MTD-determining set and will be replaced.
At the end of each treatment cohort in the dose escalation part of the study, Novartis will 
convene a teleconference with the investigators. At the dose escalation teleconference the 
clinical course (safety information including all DLTs and all ≥ Grade 2 toxicity data during 
Cycle 1 and ECG) for each patient in the current dose cohort will be described in detail. 
Updated safety data on other ongoing patients, including data in later cycles, will be discussed 
as well. The final decision to dose escalate is not based solely on DLT information, but also 
on a clinical interpretation of all the relevant toxicity (both DLT and non-DLT) using the 
BLRM's recommendation as a guideline to the decision making process. The maximum inter-
cohort dose escalation permitted is 100%. In any case, the next dose will not exceed the 
recommended dose by the BLRM. The parties must reach a consensus on whether to escalate 
the dose any further, or whether to de-escalate or expand recruitment into particular cohorts. 
Novartis will prepare minutes from these meetings and circulate them within 24 hours to each 
investigator for comment prior to finalization. 
The recommended phase II dose (RPIID) for panobinostat will be based on the overall 
assessment of the incidence of DLT of the first treatment cycle as provided by the adaptive 
BLRM in conjunction with safety data generated across treatment cycles at all tested dose 
levels.
6.6.1.5
Dose escalation
During the phase Ib part of the study, a minimum of 3 patients will be assigned sequentially to 
a cohort. A cohort consists of at least three patients eligible for the MTD determining set (see 
Section 10.1.1). Patients who are not eligible for the MTD determining set will be replaced. 
The first patient of the first cohort will start study treatment at least one week before the next 
patients start study treatment.


Novartis
Confidential
Page 63
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
The Bayesian model will be updated prior to additional enrollment under the following 
scenarios:
1. If the first 2 patients in a cohort experience DLT prior to the enrollment of the 3rd patient. 
Enrollment will be halted, the model will be updated, and any new patients will be 
enrolled at a dose satisfying the overdose criteria, no higher than the current dose level.
2. No additional patients will be enrolled until the current cohort is completed and the model 
is updated.
3. For cohorts of > 3 patients if the observed number of DLTs exceeds 25% of the currently 
enrolled patients to that dose level, enrollment will be halted until all patients complete 
one cycle of dosing or experience DLT. The model will be updated to determine the 
uncertainty about the probability of DLT at each dose level. New patients will be enrolled 
at a dose level up to the highest satisfying the overdose criteria.
A decision will be jointly made by the investigators and the sponsor as to the dose level at 
which to continue dosing. 
6.6.1.6
Dose-limiting toxicities (For phase Ib portion only)
The DLT is defined as a toxicity requiring treatment withdrawal and includes the following:

Non-hematologic toxicity qualifying for DLT: In all patients, any treatment emergent or 
new NCI-CTCAE Grade 3 or 4 non-hematological toxicity, attributable to study treatment 
(either drug in combination). Additionally, treatment-emergent or new Grade 2 peripheral 
neuropathy attributable to study treatment, customarily considered DLT in cancer clinical 
studies.

Hematologic toxicity qualifying for DLT: In all patients NCI CTCAE Grade 4 life-
threatening febrile neutropenia. A special distinction between patients evaluable or not for 
hematologic toxicity has been made in this study, considering that the majority of patients 
representing the target population will have pre-existing severe cytopenias.  Management 
of hematologic toxicity according to baseline blood count values is an integral part of the 
Vidaza label and common clinical practice in these patient populations. To overcome 
complexity in implementing the Vidaza label algorithm, a more user-friendly approach 
based on clinical experience has been used in this study protocol. Hematologic toxicity 
will not be evaluable unless patients demonstrate baseline neutrophil counts > 0.5 x 109/L 
and platelet counts > 20 x 109/L. In these patients, failure to recover neutrophil and 
platelet counts to equal or higher baseline levels AND the demonstration of persistent 
bone marrow hypoplasia (MH) (<10% overall cellularity and <5% blasts) on Day 42 of 
Cycle 1 will be considered a hematologic DLT at that dose level (see Figure 6-3). On the 
other hand, if a patient with the previous baseline values of neutrophils and platelets, 
experiences persisting cytopenias on Day 42 AND does not exhibit MH on bone marrow 
biopsy, this condition will not be considered a hematologic DLT and the patient will 
commence Cycle 2 with the same doses of 5-Aza and panobinostat, provided no non-
hematological DLT has been encountered. Patients with pre-existing cytopenias not 
evaluable for hematological toxicities (baseline neutrophil count 0.5 x 109/L or platelet 
count ≤ 20 x 109/L) will commence cycle 2 with the same doses of 5-Aza and 
panobinostat on day 29 (i.e., day 1 of next cycle), if they have not experienced any non-
hematological DLT (see Figure 6-3).


Novartis
Confidential
Page 64
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Figure 6-3
Cycle 1 DLT decision algorithm for patients not experiencing grade 3 
or 4 non-hematological toxicities
Neutrophils ≤0.5 x 109/l and/or 
platelets ≤20 x 109/l
Neutrophils > 0.5 x 109/l and platelets > 20 x 109/l
Baseline
DAY 28
DAY 42
Complete 7 doses of 5-Aza & 6 
doses of panobinostat
AND 
No Grade 3 or 4 non-
hematological toxicities
Commence Cycle 2
Complete 7 doses of 5-Aza & 6 
doses of panobinostat
AND 
No Grade 3 or 4 non-
hematological toxicities
AND
Count recovery to baseline or 
better
Complete 7 doses of 5-Aza & 6 
doses of panobinostat
AND 
No Grade 3 or 4 non-
hematological toxicities
AND
Counts not recovered to 
baseline
Counts recover prior to DAY 42
NO
Day 42 marrow hypoplastic
DLT OFF Study
Day 42 marrow NOT 
hypoplastic
The dose escalation procedure including the DLT definitions are aligned with the registered 
label for 5-Aza. This ensures that patients receiving the full dose of 5-Aza according to the 
registered label. Also the potential delay of the next treatment cycle to Day 42 is part of the 
registered 5-Aza label.
6.6.1.7
Follow-up for dose-limiting toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
including clinically significant laboratory values, must be followed at least once a week for 4 
weeks, or until resolution or stabilization of the event, whichever comes first. Patient who 
experience ECG abnormalities should be followed as per Section 6.6.1.8.
6.6.1.8
Dose modification, delay and discontinuation
For patients who are unable to tolerate the protocol-specified dosing schedule regardless of 
whether a patient is enrolled in the phase Ib or the phase IIb part of the study, dose 
adjustments are permitted in order to keep the patient on study treatment. Dose modifications 
for panobinostat must be recorded on the Dosage Administration Record CRF.


Novartis
Confidential
Page 65
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Dose adjustments due to hematological toxicity
All patients should receive supportive, hematological measures in accordance with 
institutional protocols. There will be no dose reductions for panobinostat below 10 mg (dose 
level -1). Following dose modifications, the cycle duration should return to 28 days.
In AZA-001 pivotal phase III trial (Fenaux et al 2009a), about 90% of patients experienced 
grade 3-4 neutropenia and/or thrombocytopenia. Seventy-four percent of patients (n=72) with 
baseline grade 0-2 thrombocytopenia developed grade 3-4 thrombocytopenia during treatment 
with 5-Aza. However, 151 (86%) of patients remained on 75 mg/m 2 per day throughout the 
study with no dose adjustments for a median of 9 treatment cycles The median 5 -Aza cycle 
length was 28 days and 21% of the cycles were longer than 35 days. These findings indicate 
that provided adequate hematological supportive care, patients could continue on 5-Aza 
therapy and benefit from it. Of note if that median time to response was rep orted to be 4 
months. There is mounting clinical evidence that combining a hypomethylating agent, such as 
5-Aza, with DACi may shorten time to response to two cycles (Silverman et al 2008). 
Therefore, it is paramount to manage grade 3-4 cytopenia and possible residual disease with 
optimal hematological support in order to keep the patient, if not progressing, on treatment for 
several cycles to allow study treatment activity to occur.
Hematological toxicity deriving from the combination of panobinostat and 5-Aza and the 
potential risk for bleeding and infection/sepsis should be weighted against conventional 
management of the disease and expected treatment benefit for the patients.
For phase IIb portion only: 
During the scheduled 2 weeks off of study treatment, neutropenia and thrombocytopenia are 
anticipated to be resolved to at least patient baseline CTCAE grade.  If by Day 28, there is 
failure to recover from Grade 4 neutropenia or Grade 4 thrombocytopenia to ≥ patient 
baseline CTCAE grade, then study treatment may be delayed up to Day 42.  If these 
cytopenias persist, Table 6-4 below is offered as guidance for dose reductions in the phase IIb 
part of the study. 
Management of febrile neutropenia
At least one-half of neutropenic patients who become febrile have an established or occult 
infection and at least one-fifth of patients with neutrophil of <1.0 x 109/L has bacteremia. 
Because the progression of infection in neutropenic patients can be rapid, and because such 
patients with early bacterial infections cannot be reliably distinguished from non-infected 
patients at presentation, empirical antibiotic therapy should be administered promptly to all 
neutropenic patients at the onset of fever. Afebrile patients who are neutropenic but who have 
signs or symptoms compatible with an infection should also have empirical antibiotic therapy 
begun in the same manner as do febrile patients. Selection of the initial antibiotic regimens 
should follow institutional guidance, as well as considering low vs. high risk patients and 
potential drug-drug interactions with study treatment, i.e. panobinostat (Section 6.6.2).


Novartis
Confidential
Page 66
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Dose adjustments due to non hematological toxicity
For all treatment cycles, dosing should not be delayed beyond 42 days.
No dose modifications are required for grade 1 non-hematologic toxicity. Patients 
experiencing NCI-CTCAE grade 2 non-hematologic toxicity (excluding prolonged QT 
interval and peripheral neuropathy) may continue treatment with panobinostat at the current 
dose and schedule if in the best interest for the patient. More frequent monitoring of the 
patient may be required, and patients should be informed to call the Investigator immediately 
if there is any worsening of symptoms. (Table 6-6 for phase Ib part and Table 6-7 for phase
IIb part)
Dose adjustments due to prolonged QT interval
The cardiac assessment schedule for the phase Ib and the phase IIb parts is shown in Table 7-
5. Pre-dose ECG criteria is defined as a QTcF < 480 ms. In case any single pre-dose ECG 
during the treatment cycle shows a QTcF ≥ 480 ms the administration of study drug is not 
permitted. Instead, dosing should be delayed until the next scheduled day of panobinostat 
intake and three pre-dose ECGs should be repeated. If, again, pre-dose ECG criteria are not 
met the patient should be discontinued from the study. In case pre-dose ECG criteria are met 
panobinostat treatment can be resumed.
If any single post-dose ECG shows a QTcF ≥ 480 ms or an increase of more than 60 ms from 
baseline panobinostat dosing should be delayed until the next scheduled day of panobinostat 
intake and three pre-dose ECGs done. If pre-dose ECG criteria are not met the patient should 
be discontinued from the study. In case pre-dose ECG criteria are met (QTcF < 480 ms) 
panobinostat treatment can be resumed with a 10mg dose reduction.
If any single ECG shows QTcF > 500 ms the patient is discontinued from the study.
In case of QT prolongation it is recommended to check and correct patient’s serum potassium, 
magnesium, calcium and phosphorus immediately, as well as evaluate concomitant 
medication. In case the prolongation is due to electrolyte imbalance or concomitant 
medication the patient can continue the trial once these causes can be eliminated.
The Sponsor should be notified immediately of any QT prolongation that would cause delay 
of study drug administration, change in panobinostat dose or discontinuation of the patient 
from the study.
Dose adjustments due to 5-Aza-related renal toxicity
There are no reportings of renal toxicity with panobinostat in the ongoing clinical program. 
On the other hand, renal tubular dysfunction manifesting as hypophosphatemia, hypokalemia 
or hyponatremia with or without increases in serum creatinine or blood urea nitrogen (BUN) 
may infrequently occur with 5-Aza therapy. If serum bicarbonate falls below 20mEq/L and 
the decrease is considered secondary to 5-Aza the patient should receive oral bicarbonate 
replacement. If the event cannot be controlled replacement therapy should be continued and 
the next 5-Aza cycle dosage be reduced by 50%. Other electrolyte disturbances should be 
treated with appropriate replacement therapy. If serum creatinine or BUN increase by 2-fold 


Novartis
Confidential
Page 67
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
or greater from baseline without any other reasonable explanation and is thought to be 
secondary to 5-Aza the start of the next cycle of study treatment (5-Aza and panobinostat) 
should be delayed until values return to baseline and the dosage of 5-Aza should be reduced 
by 50%. In case doses of 5-Aza are to be reduced for two consecutive times, patient should be 
removed from the study according to the locally approved label.
Dose adjustments for patients receiving single agent Vidaza 
For those patients being treated on the control arm (single agent 5-Aza) the product label 
should be followed to make dose adjustments as necessary to maintain the patient on 
treatment.
Table 6-4
Phase IIb only: Panobinostat and Vidaza dose discontinuations/
interruptions/reductions for Grade 4 neutropenia and Grade 4 
thrombocytopenia (NCI CTCAEv3.0)
Grade 4 Neutropenia
and/or 
Grade 4 
Thrombocytopenia
With Marrow
Hypoplasia
(<10% overall cellularity and <5% 
blasts)
Without Marrow Hypoplasia
Day 28
If by Day 28, there is failure to recover neutrophil and/or platelet counts ≥ 
baseline CTCAE grades or a cytopenia worsens to G4 AND a delay in study 
treatment is NOT considered to be in the patient’s best interest, the 
investigator may consider reducing panobinostat by 10 mg if the cytopenias 
are judged to be related to panobinostat*. If the cytopenia occurs in a 
consecutive cycle, than the product label must be followed for a 5-Aza dose 
reduction, and panobinostat must be reduced by 10mg. 
Day 42
If by Day 42 there is failure to 
recover neutrophil and platelet 
counts ≥baseline CTCAE grades 
or a cytopenia worsens to G4 
AND persistent bone marrow 
hypoplasia exists then the dose of 
5-Aza should be reduced 
according to the product label and 
the investigator may consider 
reducing the dose of panobinostat 
by 10 mg*.  
If this cytopenia occurs in a 
consecutive cycle, then the 
product label must be followed for 
a 5-Aza dose reduction, and 
panobinostat must be reduced by 
10mg.
A Cycle should not be delayed 
beyond day 42.
If by Day 42 there is failure to recover 
neutrophil and platelet counts ≥ 
baseline CTCAE grades or a cytopenia 
worsens to G4 AND there is NO 
demonstration of bone marrow 
hypoplasia, then the dose of 5-Aza and 
panobinostat will remain unchanged, 
BUT,
if the cytopenia occurs in a 
consecutive cycle, then the dose of 
panobinostat must be reduced by 
10mg*.
Cycle should not be delayed beyond 
day 42.
* Dose reductions below 10mg of Panobinostat are not allowed


Novartis
Confidential
Page 68
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 6-5
Phase Ib and Phase IIb: Panobinostat and Vidaza dose 
discontinuations/interruptions/reductions for febrile neutropenia (NCI 
CTCAEv3.0)
Febrile Neutropenia
Grade 3
Grade 4
ANC <1.0 x 109/L; 
fever ≥38.5*C (fever 
of unknown origin 
without clinically or 
microbiologically 
documented infection
Present
Life threatening
Promptly install institutional protocol 
for febrile neutropenia 
management. Temporarily 
discontinue panobinostat until 
recovery to ANC ≥ 1.0 x 109/L 
confirmed for at least 2 consecutive 
days, and patient becomes afebrile. 
Then resume with 10 mg 
panobinostat dose reduction
Discontinue study treatment (panobinostat and 
5-Aza) and promptly manage febrile neutropenia 
according to institutional protocol
Table 6-6
Phase Ib only: Panobinostat dose interruptions/reductions for 
treatment-emergent/new non-hematological toxicities attributable to 
study treatment (except for prolonged QT interval)
Toxicity
Grade 1
Grade 2
Grade 3 / Grade 4 (Grade 2 
peripheral neuropathy)
First 
presentation
No modification for Grade 1
For Grade 2: temporary discontinuation until grade 1 then 
resume at the same dose of panobinostat. If grade 1 not 
occurred by day 42, discuss with the Sponsor to resume 
panobinostat at one dose level below
Toxicity qualifies for a DLT#. 
Patient to be withdrawn*.
Second and 
subsequent 
presentations
No modification for grade 1
For Grade 2: temporary discontinuation until grade 1 then 
resume at a one lower dose level of panobinostat according 
to the Investigator’s judgement. Cycle should not be delayed 
beyond day 42.
Patient to be withdrawn.
*No further panobinostat. Consider to continue off study with 5-Aza alone according to Product Label
# DLT only applicable for the first Cycle of the phase Ib part.
Table 6-7
Phase IIb only: Panobinostat dose interruptions/reductions for 
treatment emergent/new non-hematological toxicities attributable to 
study treatment (except for prolonged QT interval)
Toxicity
Grade 3
Any Grade 3 for ≥7 days:
If this grade 3 Nausea is uncontrolled despite use of 
standard anti-emetics.
If this grade 3 Total bilirubin has a coincident Direct 
Bilirubin ≥0.5 mg/dl
With the exception of ≥Grade 3 QTcF prolongation 
(QTcF > 500ms) which has separate guidelines
Temporary dose interruption until 
Grade 1 or patient baseline and 
then resume panobinostat with a 
10mg dose reduction
Grade 4
Any Grade 4 non-hematologic toxicity
Temporary dose interruption until 
Grade 1 or patient baseline and 
then resume panobinostat with a 
10mg dose reduction


Novartis
Confidential
Page 69
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
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 loperamide 
regimen should interrupt treatment with panobinostat as described in Table 6-6. If the above 
regimen is inadequate then additional evaluation and treatment should be pursued as 
medically indicated. Institution of oral fluoroquinolone therapy for patients with persistent 
diarrhea lasting more than 24 hours and for patients with diarrhea who develop either fever or 
neutropenia while on chemotherapy has been recommended by experts panel, prompted by 
the experience from two large phase III studies reporting toxic deaths related to 
gastrointestinal symptoms frequently attributed to sepsis, sometimes with concurrent 
neutropenia (Rothenberg et al 2001). 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 published guidelines.
6.6.2
Other concomitant medications
The investigator should instruct the patient to notify the study site about any new medications 
taken after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies administered after the patient starts treatment must be listed on the 
Concomitant medications/Significant non-drug therapies after start of study drug CRF.
Since panobinostat is metabolized in vitro by CYP3A4/5, a clinical drug-drug interaction 
study between panobinostat and one of the most potent CYP3A4 inhibitors, ketoconazole was 
conducted in cancer patients [LBH589B2110]. Recent results indicated that following 4 
consecutive ketoconazole doses at 400 mg and co-administration of a single oral panobinostat 
dose of 20 mg, mean Cmax and AUC of panobinostat increased by 60%. Patients using 
concomitant medications known to be metabolized by these isoenzymes will not be excluded 
from the study; however, should be carefully monitored for potentiation of toxicity due to 
these medications. A list of drugs known to inhibit CYP3A4/5 is provided in [Post-text 
supplement 3].
5-Aza as well as panobinostat therapy is commonly associated with thrombocytopenia. This 
may lead to an increased risk of bleeding if concomitantly used with sodium warfarin therapy. 
It is recommended that patients who require chronic anticoagulation therapy, while on 
panobinostat therapy, use low molecular weight heparin (LMWH). However, if the use of 
LMWH is not feasible, such patients may continue on sodium warfarin while on panobinostat, 
but a close monitoring of common coagulation parameters, including PTT should be 
conducted.
In vitro assays, panobinostat was shown to inhibit the cytochrome P450 isoenzyme CYP2D6 
at low micromolar ranges, thereby suggesting a potential risk of drug-drug interactions with 
concomitant medications that are also metabolized by CYP2D6. A clinical drug-drug 


Novartis
Confidential
Page 70
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
interaction study with dextromethorphan (a CYP2D6 probe drug) and panobinostat is 
currently ongoing in cancer patients. In the meantime, patients using concomitant medications 
known to be CYP2D6 substrates will not be excluded from the study; however, should be 
monitored for potentiation of toxicity. A list of drugs known to inhibit CYP2D6 is provided in 
[Post-text supplement 3].
Patients who are currently receiving treatment with any of the medications which are known 
to have a relative risk of prolonging the QT interval or inducing Torsade de Pointes, who can 
not either discontinue or switch to a different medication prior to study enrollment, will be 
excluded from the study. Concomitant administration of agents known to prolong the QT 
interval or induce Torsade de Pointes while patients are receiving panobinostat is 
contraindicated. Patients may not begin treatment with these medications unless proactively 
discussed with the Sponsor. A list of medications known to prolong QT interval is provided in 
[Post-text supplement 3].
6.6.3
Study treatment discontinuation
At the time the decision is made to discontinue study treatment, an End of Treatment Visit 
should be scheduled as soon as possible after the last dose of study treatment. All assessments 
listed for the ‘End of Treatment Visit’ should be performed (Table 7-1) and the End of 
Treatment CRFs should be completed with the date and reason for stopping study drug. 
As of protocol amendment 5, all assessments listed for the ‘End of Treatment Visit’ are not 
mandatory and will be performed at the discretion of the investigator (Table 7-3). However, 
the End of Treatment CRF pages must be completed with the date and reason for stopping 
study drug.
All patients must have evaluations for 4 weeks after the last dose of study treatment, including 
the monitoring of adverse events and concomitant medications (including antineoplastic 
therapy). If applicable, any adverse events marked as ‘continuing’ as of the last dose of study 
medication must be followed at least once per week for at least 4 weeks or until resolution of 
the event, return to baseline status, or clinical stability is reached. At a minimum, all patients 
who discontinue study treatment, including those who refuse to return for a final visit, will be 
contacted by telephone and/or mail for safety evaluations during the 4 weeks following the 
last dose of study drug. Patients lost to follow-up should be recorded as such on the CRF. If 
patients refuse to return for these visits or are unable to do so, the patient should be considered 
off-study, and the ‘Study Evaluation Completion’ CRF should be completed. Female patients 
who become pregnant while on panobinostat must be immediately and permanently 
discontinued from panobinostat treatment and reported to the local Novartis Integrated 
Medical Safety Department as per Section 8.4.
6.6.4
End of treatment
Once study treatment is permanently discontinued, the patient will be considered to have 
completed treatment and no more additional study assessments will be performed other than 
the collection of the 28 day safety follow up data and survival information. The reason for end 
of treatment will be recorded on the End of Treatment CRF. 
The reasons for which a patient may end participation on this study are one of the following:


Novartis
Confidential
Page 71
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

Subject’s condition no longer requires study drug 

Adverse event(s)

Protocol deviation

Subject withdrew consent

Lost to follow-up

Administrative problems

Death

Disease progression/relapse
6.6.5
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to understand the primary reason for this decision and record this information.
Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
6.6.6
Follow-up for safety evaluation
All patients must be carefully monitored for AEs and concomitant medications (including 
antineoplastic therapy) for 30 days after the last dose of study treatment. 
Data collected should be added to the Adverse Events CRF and the Concomitant Medication 
CRF.
6.6.7
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.


Novartis
Confidential
Page 72
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
6.6.8
End of study (study evaluation completion)
In this protocol, End of Study (or Study Evaluation Completion) is defined as the time when 
the 28 day safety follow up is completed and no more additional study assessments (other 
than the collection of survival information) are planned to be performed. In the Study 
Completion CRF one of the following (primary) reasons for End of Study should be recorded:

Significant protocol deviation

Patient withdrew consent

Lost to follow-Up

Administrative problems

Death

New anti-cancer treatment

Disease progression/relapse

Follow up phase completed as per protocol
Survival information will be collected by telephone contact every three months for the first 
year after study evaluation completion, thereafter every six months till death or lost of follow-
up. The information is to be recorded in the Survival Information CRF page. The investigator 
should show ‘due diligence’ by documenting in the source documents steps taken to contact 
the patient, e.g., dates of telephone calls.
The core clinical study report will be based on a data cut-off corresponding to the time point 
where all patients have either completed 12 cycles of study treatment or discontinued study 
treatment for any other reason whichever comes first. An addendum to the core clinical study 
report will be provided at the completion of the study to summarize and/or list the additional 
safety and efficacy data as appropriate. 
Patients who have completed 12 cycles of study treatment and are assessed by the Investigator 
to have the potential to benefit from ongoing treatment will continue their assigned treatment 
allowing collecting and reviewing safety, efficacy and survival data. After the data-cut off 
point for the CSR, a reduced visit evaluation schedule will be applied. All sites will be 
informed per Novartis Investigator Notification when the data cut-off date has been reached 
and the patient’s can move to the reduced schedule of assessments.
As of protocol amendment 5, data collection for the ongoing patients is further limited as 
described in Table 7-3.
6.6.9
Emergency unblinding of treatment assignment
Not applicable.


Novartis
Confidential
Page 73
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
7
Visit schedule and assessments
For the phase IIb part, following registering in IRT for screening, patient eligibility will be 
checked once all screening procedures are completed. The eligibility check will be embedded 
in IRT system. Please refer and comply with detailed guidelines in the IRT manual. 
Table 7-1 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.


Novartis
Confidential
Page 74
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 7-1
Visit evaluation schedule for Phase Ib and Phase IIb part 
Examination
Screening Cycle 1
(28 days - additional visit in () if cycle is 
extended beyond day 28)
Cycle 2 through CSR cut off date
(28 days - additional visits in () if cycle is extended 
beyond day 28)
EOT15 28d 
Fu16
EOS17
Survival 
Fu18
Visit
1
2
3
6
601 7
8
9
10
11
12
13 14
15
777
501
778
Day of cycle
-14 to -1
1
2 3
4 5 6 7 8
10 12
15 22 (29) 1
2
3
4
5
6
7
8
10 12 15 22
(29)
Demography/Informed 
Consent
X
Inclusion/Exclusion 
Criteria
X
Relevant medical 
history/
Current medical 
conditions
X
Diagnosis and extent 
of disease
X
Prior antineoplastic 
therapy
X
Height2
X
IPSS score
X
Transfusion 
dependency14
X
X
X
X
Weight, vital signs2
X
X
X
X
ECOG Performance 
Status3
X
X
X
X
Hematology4,14
X
X
X
X X (X) X
(X)
X
Coagulation5
X
X
X
X
Biochemistry6
X
X
X
X X (X) X
X¥
X
X¥
(X)
X
Urinalysis7
X
X


Novartis
Confidential
Page 75
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Examination
Screening Cycle 1
(28 days - additional visit in () if cycle is 
extended beyond day 28)
Cycle 2 through CSR cut off date
(28 days - additional visits in () if cycle is extended 
beyond day 28)
EOT15 28d 
Fu16
EOS17
Survival 
Fu18
Visit
1
2
3
6
601 7
8
9
10
11
12
13 14
15
777
501
778
Day of cycle
-14 to -1
1
2 3
4 5 6 7 8
10 12
15 22 (29) 1
2
3
4
5
6
7
8
10 12 15 22
(29)
Pregnancy test for 
WOCBP8
X
X
X
Thyroid function test9
X
X
Echocardiogramm or 
MUGA
X
5-Aza
X X X
X X X X
X X
X
X
X
X
X
Panobinostat dosing
X
X
X
X
X
X
X
X
X
X
X X
Prior/concomitant 
medications11
CONTINUOUS
X
X
Adverse events12
CONTINUOUS
X
X
ECG13
X
X
X
X
X
X
Antineoplastic therapy 
since discontinuation 
of study treatment16
X
X
PK assessment
Table 7-6
Bone marrow exam / 
Response 
assessment14
X
End of cycle14
X
Extramedullary 
disease evaluation14
X
End of cycle14
X


Novartis
Confidential
Page 76
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Examination
Screening Cycle 1
(28 days - additional visit in () if cycle is 
extended beyond day 28)
Cycle 2 through CSR cut off date
(28 days - additional visits in () if cycle is extended 
beyond day 28)
EOT15 28d 
Fu16
EOS17
Survival 
Fu18
Visit
1
2
3
6
601 7
8
9
10
11
12
13 14
15
777
501
778
Day of cycle
-14 to -1
1
2 3
4 5 6 7 8
10 12
15 22 (29) 1
2
3
4
5
6
7
8
10 12 15 22
(29)
Survival
X
¥        done in cycle 2 only
1.
Screening evaluations must be performed ≤ 14 days prior to cycle 1 administration of panobinostat and 5-Aza, unless otherwise stated. Baseline 
demographics will be captured for screening failures as well as the reason for failure.
2.
Physical examinations, vital signs, and weight will be performed on the scheduled day, even if study medication is being held. More frequent 
examinations may be performed at the investigator’s discretion, if medically indicated.
3.
ECOG performance status - Section 8.1. Assessment of ECOG Performance Status will be performed on the scheduled day, even if study medication 
is being held. More frequent examinations may be performed at the investigator’s discretion, if medically indicated. If the baseline assessment was 
performed ≤ 72 hours prior to the first dose of panobinostat, then it does not need to be repeated on day 1 of cycle 1.
4.
Hematology - Section 7.6.3.1
5.
Coagulation - Section 7.6.3.2
6.
Biochemistry - Section 7.6.3.3
7.
Urinalysis - Section 7.6.3.4
8.
Pregnancy test - Section 7.6.3.6. All females of childbearing potential should complete a serum pregnancy test ≤ 72 hours prior to the administration 
of study treatment on day 1 of cycle 1 and at the end of treatment. In addition, a urine pregnancy test will be performed in monthly intervals pre-dose 
on day 1 of each subsequent cycle during study duration.
9.
Thyroid function test - Section 7.6.3.5
 
11. Prior/concomitant medications - Record all medications administered ≤ 4 weeks prior to the administration of study treatment. Record all medications 
taken during the study on the Concomitant Medications CRF.
12. Adverse events - Section 8.1
13. ECG - 12-lead ECG will be performed at scheduled time points as indicated in Table 7-5.  Single ECGs will be done at screening; triplicate ECGs will 
be done in cycle 1 on days 3, 8, 12 and all subsequent treatment cycles on Day 3 and at EOT.
 


Novartis
Confidential
Page 77
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Examination
Screening Cycle 1
(28 days - additional visit in () if cycle is 
extended beyond day 28)
Cycle 2 through CSR cut off date
(28 days - additional visits in () if cycle is extended 
beyond day 28)
EOT15 28d 
Fu16
EOS17
Survival 
Fu18
Visit
1
2
3
6
601 7
8
9
10
11
12
13 14
15
777
501
778
Day of cycle
-14 to -1
1
2 3
4 5 6 7 8
10 12
15 22 (29) 1
2
3
4
5
6
7
8
10 12 15 22
(29)
 
15. End of treatment visit (EOT) - Patients who permanently discontinue study drug for any reason, will be considered to have completed study treatment, 
and should not be considered withdrawn from the study. Such patients should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed should be performed..
16. Follow-up - Section 6.6.6. All patients must be carefully monitored for adverse events and concomitant medications (including antineoplastic therapy) 
for 28 days following the end of study treatment.
17. Study evaluation completion (EOS) - Section 6.6.8. Once the patient discontinues study drug treatment and no additional study assessments will be 
performed, the Study Evaluation Completion CRF should be completed.
18. Survival Follow up - Section 6.6.8 - Survival information will be collected by telephone contact every three months for the first year after EOS visit, 
hereafter every six months.


Novartis
Confidential
Page 78
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 7-2
Visit evaluation schedule after CSR data cut off date (for the phase Ib and IIb part)
All sites will be informed per Novartis Investigator Notification when the data cut-off date has been reached and the patients can move to 
the reduced schedule of assessments.
Examination
(28 days - additional visits in () if cycle is extended beyond day 28)
EOT11
28d Fu12
EOS13
Survival 
Fu14
Visit
10
11
12
13
14
15
777
501
778
Day of cycle
1
2
3
4
5
6
7
8
10
12
15
22
(29)
Transfusion dependency
X
X
Weight, vital signs
X
X
ECOG Performance 
Status
X
X
Hematology,1
X
(X)
X
Coagulation2
X
X
Biochemistry3
X
X
(X)
X
Urinalysis4
X
Pregnancy test for 
WOCBP15
X
X
Thyroid function test5
X
5-Aza
X
X
X
X
X
X
X
Panobinostat dosing
X
X
X
X
X
X
Prior/concomitant 
medications7
CONTINUOUS


Novartis
Confidential
Page 79
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Examination
(28 days - additional visits in () if cycle is extended beyond day 28)
EOT11
28d Fu12
EOS13
Survival 
Fu14
Visit
10
11
12
13
14
15
777
501
778
Day of cycle
1
2
3
4
5
6
7
8
10
12
15
22
(29)
Adverse events8
CONTINUOUS
ECG9
X
Antineoplastic therapy 
since d/c of study 
treatment 
X
X
Bone marrow exam/ 
Response assessment 10
End of Cycle 
X
Extramedullary disease 
evaluation10
End of Cycle
X
Survival
X
1. Hematology - Section 7.6.3.1
2. Coagulation - Section 7.6.3.2
3. Biochemistry - Section 7.6.3.3
4. Urinalysis - Section 7.6.3.4
5. Thyroid function test- Section 7.6.3.5
 
7. Prior concomitant medications -Record all medications taken during the study on the Concomitant Medications CRF.
8. Adverse Events - Section 8.1
9. ECG - Table 7-5
10. Response assessment - Section 7.5.1 - Bone marrow aspiration and /or biopsy after the data cut off date will be obtained at the discretion of the investigator. 
11. End of Treatment visit (EOT) - Section 6.6.4
12. Follow-up - Section 6.6.6 Survival information will be collected by telephone contact every three months for the first year after EOS visit, hereafter every six months.
13. Study Evaluation Completion (EOS) Section 6.6.8
14. Survival follow up - Section 6.6.8
15. Pregnancy test – Section 7.6.3.6


Novartis
Confidential
Page 80
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Table 7-3
Visit evaluation schedule as of protocol amendment 5 (for the phase Ib and IIb part)
Examination
(28 days - additional visits in () if cycle is extended beyond day 28)
EOT1
28d Fu2
EOS3
Survival 
Fu4
Visit
777
501
778
Day of cycle
1
2
3
4
5
6
7
8
10
12
15
22
(29)
MANDATORY ASSESSMENTS
5-Aza
X
X
X
X
X
X
X
Panobinostat dosing
X
X
X
X
X
X
Prior/concomitant 
medications5
CONTINUOUS
Adverse events6
CONTINUOUS
Survival
X
OPTIONAL ASSESSMENTS (to be performed at the discretion of the Investigator)
Weight, vital signs
X
X
ECOG Performance 
Status
X
X
Hematology7
X
(X)
X
Coagulation8
X
X
Biochemistry9
X
X
(X)
X
Urinalysis10
X
Thyroid function test11
X
ECG12
X
X
Transfusion 
X
X


Novartis
Confidential
Page 81
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Examination
(28 days - additional visits in () if cycle is extended beyond day 28)
EOT1
28d Fu2
EOS3
Survival 
Fu4
Visit
777
501
778
Day of cycle
1
2
3
4
5
6
7
8
10
12
15
22
(29)
dependency13
Bone marrow exam/ 
Response assessment 13
End of Cycle X
Extramedullary disease 
evaluation13
End of Cycle X
Antineoplastic therapy 
since d/c of study 
treatment 
X
X
1. End of Treatment visit (EOT) - Section 6.6.4
2. Follow-up - Section 6.6.6
3. Study Evaluation Completion (EOS) Section 6.6.8
4. Survival follow up - Section 6.6.8 Survival information will be collected by telephone contact every three months for the first year after EOS visit, hereafter every six 
months.
5. Concomitant medications -Record all medications taken during the study on the Concomitant Medications CRF.
6. Adverse Events - Section 8.1
7. Hematology - Section 7.6.3.1
8. Coagulation - Section 7.6.3.2
9. Biochemistry - Section 7.6.3.3
10. Urinalysis - Section 7.6.3.4
11. Thyroid - Section 7.6.3.5
12. ECG - Table 7-5
13. Response assessment - Section 7.5.1


Novartis
Confidential
Page 82
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
7.1
Disease classification/qualification at baseline
A diagnostic bone marrow collection is required to be obtained within 2 weeks of starting 
study treatment.  If cytogenetic results are obtained within 6 weeks prior to start of study 
treatment, no confirmatory cytogenetic exam is required at baseline.
7.2
Information to be collected on screening failures
Data on patients who fail screening will not be entered into the clinical database. Only 
information from the Screening Log CRF will be entered.
7.3
Patient demographics/other baseline characteristics
The data that will be collected on patient characteristics at screening include general 
demographics, relevant medical history, the diagnosis and extent of their disease and details 
regarding anti-neoplastic treatments they have received in the past.
7.4
Treatments
Compliance to study treatment will be assessed by the investigator and/or study personnel at 
each visit using capsule counts, medication records, and information provided by the patient 
and/or caregiver. This information should be captured in the source document and Dosage 
Administration Record CRF at each visit.
7.5
Efficacy
Efficacy evaluations will be performed and recorded in order to detect anti-leukemic activity 
of the study treatment (panobinostat and/or 5-Aza). Each patient’s disease status will be 
assessed at screening and periodically throughout the study. Please refer to [Post-text 
supplement 1] for disease specific criteria for evaluating response and disease progression.
7.5.1
Efficacy assessments
Response will be assessed when a BM aspirates and/or core biopsy is collected as outlined 
below. The response to treatment will be determined as outlined in [Post-text supplement 1].

Bone marrow aspiration and/or core biopsy must be obtained at screening (within 2 
weeks prior to start study treatment), within -5 days of the end of even-numbered cycles,
and at the End of Treatment Visit, as well as, at other times at the discretion of the 
investigator.

The bone marrow differential must include any disease-specific criteria for diagnosis 
and response assessment

Peripheral Blood: Complete blood cell count including WBC; differential including 
promyelocyte, myelocyte, and metamyelocyte; blast cell count; and platelet count must be 
performed within 5 days of bone marrow aspirate/biopsies, unless clinically not feasible.

Transfusion dependency will be assessed at screening and at Day 1 of each cycle, and at 
the end of treatment visit. If additional non-study response assessments are being 
performed, the number of units for red blood cells, platelets and granulocytes transfusions 
must be recorded on the additional assessment transfusion CRF pages.


Novartis
Confidential
Page 83
Amended Protocol Version 05 Clean
Study No. CLBH589H2101

Extramedullary disease will be assessed at screening, at each response assessment, at the 
end of treatment visit and at other times at discretion of the investigator.
For potential auditing purposes, the investigator must maintain the BM smears for each study 
patient at the site for a minimum of 7 years.
As of protocol amendment 5, response assessment will be obtained at the discretion of the 
investigator (Table 7-3).
7.6
Safety
7.6.1
Performance status
Table 7-4
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
7.6.2
Cardiac assessments
Electrocardiogram (ECG)
A screening 12-lead ECG will be performed to assess study eligibility. Additional 12-lead 
ECGs will be performed at a minimum at scheduled time points as indicated in Table 7-5 .
All ECGs will be submitted to eRT for central review and results will be faxed back to the 
investigational site within 1 working day (refer to the eRT Panobinostat Lab Manual for 
instructions on the collection and transmission of ECGs to the independent reviewer). The 
centralized readings of ECGs by eRT will use the Fridericia correction: QTcF. The ECG 
interpretations from eRT will be the formal data entered into the clinical trial database. Local 
ECGs and eRT central review results will not be reconciled.
All patients treated with panobinostat on this study will have frequent QT monitoring on 
specified days during Cycle 1. A single screening ECG will be obtained for all patients to 
determine eligibility to participate. The mean of the 3 ECGs obtained pre-dose on Cycle 1 
Day 3 will be calculated by eRT, and will be used as the baseline value to compare to 
throughout the study.
Treatment decisions will 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. Any final decisions concerning dose 
modifications or permanently discontinuing the patient from study drug due to QTcF 


Novartis
Confidential
Page 84
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
prolongation will be based on the assessment performed by eRT and after discussion between 
the Investigator and Sponsor. If the patient does not meet the QT criteria for dosing the 
patient’s serum potassium, magnesium, calcium and phosphorus must be measured 
immediately, and the patient must receive supplements to correct any low values, as well as 
con-meds evaluated for possible interaction.
Note: this schedule is only permitted for patients who have had no clinically meaningful 
cardiac abnormalities identified, and whose QTcF has not increased by ≥ 60 ms from baseline 
or absolute QTcF is not ≥ 480 ms. Patients who experience a QTcF abnormality should follow 
instructions given in Section 6.6.1.8.
Table 7-5
Cardiac assessment monitoring schedule
Patients enrolled onto the control arm will have a screening 12-lead ECG only to assess study 
eligibility. Additional ECGs will be performed if clinically indicated at the discretion of the 
investigator.
Cycle
Day
Scheduled time point (hours)
Screening1
-14 to -1
Baseline/Cycle 1
3
0h (pre-dose) and 3 hours post dose2
Cycle 1
8 
0h (pre-dose) and 3 hours post dose2
12
0h (pre-dose and 3 hours post dose2
Subsequent Treatment 
cycles3
3
0h (pre-dose)2
End of study treatment
Day of End of Treatment Visit
Any time on Day of End of Treatment 
visit2
1) Screening ECG x 1 to be reviewed centrally by eRT to determine eligibility prior to first dosing
2) Three sequential ECGs separated by 5-10 minutes
3) As of protocol amendment 5, ECGs will be performed at the discretion of the investigator
Note: (a) If the dose is withheld for any reason other than QTc prolongation, the extensive ECG 
monitoring will not be required. (b) QTc/QTcF > 500 ms requires the patient is permanently withdrawn 
from study.
Echocardiogram or MUGA (multiple uptake gated acquisition) scan
A MUGA scan or echocardiogram to assess LVEF will be performed within the screening 
period prior to the first administration of study treatment. If the LVEF is < 45% by 
echocardiogram or MUGA, the patient is not eligible for the study. MUGA scan or 
echocardiogram may be repeated at the Investigator’s discretion if there are signs or 
symptoms of cardiac dysfunction. Patients should be monitored and assessed with the same 
technique throughout the study if clinically indicated.
7.6.3
Laboratory evaluations
The following laboratory evaluations will be performed by the institutions’ clinical 
laboratories, or by a laboratory local to the patient, according to the visit schedule in 
Table 7-1, Table 7-2 and Table 7-3. Novartis must be provided a copy of the laboratory 
certification and tabulation of the normal ranges for each parameter required. Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical signs or 


Novartis
Confidential
Page 85
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
symptoms, and are considered clinically significant (e.g., 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 Adverse 
Events CRF, as well as the appropriate laboratory CRF and/or comment CRF page. 
Screening labs may be repeated, if needed, to obtain acceptable values before the patient 
would fail screening. Laboratory tests should be collected and analyzed immediately prior to 
dosing on the scheduled day.
7.6.3.1
Hematology
Hematology tests include the following parameters: Complete blood count (CBC) including a 
total white blood cell count (WBC), neutrophil count, red blood cell count (RBC), lymphocyte, 
monocyte, eosinophil, basophil, promyelocyte, metamyelocyte, myelocyte, and blast counts, 
hemoglobin (Hgb), hematocrit, and platelet count. Automated differential blood counts should 
be accompanied by peripheral blood smear assessed by a pathologist and results reported in 
the CRF.
Hematology is done at screening and within 72 hours, on Day 1 of each cycle; then on Day 8, 
15, 22 in Cycle 1, and continues weekly in case the treatment cycle is extended beyond Day 
28; and at End of Treatment Visit. As of protocol amendment 5, hematology tests will be 
performed at the discretion of the investigator (Table 7-3).
More frequent examinations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded on the Unscheduled Visit CRFs.
7.6.3.2
Coagulation
The coagulation profile includes prothrombin time (PT) or International Normalized Ratio 
(INR), partial thromboplastin time (PTT), and fibrinogen. The coagulation profile should be 
performed at the following time points: Screening (does not need to be repeated at Cycle 1 
Day 1 if obtained within -7 days before Cycle 1 Day 1); Pre-dose on Day 1 of every cycle 
through Cycle 6; Pre-dose on Day 1 of every other cycle there after; End of Treatment visit.
As of protocol amendment 5, coagulation tests will be performed at the discretion of the 
investigator (Table 7-3).
7.6.3.3
Biochemistry
Biochemistry includes the following parameters: urea or BUN, creatinine, sodium, potassium, 
glucose, calcium, albumin, total protein, total bilirubin (direct and indirect), alkaline 
phosphatase, AST, ALT, inorganic phosphorous, magnesium, bicarbonate, LDH (screening 
only), and uric acid.
Biochemistry is done at screening and within 72 hours, on Day 1 of each cycle; then on Day 8, 
15, 22 in Cycle 1 and Cycle 2; On Day 15 of each subsequent Cycle, and continues weekly in 
case the treatment cycle is extended beyond Day 28; and at End of Treatment Visit. If the 
baseline examination was performed ≤72 hours prior to the first dose of study treatment, it 
need not be repeated on Day 1. As of protocol amendment 5, biochemistry will be performed 
at the discretion of the investigator (Table 7-3).


Novartis
Confidential
Page 86
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
The biochemistry results must be reviewed prior to each administration of study treatment. 
More frequent examinations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded on the Unscheduled Visit CRFs.
7.6.3.4
Urinalysis
Urinalysis tests include assessment of protein, glucose, blood, and specific gravity. 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.  Urinalysis should be performed during the screening period and at End of 
Treatment Visit. As of protocol amendment 5, urinalysis will be performed at the discretion of 
the investigator (Table 7-3).
No other urinalyses are required, however, more frequent examinations may be performed at 
the Investigator’s discretion if medically indicated; such results should be recorded on the 
Unscheduled Visit CRF.
7.6.3.5
Thyroid function tests
Thyroid Stimulating Hormone (TSH) and free T4 (free thyroxin) will be measured at 
screening and at End of Treatment Visit. As of protocol amendment 5, thyroid function tests
will be performed at the discretion of the investigator (Table 7-3).
7.6.3.6
Pregnancy test
All women of childbearing potential (WOCBP) should complete a serum pregnancy test 
within three days prior to the first dose of study treatment on Cycle 1 Day 1 and at the ‘End of 
Treatment Visit’. In addition, a urinary pregnancy test at monthly intervals on Day 1 of each 
subsequent cycle during study duration must be performed. Women are considered post-
menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms), total hysterectomy, or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential. 
As of protocol amendment 5, pregnancy tests are not required as all the ongoing patients are 
considered not of child bearing potential. 
7.7
Tolerability
Not applicable.
7.8
Resource utilization
Not applicable.
7.9
Patient-reported outcomes
Not applicable.


Novartis
Confidential
Page 87
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
7.10
Pharmacokinetic assessment
Part of the phase Ib part of this study is to collect panobinostat plasma trough levels during 
cycle 1 on days 4, 5, and 8 in combination with 5-Aza.  Trough levels (Cmin values) will be 
summarized at the study conclusion. No PK assessment will be performed in the phase IIb 
part of the study.
Three (3 mL) of whole blood per sample will be collected (Table 7-6 ) in tubes containing 
sodium heparin. Immediately after collection, the tube should be inverted several times to 
prevent clotting. Blood samples should then be kept on an ice-water bath at approximately 
4ºC until centrifugation. The tubes should be centrifuged as soon as possible but no more than 
30 minutes after collection at approximately =800 g at least for 15 minutes to separate plasma. 
The plasma is to be transferred to a polypropylene screw-cap tube (1.5 mL plasma per tube), 
the tube capped, and the sample mixed briefly and then immediately placed in a freezer set at 
< -60ºC until shipment, on dry ice, to Novartis or designated CRO for analysis.
Table 7-6
PK blood sampling
Sample
Volume
[mL]
Cycle
Day
PK collection 
No.
Sample 
No.
Scheduled 
time
Blood
3
1
4b
1
1
Pre-dosea
Blood
3
1
5b
2
2
Pre-dosea
Blood
3
1
8b
3
3
Pre-dosea
a. Take sample within 5 minutes prior to panobinostat dosing; b. If panobinostat treatment is delayed 
from Cycle 1 Day 4 to Day 4, PK sampling days should be shifted accordingly.
Plasma panobinostat concentrations will be measured by a validated LC/MS/MS method with 
a LLOQ of 0.5 ng/mL or lower. Values below LLOQ will be reported as zero ng/mL.


Novartis
Confidential
Page 88
Amended Protocol Version 05 Clean
Study No. CLBH589H2101


Novartis
Confidential
Page 89
Amended Protocol Version 05 Clean
Study No. CLBH589H2101


Novartis
Confidential
Page 90
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
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 occur 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 CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. 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 and graded according to the Common Toxicity Criteria for 
Adverse Events (CTCAE) version 3.0.
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, this information will be collected in the End of Treatment or 
Survival Information CRF page. 
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 relationship to study treatment (Reasonable possibility that AE is related: No, Yes)
3. Its duration (start and end dates or if continuing at final exam)
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 was given (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
and which seriousness criteria have been met.


Novartis
Confidential
Page 91
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4.
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 CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and 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 malignancy (including fatal outcomes), if documented by use of appropriate 
method (as per International Working Group (IWG) response criteria (Cheson 2003, Cheson 
2006), as implemented in the [Post-text supplement 1]), should not be reported as a serious 
adverse event
Adverse events separate from the progression of malignancy (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 study treatment.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
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 (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 in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may 


Novartis
Confidential
Page 92
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
be appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure.
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,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (e.g. hospitalization to receive blood transfusions)

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

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event

Protocol exempt SAEs:
a. Progression of disease (including fatal outcomes), if documented by use of 
appropriate method, should not be reported as serious adverse event.
b. Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements. Despite the clinical description of “life-threatening or 
disabling” provided as general guidance for severity of Grade 4 events in the 
introduction to CTCAE v. 3.0, this does not automatically indicate that all Grade 4 
adverse events or lab abnormalities are SAEs unless they meet the definition of 
serious as indicated above and as per investigator discretion.
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 hours of learning of its occurrence.
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 


Novartis
Confidential
Page 93
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
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.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form: all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert of 
Vidaza® (new occurrence) and is thought to be related to the Novartis study treatment, an 
oncology Novartis Drug Safety and Epidemiology (DS&E) department associate may 
urgently require further information from the investigator for Health Authority reporting. 
Novartis may need to issue an Investigator Notification (IN), to inform all investigators 
involved in any study with the same drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.


Novartis
Confidential
Page 94
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
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. 
8.5
Warning 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 
Brochure. 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 for this study. 
8.7
Steering committee
For the phase IIb part of the study a steering committee will be established. The organization 
and working principles including a list of members and contact information will be provided 
in a separate steering committee charter prior to enrollment of the first patient into the phase 
IIb part of the study.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.


Novartis
Confidential
Page 95
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
9.3
Data collection
For studies using paper CRFs, designated investigator staff must record the information 
required by the protocol onto the Novartis CRFs that are printed on multi-part, non-carbon-
required paper. Field monitors will review the CRFs for completeness and accuracy and 
instruct site personnel to make any required corrections or additions. The harvested CRFs will 
be forwarded to the Medical Documents Reception Center of Novartis (or applicable CRO) by 
field monitors or by the investigational site, with one copy being retained at the 
investigational site.
The Principal Investigator is responsible for assuring that the data recorded on CRFs is 
complete, accurate, and that entry and updates are performed in a timely manner.
9.3.1
Electrocardiogram
ECG data will be collected with a portable, diagnostic electrocardiograph and transmitted 
electronically to a designated CRO.


Novartis
Confidential
Page 96
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
9.4
Database management and quality control
For studies using paper CRFs, data will be entered into a fully validated study database by 
Novartis Data Management personnel (or designated CRO). Following entry from the CRFs, 
the data are systematically checked by Novartis Data Management personnel (or designated 
CRO) using programmed checks and data review tools/reports. Data Query Forms (DQF) are 
created for discrepancies or missing values and sent to the investigational site for resolution. 
Original signed responses to the DQFs must be returned to Novartis Data Management (or 
designated CRO) so that resolutions can be entered into the database. Copies of the resolved 
DQFs are kept with the CRFs at the investigator site.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The 
system will be supplied by a vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel (or designated CRO). At the conclusion of the study, 
the occurrence of any emergency code breaks will be determined after return of all code break 
reports and unused drug supplies to Novartis personnel (or designated CRO). The occurrence 
of any protocol violations will be determined. After these actions have been completed and 
the data has been verified to be complete and accurate, the database will be declared locked 
and the treatment codes will be unblinded and made available for data analysis. Authorization
is required prior to making any database changes to locked data, by joint written agreement 
between the Global Head of Biostatistics and Data Management and the Global Head of 
Clinical Development.
10
Statistical methods and data analysis
The data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation.
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis.
The clinical study report (encompassing both phase Ib and phase IIb parts) will be based on a 
data cut-off corresponding to the time point where all patients from the phase IIb part have 
either completed 12 cycles of study treatment or discontinued study treatment for any other 
reason whichever comes first. An addendum to the core clinical study report will be provided 
at the completion of the study to summarize and/or list the additional safety and efficacy data 
as appropriate. Patients who have completed 12 cycles of study treatment at the data cut-off 
and are assessed by the Investigator to have the potential to benefit from ongoing will 
continue their assigned treatment on a reduced assessment schedule allowing collecting and 
reviewing safety, efficacy and survival data.


Novartis
Confidential
Page 97
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
10.1
Phase Ib part
10.1.1
Populations for analysis
Safety Set: The safety set includes all patients who received at least one dose of any one 
compound of the study treatment
MTD determining set: consists of all patients of the safety set who either received sufficient 
study treatment as defined in the minimum exposure criteria in cycle 1 (patients need to have 
100% of the planned dose of each compound, see Table 10-1) and had sufficient safety 
evaluations (Section 7.6) or discontinued due to DLT in Cycle 1. Patients who do not meet 
these minimum safety evaluation requirements in cycle 1 will be regarded as ineligible for the 
MTD determining set.
Table 10-1
Minimum exposure criteria (Cycle 1)
Compound
Scheduled doses
Minimum exposure criterion
Panobinostat
6
6
5-Aza
7
7
Full analysis set: consists of all patients who received at least one dose of study treatment.
10.1.2
Patient demographics/other baseline characteristics
Demographic and other baseline data will be listed by patient and/or summarized 
descriptively by initial doses of panobinostat for the full analysis  set (FAS). Categorical data 
will be presented as frequencies and percentages. For continuous data, summary statistics will 
be presented.
10.1.3
Treatments (study drug, concomitant therapies, compliance)
The actual dose and duration in days of panobinostat and 5-Aza as well as the actual dose 
intensity (computed as cumulative dose received/actual duration) and relative dose intensity 
(computed as actual dose intensity/planned dose intensity [= planned cumulative 
dose/scheduled duration]), will be listed and summarized by means of descriptive statistics by 
dose cohort, compound and cycle. The daily dose for each patient will be summarized using 
descriptive statistics (e.g. mean, median, and modal daily doses).
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized by ATC term descriptively.
10.1.4
Primary objective
Refer to Section 3.1.1.1
10.1.4.1 Variable
Estimation of the MTD will be based upon the estimation of the probability of DLT in cycle 1 
in the MTD determining set. This probability is estimated by the Bayesian logistic model 
described in the [Post-text supplement 2]. Estimation of the RPIID will be based on 
considerations of the MTD estimation process by the use of the BLRM, together with an 


Novartis
Confidential
Page 98
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
overall clinical assessment of safety taking into consideration safety and tolerability data from 
all cycles. 
10.1.4.2 Statistical hypothesis, model, and method of analysis
An adaptive Bayesian logistic regression model (BLRM) and dose escalation criteria similar 
to that proposed by (Babb Rogatko and Zacks 1998) will be used to guide the dose escalation 
to determine the MTD of panobinostat in combination with a fixed dose of 5-Aza. Informative 
priors for panobinostat will be derived based on the DLT rate obtained from a similar trial 
[CLBH589B2102, arm X] with the similar populations, formulations, dose regimens and for 
5-Aza from publications. MTD will be assessed during the first treatment cycle. Each cohort 
will consist of a minimum of 3 patients fully evaluable for therapy-related toxicities over the 
first cycle of treatment. Posterior probabilities of the DLT from the model will be summarized. 
Selection of the next dose will be based on these probabilities as well as on other safety and 
laboratory data. For details please refer to the [Post-text supplement 2].
Dose recommendation will be based on posterior summaries for each dose combination and 
the interval probabilities for underdosing, targeted, excessive, and unacceptable toxicity for 
intervals. Once updated, the distribution summarizes the probability that the true probability 
of a DLT for each dose combination lies in one of the following categories:

[0, 20%) under-dosing

[20%, 35%) targeted toxicity

[35%,60%) excessive toxicity

[60, 100%] unacceptable toxicity.
Following the principle of EWOC, after each cohort of patients the recommended dose 
combination is the one with the highest posterior probability of DLT in the target interval 
[20%, 35%) among the doses fulfilling the overdose criteria: there is less than 25% chance of 
either excessive or unacceptable toxicity. The maximum inter-cohort dose escalation 
permitted is 100%. The dose recommended by the adaptive BLRM may be regarded as 
information to be integrated with a clinical assessment of the safety data observed thus far in 
determining the next dose to be investigated. In any case, the next dose will not exceed the 
recommended dose by the BLRM. Cohorts of at least 3 and up to a maximum of 12 MTD-
evaluable patients will be enrolled in the dose-escalation part including at least 9 patients at 
the MTD. The Bayesian model will be updated prior to additional enrollment under the 
following scenarios:
1. If the first 2 patients in a cohort experience DLT prior to the enrollment of the 3rd patient. 
Enrollment will be halted, the model will be updated, and any new patients will be 
enrolled at a dose satisfying the overdose criteria, no higher than the current dose level.
2. No additional patients will be enrolled until the current cohort is completed and the model 
is updated.
3. For cohorts of > 3 patients if the observed number of DLTs exceeds 25% of the currently 
enrolled patients to that dose level, enrollment will be halted until all patients complete 
one cycle of dosing or experience DLT. The model will be updated to determine the 
uncertainty about the probability of DLT at each dose level. New patients will be enrolled 
at a dose level up to the highest satisfying the overdose criteria.


Novartis
Confidential
Page 99
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
The recommended phase II dose (RPIID) will be based on considerations of the MTD 
estimation process by the BLRM, together with an overall clinical assessment of safety taking 
into consideration safety and tolerability data from all cycles at all dose levels tested.  The 
RPIID could be the same as the MTD, but will not exceed it under any circumstance. Cohorts 
may be expanded at any dose level (or dose combination) below the MTD for further 
elaboration of safety parameters as required.
For further details of the statistical model and results under a variety of scenarios, please refer 
to [Post-text supplement 2].
10.1.4.3 Handling of missing values/censoring/discontinuations
Patients who are inevaluable for MTD determination (i.e. patients who are not in MTD 
determining set) will be replaced. Patients in whom clinical response is unknown will be 
treated as non-responders. Patients, for whom the post-baseline response assessments cannot 
be computed because of missing baseline response assessment, will be excluded from the 
relevant efficacy analyses. Other missing data will be noted as missing on appropriate 
tables/listings. 
10.1.4.4 Supportive analyses
Response will be calculated per patient based on [Post-text supplement 1] for plausibility 
control of investigator's assessment and will be listed.
10.1.5
Secondary objectives
The secondary objectives are given in Section 3.1.2.1
10.1.6
Population and grouping for the analyses
For all safety analyses, the safety set will be used. For efficacy analyses, the full analysis set 
will be used. All listings and tables will be presented by initial dose group of panobinostat. 
Determination of MTD will be based on the MTD determining set.
10.1.6.1 Efficacy variables and analyses
Evidence of anti-tumor activity of panobinostat in combination with 5-Aza will be evaluated 
based on frequency of best post-baseline response of hematological malignancy assessment. 
The efficacy population will be used in this analysis.
10.1.6.2 Safety variables and analyses
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., 
electrocardiogram, vital signs, etc.) will be considered as appropriate. All safety data will be 
listed. Patients will be summarized by initial dose level of panobinostat.
Those MTD-determining patients who experience dose-limiting toxicity (DLT) will be listed 
individually by initial dose level and reason for the DLT.


Novartis
Confidential
Page 100
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
10.1.6.2.1
Adverse events (AE)
All adverse events recorded during the study will be summarized. The incidence of treatment-
emergent adverse events (new or worsening from baseline) will be summarized by body 
system, severity (based on CTCAE grades), type of adverse event, and relation to the study 
drug. Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient 
and tabulated by initial dose group and type of adverse event.
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
electrocardiogram, vital signs, and special tests) will be considered as appropriate.
The probability to detect at least one AE with a certain incidence by as a function of the 
cohort size is depicted in Table 10-2. Thus, the probability to detect an AE with an incidence 
of 10% in a cohort of at least 20 patients is higher than 87%.
Table 10-2
Probability of detecting at least one adverse event in cohort as a 
function of the cohort size
10.1.6.2.2
Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common terminology criteria for adverse events (CTCAE, version 3.0) unless 
otherwise indicated.
A listing of laboratory values will be provided by laboratory parameter, patient, and initial 
dose cohort in the clinical study report (CSR). The frequency of notable lab abnormalities will 
be displayed by parameter, cycle and dose cohort in the CSR. Similarly, the frequency of all 
laboratory abnormalities will be displayed by parameter, worst CTCAE v3 grade experienced 
and dose cohort in the CSR.
Laboratory data will be also be displayed by presenting summary statistics of raw data and 
change from baseline values (means, medians, standard deviations, ranges).
10.1.6.2.3
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. Any statistical 
tests performed to explore the data will be used only to highlight any interesting comparisons 
that may warrant further consideration.


Novartis
Confidential
Page 101
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
10.1.6.2.4
Tolerability
Not applicable.
10.1.7
Resource utilization
Not applicable.
10.1.8
Patient-reported outcomes
Not applicable.
10.1.9
Pharmacokinetics
Plasma panobinostat trough levels (Cmin in ng/mL) will be summarized by study day.
10.1.12
Interim analysis
There is no plan for interim analysis.
10.1.13
Sample size calculation
Sample size is expected to be 26 in total.
Cohorts of at least three MTD evaluable patients per dose level will be enrolled in the phase 
Ib part including at least nine patients at the MTD and/or RPIID level.
Sample size is expected to be at least 26 assuming two cohorts of six patients each treated at 
dose levels distinct from the MTD and/or RPIID, and two cohorts of 7 patients each treated at 
the MTD and/or RPIID.


Novartis
Confidential
Page 102
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
10.1.14
Power for analysis of critical secondary variables
There are no critical secondary variables in this study.
10.2
Phase IIb part
10.2.1
Population for analysis
Safety Set: The safety set includes all patients who received at least one dose of any one 
compound of the study treatment
Full analysis set: consists of all patients who were randomized to one of the two treatment 
arms.
10.2.2
Population and grouping for the analyses
For all safety analyses, the safety set will be used. For efficacy, demographics, and baseline 
characteristics analyses, the full analysis set will be used. All listings and tables will be 
presented by treatment arm (‘as treated’ for the safety analyses, and ‘as randomized’ for the 
efficacy analyses, demographics and baseline characteristics). 
10.2.3
Patient demographics/other baseline characteristics
Demographic and other baseline data will be listed by patient and summarized descriptively 
by treatment arm for the full analysis  set. Categorical data will be presented as frequencies 
and percentages. For continuous data, summary statistics will be presented.
10.2.4
Treatments (study drug, concomitant therapies, compliance)
The actual dose and duration in days of panobinostat and 5-Aza as well as the actual dose 
intensity (computed as cumulative dose received/actual duration) and relative dose intensity 
(computed as actual dose intensity/planned dose intensity [= planned cumulative 
dose/scheduled duration]), will be listed and summarized by means of descriptive statistics by 
treatment arm, component and cycle. The daily dose for each patient will be summarized 
using descriptive statistics (e.g. mean, median, and modal daily doses).
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized by ATC term and treatment arm descriptively.
10.2.5
Primary objective
The primary objective for the phase IIb part is given in Section 3.1.1.
10.2.6
Secondary objectives
The secondary objective for the phase IIb part is given in Section 3.1.2.


Novartis
Confidential
Page 103
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
10.2.8
Efficacy variables and analysis
The primary efficacy endpoint will be the composite CR (CR or CRi or bone marrow CR) 
among all patients in the FAS. 
The following efficacy endpoints will be considered. 

Clinical response for AML: CR, CRi, PR

Clinical response for MDS/CMML: CR, bone marrow CR, PR and Hematologic 
Improvement (HI)

1-year survival rate

Time to Progression (TTP)
Clinical responses will be summarized by treatment arm, overall and within disease type (i.e. 
AML or MDS/CMML). Percentage rates for the composite CR rate (CR or CRi or bone 
marrow CR), overall response rate (CR or CRi or bone marrow CR or PR) will be reported 
along with 95% confidence intervals for both arms. Exact binomial confidence interval
(implemented using SAS procedure FREQ with EXACT statement for one-way tables) will be 
calculated Clopper and Pearson 1934. Point estimates and confidence intervals for the 
difference in rates between the treatment arms will also be reported. The 1-year survival rate 
will be obtained from the Kaplan-Meier curve and its variance will be estimated by 
Greenwood’s formula. Time to progression will also be analyzed through Kaplan Meier 
curves.
10.2.9
Safety variables and analysis
All adverse events recorded during the study will be summarized by treatment arm. The 
incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by body system, severity (based on CTCAE grades), type of adverse event, and 
relation to the study treatment. Deaths reportable as SAEs and non-fatal serious adverse 
events will be listed by patient, type of adverse event, and treatment arm.
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
electrocardiogram, vital signs, and special tests) will be considered as appropriate.
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common terminology criteria for adverse events (CTCAE, v 3.0) unless otherwise 
indicated. Summary data will be reported by treatment arm.
A listing of laboratory values will be provided by laboratory parameter, patient, and treatment 
arm, in the clinical study report (CSR). The frequency of notable lab abnormalities will be 
displayed by parameter, cycle and treatment arm in the CSR. Similarly, the frequency of all 
laboratory abnormalities will be displayed by parameter, worst CTCAE v3 grade experienced 
and treatment arm in the CSR.
Laboratory data will be also be displayed by presenting summary statistics of raw data and 
change from baseline values (means, medians, standard deviations, ranges).
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. 


Novartis
Confidential
Page 104
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
10.2.10
Sample size calculation
The planned sample size is 40 per arm, or, in other words, 80 in total. It is deemed that an 
observed relative improvement of 50% in the composite CR rate (CR or CRi or bone marrow 
CR) in the investigational arm over the active control arm is clinically relevant in the phase 
IIb part of the study. Under the assumption that the composite response rate in the active 
control arm is 17% (estimate based on Fenaux et al 2009a), the following table gives the 
estimated probabilities of observing clinically relevant improvement , under different values 
of the true composite CR rate in the experimental arm. The chance of observing a clinically 
relevant improvement when there is actually no difference in the true composite CR rates 
between the arms) is estimated to be 23% while the chance of not observing a clinically 
relevant improvement when there is indeed a substantial difference in the true composite CR 
rates (true composite response rates in investigational and active control arms are 35% and 
17% respectively) is estimated to be 19%. Since there is no hypothesis being tested, a formal 
power analysis has not been done. The aforementioned estimated probabilities of 23% and 
19% are only analogous to the probabilities of type I and type II errors (in the setting of 
hypothesis testing). These probabilities (as well as, the others shown under [4] in the 
following table) have been derived by simulating response data using independent binomial 
distributions for the investigational and active control arms with the probability parameter of 
the distribution being specified according to the assumed true underlying composite CR rates 
as shown under [1], and [2] of the table below. Thus, given that the true composite CR rates 
are as in [1] and [2] (and, the true percentage improvement as in [3]), [4] represents the 
probability of observing clinically relevant improvement. More specifically, [4] represents the 
following:
Pr[(observed composite CR rate in investigational arm - observed composite CR rate in 
active control arm) ≥ 50% of observed composite CR rate in active control arm]
Table 10-3
Probability of observing clinically relevant improvement based on an 
assessment of composite CR (CR or CRi or bone marrow CR) 
True composite CR 
rate  in active control 
arm
[1]
True composite CR 
rate  in investigational  
arm 
[2]
True improvement (as 
a percentage of the 
true composite CR rate 
in the active control 
arm)
[3]
Probability of  
observing clinically 
relevant improvement
[4]
0.17 
0.17 
0
0.23
0.20 
18
0.33
0.25 
47
0.51
0.30 
76
0.68
0.35 
106
0.81
10.2.11
Interim analysis
There is no plan for interim analysis.


Novartis
Confidential
Page 105
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
10.2.12
Power for analysis of critical secondary variables
There are no critical secondary variables.
10.2.13
Handling of missing values/censoring/discontinuations
Patients for whom clinical response is unknown will be treated as non-responders. Patients for 
whom the post-baseline response assessments cannot be determined because of missing 
baseline response assessment, will be excluded from the relevant efficacy analyses. Patients 
for whom disease progression status cannot be determined because of missing baseline 
assessment, will be censored at baseline for the time to progression analysis. Other missing 
data will be noted as missing on appropriate tables/listings.
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 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
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. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. 
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 CRFs. Novartis will provide to 
investigators in a separate document a proposed informed consent form (ICF) that is 
considered appropriate for this study and complies with the ICH GCP guideline and 


Novartis
Confidential
Page 106
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
regulatory requirements. Any changes to this ICF suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the approved 
version must be provided to the Novartis monitor after IRB/IEC/REB approval.
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.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov, before study 
start. In addition, results of interventional clinical trials in adult patients are posted 
on ...novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 
year of study completion (i.e., LPLV).
Novartis follows the ICMJE authorship guidelines (...icmje.org) and other specific guidelines 
of the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no 
honorarium provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to ...novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site 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. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.


Novartis
Confidential
Page 107
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
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 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 case report form (CRF) 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 CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
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 Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start


Novartis
Confidential
Page 108
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
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 
trial 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 by
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
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 Novartis, Health Authorities where required, and 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 at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


Novartis
Confidential
Page 109
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
13
References (available upon request)
Aggerholm A, Holm MS, Guldberg P, et al (2006) Promoter hypermethylation of p15INK4B, 
HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in 
early-stage patients. Eur.J.Haematol.; 76 (1):23-32.
 
Albitar M, Manshouri T, Shen Y, et al (2002) Myelodysplastic syndrome is not merely 
"preleukemia". Blood; 100 (3):791-798.
Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): Successes 
and challenges. Cancer Lett.
Aul C, Giagounidis A, Germing U, et al (2002) Evaluating the prognosis of patients with 
myelodysplastic syndromes. Ann.Hematol. 81 (9):485-97. 0939-5555.
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Statistics in medicine; 17:1103-1120.
Cameron EE, Bachman KE, Myohanen S, et al (1999) Synergy of demethylation and histone 
deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genetics; 21 
(1):103-107.
Cheson BD, Bennett JM, Kantarjian H, et al (2000) Report of an international working group 
to standardize response criteria for myelodysplastic syndromes. Blood; 96:3671-3674.
Cheson BD, Bennett JM, Kopecky KJ, et al (2003) Revised recommendations of the 
international working group for diagnosis, standardization of response criteria, treatment 
outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. Journal of 
Clinical Oncology; 21 (24):4642-4649.
Cheson BD, Greenberg E, Bennett J, et al (2006) Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood; 108:419-425.
Clopper CJ, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26:404-413
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al (2009a) Efficacy of azacitidine compared 
with that of conventional care regimens in the treatment of higher-risk myelodysplastic 
syndromes: a randomised, open-label, phase III study. Lancet Oncol.; 10 (3):223-232.
Fenaux P, Ades L (2009b) Review of azacitidine trials in Intermediate-2- and High-risk 
myelodysplastic syndromes. Leukemia Research; 33 Suppl. 2 S7-S11
Gore SD, Baylin S, Sugar E, et al (2006) Combined DNA methyltransferase and histone 
deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res.; 66 (12):6361-6369.


Novartis
Confidential
Page 110
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Greenberg P, Cox C, LeBeau MM, et al (1997) International scoring system for evaluating 
prognosis in myelodysplastic syndromes. Blood; 89 (6):2079-2088.
Leone G, D'Alo F, Zardo G, et al (2008) Epigenetic treatment of myelodysplastic syndromes 
and acute myeloid leukemias. Curr.Med.Chem.; 15 (13):1274-1287.
 
Maslak P, Chanel S, Camacho LH, et al (2006) Pilot study of combination transcriptional 
modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute 
myeloid leukemia or myelodysplastic syndrome. Leukemia 20 (2):212-7. 0887-6924.
Moe-Behrens GH, Pandolfi PP (2003) Targeting aberrant transcriptional repression in acute 
myeloid leukemia. Rev.Clin.Exp.Hematol.; 7 (2):139-159.
Mufti GJ, Bennett JM, Goasguen J, et al (2008) Diagnosis and classification of 
myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic 
syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of 
myeloblasts and ring sideroblasts. Haematologica; 93 (11):1712-1717.
Muller-Berndorff H, Haas PS, Kunzmann R, et al (2006) Comparison of five prognostic 
scoring systems, the French-American-British (FAB) and World Health Organization (WHO) 
classifications in patients with myelodysplastic syndromes: Results of a single-center analysis. 
Ann.Hematol.; 85 (8):502-513.
Odenike OM, Green M, Larson R, et al (2008) Phase I study of belinostat (PXD101) plus 
azacitidine (AZC) in patients with advanced myeloid neoplasms [abstract]. 2008 ASCO 
Annual Meeting.
Ottmann OG, Spencer A, Prince HM, et al (2008) Phase IA/II Study of Oral Panobinostat 
(LBH589), a Novel Pan-Deacetylase Inhibitor (DACi) Demonstrating Efficacy in Patients 
with Advanced Hematologic Malignancies [abstract]. 50th ASH Annual Meeting.
Raj K, Mufti GJ (2006) Azacytidine (Vidaza®) in the treatment of myelodysplastic syndromes. 
Ther.Clin.Risk Manag.; 2 (4):377-388.
Rothenberg ML, Meropol NJ, Poplin EA, et al (2001) Mortality associated with irinotecan 
plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J.Clin.Oncol.; 
19 (18):3801-3807.
Rudek MA, Zhao M, He P, et al (2005) Pharmacokinetics of 5-azacitidine administered with 
phenylbutyrate in patients with refractory solid tumors or hematologic malignancies. 
J.Clin.Oncol.; 23 (17):3906-3911.
Sezer O, San Miguel JF, Mateos M-V, et al (2008) A Phase IB, Multicenter, Open-Label,
Dose-Escalation Study of Oral Panobinostat (LBH589) and I.V. Bortezomib in Patients with 
Relapsed Multiple Myeloma [abstract]. ASH 2008, 6-9 December San Francisco.


Novartis
Confidential
Page 111
Amended Protocol Version 05 Clean
Study No. CLBH589H2101
Silverman LR, Demakos EP, Peterson BL, et al (2002) Randomized controlled trial of 
azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia 
group B. J.Clin.Oncol.; 20 (10):2429-2440.
Silverman LR, McKenzie DR, Peterson BL, et al (2006) Further analysis of trials with 
azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the 
Cancer and Leukemia Group B. J.Clin.Oncol.; 24 (24):3895-3903.
Silverman LR, Verma A, Odchimar-Reissig R, et al (2008) A phase I/II study of vorinostat, 
an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the 
myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the 
phase I trial: A New York Cancer Consortium. [abstract]. 2008 ASCO Annual Meeting.
Soriano AO, Yang H, Faderl S, et al (2007) Safety and clinical activity of the combination of 
5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and 
myelodysplastic syndrome. Blood; 110 (7):2302-2308.
Spencer A, Price CGA, DeAngelo D, et al (2007) Phase IA/II Study of Oral LBH589, a Novel 
Deacetylase Inhibitor (DACi), Administered on 2 Schedules, in Patients with Advanced 
Hematologic Malignancies [abstract]. ASH Annual Meeting Abstracts 2007 : Abstract 907.
Tefferi A, Vardiman JW (2008) Classification and diagnosis of myeloproliferative neoplasms: 
the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. 
Leukemia; 22 (1):14-22.
WHO (2008) WHO classification of Tumours of Haematopoietic and Lymphoid tissues. 4th 
Edition ed; Lyon: International Agency for research on Cancer.
Zhu W-G, Lakshmanan RR, Beal MD, et al (2001) DNA methyltransferase inhibition 
enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res;61:1327-1333.
Zhu WG, Otterson GA (2003) The interaction of histone deacetylase inhibitors and DNA 
methyltransferase inhibitors in the treatment of human cancer cells. 
Curr.Med.Chem.Anticancer Agents; 3 (3):187-199.

SAP_000.pdf: 
Clinical Development 
Panobinostat 
CLBH589H2101 / NCT00946647
A phase Ib/IIb, open-label, multi-center, dose-escalation 
study of oral Panobinostat (LBH589) administered with 5-
Azacitidine (Vidaza®) in adult patients with Myelodysplastic 
Syndromes (MDS), Chronic Myelomonocytic Leukemia 
(CMML) or Acute Myeloid Leukemia (AML)
RAP Module 3 – Detailed Statistical Methodology 
(Amendment 2) 
Author: 
  
Document type: 
RAP Documentation 
Document status: 
Version 2.1, Final 
Release date: 
29-Oct-2014
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Change history 
CREDI Version 
Date 
Changes 
 
 
 
Amendment 1  
23-Jun-2014 
Analysis plans corresponding to the phase IIb part have been 
added 
Minor changes to existing analysis descriptions have been made 
to align with the current project MAP 
 
 
 
Amendment 2 
29-Oct-2014 
The sections on dose intensity calculation in the M3 were 
revised to simplify definitions of dose intensity and relative dose 
intensity, as they applied to this study. 
For the purpose of dose intensity calculations, a general 
algorithm was put in place to assign doses to days.  
 
 


Novartis 
Confidential 
Page 3 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Table of contents 
Clinical Development ............................................................................................................ 1 
1 
Introduction .................................................................................................................... 7 
Document content ........................................................................................................... 7 
2 
Study design ................................................................................................................... 8 
3 
Objectives ....................................................................................................................... 9 
3.1 
Phase Ib part ........................................................................................................ 9 
3.1.1 
Primary objective ................................................................................. 9 
3.1.2 
Secondary objectives ......................................................................... 10 
 
 10 
3.2 
Phase IIb part ..................................................................................................... 10 
3.2.1 
Primary objective ............................................................................... 10 
3.2.2 
Secondary objectives ......................................................................... 11 
 
 11 
4 
Population ..................................................................................................................... 11 
5 
Draft of Section 9.7 of CSR on Statistical methods ........................................................ 12 
5.1 
Statistical methods and data analysis .................................................................. 12 
5.1.1 
Phase Ib part ...................................................................................... 12 
5.1.2 
Phase IIb part ..................................................................................... 13 
5.2 
Populations for analysis: definitions ................................................................... 13 
5.2.1 
Phase Ib part ...................................................................................... 13 
5.2.2 
Phase IIb part ..................................................................................... 13 
5.3 
Population and grouping for the analyses ........................................................... 14 
5.4 
Patient disposition, demographics and other baseline characteristics .................. 14 
5.5 
Treatments (study drug, concomitant therapies, compliance).............................. 14 
5.6 
Pharmacokinetics ............................................................................................... 15 
5.7 
Safety variables and analyses ............................................................................. 15 
5.7.1 
Adverse events (AE) .......................................................................... 15 
5.7.2 
Laboratory abnormalities ................................................................... 15 
5.7.3 
Other safety data ................................................................................ 15 
5.7.4 
Tolerability ........................................................................................ 15 
5.8 
Efficacy variables and analyses .......................................................................... 15 
5.8.1 
Phase Ib part ...................................................................................... 16 
5.8.2 
Phase IIb part ..................................................................................... 16 
 
 17 


Novartis 
Confidential 
Page 4 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
 
 17 
 
17 
5.10 
Handling of missing values/censoring/discontinuations ...................................... 17 
5.11 
Subgroup analyses ............................................................................................. 17 
5.12 
Interim analysis ................................................................................................. 17 
5.13 
Sample size calculation ...................................................................................... 18 
5.13.1 
Phase Ib part ...................................................................................... 18 
5.13.2 
Phase IIb part ..................................................................................... 18 
5.14 
Power for analysis of critical secondary variables .............................................. 19 
6 
Changes in analyses specified in the protocol ................................................................ 19 
Draft of Appendix 16.1.9 ..................................................................................................... 20 
1 
Table of contents ........................................................................................................... 22 
2 
Introduction .................................................................................................................. 25 
3 
Definitions and general methodology ............................................................................ 26 
3.1 
Definitions ......................................................................................................... 26 
3.1.1 
Study drug and study treatment .......................................................... 26 
3.1.2 
Phase Ib part ...................................................................................... 26 
3.1.3 
Phase IIb part ..................................................................................... 26 
3.1.4 
Date of first administration of study drug ........................................... 26 
3.1.5 
Date of last administration of study drug ............................................ 26 
3.1.6 
Date of first administration of study treatment.................................... 26 
3.1.7 
Date of last administration of study treatment .................................... 26 
3.1.8 
Study day ........................................................................................... 27 
3.1.9 
Baseline ............................................................................................. 27 
3.1.10 
On-treatment assessment/event/period ............................................... 28 
3.1.11 
Time windows ................................................................................... 28 
3.1.12 
Screening failure ................................................................................ 28 
3.2 
Data included in analyses ................................................................................... 28 
3.3 
Definition of analysis sets .................................................................................. 29 
3.3.1 
Phase Ib part ...................................................................................... 29 
3.3.2 
Phase IIb part ..................................................................................... 29 
3.4 
Population and grouping for the analyses ........................................................... 30 
3.5 
Protocol deviations ............................................................................................ 30 
3.6 
Concomitant therapy .......................................................................................... 30 
3.6.1 
Concomitant medications with specific impact on the analysis ........... 31 
3.7 
General statistical methodology ......................................................................... 31 


Novartis 
Confidential 
Page 5 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
3.7.1 
Baseline comparability ....................................................................... 31 
3.7.2 
Multiple assessments within post-baseline visits ................................ 31 
3.7.3 
Center pooling ................................................................................... 31 
3.7.4 
1-sided vs. 2-sided test ....................................................................... 31 
3.7.5 
Between group comparisons .............................................................. 32 
3.7.6 
Conversion factors ............................................................................. 32 
3.8 
Implementation of efficacy criteria .................................................................... 32 
4 
Statistical methods used in reporting ............................................................................. 32 
4.1 
Background and demographic characteristics ..................................................... 32 
4.1.1 
Basic demographic and background data ............................................ 32 
4.1.2 
Protocol eligibility criteria ................................................................. 33 
4.1.3 
Diagnosis and characteristics of disease ............................................. 33 
4.1.4 
Medical history .................................................................................. 34 
4.1.5 
Prior anti-neoplastic therapy .............................................................. 34 
4.1.6 
Other ................................................................................................. 35 
4.2 
Protocol deviation summaries ............................................................................ 35 
4.3 
Groupings for Analysis ...................................................................................... 35 
4.4 
Patient disposition .............................................................................................. 35 
4.5 
Follow-up .......................................................................................................... 36 
4.6 
Last contact date ................................................................................................ 36 
4.7 
Study treatment and duration of study treatment exposure .................................. 37 
4.7.1 
Duration of study treatment exposure ................................................. 37 
4.7.2 
Cycle definition ................................................................................. 38 
4.7.3 
Partial dates ....................................................................................... 40 
4.7.4 
Cumulative dose ................................................................................ 40 
4.7.5 
DI and RDI ........................................................................................ 40 
4.7.6 
Dose intensity over study period ........................................................ 41 
4.8 
Concomitant therapy .......................................................................................... 42 
4.8.1 
Concomitant medications with specific impact on the analysis ........... 43 
4.9 
Primary safety variable ...................................................................................... 43 
4.9.1 
Analysis of the primary safety variable .............................................. 43 
4.9.2 
Sensitivity and other supportive analyses ........................................... 43 
4.10 
Safety evaluation ............................................................................................... 43 
4.10.1 
Adverse events ................................................................................... 43 
4.10.2 
AE summaries ................................................................................... 44 
4.10.3 
Clinical notable AE ............................................................................ 45 


Novartis 
Confidential 
Page 6 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
4.10.4 
Laboratory data .................................................................................. 46 
4.10.5 
Vital signs .......................................................................................... 47 
4.10.6 
Handling of missing values ................................................................ 48 
4.10.7 
ECG................................................................................................... 48 
4.10.8 
ECOG performance status .................................................................. 50 
4.11 
Efficacy analysis ................................................................................................ 50 
4.11.1 
Efficacy analysis for the phase Ib part ................................................ 50 
4.11.2 
Efficacy analysis for the phase IIb part ............................................... 50 
4.11.3 
Kaplan-Meier analysis ....................................................................... 52 
4.11.4 
Handling of missing values/discontinuations ...................................... 53 
4.11.5 
Transfusions ...................................................................................... 53 
4.12 
Handling of missing values/discontinuations ...................................................... 55 
4.13 
Subgroup analysis .............................................................................................. 55 
4.14 
Pharmacokinetic analyses .................................................................................. 55 
 
 55 
 
 55 
 
56 
4.16 
Interim analyses ................................................................................................. 56 
5 
References .................................................................................................................... 56 
6 
Appendix ...................................................................................................................... 57 
A1 
Instructions given to sites for completion of the DAR forms .............................. 57 
 
Abbreviations 
Abbreviation 
Detail 
5-Aza 
5-Azacytidine, trade name: Vidaza® 
AE 
Adverse event 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ATC 
Anatomical, therapeutical, chemical 
BLRM 
Bayesian logistic regression model 
bpm 
beats per minute 
BSA 
body surface area 
CMML 
Chronic myelomonocytic leukemia 
CNAE 
Clinical notable adverse event 
CNS 
central nervous system 
CR 
Complete remission 
CRF 
Case report form 


Novartis 
Confidential 
Page 7 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Abbreviation 
Detail 
CRi 
Complete remission with incomplete blood count recovery 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DAR 
Dose administration record 
DLT 
Dose-limiting toxicity 
ECG 
12 lead electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EWOC 
Escalation with overdose control 
FAB 
French-American-British 
FAS 
Full analysis set 
HI 
Hematologic improvement 
HSCT 
Hematopoeitic stem cell transplantation  
IPSS 
International prognostic scoring system 
LLOQ 
Lower limit of quantitation 
MAP 
Master analysis plan 
MDS 
myelodysplastic syndrome 
MedDRA 
medical dictionary for regulatory activities 
ms 
Milliseconds 
MTD 
Maximum tolerated dose 
NCI 
National cancer institute 
PAN 
Panobinostat 
PK 
Pharmacokinetic 
PR 
Partial remission 
PT 
Preferred Term (category of MedDRA) 
RAP 
Report and analysis plan 
SAE 
Serious Adverse Event 
SD 
Stable disease 
SI 
Système internationale 
SOC 
System organ class (category of MedDRA) 
T4 
thyroxine 
TSH 
thyroid stimulating hormone 
VAP 
Validation and planning 
WHO 
World Health Organization 
1 
Introduction 
Document content 
This RAP module describes the planned statistical methods. It is structured as 


Novartis 
Confidential 
Page 8 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
• A draft of Section 9.7 of the clinical study report (CSR) [Statistical methods planned in 
the protocol and determination of sample size] 
• A draft of Appendix 16.1.9 (Documentation of statistical methods).  
Appendix 16.1.9 text will contain details of statistical methods and issues that are too long to 
include in the CSR text. (Appendix 16.1.9 is not mandatory for abbreviated and synoptic 
reports). 
It is written in future tense. It will be reviewed and updated (including conversion to past 
tense) for entry into the CSR after the statistical analysis has taken place. 
The data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. 
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data from the phase Ib and 
phase IIb parts will be separately analyzed, but presented in the same CSR. Unless, otherwise 
specified in this document, the same conventions and working definitions will apply to 
analyses conducted in the two phases of this study. 
The core CSR, encompassing both phase Ib and phase IIb parts, will be based on a data cut-
off corresponding to the time point where all patients from the phase IIb part have either 
completed 12 cycles of study treatment or discontinued study treatment for any reason 
whichever comes first. An addendum to the core clinical study report will be provided at the 
time of completion of the study to summarize and/or list the additional safety and efficacy 
data as appropriate. Patients who are continuing their treatment at the time of data cut-off and 
are assessed by the Investigator to have the potential to benefit from their treatment will 
continue their assigned treatment on a reduced assessment schedule allowing collection and 
review of safety, efficacy, and survival data. 
 
2 
Study design 
This is an open-label, multi-center, phase Ib/IIb study. The phase Ib part of the study is 
designed to determine the maximum tolerated dose (MTD) and/or the recommended phase II 
dose (RPIID) of panobinostat administered in a fixed combination of 5-Aza in adult patients 
with IPSS INT-2 or high-risk MDS, CMML or AML not eligible for HSCT.  
The phase IIb part, that will commence once MTD and/or RPIID is established, has a 
randomized, two arm design and is designed to assess preliminary efficacy of panobinostat (in 
combination with 5-Aza) at RPIID compared to 5-Aza alone, the current standard of care, and 
to further characterize safety and tolerability of this combination. 
In the phase Ib part, patients will receive escalating oral doses of the study drug panobinostat. 
The starting dose of Panobinostat will be 10 mg and will be administered intermittently (Day 
3, 5, 8, 10, 12, and 15) over 2 weeks. As per registered label, 5-Aza will be given 
subcutaneously (sc) at a dose of 75 mg/m2/day for 1 week (Day 1- 7). A treatment cycle is 
defined as 28 Days in duration. Patients should be treated for a minimum of 6 cycles. Study 
treatment should be continued as long as the patient continues to benefit or until disease 


Novartis 
Confidential 
Page 9 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
progression or unacceptable toxicity is encountered or consent withdrawal whatever comes 
first. 
At least 3 patients per cohort must be enrolled. During the phase Ib part, patients will be 
evaluated for DLT (Section 6.6.1.6 of the protocol) using an adaptive Bayesian logistic 
regression model with overdose control (EWOC) to guide the dose escalation process.  
After completion of a given dose cohort, the decision on the dose chosen for the next cohort 
will depend on the risk assessment using the Bayesian logistic regression method and a 
medical review of available clinical and laboratory data. Dose-limiting toxicity will be 
assessed from the safety data of Cycle 1 for each dose level. Prior to declaring a dose to be 
MTD, at least 9 evaluable patients need to be treated at that dose level. 
The MTD is defined to be the highest daily dose of panobinostat given together with 5-Aza in 
the first treatment cycle in which the probability to produce medically unacceptable, dose 
limiting  toxicity (DLT) in more than 35% of the patients is less or equal to 25%. The 
recommended phase II dose (RPIID) will be based on considerations of the MTD estimation 
process by the adaptive Bayesian logistic regression model, and on an overall assessment of 
safety taking into consideration tolerability data from subsequent cycles at all the different 
dose levels tested. 
As of August 2011, the recommended phase II dose (RPIID) has been determined to be 30 mg 
of oral panobinostat once daily on day 3, 5, 8, 10, 12, and 15 in combination with azacytidine 
(5-Aza/Vidaza®) administered at a dose of 75mg/m2 daily for 7 days). 
Additional 80 patients will be randomly assigned in a 1:1 ratio into the phase IIb part of the 
study receiving 30 mg of panobinostat plus 5-Aza (investigational arm) or single agent 5-Aza 
(active control arm). Single agent 5-Aza will be administered according to the locally 
approved label (75mg/m2 daily for 7 days). 
Patients will continue treatment until disease progression, unacceptable toxicity or consent 
withdrawal, whichever comes first. The core clinical study report (encompassing both, the 
phase Ib and the phase IIb part of the study) will be based on a data cut-off corresponding to 
the time point where all patients have either completed 12 cycles of study treatment in phase 
IIb or discontinued study treatment for any reason whichever comes first. An addendum to the 
core clinical study report will be provided at the completion of the study to summarize and/or 
list the additional safety and efficacy data as appropriate. 
Patients who are continuing their treatment at the time of data cut-off for the core CSR and 
are assessed by the Investigator to have the potential to benefit from ongoing treatment will 
continue their assigned treatment allowing collecting and reviewing safety, efficacy and 
survival data. After the data-cut off point for the core CSR, a reduced visit evaluation 
schedule will be applied. 
3 
Objectives 
3.1 
Phase Ib part 
3.1.1 
Primary objective 
• To determine the MTD and/or RPIID of oral panobinostat in combination with a fixed 
dose of 5-Aza in adult patients with IPSS INT-2 or high risk MDS, CMML, or AML. 


Novartis 
Confidential 
Page 10 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
3.1.1.1 
End-point for primary objective 
• Incidence of DLT 
3.1.2 
Secondary objectives 
• To characterize the safety and tolerability of panobinostat in combination with 5-Aza in 
the target patient population. 
3.1.2.1 
End-points for secondary objectives 
• Type, duration, frequency and relatedness of Adverse Events (AE). AE severity will also 
be assessed according to NCI Common Terminology Criteria for Adverse Events 
(CTCAE), version 3.0 
• Laboratory (biochemistry, hematology) 
• ECG monitoring (central review by eRT) 
3.2 
Phase IIb part 
3.2.1 
Primary objective 
• To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination 
at the RPIID relative to treatment with single agent 5-Aza through the assessment of 
composite CR (CR or CRi or bone marrow CR).  
3.2.1.1 
End-point for primary objective 
• Composite CR (CR or CRi or bone marrow CR) 


Novartis 
Confidential 
Page 11 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
3.2.2 
Secondary objectives 
• To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination 
at the RPIID relative to treatment with single agent 5-Aza through the assessment of 
clinical responses other than the composite CR specified in the primary objective, 1 year 
survival, and time to progression (TTP).  
• To characterize the safety and tolerability of panobinostat at the  RPIID in combination 
with 5-Aza, as well as, 5-Aza alone in the target patient population. 
3.2.2.1 
End-points for secondary objectives 
• Clinical response for AML: PR; for MDS/CMML: PR, Hematologic Improvement (HI) 
• Overall response (CR or CRi or bone marrow CR or PR) 
• 1-year survival rate 
• Time to progression (TTP) based on the Guidelines for Implementation of IWG response 
criteria in AML, MDS and CMML according to Cheson 2003 and 2006 and specified in 
[Post-text supplement 1]. 
• Type, duration, frequency and relatedness of Adverse Events (AE). AE severity will be 
assessed according to NCI Common Terminology Criteria for Adverse Events (CTCAE), 
version 3.0 
• Laboratory (biochemistry, hematology) 
• ECG monitoring (central review by eRT) 
4 
Population 
Adult patients with intermediate-2 or high-risk MDS as per IPSS, AML with multilineage 
dysplasia and maximum of 30% bone marrow blasts (former RAEB-T according to FAB, 
currently AML according to WHO definition),), or Chronic Myelomonocytic Leukemia 
(CMML) who are candidates for the treatment with 5-Aza will be enrolled onto the study. 
 


Novartis 
Confidential 
Page 12 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
5 
Draft of Section 9.7 of CSR on Statistical methods 
5.1 
Statistical methods and data analysis 
5.1.1 
Phase Ib part 
An adaptive Bayesian logistic regression model (BLRM) and dose-escalation criteria similar 
to that proposed by (Babb, Rogatko and Zacks 1998) including the escalation with overdose 
control (EWOC) principle will be used to guide the dose escalation to determine the MTD of 
PAN in combination with a fixed dose of 5-Aza. Informative priors for PAN will be derived 
based on the DLT rate obtained from a similar trial [CLBH589B2102, arm X] with similar 
populations, formulations, dose regimens and for 5-Aza from publications. The MTD will be 
assessed during the first treatment cycle. Each cohort will consist of a minimum of 3 patients 
fully evaluable for therapy-related toxicities over the first cycle of treatment. Posterior 
probabilities of the DLT from the model will be summarized. Selection of the next dose will 
be based on these probabilities as well as on other safety and laboratory data. For details 
please refer to the Post-text supplement 2.  
Dose recommendation will be based on posterior summaries for each dose combination and 
the interval probabilities for underdosing, targeted, excessive, and unacceptable toxicity for 
intervals. Once updated, the distribution summarizes the probability that the true probability 
of a DLT for each dose combination lies in 1 of the following categories: 
• [0, 20%) under-dosing 
• [20%, 35%) targeted toxicity 
• [35%,60%) excessive toxicity 
• [60, 100%] unacceptable toxicity. 
Following the principle of EWOC, the recommended dose combination is the one with the 
highest posterior probability of DLT in the target interval [20%, 35%) among the doses 
fulfilling the overdose criteria after each cohort of patients: there is less than 25% chance of 
either excessive or unacceptable toxicity. The maximum inter-cohort dose escalation 
permitted is 100%. The dose recommended by the adaptive BLRM may be regarded as 
information to be integrated with a clinical assessment of the safety data observed thus far in 
determining the next dose to be investigated. In any case, the next dose will not exceed the 
recommended dose by the BLRM. Cohorts of at least 3 and up to a maximum of 12 MTD 
evaluable patients will be enrolled in the dose-escalation part including at least 9 patients at 
the MTD. The Bayesian model will be updated prior to additional enrollment under the 
following scenarios: 
1. If the first 2 patients in a cohort experience DLT prior to the enrollment of the 3rd patient 
enrollment will be halted, the model will be updated, and any new patients will be enrolled 
at a dose satisfying the overdose criteria, no higher than the current dose level. 
2. No additional patients will be enrolled until the current cohort is completed and the model 
is updated. 
3. For cohorts of > 3 patients if the observed number of DLTs exceeds 25% of the currently 
enrolled patients to that dose level, enrollment will be halted until all patients complete 1 
cycle of dosing or experience DLT. The model will be updated to determine the 


Novartis 
Confidential 
Page 13 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
uncertainty about the probability of DLT at each dose level. New patients will be enrolled 
at a dose level up to the highest satisfying the overdose criteria. 
Estimation of the MTD will be based upon the estimation of the probability of DLT in cycle 1 
in the MTD determining set. Estimation of the RPIID will be based on considerations of the 
MTD estimation process by the use of the BLRM, together with an overall clinical assessment 
of safety taking into consideration safety and tolerability data from all cycles. The RPIID 
could be the same as the MTD, but will not exceed it under any circumstance. Cohorts may be 
expanded at any dose level (or dose combination) below the MTD for further elaboration of 
safety parameters as required. 
For further details of the statistical model and results under a variety of scenarios, please refer 
to Clinical Study Protocol Post-text supplement 2. 
5.1.2 
Phase IIb part 
There will be no formal testing of statistical hypotheses. Descriptive summaries of safety and 
efficacy by treatment group will be provided. Point estimates of efficacy endpoints (such as 
response rate) along with appropriate confidence intervals may be reported by treatment group.   
5.2 
Populations for analysis: definitions 
5.2.1 
Phase Ib part 
Safety Set: The safety set includes all patients who received at least 1 dose of any 1 
compound of the study treatment.  
MTD-determining set: consists of all patients of the safety set who either received sufficient 
study treatment as defined in the minimum exposure criteria in cycle 1 (patients need to have 
100% of the planned dose of each compound, see Table 5-1) and had sufficient safety 
evaluations or discontinued due to DLT in Cycle 1. Patients who do not meet these minimum 
safety evaluation requirements in cycle 1 will be regarded as ineligible for the MTD-
determining set. From a programming point, a patient will be considered to have sufficient 
safety evaluations if he or she has information on vital signs and/or lab assessments taken 
during cycle 1. The information on whether a patient experienced a DLT during cycle 1 will 
be taken from the ‘End-Of-Cycle’ page for the first cycle.  
Table 5-1 
Minimum exposure criteria (Cycle 1) 
Compound 
Scheduled doses 
Minimum exposure criterion 
PAN 
6 
6 
5-Aza 
7 
7 
Full analysis set: This will be the same as the safety set. 
PK set: consisted of all patients with at least 1 evaluable PK profile of PAN. 
5.2.2 
Phase IIb part 
Safety Set:  The safety set includes all patients who received at least one dose of any one 
component of the study treatment. Patients in the safety set will be analyzed as treated. The 


Novartis 
Confidential 
Page 14 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
“as treated” information will be taken from the IVRS medication package that was actually 
dispensed. However, patients who are randomized to the PAN+5-Aza group, and have not 
taken a non-zero dose of PAN as per the DAR panel, at the time of data cutoff, will be 
reported under the 5-Aza group for analyses based on the safety set. 
 
 
Full analysis set: consists of all patients who were randomized to one of the two treatment 
arms. Following the intent-to-treat (ITT) principle, the patients in the FAS will be analyzed in 
the treatment group they were assigned to at randomization. The randomized treatment 
information will be taken from the IVRS patient randomization listing. 
 
5.3 
Population and grouping for the analyses 
For all safety analyses in phase Ib/IIb, the safety set will be used. The FAS will be used for all 
efficacy analyses, as well as, for analysis of patient disposition, demography and baseline 
characteristics in phase Ib/IIb. For the determination of the MTD in phase Ib part, the MTD-
determining set will be used. For the analysis of PK data in phase Ib part, the PK set will be 
used. The MTD determining set and the PK set are defined and applicable only for the phase 
Ib part. 
 
5.4 
Patient disposition, demographics and other baseline 
characteristics 
 
Patient disposition, demographic and other baseline data will be listed by patient and/or 
summarized descriptively by initial dose group of PAN in the phase Ib part, and, by treatment 
group in the phase IIb part. The analyses will be based on the full analysis set. Categorical 
data will be presented as frequencies and percentages. For continuous data, summary statistics 
will be presented including mean, standard deviation, median, minimum, and maximum. 
5.5 
Treatments (study drug, concomitant therapies, compliance) 
The actual dose and duration in days of PAN and 5-Aza as well as the actual dose intensity 
(computed as cumulative dose received / actual duration) and relative dose intensity 
(computed as actual dose intensity / planned dose intensity [= planned cumulative dose / 
scheduled duration]), will be listed and summarized by means of descriptive statistics by 
initial dose group of PAN in the phase Ib part, and, by treatment group in the phase IIb part.   
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by ATC term descriptively.  


Novartis 
Confidential 
Page 15 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
5.6 
Pharmacokinetics 
 Trough plasma PAN sample levels collected during Cycle 1 of the phase Ib part of the study, 
on Days 4, 5, and 8 will be summarized by study day. Concentrations of pre-dose levels of 
PAN (Cmin values) will be summarized at the study conclusion by study day and actual dose 
group of PAN. Values below the lower limit of quantification (LLOQ) of approximately 0.5 
ng/mL will be reported as 0 ng/mL. Missing values will be labeled accordingly. 
 
5.7 
Safety variables and analyses 
5.7.1 
Adverse events (AE) 
All AEs recorded during the study will be summarized. The incidence of treatment-emergent 
AEs (new or worsening from baseline) will be summarized by system organ class, severity 
(based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events 
[NCI CTCAE version 3]), type of AE and relation to the study treatment. SAEs resulting in 
death and non-fatal serious AEs (SAEs) will be listed by patient and tabulated by type of AE 
and initial dose group of PAN. 
Listings of deaths, SAEs, AEs requiring dose interruption or adjustment, AEs requiring 
additional therapy, Grade 3/4 AEs, and AEs leading to early termination of study treatment or 
premature withdrawal from study will be also provided. 
5.7.2 
Laboratory abnormalities 
All laboratory values for hematology, biochemistry, coagulation, free T4, TSH and urinalysis 
will be converted into SI units, if appropriate, and the severity Grade calculated using 
appropriate common toxicity criteria (CTC). 
By-patient listings of laboratory values will be provided by laboratory parameter and patient.  
Separate listings will display notable laboratory abnormalities based on the laboratory normal 
ranges. The frequency of laboratory abnormalities will be displayed by parameter. Laboratory 
data will be summarized by presenting shift tables by initial dose group of PAN. 
5.7.3 
Other safety data 
Data from ECGs, vital signs and ECOG performance status will be listed, notable values will 
be flagged, and any other information collected will be listed as appropriate. Any QT and 
QTcF outliers (as defined in section 4.10.6 on ECG in the later part of this document) will be 
summarized and listed. 
5.7.4 
Tolerability 
Not applicable. 
5.8 
Efficacy variables and analyses 
 


Novartis 
Confidential 
Page 16 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
5.8.1 
Phase Ib part 
Summaries of the following efficacy endpoints will be reported by initial dose group of PAN. 
 
• Clinical response for AML: complete remission (CR), complete remission with 
incomplete blood count recovery (CRi), partial remission (PR) 
• Clinical response for MDS/CMML: CR, bone marrow CR, PR, hematologic 
improvement (HI) 
Evidence of anti-leukemic activity of PAN in combination with 5-Aza will be evaluated using 
best response based on the Novartis’ implementation of the recommendations of the 
'International Working Group for Diagnosis, Standardization of response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in MDS and Acute Myeloid 
Leukemia' (Cheson 2003, Cheson 2006) as implemented in Post-text supplement 1. The best 
on-study response as categorized by the response criteria will be listed by patient, as well as, 
summarized, based on investigator’s assessment. Exact binomial confidence interval 
(implemented using SAS procedure FREQ with EXACT statement for one-way tables) will be 
calculated Clopper and Pearson 1934. 
5.8.2 
Phase IIb part 
The primary efficacy endpoint will be the composite CR (CR or CRi or bone marrow CR) 
among all patients in the FAS.  
The following efficacy endpoints will be considered.  
• Clinical response for AML: CR, CRi, PR 
• Clinical response for MDS/CMML: CR, bone marrow CR, PR and Hematologic 
Improvement (HI) 
• 1-year survival rate 
• Time to Progression (TTP) 
Clinical responses will be summarized by treatment arm, overall and within disease type (i.e. 
AML or MDS/CMML). Percentage rates for the composite CR rate (CR or CRi or bone 
marrow CR), overall response rate (CR or CRi or bone marrow CR or PR) will be reported 
along with 95% confidence intervals for both arms. Exact binomial confidence interval 
(implemented using SAS procedure FREQ with EXACT statement for one-way tables) will be 
calculated (Clopper and Pearson 1934.). Point estimates and confidence intervals for the 
difference in rates between the treatment arms will also be reported. The 1-year survival rate 
will be obtained from the Kaplan-Meier curve and its variance will be estimated by 
Greenwood’s formula. Time to progression will also be analyzed through Kaplan Meier 
curves. 
 


Novartis 
Confidential 
Page 17 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
5.10 
Handling of missing values/censoring/discontinuations 
 
Patients who are not evaluable for MTD determination (i.e. patients who are not in MTD 
determining set) will be replaced. Patients in whom clinical response is unknown will be 
treated as non-responders. Patients, for whom the post-baseline response assessments cannot 
be computed because of missing baseline response assessment, will be deemed as patients 
with ‘unknown’ response. Other missing data will be noted as missing on appropriate 
tables/listings.  
 
5.11 
Subgroup analyses 
No subgroup analyses will be performed. 
5.12 
Interim analysis 
Not applicable. 


Novartis 
Confidential 
Page 18 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
5.13 
Sample size calculation 
5.13.1 
Phase Ib part 
 
Sample size is expected to be 26 in total. Cohorts of at least three MTD evaluable patients per 
dose level will be enrolled in the phase Ib part including at least nine patients at the MTD 
and/or RPIID level. 
Sample size is expected to be at least 26 assuming two cohorts of six patients each treated at 
dose levels distinct from the MTD and/or RPIID, and two cohorts of 7 patients each treated at 
the MTD and/or RPIID. 
 
5.13.2 
Phase IIb part 
The planned sample size is 40 per arm, or, in other words, 80 in total. It is deemed that an 
observed relative improvement of 50% in the composite CR rate (CR or CRi or bone marrow 
CR) in the investigational arm over the active control arm is clinically relevant in the phase 
IIb part of the study. Under the assumption that the composite response rate in the active 
control arm is 17% (estimate based on Fenaux et al 2009a), the following table gives the 
estimated probabilities of observing clinically relevant improvement , under different values 
of the true composite CR rate in the experimental arm. The chance of observing a clinically 
relevant improvement when there is actually no difference in the true composite CR rates 
between the arms) is estimated to be 23% while the chance of not observing a clinically 
relevant improvement when there is indeed a substantial difference in the true composite CR 
rates (true composite response rates in investigational and active control arms are 35% and 
17% respectively) is estimated to be 19%. Since there is no hypothesis being tested, a formal 
power analysis has not been done. The aforementioned estimated probabilities of 23% and 
19% are only analogous to the probabilities of type I and type II errors (in the setting of 
hypothesis testing). These probabilities (as well as, the others shown under [4] in the 
following table) have been derived by simulating response data using independent binomial 
distributions for the investigational and active control arms with the probability parameter of 
the distribution being specified according to the assumed true underlying composite CR rates 
as shown under [1], and [2] of the table below. Thus, given that the true composite CR rates 
are as in [1] and [2] (and, the true percentage improvement as in [3]), [4] represents the 
probability of observing clinically relevant improvement. More specifically, [4] represents the 
following: 
Pr[(observed composite CR rate in investigational arm - observed composite CR rate in 
active control arm) ≥ 50% of observed composite CR rate in active control arm] 
Table 5-2 
Probability of observing clinically relevant improvement based on an 
assessment of composite CR (CR or CRi or bone marrow CR)  
True composite CR 
rate  in active control 
arm  
True composite CR 
rate  in investigational  
arm  
True improvement (as 
a percentage of the 
true composite CR rate 
Probability of  
observing clinically 
relevant improvement  


Novartis 
Confidential 
Page 19 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
[1] 
[2] 
in the active control 
arm)  
[3] 
[4] 
0.17  
0.17  
0 
0.23 
 
0.20  
18 
0.33 
 
0.25  
47 
0.51 
 
0.30  
76 
0.68 
 
0.35  
106 
0.81 
 
5.14 
Power for analysis of critical secondary variables 
There is no critical secondary variable. 
  


Novartis 
Confidential 
Page 20 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Draft of Appendix 16.1.9 
 
 


Novartis 
Confidential 
Page 21 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Clinical Development 
Panobinostat 
Appendix 16.1.9: Documentation of statistical methods 
Document type: 
Clinical Study Report - Appendix 16.1.9 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 22 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
1 
Table of contents 
Clinical Development ............................................................................................................ 1 
1 
Introduction .................................................................................................................... 7 
Document content ........................................................................................................... 7 
2 
Study design ................................................................................................................... 8 
3 
Objectives ....................................................................................................................... 9 
3.1 
Phase Ib part ........................................................................................................ 9 
3.1.1 
Primary objective ................................................................................. 9 
3.1.2 
Secondary objectives ......................................................................... 10 
 
 10 
3.2 
Phase IIb part ..................................................................................................... 10 
3.2.1 
Primary objective ............................................................................... 10 
3.2.2 
Secondary objectives ......................................................................... 11 
 
 11 
4 
Population ..................................................................................................................... 11 
5 
Draft of Section 9.7 of CSR on Statistical methods ........................................................ 12 
5.1 
Statistical methods and data analysis .................................................................. 12 
5.1.1 
Phase Ib part ...................................................................................... 12 
5.1.2 
Phase IIb part ..................................................................................... 13 
5.2 
Populations for analysis: definitions ................................................................... 13 
5.2.1 
Phase Ib part ...................................................................................... 13 
5.2.2 
Phase IIb part ..................................................................................... 13 
5.3 
Population and grouping for the analyses ........................................................... 14 
5.4 
Patient disposition, demographics and other baseline characteristics .................. 14 
5.5 
Treatments (study drug, concomitant therapies, compliance).............................. 14 
5.6 
Pharmacokinetics ............................................................................................... 15 
5.7 
Safety variables and analyses ............................................................................. 15 
5.7.1 
Adverse events (AE) .......................................................................... 15 
5.7.2 
Laboratory abnormalities ................................................................... 15 
5.7.3 
Other safety data ................................................................................ 15 
5.7.4 
Tolerability ........................................................................................ 15 
5.8 
Efficacy variables and analyses .......................................................................... 15 
5.8.1 
Phase Ib part ...................................................................................... 16 
5.8.2 
Phase IIb part ..................................................................................... 16 
 
 17 


Novartis 
Confidential 
Page 23 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
5.9.1 
Phase Ib part ...................................................................................... 17 
5.9.2 
Phase IIb part ..................................................................................... 17 
5.10 
Handling of missing values/censoring/discontinuations ...................................... 17 
5.11 
Subgroup analyses ............................................................................................. 17 
5.12 
Interim analysis ................................................................................................. 17 
5.13 
Sample size calculation ...................................................................................... 18 
5.13.1 
Phase Ib part ...................................................................................... 18 
5.13.2 
Phase IIb part ..................................................................................... 18 
5.14 
Power for analysis of critical secondary variables .............................................. 19 
6 
Changes in analyses specified in the protocol ................................................................ 19 
Draft of Appendix 16.1.9 ..................................................................................................... 20 
1 
Table of contents ........................................................................................................... 22 
2 
Introduction .................................................................................................................. 25 
3 
Definitions and general methodology ............................................................................ 26 
3.1 
Definitions ......................................................................................................... 26 
3.1.1 
Study drug and study treatment .......................................................... 26 
3.1.2 
Phase Ib part ...................................................................................... 26 
3.1.3 
Phase IIb part ..................................................................................... 26 
3.1.4 
Date of first administration of study drug ........................................... 26 
3.1.5 
Date of last administration of study drug ............................................ 26 
3.1.6 
Date of first administration of study treatment.................................... 26 
3.1.7 
Date of last administration of study treatment .................................... 26 
3.1.8 
Study day ........................................................................................... 27 
3.1.9 
Baseline ............................................................................................. 27 
3.1.10 
On-treatment assessment/event/period ............................................... 28 
3.1.11 
Time windows ................................................................................... 28 
3.1.12 
Screening failure ................................................................................ 28 
3.2 
Data included in analyses ................................................................................... 28 
3.3 
Definition of analysis sets .................................................................................. 29 
3.3.1 
Phase Ib part ...................................................................................... 29 
3.3.2 
Phase IIb part ..................................................................................... 29 
3.4 
Population and grouping for the analyses ........................................................... 30 
3.5 
Protocol deviations ............................................................................................ 30 
3.6 
Concomitant therapy .......................................................................................... 30 
3.6.1 
Concomitant medications with specific impact on the analysis ........... 31 
3.7 
General statistical methodology ......................................................................... 31 


Novartis 
Confidential 
Page 24 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
3.7.1 
Baseline comparability ....................................................................... 31 
3.7.2 
Multiple assessments within post-baseline visits ................................ 31 
3.7.3 
Center pooling ................................................................................... 31 
3.7.4 
1-sided vs. 2-sided test ....................................................................... 31 
3.7.5 
Between group comparisons .............................................................. 32 
3.7.6 
Conversion factors ............................................................................. 32 
3.8 
Implementation of efficacy criteria .................................................................... 32 
4 
Statistical methods used in reporting ............................................................................. 32 
4.1 
Background and demographic characteristics ..................................................... 32 
4.1.1 
Basic demographic and background data ............................................ 32 
4.1.2 
Protocol eligibility criteria ................................................................. 33 
4.1.3 
Diagnosis and characteristics of disease ............................................. 33 
4.1.4 
Medical history .................................................................................. 34 
4.1.5 
Prior anti-neoplastic therapy .............................................................. 34 
4.1.6 
Other ................................................................................................. 35 
4.2 
Protocol deviation summaries ............................................................................ 35 
4.3 
Groupings for Analysis ...................................................................................... 35 
4.4 
Patient disposition .............................................................................................. 35 
4.5 
Follow-up .......................................................................................................... 36 
4.6 
Last contact date ................................................................................................ 36 
4.7 
Study treatment and duration of study treatment exposure .................................. 37 
4.7.1 
Duration of study treatment exposure ................................................. 37 
4.7.2 
Cycle definition ................................................................................. 38 
4.7.3 
Partial dates ....................................................................................... 40 
4.7.4 
Cumulative dose ................................................................................ 40 
4.7.5 
DI and RDI ........................................................................................ 40 
4.7.6 
Dose intensity over study period ........................................................ 41 
4.8 
Concomitant therapy .......................................................................................... 42 
4.8.1 
Concomitant medications with specific impact on the analysis ........... 43 
4.9 
Primary safety variable ...................................................................................... 43 
4.9.1 
Analysis of the primary safety variable .............................................. 43 
4.9.2 
Sensitivity and other supportive analyses ........................................... 43 
4.10 
Safety evaluation ............................................................................................... 43 
4.10.1 
Adverse events ................................................................................... 43 
4.10.2 
AE summaries ................................................................................... 44 
4.10.3 
Clinical notable AE ............................................................................ 45 


Novartis 
Confidential 
Page 25 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
4.10.4 
Laboratory data .................................................................................. 46 
4.10.5 
Vital signs .......................................................................................... 47 
4.10.6 
Handling of missing values ................................................................ 48 
4.10.7 
ECG................................................................................................... 48 
4.10.8 
ECOG performance status .................................................................. 50 
4.11 
Efficacy analysis ................................................................................................ 50 
4.11.1 
Efficacy analysis for the phase Ib part ................................................ 50 
4.11.2 
Efficacy analysis for the phase IIb part ............................................... 50 
4.11.3 
Kaplan-Meier analysis ....................................................................... 52 
4.11.4 
Handling of missing values/discontinuations ...................................... 53 
4.11.5 
Transfusions ...................................................................................... 53 
4.12 
Handling of missing values/discontinuations ...................................................... 55 
4.13 
Subgroup analysis .............................................................................................. 55 
4.14 
Pharmacokinetic analyses .................................................................................. 55 
 
 55 
 
 55 
 
56 
4.16 
Interim analyses ................................................................................................. 56 
5 
References .................................................................................................................... 56 
6 
Appendix ...................................................................................................................... 57 
A1 
Instructions given to sites for completion of the DAR forms .............................. 57 
2 
Introduction 
The statistical methodology used (Section 9.7) will be described and discussed in the main 
part of the clinical study report.  In Appendix 16.1.9, details of the statistical methods and 
their justification are provided for the statistical reviewers. 
The statistical analysis of this study will be performed by Novartis personnel. SAS® version 
9.2 (SAS Institute Inc., Cary, NC, USA) will be used for all analyses. The simulations for the 
adaptive Bayesian logistic regression model (BLRM) will be performed by WinBUGS for 
Windows® version 1.4 and R for Windows® version 2.8 using the module OncoBayes 
developed internally by Novartis. All data are part of the Clinical Database and will be 
exported to SAS® files for analysis.  


Novartis 
Confidential 
Page 26 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
3 
Definitions and general methodology 
3.1 
Definitions 
3.1.1 
Study drug and study treatment 
3.1.2 
Phase Ib part 
Study drug refers to single agent PAN.  
Study treatment refers to of PAN plus 5-Aza (combination therapy).  
Study combination partner refers to 5-Aza. 
3.1.3 
Phase IIb part 
Study drug refers to single agent PAN in the treatment arm and to 5-Aza in the control arm.  
Study treatment refers to of PAN plus 5-Aza (combination therapy) in the treatment arm and 
to 5-Aza alone in the control arm.  
Study combination partner refers to 5-Aza in the treatment arm. There is no study combination 
partner in the control arm. 
 
3.1.4 
Date of first administration of study drug 
The date of first administration of study drug is derived as the first date when a nonzero dose 
of study drug was administered and recorded on the dose administration record (DAR) case 
report form (CRF). For the sake of simplicity, the date of first administration of study drug 
will also be referred as start of study drug. 
3.1.5 
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a non-zero dose 
of study drug was administered and recorded on the end-of-treatment CRF.  
3.1.6 
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of study treatment was administered and recorded on DAR CRF. For 
example, if in the phase Ib part, the 1st dose of PAN is administered on 05JAN2010, and the 
1st dose of 5-Aza is administered on 03JAN2010, the date of first administration of study 
treatment is on 03JAN2010. For the sake of simplicity, the date of first administration of 
study treatment will also be referred as the start of study treatment. 
3.1.7 
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a non-zero 
dose of any component of study treatment was administered and recorded on end-of-treatment 
CRF. For example, if in the phase Ib part, the last dose of PAN dose is administered on 


Novartis 
Confidential 
Page 27 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
15APR2010, the last dose of 5-Aza is administered on 17MAY2010, the date of last 
administration of study treatment is then on 17MAY2010.  
3.1.8 
Study day 
3.1.8.1 
Phase Ib part 
The study day for all assessments (efficacy, safety) will be calculated as the difference 
between the date of the event (e.g., visit date, onset date of an event, assessment date) and the  
treatment start date plus 1 day. The first day of study treatment is therefore Study Day 1. For 
example: if the start of study treatment is on 05JAN2010 and the start date of an Adverse 
Event (AE) is on 09JAN2010, the study day of the AE onset is calculated to have occurred on 
Study Day 5. 
If the event or assessment date happens to be before the treatment start date, the calculation 
will be without “+1” and the resulting day(s) is a negative number. 
3.1.8.2 
Phase IIb part 
The study day for safety assessments (e.g., adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) will be calculated as: 
Date of the assessment/event - start date of study treatment + 1. 
The study day for all other, i.e. non-safety assessments/events (e.g., response assessment, 
disease progression, ECOG performance status, etc.) will be calculated as: 
Date of assessment/event - randomization date + 1. 
Example: if randomization date is 02-Jan-2011, start of study treatment is on 05JAN2011, and 
the date of death is 09JAN2011 then the study day when the death occurred is 8. 
For events that occur before randomization/first treatment day, the “+1” from the 
formulas above will be removed and the study day will be a negative number by definition: 
Study day = Event date - Date of first study treatment/randomization. 
Note that the day of first dose of study treatment is day 1 and the day before the date of first 
study treatment is day – 1, not day 0.  
Death may be analyzed as a safety or an efficacy variable depending on the context.  
If death is analyzed as a safety variable (such as a listing of deaths),  then “study day” must be 
calculated following the rules for safety assessment.  When death is used as an efficacy 
variable , such as, in the analysis of overall survival or progression-free-survival,  then the 
non-safety rule must be used.     
3.1.9 
Baseline 
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient. 
Phase Ib part (non-randomized):  


Novartis 
Confidential 
Page 28 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Baseline is defined to be the last available value or assessment, assessed prior to or on the date 
of start of study treatment.  
Phase IIb part (randomized):  
For efficacy evaluations, the last available assessment before or on the date of randomization 
is taken as “baseline” value or assessment. In the context of baseline definition, the efficacy 
evaluations include ECOG performance status.     
For safety evaluations (i.e. AEs, laboratory values, and vital signs), the last available 
assessment before or on the date of start of study treatment, is taken as “baseline’ assessment. 
For ECG, please refer to section 3.8.5. 
If patients have no value as defined above, the baseline result will be considered to be missing. 
Any assessment which is obtained outside of the protocol-defined screening period will not be 
considered for baseline unless otherwise specified. 
Baseline definition for ECG assessments is given in section 4.9.6. 
 
3.1.10 
On-treatment assessment/event/period 
On-treatment assessment/event is any assessment/event obtained in the on-treatment period 
which is defined as the following time interval: 
[date of first administration of study treatment; date of last administration of study 
treatment +28 days], i.e. inclusive of the lower and upper limits.   
The calculation of study treatment duration may use different rules as specified in Section 
3.5.1. 
3.1.11 
Time windows 
For response assessment, the time window as defined in Clinical Study Protocol Post-text 
supplement 1 to the protocol will be applied. 
3.1.12 
Screening failure 
Screening failures are patients who will have been enrolled but subsequently fail the screening 
criteria on the  study.  These patients will not be treated.   
3.2 
Data included in analyses 
A unique data cut-off date will be determined. Only data from an assessment or event start 
date (e.g., vital sign assessment date or start date of an AE) prior to or on the cut-off date will 
be included in the analysis. For example, if the cut-off date is 15JUN2011, an AE starting on 
13JUN2011 will be reported, whereas an AE with a start date of 17JUN2011 will not be 
reported. 
All events with a start date before or on the cut-off date and an end date after the cut-off date 
will be reported as ‘continuing at the cut-off date’. The same rule will be applied to events 


Novartis 
Confidential 
Page 29 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
starting before or on the cut-off date and not having a documented end date. This approach 
applies in particular to AE and concomitant medication reports.  
If imputation of an end date is required for a specific analysis (e.g., for a dose administration 
record with a missing end date or an end date after the cut-off date, the latter of which must be 
imputed as an end date to allow for the calculation of treatment exposure duration), the 
imputed date will be displayed and flagged in the listings. 
The data cut-off date for the core CSR will be taken as April 30, 2014. This corresponds to the 
time-point when the last enrolled patient in the phase IIb part completed 12 cycles of 
treatment.  
 
3.3 
Definition of analysis sets 
3.3.1 
Phase Ib part 
Safety Set: The safety set includes all patients who received at least 1 dose of any 1 
compound of the study treatment.  
MTD-determining set: consists of all patients of the safety set who either received sufficient 
study treatment as defined in the minimum exposure criteria in cycle 1 (patients need to have 
100% of the planned dose of each compound, (as shown in the table below) and had sufficient 
safety evaluations or discontinued due to DLT in Cycle 1. Patients who do not meet these 
minimum safety evaluation requirements in cycle 1 will be regarded as ineligible for the 
MTD-determining set. From a programming point, a patient will be considered to have 
sufficient safety evaluations if he or she has information on vital signs and/or lab assessments 
taken during cycle 1. The information on whether a patient experienced a DLT during cycle 1 
will be taken from the ‘End-Of-Cycle’ page for the first cycle.  
Table 3-1 
Minimum exposure criteria (Cycle 1) 
Compound 
Scheduled doses 
Minimum exposure criterion 
PAN 
6 
6 
5-Aza 
7 
7 
Full analysis set: This will be the same as the safety set. 
PK set: consisted of all patients with at least 1 evaluable PK profile of PAN.  
3.3.2 
Phase IIb part 
Safety Set: The safety set includes all patients who received at least one dose of any one 
component  of the study treatment. Patients in the safety set will be analyzed as treated. The 
“as treated” information will be taken from the IVRS medication package that was actually 
dispensed. . However, patients who are randomized to the PAN+5-Aza group, and have not 
taken a non-zero dose of PAN as per the DAR panel, at the time of data cutoff, will be 
reported under the 5-Aza group for analyses based on the safety set. 
Patients who have been randomized but did not take at least one dose of any component of 
study treatment will not be included in the safety set. 


Novartis 
Confidential 
Page 30 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
 
Full analysis set: consists of all patients who were randomized to one of the two treatment 
arms. Following the intent-to-treat (ITT) principle, the patients in the FAS will be analyzed in 
the treatment group they were assigned to at randomization. The randomized treatment 
information will be taken from the IVRS patient randomization listing. 
 
3.4 
Population and grouping for the analyses 
For all safety analyses in phase Ib/IIb, the safety set will be used. The FAS will be used for all 
efficacy analyses, as well as, for analysis of patient disposition, demography and baseline 
characteristics in phase Ib/IIb. For the determination of the MTD in phase Ib part, the MTD-
determining set will be used. For the analysis of PK data in phase Ib part, the PK set will be 
used. The MTD determining set and the PK set are defined and applicable only for the phase 
Ib part. 
 
 
3.5 
Protocol deviations 
All protocol deviations and patient classification rules as specified in the VAP module 3, will 
be finalized before database lock.  
Protocol deviations will be , summarized and listed by initial dose group of PAN for the phase 
Ib part and by treatment arm for the phase IIb part.  
3.6 
Concomitant therapy 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment, that were intentionally administered to a patient preceding or 
coincident with the study assessment period. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List to allow for categorization by preferred term. In addition to categorizing 
medication data by preferred term, drugs are classified according to their ATC classification 
in order to present and compare how they are being utilized. The ATC classification allows 
for the summary of medications by a high-level common drug class. 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
treatment will be listed and summarized by ATC class, preferred term and initial dose group 
of PAN by means of frequency counts and percentages. These summaries will include 
medications starting on or after the start of study treatment or medications starting prior to the 
start of study treatment and continuing after the start of study treatment.  
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed.  


Novartis 
Confidential 
Page 31 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
3.6.1 
Concomitant medications with specific impact on the analysis 
3.6.1.1 
Further anti-neoplastic therapy 
Patients who take additional anti-neoplastic therapy before discontinuing study treatment (i.e., 
anti-neoplastic therapy other than study treatment) will be identified as protocol deviations. 
Their efficacy data will be censored so that response assessments made after the first intake of 
an anti-neoplastic drug will not be included in analyses.  
 
 
3.7 
General statistical methodology 
3.7.1 
Baseline comparability 
Baseline variables refer to characteristics of patients at the start of a study. 
As this is not a comparative study, no assessment of baseline comparability will be done. 
Instead, baseline characteristics will be described by initial dose group of PAN in the phase Ib 
part and by treatment group in the phase IIb part. 
3.7.2 
Multiple assessments within post-baseline visits 
If there are multiple measurements/samples within the same post-baseline visit, the last 
measurement/sample within the visit (sorted by date and as available by time or repeat 
measurements) will be used in the analysis by visit or overall. For any analysis regarding 
outlier or abnormal assessments, all post-baseline values will be included (scheduled, 
unscheduled, repeat). For any other analyses, only scheduled visits will be included. This 
applies to quantitative and qualitative variables. For composite assessments, these rules apply 
for the complete sample (e.g., bone marrow differential counts, differential blood counts). It is 
not allowed to mix these variables across samples. 
3.7.2.1 
12-lead ECG assessments  
The visit day recorded in the database will be used as the day of ECG. For all patients, a 
minimum of 3 ECGs are measured at all assessment time points except at screening (one ECG 
only). If any patient has more than 1 measurement at a specific time point, the average of all 
available measurements will be used for the analysis of change from baseline. Unscheduled 
measurements will be included for analysis of outliers and listings. 
3.7.3 
Center pooling  
All study centers will be combined for the analysis unless otherwise specified. Due to 
expected small size of centers, no center effect will be assessed. However, number of patients 
will be summarized by analysis set, center and country. 
3.7.4 
1-sided vs. 2-sided test  
No statistical testing will be performed. 


Novartis 
Confidential 
Page 32 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
3.7.5 
Between group comparisons 
Not applicable. 
3.7.6 
Conversion factors 
A month will be calculated as (365.25 / 12) = 30.4375 days.  
For the conversion of laboratory values measured in units as used by local laboratories to SI 
units, standard Novartis’ conversion factors will be used.  
3.8 
Implementation of efficacy criteria 
Response evaluation will be performed according to the Cheson (2003, 2006) criteria as 
implemented in the Clinical Study Protocol Post-text supplement 1.  
4 
Statistical methods used in reporting 
4.1 
Background and demographic characteristics 
The full analysis set will be used for all baseline and demographic summaries and listings.  
4.1.1 
Basic demographic and background data 
All demographic and background data will be listed in detail. Qualitative data will be 
summarized by means of contingency tables  and quantitative data will be summarized by 
appropriate descriptive statistics (mean, standard deviation, median, minimum, and maximum) 
Data will be reported by the initial dose group of PAN for the phase Ib part and by treatment 
group for the phase IIb part. The following variables will be summarized: 
• Age [years], (< 65 years, ≥ 65 years) 
• Height [cm] 
• Weight [kg] 
• Sex (male/ female) 
• Race (Caucasian/ Black/ Asian/ Native American/ Pacific Islander/ Other) 
• Ethnicity (Hispanic/latino/ Chinese/ Indian (Indian subcontinent)/ Japanese/ Mixed 
ethnicity/ Other) 
• ECOG status (0/ 1/ 2/ >2) 
• Respiratory rate [/min] 
• Body temperature [°C] 
• BMI [kg/m2] 
• Body surface area (BSA) [m2] 
• Transfusion-dependent (yes/ no) 
• Number of patients by disease (MDS/ AML/ CMML) 


Novartis 
Confidential 
Page 33 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
4.1.2 
Protocol eligibility criteria  
Protocol eligibility criteria on CRFs will be summarized and listed by initial dose group of 
PAN for the phase Ib part and by treatment group for the phase IIb part. 
4.1.3 
Diagnosis and characteristics of disease 
Summary statistics will be tabulated (by initial dose group of PAN for the phase Ib part and 
by treatment group for the phase IIb part) for diagnosis and characteristics of AML, CMML 
and MDS and depending on the data collected on the CRF include the following:  
• WHO classification of MDS at initial diagnosis 
o Refractory anemia (RA) 
o Refractory anemia with ringed sideroblasts (RARS) 
o Refractory cytopenia with multilineage dysplasia (RCMD) 
o Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) 
o Refractory anemia with excess blasts-1 (RAEB-1) 
o Refractory anemia with excess blasts-2 (RAEB-2) 
o Myelodysplastic syndrome , unclassified (MDS-U) 
• FAB classification of MDS at initial diagnosis 
o Refractory anemia (RA) 
o Refractory anemia with ringed sideroblasts (RARS) 
o Refractory anemia with excess blasts (RAEB) 
• Cytogenetics of MDS at initial diagnosis (Not done/ Favorable/ Intermediate/ Unfavorable) 
• MDS IPSS risk category (low/ intermediate-1/ intermediate-2/ high) 
• MDS disease status at enrolment (previously untreated/ previously treated) 
• WHO classification of AML at initial diagnosis 
 
o AML with multilineage dysplasia (BM blasts 21-30%) 
o 
Following MDS 
o 
Following MDS/MPD 
o 
Without antecedent MDS or MDS/MPD but dysplasia in at least 50% of cells in 2 or more myeloid 
lineages 
o 
Other 
o AML (BM blasts > 30%) 
• FAB classification of AML at initial diagnosis 
o M0: Minimally differentiated acute myeloblastic leukemia 
o M1: Acute myeloblastic leukemia, without maturation 
o M2: Myeloblastic with granulocytic maturation 
o M3: Acute promyelocytic leukemia 
o M4: Acute myelomonocytic leukemia 
o M4eo: Myelomonocytic together with bone marrow eosinophilia 
o M5: Acute monoblastic leukemia without differentiation or acute monocytic leukemia 


Novartis 
Confidential 
Page 34 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
o M6: Acute erythroid leukemia including erythroleukemia and very rare pure erythroid 
leukemia 
o M7: Acute megakaryoblastic leukemia 
o Acute myeloid leukemia, not otherwise categorized 
o Other 
• time since initial diagnosis of AML until start of treatment (phase Ib part) or 
randomization date (phase IIb part)  and by categories: 
• < 1 month 
• ≥ 1 month to ≤ 3 months 
• 3 months to ≤ 6 months 
• months to ≤ 12 months 
• 12 months to ≤ 24 months 
• 24 months 
• unknown 
• duration of first CR to AML 
o refractory 
o ≤ 6 months  
o > 6 month to ≤ 12 months 
o > 12 months to ≤ 24 months 
o > 24 months 
o unknown 
• AML disease status (previously treated/ previously untreated) 
• Cytogenetics AML (favorable/ intermediate/ poor/ not done) 
• WHO classification of CMML 
o Chronic myelomonocytic leukemia (CMML) Myelodysplastic disease (WBC < 13 x 
109/L, BM blasts 10-29%) 
o Chronic myelomonocytic leukemia (CMML) Myeloproliferative disease (WBC ≥ 13 
x 109/L) 
• CMML status at enrolment (previously untreated/ previously treated). 
• Time since diagnosis [months] (all diseases) 
4.1.4 
Medical history 
Medical history and ongoing conditions, including leukemia-related conditions and symptoms 
will be summarized and listed. Separate summaries will be presented for ongoing and 
historical medical conditions. The summaries will be presented by primary system organ class 
and preferred term (by initial dose group of PAN for the phase Ib part and by treatment group 
for the phase IIb part). Medical history/current medical conditions are coded using the 
Medical dictionary for regulatory activities MedDRA terminology.  
4.1.5 
Prior anti-neoplastic therapy 
Prior anti-neoplastic therapy will be listed for medications, radiotherapy and surgeries. 


Novartis 
Confidential 
Page 35 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
The number and percentage of patients receiving any prior anti-neoplastic therapy, surgeries, 
radiotherapy, and prior anti-neoplastic medications will be summarized.  
4.1.6 
Other 
All data collected at baseline, including source of patient referral, childbearing potential, 
pregnancy test results, cytogenetics, 
, will be 
listed (by initial dose group of PAN for the phase Ib part and by treatment group for the phase 
IIb part). 
Demographic information on screening failures will be listed together with the reason for 
screening failure. 
4.2 
Protocol deviation summaries 
The number and percentage of patients in the FAS with any protocol deviation will be 
tabulated by the deviation category (as specified in the Validation and Analysis Plan [VAP] 
documents). Protocol deviations will also be listed. The tabulation and listing will be done by 
the initial dose group of PAN for patients in the phase Ib part, and by treatment group for 
patients in the phase IIb part.  
4.3 
Groupings for Analysis 
The number and percentage of patients in each analysis set (definitions are provided in 
Section 2.3) will be summarized by initial dose group of PAN for the phase Ib part and by 
treatment group for the phase IIb part). 
4.4 
Patient disposition  
The full analysis  set will be used for the patient disposition summaries.  
The following frequencies will be provided by initial dose group of PAN for the phase Ib part 
and by treatment group for the phase IIb part: 
• Number (%) of patients who were enrolled  
• Number (%) of patients who are still in the treatment phase at the cut-off date  
• Number (%) of patients who discontinued the study treatment (based on ‘End of 
Treatment’ page) 
• Number of patients (%) by primary reason for treatment discontinuation (based on ‘End of 
Treatment’ page: AE(s)/ Abnormal laboratory value(s)/ Abnormal test procedure result(s)/ 
Patient withdrew consent/ Lost to follow-up/ Administrative problems/ Death/ Disease 
progression/ Protocol deviation/ Reason missing) 
• Number (%) of patients who entered the post-treatment evaluation phase (based on ‘End 
of Treatment’ page 
• Number (%) of patients who entered the post-treatment evaluation and completed the 
study (based on ‘Study Evaluation Completion’ page) 
• Number (%) of patients who entered the post-treatment evaluation and who discontinued 
the study (based on ‘Study Evaluation Completion’ page) 


Novartis 
Confidential 
Page 36 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
• Reasons for discontinuation from the post-treatment evaluation phase (based on ‘Study 
Evaluation Completion’ page: Patient withdrew consent/ Lost to follow-up/ 
Administrative problems/ Death/ New cancer therapy/ Disease progression/ Protocol 
deviation/ Follow-up phase completed/ Reason missing).  
4.5 
Follow-up 
To describe the maturity of data and quality of follow-up, the following summaries on the 
follow-up of patients will be provided by treatment group for the phase IIb part.  
Median duration of follow-up described as the duration of time elapsed from the first visit 
(per the visit record) of the median patient enrolled to date of data cut-off. 
Time elapsed from last contact (or death) of patient to date of data cut-off summarized by the 
following interval times. 
• 0 to <1 month 
• ≥1 to <3 months 
• ≥3 to < 6 months 
• ≥6 to < 12 months 
• ≥12 months 
The date of last contact is defined as the last date the patient was known to be alive as 
derived from different CRF pages as described below. 
4.6 
Last contact date 
The last contact date should be derived as the latest date on or before the data cut-off date 
from the dates listed in the 1st column of Table 4-1. For each of the sources specific conditions 
(2nd column of Table 4-1) have to be fulfilled to ensure that there was true contact with the 
patient.  
No additional dates are allowed to be used, e.g. dates coming from concomitant 
medications, QoL, ECG, etc. The rationale for excluding those additional potential sources is 
the following: 
• Use of a transparent and easy to implement approach that can be standardized across 
most of the studies. 
• The risk of disregarding important information is low since the last contact date is 
expected to be obtained from the main sources listed in Table 4-1. 
Table 4-1 
Last contact date data sources  
Source data 
Conditions 
Date of Randomization  
 
No Condition 
Last contact date/last date patient was known to 
be alive from Survival Follow-up page  
 
- Patient status is reported to be alive. 
- Do not use if patient status is reported 
unknown. 
Start/End dates from further antineoplastic 
Non-missing medication/procedure term. 


Novartis 
Confidential 
Page 37 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Source data 
Conditions 
therapy 
Start/End* dates from drug administration record  
 
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from end of treatment page
 
No condition. 
Efficacy (any specific assessment) assessment 
date 
Evaluation is marked as ‘done’. 
Laboratory/PK collection dates 
 
Sample collection marked as ‘done’.  
Vital signs date 
 
At least one parameter value 
Performance Status date 
 
Non-missing performance status 
 
4.7 
Study treatment and duration of study treatment exposure 
All summaries mentioned below will be presented (in addition to groupings mentioned below) 
by initial dose group of PAN for the phase Ib part and by treatment group for the phase IIb 
part. Duration of study treatment exposure [days] will be summarized overall, and by 
compound. . The cumulative dose [mg], dose intensity (DI) [mg/day] and relative dose 
intensity (RDI) [%] will be summarized by compound.  The number of patients who have 
dose reductions or interruptions and the reasons will be summarized.  
Listings of all doses of the study treatment, along with dose change reasons, will be produced 
by compound.   
The safety set will be used for all summaries and listings of study treatment.  
4.7.1 
Duration of study treatment exposure 
In summarizing the  duration of exposure to  study treatment  and study treatment component 
the following working definitions and conventions will be used. 
Duration of study treatment exposure 
Duration of exposure (days) = [(date of last administration of study treatment) – (date 
of first administration of study treatment) + 1 day] 
Duration of study treatment component exposure 
Duration of exposure to any single component of study treatment will be calculated as 
Duration of exposure (days) = [(date of last administration of study treatment 
component) – (date of first administration of study treatment component) + 1 day] 
The date of last administration of study treatment  is taken from CRF treatment completion 
page ‘last dose taken’. For the date of last administration of the treatment component, the 
DAR page must be used. 


Novartis 
Confidential 
Page 38 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
 The calculation of ‘duration of exposure’ does not consider the potential ‘lagging effect’ from 
the last dose. 
The duration includes the periods of temporary interruption (of any component of the study 
treatment for any reason). ‘Date of last administration of study drug /component’ and ‘date of 
first administration of study drug /component’ is defined in Section 2.1. For patients who did 
not take any study treatment the duration of exposure is defined as zero days. 
The following categories for exposure to study treatment (by component) will be analyzed: 
• < 1 week 
• 1 week to < 3 weeks 
• 3 weeks to < 6 weeks 
• 6 weeks to < 9 weeks  
• 9 weeks to < 12 weeks 
• ≥ 12 weeks 
4.7.2 
Cycle definition 
Cycle length will be calculated based on the cycle panel for this study.  
Using cycle panel (except last cycle), 
Cycle length= (date of day 1 of the next cycle – date of day 1 of the current cycle). 
The actual length of a treatment cycle might differ from the scheduled length: 
• 
In case of Adverse Events which led to a dose delay, the duration of the cycle might be 
longer than the scheduled length. 
• 
In case a patient was withdrawn from the study, the length of the last treatment cycle 
might be shorter than the scheduled length 
4.7.2.1 
Last cycle  
Since patient can discontinue the study early, last cycle may not be a complete cycle for 
treatment.  The calculation of last cycle length needs special attention, i.e.,  
Last Cycle Length= [(date of last administration of study treatment component +X) – (day 1 
of the last cycle date) + 1]. 
where X is the number of days remaining to complete the exposure time of the last dose of the 
study treatment component or the number of days from last administered  dose to the next 
planned dose.  This can be better understood by referring to the dosing schedule for the phase 
IIb part given in Figure 4-1 (note: dosing schedule for the phase Ib part would follow the 
investigational arm of the phase IIb part). The dose is given on days marked by the dark 
filled-in slots. X would equal the number of unfilled slots between the filled-in slot that marks 
the last dose and the next filled-in slot that would mark the next scheduled dose.   
For PAN: 
If last dose is given on day 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 13, 14 of the cycle, X = 1 


Novartis 
Confidential 
Page 39 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
If last dose is given on day 5, 12 of the cycle, X = 2 
If last dose is given on day 15 to 27 the cycle, X = 28 – day of last dose 
If last dose is given on day 28 and beyond, X = 0 
 
For 5-Aza: 
If last dose is given on day 1 through day 6 of the cycle, X = 0. 
If last dose is given on day 7 to day 27 of the cycle, X = 28 – day of last dose. 
If last dose is given on day 28 and beyond, X = 0 
 
The special handling of the last cycle length is to carefully calculate dose intensity. This is 
different from the purpose of calculating ‘duration of exposure’ where ‘last dose lagging 
effect’ is not included. 
 


Novartis 
Confidential 
Page 40 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Figure 4-1 
Treatment schedule (Phase IIb part) 
Investigational arm: 
 
Active control arm:  
 
 
 
 
 
4.7.3 
Partial dates 
Partial dates will be listed as partial dates. The general approach is to impute partial dates only 
when further analysis is required.  
 
As a common rule, whenever an imputation is implemented, the imputed date needs to be in 
the reasonable range of the event. In general, no imputation will be made when the year is 
missing (exceptions if any will be described in RAP Module 8). In case the imputation 
process results in a date that is not plausible given known key study dates, the imputed date is 
to be replaced with a date that is aligned with those known key dates. As an example, when 
imputing an AE start date results in a date prior to start of study treatment then the AE start 
date will be set to the study treatment start date. Or for example, if a date is known to be 
within the trial period and imputation makes it after the last known contact date, the last 
known contact date will be used. 
The details for the different scenarios will be specified in RAP module 8. 
 
4.7.4 
Cumulative dose 
Cumulative dose [mg] is defined as the total dose given during the study treatment exposure. 
For patients who did not take any drug the cumulative dose is by definition equal to zero.  
4.7.5 
 DI and RDI 
The following DI or planned DI (PDI) calculations apply for both PAN and 5-AZA.  For 5-
AZA, where the dose was given based on BSA, the cumulative dose or the total planned dose 
may need to be divided by BSA, in the calculation of DI or PDI depending on how actual 
dose information is collected in the database.  If the reported actual dose is already adjusted 
for BSA (e.g. the unit is mg/m2), then adjustment for BSA is not needed. It should be noted 


Novartis 
Confidential 
Page 41 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
that if RDI alone is being reported, the calculation of BSA (which appears in both the 
numerator and the denominator of the formula for RDI and hence cancels out), is not 
necessary. If BSA is not collected in the CRF then the weight provided at Day 1 of each cycle 
will be used to calculate the actual BSA (if needed) for each cycle as:  
Body Surface Area (Gehan and George):  
BSA [m2] =234.94*(height (cm)**0.422)*(weight(kg)**0.515)/10000. 
 
4.7.6 
Dose intensity over study period 
PAN and 5-AZA 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
[
]
[
]
[
]
∑
=
=
k
i
i
1
day
)
lengths
cycle
actual
(
mg
 
dose
 
Cumulative
mg/day
DI
 
and i =1,2,3,…,k are the indices for the cycle. 
For patients who did not take any drug the DI is by definition equal to zero. 
Note: 
(
)
∑
i
i
length
 
cycle
 
actual
may not be equal to the duration of the study treatment 
exposure. 
Planned dose intensity (PDI) for patients with non-zero duration of exposure is defined as 
follows: 
1. Last cycle length is shorter as or equal to the planned length 
[
]
[
]
[
]
∑
-
=
+
=
1
1
lentgh
cycle
last
actual
)
lengths
cycle
Planned
(
mg
 
dose
 
planned
Total
mg/day
PDI
k
i
i
day
 
i =1,2,3,…,k are the indices for the cycle. k is the actual total number of cycles 
2. Last cycle length is longer than planned 
[
]
[
]
[
]
∑
=
=
k
i
i
1
day
lengths)
cycle
Planned
(
mg
 
dose
 
planned
Total
mg/day
PDI
 
i =1,2,3,…,k are the indices for the cycle. k is the actual total number of cycles 
For patients who did not take any drug the PDI is by definition equal to zero. 
Relative dose intensity (RDI) is defined as follows: 
RDI [%] = DI [mg/day] / PDI [mg/day] * 100 
The definition and analysis will be applicable only for patients with non-zero PDI. 


Novartis 
Confidential 
Page 42 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Relative dose intensity will be summarized by compound.   This will be done by initial dose 
group of PAN for the phase Ib part and by treatment group for the phase IIb part.  
The number of patients who have dose reductions or interruptions, and the reasons, will be 
summarized by initial dose group of PAN for the phase Ib part and by treatment group for the 
phase IIb part . The instructions given to sites regarding completion of dose administration 
records are provided in the appendix and should be referred to when developing the program 
code or logic as appropriate. 
A continuous dose recording scheme (whereby a new entry is made only when there is a 
change/delay/interruption to the planned dose and schedule) is used for this study. For the 
purpose of dose intensity calculations, the following algorithm will be used to assign doses: 
- 
For 5-Aza: a dose will be assigned daily from start to end date 
 
- 
For PAN: 
o For records with a dose starting on any of the protocol days (3,5,8,10,12,15) 
=>  doses will be assigned on the days as per planned. 
 e.g.  if PAN started on C1D3 and ended on C1D14, 5 doses will be 
assigned (on days 3,5,8,10, and 12) 
 
o For records with doses starting on a non-protocol day => a dose will be 
assigned every other day, upto a maximum of 6 doses per cycle.  
 
4.8 
Concomitant therapy 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment, which were intentionally administered to a patient preceding or 
coincident with the study assessment period. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List to allow for categorization by preferred term. In addition to categorizing 
medication data by preferred term, drugs are classified according to their ATC classification 
in order to present and compare how they are being utilized. The ATC classification allows 
for the summary of medications by a high-level common drug class. 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
treatment will be listed and summarized by ATC class, preferred term.This will be done by 
the initial dose group of PAN in the phase Ib part and by treatment group in the phase IIb part.  
Separate summaries and listings will be generated for concomitant medications started prior to 
the start of study treatment, and those started after the start of study treatment.  
The safety set will be used for all concomitant medication summaries and listings.  


Novartis 
Confidential 
Page 43 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
4.8.1 
Concomitant medications with specific impact on the analysis 
4.8.1.1 
Further anti-neoplastic therapy 
Patients who take additional anti-neoplastic therapy before discontinuing study treatment (i.e., 
anti-neoplastic therapy other than study treatment) will be identified as protocol deviations. 
Their efficacy data will be censored so that response assessments made after the first intake of 
an anti-neoplastic drug will not be included in analyses.  
 
4.9 
Primary safety variable 
The primary safety variable is the incidence of DLT as observed in the phase Ib part. 
4.9.1 
Analysis of the primary safety variable 
There is no formal testing of statistical hypotheses. An adaptive Bayesian logistic regression 
model with overdose control will be used to guide the dose-escalation procedure. This model 
will be used to estimate probabilities for toxicity categories (underdosing, target toxicity, 
excessive and unacceptable toxicity) as taken from the posterior distribution. For details refer 
to the Post-text supplemental 1. The MTD-determining set is the primary analysis set.  
The probability for each of the toxicity classes will be provided for the determined MTD in 
terms of simulations as obtained by the BLRM.  
4.9.2 
Sensitivity and other supportive analyses 
None are planned. 
4.10 
Safety evaluation 
The assessment of safety will be based mainly on the frequency of AEs and on the number of 
laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
electrocardiogram, vital signs, special tests) will be considered as appropriate. Unless 
otherwise mentioned, all summary safety outputs (including deaths, adverse events, laboratory 
values, vital signs, ECGs, and ECOG performance status) will be reported by initial dose 
group of PAN for the phase Ib part and by treatment group for the phase IIb part, in addition 
to other groupings specified for that analysis.  
All safety outputs will use the safety set. The safety summary tables will include only 
assessments collected no later than 28 days after study treatment discontinuation. All safety 
assessments will be listed and those collected later than 28 days after study treatment 
discontinuation will be flagged. 
4.10.1 
Adverse events 
Coding of AEs 
AEs are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology version 16.0  or later. 


Novartis 
Confidential 
Page 44 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Grading of AEs 
AEs will be assessed according to the Common Terminology Criteria for AEs (CTCAE 
version 3.0 or later). If CTCAE grading does not exist for an AE, grades 1 – 4 corresponding 
to the severity of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 
(death) is not be used in studies; rather, this information will be collected in the “End of 
Treatment” or “Study Completion Evaluation” CRF pages.  
Reporting of AEs 
AE summaries will include all treatment emergent AEs starting on or after Study Day 1 (i.e. 
on or after the day of the first intake of study treatment) and starting no later than 28 days 
after study treatment discontinuation. All AEs will be listed. AEs starting prior to Study Day 1 
and AEs starting later than 28 days after study treatment discontinuation will be flagged in the 
listings. 
A patient with multiple occurrences of an AE will be counted only once in the respective AE 
category. 
AE summaries will be presented by primary system organ class, preferred term, and 
maximum CTC grade. A patient with multiple CTC grades for an AE category will be 
summarized under the maximum CTC grade recorded for the event. In the summaries 
presented by grade, all AEs will be pooled regardless of whether they are CTC gradable or not, 
i.e. regardless of whether the question “CTCAE” on the AEs CRF is answered ‘Yes’ or ‘No’. 
The frequency of all CTC grades and grade 3 and 4 AEs will be summarized separately. Any 
information collected (e.g. CTC grades, relatedness to study treatment, action taken etc.) will 
be listed as appropriate.  
Summaries of AEs with suspected relationship to study treatment will be provided. 
Deaths reportable as serious AEs (SAEs) and non-fatal SAEs will be listed by patient and 
tabulated.  
4.10.2 
AE summaries 
The following incidences of AE summaries will be produced: 
• AEs, regardless of study treatment relationship by primary system organ class and 
preferred term  
• AEs with suspected relationship to study treatment by primary system organ class, 
preferred term 
• AEs with an overall incidence rate of 10%, regardless of study treatment relationship by 
primary system organ class and preferred term  
• CTC grade 3 or 4 AEs, regardless of study treatment relationship by primary system organ 
class and preferred term  
• CTC grade 3 or 4 AEs with suspected study treatment relationship by primary system 
organ class and preferred term  
• Deaths up to 28 days after end of treatment by primary system organ class and preferred 
term  


Novartis 
Confidential 
Page 45 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
• Deaths after 28 days after end of treatment by primary system organ class and preferred 
term 
• Serious AEs, regardless of study treatment relationship, by primary system organ class 
and preferred term  
• AEs leading to study treatment discontinuation, regardless of study treatment relationship, 
by primary system organ class and preferred term  
• AEs requiring dose adjustment or study-treatment interruption, regardless of study 
treatment relationship, by primary system organ class and preferred term  
• AEs requiring additional therapy, regardless of study treatment relationship, by primary 
system organ class and preferred term. 
 
 
4.10.3 
Clinical notable AE 
Specific groupings of clinically notable AEs will be considered and the number of patients 
with at least 1 AE within each grouping will be reported. Such groups consist of AEs for 
which there is a specific clinical interest in connection with PAN (i.e. where PAN may 
influence a common mechanism of action responsible for triggering them) or which are 
similar in nature (although not identical). The groups are defined as per Table 4-2 below and 
in RAP Module 8.). These groupings are based on standardized MedDRA queries and 
Novartis MedDRA queries. A NMQ is a customized group of search terms which defines a 
medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit to the need.  It may include a combination of single terms and/or an existing 
SMQ, narrow or broad. 
Table 4-2 
Clinical notable AE 
Clinically notable adverse events grouping 
Source 
Identified risks 
 
  QT prolongation 
SMQ - Broad 
  Myelosuppression 
 
    Haematopoietic erythropenia 
SMQ – Broad 
    Haematopoietic cytopenias 
SMQ – Broad 
    Haematopoietic leukopenia 
SMQ – Broad 
    Haematopoietic thrombocytopenia 
SMQ - Broad 
  Hemorrhage 
SMQ - Narrow 
  Hepatic dysfunction  
SMQ - Broad 
  Renal dysfunction 
SMQ - Broad 
  Severe infections 
 
    Pneumonia 
NMQ - Broad [selected relevant PTs for 
infectious pneumonia] 
    Sepsis 
NMQ -  Broad [selected relevant PTs for 
infectious sepsis] 
Potential risks 
 


Novartis 
Confidential 
Page 46 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Clinically notable adverse events grouping 
Source 
  Acute pancreatitis 
NMQ - Broad [SMQ acute pancreatitis, excluding 
PTs for non-specific symptoms] 
  Cardiac failure 
SMQ - Narrow 
  Hypothyroidism 
SMQ - Broad 
  Interstitial lung disease  
SMQ – Broad 
  Ischemic colitis  
SMQ – Broad 
  Ischemic heart disease 
SMQ - Narrow 
  Reactivation of Hepatitis B infection 
NMQ – Broad [selected PTs including relevant 
serology tests] 
  Tachyarrhythmias  
NMQ - Broad [SMQ tachyarrhythmias (including 
supraventricular and ventricular) and additional 
selected PTs] 
  Venous Thromboembolism 
SMQ - Narrow 
  Pericardial effusion 
NMQ – Broad [selected relevant PTs for 
pericardial effusion] 
Further 
 
  Peripheral neuropathy 
SMQ  
  Asthenia / fatigue 
PT 
 
A summary of these clinical notable AEs will be provided by treatment group for the phase 
IIb part.  
 
4.10.4 
Laboratory data 
On analyzing laboratory assessments, data from all sources (central and local laboratories) 
will be combined. The summaries will include all laboratory assessments collected no later 
than 28 days after study treatment discontinuation. All laboratory assessments will be listed 
and those collected later than 28 days after study treatment discontinuation will be flagged in 
the listings. 
Laboratory data will be classified into CTC grades according to the NCI CTCAE. A severity 
grade of 0 will be assigned when the value is within normal limits. In the unlikely case when a 
local laboratory normal range overlaps into the higher (i.e. non-zero) CTC grade, the 
laboratory value will still be taken as within normal limits and assigned a CTC grade of zero. 
In case the lab presented blood counts as percentage of the total white blood cell count, the 
absolute blood counts will be derived. Both the percent blood count and the total white blood 
cell count have to be taken from the same blood sample. 
For all the differential counts, percentages will be converted to absolute values, if necessary, 
as 
Absolute value = (percentage * WBC) / 100 
 


Novartis 
Confidential 
Page 47 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
In order to derive the corresponding absolute normal range, the following scenarios 
(depending on the availability of the % range and the absolute range for the differential) will 
be considered: 
 
• 1st scenario: % range missing and absolute range missing 
Use pre-defined normal range reported in the Merck manual     
 
• 2nd scenario: % range missing and absolute range NOT missing 
Use the absolute range provided by the site  
 
• 3rd scenario: % range NOT missing and absolute range NOT missing 
Use the absolute range provided by the site  
 
• 4th scenario: % range NOT missing and absolute range missing 
Approved rule: the % normal limits (i.e. LLN and ULN) are divided by 100 and multiplied by 
the corresponding normal limits of WBC count, e.g. for neutrophils (NEU): 
• LLN for NEU count = (LLN for WBC count) * (LLN for NEU % / 100) 
• ULN for NEU count = (ULN for WBC count) * (ULN for NEU % / 100) 
 
The following summaries will be produced for the laboratory data (by laboratory variable): 
• Number and percentage of patients with worst post-baseline CTC grade (regardless of the 
baseline status). Each patient will be counted only for the worst grade observed post-
baseline. 
• Shift tables using CTC grades to compare baseline to the worst post-baseline value will be 
produced for hematology and biochemistry laboratory parameters with CTC grades. 
• For laboratory parameters where CTC grades are not defined (eg. thyroid hormones), shift 
tables to the worst post-baseline value will be produced using the low/normal/high 
classifications based on laboratory reference ranges.   
The number of granulocytes blood count will be calculated as sum of the neutrophil, basophil 
and eosinophil blood count. 
The following listings will be produced for the laboratory data: 
• Listing of patients with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative to 
the laboratory reference ranges 
• Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges.   
4.10.5 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
variables collected are:  


Novartis 
Confidential 
Page 48 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
• Weight [kg] 
• Body temperature [°C] 
• Heart rate [beats per minute] 
• Systolic and diastolic blood pressure [mmHg] 
• Respiratory rate [breaths per minute]. 
Patients with clinically notable vital sign abnormalities will be listed and assessments 
collected later than 28 days after study treatment discontinuation will be flagged in the listings. 
The criteria for clinically notable abnormalities are depicted in Table 4- and Table 4-4. 
Table 4-3 
Clinically notable elevated values 
Variable 
Criteria 
Systolic BP 
‡ 180 mmHg and an increase ‡ 20 mmHg from baseline 
Diastolic BP 
‡ 105 mmHg and an increase ‡ 15 mmHg from baseline. 
Body temperature 
‡ 39.1°C (102.3°F) 
Weight 
increase from baseline of ‡ 10% 
Heart rate 
‡ 120 bpm with increase from baseline of ‡ 15 bpm 
Respiratory rate 
≥ 30 breaths per minute 
Table 4-4 
Clinically notable below normal values 
Variable 
Criteria 
Systolic BP 
£ 90 mmHg and a decrease ‡ 20 mmHg from baseline 
Diastolic BP 
£ 50 mmHg and a decrease ‡ 15 mmHg from baseline 
Body temperature 
£ 35°C (95°F) 
Weight 
decrease from baseline of ‡ 10% 
Heart rate 
£ 50 bpm with decrease from baseline of ‡15 bpm 
Respiratory rate 
≤ 10 breaths per minute 
4.10.6 
Handling of missing values 
Any post-baseline AE with a missing grade will be substituted by grade 4.  
4.10.7 
ECG 
 
Definition of baseline and post-baseline QTcF 
4.10.7.1 Baseline definition 
Quantitative ECG: 
Baseline is defined as an average of all pre-dose ECGs performed on Cycle 1 Day 1 if 
available. Otherwise, the average of all pre-dose ECG measurements taken on most recent day 
prior to the start of study treatment within the protocol-defined time window is considered as 
baseline. Unscheduled visits are included. 


Novartis 
Confidential 
Page 49 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
Note: if the unscheduled visits have been done on Cycle 1 Day 1 but without time, these 
assessments will not be included in baseline derivation.  
Qualitative ECG: 
Baseline is defined as the last assessment (or set of assessments) prior to the first dose of 
study treatment within the protocol-defined time window. Unscheduled visits are included. 
4.10.7.2 Post-Baseline value  
All measurements taken after first dose of study treatment will be considered as post baseline. 
4.10.7.3 Population for analysis 
Quantitative ECG: 
Patients will be considered evaluable (included in “Total”) for outlier analysis if they are at 
risk at baseline and have at least one post-treatment ECG measurement. For change from 
baseline analyses they have to have at least one baseline ECG measurement and one post-
baseline measurement. 
A patient is considered at risk at baseline for the respective outlier category, if the baseline of 
this patient is: 
• Missing or ≤450 msec for category “New > 450 and ≤ 480 ms” 
• Missing or ≤480 msec for category “New > 480 and ≤ 500 ms” 
• Missing or ≤500 msec for category “New of > 500 ms” 
Qualitative ECG 
A patient is considered at risk for each individual finding if the baseline of the patient is: 
• Missing or with baseline being normal for that particular finding. 
4.10.7.4 QTcF prolongation summary 
Notable abnormalities will be summarized for the following: 
• an increase of 30- 60 ms compared to baseline 
• an increase of > 60 ms compared to baseline 
• patients with any value of > 450 ms and ≤ 480 ms 
• patients with any value of > 480 ms and ≤ 500 ms 
• patients with any value of > 500 ms 
For outlier abnormalities, similar analysis will be made excluding missing baseline (optional). 
For the following Quantitative ECG summaries, the patients with baseline and with at least 
one post baseline value will be included. 
4.10.7.5 Qualitative ECG summary 
Summary of newly occuring of All qualitative ECG findings will be reported: 
• Including missing baseline values 


Novartis 
Confidential 
Page 50 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
• Excluding missing baseline values (optional) 
 
4.10.8 
ECOG performance status 
ECOG PS scale is used to assess physical health of patients, ranging from 0 (most active) to 5 
(least active): 
Table 4-5 
ECOG performance scale 
Score 
Description 
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 
 
Shift tables comparing the baseline performance status with the worst result during study will 
be summarized. 
4.11 
 Efficacy analysis 
4.11.1 
Efficacy analysis for the phase Ib part  
 Listing of the data on 
response variables as assessed by the investigator will be provided.  
The best overall response as categorized by the criteria used and assessed by the investigator 
will be reported by patient. These assessments will be performed for all patients of the FAS 
and results will be presented per initial dose group of PAN in tabular form. Point estimates 
and 95% CIs according to Clopper-Pearson will be provided for best response based on the 
FAS. 
 
4.11.2 
Efficacy analysis for the phase IIb part 
The primary efficacy endpoint will be the composite CR (CR or CRi or bone marrow CR) 
among all patients in the FAS.  
The following efficacy endpoints will be considered.  
• Clinical response for AML: CR, CRi, PR 
• Clinical response for MDS/CMML: CR, bone marrow CR, PR and Hematologic 
Improvement (HI) 


Novartis 
Confidential 
Page 51 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
• 1-year survival rate 
• Time to Progression (TTP) 
No formal statistical test comparing the two arms will be done on any of the endpoints since 
the study was not powered to do that. 
4.11.2.1 Clinical response for AML and MDS/CMML 
 
Clinical responses will be summarized by treatment arm, overall and within disease type (i.e. 
AML or MDS/CMML). Percentage rates for the composite CR rate (CR or CRi or bone 
marrow CR), overall response rate (CR or CRi or bone marrow CR or PR) will be reported 
along with 95% confidence intervals for both arms. Exact binomial confidence interval 
(implemented using SAS procedure FREQ with EXACT statement for one-way tables) will be 
calculated Clopper and Pearson 1934. Point estimates and confidence intervals for the 
difference in rates between the treatment arms will also be reported.  
4.11.2.2 1-year survival rate 
The 1-year survival rate will be obtained from the Kaplan-Meier analysis of overall survival, 
and its variance will be estimated by Greenwood’s formula. Overall survival is defined as the 
time from date of randomization to date of death due to any cause. If a patient is not known to 
have died, survival will be censored at the date of last contact. Patients not known to have 
died will be censored for ‘Lost to follow-up’ if the time between their last contact date and the 
analysis cut-off date is longer than 3 months and 2 weeks (104 days) during the first year after 
study evaluation completion, and longer than 6 months and 2 weeks (194 days), thereafter. 
This takes into account the fact that survival follow-up is every 3 months during the first year 
after completion of study evaluation, and every 6 months thereafter, and allows for a window 
of 2 weeks to accommodate reasonable delays in reporting. 
4.11.2.3 Time to Progression (TTP) 
Time to progression (TTP) is defined as the time from the date of randomization to the date of 
the first documented PD per investigator’s assessment or death due to study indication. Time 
to progression will be analyzed by the Kaplan Meier method. The 25th, 50th (median), and 
75th percentiles of the TTP and the 2-sided 95% CIs will be reported for both arms. 
The event and censoring times for TTP are depicted in Table 4-6 below. 
 
Table 4-6 
Event and censoring dates used in TTP 
 
Situation 
 End-date 
 
Outcome
A 
No baseline assessment  
Date of randomization 
Censor 
B 
PD/relapse at scheduled assessment 
date or before next scheduled 
assessment 
Date of PD/relapse 
Event 


Novartis 
Confidential 
Page 52 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
 
Situation 
 End-date 
 
Outcome
C1 
PD/relapse or death due to study 
indication after exactly one missing 
assessment 
Date of PD/relapse/death  
Event 
 
C2 
PD/relapse or death due to study 
indication after two or more missing 
assessments 
Date of last adequate assessment 
before PD/relapse or death due to 
study indication (i.e. before the 2 or 
more missing assessments) 
Censor 
 
 
 
 
 
 
D 
No PD/relapse/death due to study 
indication 
Date of last adequate assessment1  
Censor 
E 
Treatment discontinuation due to 
‘Disease PD/relapse’ without 
documented PD/relapse, i.e. clinical 
PD/relapse based on investigator 
claim  
N/A 
 
 
Ignored 
 
 
F 
New anticancer therapy given2 
Date of last adequate assessment 
before start of new anticancer 
therapy 
Censor 
 
 
 
 
1 In case there is no adequate assessment, the end date is the date of randomization 
2 New anticancer therapy given without documented evidence of PD/relapse  
 
  
4.11.3 
Kaplan-Meier analysis 
The analysis will be conducted via use of the SAS procedure LIFETEST where statement 
STRATA will include only the treatment group variable (trt in the example below). The 
TIME statement will include a variable with survival times (survtime in the example below) 
and a (right) censoring variable (censor in the example below) with one representing 
censoring: 
PROC 
LIFETEST 
data=dataset 
 
TIMELIST=t1 
t2 
t3 
METHOD=KM 
CONFTYPE=LOGLOG;  
TIME survtime*censor(1); 
STRATA trt; 
RUN; 


Novartis 
Confidential 
Page 53 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
• 
survtime represents variable containing event/censor times    
• 
censor represents censoring variable (1=censored, 0=event)  
• 
trt represents treatment group variable 
• 
t1, t2, and t3 represent the times at which survival estimates 
are to be reported, e.g. at 6 months, 9 months, and 1 year, say. 
 
 
 
4.11.4 
Handling of missing values/discontinuations 
Patients with best overall response of ‘Unknown’ by the respective efficacy criteria will be 
treated as non-responders in the calculation of the objective response rate in the full analysis 
set. 
4.11.5 
Transfusions 
The total number of transfusion units by patient will be summarized by transfusion type 
indication (MDS/CMML, AML) and  adjusted for the respective study period. This will be 
done by the initial dose group of PAN for patients in the phase Ib part and by treatment group 
for patients in the phase IIb part. 
 
Number of units of transfusion of a specific type, for a patient, adjusted for the study period =  
(Total number of transfusion units of the specific type during the on-treatment period) / (on-
treatment period in months) 
where on-treatment period is defined as the following time interval: 
[date of first administration of study treatment; date of last administration of study 
treatment +28 days], i.e. inclusive of the lower and upper limits.   
 
Transfusion-dependence will be assessed throughout the study. At baseline, a patient is to be 
considered transfusion-dependent if he/she has had an infusion of 4 or more units within the 8 
weeks preceding treatment and 1 of those units was administered within 1 week immediately 
preceding treatment.  
Post-baseline, a patient is considered not to be transfusion dependent until the start of the first 
transfusion notwithstanding transfusions during baseline. After start of treatment, a period of 
7 days without any transfusion would define a patient as transfusion-independent. 
Bone marrow assessment 
Bone marrow variables as assessed by aspirate and/or biopsy will be listed. Differential cell 
counts as provided by aspirate will be listed by initial dose group of PAN in the phase Ib part 
and by treatment group in the phase IIb part.  The last measurement per cycle will be used in 


Novartis 
Confidential 
Page 54 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
case of more than 1 assessment per cycle. In this case, all variables need to be from the same 
sample. 
The differential cell counts include the following variables which will be listed: 
Bone marrow aspirate 
• Blasts [%] 
• Promyelocytes [%] 
• Metamyelocytes [%] 
• Bands [%] 
• Neutrophil [%]s 
• Eosinophils [%] 
• Basophils [%] 
• Lymphocytes [%] 
• Monocytes [%] 
• Pronormoblasts/Proerythroblasts [%] 
• Normoblasts/Erythroblasts [%] 
• Plasma Cells [%] 
• Other [%] 
Bone marrow biopsy 
• Blasts [%] 
The following variables will be listed: 
Bone marrow aspirate 
• Was the specimen adequate for assessment (yes/ no) 
• if no: Dry tap/ hemodiluted/ other 
• Are the differential results from smear/ touch imprints? (yes/ no) 
• Auer rods present? (yes/no) 
• Myeloid/ erythroid ratio 
• Erythroid cells (absent/ decreased/ normal/ increased/ unknown, not done) 
• Myeloid cells (absent/ decreased/ normal/ increased/ unknown, not done) 
• Megakaryotype cells (absent/ decreased/ normal/ increased/ unknown, not done) 
• Dysplasia (no/ yes) 
• If yes: erythroid/ myeloid/ megakaryocyte 
• Cellularity done (yes/ no) 
• If yes:  
• aplastic 
• hypocellular (mild/ moderate/ severe) 
• normocellular 
• hypercellular (mild/ moderate/ severe) 


Novartis 
Confidential 
Page 55 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
• not available 
Bone marrow biopsy 
• Was the specimen adequate for assessment (yes/ no) 
• Auer rods present? (yes/no) 
• Cellularity done (yes/ no) 
• If yes:  
• aplastic 
• hypocellular (mild/ moderate/ severe) 
• normocellular 
• hypercellular (mild/ moderate/ severe) 
• not available 
• Cellularity available? (yes/ no) 
• If yes: 
• %age of cellularity 
• Megakaryotype cells (absent/ decreased/ normal/ increased/ unknown, not done) 
• Dysplasia (no/ yes) 
• If yes: erythroid/ myeloid/ megakaryocyte 
4.12 
Handling of missing values/discontinuations 
Patients with best overall response of ‘Unknown’ by the respective efficacy criteria will be 
treated as non-responders. 
Missing values for CTC grading of AEs and laboratory values at baseline will be set to CTC 
grade 0. 
4.13 
Subgroup analysis 
Not applicable. 
4.14 
Pharmacokinetic analyses 
Plasma PAN levels collected during Cycle 1 of the phase Ib part of the study, on Days 4, 5, 
and 8 will be summarized by study day. Pre-dose levels of PAN (Cmin values) will be 
summarized at the study conclusion by study day and actual dose group of PAN. Values 
below the lower limit of quantification (LLOQ) of approximately 0.5 ng/mL will be reported 
as 0 ng/mL. Missing values will be labeled accordingly. 


Novartis 
Confidential 
Page 56 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
 
4.16 
Interim analyses 
Not applicable. 
5 
References 
[Babb J, Rogatko A, Zacks S (1998)] Cancer Phase I clinical trials: efficient dose escalation 
with overdose control. Stat Med; 17: 1103-1120   
[Cheson B, Bennet JM, Kopecky K, et al (2003)] Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. 
Journal of Clinical Oncology; 21(24):4642-4649 
[Cheson BD, Greenberg PL, Bennet JM, et al (2006)] Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood (108):419-425 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 57 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
 
 
 
6 
Appendix 
 
A1 
Instructions given to sites for completion of the DAR forms 
1. GENERAL INSTRUCTIONS  
- In general, the site must enter at least 1 record per cycle 
- For patient WITHOUT dose delay/interruption, it is acceptable to have just one record for 
the cycle, with start date = day1/ 3 and end date = day 7/15 of the cycle for 5-Aza/Pan   
- Planned dose is always the dose defined by the protocol (30 mg for Panobinostat for phase II, 
75 mg/m2 for Vidaza). The most important is the first planned dose (C1D1 for 5-Aza and 
C1D3 for PAN). Note: for phase I, PAN could be from  10-60mg 
 
2. DOSE CHANGE  
Dose Change: To decide whether the dose was changed or not, it must be compared to 
previous non-zero dose received (and not to the planned dose) 
Example:            
Administration 1: Planned Dose 30 mg, Actual Dose 30 mg (Dose Change = No) 
Administration 2: Planned Dose 30 mg, Actual Dose 20 mg (Dose Change = Yes) 
Administration 3: Planned Dose 30 mg, Actual Dose 20 mg (Dose Change = No) 
Administration 4: Planned Dose 30 mg, Actual Dose 0 mg (Dose Change = No – e.g. 
interruption, see below) 
Administration 5: Planned Dose 30 mg, Actual Dose 20 mg (Dose Change = No) 
 
3. DOSE DELAY 
There are two situations to be considered in this study: 
• 
Situation 1: Delay of a cycle (duration>28 days)  
If the cycle is >28 days, Day 29 to the end of the cycle will be considered as dose delay and 
one record with 0 dose should be entered 
Example: cycle start date is 1-April-2013 and end of cycle is 5-May-2013, 3 records should be 
entered: 
a. For 5-Aza: 


Novartis 
Confidential 
Page 58 
RAP Module 3 
28-Oct-2014 
CLBH589H2101 
 
1. 1-April-2013 – 7-April-2013, dose delay=no, dose change=no, planned dose=75mg/m2, 
actual dose=75mg/m2 
2. 29-April-2013 – 5-May-2013, dose delay=yes, dose change=no, planned dose=75mg/m2, 
actual dose=0mg/m2 
3. 6-May-2013 – 12-May-2013, dose delay=no, dose change=no, planned dose=75mg/m2, 
actual dose=75mg/m2 
 
b. For Pan: 
1. 3-April-2013 – 15-April-2013, dose delay=no, dose change=no, planned dose=30mg, actual 
dose=30mg 
2. 29-April-2013 – 7-May-2013, dose delay=yes, dose change=no, planned dose=30mg, 
actual dose=0mg 
3. 8-May-2013 – 20-May-2013, dose delay=no, dose change=no, planned dose=30mg, actual 
dose=30mg 
 
• 
Situation 2: Dose interruption: 
If one or more administrations have been skipped in one cycle, they must be considered as 
Dose Delays (there is no option for Interruption in the CRF).   
Example:  5-Aza Cycle starts on 20-Jan-13, dose not administered on 23-Jan and 24-Jan, 
cycle ends on 26-Jan-13). Three records are needed:    
1) enter the actual dose received, the true start date and the date of the last administration 
before the interruption (e.g. 20-Jan-2013 – 22-Jan-2013) 
2) enter actual dose = 0 mg, select dose Change = No and Dose delay = Yes, and the start and 
end date of the interruption (e.g. 23-Jan-2013 – 24-Jan-2013) 
3) enter the actual dose received, the date of the restart of the treatment and the true end date 
(e.g. 25-Jan-2013 – 26-Jan-2013)