Clinical trial NCT01787552
Conditions: Primary Myelofibrosis Thrombocytosis Essential Thrombocythemia Polycythemia Vera Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Blood Coagulation Disorders Blood Platelet Disorders Hemorrhagic Disorders
Keywords: Dose escalation Maximum Tolerated Dose MTD Safety Expansion Safety Efficacy Myelofibrosis Post-polycythemia vera myelofbrosis (Post PV-PMF) Post essential thrombocythemia myelofibrosis (Post ET-MF) Primary myelofibrosis (PMF) Intermediate risk myelofibrosis High risk myelofibrosis Combination Treatment Hedgehog Signaling Pathway Smoothened inhibitor JAK inhibitor
Sponsor: Novartis Pharmaceuticals
Start date: 2013-05-08; Completion date: 2018-04-10
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this phase Ib/II clinical trial was to: a) evaluate the safety of the co-administration of LDE225 and INC424 in myelofibrosis patients and establish a maximum tolerated dose and/or Recommended Phase II dose of the combination and b) to assess the efficacy of the co-administration of LDE225 and INC424 on spleen volume reduction.

Detailed description:
The study is considered to have been completed because the participants completed the study as per study design at the time of trial termination. If participants were already in extension phase until discontinuation criteria were met or alternative setting was available, they were considered as completed. The study was terminated due to one of the compounds being divested.

Arms: arm 1: LDE225 and INC424 in combination
Interventions: intervention 1: LDE225 intervention 2: INC424
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 
Clinical Development
LDE225 (Sonidegib) and INC424 (Ruxolitinib)
Oncology Clinical Protocol CLDE225X2116 / NCT01787552
A Phase Ib/II, open-label, multi-center, dose-finding study 
to assess the safety and efficacy of the oral combination of 
LDE225 and INC424 (Ruxolitinib) in patients with 
myelofibrosis
Authors
Document type
Amended Protocol Version (Clean)
EUDRACT number
2012-004023-20
Version number
02
Development phase
Ib/II
Document status
Final
Release date
26-Feb-2015
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Protocol No. CLDE225X2116
Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Amendment 2 ....................................................................................................................13
Protocol summary..............................................................................................................20
1
Background........................................................................................................................24
1.1
Overview of myelofibrosis and current treatment options ....................................24
1.2
Role of hedgehog signaling in cancer....................................................................25
1.3
Janus kinases (JAKs) in myelofibrosis..................................................................26
1.4
Introduction to investigational treatment(s) and other study treatment(s).............27
1.4.1
Overview of LDE225............................................................................27
1.4.2
Overview of INC424 (ruxolitinib) ........................................................35
2
Rationale............................................................................................................................42
2.1
Study rationale and purpose...................................................................................42
2.2
Rationale for the study design ...............................................................................43
2.3
Rationale for dose and regimen selection..............................................................44
2.4
Rationale for choice of combination drugs............................................................44
3
Objectives and endpoints...................................................................................................45
4
Study design ......................................................................................................................49
4.1
Description of study design ...................................................................................49
4.1.1
Phase Ib dose escalation and safety expansion .....................................50
4.2
Timing of interim analyses and design adaptations...............................................51
4.3
Definition of end of the study................................................................................51
4.3.1
End of study treatment ..........................................................................51
4.3.2
End of study ..........................................................................................52
4.4
Early study termination..........................................................................................52
5
Population..........................................................................................................................52
5.1
Patient population..................................................................................................52
5.2
Inclusion criteria ....................................................................................................53
5.3
Exclusion criteria...................................................................................................53
6
Treatment...........................................................................................................................56
6.1
Study treatment......................................................................................................56
6.1.1
Dosing regimen.....................................................................................56


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6.1.2
Ancillary treatments..............................................................................57
6.1.3
Rescue medication ................................................................................57
6.1.4
Guidelines for continuation of treatment ..............................................57
6.1.5
Treatment duration................................................................................57
6.2
Dose escalation guidelines.....................................................................................58
6.2.1
Starting dose rationale...........................................................................58
6.2.2
Provisional dose levels..........................................................................58
6.2.3
Guidelines for dose escalation and determination of MTD and/or 
RPIID ....................................................................................................59
6.2.4
Dose cohort modification......................................................................61
6.2.5
Definitions of dose limiting toxicities (DLTs)......................................62
6.3
Dose modifications................................................................................................63
6.3.1
Dose modification and dose delay ........................................................63
6.3.2
Follow-up for toxicities.........................................................................68
6.3.3
Anticipated risks and safety concerns of the study drug.......................70
6.4
Concomitant medications ......................................................................................70
6.4.1
Permitted concomitant therapy .............................................................70
6.4.2
Permitted concomitant therapy requiring caution and/or action...........70
6.4.3
Prohibited concomitant therapy ............................................................71
6.5
Patient numbering, treatment assignment or randomization .................................73
6.5.1
Patient numbering .................................................................................73
6.5.2
Treatment assignment or randomization...............................................73
6.5.3
Treatment blinding................................................................................73
6.6
Study drug supply..................................................................................................73
6.6.1
Study drug preparation and dispensation..............................................73
6.6.2
Study drug packaging and labeling.......................................................74
6.6.3
Drug supply and storage........................................................................74
6.6.4
Study drug compliance and accountability ...........................................75
6.6.5
Disposal and destruction .......................................................................76
7
Visit schedule and assessments .........................................................................................76
7.1
Study flow and visit schedule................................................................................76
7.1.1
Screening...............................................................................................83
7.1.2
Treatment period...................................................................................85
7.1.3
Discontinuation of Study Treatment.....................................................85
7.1.4
Withdrawal of Consent .........................................................................87
7.1.5
Follow-up for Safety Evaluations .........................................................87


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7.1.6
Lost to follow-up...................................................................................87
7.2
Assessment types...................................................................................................88
7.2.1
Efficacy assessments.............................................................................88
7.2.2
Safety and tolerability assessments.......................................................90
7.2.3
Pharmacokinetics ..................................................................................94
7.2.4
Biomarkers............................................................................................97
7.2.5
Resource utilization...............................................................................98
7.2.6
Patient reported outcomes (PROs)........................................................98
8
Safety monitoring and reporting......................................................................................100
8.1
Adverse events.....................................................................................................100
8.1.1
Definitions and reporting ....................................................................100
8.1.2
Laboratory test abnormalities..............................................................101
8.2
Serious adverse events.........................................................................................102
8.2.1
Definitions...........................................................................................102
8.2.2
Reporting.............................................................................................102
8.3
Emergency unblinding of treatment assignment .................................................103
8.4
Pregnancies..........................................................................................................104
8.5
Warnings and precautions....................................................................................104
8.6
Data Monitoring Committee................................................................................104
8.7
Steering Committee .............................................................................................104
9
Data collection and management.....................................................................................104
9.1
Data confidentiality .............................................................................................104
9.2
Site monitoring ....................................................................................................105
9.3
Data collection.....................................................................................................106
9.4
Database management and quality control..........................................................106
10 Statistical methods and data analysis ..............................................................................107
10.1
Analysis sets ........................................................................................................107
10.1.1
Full Analysis Set .................................................................................107
10.1.2
Safety Set ............................................................................................107
10.1.3
Dose-determining analysis set.............................................................108
10.1.4
Pharmacokinetic analysis set...............................................................108
10.1.5
Biomarker analysis set ........................................................................108
10.2
Patient demographics/other baseline characteristics ...........................................109
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................109
10.3.1
Study treatment ...................................................................................109
10.3.2
Concomitant therapies.........................................................................109


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10.3.3
Compliance .........................................................................................109
10.4
Primary objective.................................................................................................109
10.4.1
Variable...............................................................................................109
10.4.2
Statistical hypothesis, model, and method of analysis........................110
10.4.3
Handling of missing values/censoring/discontinuations.....................112
10.4.4
Supportive analyses.............................................................................112
10.5
Secondary objectives ...........................................................................................112
10.5.1
Safety...................................................................................................112
10.5.2
Pharmacokinetics ................................................................................114
10.5.3
Biomarkers..........................................................................................115
10.5.4
Patient Reported Outcomes (Seven-day modified MFSAF v2.0 and 
EORTC QLQ-C30).............................................................................117
117
10.7
Interim analysis....................................................................................................119
10.8
Sample size calculation........................................................................................120
10.9
Power for analysis of key secondary variables....................................................121
11 Ethical considerations and administrative procedures ....................................................121
11.1
Regulatory and ethical compliance......................................................................121
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................121
11.3
Informed consent procedures...............................................................................121
11.4
Discontinuation of the study................................................................................122
11.5
Publication of study protocol and results.............................................................122
11.6
Study documentation, record keeping and retention of documents.....................122
11.7
Confidentiality of study documents and patient records .....................................123
11.8
Audits and inspections.........................................................................................123
11.9
Financial disclosures............................................................................................123
12 Protocol adherence ..........................................................................................................123
12.1
Amendments to the protocol................................................................................123
13 References (available upon request)................................................................................125
14 Appendices ......................................................................................................................128
14.1
Appendix 1: List of prohibited concomitant medications and concomitant 
medications requiring caution..............................................................................128
14.1.1
Concomitant medications requiring caution .......................................128
14.1.2
Prohibited co-medications...................................................................129
14.2
Appendix 2: Eastern Cooperative Group Performance Scale..............................130
14.3
Appendix 3: Seven-Day Modified Myelofibrosis Symptom Assessment Form 
v2.0 ......................................................................................................................130


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14.4
Appendix 4: EORTC QLQ C-30.........................................................................131
14.5
Appendix 5: MDRD-eGFR Formula...................................................................133
14.6
Appendix 6: Hepatic encephalopathy grading according to West Haven 
Criteria.................................................................................................................133
133
133
134
138
139
140
143
List of figures
Figure 1-1
Schematic representation of the JAK pathway .....................................27
Figure 1-2
Schematic representation of Smo activation of the Hh pathway ..........28
34
Figure 1-4
Pk-Gli1 inhibition relationship to LDE225...........................................35
Figure 4-1
Study design..........................................................................................49
List of tables
Table 1-1
Median survival of MF patients according to risk category .................24
Table 1-2
Incidence of dose limiting toxicities in study CLDE225X2101 ...........31
Table 1-3
Adverse events suspected to be related to LDE225 by preferred 
term, occurring in 5% or more of patients in study 
CLDE225X2101 ...................................................................................31
Table 1-4
Anti-tumor activity in adult patients with recurrent 
medulloblastoma ...................................................................................32
Table 1-5
PK parameters of LDE225 in adult patients with advanced solid 
tumors....................................................................................................33
Table 1-6
Volumetric spleen reduction of >/= 35% from baseline to Week 24 
(INCB 18424-351) and Week 48 (CINC424A2352)............................39
Table 3-1
Objectives and related endpoints ..........................................................46
Table 6-1
Dose and treatment schedule.................................................................56
Table 6-2
Provisional dose levels..........................................................................59
Table 6-3
Criteria for defining dose-limiting toxicities.........................................62


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Table 6-4
Criteria for interruption and re-initiation of INC424 and LDE225 
treatment................................................................................................65
Table 6-5
Recommended LDE225 dose modifications and dose delays for 
suspected treatment-related muscle toxicities.......................................67
Table 6-6
Dose restart guidelines and allowed maximum doses for patients 
who have previously interrupted dose for grade 4 
thrombocytopenia and grade 4 neutropenia ..........................................68
Table 6-7
Follow-up evaluations for selected toxicities........................................69
Table 6-8
Preparation and dispensing ...................................................................74
Table 6-9
Packaging and labeling .........................................................................74
Table 6-10
Supply and storage of study treatments ................................................75
Table 7-1
Visit evaluation schedule ......................................................................77
Table 7-2
Visit evaluation schedule for Extension Phase (after Week 105 Day 
1) ...........................................................................................................81
Table 7-3
Spleen volumetric imaging (MRI/CT) collection plan .........................88
Table 7-4
Fibrosis grading.....................................................................................89
Table 7-5
Bone marrow collection plan ................................................................90
Table 7-6
Local clinical laboratory parameters collection plan ............................92
Table 7-7
Pharmacokinetic blood collection log: Phase Ib and Phase II, Stage 
1.............................................................................................................94
Table 7-8
Pharmacokinetic collection log for bone marrow aspirate PK and 
corresponding blood collection PK for LDE225: Phase II, Stage 1 
or Stage 2...............................................................................................96
Table 7-9
Pharmacokinetic blood collection log: Phase II, Stage 2......................96
Table 7-10
Biomarker sample collection plan.........................................................98
Table 7-11
MFSAF v2.0 and EORTC QLQ-C30 collection plan.........................100
Table 10-1
Prior specifications..............................................................................110
Table 10-2
The analysis for the list of secondary objectives ................................112
Table 10-3
Noncompartmental pharmacokinetic parameters for LDE225 
(Phase Ib and Phase II Stage 1 only)...................................................114
Table 10-4
Noncompartmental pharmacokinetic parameters for INC424 (Phase 
Ib and Phase II Stage 1 only) ..............................................................114
117
Table 10-6
Predictive probability of observing response rate of 50% (n=18) or 
greater in the FAS at the primary analysis (46 patients) under 
different interim results.......................................................................120
Table 10-7
Decision of operating characteristics for the primary endpoint of 
CLDE225X2216 study design ............................................................120


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Table 14-1
Medications that are known substrates of BCRP to be used with 
caution.................................................................................................128
Table 14-2
List of weak CYP3A inducers or inhibitors to be used with caution..128
Table 14-3
List of CYP2B6 and 2C9 substrates to be used with caution .............128
Table 14-4
List of permitted antifungal and antibiotic agents to be used with 
caution.................................................................................................129
Table 14-5
List of prohibited CYP3A inducers or inhibitors................................129
Table 14-6
List of prohibited CYP2B6 and CYP2C9 substrates with narrow 
therapeutic index.................................................................................129
Table 14-7
List of prohibited antifungal and antibiotic agents .............................129
Table 14-8
ECOG (WHO) Performance Status ....................................................130
Table 14-9
Incidence of dose limiting toxicities in study CLDE225X2101 .........135
Table 14-10
Parameter matching quantiles for CLDE225X2101 study..................136
Table 14-11
Historical DLT data for JAK inhibitor naive from ruxolitinib 
studies..................................................................................................136
Table 14-12
Parameter matching quantiles for JAK inhibitor naive from 
ruxolitinib studies................................................................................137
Table 14-13
Prior parameters obtained for CLDE225X2116 .................................138
Table 14-14
Provisional dose levels........................................................................139
Table 14-15
Probabilities of DLT based on prior only ...........................................139
Table 14-16
Probabilities of DLTs at various dose-levels under 5 scenarios .........141
Table 14-17
Simulated operating characteristics.....................................................143
Table 14-18
Hypothetical dose escalation scenarios (H: Platelet number greater 
than 200X109/L, L: Platelet number less than or equal to 
200X109/L)..........................................................................................143


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List of abbreviations
µM
Micromolar
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT
AML
Acute Myeloid Leukemia
ANC
Absolutely Neutrophil Count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT
AUC
Area under the concentration-time curve
AUC0-24h
Area under the concentration-time curve from zero up to 24 hours
AUC0-168h
Area under the concentration-time curve from zero up to 168 hours
AUClast
Area under the concentration-time curve from time zero to the time of last measurable 
concentration
AUCinf
Area under the concentration-time curve from time zero to infinity with extrapolation of the 
terminal phase
BAT
Best Available Therapy
BCC
Basal Cell Carcinoma
BCRP
Breast cancer resistance protein
BID
bis in diem/twice a day
BLRM
Bayesian Logistic Regression Model
BUN
Blood Urea Nitrogen
CDP
Clinical Development Plan
CK
Creatine Phosphokinase
Cmax
Maximum plasma concentration after administration
Cmin, Ctrough
Minimum (pre-dose) plasma concentration after administration
CML
Chronic myelogenous leukemia
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSC
Cancer Stem Cell
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450 Genes
DDS
Dose Determining Set
DHH
Desert Hedgehog
DHEA
Dehydroepiandrosterone
DLT
Dose Limiting Toxicity
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form
Emax
Maximum possible effect
EOT
End of treatment
ET
Essential Thrombocythemia
EU
European Union


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EWOC
Escalation with Overdose Control
FAS
Full Analysis Set
FDG-PET
Fluorodeoxyglucose Positron Emission Tomography
FSH
Follicle Stimulating Hormone
G
Grade
G-CSF
Granulocyte colony-stimulating factor
GI
Gastrointestinal
Gli
Glioma-associated oncogene homolog
GLP
Good Laboratory Practice
GPCR
G protein-coupled receptor-like
HEPM
Human embryonic palatal mesenchymal
Hh
Hedgehog
i.v.
intravenous(ly)
IC50
Half maximal inhibiting concentration
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHH
Indian Hedgehog
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IUD
intrauterine device
JAK
Janus kinases
JAK1
Janus kinase 1
JAK2
Janus kinase 2
Ki
Inhibition constant
LFS
Leukemia-Free Survival
LMWH
Low Molecular Weight Heparin
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation
MB
Medulloblastoma
MF
Myelofibrosis
MFSAF
Myelofibrosis Symptom Assessment Form
MPN
Myeloproliferative neoplasm
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic acid
MRP
Multi drug Resistance Protein
MTD
Maximum Tolerated Dose
NIH
National Institutes of Health
nM
Nanomolar
o.d.
omnia die/once a day
ORR
Overall Response Rate
OS
Overall Survival
PD
Pharmacodynamics
PD
disease progression
P-gp
P-glycoprotein
PHI
Protected Health Information
PK
Pharmacokinetics


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PMF
Primary Myelofibrosis
PMR
partial metabolic response
PML
Progressive Multifocal Leukoencephalopathy
p.o.
per os/by mouth/orally
Post-PV MF
Post-polycythemia vera myelofibrosis
Post-ET MF
Post-essential thrombocythemia myelofibrosis
PR
Partial Response
PRO
Patient Reported Outcome
PT
Prothrombin time (PT)
PTCH
protein Patched
PTT
Partial thromboplastin time (PTT)
PV
Polycythemia vera
QC
Quality Control
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia's formula
QoL
Qualiity of Life
RAP
The Report and Analysis Plan
RDC
Remote Data Capture
RDE
Recommended dose for expansion
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
RMS
Rhabdomyosarcoma
RPIID
Recommended phase two dose
qRT-PCR
Quantitative reverse Transcriptase Polymerase Chain Reaction
RU
Resource Utilization
SAE
Serious Adverse Event
SCLC
Small Cell Lung Cancer
SD
Stable Disease
sFRP1
secreted frizzled-related protein
SHH
Sonic Hedgehog
Smo
Smoothened
SOC
Standard of Care
SOP
Standard Operating Procedure
STAT
Signal transducer and activator of transcription
SuFu
Suppressor of fused
TK
Toxicokinetics
Tmax
Time to reach the highest concentration
TM3
Testicular Mouse (Leydig) cell line
ULN
Upper Limit of Normal
Vss
Volume of Distribution at steady state
WBC
White blood cell count


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes approved 
drugs used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by 
the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to one 
of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study End / Study 
Completion
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Treatment group
A treatment group defines the dose and regimen or the combination, and may consist 
of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points
Withdrawal of Consent
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 
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Amendment 2
Amendment rationale
As of 06 February 2015, 57 patients were screened, 50 patients treated (30 in the Phase Ib part 
and 20 in the Stage 1, Phase II part), and 7 patients were screen failures. Fourteen of the 
treated patients have discontinued treatment due to disease progression, adverse events, 
physician decision or patient decision. The RPIID was confirmed as the 400mg LDE225 QD 
+ 20mg INC424 BID dose level. Patients enrolled in the Stage 1, Phase II part of the study are 
currently being observed for 24 weeks, and an interim analysis will occur at the end of the 
observation period.
The purpose of this protocol amendment is to add a treatment extension phase for patients 
who complete 2 years of study treatment and are deriving clinical benefit according to the 
investigator until other alternatives to receive study treatment from the sponsor become 
available. Currently no patients have completed 2 years of study treatment. 
The amendment also includes other revisions and administrative changes for clarification 
purposes.
Changes to the protocol:
The following sections have been changed in the amended protocol:
Title page: Author list updated.
Glossary of terms updated.
Protocol summary updated
Section 1.4.1.2.1: Updated number of patients exposed to LDE225
Section 1.4.2: Updated INC424 indications to add PV; updated number of countries where 
INC424 is approved
Section 1.4.2.2: Updated number of patients exposed to INC424
Section 1.4.2.2.1: Updated the safety information for ruxolitinib per most recent IB
Figure 4-1 updated to reflect addition of extension phase
Section 4.1.1 and 4.3.1: Revised to include extension phase 
Section 4.2.1: section removed since updated information is provided elsewhere
Section 4.3.2: Removed language for final data analysis at 1 year post LPFV treatment in 
Phase II
Section 6.1.5: Revised treatment discontinuation language to include extension phase
Section 6.2.1 Revised recommended phase II to maximum tolerated dose
Section 7.1: Revised Study Flow to add visit windows for extension phase and to add 
description for SOC; revised Table 7-1 to reflect addition of an extension phase and a Week 


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105 Day 1 visit to replace the previous EOT visit; added Table 7-2 to include visit evaluation 
schedule for extension phase
Section 7.1.2: Revised treatment period language to reflect addition of extension phase
Section 7.1.2.1: Section deleted
Section 7.1.3: Updated discontinuation of study treatment per DOCE
Section 7.1.4: Section added for Withdrawal of Consent per  DOCE
Section 7.1.5: Follow up for safety evaluations language updated 
Section7.1.6: Section added for Lost to follow up per DOCE
Section 7.2: Revised all subsections for assessments and sample collection time-points to 
reflect the addition of the extension phase visits as reflected in Table 7-2, which implements a 
reduction in scheduled visit assessments after Week 105
Table 7-3: Updated to reflect assessments in extension phase
Table 7-5: Updated to reflect assessments in extension phase; EOT biopsy sample not 
required if a prior sample was collected within 24 weeks, changed from 6 weeks, of EOT to 
reduce patient burden for this exploratory analysis
Section 7.2.2.5.6: Added required pregnancy testing in extension phase as monthly or more 
frequent per local regulations, with home testing kits provided
Section 7.2.3.1: Revised language for PK analytical method
Table 7-10: Biomarker samples previously collected at End of Treatment changed to Week 
105 Day 1 or End of Treatment, whichever comes first) 
Section 7.2.6.1.1 and Table 7-11: MFSAF collection plan revised to be collected every 12 
weeks in extension phase
Section 7.2.6.1.2 and Table 7-11: EORTC QLQ-C30 MFSAF collection plan revised to be 
collected every 12 weeks in extension phase
Section 10: Modified to revise that final analysis will occur at end of study when all patients 
discontinue
Amendment 1
Amendment rationale
As of 06-Aug-2014, thirty six patients were screened, thirty patients treated, and six patients 
were screen failures in the Phase Ib part of the study. Five of the treated patients have 
discontinued treatment due to disease progression, adverse events, physician decision or 
patient decision. Out of nine patients in the Dose Determining Set at the 400mg LDE225 QD 
+ 15mg INC424 BID dose level, two DLTs occurred during the 6 week (42 day) DLT 
observation period. The MTD was not reached and instead the RPIID was defined as the 
400mg LDE225 QD + 20mg INC424 BID dose level. Patients enrolled in the Phase Ib safety 


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expansion cohort at 400mg LDE225 QD + 20mg INC424 BID are currently being observed in 
order to confirm the RPIID.
The major changes included in this amendment include: Addition of an exploratory endpoint 
to assess the levels of LDE225 in bone marrow, updates to the guidance for contraception 
based on a recent population pharmacokinetic analysis and updates to the muscle toxicity 
section for CK elevation.
Changes to contraception language
The recommendation for contraception duration has been updated based on a recent 
population pharmacokinetic analysis that showed a longer half-life of sonidegib in cancer 
patients (28 days) than in healthy subjects (10 days). Duration of pregnancy prevention was 
estimated via population pharmacokinetic model-based simulations incorporating the 
emerging data in cancer patients. The recommended duration of pregnancy prevention in 
female patients was extended from 6 months to 20 months to ensure the residual plasma 
sonidegib concentration is reduced below the safety threshold of 3pg/mL. The recommended 
condom use for 6 months for male patients with partners of child-bearing potential did not 
change as the 6-month duration is considered adequate to minimize any risk of sonidegib 
being transmitted to female partners via the seminal fluid of male patients. Female patients of 
child-bearing potential who had discontinued sonidegib before the current protocol 
amendment were informed of the need for extended contraception for 20 months.
Changes to the protocol:
The following sections have been changed in the amended protocol:


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Changes to the title page:

The LDE225 International Nonproprietary Name (INN), sonidegib, added.

Author list updated.
List of abbreviations updated.
Glossary of terms updated.
Protocol summary (Purpose and rationale): Updated number of countries INC424 is approved 
in.
Protocol summary (Exclusion criteria): revised aspirin dose to 150mg/day to be consistent 
with other INC424 studies.
Protocol summary (Other assessments): Inserted ‘Bone marrow aspirate samples for 
pharmacokinetic and pharmacodynamic analysis.
Section 1.4.1.2.1: Updated the total number of subjects, including patients that were dosed 
with LDE225 as of the most recent Investigator Brochure.
Section 1.4.1.2.3: Updated information from a food effect study. ‘In study [CLDE225A2114] 
in healthy volunteers with a 12-week follow-up period after a single dose, the geometric mean 
terminal half-life is estimated to be 10 days with a range of 3-32 days. In addition, a high-fat 
meal increased the Cmax and AUC of LDE225 capsules compared with the fasting condition. 
In anticipation of a food effect, food consumption will continue to be restricted around the 
time of dosing in clinical studies.’
Section 1.4.1.2.3 – Inserted language based on an update from a recent population 
pharmacokinetic analysis.
Section 1.4.2: Updated number of countries INC424 is approved in.
Section 1.4.2.2: Updated the total number of subjects and patients that were dosed with 
INC424 as of the most recent Investigator Brochure.
Section 1.4.2.2.1: Updated data for tuberculosis reports.
Section 1.4.2.2.1: Added PML (Progressive Multifocal Leukoencephalopathy) language.
Section 3: Table 3-1, added a new Phase II exploratory objective ‘To assess the levels of 
LDE225 in bone marrow’
Section 4.1: Figure 4-1, Clarified in the study schema that the Phase Ib part of the study is 
comprised of an escalation and safety expansion stage. Also included mention of the roll-over 
study.
Section 4.1.1: Added bone marrow aspirate sample collection for LDE225 concentration 
measurement.
Section 4.1.2: Updated section to be consistent with the LDE225 program roll-over study
language.
Section 5.1: Sentence updated to indicate that only JAK inhibitor naïve patients are allowed 
into the study to be consistent with the rest of the document.


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Section 5.3: Exclusion criteria #7, revised allowable aspirin dose level to 150mg/day to be 
consistent with other INC424 studies.
Section 5.3: Exclusion criteria #16: The time period for which women of child-bearing 
potential must use highly effective contraception after the final dose of study treatment was
increased from 6 to 20 months.
Section 5.3: Exclusion criteria #16: Clarified that male patients should use contraception and 
refrain from fathering a child for 6 months following the last dose of study drug.
Section 6.2.5: Table 6-3, updated the toxicity classification for liver function DLTs to 
“Hepatic”.
 
 
Section 6.4.3.4: Reworded this section for greater clarity.
Section 6.5.1: Removed reference to patient numbering in the setting of re-screening since re-
screening is not allowed in the study.
Section 7.1: Clarified that baseline (Week 1 Day 1) abdominal imaging (MRI/CT) and bone 
marrow samples must be performed before study medication is taken:

Added the allowable window for baseline abdominal imaging (MRI/CT) as - 1 week.

Added the allowable window for baseline bone marrow biopsy and aspirate sample 
collection as - 2 weeks.
 
Section 7.1: Table 7-1, clarified that serum and urine pregnancy testing should only be 
performed in women of child bearing potential to be consistent with other studies in the 
LDE225 program, there is no safety risk to women who do not meet this criteria.
 
 
Section 7.1.2: Roll-over protocol language added.
Section 7.2.1.3: Removed collection of bone marrow samples at Week 13, this was an error in 
the original protocol text.
 
 
Section 7.2.2.5: Table 7-5, Added “Urinalysis” label to the relevant group of analytes.


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Updated Section 7.2.2.5.6: Clarified that local serum and urine pregnancy testing is only 
required for women of child-bearing potential to be consistent with other studies in the 
LDE225 program, there is no safety risk to women who do not meet this criterion.
 
 
 
Section 9.3: Removed EMG and muscle biopsy.
Section 9.4: Removed EMG and muscle biopsy.
Section 10.2: Deleted ‘25th and 75th percentiles.’
Section 10.3.1: Deleted ‘Data may be presented by week in addition to over the entire 
treatment duration.’
Section 10.3.2: Clarified concomitant medications summaries will be based on full analysis 
set instead of safety set.
Section 10.5.1.1: Clarified the language used for deaths and SAEs.
Section 10.5.1.2: Deleted ‘Classification to compare baseline to the worst on treatment value’ 
as this analysis is covered in the shift table.
 
 
 
 
 
Section 10.7: Table 10-6, Updated to be consistent with the Beta prior.
Section 10.7: Deleted ‘independent statistician’ for ‘the number of responders needed will be 
determined at the time of interim analysis’ since this is an open label, un-blinded study.
Section 10.7: Deleted ‘and a prior sample size of less than 8 patients’ for greater clarity.


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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.
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.


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Protocol summary
Protocol number
CLDE225X2116
Title
A Phase Ib/II, open-label, multi-center, dose-finding study to assess the safety and 
efficacy of the oral combination of LDE225 and INC424 (Ruxolitinib) in patients with 
Myelofibrosis
Brief title
A study to find the maximum tolerated dose and determine the efficacy of the 
experimental combination of LDE225 and INC424 in patients with Myelofibrosis
Sponsor and Clinical 
Phase
Novartis
Ib/II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this phase Ib/II clinical trial is to: a) evaluate the safety of the co-
administration of LDE225 and INC424 in myelofibrosis patients and establish a 
maximum tolerated dose and/or Recommended Phase II dose of the combination and 
b) to assess the efficacy of the co-administration of LDE225 and INC424 on spleen 
volume reduction.
INC424 has shown efficacy in myelofibrosis (MF) and is approved in over 50 countries. 
LDE225 is a Hh pathway inhibitor. Pre-clinical data showed an encouraging effect of 
the combination on disease burden measurements, such as WBC count, spleen and 
liver weight. LDE might also demonstrate disease-modifying effects via reduction in 
bone marrow fibrosis and inhibition of cancer-initiating cells.
Combining LDE225 and INC424 could therefore potentially provide improved clinical 
benefit to MF patients.
Primary Objective(s) 
and Key Secondary 
Objective
Phase Ib: establish the MTD and/or RPIID of the combination of LDE225 (QD) and 
INC424 (BID) when administered orally to patients with MF who have not previously 
received therapy with JAK and Smo inhibitors.
Phase II: assess the efficacy of the co-administration of LDE225 and INC424 on spleen 
volume reduction as determined by centrally reviewed MRI/CT.
Secondary 
Objectives
Phase Ib:
To evaluate the safety of the co-administration of LDE225 and INC424 in patients with 
MF.
To characterize the single and multiple dose pharmacokinetics following the co-
administration of LDE225 and INC424.
Phase II:
To assess the effect of the co-administration of LDE225 and INC424 on bone marrow 
fibrosis by central review and on disease-specific pharmacodynamic biomarkers as a 
function of the molecular disease characterization of MF.
To evaluate the safety of the co-administration of LDE225 and INC424 in patients with 
MF.
To characterize the single and multiple dose pharmacokinetics following the co-
administration of LDE225 and INC424.
To assess the effect of the co-administration of LDE225 and INC424 on MF-associated 
symptoms burden.


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Study design
This is a multi-center, open-label, dose-finding phase Ib/II study to evaluate the safety 
and efficacy of the co-administration of LDE225 and INC424 in patients with 
Myelofibrosis (MF) who have not been previously treated with JAK and Smo inhibitors.
Patients will undergo a screening phase. Once eligibility (screening criteria met) has 
been confirmed patients will be enrolled to either the Phase Ib or Phase II part of the 
study.
Phase Ib: Groups of 3-6 patients will be enrolled into cohorts of increasing doses of 
LDE225 and INC424 until an MTD/RPIID is defined. If thrombocytopenia related dose 
limiting toxicities (DLTs) are observed during the dose escalation part of the study, 
different recommended dose combinations for patients with low and high baseline 
platelet counts may be suggested, in which case two MTDs/RPIIDs will be declared. 
Six additional confirmatory patients will be enrolled at each MTD/RPIID.
Phase II: Patients will receive the dose(s) declared as the MTD/RPIID(s). 
Approximately 18 patients will be enrolled into Stage 1, if following an interim analysis 
the minimum number of responders are observed, 28 additional patients will be 
enrolled into stage 2.
Patients will continue study treatment for at least 2 years after the first dose or until 
death, documented disease progression, initiation of a new MF therapy, intolerable 
toxicity, withdrawal of consent, discontinuation at the discretion of the investigator, or 
lost to follow-up, whichever comes first. Spleen volume assessments will be performed 
at Week 1, 13, 25 and 49 for Phase Ib patients enrolled to the confirmatory MTD 
level(s) and all patients enrolled in the Phase II part. Patients who complete 2 years of 
treatment and are deriving clinical benefit in the opinion of the investigator will be 
allowed to continue receiving treatment (LDE225 and INC424) in an extension phase of
this study, until discontinuation reasons are met or an alternative setting to receive 
study treatment (e.g., in form of another protocol) becomes available.  After 
discontinuing the study treatment, the patient will undergo an End Of Treatment visit as 
soon as possible and a 30-day safety follow-up evaluation.
Imaging data will be centrally collected and checked for quality by a vendor designated 
by Novartis, but the decision regarding patient management will remain with the local 
investigator.
A Steering Committee will be established and will ensure transparent management of 
the study according to the protocol through recommending and approving modifications 
as circumstances require.
Population
Adult patients, aged ≥ 18 years, with primary or secondary myelofibrosis that meet 
intermediate or high risk prognostic criteria and exhibit palpable splenomegaly ≥ 5 cm 
below the left costal margin that have not been previously treated with a JAK or Smo 
inhibitor will be eligible for this study. Approximately 36 patients will participate in the 
Phase Ib dose escalation and safety expansion part of the study. In the Phase II part of 
the study approximately 46 patients will be enrolled: 18 patients will be enrolled into 
Stage 1, if following an interim analysis at least 8 responders (i.e., patients with a 
spleen volumetric reduction from baseline of at least 35% by MRI/CT at 24 weeks) are 
observed, 28 additional patients will be enrolled into stage 2. If less than 8 responders 
are observed in Stage 1 then further enrollment will be halted for futility. Accounting for 
patients that may withdraw from the study or who may not meet the eligibility criteria, it 
is expected that approximately 82 patients will be enrolled in the entire study.
Inclusion criteria
Patient must be diagnosed with PMF per 2008 WHO criteria, or post-PV MF or post-ET 
MF per IWG-MRT criteria.
Patient is ineligible or unwilling to undergo stem cell transplantation.
Patient has a platelet count ≥ 75 x 109/L not reached with the aid of transfusions.
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
at Screening.
Patient must have palpable splenomegaly defined as ≥ 5 cm below the left costal 
margin.
Patient must be classified as intermediate risk level 1 (1 prognostic factor which is not 
age), Intermediate risk level 2, or high risk per IWG criteria.
Patient must have active symptoms of MF as demonstrated by one symptom score of 
at least 5 (0 to10 point scale) or two symptom scores of at least 3 (0 to 10 point scale) 
on the MF Symptom Assessment Form (MFSAF) at Screening.


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Exclusion criteria
Previous therapy with JAK inhibitors.
Previous therapy with a Smoothened inhibitor.
Patient has impaired cardiac function or clinically significant heart disease.
Patient is currently on medications that interfere with coagulation (including warfarin) or 
platelet function. Low dose aspirin (up to 150 mg per day) and low molecular weight 
heparin (LMWH) are allowed.
Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of INC424 or LDE225 (e.g., uncontrolled nausea, 
vomiting, diarrhea; malabsorption syndrome; small bowel resection).
Patient had splenic irradiation within 12 months prior to Screening.
Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular 
dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on 
concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such 
as HMG CoA inhibitors (statins), clofibrate and gemfibrozil. Pravastatin may be used if 
necessary, with extra caution.
Patients who plan on embarking on new (or unaccustomed) physical activities, such as 
strenuous exercise, that can result in significant increases in blood CK levels while on 
study treatment. NOTE: As a precaution, strenuous muscular activity should be avoided 
for at least 1 week prior to testing for blood CK levels.
Patients receiving treatment with medications known to be moderate and strong 
inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that 
have narrow therapeutic index, and that cannot be discontinued before starting 
treatment with LDE225. Medications that are strong CYP3A4/5 inhibitors should be 
discontinued at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to 
starting treatment with LDE225.
Investigational and 
reference therapy
Phase Ib: INC424 and LDE225 will be administered in increasing doses to cohorts of 
approximately 3-6 patients as follows:
Dose level (1): INC424 10 mg BID, LDE225 400mg QD
Dose level (2): INC424 15 mg BID, LDE225 400mg QD
Dose level (3): INC424 15 mg BID, LDE225 800mg QD
Dose level (4): INC424 20 mg BID, LDE225 800mg QD
These doses may be adjusted following the recommendation of an adaptive BLRM for 
dose escalation with overdose control (EWOC) until an MTD/RPIID is defined. If 
thrombocytopenia related dose limiting toxicities (DLTs) are observed during the dose 
escalation part of the study, different recommended dose combinations for patients with 
low and high baseline platelet counts may be suggested, in which case two 
MTDs/RPIIDs will be declared. Six additional confirmatory patients will be enrolled at 
each MTD/RPIID.
Phase II: Patients will receive the dose(s) declared as the MTD/RPIID(s).
Efficacy assessments
Measurement of palpable spleen length.
Spleen volume reduction measured by MRI/CT.
Bone marrow assessments (fibrosis and histomorphology).
PRO assessment of MF-related symptoms, inactivity, functioning, overall QOL and 
assessment of improvement using the Seven-day Modified MFSAF v2.0 and EORTC 
QLQ-C30 questionnaires.
Safety assessments
Monitor the frequency, duration and severity of dose limiting toxicities, adverse events 
and serious adverse events, vital signs, physical exam and lab test abnormalities.
Cardiac safety assessment: ECG.
Other assessments
PK assessments to characterize the pharmacokinetics of INC424 alone and in 
combination with LDE225, as well as at varying doses of the combination.
Bone marrow aspirate samples for pharmacokinetic and pharmacodynamic analysis.
Analysis of JAK mutation status and allele burden, Hh pathway activation, cytokine 
assays and pharmacogenomics to explore potential predictive biomarkers and changes 
in markers of disease burden and symptoms.


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Data analysis
Phase Ib: A 6-parameter Bayesian Logistic Regression Model (BLRM) for combination 
treatment will be fitted to the 6-week dose-limiting toxicity data (i.e. absence or 
presence of DLT) accumulated throughout the dose escalation part to model the dose-
toxicity relationship of LDE225 and INC424 when given in combination. Dose 
recommendation will be based on summaries of the posterior distribution of model 
parameters and the posterior distribution of DLT rates. 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 [16%, 35%) among the 
doses fulfilling the overdose-control criterion that there is less than 25% (posterior 
probability) chance of excessive toxicity.
Phase II, the uniformly minimum variance unbiased estimator (UMVUE; Jung 2004) for 
the proportion of subjects achieving ≥ 35% reduction from baseline in spleen volume as 
measured by MRI/CT at 24 weeks and 48 weeks, and their exact two-sided 95% 
confidence intervals will be provided.
Key words
Myelofibrosis, Post-polycythemia vera myelofbrosis (Post PV-PMF), Post essential 
thrombocythemia myelofibrosis (Post ET-MF), Primary myelofibrosis (PMF), 
Intermediate risk myelofibrosis, High risk myelofibrosis, JAK inhibitor, smoothened 
inhibitor


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1
Background
1.1
Overview of myelofibrosis and current treatment options
The four classic myeloproliferative neoplasms (MPNs) include chronic myelogenous 
leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary 
myelofibrosis (PMF). Myelofibrosis (MF) can present as a de novo disorder (PMF) or evolve 
secondarily from previous PV or ET (post-PV MF or post-ET MF). Regardless of whether 
MF is a primary or secondary disorder, it is characterized by a clonal stem cell proliferation 
associated with production of elevated serum levels of multiple inflammatory and 
proangiogenic cytokines, a characteristic bone marrow stromal pattern that includes varying 
degrees of collagen fibrosis, osteosclerosis and angiogenesis and a peripheral blood smear 
showing a leukoerythroblastic pattern with varying degrees of circulating progenitor cells. 
Clinically, myelofibrosis is characterized by progressive anemia, leukopenia or leukocytosis, 
thrombocytopenia or thrombocythemia and multi-organ extramedullary hematopoiesis most 
prominently involving the liver and spleen. Patients may experience severe constitutional 
symptoms, sequelae of massive splenomegaly (pain, limitations of movement, early satiety 
and shortness of breath, hepatic obstruction, and splenic infarction), a hypermetabolic state 
with cachexia, progressive hematopoietic failure, progression to leukemia, and premature 
death.
MF is defined by the National Institutes of Health (NIH) as a “rare disease” with a prevalence 
of 0.3 to 1.5 cases per 100,000 with a median age at diagnosis of 65 years (Mesa 1999, 
Rollison 2008).
Survival in MF varies with the presence or absence of specific risk factors. A multi-center 
analysis of risk factors and their impact on prognosis in patients with MF have recently been 
published (Cervantes 2009). Age greater than 65 years, presence of constitutional symptoms 
(weight loss > 10% of the baseline value in the year preceding PMF diagnosis, unexplained
fever, or excessive night sweats persisting for more than 1 month), anemia (Hemoglobin 
(Hgb) less than 10 g/dL), leukocytosis (white blood cell count (WBC) greater than 25 x109/L), 
and a circulating blast percentage of 1% or higher were identified as individually predictive of 
outcome. It was demonstrated that patients could be distinctly grouped into four categories 
without overlapping median survival curves based upon the number of risk factors (Table 1-
1).
Recent studies have demonstrated that transfusion need in the first year of diagnosis or the 
presence of cytogenetic abnormalities other than sole +9, 13q-, or 20q- identifies patients with 
median survival of less than 5 years (Barbui 2011).
Table 1-1
Median survival of MF patients according to risk category
No of risk factors
Risk category
Median survival (months)
0
Low
135
1
Intermediate-1
95
2
Intermediate-2
48
3 or more
High
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For a subset of patients who are younger (generally less than 65 years), otherwise healthy and 
have a histocompatible donor, allogeneic stem cell transplantation may provide a curative
option. However, substantial risk of mortality has been reported in around 30% and 20% of 
patients for standard allogeneic and for reduced intensity allo-transplants, respectively (Ballen 
2012). Drug therapies used, including hydroxyurea, busulfan, 6-mercaptopurine, anagrelide, 
thalidomide, lenalidomide, interferon, corticosteroids, and erythropoiesis stimulating agents or 
growth factors have not been shown to improve survival. Some can increase the risk of 
leukemic transformation, and/or are poorly tolerated, and all have limited effectiveness in 
improving splenomegaly and constitutional symptoms. One group determined that 
splenectomy, performed in approximately 10% of patients, is associated with significant 
morbidity and mortality (Cervantes 2009). Splenic irradiation is employed to reduce 
symptoms secondary to splenomegaly, but symptomatic improvement is variable and short-
lived; moreover, transient and life-threatening pancytopenia and an approximate 20% 
treatment-related mortality have been noted.
Thrombocytopenia, although not found to be an independent variable in the multivariate 
analysis of prognostic factors proposed by the International Working Group for Myelofibrosis 
Research and Treatment (Cervantes 2009), is considered to be an adverse risk factor by the 
Mayo Clinic group (Elliott 2007). Apart from being an indicator of diminished bone marrow 
reserve, thrombocytopenia may also be a limiting factor with regards to therapy intensity with 
multiple agents, including INC424, which constitutes a Dose Limiting Toxicity (DLT). 
Therefore, thrombocytopenic patients are often excluded from investigational studies despite 
having MF requiring therapy. Hence, new treatments that can modify the disease and improve 
bone marrow reserve are needed.
1.2
Role of hedgehog signaling in cancer
Hedgehog (Hh) signaling plays a critical role in the development and homeostasis of many 
human organs and tissues (McMohan 2003).
In the resting state, the transmembrane protein Patched (PTCH) inhibits the activity of Smo. 
The Hh family protein ligands including sonic hedgehog (SHH), desert hedgehog (DHH) and 
Indian hedgehog (IHH) can all bind to and inactivate PTCH. Upon Hh ligand binding, 
activated Smo signals through a complex of cystolic proteins, resulting in the activation of 
Glioma-associated oncogene homolog (Gli) transcription factors and their subsequent nuclear 
translocation to induce Hh target genes, such as Gli 1, PTCH1, cyclin D1, bcl-2, N-myc, and 
secreted frizzled-related protein 1 (sFRP). The Gli transcription factors, the downstream 
effectors of Hh signaling (Teglund and Toftgard 2010), promote cell proliferation, 
differentiation, and survival (Pasca di Magliano and Hebrok 2003). Therefore, the expression 
of Gli1 messenger ribonucleic acid (mRNA) in tumor or relevant surrogate tissues constitute a 
reliable indicator of Hh pathway activity (Scales and Sauvage 2009).
Several lines of evidence support 3 mechanistic roles for Hh signaling in cancer: (1) a cancer 
cell-autonomous role, in which tumor growth is driven by activating mutations in the 
pathway; (2) paracrine signaling role involving tumor and stromal interactions that promote 
tumor growth and invasion; and (3) an autocrine signaling role via cancer stem cells that 
promotes self-renewal and proliferation (Shelton and Gilmartin 2009). Ultimately, the linkage 
of aberrant Hh signaling pathway to tumor genesis is thought to be mediated through cell-


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cycle dysregulation, protection of cancer cells against apoptosis and modulation of 
angiogenesis (Scales and Sauvage 2009). Activating or inactivating mutations in genes that 
regulate the Hh pathway have been identified in approximately one-third of patients with 
medulloblastoma (MB) (mutations in PTCH, Smo and suppressor of fused (SuFu)), in >95% 
of patients with basal cell carcinoma (BCC) (mutations in PTCH or Smo), and in patients with 
rhabdomyosarcoma. In addition, aberrant upregulation of the Hh pathway via autocrine or 
paracrine signaling mechanisms is linked to a number of other tumor types, including 
pancreatic, small-cell lung cancer, (SCLC) and breast cancers as well as gliomas and CML.
It has been hypothesized that tumors are hierarchical structures, and that their capacity for 
initiation and propagation is limited to a small number of very primitive cells, the so called 
cancer stem cells (CSC). These cells are similar to their normal counterparts, and can 
proliferate and, in addition, give rise to a more differentiated progeny (Reya 2001). Such a 
population has been clearly demonstrated in CML and acute myeloid leukemia (AML), and 
there is also evidence of their existence in many other tumors, such as myeloma, lymphoma, 
glioblastoma, breast, and prostate cancer. CSCs are usually quiescent and therefore resistant 
to conventional therapies. Failure to effectively target these cells may result in residual low-
level disease and the likelihood of future relapse (Irvine 2012).
Hh pathway activation has been shown in CD34+ cells from patients with chronic 
myeloproliferative disorders, as compared to healthy controls (measured through Gli1 and 
PTCH1 expression).
 
 
Thus, it is thought that combination treatment with inhibitors of JAK2 and Hh signaling may 
provide more clinical benefit than monotherapy with a JAK2 inhibitor, such as INC424.
1.3
Janus kinases (JAKs) in myelofibrosis
A considerable number of cytokine and growth factor receptors utilize non-receptor tyrosine 
kinases, the Janus kinases (JAKs), to transmit extracellular ligand binding into an intracellular 
response (Figure 1-1) (Levine 2007). For example, erythropoietin, thrombopoietin and 
granulocyte monocyte colony stimulating factor are all known to signal through receptors that 
utilize JAK2. JAKs activate a number of downstream pathways implicated in proliferation and 
survival, including the STATs (signal transducers and activators of transcription), a family of 
important latent transcription factors.
Myelofibrosis is a clonal stem cell disease characterized by molecular (JAK2V617F, 
MPLW515L/K) and cytogenetic (13q-,20q-) markers (Pikman 2006, Scott 2007). The 
JAK2V617F mutation has been identified in over 95% of patients with PV and approximately 
50% of patients with ET and PMF. Furthermore, in a preclinical setting, animal studies have 
demonstrated that this mutation can lead to an MF-like syndrome. The JAK2V617F mutation 
alters the JAK2 tyrosine kinase making it constitutively active. As a result, polycythemia, 
thrombocythemia and leukocytosis can develop independently from growth factor regulation. 
Even in patients lacking a confirmed JAK2 mutation, the detection of STAT activation 
suggests dysregulated JAK activity. In fact, regardless of the mutational status of JAK2, the 


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malignant cells appear to retain their responsiveness to JAK activating cytokines and/or 
growth factors; and therefore, may benefit from JAK inhibition.
Figure 1-1
Schematic representation of the JAK pathway
1.4
Introduction to investigational treatment(s) and other study 
treatment(s)
1.4.1
Overview of LDE225
LDE225 is a potent, selective and orally bioavailable inhibitor of Smo from a novel structural 
class 
N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4’-(trifluoromethoxy)-
1,1’-[biphenyl]-3-carboxamide diphosphate.
1.4.1.1
Non-clinical experience
1.4.1.1.1 Summary of basic pharmacology
LDE225 is a potent, selective and orally bioavailable Smo inhibitor, which is currently in 
early stages of clinical development. Smo is a GPCR-like membrane protein which activates 
the Hh signal transduction pathway (Figure 1-2). Physiologically, Smo is blocked by PTCH, 
the Hh-ligand specific cell surface receptor. Aberrant activation of Smo as a consequence of 
loss-of-function mutations of PTCH or gain-of-function mutations of Smo is associated with 
development of Hh-pathway dependent tumor types, including MB and BCC. The Hh-
pathway is therefore an attractive target for therapeutic intervention.


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Figure 1-2
Schematic representation of Smo activation of the Hh pathway
A number of in vitro studies have been conducted to characterize the pharmacological activity 
of LDE225. LDE225 is a high-affinity ligand for human and mouse Smo, as shown by its 
ability to displace radiolabeled Smo agonists, with an IC50 of 11 nM for human Smo and 12 
nM for mouse Smo. In multiple cell-based assays, LDE225 is a potent antagonist of Hh-
dependent pathway activation. It inhibits Hh-mediated Gli1 activation in mouse TM3 and 
human HEPM cells with an IC50 of 7 nM and 13 nM, respectively. LDE225 potently inhibits 
proliferation and Gli1 expression of freshly isolated mouse MB tumor cells in vitro with an 
IC50 of 7 nM.
Treatment with LDE225 results in tumor regression in vivo in several genetically defined MB 
models. Efficacy in these tumor models is dose-related and correlates with inhibition of Hh-
pathway signaling, as measured by decreased Gli1 mRNA. LDE225 was well tolerated in 
mice with no significant body weight loss at all doses (up to 160 mg/kg daily (QD)) 
investigated. Treatment with LDE225 induced >87 % tumor regression at 20 mg/kg QD and 
10 mg/kg twice daily (BID) in PTCH+/- p53-/-, PTCH+/- Hic+/- and PTCH+/- subcutaneous 
tumor allograft mouse MB models. Following cortical implantation of PTCH+/- p53-/- cells, 
tumor volume reduction and extension of time to progression was observed following
treatment at a 20 mg/kg BID dose.
In vivo PK/PD analysis in PTCH+/- p53-/- and PTCH+/- Hic+/- MB models showed a good 
correlation between the given dose, the measured blood and tissue levels, the effects on the 
Hh-pathway as measured by Gli1 mRNA expression and the anti-tumor activity. It appeared 
that almost complete and sustained Gli1 mRNA inhibition (approximately 95%) was 
associated with tumor regression [LDE225 Investigator’s Brochure (IB)].
1.4.1.1.2 Summary of non-clinical pharmacokinetics, metabolism and toxicity
LDE225 was well absorbed with good oral bioavailability, ranging from 68 to 100% in the 
mouse, rat, dog, and monkey after oral administration either in the form of a solution or a 


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diphosphate salt suspension. The clearance was low to moderate compared to the hepatic 
blood flow for all species studied. The compound was extensively distributed into tissues and 
its volume of distribution at steady state (Vss) was greater than total body water (1.9-7.0 
L/kg). LDE225 exhibited high protein binding (approximately 98% in mouse, rat, dog and 
human plasma), independent of concentration. In rats, >85% of LDE225 related radioactivity 
was eliminated into the feces following both intravenous and oral administration, and renal 
excretion was minor, accounting for <3.0% of the administered dose.
LDE225 was extensively metabolized in rats, with the major metabolic pathway being via 
mono- or dioxygenation, demethylation, and oxidation leading to carboxylic acid formation, 
dealkylation, and dehydrogenation. Hepatic oxidative metabolism of LDE225 in vitro was 
mediated primarily by CYP3A4. The elimination of metabolites was mainly through the bile.
Studies with human liver microsomes showed inhibition of CYP2B6 (IC50 ~0.5 µM; Ki 0.045 
µM) and CYP2C9 (IC50~5 µM; Ki 1.7 µM), but very little or no inhibition of CYP1A2, 2A6, 
2C8, 2C19, 2D6, 2E1 or 3A4/5 at concentrations of up to 100 µM. No apparent time-
dependent inhibition of the major CYP450 enzymes or induction of CYP3A4 was observed. 
LDE225 was neither a substrate nor an inhibitor of P-glycoprotein (P-gp) or multi-drug 
resistance protein 2 (MRP2); but it has demonstrated inhibitory effects on breast cancer 
resistance protein (BCRP), with an estimated IC50 value of 1.5 µM. The potential of LDE225 
and its metabolites to undergo covalent binding to cellular macromolecules was found to be 
low.
The results of toxicokinetics (TK) studies with LDE225 indicated that systemic exposure after 
oral administration, as measured by Cmax and AUC generally increased less than dose-
proportionally in both rats and dogs. There was drug accumulation after once daily repeat oral 
doses, which was more pronounced and dose-dependent in dogs. There was an apparent 
gender difference in exposure in rats following multiple dosing, with female rats exhibiting 
higher exposure than male rats.
The majority of adverse effects observed in the 4-wk Good Laboratory Practice (GLP) 
toxicity studies in growing rats and dogs can be attributed to the pharmacologic action of 
LDE225, and the effects in both species were similar. The most striking effects of LDE225 
were on growing bone, and consisted of thinning or closure of growth plates in the sternum 
and femur. These effects are not likely to occur in the adult cancer patient population due to 
the maturity of their skeletal system. Likewise, effects on growing teeth in rats including 
dentine dysplasia of the incisors is not expected to occur in adult cancer patients. Other drug-
related effects, likely associated with the pharmacology of LDE225, included effects on the 
male and female reproductive tract of young rats and dogs. Gastrointestinal (GI) toxicity was 
likely dose limiting in the animal studies. In the GLP juvenile rat study, minimal to slight 
degeneration of nerve fibers was found in the sciatic nerve and, less commonly, in the 
thoracic spinal cord, but not in the cervical or lumbar spinal cord or optic nerve. Effects on 
nerves were not seen in any of the toxicity studies on more mature rats or dogs. Consistent 
with the role of Hh signaling in embryo-fetal development, LDE225 was shown to be 
teratogenic, an expected class effect of Smo inhibitors. LDE225 was not genotoxic in studies 
conducted in vitro and in vivo, and showed no potential risk for phototoxicity.


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For more details on the non-clinical toxicity, toxicokinetics and safety of LDE225 refer to the 
[LDE225 Investigator’s Brochure].
1.4.1.2
Clinical experience
1.4.1.2.1 Clinical safety and efficacy
The safety and preliminary efficacy of single-agent oral LDE225 in cancer patients has been 
assessed in three early phase studies ([CLDE225X2101], [CLDE225X2104]
and 
[CLDE225X1101]). A summary of the safety, PK and PD data from study [CLDE225X2101]
is provided in this section, as it has completed accrual and has the most mature data set.
LDE225 has been evaluated in a first-in-human, phase I, multicenter open-label dose 
escalation study [CLDE225X2101] in patients with advanced solid tumors including 
medulloblastoma that have progressed despite standard treatments or have no existing 
therapies. The primary objective was to assess the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and potential efficacy of continuous once daily oral administration. 
This study has completed enrollment.
As of November 29, 2014, a total of 1381 patients, including patients with various cancers 
and 62 pediatric patients, received LDE225 at various dose levels, administered daily up to 
3000 mg/day.
Oral LDE225 is generally well tolerated. The maximum tolerated dose (MTD) was 
determined to be 800 mg QD and 250 mg BID. The twice daily dosing regimen did not appear 
to offer any advantage over once daily, hence the recommended dose of LDE225 in adults is 
800 mg QD. Across all dose levels, grade 3 or 4 adverse events (AEs) suspected to be 
treatment-related were uncommon, except dose-limiting muscle toxicity (Table 1-2). 
Commonly reported Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or 
2 adverse events suspected to be treatment-related include: nausea, vomiting, dysgeusia, 
decreased appetite, myalgia, muscle spasms and fatigue (Table 1-3).
DLTs that are characterized by CTCAE grade 3 or 4 increases in plasma creatine 
phosphokinase (CK) were observed at once daily doses ≥ 800 mg and twice daily doses ≥ 250 
mg in an exposure-dependent manner (Table 1-2 and Figure 1-3). The higher incidence of the 
DLTs in the BID cohorts when compared with QD cohorts of the same total daily dose is 
consistent with the comparatively higher systemic drug exposures obtained with the BID 
schedule (Section 1.4.1.2.3). Some of the patients who experienced muscle toxicity also had 
grade 3 or 4 elevated serum AST and ALT. The majority of the DLT events occurred during 
the initial 4-6 weeks of treatment with LDE225, except for three events that were observed 
after 6 weeks. None of the patients experienced impairment of renal function as a result of this 
toxicity. The DLTs resolved within 4-8 weeks following discontinuation of LDE225 therapy. 
Of the 19 patients with Grade 3/4 CK elevations, 8 patients resumed treatment at reduced 
doses and none had subsequent Grade 3/4 CK elevations.


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Table 1-2
Incidence of dose limiting toxicities in study CLDE225X2101
Dose of 
LDE225
Number of 
patients 
treated
Elevated plasma CK
Number of patients with 
CTCAE grade 3
Number of patients with 
CTCAE grade 4
Total (CTCAE 
grade 3 or 4)
100 mg QD
6
0
0
0
200 mg QD
6
0
0
0
400 mg QD
5
0
0
0
800 mg QD
26
1
1
2
1000 mg QD
11
1
1
2
1500 mg QD
9
0
3
3
3000 mg QD
10
0
3
3
250 mg BID
14
1
1
2
400 mg BID
8
1
1
2
750 mg BID
8
0
5
5
Total
103
4
15
19
No treatment-related clinically significant changes in the other safety laboratory data 
(hematology, and urinalysis), vital signs or electrocardiograms (ECGs) have been observed 
for any of the patients treated in the study. Refer to [LDE225 Investigator’s Brochure] for 
further details.
Table 1-3
Adverse events suspected to be related to LDE225 by preferred term, 
occurring in 5% or more of patients in study CLDE225X2101
800 mg QD* (n=26)
All doses** (n=103)
All Grades
Grade 3/4
All Grades
Grade ¾
Blood CK increased
7 (26.9)
2 (7.7)
33 (32.0)
19 (18.4)
Muscle spasms
9 (34.6)
0 (0.0)
33 (32.0)
0 (0.0)
Dysgeusia
5 (19.2)
0 (0.0)
30 (29.1)
0 (0.0)
Nausea
4 (15.4)
0 (0.0)
26 (25.2)
0 (0.0)
Decreased appetite
4 (15.4)
0 (0.0)
19 (18.4)
0 (0.0)
Myalgia
4 (15.4)
0 (0.0)
17 (16.5)
1 (1.0)
Fatigue
1 (3.8)
0 (0.0)
15 (14.6)
0 (0.0)
Alopecia
4 (15.4)
0 (0.0)
13 (12.6)
0 (0.0)
Asthenia
5 (19.2)
1 (3.8)
13 (12.6)
3 (2.9)
Vomiting
3 (11.5)
0 (0.0)
13 (12.6)
0 (0.0)
Weight decreased
4 (15.4)
1 (3.8)
11 (10.7)
1 (1.0)
AST increased
1 (3.8)
0 (0.0)
8 (7.8)
4 (3.9)
ALT increased
1 (3.8)
0 (0.0)
7 (6.8)
3 (2.9)
Diarrhea
2 (7.7)
0 (0.0)
7 (6.8)
0 (0.0)
Lethargy
3 (11.5)
0 (0.0)
7 (6.8)
0 (0.0)
Constipation
1 (3.8)
0 (0.0)
6 (5.8)
0 (0.0)
*Maximum tolerated dose in adults
**All doses, including BID and QD schedule


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1.4.1.2.2 Clinical efficacy from Study CLDE225X2101
Preliminary antitumor activity and evidence of disease stabilization has been observed with 
LDE225 treatment. As of March 2012, 9 adult patients with recurrent MB have been treated 
in the ongoing phase I studies of LDE225 in advanced solid tumors (studies 
[CLDE225X2101] [EU/US] and [CLDE225X1101] [Asia]). Of these, 3 patients achieved 
confirmed partial tumor responses at 200 mg QD (by Response Evaluation Criteria In Solid 
Tumors, RECIST), 800 mg QD (by RECIST) and 1500 mg QD (by FDG-PET) and remained 
on treatment for approximately 6, 9 and 10 months respectively. All the MB patients are off 
therapy due to disease progression (Table 1-4).
Table 1-4
Anti-tumor activity in adult patients with recurrent medulloblastoma
Patient
Dose
Overall Best Response
Time on Study
100 mg QD
PD
1 month
200 mg QD
PR
6 months
200 mg QD
PD
2 months
800 mg QD
SD
4 months
800 mg QD
PR
9 months
800 mg QD
PD
2.5 months
1500 mg QD
PD
2 months
1500 mg QD
PMR
10 months
250 mg BID
PD
2 months
PD, disease progression; PMR partial metabolic response; PR, partial response; SD, stable disease.


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1.4.1.2.4 Effect of LDE225 treatment on Gli1 mRNA expression
In study [CLDE225X2101], analyses of skin punch biopsies taken at baseline and at the end 
of the first treatment cycle have shown evidence of potent target modulation, as measured by 
Gli1 mRNA, in a dose- and exposure (Cmin) dependent manner (Figure 1-4). The available 
data shows that LDE225 caused up to 98% mean reduction in Gli1 expression in skin 
compared with baseline values. An Emax model [Inhibition = Emax*Cmin/(EC50+Cmin)] 
was fit to the Cmin and Gli-1 log reduction data at Day 28. We found a significant 
dependency of Gli-1 inhibition on Cmin at Day 28, with a maximum inhibition (Emax) 
between 90%–100%.


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Figure 1-4
Pk-Gli1 inhibition relationship to LDE225
1.4.2
Overview of INC424 (ruxolitinib)
INC424 phosphate, designated INC424 throughout, is a novel, potent, reversible and selective 
inhibitor of JAK1- and JAK2-STAT signaling (Quintas-Cardama 2010) that is currently under 
development for treatment of MPNs and advanced hematologic malignancies. INC424 is 
approved in more than 70 countries including the USA, Canada and the EU with the following 
indication wording:
USA (under the trade name of Jakafi): INC424 is intended for the treatment of patients with 
intermediate or high-risk myelofibrosis, including primary myelofibrosis (PMF), post-
polycythemia vera myelofibrosis (post-PV MF) and post-essential thrombocythemia 
myelofibrosis (post-ET MF). INC424 is also indicated for treatment of patients with 
Polycythemia Vera who have had an inadequate response to or are intolerant of hydroxyurea.
Canada (under the trade name of Jakavi): Jakavi is indicated for the treatment of 
splenomegaly and/or its associated symptoms in adult patients with PMF (also known as 
Chronic idiopathic myelofibrosis (CIM), post-PV MF or post-ET MF.
EU (under the trade name of Jakavi): Jakavi is indicated for the treatment of disease-related 
splenomegaly or symptoms in adult patients with PMF (also known as CIM), post-PV MF or 
post-ET MF.


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1.4.2.1
Non-clinical experience
INC424 inhibited the splenomegaly and morbidity/mortality in mice resulting from 
intravenous inoculation of cells expressing the same mutated JAK2 (V617F) implicated in the 
pathogenesis of the majority of Philadelphia chromosome negative MPNs (Quintas-Cardama 
2010).
 
 
Based on safety pharmacology studies and on the results of clinical studies, the potential for 
INC424 to cause adverse alterations in respiratory, neurologic, and cardiovascular parameters 
in humans is low.
In embryo-fetal assessments in rat and rabbit, maternal toxicity and minimal embryo-fetal 
toxicity were noted at the highest doses evaluated. INC424 was not teratogenic in either rat or 
rabbit. No effects were noted on reproductive performance or fertility in male or female rats. 
Increases in post-implantation loss were noted at the higher doses. In a pre- and post-natal 
development and maternal function study in rats there were no adverse findings for fertility 
indices or for maternal and embryo-fetal survival, growth, and developmental parameters. 
INC424 passed into the milk of lactating rats with an exposure that was 13-fold higher than 
maternal plasma exposure
INC424 was not mutagenic or clastogenic nor did it demonstrate potential for carcinogenicity 
in a 6-month study in Tg.rasH2 mice or in the 2-year rat study.
More detailed information on pharmacology of INC424, single and multiple dose PK studies 
conducted in multiple species and nonclinical safety evaluations can be found in the INC424 
IB.
1.4.2.2
Clinical experience
As of July 2014, approximately 6,734 patients and healthy volunteers have been exposed to 
INC424.  Please refer to the latest IB for details.
1.4.2.2.1 Human safety and tolerability data
In single dose studies, INC424 has a well-established safety profile and has been well 
tolerated with adverse events generally mild in intensity, reversible and of similar incidence 
following INC424 treatment compared with placebo or with other control treatments.
A definitive QT study was carried out in 50 healthy volunteers, evaluating the effects of single 
doses of 25 mg or 200 mg INC424 compared with placebo and 400 mg moxifloxacin (positive 
control). The overall conclusion was that there appeared to be no adverse impact on ECG 
signaling (little change in heart rate, QRS duration, QTcF interval, and a slight, non-clinically 
significant, increase in PR interval) with the administration of INC424.
In a 10-day multiple dose study, [INCB 18424-132] a total of 71 healthy volunteers in 6 
cohorts received doses of 50 mg QD, 100 mg QD, 15 mg BID, 25 mg BID or 50 mg BID. 
INC424 or placebo. INC424 was well tolerated in the study, with most AEs reported equally 


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by both INC424-treated and placebo-treated volunteers. Neutropenia was noted in 3 
volunteers receiving the highest dose of INC424, 50 mg BID. Neutropenia at the Grade 4 
level led to study drug discontinuation on Day 5 in one volunteer and was reported as a 
Serious Adverse Event (SAE). There was a decline in mean absolute neutrophil count (ANC) 
and, to a lesser extent, in mean WBC count values with INC424 doses of 15 mg BID or 
higher. In general ANC or WBC returned to Baseline levels within 1 to 2 days following the 
last dose of study drug. Doses of 25 mg BID and 100 mg QD were determined to be the 
MTDs in this study based on the DLT of neutropenia.
Based on three studies [INCB 18424-351], [INCB 18424-251], [CINC424A2352], in the 
myelofibrosis population the majority of adverse events regardless of study drug relationship 
were grade 1 or 2 thrombocytopenia and anemia. The overall frequency of adverse events 
leading to study drug discontinuation was 10%, with 1.4% from thrombocytopenia, 1.2% 
from anemia, 0.8% from acute myeloid leukemia, and 0.6% from pneumonia. The overall 
frequency of adverse events requiring dose reduction or interruption was 55.4%, with 32.4% 
from thrombocytopenia, 10.4% from anemia, and 4.9% from platelet count decrease.
Details on anemia, thrombocytopenia, neutropenia, urinary tract infections, herpes zoster, 
tuberculosis, and increased systolic blood pressure as side effects of INC424 are presented 
below.
Anemia
In two pivotal myelofibrosis clinical studies, [INCB 18424-351] and [CINC424A2352], 
anemia of any CTCAE grade was observed in 82.4% of patients. The median time to onset of 
the first CTCAE grade 2 or higher anemia was 1.5 months in Phase III studies, with one 
patient (0.3%) discontinuing treatment due to anemia. In the randomized, placebo-controlled 
study [INCB 18424-351], 59.4% of INC424-treated patients and 37.1% of patients receiving 
placebo received red blood cell transfusions during randomized treatment. In the 
[CINC424A2352] study, the rate of packed red blood cell transfusions was 54.1% in the 
INC424 arm and 38.4% in the best-available therapy arm.
In patients receiving INC424, mean decreases of Hgb reached a nadir of approximately 15 to 
20g/L below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a 
new steady state that was approximately 10 g/L below baseline.
Thrombocytopenia
In two pivotal myelofibrosis clinical studies, [INCB 18424-351] and [CINC424A2352], 
thrombocytopenia of any CTCAE grade was observed in 69.8% of patients. The median time 
to onset for patients who experienced grade 3 or 4 thrombocytopenia was 8 weeks, which was 
generally reversible with dose reduction or dose interruption. The median time to platelet 
recovery above 50 x 109/L was 14 days. Platelet transfusions were administered to 4.5% of 
patients receiving INC424 and 5.8% of patients receiving control regimens. Patients with a 
platelet count of 100 x 109/L to 200 x 109/L before starting INC424 treatment had a higher 
frequency of grade 3 or 4 thrombocytopenia compared to patients with platelet counts over 
200 x 109/L, of 64.2% versus 35.4%.


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Neutropenia
In two pivotal myelofibrosis clinical studies, [INCB 18424-351] and [CINC424A2352], 
neutropenia of any CTCAE grade was observed in 16.6% of patients. The median time of 
onset for patients experiencing grade 3 or 4 neutropenia was 12 weeks. In Phase III 
myelofibrosis studies, the dose was held or reduced in 1.3% of patients due to neutropenia. 
Treatment was discontinued in 0.3% of patients due to neutropenia.
Urinary tract infection
In Phase III myelofibrosis clinical studies, grade 3 or 4 urinary tract infection was reported for 
1.0% of patients. Additionally, urosepsis was reported in 1.0% of patients and kidney 
infection was reported in one patient.
Herpes zoster
In Phase III myelofibrosis clinical studies, grade 3 or 4 herpes zoster infection was reported in 
one patient.
Tuberculosis
In Phase III myelofibrosis studies, tuberculosis of any grade was reported in 1.0 % of patients. 
Potential confounding factors include exposure to corticosteroids and history of hematological 
malignancies, diabetes, emphysema, BMI below 20 kg/m2, asthma, bronchitis, and smoking
as risk factors in the general population. Relation to INC424 is not clear due to the low 
number of cases and potential confounding factors involved.
Increased systolic blood pressure
In the phase III pivotal clinical studies an increase in systolic blood pressure of 20 mmHg or 
more from baseline was recorded in 31.5% of patients on at least one visit compared with 
19.5% of the control-treated patients. Relation to INC424 is not clear at this point.
PML (progressive multifocal leukoencephalopathy)
One case of PML has been reported in a myelofibrosis patient receiving INC424. It would be 
important to note that an atypical feature of this disease occurred quickly (approximately one 
month) after initiation of INC424 treatment. Infections are well known complications in 
myelofibrosis patients. PML has been reported in myeloproliferative disease patients who are 
not taking INC424.
1.4.2.2.2 Human pharmacokinetic and metabolism data
INC424 exhibits near-complete absorption with maximal plasma concentration (Cmax) 
achieved approximately 1 hour after a single oral dose. Linearity in PK was demonstrated 
over a dose range of 5 to 200 mg following single-dose administration. PK parameters were 
similar between single and multiple doses. A drug accumulation ratio of 1.12 was observed 
following twice daily dosing. The effect of food on the INC424 exposure (4% increase in 
AUC, 90% confidence interval, CI 96.8 – 113%) is not expected to be clinically significant. 


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INC424 may be administered without regard to meals. INC424 is eliminated almost 
completely by oxidative metabolism with a terminal elimination half-life of approximately 3 
h. INC424 is excreted in urine and feces with less than 1% excreted as unchanged parent drug.
In vitro metabolism studies showed that CYP3A4 was the predominant human CYP isozyme 
responsible for the metabolism of INC424 with minor contribution from CYP2C9. Systemic 
co-administration of oral ketoconazole, a potent CYP3A4 inhibitor, resulted in a 91% increase 
of plasma AUC, whereas erythromycin, a moderate CYP3A4 inhibitor, caused a 27% increase 
in exposure. Based on these results, the dose of INC424 should be decreased by 
approximately 50% when a potent CYP3A4 inhibitor is concomitantly used and no dose 
adjustment is necessary when a mild or moderate CYP3A4 inhibitor is used. INC424 is not 
known to induce or inhibit other CYP enzymes.
1.4.2.2.3 Clinical efficacy data
Results from two Phase III studies [INCB 18424-351] and [CINC424A2352] demonstrate the 
effectiveness of INC424 in patients with primary myelofibrosis, post-polycythemia vera 
myelofibrosis, and post-essential thrombocythemia myelofibrosis. Both studies met their 
primary endpoint of ≥ 35% spleen volume reduction compared with either placebo or best 
available therapy (BAT). Starting doses for both studies were 15 mg BID for patients with 
baseline platelet counts of 100 to 200 x 109/L, and 20 mg BID for patients with baseline 
platelet counts of > 200 x 109/L. The splenic reduction timepoint for both studies occurred at 
different timepoints: Week 24 in [INCB 18424-351] and Week 48 in [CINC424A2352]. 
However, the mean volumetric spleen reduction are similar at Week 24, with 31.6% in [INCB 
18424-251 ]and 29.2% in [CINC424A2352].
The volumetric spleen reduction also showed a favorable duration of response. Of the 80 
patients from [INCB 18424-351] and the 69 patients from [CINC424A2352] that showed a ≥ 
35% spleen volume reduction at any timepoint, the probability of maintaining a response on 
INC424 for
at least 24 weeks was 89% for [INCB 18424-351]
and 87% for 
[CINC424A2352], and the probability for maintaining a response for at least 48 weeks was 
52% in [CINC424A2352].
Table 1-6
Volumetric spleen reduction of >/= 35% from baseline to Week 24 
(INCB 18424-351) and Week 48 (CINC424A2352)
INCB 18424-351
INC424 (N=155)
Placebo (N=154)
Patients with ≥35% spleen volume reduction at Week 24
65 (41.9%)
1 (0.7%)
CINC424A2352
INC424 (N=144)
BAT (n=72)
Patients with ≥35% spleen volume reduction at Week 48
41 (28.5%)
0
The results of the two pivotal studies can be summarized as follows. Both pivotal registration 
studies [INCB 18424-351] and [CINC424A2352] (COMFORT-I and COMFORT-II) met 
their primary and secondary endpoints, with the expected exception of the secondary endpoint 
of OS in Study [INCB 18424-351]:

In both studies, a statistically significantly larger proportion of patients randomized to 
INC424 achieved a ≥ 35% reduction from baseline in spleen volume compared to patients 
randomized to control. This effect was seen at both Week 24, 41.9% vs. 0.7% for placebo 


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(primary endpoint in COMFORT-I) and Week 48, 28.5% vs. 0% for BAT (primary 
endpoint in COMFORT-II).

The key secondary endpoint in COMFORT-II was met; 31.9% of patients in the INC424 
arm vs. 0% of patients in the BAT arm achieved a ≥ 35% reduction from baseline in 
spleen volume at Week 24.

In both studies, a similar median and mean reduction in spleen volume at Week 24 was 
achieved of 33% (median) and 31.6% (mean) on COMFORT-I and of 28.4% (median) and 
30.1% (mean) on COMFORT-II.

In both studies, nearly all patients treated with INC424 had some decrease in spleen size 
over time, in contrast to the patients treated with placebo or BAT, who had mean increases 
in spleen volume: 8.1% at Week 24 on placebo, and 7.3% at Week 48 on BAT.

In both studies, the reduction in spleen volume was durable. The probability of 
maintaining a response after onset of spleen volume response was 89% in COMFORT-II 
for 24 weeks and 52% in COMFORT-II for 48 weeks.

In COMFORT-I, where symptom scores were measured in a double-blind, placebo 
controlled fashion, a significantly larger proportion of patients in the INC424 arm 
achieved a ≥ 50% improvement from baseline in Week 24 total MF symptom score 
compared to the placebo arm (45.9% vs. 5.3%, p<0.0001). In addition, the INC424 arm 
showed a significantly larger (p<0.0001) mean improvement from baseline in the Week 
24 total symptom score (46.1% improvement). In contrast, the mean total symptom score 
in the placebo arm worsened over time (41.8% worsening).
1. The improvement in MF symptoms was rapid. The median time to 50% reduction in 
total symptom score among patients achieving this level was 4.4 weeks.
2. The INC424 arm had significantly greater mean percent improvement from baseline 
in the individual symptoms studied: night sweats, itching, abdominal discomfort, pain 
under ribs on left, feeling of fullness (early satiety), muscle/bone pain, and degree of 
inactivity. In contrast, the placebo arm showed worsening in all 6 individual 
symptoms as well as inactivity.

In both studies, the INC424 arm showed clinically significant improvement in quality of 
life as measured by the European Organization for Research and Treatment of Cancer, 
Quality of Life Questionnaire C30 (EORTC QLQ-C30).

Neither study was powered to demonstrate a statistically significant difference in Overall 
Survival (OS) between the two arms. Though based on a low total number of events, in 
both studies the hazard ratio (95% confidence interval) for OS was directionally in favor 
of INC424 (COMFORT-I: HR=0.67 (95% CI: 0.30, 1.50); COMFORT-II: HR=0.7 (95% 
CI: 0.20, 2.49), although confidence intervals all cross one. Kaplan–Meier estimates, 
including 4 months of additional follow-up after the primary analysis for COMFORT-I, 
show a survival advantage for INC424 (HR= 0.50; 95% CI: 0.25 to 0.98; P=0.04).

In subgroup analyses of the primary endpoint, INC424 was more effective than control 
(placebo in COMFORT-I and BAT in COMFORT-II) regardless of the presence or 
absence of the JAK2V617F mutation.
Regardless of the control treatment used (placebo or BAT); a significantly larger proportion 
of patients in the INC424 arm achieved a ≥ 35% reduction from baseline in spleen volume 


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compared with the control arm. This was observed at both Week 24 (primary endpoint in 
COMFORT-I) and Week 48 (primary endpoint in COMFORT-II).
Nearly all patients treated with INC424 in both studies had some decrease in spleen size over 
time, whereas the majority of patients treated with placebo in COMFORT-I and majority of 
patients treated with BAT in COMFORT-II had an increase in spleen size over time. Patients 
treated on the control arm of COMFORT-II received the most active therapy available to them 
and these treatments represent a typical pattern of therapies, including a preponderance of 
patients receiving hydroxyurea and smaller numbers treated with other treatments; cytotoxics, 
erythropoietic-stimulating agents, glucocorticoids, interferons, and purine analogues. Despite 
these therapies, 44% of patients had an increase in their spleen volume as their best response 
to therapy. Among all patients treated with BAT, including the 56% who had some reduction 
in spleen volume as their best response to therapy, there is still a net 8.5% median increase in 
spleen volume at Week 48.
In COMFORT-I, symptom scores were measured with an instrument specifically developed 
and validated for patients with MF and MPNs (Scherber 2011), the Modified Myelofibrosis 
Symptom Assessment Form (MFSAF) v2.0 diary. In this double-blind, placebo-controlled 
study, a significantly larger proportion of patients in the INC424 arm achieved a ≥ 50% 
improvement from baseline in the Week 24 total symptom score compared with the placebo 
arm. In addition, the INC424 arm had a significantly larger mean and median improvement 
from baseline in Week 24 total symptom score compared with the placebo arm. The placebo 
arm showed mean and median worsening over time. The improvement in MF symptoms was 
rapid; the median time to 50% reduction in total symptom score was less than 4 weeks among 
patients achieving this level of improvement. The INC424 arm had significantly greater mean 
percent improvement from baseline in the individual symptoms queried as part of the 
modified MFSAF v2.0 diary (night sweats, itching, abdominal discomfort, pain under ribs on 
left, feeling of fullness (early satiety), muscle/bone pain, and degree of inactivity [degree of 
inactivity was not part of the total symptom score]) compared with the placebo arm, which 
had a worsening, for all 6 of the individual symptoms as well as inactivity. The INC424 arm 
showed significant improvement in quality of life as measured by the EORTC QLQ-C30 in 
COMFORT-I, which was supported by similar patient reported outcome results in 
COMFORT-II.
The aforementioned improvements in quality of life have been measured in a variety of ways 
with validated patient-reported outcome instruments and demonstrate consistent findings of 
the beneficial effect of INC424 for patients with MF with regard to improvement or resolution 
of constitutional symptoms, relief of abdominal pain and discomfort, improvement in appetite 
and restoration of more normal weight, and generally improved functional activity. Apart 
from the beneficial effects of INC424 on decreasing splenomegaly and, therefore, 
extramedullary hematopoiesis, these additional beneficial effects on patients’ quality of life 
are clinically relevant.
Longer-term outcomes such as Leukemia-Free Survival (LFS) and OS were not expected to 
show benefits over this period of follow-up. No detriment in long-term outcomes was seen, 
and follow-up will continue despite being affected by the cross-over design of both studies.


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The consistency of efficacy findings, especially with regard to mean and median spleen 
volume reductions at the respective primary endpoints of 24 and 48 weeks is reassuring for 
estimating the potential benefits of INC424 and its durability of response. Importantly, other 
endpoints including symptom assessments, spleen length, and body weight all demonstrate a 
clinically important and beneficial effect of treatment with INC424. These improvements are 
all manifested early in the course of treatment and are durable over 24 and 48 weeks in the 
respective Phase III studies. This translates into an overall benefit for patients with MF, both 
in the rapid and durable reduction of extramedullary hematopoiesis that is the direct 
consequence of bone marrow fibrosis and in the marked improvement or resolution of 
constitutional and other symptoms that helps to restore a more normal quality of life.
The results from these two adequate and well-controlled Phase III studies demonstrated the 
efficacy of INC424 in patients with PMF, post-PV MF or post-ET MF.
Additional details for INC424 may be found in the [INC424 Investigator’s Brochure].
2
Rationale
2.1
Study rationale and purpose
Myelofibrosis is a clonal proliferative disease of hematopoietic stem cells driven by a 
dysregulated and overactive Janus Activating Kinase 2 (JAK) pathway, leading to an 
inappropriate cytokine release, fibrosis of the bone marrow, constitutive mobilization of 
committed progenitor cells into the peripheral blood, and extra-medullary hematopoiesis, 
mainly expressed as prominent splenomegaly (Rambaldi 2008).
INC424 is a preferential JAK1 and JAK2 inhibitor with selectivity over other kinases. Data 
from a Phase I/II study in MF (INCB 18424-251) showed that 57% of patients treated 
obtained at least a 50% reduction in palpable spleen protrusion below the left costal margin 
corresponding to an approximate 35% reduction in volumetric spleen size, and tolerated doses 
up to 25 mg BID, with activity seen at multiple dose levels from 5 mg BID to 25 mg BID. 
Data from this phase I/II study showed patient responses independent of the JAK2 mutation, 
which is consistent with dysregulated JAK signaling in MF patients. Within 1 month of 
initiating treatment, levels of pro-inflammatory cytokines and angiogenic growth factors were 
reduced, and patients noted improvement in symptoms. This improvement in symptoms was 
even seen at the lowest end of the dosing spectrum (10 mg BID) when clinically noticeable 
reduction in splenic size was rarely seen. Results from the phase I/II study were confirmed by 
two randomized phase III trials (COMFORT-I and COMFORT-II) that met their primary and 
secondary end points with high statistical significance (See Section 1.4.2.2.3).
It has been observed that Hh target genes (Gli1 and PTCH1) are overexpressed in primary 
MPN cells from patients. While JAK2 inhibition of a preclinical model of MF (MPLW515L) 
has been shown to attenuate Hh signaling, the latter is not completely shut down. 
 
 
 
Furthermore, encouraging clinical activity, in terms of post-treatment reduction in reticulin 
staining in a bone marrow sample, has been reported in a phase I dose escalation study of an 


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oral Hh inhibitor as single agent, in 1 out of 6 patients with myelofibrosis (Jamieson 2011).
This data suggest that Hh inhibition may have the potential to modify the disease process 
through reduction in bone marrow fibrosis.
Taken together, it is thought that the combination of LDE225 and INC424 could potentially 
provide improved clinical benefit to patients. Therefore, the purpose of this study is to 
determine the MTD/RPIID and to assess the safety and efficacy of the LDE225 and INC424 
combination in MF patients.
2.2
Rationale for the study design
A Bayesian Logistic Regression Model (BLRM) guided by the escalation with overdose 
control (EWOC) principle will be employed in the Phase Ib part of the study to determine the 
MTD and/or RPIID of the oral co-administration of LDE225 and INC424. This is an 
established method for dose escalation in oncology trials and is used extensively as a means 
of avoiding excessive toxicity. The dose escalation process will determine the safety and 
tolerability of the oral co-administration, as well as assess PK/PD interactions and preliminary 
efficacy based on palpable splenic length reduction at each dose level. The initial doses 
selected are lower than the respective MTD and/or clinically approved doses. Once the 
combined doses are found to be well tolerated, dose increment will be implemented one agent 
at a time to minimize potential difficulties in determining the attribution of causality of 
treatment-emergent adverse events.
Although the COMFORT I and II trials only enrolled patients with platelet counts ≥ 
100x109/L, patients with baseline platelet counts ≥ 75 x109/L will be allowed to enroll in this 
combination study. This is supported by the fact at least 20% of the exposure in the 
COMFORT II trial has been in patients experiencing thrombocytopenia. Furthermore, there is 
emerging evidence, from an ongoing Phase I trial, suggesting that patients with platelets ≥ 50 
x 109/L can tolerate increasing doses of ruxolitinib (INC424) without thrombocytopenia-
related DLTs (Expand: a Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib in 
Patients with Myelofibrosis and Baseline Platelet Counts Between 50 × 109/L and 99 × 109/L 
study [CINC424A2201-NCT01317875]).
Finally, it is hypothesized that LDE225 could reduce bone marrow fibrosis and lead to 
reductions in the doses of INC424 necessary to achieve therapeutic benefit, with the 
corresponding decrease in drug-induced cytopenias.
Once the MTD and/or RPIID is determined a safety expansion cohort of 6 patients will be 
enrolled at that dose level to further define the safety and tolerability of the combination. If 
two MTDs/RPIIDs are established, then patients enrolled in the Phase II portion will receive 
the corresponding dose based on their baseline platelet counts.
The efficacy of the co-administration of LDE225 and INC424, as determined by splenic 
volume reduction from baseline, will be evaluated using a Bayesian predictive probability of 
success (PPOS) index during the phase II portion of the study. Phase II will have a two-stage 
design. In phase II, encouraging efficacy will be concluded if the proportion of patients 
achieving a ≥ 35% reduction in spleen volume from baseline, as measured by MRI/CT at 24 
weeks, is ≥ 50%. At the initial stage (stage 1), 18 patients will be enrolled. An interim 
analysis will be conducted after the 18 patients in Stage 1 have been observed for 24 weeks or


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until death, documented disease progression, initiation of a new MF therapy, intolerable 
toxicity, withdrawal of consent, discontinuation at the discretion of the investigator or lost to 
follow-up. If the PPOS exceeds 20% based on Stage 1 patients, equivalent to observing at 
least 8 responders (i.e., spleen volumetric reduction of at least 35% through MRI/CT) 
observed over a 24 week period, an additional 28 patients will be enrolled into Stage 2. 
Encouraging efficacy will be concluded if the observed Overall Response Rate (ORR) 
exceeds 50% (i.e. 23/46). Additionally, in this Phase II part, the effect of the combination of 
bone marrow fibrosis and disease-specific pharmacodynamics biomarkers as a function of the 
molecular disease characterization of myelofibrosis will be evaluated to support the 
development of patient pre-selection markers.
2.3
Rationale for dose and regimen selection
The MTD of LDE225 (800 mg QD) and approved INC424 doses (15 mg or 20 mg BID) as 
single agents have been previously established in several phase I and later stage studies, 
respectively.
Since this is the first co-administration study with LDE225 and INC424, starting doses that 
are lower than the respective MTD and/or clinically approved doses have been chosen 
(LDE225 400 mg QD plus INC424 10 mg BID). Preliminary clinical safety data from the 
single-agent studies of LDE225 and INC424 do not suggest a tendency for significant 
overlapping toxicities. In particular, no evidence of bone marrow suppression has been 
observed with LDE225 monotherapy, up to 3000 mg QD. Thus, the starting dose and regimen 
are considered safe.
Both LDE225 and INC424 are primarily metabolized by CYP3A4. In vitro, LDE225 did not 
inhibit CYP1A2, 2A6, 2C8, 2C19, 2D6, 2E1 or 3A4/5 at concentrations of up to 100 μM, 
which is much higher than the expected steady-state Cmax of approximately 3 μM based on 
the preliminary population PK model at 800mg QD. No apparent time-dependent inhibition of 
the major CYP450 enzymes or induction of CYP3A4 was observed. LDE225 was found to be 
an inhibitor of CYP2B6 which did not contribute to INC424 turnover. LDE225 was also 
found to be an inhibitor of CYP2C9. Since CYP2C9 is a minor metabolic pathway of 
INC424, the inhibition effect from LDE225 is not expected to be clinically significant. 
Therefore, LDE225 is not expected to affect the PK of INC424. In vitro, INC424 and its M18 
(main metabolite in human circulation) were not potent inhibitors of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 (IC50 >25 µM for INC424 and >3 µM 
for M18). In addition, INC424 did not exhibit time-dependent inhibition of CYP3A4 activity 
or induction of CYP3A4 at clinically relevant concentrations. As the clinical steady state 
plasma Cmax values of INC424 and M18 following the highest proposed therapeutic dose of 
25 mg twice daily are 1.2 μM and 0.14 μM, respectively, it is unlikely that INC424 or M18 at 
therapeutic concentrations will cause clinical drug interactions with LDE225. No transporter 
drug-drug interaction is expected between LDE225 and INC424 since neither is a substrate of 
transporters or inhibitor of transporters examined. Therefore, no drug-drug interaction is 
expected from the co-administration of LDE225 and INC424.
2.4
Rationale for choice of combination drugs
The rationale for the co-administration of LDE225 and INC424 is as follows:


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
Several lines of evidence suggest that the hedgehog (Hh) signaling pathway plays an 
important role in many hematological malignancies.

It has been shown that the Hh pathway is activated in MPN CD34+ cells compared to 
controls, as measured by Gli1 and PTCH1 expression. Also, this pathway has been shown 
to be activated in the MPLW515L murine model of PMF [Levine 2012].

There is preclinical evidence that the Hh pathway is attenuated, but not eliminated, by 
treatment with a JAK2 inhibitor in the aforementioned PMF mouse model [Levine 2012].

It is hypothesized that Smo inhibition might have disease-modifying effects via reduction 
in bone marrow fibrosis and inhibition of cancer-initiating cells.

Potential to reduce the doses of INC424 necessary to achieve a therapeutic effect while 
reducing INC424-associated dose limiting toxicity (anemia and thrombocytopenia). 
Reduction of toxicity may allow for non-interrupted exposure to agents, bestowing a 
higher chance for a disease-modifying effect that may only take place upon prolonged 
treatment.

Finally, no drug-drug interactions are predicted. Minimal overlapping toxicities are 
expected based on prior monotherapy experience for either agent. No significant 
myelotoxicity has been noted with the use of LDE225.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Phase Ib
Primary
To establish the MTD and/or RPIID of the co-administration of 
LDE225 and INC424 in patients with MF, who have not 
previously received therapy with a JAK inhibitor
Dose Limiting Toxicities (DLTs) occurring during the first 6 weeks of 
the co-administration of INC424 and LDE225
Refer to Section 10.4.
Secondary
To evaluate the safety of the co-administration of LDE225 and 
INC424 in patients with MF
Adverse and serious adverse events, abnormalities in physical 
examinations, vital signs and laboratory test values, including ECG 
data
Refer to Section 10.5.1.
To characterize the single and multiple dose pharmacokinetics 
following the co-administration of LDE225 and INC424
LDE225 and INC424 PK parameters
Refer to Section 10.5.2.
Exploratory
To assess the preliminary efficacy of the co-administration of 
LDE225 and INC424 as determined by physical examination of 
the spleen
Proportion of patients achieving ≥ 50% reduction in palpable spleen 
length measured below the left costal margin from baseline compared 
to Week 24
Refer to Section 10.6.
To assess the preliminary efficacy of the co-administration of 
LDE225 and INC424 as determined by centrally reviewed 
MRI/CT of the spleen at the MTD(s) and/or RPIID(s) in the 
expansion cohort only
Proportion of patients achieving ≥ 35% reduction in spleen volume 
from baseline as measured by MRI/CT at Week 24
Refer to Section 10.6.
To assess the effect of the co-administration of LDE225 and 
INC424 on bone marrow fibrosis by central review
Proportion of patients experiencing improvement in bone marrow 
fibrosis by at least one grade according to the European consensus on 
grading bone marrow fibrosis and assessment of cellularity (Thiele 
2005) at Week 24
Refer to Section 10.6.
To assess efficacy of the co-administration of LDE225 and 
INC424 and the effect on disease- specific pharmacodynamic 
biomarkers as a function of the molecular disease 
characterization of MF
Efficacy parameters such as, reduction in bone marrow fibrosis and 
palpable spleen length from baseline compared to Week 24
Change in JAK2V617F allele burden from baseline compared to Week 
24
Change in cytokine levels from baseline compared to Week 24
Refer to Section 10.6.
To assess the PK-PD relationship
Relationship of PK exposure parameters of LDE225 and INC424 with 
changes in safety, pharmacodynamic biomarkers and efficacy 
parameters
Refer to Section 10.6.


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Objective
Endpoint
Analysis
To assess the effect of the co-administration of LDE225 and 
INC424 on MF-associated symptoms burden at the MTD and/or 
RPIID
Change from baseline in total symptom score as measured by the 
modified MFSAF v2.0 at Week 24
Proportion of patients having ≥ 50% reduction in total symptom score 
from baseline as measured by the modified MFSAF v2.0 at Week 24
Change in EORTC QLQ-C30 scores from baseline compared to Week 
24
Refer to Section 10.6.
Assess the effect of the co-administration of LDE225 and 
INC424 on Hh pathway target gene expression
Changes from baseline values in key components of the Hh pathway 
such as Gli1
Refer to Section 10.6.
Phase II
Primary
To assess the efficacy of the co-administration of LDE225 and 
INC424 on spleen volume reduction as determined by centrally 
reviewed MRI/CT
Proportion of patients achieving ≥ 35% reduction in spleen volume 
from baseline as measured by MRI/CT at Week 24 and Week 48
Refer to Section 10.4.
Secondary
To assess the effect of the co-administration of LDE225 and 
INC424 on bone marrow fibrosis by central review and on 
disease-specific pharmacodynamic biomarkers as a function of 
the molecular disease characterization of MF
Proportion of patients experiencing improvement in bone marrow 
fibrosis by at least one grade according to the European consensus on 
grading bone marrow fibrosis and assessment of cellularity (Thiele 
2005) at Week 24 and Week 48
Change in JAK2V617F allele burden from baseline compared to Week 
24 and Week 48
Change in cytokine levels from baseline compared to Week 24 and 
Week 48
Refer to Section 10.5.
To evaluate the safety of the co-administration of LDE225 and 
INC424 in patients with MF
AEs, SAEs, changes in hematology and chemistry values, and 
assessment of physical examinations, vital signs and 
electrocardiograms
Refer to Section 10.5.1.
To characterize the pharmacokinetics following the co-
administration of LDE225 and INC424
Stage 1: LDE225 and INC424 PK parameters
Stage 2: Ctrough of LDE225 and INC424
Refer to Section 10.5.2.


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Objective
Endpoint
Analysis
To assess the effect of the co-administration of LDE225 and 
INC424 on MF-associated symptoms burden
Change from baseline in total symptom score as measured by the 
modified MFSAF v2.0 at Week 24 and Week 48
Proportion of patients having ≥ 50% reduction in total symptom score 
from baseline as measured by the modified MFSAF v2.0 at Week 24 
and Week 48
Change in EORTC QLQ-C30 scores from baseline compared to Week 
24 and Week 48
Refer to Section 10.5.4.
Exploratory
Assess the effect of the co-administration of LDE225 and 
INC424 on Hh pathway target gene expression 
Changes from baseline values in key components of the Hh pathway 
such as Gli1 at Week 24 and Week 48
Refer to Section 10.6.


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4
Study design
4.1
Description of study design
This study consists of an open-label, multi-center, dose-finding Phase Ib followed by an open-
label, two stage, Phase II part enrolling patients with primary myelofibrosis (PMF), post-
polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia 
myelofibrosis (post-ET MF).
Figure 4-1
Study design


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4.1.1
Phase Ib dose escalation and safety expansion
Approximately five cohorts of 3-6 newly enrolled patients will receive increasing doses of 
LDE225 and INC424 until the MTD and/or RPIID is reached. A minimum of 3 evaluable 
patients are required in each cohort for making dose escalation decisions. For the purpose of 
dose escalation, the DLT observation period will be the first 6 weeks (42 days) following 
initiation of study treatment. The dose escalation part will start at 400 mg QD of LDE225 and 
10 mg BID of INC424. The LDE225 dose represents 50% of the MTD and the INC424 dose 
represents 50% of the highest recommended starting dose when administered as monotherapy.
The minimum treatment and safety evaluation requirements for dose escalation will have been 
met if:

The patient has been treated with at least 75% of the assigned treatment of LDE225 and 
INC424 during the first 6 weeks of study treatment (42 days) and observed for at least 6 
weeks (42 days) following the first dose, and

The patient has completed sufficient safety evaluations, as agreed by the investigators and 
the Sponsor, to determine whether a DLT has occurred or not.
A Bayesian Logistic Regression Model (BLRM) with overdose control (EWOC) will be used 
to guide dose escalation (see Section 6.2.3.2). Various dose pairs will be explored following 
the recommendation of an adaptive BLRM until a combination MTD and/or RPIID is 
determined. When enrollment of the cohort is complete, further enrollment will only resume 
after Novartis and the investigators have jointly reviewed the data and decided on the next 
dose escalation step of this combination. At each decision time point, the adaptive BLRM will 
provide the upper boundary for the combinations that meet the EWOC criteria. A clinical 
synthesis of the available toxicity information, PK, PD, and efficacy information as well as 
the recommendations from the Bayesian model is used to determine the combination dose for 
the next cohort at a dose escalation meeting or teleconference.
Each dose escalation cohort will consist of patients with low (≤ 200 x109/L), high (> 200 
x109/L) or both low and high baseline platelet counts. Decisions for the next dose will be 
made together for all patients, unless thrombocytopenia related dose limiting toxicities 
(DLTs) are observed, leading to different recommended dose combinations for patients with 
low and high baseline platelet counts. In this case, Novartis and study investigators may also 
decide to continue to treat both groups of patients together at the lower of the recommended 
dose combinations.
If a single MTD and/or RPIID is established for both low and high platelet sub-groups then an 
additional safety expansion cohort of 6 patients will be enrolled at that dose level to further 
define the safety and tolerability of the combination. If a single MTD/RPIID is established 
then all patients in Phase II will receive that dose irrespective of baseline platelet levels.
If separate MTDs and/or RPIIDs are declared for low and high platelet sub-groups due to 
differential experience relating to thrombocytopenia-related DLTs then a safety expansion 
cohort of 6 patients per sub-group will be enrolled and treated at the respective 
MTDs/RPIIDs. However, if deemed appropriate Novartis and the investigators may decide to 
use the lower MTD/RPIID for all patients in the Phase II portion, regardless of the baseline 
platelet count. Refer to Section 6.2.3.1 for the definition of the MTD and/or RPIID.


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Approximately 36 patients are expected to participate in the dose escalation and safety 
expansion part. The total number of patients enrolled in the entire study will depend on the 
number of dose escalation steps and drop-outs.
Once the MTD and/or RPIID is established, efficacy of the oral co-administration therapy 
through MRI/CT scans measuring splenic volume reduction from baseline will be evaluated 
using a Bayesian predictive probability of success (PPOS) index during the Phase II portion of 
the study. In Phase II, encouraging efficacy will be concluded if the proportion of patients 
achieving a ≥ 35% reduction in spleen volume from baseline, as measured by MRI/CT at 24 
weeks, is ≥ 50%. Additionally, in this Phase II part, the effect of the combination on bone 
marrow fibrosis and disease-specific pharmacodynamics biomarkers as a function of the 
molecular disease characterization of myelofibrosis will be evaluated. 
 
 
 
 
. 
 
 If two MTDs/RPIIDs are 
established, all patients in Phase II will receive the corresponding dose based on their platelet 
status.
Approximately 46 patients in total will be enrolled in two stages in the Phase II part. An 
interim analysis will be conducted after Stage 1, see Section 4.2 for details.
Patients will continue the study treatment for at least 2 years after the first dose or until death,
documented disease progression, intolerable toxicity, withdrawal of consent, discontinuation 
at the discretion of the investigator, lost to follow-up or discontinuation from the study, 
whichever comes first. Patients who complete 2 years of treatment and are deriving clinical 
benefit in the opinion of the investigator will be allowed to continue receiving treatment 
(LDE225 and INC424) in an extension phase of this study, until discontinuation reasons are 
met or an alternative setting to receive study treatment (e.g., in form of another protocol) 
becomes available.
4.2
Timing of interim analyses and design adaptations
An interim analysis will occur after 18 patients enroll into Stage 1 of the phase II part of the 
study and have been observed for a minimum of 24 weeks or until death, documented disease 
progression, intolerable toxicity, withdrawal of consent, discontinuation at the discretion of 
the investigator, or lost to follow-up. After this timeframe, enrollment will be halted for 
futility if there are less than 8 responders (i.e., patients with a spleen volumetric reduction 
from baseline of at least 35% by MRI/CT at 24 weeks). If at least 8 patients respond over the 
minimum observation period of 24 weeks, 28 additional patients will be enrolled into stage 2.
4.3
Definition of end of the study
4.3.1
End of study treatment
Patients will be treated for at least 2 years or until they permanently discontinue both study 
drugs due to any cause. Patients who complete 2 years of treatment and are deriving clinical
benefit in the opinion of the investigator will be allowed to continue receiving treatment 


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(LDE225 and INC424) in an extension phase of this study, until discontinuation reasons are 
met or an alternative setting to receive study treatment (e.g., in form of another protocol) 
becomes available.
If either of the combination drugs is permanently discontinued then the other combination 
partner must also be permanently discontinued.
4.3.2
End of study
The study will end when the last patient completes treatment, or 30 days after the last patient 
discontinues from the study, or early termination of the study, whichever comes first.
The Clinical Study Report (CSR) will be written at the end of the trial when all patients have 
discontinued. 
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Adult patients, aged ≥ 18 years who have been diagnosed with PMF, post-PV MF, or post-ET 
MF, as defined by the World Health Organization (2008) and:

Are classified as high risk (3 or more prognostic factors) OR intermediate risk level 2 (2 
prognostic factors) OR intermediate risk level 1 (1 prognostic factor which is not age), as 
defined by the International Working Group, IWG (Cervantes 2009).

Exhibit palpable splenomegaly ≥ 5 cm below the left costal margin and MF-related active 
symptoms.

Exhibit platelet counts of ≥ 75 x 109/L without the aid of transfusions.
Only JAK inhibitor naïve patients will be eligible for the study.
The total number of patients expected to enroll into the entire study, allowing for dropouts and 
non-evaluable patients, is approximately 82. The actual number of patients recruited will 
depend upon the number of dose levels tested in the dose escalation set, the number of 
patients enrolled into the safety expansion and the Phase II part.
Patients enrolled in the study cannot participate in any concurrent clinical study investigating 
other investigational agents or devices. Patients who have completed or discontinued the 
study may not be re-enrolled in the study.
The investigator or designee must ensure that only patients who meet all of the following 
inclusion and none of the exclusion criteria are offered treatment in the study.


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5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures.
2. Patients must be 18 years or older.
3. Patients must be diagnosed with PMF, post-PV MF or post-ET MF, as established in the 
2008 World Health Organization (WHO) criteria for PMF (Tefferi 2008), and the 
proposed criteria for post-PV MF and post-ET MF outlined by the International Working 
Group for Myelofibrosis Research and Treatment (IWG-MRT) (Barosi 2008).
4. Ineligible or unwilling to undergo stem cell transplantation.
5. Platelet count ≥ 75 x 109/L not reached with the aid of transfusions.
6. ANC > 1.5 x 109/L, without the use of G-CSF within two weeks prior to Screening.
7. INR < 1.5.
8. ECOG performance status ≤ 2.
9. Palpable splenomegaly defined as ≥ 5 cm below the left costal margin.
10. Patients must be classified as intermediate risk level 1 (1 prognostic factor which is not 
age), Intermediate risk level 2, or high risk. The prognostic factors, defined by the 
International Working Group (Cervantes 2009) are:

age > 65 yrs,

presence of constitutional symptoms (weight loss > 10% in the year preceding the 
Screening Visit, unexplained fever, or excessive night sweats persisting for more than 
1 month),

marked anemia (Hgb < 10g/dL),

leukocytosis (history of WBC > 25 x109/L),

circulating blasts ≥ 1%,
* A hemoglobin value < 10 g/dL must be demonstrated during Screening for patients 
who are not transfusion dependent. Patients receiving regular transfusions of packed 
red blood cells will be considered to have hemoglobin < 10 g/dL for the purpose of 
evaluation of risk factors.
11. Patients must have active symptoms of MF as demonstrated by one symptom score of at 
least 5 (0 to 10 point scale) or two symptom scores of at least 3 (0 to 10 point scale) on the 
MF Symptom Assessment Form (MFSAF).
12. Patients must have discontinued all drugs used to treat their underlying MF disease for at 
least 7 days prior to Screening. Corticosteroids used for conditions other than MF are 
allowed, as long as the daily dose is less than the equivalent of 10 mg of prednisolone, and 
has been stable (or decreasing) for at least 5 days before initiating study therapy.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Previous therapy with JAK inhibitors.
2. Previous therapy with a Smo inhibitor.
3. Patients with inadequate organ function as demonstrated by:


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
encephalopathy grade 1 or more, as per West Haven Criteria (Ferenci 2002, Appendix 
6),

known hepatocellular disease (e.g. active hepatitis or cirrhosis),

Total bilirubin ≥ 2 x upper limit of normal (ULN) range of values, unless due to 
elevated indirect bilirubin (e.g. Gilbert’s syndrome or hemolysis),

alanine aminotransferase (ALT) > 3 ULN,

MDRD eGFR < 30 mL/min/1.73m2 or on dialysis (Appendix 5),

Creatine phosphokinase (CPK) > 1.5 x ULN.
4. Patient has impaired cardiac function or clinically significant heart disease, including any 
one of the following:

Clinically significant heart disease (e.g., congestive heart failure, uncontrolled 
hypertension, history of labile hypertension, or history of poor compliance with an 
antihypertensive regimen),

QTc interval corrected for heart rate using Fridericia’s formula (QTcF) > 450 msec 
for males and > 470 msec for females on the screening ECG,

A past medical history of clinically significant ECG abnormalities or a family history 
of prolonged QT-interval syndrome,

Angina pectoris within 3 months before first dose of study treatment,

Acute myocardial infarction within 3 months before first dose of study treatment.
5. Patient has evidence of an active malignancy, with the exception of controlled prostate 
cancer, basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the 
cervix or breast and has been disease-free for more than 3 years.
6. Patients with acute bacterial infections requiring antibiotic therapy should delay 
screening/enrollment until the course of antibiotics has been completed.
7. Patient is currently on medications that interfere with coagulation (including warfarin) or 
platelet function. Low dose aspirin (up to 150 mg per day) and low molecular weight 
heparin (LMWH) are allowed.
8. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of INC424 or LDE225 (e.g., uncontrolled nausea, 
vomiting, diarrhea; malabsorption syndrome; small bowel resection).
9. Patient had major surgery within 2 weeks of initiation of study medications.
10. Patients who have had splenic irradiation within 12 months prior to Screening.
11. Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular 
dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on 
concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as 
HMG CoA inhibitors (statins), clofibrate and gemfibrozil. Pravastatin may be used if 
necessary, with extra caution.
12. Patients who plan on embarking on new (or unaccustomed) physical activities, such as 
strenuous exercise, that can result in significant increases in blood CK levels while on 
study treatment. NOTE: As a precaution, strenuous muscular activity should be avoided 
for at least 1 week prior to testing for blood CK levels.


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13. Use of other investigational drugs within 30 days of or 5 half-lives of initiation of study 
treatment, whichever is longer.
14. Patients who are receiving treatment with medications known to be moderate and strong 
inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that 
have narrow therapeutic index, and that cannot be discontinued before starting treatment 
with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued at 
least 7 days and strong CYP3A4/5 inducers for at least 2 weeks prior to starting treatment 
with LDE225.
15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (> 5 mIU/mL).
16. Patients who are not willing to apply highly effective contraception during the study and 
through the duration as defined below after the final dose of study treatment.
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective contraception during the study and through 
20 months after the final dose of study treatment. Highly effective contraception is 
defined as either:

Total abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception,

Sterilization: Patient has had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment,

Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). [For female study patients, the vasectomised male 
partner should be the sole partner for that patient],

Use a combination of the following (both a+b):
a. Placement of a non-hormonal intrauterine device (IUD) or non-hormonal 
intrauterine system (IUS),
b. Barrier method of contraception: Condom or Occlusive cap (diaphragm or 
cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
Note:
i)
Hormonal contraception methods (e.g. oral, injected, implanted) are not allowed 
as it cannot be ruled out that the study drug decreases the effectiveness of 
hormonal contraception.
ii) Women are considered post-menopausal and not 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) or six 
months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and 
estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or 
without hysterectomy) 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.


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iii) Male patient must use highly effective (double barrier) methods of contraception 
(e.g., spermicidal gel plus condom) for the entire duration of the study, and 
continue to use contraception and refrain from fathering a child for 6 months 
following the last dose of study drug. A condom is also required to be used by 
vasectomized men in order to prevent delivery of the study treatment via seminal 
fluid.
17. Inability to understand the protocol requirements, instructions and related restrictions, the 
nature, scope and possible consequences of the study.
18. Unlikely to comply with the protocol requirements, instructions and study related 
restrictions (e.g. uncooperative attitude, inability to return for follow up visits, 
psychological illness, and improbability of completing the study).
6
Treatment
6.1
Study treatment
In this study, the terms “investigational drug”, “study drug” or “study treatment” refers to the 
oral co-administration of LDE225 QD and INC424 BID administered to patients daily. The 
investigational treatment for this trial, which is the drug combination whose properties are 
being tested in this study, is LDE225 and INC424.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study 
treatment
s
Pharmaceutical form and 
route of administration
Dose
Frequency 
and/or Regimen
LDE225
Capsule for oral use
Starting dose 400 mg to be increased or 
decreased per Bayesian design (see Section 
6.2.1)
Once a day/QD
INC424
Tablet for oral use
Starting dose 10 mg to be increased per 
Bayesian design (see Section 6.2.1)
Twice a day/BID
Patients should be instructed to take their daily dose of LDE225 once in the morning and 
INC424 twice a day, at approximately the same time each day. Each daily dose of LDE225 
(including days which involve PK blood sampling) must be taken approximately 2 hours after 
a light breakfast (e.g., consisting of milk, toast and jam). For example, if breakfast was 
completed at 08:00 a.m., then study drug administration should occur at 10:00 a.m. Patients 
must also then fast from food and drinks (except water) for 1 hour following dosing. A light 
snack may be taken if absolutely necessary (eg, crackers or toast), but high-fat meals must be 
avoided for 2 hours before and 1 hour after each dose. INC424 can be taken with or without 
food, therefore the morning dose of INC424 can be taken concurrently with LDE225. The 
afternoon/evening dose of INC424 can be taken with or without food, approximately 12 hours 
after the morning dose. LDE225 and INC424 should be taken with a glass of water and should 
be swallowed whole. Patients must avoid consumption of Seville (sour) oranges/ juice, 
grapefruit products/juice, grapefruit hybrids, pummelos and exotic citrus fruits during the 


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entire study and preferably 7 days before the first dose of study medications, due to potential 
CYP3A4 interaction with the study medications. Orange juice is allowed.
If the patient forgets to take his/ her daily LDE225 dose, then they should take it within 6 
hours after the missed dosing time. If more than 6 hours have passed, then that day’s dose 
must be omitted and the patient should continue treatment with the next scheduled dose.
If a patient misses a dose of INC424, then he/she should take INC424 within 3 hours after the 
missed dose. If more than 3 hours have passed, then that missed dose should be omitted and 
the patient should continue treatment with the next scheduled dose. Patients should not take 2 
doses at the same time.
Patients should inform the investigational site staff of any missed or delayed doses.
If vomiting occurs during the course of the study treatment, then no re-dosing of the patient is 
allowed before the next scheduled dose. The occurrence and frequency of any vomiting must 
be noted in the adverse events section of the eCRF.
On days when pre-dose PK sampling is required, the patient should take his/her dose at the 
clinic after the sampling and a light meal. The patient must not eat until instructed to do so at 
the clinic.
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guidelines for continuation of treatment
For guidelines on the continuation of treatment, refer to Section 6.3 Dose modifications.
6.1.5
Treatment duration
The planned duration of treatment is at least 2 years.  Patients may be discontinued from 
treatment with the study drugs due to documented disease progression, intolerable toxicity, 
withdrawal of consent, discontinuation at the discretion of the investigator, or lost to follow-
up, whichever comes first.
Patients who complete 2 years of treatment and are deriving 
clinical benefit in the opinion of the investigator will be allowed to continue receiving 
treatment (LDE225 and INC424) in an extension phase of this study, until discontinuation 
reasons are met or an alternative setting to receive study treatment (e.g., in form of another 
protocol) becomes available.
The extension phase will begin on the day after the Week 105 visit. The first extension phase 
visit will occur 12 weeks after the Week 105 visit.  See Table 7-2 for the schedule of 
assessments during the study extension phase.
A safety follow-up will be conducted 30 days (+3 days) after the last dose of study medication 
is received and a study completion form will be completed in the eCRF. The safety follow-up 


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may be waived if the patient is continuing on INC424 and LDE225 treatment in an alternative 
setting.
6.2
Dose escalation guidelines
6.2.1
Starting dose rationale
INC424 as a single agent has been tolerated up to doses of 25 mg BID and a minimum 25% 
reduction in splenomegaly was seen in the majority of patients treated at 10 mg BID, 15 mg 
BID, and 25 mg BID (Verstovsek 2010). From [INCB018424-251] and supported by results 
from [CINC424A2352] (See Section 1.4.2.2.3), 15 mg BID and 20 mg BID were established 
as the most effective and safest starting doses followed by individualized dose titration 
(Verstovsek 2010).
LDE225 as a single agent has been evaluated in dose levels of 100, 200, 400, 800, 1000, 1500 
and 3000 mg QD, and 250, 400 and 750 mg BID. Based on the available data from 
[CLDE225X2101], the maximum tolerated dose of LDE225 in adult patients is 800 mg QD. 
Since this is the first study of LDE225 in combination with INC424, starting doses that are 
lower than the respective MTDs and/or clinically approved doses have been chosen as 
LDE225 400 mg QD plus INC424 10 mg BID.
The starting dose and regimen are considered safe. In addition, no drug-drug interaction is 
expected from the combination.
The starting doses for each drug have been selected based on prior monotherapy experience 
where these doses have shown some degree of clinical activity as single agents and 
pharmacodynamic data supports the activity observed. In the interest of patient safety, both of 
these compounds will start at dose levels at or near 50% of their respective maximum 
tolerated doses. The provisional doses for dose escalation are shown in Table 6-2.
6.2.2
Provisional dose levels
The first cohort will start at low doses for both drugs (LDE225 at 400 mg QD and INC424 at 
10 mg BID). The doses will then be escalated following the recommendation of an adaptive 
Bayesian logistic regression model for dose escalation with overdose control (EWOC) until 
the MTD and/or RPIID is defined.
Dose escalation will be guided by the following considerations:

At all decision time points, the adaptive Bayesian logistic model permits alterations in the 
dose increments based on the observed DLTs. Only one of the 2 combination partners can 
be escalated and the maximum inter-cohort dose escalation is limited to 100%, i.e. up to 
100% and 0% increase for LDE225 and INC424 respectively or 0% and up to 100% 
increase for LDE225 and INC424 respectively.

The proposed combination meets the EWOC criteria (i.e. less than 25% chance that the 
true rate of DLT lies within the interval [35% - 100%].

If at any time ≥ 35% of patients in a cohort experience a DLT and 2 or more DLTs have 
occurred in that cohort, one of the following actions will be implemented:
1. Reduce the dose of one of the combination partners or both and enroll a new cohort


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2. Termination of any further escalation of the combination partners
If two MTDs/RPIIDs are established all patients in Phase II will receive the corresponding 
dose based on their platelet status. The selected action may only be permitted if the respective 
dose combination satisfies the overdose control criteria.
Table 6-2 describes the starting dose and the dose levels that may be evaluated during this 
trial.
Table 6-2
Provisional dose levels
Dose level
Proposed daily dose*
Increment from previous dose
Cohort
-1**
INC424 10 mg BID, LDE225 200 mg QD
-50% LDE225 dose
Cohort
1
INC424 10 mg BID, LDE225 400 mg QD
(starting dose)
Cohort
2
INC424 15 mg BID, LDE225 400 mg QD
+50% INC424 dose
Cohort
3
INC424 15 mg BID, LDE225 800 mg QD
+100 % LDE225 dose
Cohort
4
INC424 20 mg BID, LDE225 800 mg QD
+33% INC424 dose
*Depending on the emerging data, it is possible to explore other combination dose levels without exceeding the 
highest admissible combination dose-level per the BLRM. Thus, intermediate dose levels other than those listed
above may be evaluated.
**Dose level -1 represents the treatment dose for patients requiring a dose reduction from the starting dose level. 
No dose reduction below dose level -1 is permitted for this study, however if patients experience 
thrombocytopenic DLTs in Cohort 1 then those patients will receive INC424 5 mg BID and LDE225 200 mg QD.
6.2.3
Guidelines for dose escalation and determination of MTD and/or RPIID
6.2.3.1
Definitions of MTD and/or RPIID
The MTD for this study is defined to be the highest dose of LDE225 and INC424 not 
expected to cause dose limiting toxicity (DLT) in more than 35% of patients.
The RPIID may be determined to be the same as the MTD or may be lower if the evolving 
safety profile and other assessments (e.g. PK) suggest a better safety profile without 
substantial loss of benefit in exposure/potential antitumor activity. The RPIID may also be 
determined without reaching MTD (e.g. no substantive increases in exposure with increases in 
dose), if evolving safety and other assessments indicate further increases in dose will result in 
excessive toxicity without additional benefit.
6.2.3.2
Implementation of dose escalation decisions
A 6-parameter Bayesian Logistic Regression Model (BLRM) for combination treatment will 
be fitted on the 6-week dose-limiting toxicity data (i.e. absence or presence of DLT) 
accumulated throughout the dose escalation to model the dose-toxicity relationship of 
LDE225 and INC424 when given in combination.
The general plan is that cohorts of patients will receive escalating doses of LDE225 or 
INC424 until the MTD of the combination is reached. Each cohort will consist of newly 
enrolled patients. The following provides a full description of the algorithm of dose 
escalation/de-escalation for the study:
a. A cohort of 3 to 6 evaluable patients will typically be treated at each dose level of 
LDE225 in combination with INC424.


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b. Patients will be considered evaluable for dose escalation if they have met the minimum 
treatment and safety evaluation requirements listed below or if they experience a DLT 
during the first 6 weeks. Patients who do not meet the minimum treatment and safety 
evaluation requirements provided below will be regarded as ineligible for inclusion in the 
dose determining set (DDS: see Section 10.1.3) and additional patients may be enrolled to 
ensure an adequate number of evaluable patients in each cohort. The minimum treatment 
and safety evaluation requirements for dose escalation will have been met if:
1. The patient has been treated with at least 75% of the planned doses of LDE225 and 
INC424 in 6 weeks (42 days) (i.e. no more than 10 missed doses of LDE225 and no 
more than 20 missed doses of INC424 in 6 weeks are permitted).
2. The patient has been observed for at least 6 weeks following the first dose, and
3. The patient has completed sufficient safety evaluations, as agreed by the investigators 
and the Sponsor, to determine that a DLT did not occur.
c. After completion of each cohort the BLRM will be used to make recommendations about 
the next dose level, with the following two exceptions:

If 2 of the first 2-3 patients in a cohort experience a DLT, further enrollment to that 
cohort will be suspended. The Bayesian logistic regression model will be updated 
with this new information before additional patients are enrolled to the study.

If a decision is made to escalate to a higher dose level, but one or more additional 
patient(s) (under the condition e) treated at any previous dose level experiences a 
DLT in 42 days, then the BRLM will be updated before any additional patient is 
enrolled to the higher dose level.
d. Following the principle of EWOC, after completion of each cohort of patients the 
recommended dose is one among the doses fulfilling EWOC, and typically, the one with 
the highest posterior probability of the DLT rate falling in the target interval [0.16, 0.35). 
Per EWOC it should be unlikely (< 25% posterior probability) that the DLT rate at the 
dose will induce excessive toxicity [0.35, 1.00]. The maximum dose increments specified 
in Section 6.2.2 will not be exceeded.
e. For further understanding of the safety, tolerability and PK of LDE225 and INC424, 
additional patients may be enrolled at dose levels established to be safe before or while 
proceeding with further dose escalation.
To determine the dose regimen for the next cohort, the available toxicity information 
(including adverse events that are not DLTs), PK, PD, and efficacy information, as well as the 
recommendations from the BLRM will be evaluated by the Investigators and Novartis study 
personnel (including the study physician and statistician) at a dose decision meeting or 
teleconference.
Dose escalation will continue until identification of the MTDs and/or RPIIDs. This will occur 
when the following conditions are met:
1. at least 9 patients have been treated at each MTD and/or RPIID dose,
2. this dose satisfies one of the following conditions:
a. the posterior probability of targeted toxicity at this dose exceeds 50%, or
b. a minimum of 24 patients have already been treated in Phase Ib.


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Drug administration at the next dose level may not proceed until the investigator receives 
written confirmation from Novartis that the results of the previous dose level were evaluated 
and it is safe to proceed to a higher dose level. The Dose Determining Set (DDS: See Section 
10.1.3) will be used for the determination of the MTD and/or RPIID.
6.2.4
Dose cohort modification
Provisional dose levels are listed in Table 6-2. Possible changes in dose administration 
according to the BLRM include but are not limited to:
a.
Expansion of the current dose group to further assess suspected treatment-related adverse 
events
b. Administration of a dose below the starting dose for the study
c.
Administration of an intermediate dose between the current and preceding dose
d. Administration of an intermediate dose between the current and the next planned dose
e.
Termination of any further escalation of study drug
If a decision is made to escalate to a higher dose level, and subsequently additional patient(s) 
on the lower dose level experiences a DLT in the first 6 weeks of treatment, then further 
enrollment of patients to the higher current dose will be put on hold until the statistical model 
has been updated with the new safety information. Enrollment to the higher dose level may be 
resumed only if it is still recommended by the updated model and considered acceptable 
following a medical review.
Clinically relevant toxicities will be those assessed as unrelated to disease, disease 
progression, inter-current illness, or concomitant medications.
Additional patients may be enrolled if the minimum number of evaluable patients required to 
meet study objectives are not available.
6.2.4.1
Implementation of dose escalation decisions
To implement dose escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the 
BLRM, and the available PK and PD information will all be evaluated by the Investigators 
and Novartis study personnel (including the study physician and statistician) during a dose 
decision meeting by teleconference. Drug administration at the next higher dose level may not 
proceed until the investigator receives written confirmation from Novartis indicating that the 
results of the previous dose level were evaluated and that it is permissible to proceed to a 
higher dose level.
6.2.4.2
Intra-patient dose escalation during Phase Ib
Intra-patient dose escalation is not permitted at any time within the first 24 weeks of study 
treatment. At Week 25, individual patients on INC424 doses of 10 mg or 15 mg BID may be 
considered for treatment at one INC424 dose level higher than the dose level to which they 
were initially assigned, the LDE225 dose must remain constant. Patients may only intra-
patient dose escalate by one INC424 level every 4 weeks up to a maximum dose of INC424 
20 mg BID. In order for a patient to be treated at a higher dose level of INC424, he or she 
must have tolerated the initial dose level for at least 24 weeks of therapy (e.g., he or she must 


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not have previously experienced a toxicity of CTCAE grade ≥ 2 for which relationship to 
study drug cannot be ruled out). Moreover, the new, higher dose level with which the patient 
is to be treated must be a dose level that has been declared to be well-tolerated at a dose 
escalation meeting and does not exceed the MTD.
Consultation with Novartis must occur prior to any intra-patient dose escalation occurring. 
These changes must be recorded on the Dosage Administration Record CRF.
6.2.5
Definitions of dose limiting toxicities (DLTs)
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as unrelated to disease progression, inter-current illness, or concomitant medications 
that meets any of the following criteria in Table 6-3.
For the purpose of dose escalation decisions, only DLTs occurring during the first 6 weeks of 
study treatment will be necessarily considered and included in the BLRM.
Toxicity will be assessed using the NCI Common Terminology Criteria for Adverse Events, 
version 4.03 (evs.nci.nih.gov/ftp1/CTCAE) unless otherwise specified.
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all patients at the current dose level.
For toxicities which, by definition, require a time-window in order to be defined as DLTs 
(grade 3 non-hematologic toxicity for ≥ 7 consecutive days), a subsequent visit and/or 
laboratory assessments must be scheduled accordingly. For example, if a grade 3 non-
hematologic toxicity is observed, it must also be observed at least 7 days later, with no 
intervening lower grades, in order to qualify as a DLT.
Table 6-3
Criteria for defining dose-limiting toxicities
TOXICITY
DLT CRITERIA
Hematologic
Blood and lymphatic system 
disorders
Neutropenia CTCAE Grade 4*
Febrile neutropenia CTCAE Grade ≥ 3
(ANC < 1.0 x 109/L + Fever ≥ 38.5 degrees C)
Thrombocytopenia CTCAE Grade 4 (Platelets < 25 x 109/L)*
Hemorrhagic Event CTCAE Grade ≥ 2
Anemia CTCAE Grade 4 for ≥ 7 days despite PRBC transfusions
Non-Hematologic
Gastrointestinal disorders
Vomiting CTCAE Grade ≥ 3 for > 7 days in duration
Nausea CTCAE Grade 3 despite the use of anti-emetic therapy
Hepatic
Total bilirubin CTCAE Grade ≥ 3, with Direct Bilirubin ≥ 0.5 mg/dL
AST/SGOT or ALT/SGPT CTCAE Grade 3 for ≥ 5 consecutive days
AST/SGOT or ALT/SGPT CTCAE Grade 4
CK elevation
CTCAE Grade ≥ 3
Other
Any CTCAE Grade 3 non-hematologic toxicity for ≥ 7 days
Any CTCAE Grade 4 non-hematologic toxicity
CTCAE version 4.03 will be used for all grading.
* In two consecutive assessments (the second assessment will be considered valid and final)


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Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol.
Patients who experience a DLT will have their therapy with LDE225 and INC424 interrupted 
and will be followed as described in Table 6-4. After recovery from the toxicity in question, if 
the Investigator believes that it is in the patient’s best interest to resume therapy with LDE225 
and INC424, the patient may resume therapy, only after consultation with the Sponsor, 
according to the guidelines described in Section 6.3.1 and Table 6-4.
However, the patient must be permanently discontinued from study medication and 
withdrawn from the study, if any of the following DLTs occur:

any grade ≥ 3 hemorrhagic event

grade 4 anemia for ≥ 7 consecutive days despite PRBC transfusions

2nd episode of grade ≥3 febrile neutropenia

grade 3 renal toxicity for ≥ 7 consecutive days

grade 4 renal toxicity

grade 4 non-hematologic toxicity
If during the first 6 weeks a patient misses > 10 doses of LDE225 or > 20 doses of INC424, 
the patient will not be evaluable for DLTs. The patient can continue in the study, but another
patient has to be enrolled at the same dose level in order to reach the required minimum
number of patients in the cohort.
6.2.5.1
Follow-up for dose-limiting toxicities
Patients whose treatment is discontinued or interrupted due to a DLT, must be followed until 
resolution or stabilization of the DLT event, whichever comes first, as described in Section 
6.3.1.
In case of a hemorrhagic event, of any grade (CTCAE grade 1 included), the Investigator is 
advised to perform coagulation tests and an albumin assessment.
Additional guidance on the management of grade 4 thrombocytopenia and grade 4 
neutropenia is described in Section 6.3.2.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following 
guidelines need to be applied. Any plan to deviate from these guidelines in view of patient 
safety must be discussed with the sponsor unless there is an urgent need for action.
All dose modifications should be based on the worst preceding toxicity as graded by the NCI 
Clinical Toxicity Criteria (NCI-CTCAE version 4.03). If study treatment is held due to 
toxicity, scheduled visits and all assessments as described in Table 7-1 should continue as 
scheduled, except without dosing. Dose modification guidelines are described in Table 6-4.


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If an adverse event is clearly associated to one of study drugs, the dose adjustment directed 
for that study drug will be followed; however, if the causality is not clear, then it may be 
necessary to adjust both study drugs. Dosing adjustments will be discussed with the sponsor.
If a patient experiences a DLT then treatment with LDE225 plus INC424 must be stopped and 
the patient may be discontinued from the study. However, following resolution of the DLT to 
CTCAE grade 1 or to the patient’s baseline value, the patient may continue to receive study 
treatment at a reduced combination dose level, if appropriate, at the discretion of the 
investigator and after discussion with the Sponsor.
For each patient, a maximum of 2 dose reductions will be allowed, after which the patient will 
be required to discontinue study treatment. If the same toxicity returns after re-initiation of
treatment at the same dose level, the second re-initiation must resume at a lower dose level. 
The patient must also discontinue study treatment if, after the treatment is resumed at the 
lower dose level, the same toxicity recurs with the same or worse severity (except for 
thrombocytopenia, anemia and neutropenia).
Dose level (-1) is the lowest acceptable dosing level for a patient participating in the study. If 
a patient cannot tolerate dose level (-1), then study treatment must be discontinued and the 
patient must be withdrawn from the study. However, if patients in Cohort 1 experience 
thrombocytopenic DLTs then patients in dose level (-1) will receive INC424 5mg BID and 
LDE225 200 mg QD.
If a patient requires a dose delay from either study drug of > 21 days due to an LDE225 or 
INC424 related toxicity, then the patient must be discontinued from the study; however, if the 
patient is obtaining clinical benefit in terms of response, the patient may continue treatment at 
the same or at a reduced dose following discussion between the investigator and Novartis. All 
patients will be followed for AEs and SAEs for 30 days following the last dose of LDE225 
and/or INC424.
Dose modifications for toxicities occurring during the DLT-definition period (6 weeks or 42 
days) will not be allowed unless the toxicity qualifies as a DLT. After a toxicity has been 
characterized as a DLT, a patient can resume therapy with a reduced treatment dose according 
to the guidelines provided in Section 6.2.5.1.
If the administration of study treatment was interrupted for reasons other than toxicity, then 
treatment with LDE225 and INC424 may be resumed at the same dose.
Patients who experience muscle toxicity, regardless of whether the toxicity meets the criteria 
described for a DLT, should be followed according to the dosing modifications for LDE225 
as per Table 6-5.
Patients who experience hematologic, renal, or hepatic toxicities should receive follow up 
evaluations as outlined in Table 6-7.
All interruptions or changes to study drug administration must be recorded on the Dosage and 
Administration Record eCRF.


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Table 6-4
Criteria for interruption and re-initiation of INC424 and LDE225 
treatment
Dose modifications for toxicities occurring during the DLT-definition period (6 weeks or 42 days), and considered 
as treatment-related, will not be allowed until the toxicity qualifies as a DLT.
Worst toxicity (CTCAE 4.03 Grade)
Dose Modifications for INC424 and LDE225
HEMATOLOGICAL
Neutropenia (ANC) (for 2 consecutive assessments within 48 hrs except febrile neutropenia)
Grade 1 (ANC < LLN - 1.5 x 109/L)
Grade 2 (ANC < 1.5 - 1.0 x 109/L)
Grade 3 (ANC < 1.0 - 0.5 x 109/L)
INC424: Maintain dose level
LDE225: Maintain dose level
Grade 4 (ANC < 0.5 x 109/L)
INC424: Hold dose until resolved to ≤ grade 1, then maintain dose 
level
LDE225: Hold dose until resolved to ≤ grade 1, then maintain dose 
level
Febrile neutropenia (Grade ≥ 3)
(ANC < 1.0 x 109/L, with a single 
temperature of ≥ 38.3 °C or a sustained 
temperature of ≥ 38 °C for more than one 
hour )
INC424: Discontinue study treatment
LDE225: Discontinue study treatment
Thrombocytopenia (for 2 consecutive assessments within 48 hrs)
Grade 1 (PLT < LLN - 75 x 109/L)
INC424: Maintain dose level
LDE225: Maintain dose level
Grade 2 (PLT < 75 - 50 x 109/L)
INC424: Reduce to 10 mg BID or continue at same dose level 
(whichever is lower)
LDE225: Maintain dose level
Grade 3 (PLT < 50-25 x 109/L)
INC424: Reduce to 5mg BID
LDE225: Maintain dose level
Grade 4 (PLT < 25 x 109/L)
INC424: Hold dose until resolved to ≤ grade 1, then maintain dose 
level
LDE225: Hold dose until resolved to ≤ grade 1, then maintain dose 
level
Hemorrhagic event of any kind (if related to study treatment)
Grade 1
INC424: Maintain dose level
LDE225: Maintain dose level
Grade 2
INC424: Hold dose until resolved completely, then ↓ by 5 mg BID
LDE225: Hold dose until resolved completely, then maintain dose 
level
Grade 3 or 4
INC424: Discontinue study treatment
LDE225: Discontinue study treatment
RENAL
Serum creatinine
< 2 x ULN
INC424: Maintain dose level
LDE225: Maintain dose level
2 – 3 x ULN
INC424: Hold dose until resolved to ≤ grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ by 5 mg BID
LDE225: Hold dose until resolved to ≤ grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 3 (> 3.0 – 6.0 x ULN)
INC424: Discontinue study treatment
LDE225: Discontinue study treatment
Grade 4 ( > 6.0 x ULN)
INC424: Discontinue study treatment
LDE225: Discontinue study treatment


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Dose modifications for toxicities occurring during the DLT-definition period (6 weeks or 42 days), and considered 
as treatment-related, will not be allowed until the toxicity qualifies as a DLT.
Worst toxicity (CTCAE 4.03 Grade)
Dose Modifications for INC424 and LDE225
HEPATIC
Bilirubin
(*for patients with Gilbert Syndrome these dose modifications apply to changes in direct bilirubin only). Bilirubin
will be fractionated if elevated
Up to 2.0 x ULN
INC424: Maintain dose level
LDE225: Maintain dose level
> 2.0 – 3.0 x ULN with ALT or AST ≤ 3.0 x 
ULN
INC424: Hold dose until resolved to ≤ grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ by 5 mg BID
LDE225: Hold dose until resolved to ≤ grade 1, then:
If resolved in ≤ 7 days, then maintain dose
If resolved in > 7 days, then ↓ 1 dose level
> 3.0 - 10.0 x ULN with ALT or AST ≤ 3.0 
x ULN
INC424: Hold dose until resolved to ≤ grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then discontinue treatment
LDE225: Hold dose until resolved to ≤ grade 1, then ↓ 1 dose level
> 10.0 x ULN
INC424: Discontinue study treatment
LDE225: Discontinue study treatment
AST or ALT
Grade 1 (> ULN – 3.0 x ULN)
INC424: Maintain dose level
LDE225: Maintain dose level
Grade 2 (> 3.0 - 5.0 x ULN) without total 
bilirubin elevation to > 2.0 x ULN
INC424: Maintain dose level
LDE225: Maintain dose level
Grade 3 (> 5.0 - 20.0 x ULN) without total 
bilirubin elevation to > 2.0 x ULN
INC424: Hold dose until resolved to ≤ grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓by 5 mg BID
LDE225: Hold dose until resolved to ≤ grade 1, then ↓ 1 dose level
Grade 4 (> 20.0 x ULN) without bilirubin 
elevation to > 2.0 x ULN
INC424: Hold dose until resolved to ≤ grade 1, then ↓ by 5 mg BID
LDE225: Hold dose until resolved to ≤ grade 1 or baseline, then ↓ 1 
dose level
CARDIAC
Cardiac – QTc prolongation
QTcF > 500 ms (≥ Grade 3)
or > 60 ms change from baseline
on at least two separate ECGs
Perform an analysis of serum potassium and magnesium, and if 
below lower limit of normal, correct with supplements to within 
normal limits. Concomitant medication usage must be reviewed.
Perform a repeat ECG within one hour of the first QTcF of > 500 ms
If QTcF remains > 500 ms, repeat ECG as clinically indicated but at 
least once a day until the QTcF returns to < 480 ms.
INC424: Hold dose until QTcF prolongation has resolved, then by 
5 mg BID
LDE225: Hold dose. Once QTcF prolongation has resolved, study 
treatment may be restarted at ↓ 1 dose level
Second Occurrence:
Discontinue patient from further study treatment with both 
medications
Other non- hematological adverse events
Grade 1 or 2
INC424: Maintain dose level
LDE225: Maintain dose level


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Dose modifications for toxicities occurring during the DLT-definition period (6 weeks or 42 days), and considered 
as treatment-related, will not be allowed until the toxicity qualifies as a DLT.
Worst toxicity (CTCAE 4.03 Grade)
Dose Modifications for INC424 and LDE225
Grade 3
INC424: Hold dose until resolved to ≤ grade 1, then ↓ by 5 mg BID
LDE225: Hold dose until resolved to ≤ grade 1, then ↓ by 1 dose 
level
Grade 4
INC424: Discontinue study treatment
LDE225: Discontinue study treatment
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Hold dose for ≥ Grade 3 vomiting or Grade 3 nausea only if the vomiting or nausea cannot be controlled with 
optimal antiemetic.
If the investigator deems that a recommended dose reduction or the recommendation to maintain the same dose 
is not in the best interest of the patient, this decision may be discussed with Novartis on a case-by-case basis.
Table 6-5
Recommended LDE225 dose modifications and dose delays for 
suspected treatment-related muscle toxicities
Severity of CK elevation
Dose modifications and management recommendations
Asymptomatic CK elevation
Grade 2
[CK elevation >2.5 x ULN - 5 x ULN]
● Continue treatment on the same dose and monitor CK levels 
weekly until resolution to baseline level. Check renal function 
(serum creatinine) regularly and ensure that patient is 
adequately hydrated.
Symptomatic (new-onset or worsening of pre-existing muscle symptoms such as myalgia, myopathy, and/or 
spasms) CK elevation
Grade 1
[CK elevation >ULN - 2.5 x ULN)]
● Continue treatment at the same dose and monitor CK levels 
weekly until resolution to baseline level and then monthly 
thereafter. Monitor muscle symptoms for changes until resolution 
to baseline. Check renal function (serum creatinine) regularly 
and ensure that patient is adequately hydrated.
Grade 2
[CK elevation >2.5 x ULN - 5 x ULN]
● Interrupt treatment and monitor CK levels weekly until 
resolution to baseline level. Monitor muscle symptoms for 
changes until resolution to baseline. Upon resolution, resume 
treatment at the reduced dose level and measure CK monthly 
thereafter. Check renal function (serum creatinine) regularly and 
ensure that patient is adequately hydrated.
Asymptomatic or Symptomatic CK elevation
Grade 3 or 4 without renal impairment
[Grade 3 (CK elevation >5 x ULN - 10 x ULN)] 
[Grade or 4 (CK elevation >10 x ULN)]
● Interrupt treatment and monitor CK levels weekly until 
resolution to baseline level. Monitor muscle symptoms for 
changes until resolution to baseline.
● Check renal function (serum creatinine) regularly and ensure 
that patient is adequately hydrated. If renal function is not 
impaired (normal serum creatinine) and CK resolves to baseline 
level, consider resuming treatment at a reduced dose. CK levels 
should be measured weekly for 2 months after re-administration 
of sonidegib and monthly thereafter.
Grade 3 or 4 with renal impairment
● Interrupt treatment and monitor CK levels weekly until 
resolution to baseline level. Monitor muscle symptoms for 
changes until resolution to baseline.
● If renal function is impaired (≥50% above the baseline level), 
interrupt treatment. Ensure patient is adequately hydrated and 
evaluate other secondary causes. Continue monitoring of CK 
and creatinine levels weekly. If CK levels return to baseline level 
and creatinine levels return to baseline, consider resuming 
treatment at the reduced dose otherwise discontinue treatment 
permanently.


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Table 6-6
Dose restart guidelines and allowed maximum doses for patients who 
have previously interrupted dose for grade 4 thrombocytopenia and 
grade 4 neutropenia
Current PLT Count
▼ Dose Restart or Dose Increase Guidelines ▼
INC424
LDE 225
< 50 x109/L
Continue to hold
Continue to hold
50 to < 75 x109/L
Restart at 5 mg BID for at least 14 days
If stable, may increase to 10 mg BID or original 
dose (whichever is lower)
Restart at original dose level
75 to < 100 x109/L
Restart at 10 mg BID for at least 14 days
If stable, may increase to 15 mg BID or original 
dose, (whichever is lower)
Restart at original dose level
100 to < 125 x109/L
Restart at original dose
Restart at original dose level
≥ 125 x109/L
Restart at original dose
Restart at original dose level
Current ANC Level
▼ Dose Restart or Dose Increase Guidelines ▼
< 0.5 x109/L
Continue to hold
Continue to hold
0.5 to < 0.75 x109/L
5 mg BID for at least 2 weeks; if stable, may 
increase to 10 mg BID or original dose, 
(whichever is lower)
Restart at original dose level
0.75 to <1 x109/L
10 mg BID for at least 2 weeks; if stable, may 
increase to 15 mg BID or original dose, 
(whichever is lower)
Restart at original dose level
1 to < 1.5 x109/L
Restart at original dose
Restart at original dose level
≥ 1.5 x109/L
Restart at original dose
Restart at original dose level
6.3.1.1
Optional dose tapering strategy for INC424 in the event of 
discontinuation
When INC424 therapy is stopped, return of constitutional symptoms associated with elevated 
cytokines (e.g. night sweats, fever, fatigue) that had been suppressed while on therapy is 
expected. When a decision is made to permanently discontinue INC424 therapy for reasons 
other than for hematologic safety, a dose tapering strategy may be considered, based on 
evaluation of the condition of the patient, current dosing regimen and the clinical judgment of 
the Investigator, so that symptoms may return to pre-treatment condition more slowly. If 
considered to be medically necessary, the Investigator may use any treatment to manage 
withdrawal from INC424 including a gradual tapering of the study drug dosage or use of other 
medications to manage events occurring after discontinuation. Short-term courses of 
corticosteroids at doses > 10 mg/day have been used in patients with MF and may be 
considered as part of a tapering strategy. Corticosteroids may be started prior to, or concurrent 
with, INC424 tapering. When a decision has been made to discontinue the patient with 
utilization of a tapering strategy, regardless of the use of concomitant medications, safety data 
will continue to be assessed in accordance with the protocol for a period of time as least 
through the continued administration on INC424 and 30 days after for AEs.
6.3.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 


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frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical specialists should be consulted as deemed 
necessary. Further guidelines and recommendations for the management of specific study 
drug combination induced toxicities (thrombocytopenia and neutropenia) are provided in 
Section 6.3.2.1 and Section 6.3.2.2. All patients must be followed up for adverse events and 
serious adverse events for 30 days following the last dose of LDE225 and/or INC424.
Table 6-7
Follow-up evaluations for selected toxicities
Toxicity
Follow-Up Evaluation
Hematology
If any hematological DLT has occurred, the relevant parameters must be repeated at least twice 
a week until resolution to ≤ CTCAE grade 1, and then at least weekly until either initiation of 
treatment or until stabilization.
Renal
If any renal DLT has occurred, the relevant parameters must be repeated at least twice a week 
until resolution to ≤CTCAE grade 1 or baseline, and then at least weekly until either initiation of 
re-treatment or until stabilization.
Hepatic
If any hepatic DLT has occurred, the relevant parameters must be repeated at least twice a 
week until resolution to ≤ CTCAE grade 1 or baseline, and then at least weekly until either 
initiation of re-treatment or until stabilization.
Patients with total bilirubin > ULN (any duration) should have fractionation of bilirubin into 
total/direct or indirect/direct components and any additional assessments as clinically indicated 
by these results.
Non-
laboratory
Patients who experience non-laboratory DLTs must be evaluated at least once a week following 
demonstration of the toxicity until resolution of the toxicity, to allow for retreatment, until 
stabilization of the toxicity, or EOT.
Cardiac
If ≥ grade 3 (QTcF > 500 msec as identified by the investigator on the ECG reading or >60 ms 
change from baseline on at least 2 separate ECGs taken within 1 hour):
The patient must be hospitalized or monitored by the investigators with hourly ECGs until the 
QTcF is ≤ 500 msec and < 30 msec from baseline. Immediate attention to potassium and 
magnesium and other clinical factors such as oxygenation, ischemia, and the like will be 
addressed. A plasma sample should be drawn to assess the concentration of LDE225, 
magnesium and potassium at the time when the absolute QTcF > 500 msec.
Once QTcF prolongation has resolved, reinitiate treatment according to Table 6-4 and perform 
ECG monitoring weekly. If the ECGs obtained in the first 6 weeks after dose reduction are 
without any QTcF > 500 msec and QTcF change from baseline ≥ 60 msec, then ECG monitoring 
should be performed every 4 weeks.
6.3.2.1
Management of thrombocytopenia
It is recommended that patients who are dose reduced for thrombocytopenia have more 
frequent hematology assessments. Platelet counts must be obtained at least weekly for 4 
weeks, and then at least every second week for the next 4 weeks. Thereafter, they may resume 
normal scheduled evaluations.
Dose escalation guidelines which allow maximum doses for patients who have previously 
decreased dosing for thrombocytopenia are described in Table 6-6.
In the case of grade 4 thrombocytopenia, assessment of platelet count is recommended to be 
repeated twice weekly, until resolution to grade ≤ 3 thrombocytopenia.
Dose restart guidelines and allowed maximum doses for patients who have previously 
interrupted dose for grade 4 thrombocytopenia can be found in Table 6-6.


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6.3.2.2
Management of neutropenia
In the case of grade 4 neutropenia, assessment of ANC count is recommended to be repeated 
at least twice a week until resolution to grade ≤ 3 neutropenia.
Dose restart guidelines and allowed maximum doses for patients who have previously 
interrupted dose for grade 4 neutropenia can be found in Table 6-6.
6.3.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Refer to preclinical toxicity and 
or clinical data found in the [LDE225 and INC424 Investigator’s Brochures].
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy and herbal/natural medications) administered 
during the study must be listed on the Concomitant Medications or the Surgical and Medical 
procedures eCRF. Blood Transfusions will be recorded on the Blood component transfusion 
eCRFs.
6.4.2
Permitted concomitant therapy requiring caution and/or action
Patients receiving these medications listed below must be monitored closely for any 
potentiation of toxicity or decrease of clinical benefit due to any individual concomitant 
medications, and may require dose adjustment.
6.4.2.1
Breast cancer resistance protein (BCRP)
LDE225 is an inhibitor of breast cancer resistance protein (BCRP) in vitro. Therefore 
substrates, especially those with a narrow therapeutic range, should be used with caution. 
BCRP substrates include zidovudine, pantoprazole, cimetidine, sulfasalazine, nitrofuratoin, 
mitoxantrone, methotrexate, topotecan, imatinib, and irinotecan. However, the use of 
mitoxantrone, methotrexate, topotecan, imatinib, irinotecan or statins is generally prohibited 
during this study (see Appendix 1; Table 14-1).
6.4.2.2
Drugs that are metabolized by or affect CYP450 enzymes
In vitro drug metabolism studies suggest that the metabolism of LDE225 and INC424 are both 
primarily mediated by CYP3A4. Therefore, caution is advised for co-administration of drugs 
that are weak inhibitors or inducers of CYP3A4 (Appendix 1; Table 14-2). Concomitant 
treatment with weak inducers of CYP3A4 is permitted, however, duration of concomitant 
treatment should be kept as short as possible (e.g, less than 1 week), or fully avoided 
whenever possible. Weak inducers include, but are not limited to armodafinil, nevirapine, 
oxcarbazepine, 
pioglitazone, 
pleconaril, 
rufinamide 
and 
troglitazone. 
Note 
that 


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coadministration of study drug with strong and moderate CYP3A inducers (Appendix 1) is 
prohibited.
LDE225 was shown to inhibit CYP2B6 and CYP2C9 in vitro, therefore, CYP2B6 and 
CYP2C9 substrates should be used in caution. Refer to Table 14-3 in Appendix 1 for a list of 
CYP2B6 and CYP2C9 substrates to be used with caution. Narrow therapeutic index or 
sensitive substrates of CYP2B6 and CYP2C9 are not permitted (refer to the prohibited section 
below).
6.4.2.3
Corticosteroids
Chronic dosing of corticosteroids (e.g. dexamethasone and prednisone) is known to induce 
CYP3A enzymes, thereby increasing the risk of reducing drug exposure to sub-therapeutic 
levels. Systemic corticosteroid doses greater than the equivalent of 10 mg of prednisolone per 
day are not permitted, unless its use is part of a INC424 dose tapering strategy (Section 
6.3.1.1) as this may impact splenic size and cytokine reduction and interfere with the ability to 
assess the clinical activity of this drug treatment combination in this patient population. Stable 
corticosteroids used for conditions other than MF are allowed if the doses are less than the 
equivalent of 10 mg of prednisolone per day during the course of the study but the dose must 
have been stabilized (or decreasing) for at least 5 days before initiating study therapy and any 
ongoing corticosteroid use during study treatment must be clearly documented on the 
concomitant medication eCRF.
6.4.2.4
Permitted antifungal and antibiotic medications
Permitted antifungal and antibiotic agents, including those that are weak inhibitors or inducers 
of CYP3A4 are listed in Appendix 1, Table 14-4. Topical and vaginal antifungals are 
generally allowed with caution.
6.4.2.5
Hematopoietic growth factors
Therapeutic use of hematopoietic growth factors is allowed according to institutional 
guidelines. Granulocyte growth factors (G-CSF) are not allowed while study medication is 
being administered but may be used for severe neutropenia at the Investigator’s discretion 
while study medication is being withheld.
6.4.3
Prohibited concomitant therapy
The following medications have restrictions on their use and may require changes in dosing 
when INC424 and/or LDE225 are administered during the study. Refer to Appendix 1 for a 
list of prohibited medications. This list may not be comprehensive.
6.4.3.1
Other investigational therapies
Use of any other investigational medication (other than LDE225 and INC424) that is not 
approved for any indication is not allowed. Use of such medications within 30 days, prior to 
the first dose of study drug and during the study through the Safety Follow-up Visit is 
prohibited. Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) 
other than the study treatments (LDE225 and INC424) must not be given to patients while the 


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patient is on the study medication. If such agents are required for a patient then the patient 
must be discontinued from the treatment portion of the study.
6.4.3.2
Strong and moderate CYP3A4 inhibitors and inducers
In vitro drug metabolism studies suggest that the metabolism of LDE225 and INC424 are both
primarily mediated by CYP3A4. Co-administration with strong and moderate CYP3A4 
inhibitors and inducers is predicted to respectively increase or decrease the systemic exposure 
to the study drugs (Appendix 1; Table 14-5), and is therefore prohibited.
6.4.3.3
Narrow therapeutic index or sensitive substrates of CYP2C9 and 
CYP2B6
Because of the potential risk for drug-drug interactions with LDE225, using concomitant 
medications known to be metabolized by the cytochromes CYP2C9 and CYP2B6 that have 
low therapeutic index is not permitted in the study (Appendix 1; Table 14-6). In the absence 
of clinical drug interaction data, therapeutic doses of warfarin or any other Coumadin-
derivative anticoagulants are not permitted since LDE225 is a competitive inhibitor of 
CYP2C9 based on the in vitro data.
6.4.3.4
Drugs that interfere with coagulation or inhibit platelet function
Drugs that interfere with coagulation or inhibit platelet function (including non-steroidal anti-
inflammatory drugs) are not permitted. Aspirin (≤ 150 mg/day) and LMWH (INR less than 
1.5) are allowed.
Any other medication for the treatment of myelofibrosis, including but not limited to:
hydroxyurea, busulfan, interferon, lenalidomide, thalidomide, anagrelide are prohibited.
6.4.3.5
Drugs with a known risk of myopathy and rhabdomyolysis
Selected drugs that may increase risk of myopathy and rhabdomyolysis when used 
concomitantly with LDE225 should be avoided. Such drugs should be discontinued for at 
least 2 weeks prior to initiation of LDE225 and it must be ensured that plasma creatine kinase 
(CK) is within the normal range at screening.
6.4.3.6
Herbal medications
Herbal preparations/medications are not allowed throughout the study, as a potential drug-
drug interaction is always possible. These herbal medications include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. Patients must stop using these herbal medications at 
least 7 days prior to first dose of study treatment.
6.4.3.7
Prohibited antifungal and antibiotic medications
Antifungal and antibiotic agents that are moderate/strong inhibitors or inducers of CYP3A4 
are prohibited due to the potential to affect the PK of LDE225 and INC424 (see Appendix 1; 
Table 14-7).


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6.4.3.8
Anti-virus vaccines and medications
Live anti-virus vaccines such as Zostavax® are prohibited given INC424’s potential for 
causing immunosuppression. Other anti- herpes virus medications such as acyclovir, 
gancyclovir, valacyclovir should be used with caution especially if Zoster reactivation 
continues to increase over time during the course of the study. Other antivirus medications 
which are strong and moderate inhibitors of CYP3A4 are also prohibited.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient ID), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient Number consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
patient number suffixed to it, so that each subject is numbered uniquely across the entire 
database. The procedures for obtaining a Patient Number will be provided in a separate 
instructional document prior to study start. Once assigned, the Patient Number must not be 
reused for any other patient and the Patient Number for that individual must not be changed.
6.5.2
Treatment assignment or randomization
Patients will not be randomized; the assignment of a patient to a particular cohort in the Phase 
Ib part of the study will be coordinated by the sponsor. The procedures for obtaining a patient 
number will be provided in a separate instructional document prior to study start.
6.5.3
Treatment blinding
This is an open-label study, treatment blinding is not applicable.
6.6
Study drug supply
6.6.1
Study drug preparation and dispensation
Study medication will be dispensed by an authorized person at the investigator’s site. Patients 
will be provided with an adequate supply of study drug for self-administration at home, 
including instructions for administration, until at least their next scheduled study visit. 
Patients will receive LDE225 and INC424 study treatment on an outpatient basis. The 
investigator shall provide the patient with instructions for study treatment administration 
according to the protocol.
All dosages prescribed to the patient and all dose changes and/or missed doses during the 
study must be recorded on the Dosage Administration Record eCRF.
When possible, individual doses will consist of the minimum number of capsules/tablets 
equaling the total dose given the available capsule/tablet sizes.


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Table 6-8
Preparation and dispensing
Study treatments
Dispensing
Preparation
LDE225
Continuous daily QD dosing
Not applicable
INC424
Continuous daily BID dosing
Not applicable
6.6.2
Study drug packaging and labeling
6.6.2.1
LDE225
LDE225 capsules will be packed and labeled by Novartis Drug Supply Management. LDE225 
is formulated as capsules of 50mg, 100mg, 200mg, and 250mg strengths. Not all of the 
strengths listed may be used in this study. The capsules are packaged in bottles. LDE225 will 
be administered orally once a day.
Medication labels will conform to local legal requirements. Patient number will be added by 
the site pharmacist or authorized site personnel. The storage conditions for study drug will be 
described on the medication label.
6.6.2.2
INC424 (ruxolitinib)
INC424 tablets can be provided as local commercial material or global supply where 
appropriate and as per local regulations. Global supply will be open-label, packed and labeled 
by Novartis Drug Supply Management. Study treatment labels will be in the local language 
and will comply with the legal requirements of each country. Patient number will be added by 
the site pharmacist or authorized site personnel. The storage conditions for study drug will be 
described on the medication label.
INC424 tablets are formulated in strengths of 5mg, 10mg, 15mg and 20mg. INC424 in 
different formulations and strengths can be used once they are approved and marketed. 
INC424 will be administered orally twice a day.
If INC424 is sourced and labeled in-country, the locally approved form and packaging of 
INC424 will be used. When INC424 tablets are packaged in bottles they will be supplied in 
HDPE bottles with a plastic child resistant closure. These bottles must be kept out of the reach 
and sight of children.
Refer to the latest [INC424 Investigator’s Brochure] for dosing instructions and storage 
conditions.
Table 6-9
Packaging and labeling
Study 
treatments
Packaging
Labeling (and dosing 
frequency)
LDE225
Capsules in bottles
Refer to study treatment label
Once daily
INC424
Global supply: Tablets in bottles
Locally sourced supply: Locally approved form and packaging
Refer to study treatment label
Twice daily
6.6.3
Drug supply and storage
The study drugs must be received at the study site by a designated person, handled and stored 
safely and properly, and kept in a secured location to which only the pharmacist or authorized 


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site personnel have access. Upon receipt, the investigational drugs should be stored according 
to the instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol.
Investigational drug (LDE225 and INC424) global supply will be provided by Drug Supply 
Management, Novartis. Local commercial material will be provided by each local Country 
Pharmaceutical Organization (CPO). Please refer to study treatment label for storage 
instructions.
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/or at the completion of the study. All drug supplies are to be used only 
for this protocol and not for any other purpose. Unless specifically instructed by Novartis, the 
investigator must not destroy any drug labels, or any partly used or unused drug supply. Only 
after receiving written authorization by Novartis, the investigator will be instructed to either 
send all of the unused and partly used drug supplies as well as the empty containers to the 
address provided at the time of authorization for destruction or to dispose of unused drug 
according to local regulations.
Table 6-10
Supply and storage of study treatments
Study 
treatments
Supply
Storage
LDE225
Centrally supplied by Novartis
Refer to study treatment label
INC424
Centrally supplied by Novartis or Locally supplied by the 
CPO
Refer to study treatment label
6.6.4
Study drug compliance and accountability
6.6.4.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. On PK sampling days, compliance will also be assured by administrations of the 
study treatment under the supervision of investigator or his/her designee.
6.6.4.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.


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6.6.4.3
Handling of other study treatment
Not applicable.
6.6.5
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 and Table 7-2 (Extension Phase) 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.
For Table 7-1, the following visit windows will be allowed: +/- 1 day during the first 8 weeks 
(except Week 1 Day 1 and Week 1 Day 2), +/- 2 days during Weeks 9-13 and +/- 3 days from 
Week 17 onwards. Imaging has an allowable window of +/- 1 week (the window for the 
baseline, Week 1 Day 1, scan is -1 week) and the collection of the bone marrow biopsy and 
aspirate has an allowable window of +/- 2 weeks (the window for the baseline, Week 1 Day 1,
bone marrow biopsy and aspirate is -2 weeks).
For Table 7-2, the following visit windows will be allowed: +/- 4 weeks for study visits and 
assessments, including imaging, bone marrow biopsy and aspirate.Standard of care (SOC) 
visits and assessments should be performed as per local treatment practices and Investigator 
discretion. Patient information from SOC assessments should be entered into the eCRF only if 
it is clinically relevant to the study treatment. 


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Table 7-1
Visit evaluation schedule
Week
Category
Protocol 
Section
Screening 
Phase
Treatment Phase
Follow up Phase
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 11
Week 13 Day 1 and
every 4 weeks 
until Week 105 
Day 1
End of treatment 
(EOT) – if before 
extension phase
Follow 
Up/Study 
Completion
Study Day
-21 to -1
1
2
1
1
1
1
1
1
1
1
2
1
1
Date of last dose
30 days 
post-dose
Obtain Informed Consent
D
7.1.1.
X
Patient history
Demography
D
7.1.1.2.
X
Inclusion/exclusion criteria
S
7.1.1 and 
5.2/5.3.
X
Relevant medical history/current 
medical conditions
D
7.1.1.2.
X
Diagnosis of PMF, P-PV MF, or P-
ET MF
D
7.1.1.2.
X
Cytogenetics
D
7.1.1.2.
X
Prognostic factors for MF
D
7.1.1.2.
X
Prior antineoplastic medications, 
radiation therapy, or prior surgery
D
7.1.1.2.
X
Prior Medical and Surgical 
procedures
D
7.1.1.2.
X
Prior and current concomitant 
medications/significant non-drug 
therapies
D
7.1.1.2
and 
6.4.1.
Record prior significant medications up to 30 days before Screening
Record current medications/therapies at each visit through 30 days post last dose of study treatment
Measurement of spleen by 
Palpation
D
7.2.1.1.
X
X
X
X
X
X
X
X
Physical examination
S
7.2.2.1.
X
X


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Week
Category
Protocol 
Section
Screening 
Phase
Treatment Phase
Follow up Phase
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 11
Week 13 Day 1 and
every 4 weeks 
until Week 105 
Day 1
End of treatment 
(EOT) – if before 
extension phase
Follow 
Up/Study 
Completion
Study Day
-21 to -1
1
2
1
1
1
1
1
1
1
1
2
1
1
Date of last dose
30 days 
post-dose
Abbreviated Physical
S
7.2.2.1.
X
X
X
ECOG Performance status
D
7.2.2.4.
X
X
X
X
X
X
Height
D
7.2.2.3.
X
Weight
D
7.2.2.3.
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
X
X
X
Laboratory assessments
Phase Ib patients ONLY 
Hematology/Chemistry
D
7.2.2.5.1
and
7.2.2.5.2.
X
X
X
X
X
X
X
X
X
X
X
X
X
Phase II patients ONLY 
Hematology/Chemistry
D
7.2.2.5.1
and
7.2.2.5.2.
X
X
X
X
X
X
X
X
X
CK
D
7.2.2.5.3.
X
X
X
X
X
X
X
X
X
Coagulation (INR and PTT)
D
7.2.2.5.4.
X
X
X
X
X
X
Urinalysis
D
7.2.2.5.5.
X
As clinically indicated
X
Pregnancy Serum test (women of 
childbearing potential only)
D
7.2.2.5.6.
X (to be 
done ≤ 
7days prior 
to first 
dose)
X
Pregnancy Urine test
(women of childbearing potential 
only)
D
7.2.2.5.6.
X
X
X
Imaging
ECG
D
7.2.2.5.7.
X
X
X
X
X
X
Chest X-ray
D
7.2.2.5.8.
As clinically indicated


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Week
Category
Protocol 
Section
Screening 
Phase
Treatment Phase
Follow up Phase
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 11
Week 13 Day 1 and
every 4 weeks 
until Week 105 
Day 1
End of treatment 
(EOT) – if before 
extension phase
Follow 
Up/Study 
Completion
Study Day
-21 to -1
1
2
1
1
1
1
1
1
1
1
2
1
1
Date of last dose
30 days 
post-dose
Abdominal MRI/CT:
Phase Ib- Only patients enrolled to 
the confirmatory MTD level(s). 
Phase II- ALL patients
D
7.2.1.2.
X
X (and at week 25,
week 49, and week 
105)
X
Bone Marrow biopsy and aspirate
D
7.2.1.3.
X
X (at Week 25, 
Week 49, Week 73, 
and Week 97)
X
Safety
Adverse events
Perform at each visit through 30 days post last dose of study treatment
Biomarkers
Whole blood sample for 
JAK2V617F mutational status and 
allelic burden analysis
D
7.2.4.1.
X
X (and at Week 25, 
Week 49, Week 73, 
and Week 97)
X (only if before 
the Week 97 visit)
Whole blood sample for plasma 
cytokine assays
D
7.2.4.2.
X
X
X
X (and at Week 
25,Week 49, and 
Week 105)
X
Whole blood sample for Hh 
pathway analysis
D
7.2.4.3.
X
X
X
X (at Week 17, 
Week 25, Week 49, 
and Week 105)
X
Patient reported Outcomes
EORTC QLQ-C30
D
7.2.6.1.2.
X
X
X
X
X
Modified MFSAF v 2.0 
questionnaire
D
7.2.6.1.1.
X
X
X
X
X
X
LDE225 and INC424 
administration
D
6.1.1.
Continuous daily dosing


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Week
Category
Protocol 
Section
Screening 
Phase
Treatment Phase
Follow up Phase
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 11
Week 13 Day 1 and
every 4 weeks 
until Week 105 
Day 1
End of treatment 
(EOT) – if before 
extension phase
Follow 
Up/Study 
Completion
Study Day
-21 to -1
1
2
1
1
1
1
1
1
1
1
2
1
1
Date of last dose
30 days 
post-dose
PK
Meal Record (Phase Ib and Phase 
II, stage 1 only)
D
7.2.3.
X
X
PK sample (Phase Ib and Phase 
II, stage 1 only)
D
7.2.3.
X
X
X
X
X
X
X
X
(up to Week 49)
PK sample ( Phase II stage 2 only)
D
7.2.3.
X
X
X
X
X
X
(up to Week 49)
PK sample from bone marrow 
aspirate (Phase II, Stage 1 or 
Stage 2) from at least 10 patients)
D
7.2.3.
Refer to Bone Marrow biopsy and aspirate (up to Week 49)
X
Antineoplastic therapies since 
discontinuation of study treatment
D
7.1.5.
X
X
Disposition assessment
D
7.1.3.
X
X


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Table 7-2
Visit evaluation schedule for Extension Phase (after Week 105 Day 1)
Category
Protocol 
Section
Treatment Phase
Follow up Phase
Week
Every 12 weeks from 
Week 105
Every 24 weeks
from Week 105
Every 48 weeks
from Week 105
End of Extension 
Treatment (EOT)
Follow Up/Study 
Completion
Study Day
1
1
1
Date of last dose
30 days post-dose
Adverse events
D
Continuously captured until Follow Up/Study Completion
Concomitant 
medications/significant non-drug 
therapies
D
6.1
Continuously captured until Follow Up/Study Completion
Chest X-ray
D
7.2.2.5.8
As clinically indicated
Abbreviated Physical Exam
S
7.2.2.1
As per SOC
ECOG Performance status
D
7.2.2.4
As per SOC
Vital signs including weight
D
7.2.2.2
As per SOC
Urinalysis
D
7.2.2.5.5
As per SOC
Measurement of spleen by 
Palpation
D
7.2.1.1
X
X
Hematology/Chemistry
D
7.2.2.5.1
and 
7.2.2.5.2
X
X
CK
D
7.2.2.5.3
X
X
Coagulation (INR and PTT)
D
7.2.2.5.4
X
X
Pregnancy Urine test
(women of childbearing potential 
only)
D
7.2.2.5.6
X
Monthly at Home Pregnancy 
Testing (women of childbearing 
potential only)
S
7.2.2.5.6
Continuous testing during months with no visits


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Category
Protocol 
Section
Treatment Phase
Follow up Phase
Week
Every 12 weeks from 
Week 105
Every 24 weeks
from Week 105
Every 48 weeks
from Week 105
End of Extension 
Treatment (EOT)
Follow Up/Study 
Completion
Study Day
1
1
1
Date of last dose
30 days post-dose
Pregnancy Serum test
(women of childbearing potential 
only)
D
7.2.2.5.6
X
Modified MFSAF v2.0 
questionnaire
D
7.2.6.1.1
X
X
EORTC QLQ-C30
D
7.2.6.1.2
X
ECG
D
7.2.2.5.7
As per SOC
Dispense LDE225 and INC424
6.1
X
LDE225 and INC424 
administration
D
6.1.1
Continuous daily dosing
Antineoplastic therapies since 
discontinuation of study treatment
D
7.1.5
X
X
Disposition assessment in 
EOT/Follow up phase
D
7.1.3
X
Phase Ib- Only patients enrolled to the confirmatory RP2D level (expansion cohort). Phase II- ALL patients
Abdominal MRI/CT
D
7.2.1.2
X
X
Bone Marrow biopsy and aspirate
D
7.2.1.3
X
X


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7.1.1
Screening
Written informed consent must be obtained before any study specific assessments are 
performed, including screening.
Screening assessments must be performed within ≤ 21 days prior to receiving the first study 
treatment, with the exception of the serum pregnancy test, which must be performed ≤ 7 days 
prior to receiving the first study treatment.
Laboratory assessments that are performed as standard of care prior to consent can be used for 
this trial upon consenting to enter the trial if performed within ≤ 21 days prior to receiving the 
first study treatment.
Laboratory assessments performed as part of the screening evaluations and within 72 hours of 
the first dose of study treatment, are not required to be repeated on the first dosing day.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. If the 
repeated laboratory result does not meet the criteria, the patient will be considered a screening 
failure.
Patient eligibility will be confirmed by the investigative staff and captured within the source 
documents maintained at the site. This information will be made available during planned 
interim monitoring visits and compared against the clinical database for accuracy. In addition, 
the patient eligibility eCRF should be completed, automated queries will be generated for 
immediate resolution should patient eligibility be in question based on the patient information 
entered.
Please refer to and comply with the detailed guidelines provided in the Cohort Allocation 
Process document and Allocation Request form.
For details on screening assessments, refer to Table 7-1.
7.1.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure.
The following eCRFs must be completed for a screen failure patient:

Screening phase disposition page of eCRF (including reason for not being started on
treatment)

Informed Consent, including additional biomarker ICF if relevant.

Inclusion/Exclusion Criteria

Demography

Adverse Events (only if the patient experienced a Serious Adverse Event during the 
screening period after signing the ICF (see Section 8 for SAE reporting details)


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If a screen failure patient experiences an AE which does not meet the SAE criteria, 
detailsabout the AE will be recorded only in the investigator’s source documents. In case of 
an SAE, data must be recorded on both the AE and SAE forms.
No other data will be entered into the clinical database for patients who are screen failures.
7.1.1.2
Patient demographics and other baseline characteristics
The following patient demographics and baseline characteristics will be collected on the 
eCRF:

Demography including date of birth, race and ethnicity

Height, weight (See Section 7.2.2.3)

Diagnosis of Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-
Essential thrombocythemia Myelofibrosis

Myelofibrosis history and prior/concomitant myelofibrosis treatment

Cytogenetics

Complete Medical History and current medical conditions

Prior Myeloproliferative neoplasm directed therapy-medications

Prior Anti-neoplastic Radiotherapy

Prior Anti-neoplastic Surgery

Transfusion history for the last 12 weeks prior to screening

All other medications and non-drug therapies (including physical therapy and oxygen) 
administered to the patient within 30 days prior to the first dose of study drug) must be
reported on the Concomitant Medications or the Surgical and Medical Procedures eCRFs

Patient self-rating quality of life questionnaire (EORTC QLQ C-30) (See Section 
7.2.6.1.2)

Biomarker assessments (See Section 7.2.4)
Furthermore the following assessments will be performed to assess the eligibility of the 
patient:

Inclusion/Exclusion (see Section 5.2 and Section 5.3)

Physical Examination (See Section 7.2.2.1)

Vital signs (See Section 7.2.2.2)

ECOG performance status (See Section 7.2.2.4)

Measurement of spleen by palpation (See Section 7.2.1.1)

Prognostic factors for MF

Myelofibrosis Symptom Assessment Form

Bone Marrow Biopsy and aspirate (see Section 7.2.1.3)

ECG (See Section 7.2.2.5.7)

Laboratory evaluations (See Section 7.2.2.5)

Serum pregnancy test (See Section 7.2.2.5.6)


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7.1.2
Treatment period
Patients will be treated with LDE225 and INC424 for at least 2 years after the first dose or 
until death, documented disease progression, initiation of a new MF therapy, intolerable 
toxicity, withdrawal of consent, discontinuation at the discretion of the investigator, or lost to 
follow-up, whichever comes first. Patients who complete 2 years of treatment and are deriving 
clinical benefit in the opinion of the investigator will be allowed to continue receiving 
treatment (LDE225 and INC424) in an extension phase of this study, until discontinuation 
reasons are met or an alternative setting to receive study treatment (e.g., in form of another 
protocol) becomes available.
For details of assessments, refer to Table 7-1 and Table 7-2.
7.1.3
Discontinuation of Study Treatment
Patients may voluntarily discontinue from study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make every 
effort (e.g., telephone, e-mail, letter) to determine the primary reason for this decision and 
record this information in the patient’s chart and on the appropriate eCRF pages. Patients may 
be considered withdrawn if they state an intention to withdraw, fail to return for visits, or 
become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances:

Emergence of the following adverse events:

Grade 3 or 4 hemorrhagic event of any kind

Grade 3 renal toxicity for ≥ 7 consecutive days

Grade 4 renal toxicity

Grade 4 non-hematologic toxicity

Second occurrence of QTcF > 500 ms (≥ Grade 3) or > 60 ms change from baseline 
on at least two separate ECGs

Patient requires or undergoes splenic irradiation

Patient requires or undergoes splenectomy

Any of the following laboratory abnormalities:

Grade 4 anemia for ≥ 7 consecutive days despite PRBC transfusions

Febrile neutropenia (Grade ≥ 3) (ANC < 1.0 x 109/L, with a single temperature of ≥ 
38.3 °C or a sustained temperature of ≥ 38 °C for more than one hour )

Grade 3 or 4 serum creatinine

Bilirubin > 10.0 x ULN

Grade 3 or 4 asymptomatic or symptomatic CK elevation with renal function 
impairment in which CK and creatinine levels do not return to baseline after 
interrupting treatment

Pregnancy


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
The following deviations from the prescribed dose regimen for LDE225 and INC424:

Interruption of study treatment for > 21 days, regardless of reason, from the intended 
day of the next scheduled dose. However, if the patient is obtaining clinical benefit in 
terms of response, the patient may continue treatment at the same or at a reduced dose 
following discussion between the investigator and Novartis.

If after 2 dose reductions and after the treatment has resumed at the lower dose, the 
same toxicity recurs with the same or worse severity (except for thrombocytopenia, 
anemia, and neutropenia)

If a patient cannot tolerate dose level (-1), which is the lowest acceptable dosing level 
for this study, except for patients in Cohort 1 who experience thrombocytopenic 
DLTs and can receive INC424 5mg BID and LDE225 200mg QD.

Disease Progression

Use of prohibited treatments (refer to Appendix 1) as determined by Novartis

Use of another myeloproliferative neoplasm directed therapy

Any other protocol deviation that results in a significant risk to the patient’s safety

Study is terminated by the Sponsor
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study.  They should return for the assessments indicated in Table 7-1 and Table 7-2. If they 
fail to return for these assessments for unknown reasons, every effort (e.g. telephone, email, 
letter) should be made to contact them as specified in Section 7.1.5. 
7.1.3.1
Replacement policy
Phase Ib
Dose escalation:
Patients will not be replaced on study. However, enrollment of new patients to a cohort will 
be considered if there is less than the minimum number of evaluable patients for the DDS.
If a patient is not treated with at least 75% of the planned doses of LDE225 and INC424 in 6 
weeks (42 days) (i.e. more than 10 missed doses of LDE225 and more than 20 missed doses 
of INC424 in 6 weeks), the patient can continue in the study without being evaluable for 
DDS. Consequently, another patient has to be enrolled into the same dose level in order to 
reach the required number of patients in the cohort.
Enrollment of new subjects may be considered until at least the minimum number (3) or at 
most the maximum number (6) of evaluable subjects is achieved within a cohort, see Section 
4.1.1.
Dose expansion:
No replacements will be needed, see Section 4.1.1.


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Phase II
During Stage 1 and Stage 2 of the Phase II part of the study no replacements will be made.
7.1.4
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 visit 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 determine 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.
7.1.5
Follow-up for Safety Evaluations
All patients, including those who discontinue study treatment and those who refuse to return 
for an EOT visit, will be contacted for safety evaluations 30 days after the last dose of study 
treatment. Patients must be followed for the occurrence of Adverse Events, Serious Adverse 
Events, concomitant medications, antineoplastic therapies used for treating Myelofibrosis 
disease since discontinuation of study drug, and transfusion use. Patients whose treatment is 
interrupted or permanently discontinued due to an adverse event, including abnormal 
laboratory value, must be followed until resolution or stabilization of the event, whichever 
comes first. See Table 7-1 and Table 7-2 for a complete list of assessments for the 30 day 
follow up evaluation.
The safety follow-up may be waived if the patient is continuing INC424 and LDE treatment 
in an alternative setting.
Data collected should be added to the Adverse Events eCRF and the Concomitant 
Medications eCRF.
7.1.6
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 the 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 eCRF.


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7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Measurement of spleen length by manual palpation
The response assessment in the Phase Ib part of the study will consist of measuring the spleen 
length by manual palpation at the end of Week 24 compared to the Week 1 Day 1
measurement. Patients who have a ≥ 50% reduction in spleen size by palpation at the end of 
Week 24 compared to the measurement at Week 1 Day 1 will be considered responders, 
otherwise they will be considered non-responders. Spleen length measurements will be taken 
at Screening, Week 1 Day 1, every 2 weeks until Week 9 Day 1, and every 4 weeks until 
Week 105 Day 1. Patients in the extension phase will undergo spleen length measurements 
every 12 weeks from Week 105. All patients will undergo spleen length measurements at the 
End of Treatment visit.
The edge of the spleen shall be determined by palpation from the left costal margin to the 
point of greatest splenic protrusion. Palpable spleen length should be measured in centimeters 
and not in finger breadths.
7.2.1.2
Measurement of spleen volume by MRI/CT
Patients enrolled to the confirmatory MTD level(s) in the Phase Ib part and all patients 
enrolled in the Phase II part of the study will have MRI/CT of the abdomen performed at 
Week 1 Day 1, Week 13 Day 1, the end of Week 24, the end of Week 48, and at Week 105
Day 1. Patients in the extension phase will undergo MRI/CT of the abdomen every 24 weeks 
from Week 105. All patients will undergo MRI/CT of the abdomen at the End of Treatment 
visit. Patients who have a ≥35% spleen volume reduction at the end of Week 24 and Week 48 
compared to Week 1 Day 1 will be considered responders, otherwise they will be considered 
non-responders. See Table 7-3 for the imaging collection plan.
Table 7-3
Spleen volumetric imaging (MRI/CT) collection plan
Procedure
Collection time points
Abdominal MRI of the spleen (or CT if MRI not permitted)
Phase Ib- Patients enrolled to the confirmatory MTD level(s)
Phase II- All Patients
Week 1 Day 1
Week 13 Day 1
At the end of Week 24 and the end of Week 48, 
and Week 105 Day 1
Every 24 weeks from Week 105 for patients in the 
extension phase
End of Treatment
Central Reader: MRI/CT scans will be sent to a central lab for analysis
MRIs will be performed locally according to the guidelines provided by the designated 
imaging vendor. The scans from an individual patient will be sent to the designated imaging 
vendor, who will then provide an independent quantitative assessment of the spleen volume 
for the study. Spleen volume will be obtained by outlining the circumference of the organ and 
determining the volume using a validated technique. The MRI will not determine spleen 
length below the left costal margin, as there are no validated approaches for determining this 


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measurement. Specific image acquisition parameters and procedures will be provided by the 
designated imaging vendor.
MRI is the preferred method for obtaining spleen volume data. However, CT scans may be 
performed if MRI cannot be performed (because of the presence of metal clips in the body, or 
because of claustrophobia, for example), or if MRI is unavailable to the study site. CT scans 
will be similarly processed by the designated imaging vendor.
NOTE: Generally, the same method (MRI or CT) should be used for all visits for a given 
subject unless a new contraindication to the use of MRI (e.g., pacemaker insertion) occurs. 
Please contact the sponsor if a modality change is required.
7.2.1.3
Change in bone marrow histomorphology
Bone marrow fibrosis will be measured in grades (see Table 7-4) on biopsy samples obtained 
for all patients at Week 1 Day 1, Week 25 Day 1, Week 49 Day 1, Week 73 Day 1, and Week 
97 Day 1.  For patients in the extension phase, biopsy samples will be obtained every 48 
weeks from Week 105. Biopsy samples will also be obtained at the End of Treatment visit, if 
a sample has not already been obtained in the past 24 weeks (see Table 7-5). Collection, 
processing and staining of bone marrow aspirations and biopsy samples will be done in 
accordance with standard procedures at the investigative sites. The bone marrow biopsy and 
aspirate should be assessed by an experienced hematopathologist using his/her standard 
examination. Bone marrow fibrosis should be graded using the European consensus grading 
system (Tefferi 2006).
Table 7-4
Fibrosis grading
Fibrosis Grade
Description
0
Scattered linear reticulin with no intersections corresponding to normal bone marrow
1
Loose network of reticulin with many intersections, especially in perivascular areas
2
Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal 
bundles of collagen and/or focal osteosclerosis
3
Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of 
collagen, often associated with significant osteosclerosis
Note: Fibrosis density should be assessed in hematopoietic areas.
The following analyses should be performed:

Assessment of cellularity.

500-cell differential of aspirate, correlated, if possible, with data from appropriate marrow 
biopsy section. Percentage of pronormoblasts, blasts, normoblasts, myelocytes, 
metamyelocytes

Blast percentage, indicating what cellular types are being considered as blast equivalents, 
and the degree of maturation and dysplastic abnormalities within the neoplastic population 
should be described.

Characterization of erythrocyte and megakaryocyte morphology.

Characterization and gradation of fibrosis within hematopoietic cellular areas.

Diagnostic interpretation with specific mention of (expected) absence of an infiltrative or 
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Cytogenetic analysis should include karyotyping and any other tests for which an abnormality 
has been previously identified in that subject. Any other tests that are considered standard by 
the Investigator may also be performed.
If samples allow, 3 unstained slides of bone marrow aspirate and half of the bone marrow 
biopsy sample will be sent to a central lab for central analysis. During or following the study 
conduct, at the Sponsor’s discretion, a central review of any or all of the bone marrow studies 
may be conducted by external expert(s) in hematopathology.
Table 7-5
Bone marrow collection plan
Procedure
Collection time points
Bone Marrow biopsy and aspirate for local 
analysis
(Mandatory for all patients)
Week 1 Day 1
Week 25 Day 1, Week 49 Day 1, Week 73 Day 1, and Week 97 Day 
1
Every 48 weeks in the extension phase from Week 105
End of Treatment (if not performed in the past 24 weeks)
* If a patient is considered to be a non-responder at the end of Week 24 then further bone marrow aspirates 
and/or biopsies may not be collected
To central lab: if samples allow, send 3 unstained slides of bone marrow aspirate and half of bone marrow biopsy 
sample. 
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing adverse events, serious adverse events, laboratory 
evaluations (including creatine kinase), physical examinations, weight, vital signs, ECOG 
performance status, ECG, and chest x-rays. For details on AE collection and reporting, refer 
to Section 8.
7.2.2.1
Physical examination
A complete physical examination will be performed at screening and at the EOT visit. The 
complete physical examination comprises of a total body examination that should include: 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph-nodes, extremities, vascular and neurological review. If indicated, 
rectal, external genitalia, breast and pelvis exams will be performed. Subsequently, an 
abbreviated physical examination will be performed at Week 5 Day 1 and then monthly until 
Week 105 Day 1 and includes an examination of general appearance, skin, lungs, heart, and 
abdomen. Additional examinations may be performed at the Investigator’s discretion. Patients 
in the extension phase will undergo abbreviated physical examinations after Week 105 per 
standard of care as noted in Table 7-2.
Information about the physical examination must be present in the source documentation at 
the study site.
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the patient’s eCRF.


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7.2.2.2
Vital signs
Vital signs (blood pressure, pulse and body temperature) will be collected according to the 
Visit Schedule outlined in Table 7-1 and Table 7-2 for patients in the extension phase or more 
frequently as per standard of care. Vital signs will be taken with the patient in the sitting 
position after 5 minutes of rest. Body temperature may be measured orally or via ear.
7.2.2.3
Height and weight
Height in centimeters (cm) will be measured only at screening. Body weight will be measured 
in indoor clothing (without shoes) at the timepoints defined in Table 7-1 and Table 7-2 for 
patients in the extension phase or more frequently as per standard of care.
7.2.2.4
ECOG performance status
The performance status will be assessed according to the ECOG (WHO) performance status 
scale (Oken 1982) at the timepoints defined in Table 7-1 and Table 7-2 for patients in the 
extension phase or more frequently as per standard of care. The ECOG performance status is 
graded on a six point scale (range 0 to 5) (See Appendix 2).
7.2.2.5
Laboratory evaluations
All safety laboratory assessments will be performed locally, at the Investigator’s site 
laboratory according to the schedule of assessments and collection plan outlined respectively 
in Table 7-1 and Table 7-2 The following visit windows are allowed: +/- 1 day during the first 
8 weeks (except at Week 1 Day 1 and Week 1 Day 2), +/- 2 days during Weeks 9-13 and +/- 3
days from Week 17 onwards. Laboratory-only visits can be performed at the clinic site or at 
any local laboratory provided that the investigator reviews the results within 2 business days 
to ensure subject’s safety.
Novartis must be provided with a copy of the local laboratory’s certification and a tabulation 
of the normal ranges and units of each parameter collected in the eCRF. Any changes 
regarding normal ranges and units for laboratory values assessed during the study must be 
reported via an updated tabulation indicating the date of revalidation. Additionally, if at any 
time a patient has laboratory parameters obtained from a different laboratory, Novartis must 
be provided with a copy of the certification and a tabulation of the normal ranges and units for 
this laboratory as well. The investigator is responsible for reviewing all laboratory reports for 
patients in the study and evaluating any abnormalities for clinical significance.
Non-safety laboratory samples (PK, biomarkers, biopsies) will be handled, stored and 
analyzed by a Novartis assigned laboratories or contracted central laboratories. Details of the 
collection and shipment of samples will be provided to the investigators in the laboratory 
manual.
At any time during the study, abnormal laboratory parameters which are clinically significant 
and require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the Common Terminology Criteria for 


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Adverse events (CTCAE) version 4.0.3. Additional laboratory evaluations are left to the 
discretion of the investigator.
Table 7-6
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cell count (RBC), White 
blood cell count (WBC), RBC Morphology with Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, and Blasts)
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Sodium, Potassium, Calcium, 
Chloride, Phosphate, Magnesium, Creatinine, Glucose, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) 
or Urea, Uric Acid
Muscle Toxicity 
Markers
Creatine kinase
Urinalysis
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial 
cells)
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Coagulation
International normalized ratio [INR], Partial thromboplastin time (PTT)
Additional test
Pregnancy test
7.2.2.5.1 Hematology
Hematocrit, hemoglobin, MCH, MCHC, MCV, platelets, red blood cell count (RBC), white 
blood cell count (WBC), RBC Morphology with Differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils, and blasts) will be measured locally for Phase 1b and 
Phase II patients at different timepoints according to Table 7-1 and Table 7-2 for patients in 
the extension phase or more frequently as per standard of care.
7.2.2.5.2 Clinical chemistry
Albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), sodium, potassium, calcium, 
chloride, phosphate, magnesium, creatinine, glucose, direct bilirubin, indirect bilirubin, total 
bilirubin, total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), 
total protein, triglycerides, blood urea nitrogen (BUN) or urea, and uric acid will be measured 
locally for Phase 1b and Phase II patients at different timepoints according to Table 7-1 and
Table 7-2 for patients in the extension phase or more frequently as per standard of care.
7.2.2.5.3 Muscle toxicity markers
CK will be performed according to Table 6-5 (if applicable), Table 7-1, and Table 7-2 for 
patients in the extension phase or more frequently to follow up on significant toxicities.
7.2.2.5.4 Coagulation
International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT) will be 
performed locally according to Table 7-1 and Table 7-2 for patients in the extension phase or 
more frequently to follow up as per standard of care. In case of a hemorrhagic event of any 
grade (CTCAE grade 1 included) the Investigator is advised to perform unscheduled 
coagulation tests.


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7.2.2.5.5 Urinalysis
Dipstick evaluations for color, bilirubin, blood, glucose, ketones, leukocytes esterase, nitrite, 
pH, protein, specific gravity and urobilinogen will be performed according to the visit 
schedule in Table 7-1 and Table 7-2 for patients in the extension phase at the local institution. 
If clinically indicated, any significant findings will be followed up with a microscopic 
evaluation to assess red blood cells, white blood cells, casts, crystals, bacteria, and epithelial 
cells.
7.2.2.5.6 Pregnancy and assessments of fertility
Female patients of childbearing potential must undergo a local serum pregnancy test at 
screening to confirm eligibility in the trial (≤ 7 days before first dose of either study drug),
and at EOT as well as a urine pregnancy test locally according to the schedule of assessments 
outlined in Table 7-1 and Table 7-2 for patients in the extension phase.
For patients in the extension phase, monthly (or more frequently if required per local 
regulation) pregnancy testing is required.  Women of child bearing potential will be provided 
with home pregnancy test kits for the duration of the study. Patients must be instructed to call 
the site staff for further instruction immediately if at least one of the home pregnancy tests is 
positive.
If an additional pregnancy test is indicated during the trial, a serum test should be performed. 
In case of pregnancy, the patient must permanently stop study treatment immediately, 
withdraw from the trial, and the pregnancy must be reported on the Clinical Trial Pregnancy 
Form.
7.2.2.5.7 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed locally at Screening, Week 1 Day 1, every 4 
weeks until Week 105 Day 1, and at the End of Treatment (EOT) visit if before Week 105, as 
per Table 7-1. Patients in the extension phase (after Week 105 Day 1) will have 12 lead ECGs 
performed per standard of care as per Table 7-2. ECGs should be taken pre-dose while on 
study treatment.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG eCRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History eCRF page. Significant findings may be 
discussed with Novartis. New or worsened clinically significant findings occurring after 
informed consent must be recorded on the Adverse Events eCRF page.
7.2.2.5.8 Chest X-ray
If at any time during the study there is suspicion of any lung disease a chest x-ray should be 
performed for any patient including those in the extension phase of the study and the results 
recorded on the Chest X-ray eCRF and AE eCRF if applicable.


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7.2.3
Pharmacokinetics
Blood collection
The blood sampling schedule for determining the PK of LDE225 and INC424 are provided in 
Table 7-7 (for Phase Ib and Phase II, Stage 1) and Table 7-9 (for Phase II, Stage 2). Blood 
samples for PK determinations will not be obtained during the extension phase of the study. 
The 24 hours plasma concentration-time profiles of LDE225 and INC424 will be 
characterized after single dose (Week 1 Day 1) and after multiple doses (Week 9 Day 1) in 
Phase Ib and Phase II Stage 1. Trough (pre-dose) samples will be collected on Week 3 Day 1, 
Week 5 Day 1, Week 7 Day 1, Week 9 Day 1 and Day 1 of every 4 weeks thereafter until 
Week 49. Only trough samples will be collected in Phase II, Stage 2. On the day of trough 
samples, the doses of LDE225 and INC424 should be taken at the clinic after pre-dose 
collection. At each scheduled time point, a single blood draw (4mL) will be collected into 
tubes containing K2EDTA, and the plasma will be split into 2 tubes (approximately 1 mL for 
LDE225 and approximately 1 mL for INC424concentration measurement). Complete 
instructions for sample processing, handling and shipment will be provided in the [Laboratory 
Manual].
If a patient experiences an adverse event that results in an unscheduled visit or fits the criteria
of an SAE as determined by the Investigator, a blood sample should be collected for
measurement of plasma drug concentrations.
Exact dates and clock times of drug administration and actual PK blood draw will be recorded 
on the appropriate eCRF. If vomiting occurs within 4 hours of dosing during the course of 
treatment, no re-dosing of the patient is allowed before the next scheduled dose. The time of 
vomiting should be recorded on the appropriate eCRF.
Meal records will be collected on Week 1 Day 1 and Week 9 Day 1 for Phase Ib and Phase II 
Stage 1 only. The start and end time of meals will be recorded.
Table 7-7
Pharmacokinetic blood collection log: Phase Ib and Phase II, Stage 1
Week/Day
LDE225
INC424
Time (hours)
Dose 
reference ID
Sample 
No.
Time (hours)
Dose 
reference ID
Sample No.
Week 1 day 1
Pre-dose
101
101
Pre-dose
201
201
0.5
101
102
0.5
201
202
1
101
103
1
201
203
1.5
101
104
1.5
201
204
2
101
105
2
201
205
4
101
106
4
201
206
6
101
107
6
201
207
8
101
108
8
201
208
Week 1 day 2
Pre-dose
101*/102**
109
Pre-dose
201*/202**
209
Week 3 day 1
Pre-dose
103
110
Pre-dose
203
210
Week 5 day 1
Pre-dose
104
111
Pre-dose
204
211
Week 7 day 1
Pre-dose
105
112
Pre-dose
205
212
Week 9 day 1
Pre-dose
106
113
Pre-dose
206
213


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Week/Day
LDE225
INC424
Time (hours)
Dose 
reference ID
Sample 
No.
Time (hours)
Dose 
reference ID
Sample No.
0.5
106
114
0.5
206
214
1
106
115
1
206
215
1.5
106
116
1.5
206
216
2
106
117
2
206
217
4
106
118
4
206
218
6
106
119
6
206
219
8
106
120
8
206
220
Week 9 day 2
Pre-dose
106*/107**
121
Pre-dose
206*/207**
221
Week 13 day 1
Pre-dose
108
122
Pre-dose
208
222
Week 17 day 1
Pre-dose
109
123
Pre-dose
209
223
Week 21 day 1
Pre-dose
110
124
Pre-dose
210
224
Week 25 day 1
Pre-dose
111
125
Pre-dose
211
225
Week 29 day 1
Pre-dose
112
126
Pre-dose
212
226
Week 33 day 1
Pre-dose
113
127
Pre-dose
213
227
Week 37 day 1
Pre-dose
114
128
Pre-dose
214
228
Week 41 day 1
Pre-dose
115
129
Pre-dose
215
229
Week 45 day 1
Pre-dose
116
130
Pre-dose
216
230
Week 49 day 1
Pre-dose
117
131
Pre-dose
217
231
NA
unscheduled
NA
1001+
unscheduled
NA
2001+
Note: Pre-dose samples are taken immediately prior to LDE225 or INC424 morning dose administration.
*The former dose reference ID refers to the last dose prior to collection of the corresponding PK sample (i.e., the 
dose taken on the day before the trough PK sampling).
**The latter dose reference ID refers to the dose taken on the day of the PK sampling.
In Phase II Stage 1 or Stage 2, a minimum of 0.5 mL, if available, of fresh bone marrow 
aspirate (prior to formalin fixation) will be obtained from at least 10 patients enrolled globally 
at Week 25, Week 49 and EOT and will be transferred to a 1.8 mL NUNC 2D coded cryovial 
and centrifuged for 10 minutes at 2000 g at 3-5 degrees Celsius or room temperature. A 
minimum of 200 microliters of supernatant) will be transferred to a new 1.8 mL NUNC 2D 
coded cryovial and be frozen immediately over dry ice or in a freezer at -70 degrees Celsius. 
The bone marrow samples will be used for exploratory measurement of LDE225 
concentrations in bone marrow (Table 7-8). A blood sample should be also collected at the 
time of bone marrow aspirate collection, for concurrent measurement of plasma LDE225 
concentrations according to the instructions for unscheduled blood PK in the [Laboratory 
Manual] to understand relative distribution of LDE225 to bone marrow versus plasma.
The exact dates and clock times of bone marrow aspirate and corresponding blood PK 
sampling must be recorded on the respective PK blood collection CRF.


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Table 7-9
Pharmacokinetic blood collection log: Phase II, Stage 2
Week/Day
LDE225
INC424
Time (hours)
Dose 
reference 
ID
Sample 
No.
Time (hours)
Dose 
reference ID
Sample No.
Week 1 day 1
Pre-dose
301
301
Pre-dose
401
401
Week 3 day 1
Pre-dose
302
302
Pre-dose
402
402
Week 5 day 1
Pre-dose
303
303
Pre-dose
403
403
Week 7 day 1
Pre-dose
304
304
Pre-dose
404
404
Week 9 day 1
Pre-dose
305
305
Pre-dose
405
405
Week 13 day 1
Pre-dose
306
306
Pre-dose
406
406
Week 17 day 1
Pre-dose
307
307
Pre-dose
407
407
Week 21 day 1
Pre-dose
308
308
Pre-dose
408
408
Week 25 day 1
Pre-dose
309
309
Pre-dose
409
409
Week 29 day 1
Pre-dose
310
310
Pre-dose
410
410
Week 33 day 1
Pre-dose
311
311
Pre-dose
411
411
Week 37 day 1
Pre-dose
312
312
Pre-dose
412
412
Week 41 day 1
Pre-dose
313
313
Pre-dose
413
413
Week 45 day 1
Pre-dose
314
314
Pre-dose
414
414
Week 49 day 1
Pre-dose
315
315
Pre-dose
415
415
NA
unscheduled
NA
3001+
unscheduled
NA
4001+
Note: Pre-dose samples are taken immediately prior to LDE225 or INC424 morning dose administration.
7.2.3.1
PK analytical method
Plasma LDE225 concentrations and plasma INC424 concentrations will be measured at 
Novartis or a designated CRO using a validated liquid chromatography-tandem mass 


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spectrometry (LC-MS/MS) method for each analyte. Bone marrow LDE225 concentrations 
will be measured at Novartis or a designated CRO using a liquid chromatography-tandem 
mass spectrometry (LC-MS/MS) method (e.g., exploratory or validated).
7.2.4
Biomarkers
Biomarkers are objectively measured and evaluated indicators of normal biological, 
pathogenic and/or pharmacologic responses to a therapeutic intervention. Investigating the 
Hedgehog (Hh) and JAK signaling pathways in participants enrolled in this study may 
illuminate any potential predictive measures of response and/or resistance to LDE225 in 
combination with INC424 in myelofibrosis.
 
 
All assessments will be performed by a Novartis designated laboratory. Instructions for 
collection, preparation and shipment can be found in the laboratory manual.
7.2.4.1
Blood sample for JAK status and allele burden analysis
Blood for JAK2V617F mutation status and allele burden quantitation will be analyzed at a 
Novartis designated laboratory.
 
 
7.2.4.3
Blood sample for Hedgehog pathway expression analysis
A blood sample will be collected to assess the Hh pathway activation status of each 
participant. This assessment will be performed by a Novartis designated laboratory and may 
include targets such as Gli1.


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Table 7-10
Biomarker sample collection plan
Sample Type
Volume
Visit
Time point
Blood Samples
Mandatory
Whole Blood sample for JAK2V617F 
mutational status and allelic burden 
analysis
6mL (per 
time point)
Screening
Anytime for Screening 
and End of Treatment
Pre-dose for all other 
collection timepoints
Week 13
Week 25, Week 49, Week 73, 
and Week 97
End of Treatment (if before 
Week 97 visit)
Mandatory
Whole Blood sample for Hh pathway 
expression analysis
2 x 2.5mL 
(per time 
point)
Screening
Anytime
Week 3 Day 1
Pre-dose
Week 9 Day 1
Pre-dose
Week 17 Day 1
Pre-dose
Week 25 Day 1
Pre-dose
Week 49 Day 1
Pre-dose
End of Treatment or Week 105
Day 1 (whichever comes first)
Anytime
Other assessments
No additional tests will be performed on patients entered into this study.
7.2.5
Resource utilization
Not applicable.
7.2.6
Patient reported outcomes (PROs)
This study will include two efficacy questionnaires; the Seven-Day Modified Myelofibrosis 
Symptom Assessment Form v2.0 (MFSAF) and the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (see Section 7.2.6.1). 
Instructions for each instrument will be provided in a separate document. All PRO 
questionnaires should be administered in the patient’s local language at the beginning of the 
study visit prior to any interaction with the study investigator including any tests, treatments 


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or receipt of results from any tests to avoid biasing the patient’s perspective. This is to avoid 
potentially biasing patients or their responses to study questionnaires. The questionnaires can 
be given in any order.
General instructions
Patients should be given sufficient space and time to complete all study questionnaires and all 
administered questionnaires should be reviewed for completeness. If missing responses are 
noted, patients should be encouraged to complete any missing responses. Attempts should be 
made to collect responses to all questionnaires for all patients, including from those who 
discontinue prior to the study evaluation completion visit; however, if patients refuse to 
complete questionnaires, this should be documented in study source records. Patient’s refusal 
to complete study questionnaires are not protocol deviations.
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, should be reviewed and assessed by the investigator before 
the clinical examination for responses which may indicate potential AEs or SAEs. This review 
should be documented in study source records.
7.2.6.1
Efficacy PRO questionnaires
7.2.6.1.1 Seven-day modified MFSAF v2.0
The symptoms of MF will be assessed using the Seven-day modified MFSAF v2.0 paper 
questionnaire. The Seven-day modified MFSAF v2.0 is a 7-item PRO instrument based on the 
modified MFSAF v2.0 diary (Mesa 2009, Appendix 3) to be administered at specified visits 
(see visit schedule). The first 6 items assess MF symptom severity at its worst as recalled in 
the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, 
itching, abdominal discomfort, pain under the ribs (left side), early satiety, and bone/muscle 
pain. The seventh item captures MF-related inactivity in the past 7 days prior to the clinic visit 
assessment. All seven items ask subjects to record their answers on an 11-point numeric rating 
scale, or NRS, (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus 
on MF symptoms and are summed to create a Total Symptom score.
The Seven-day modified MFSAF v2.0 will be collected at Screening, Week 1 Day 1, then 
every 4 weeks until Week 105 Day 1. For patients in the extension phase, the MFSAF will be 
collected every 12 weeks from Week 105. All patients will complete the MFSAF at the End 
of Treatment visit (See Table 7-11).
7.2.6.1.2 EORTC QLQ-C30
The EORTC QLQ-C30 (Appendix 4) is one of the most widely used and validated 
instruments to measure health-related Quality of Life (QoL) in subjects with cancer. The 
EORTC QLQ-C30 includes 5 functional scales (physical functioning, role functioning, 
emotional functioning, cognitive functioning and social functioning), global health status/QoL 
and 9 symptom scale/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite 
loss, constipation, diarrhea, and financial difficulties). This instrument asks the subject to 
respond according to the past week, with the exception of the first 5 questions that represent 
physical functioning and capture the subject’s current status. The range of scores for all of the 


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scales is from 0 to 100. For functional and global health status/QoL scales, higher scores 
indicate better QoL and level of functioning; for symptom scales, higher scores indicate 
greater level of symptoms or difficulties.
The EORTC QLQ-C30 will be collected at Week 1 Day 1, then every 4 weeks until Week 105
Day 1. For patients in the extension phase, the QLQ-C30 will be collected every 12 weeks 
from Week 105. All patients will complete the QLQ-C30 at the End of Treatment visit (See
Table 7-11).
Table 7-11
MFSAF v2.0 and EORTC QLQ-C30 collection plan
Patient Questionnaire
Visit
Time point
MFSAF v2.0
Screening
Prior to any clinical 
assessments, study 
drug dosing, or 
diagnostic testing
Week 1 Day 1, then every 4 weeks until Week 105 Day 1
Every 12 weeks for patients in the extension phase
End of Treatment
EORTC QLQ-C30
Week 1 Day 1, then every 4 weeks until Week 105 Day 1
Every 12 weeks for patients in the extension phase
End of Treatment
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).
For patients who sign the ICF, all AEs will be captured in the AE eCRF from time of 
signature through 30 days after permanent study drug discontinuation. For patients who fail 
screening, only SAEs will be captured in the AE eCRF page.
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 


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severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected on the appropriate eCRF.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
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 (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines 
for hematological malignancies), 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 drug.
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 


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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.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

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

Protocol exempt SAEs: Any SAEs that are expected due to the condition being treated and
where there has been a clear agreement with regulators not to collect these SAEs in the 
safety database, provided the information is collected elsewhere. For example, this may 
include serious adverse events that are also a primary outcome measure, such as mortality, 
survival rate or number of flares of the condition being studied.
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main 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.
SAE collection starts at time of main ICF signature whether the patients is a screen failure or 
not.


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Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form within the remote data capture (RDC) system (where available or on the paper SAE 
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 send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department.
When SAEs are recorded electronically in the RDC system, these should be entered, saved 
and e-signed within 24 hours of awareness of the SAE. These data will automatically be 
submitted to Novartis Drug Safety & Epidemiology immediately after investigator signature 
or 24 hours after entry, whichever occurs first.
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable.


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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 of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided 
Investigator’s Brochure. 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
Not applicable.
8.7
Steering Committee
A steering committee (SC) will be established for the Phase II part of the study and will be 
comprised of investigators participating in the study and Novartis representatives.
The SC will ensure transparent management of the study according to the protocol by 
recommending and approving modifications as circumstances require. The SC will review
protocol amendments as appropriate and key safety data at regular intervals during the study.
Together with the clinical trial team, the SC will also develop recommendations for
publications of study results including authorship rules. Full details on the role of the SC will 
be defined in a SC charter.
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:


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
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.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
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 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 recorded on CRFs must be traceable to 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 and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.


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9.3
Data collection
Electronic Data Capture (EDC) is used for this study. Designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
Electronic versions of the EORTC QLQ-30 and MFSAF v 2.0 questionnaires will be provided 
to the sites, sites will print paper copies of these questionnaires for the patients. The 
questionnaires must be completed by patients, scored and interpreted at each applicable visit 
(see Table 7-1). The total score will be determined by the investigator (or designee) and will 
be interpreted for each questionnaire separately. Answers provided by the patients on the 
questionnaires will be entered manually by the investigator site staff into the eCRF. Original 
questionnaires will be archived in patient medical files. The field monitor will review the 
relevant questionnaires and eCRFs for accuracy and completeness.
All ECGs will be read locally.
PK, biomarker (blood and derivative) and bone marrow biopsy/aspirate samples obtained 
during the course of the study will be collected from the investigator sites and analyzed by 
Novartis assigned laboratories or contracted central laboratories. The site staff designated by 
the investigator will enter the information required by the protocol onto the respective sample 
collection eCRFs, as well as onto the designated CRO’s requisition form. One copy of the 
requisition form will be sent to the designated laboratory (including study number, subject ID, 
etc.) and one copy will be retained by the site. The field monitor will review the relevant 
eCRFs for accuracy and completeness and will work with the site staff to adjust any 
discrepancies as required. The field monitor will also review the requisition forms for 
completeness.
Imaging Data used to assess spleen volume will be centrally collected and subjected to quality 
control.
9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
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.


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ECGs will be read locally. Samples and/or data for imaging, PK, Biomarker (blood and 
derivative), and bone marrow biopsies/aspirates will be processed centrally and the results 
will be sent electronically to Novartis (or a designated CRO).
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site.
10
Statistical methods and data analysis
Data from this trial will be analyzed by Novartis and/or a designated CRO. All data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
All data from participating centers in this protocol will be combined so that an adequate 
number of patients will be available for analysis. The data related to demographic and 
baseline characteristics, efficacy observations and measurements, safety observations and 
measurements, and all relevant PK and PD measurements will be summarized using 
descriptive statistics (quantitative data) and contingency tables (qualitative data).
The final analysis of study data for the purposes of generating the Clinical Study Report 
(CSR) will be based on all patient data from phase I (including dose escalation and safety 
expansion phases), phase II, and the extension phase, when all patients have discontinued the 
study. 
Details of the statistical analysis and data reporting will be provided in the Novartis Report 
and Analysis Plan (RAP) document finalized before database lock.
10.1
Analysis sets
The following analysis sets will be used for statistical analysis and data reporting.
10.1.1
Full Analysis Set
Phase Ib:
The Full Analysis Set (FAS) comprises all patients in phase Ib who received at least one dose 
of LDE225 and/or INC424. This includes the dose escalation and safety expansion portions of 
the study.
Phase II:
The FAS comprises all patients in phase II who received at least one dose of LDE225 and/or 
INC424.
Patients will be classified according to the assigned treatment combination. Unless otherwise 
specified the FAS will be the default analysis set used for all analysis.
Patients who are screened but never start treatment will be listed and will not be included in 
any of the summary tables.
10.1.2
Safety Set
Phase Ib:


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The Safety Set includes all patients in phase Ib who received at least one dose of LDE225 
and/or INC424.
Phase II:
The Safety Set includes all patients in Phase II who received at least one dose of LDE225 
and/or INC424.
Patients will be analyzed according to the study treatment (regimen) they actually received, 
where treatment received for each drug is defined as (i) the treatment assigned if it was 
received at least once, or (ii) the first treatment received when starting study medication. Each 
patient will be classified into and analyzed consistently within one (and only one) treatment 
group.
10.1.3
Dose-determining analysis set
The dose-determining set (DDS) consists of all patients from the safety set of phase Ib who 
either meet the following minimum exposure criterion and have sufficient safety evaluations 
(as determined by the investigators and Novartis), or discontinue earlier due to DLT. This 
constitutes an evaluable patient for the determination of the MTD.
A patient is considered to have met the minimum exposure criterion at treatment group if the 
patient receives at least 75% of the planned doses of LDE225 and INC424 within 6 weeks (42 
days) following the first dose (i.e., no more than 10 missed doses of LDE225 and no more 
than 20 missed doses of INC424 in 6 weeks are permitted). Patients who do not meet these 
minimum exposure and safety evaluation requirements will be regarded as ineligible for 
inclusion into the DDS. Patients in the DDS will be identified before database lock
10.1.4
Pharmacokinetic analysis set
Phase Ib:
The pharmacokinetic analysis set (PAS) consists of all patients in Phase Ib who receive at 
least one (full or partial) dose of LDE225 and/or INC424 and provide at least one evaluable 
PK blood sample for LDE225 and/or INC424.
Phase II:
The PAS of phase II consists of all patients in Phase II who receive at least one (full or 
partial) dose of LDE225 and/or INC424 and provide at least one evaluable PK blood sample 
for LDE225 and/or INC424 or both).
The PAS will be used for summaries of PK data (Tables and Figures) as well as for listing of 
derived parameters.
10.1.5
Biomarker analysis set
The Biomarker Analysis Set (BAS) consists of all patients who receive at least one (full or 
partial) dose of LDE225 and/or INC424 and provide at least one evaluable biomarker sample.


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10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics and ECOG (WHO) 
performance status) will be summarized descriptively by study phase (phase Ib and phase II). 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
10.3.1
Study treatment
The actual dose and duration in days of LDE225 and INC424 treatment as well as the dose 
intensity (computed as the ratio of actual received and actual duration) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose received/planned duration) 
will be listed and summarized by means of descriptive statistics by treatment group and by 
study phase in the clinical study report.
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized for the full analysis set by study phase.
10.3.3
Compliance
Compliance with the study protocol will be assessed by reporting the number and type of 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized by study phase.
10.4
Primary objective
The primary objective of Phase Ib is to establish the MTD and/or RPIID of the combination of 
LDE225 (QD) and INC424 (BID) when administered orally to patients with myelofibrosis 
who have not previously received therapy with a JAK inhibitor.
The primary objective of Phase II is to assess the efficacy of the co-administration of LDE225 
and INC424 on spleen volume reduction as determined by centrally reviewed MRI/CT.
10.4.1
Variable
Phase Ib:
The primary variable is the frequency of DLTs associated with continuous daily 
administration of LDE225 in combination with INC424 as a function of dose. Estimation of 
the MTD of the combination treatment will be based upon the estimation of the probability of 
DLT at each dose level using BLRM and guided by EWOC (Section 10.4.2).
Phase II:
The primary endpoint is the proportion of subjects achieving ≥ 35% reduction in spleen 
volume from baseline by centrally reviewed MRI/CT at the end of Week 24 and Week 48.


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10.4.2
Statistical hypothesis, model, and method of analysis
Phase Ib:
Dose escalation
An adaptive Bayesian logistic regression model (BLRM) similar to the proposal by (Thall 
2003) and dose escalation criteria proposed by (Babb 1998) will be used for the dose 
escalation.
A 6-parameter Bayesian Logistic Regression Model (BLRM) for combination treatment will 
be fitted to the 6-week dose-limiting toxicity data (i.e. absence or presence of DLT) 
accumulated throughout the dose escalation part to model the dose-toxicity relationship of 
LDE225 and INC424 when given in combination. The model is formulated in the following 
way: let π1(d1) be the probability of a DLT if INC424 is given as a single agent as dose d1, and 
let π2(d2) the probability of a DLT if LDE225 is given as a single agent at dose d2, further let 
π12(d1,d2) be the probability of a DLT when LDE225 and INC424 are given in combination at 
doses d1 and d2 respectively. The dose-DLT relationship is then modeled as:
For a single-agent INC424: logit(π1(d1))=log(α1)+β1log(d1/d1
*)+γI(PLT≤200X109),
For a single-agent LDE225: logit(π2(d2))=log(α2)+β2log(d2/d2
*),
For the combination of LDE225 and INC424:
Odds(π12(d1,d2))= π12(d1,d2)/(1- π12(d1,d2))
=exp(η d1/ d1
* d2/ d2
*)(π1(d1)+ π2(d2)- π1(d1) π2(d2))/((1- π1(d1))(1- π2(d2))),
Where I is the indicator function, logit(π(d))=log[π(d)/{1- π(d)}], d1*=30 mg total daily dose 
(15 mg BID) and d2*=700 mg(QD) are the reference doses of INC424 and LDE225 
respectively, α1, α2, β1, β2, η and γ>0 are model parameters. The parameter γ is related to the 
binary baseline covariate (platelet count at baseline ≤200X109/L) and η is an interaction term
between the two drugs.
Prior specifications: LDE225 and INC424
The priors used in this study are listed in Table 10-1.
Table 10-1
Prior specifications
Parameter
Means
Standard deviations
Correlation
INC log(α1),log(β1)
(-2.141,-0.180)
0.602,0.634
0.085
LDE log(α2),log(β2)
(-2.291,0.721)
0.894,0.773
-0.117
η (normal)
0.250
2.028
n/a
γ (log-normal)
-1.426
1.61
n/a
The derivation of these priors and simulated operating characteristics can be found in detail in 
Appendix 7 (Section 14.7).
Dose recommendation
Dose recommendation will be based on summaries of the posterior distribution of model 
parameters and the posterior distribution of DLT rates, including the mean, median, standard 


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deviation, 95%-credibility interval, and the probability that the true DLT rate for each dose 
combination lies in one of the following categories:

[0%, 16%) under dosing

[16%, 35%) targeted toxicity

[35%, 100] excessive 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 
[16%, 35%) among the doses fulfilling the overdose-control criterion that there is less than 
25% (posterior probability) chance of excessive toxicity. In addition, the maximum inter-
cohort dose escalation is limited to 100% (i.e. up to 100% and 0% increase for LDE225 and 
INC424 respectively or 0% and up to 100% increase for LDE225 and INC424 respectively). 
The proposed combination meets the EWOC criteria (i.e. less than 25% chance that the true 
rate of DLTs lies within the interval [35% - 100%]. A clinical synthesis of the available 
toxicity information (including AEs that are not DLTs), PK, PD, and efficacy information as 
well as the recommendations from the BLRM will be used to determine the dose combination 
for the next cohort at a dose escalation teleconference. The determination of MTD/RPIID will 
occur when the following conditions are met:
1. at least 9 patients have been treated at each MTD and/or RPIID dose,
2. this dose satisfies one of the following conditions:
a. the posterior probability of targeted toxicity at this dose exceeds 50%, or
b. minimum of 24 patients have already been treated on the trial.
Safety Expansion
After declaration of MTD and/or RPIID, the dose will be expanded by an additional 6 patients 
in order to further assess tolerability, safety and early efficacy. If two MTDs/RPIIDs are 
established, each MTD/RPIID will enroll an additional 6 patients in the safety expansion. 
After these confirmatory patients have been treated for 6 weeks, if 2 or more DLTs are 
observed at the selected dose (MTD/RPIID), the BLRM will be ran again to confirm that the 
current dose still satisfies the overdose criteria of the model. If the dose fails to satisfy the 
criteria, a change to the dose under study will be made subject to the BLRM recommendation.
Listing of DLTs
DLTs will be listed and their incidence summarized by primary system organ class, worst 
grade based on the CTCAE version 4.03, type of adverse event, and by dose cohort. The dose-
determining set will be used for these summaries.
Phase II:
In the final analysis, the uniformly minimum variance unbiased estimator (UMVUE; Jung 
2004) for the proportion of subjects achieving ≥ 35% reduction from baseline in spleen 
volume as measured by MRI/CT at the end of Week 24 weeks Week 48, and their exact two-
sided 95% confidence intervals will be provided. Patients with unknown response will be 
treated as non-responders (see Section 10.4.3).


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10.4.3
Handling of missing values/censoring/discontinuations
The reasons for discontinuation from the study will be summarized and listed, along with 
dates of first and last study drug taken, duration of exposure to study drug and date of 
discontinuation for each patient. Other missing data will simply be noted as missing on the 
appropriate tables/listings.
Phase Ib:
Patients in the dose escalation phase are ineligible for the dose-determining set will not be 
replaced. However, if adequate numbers of evaluable patients are not available per cohort 
then additional patients may be enrolled.
Phase II:
Patients with unknown clinical response (e.g. patients with missing assessments at the end of 
24 or 48 weeks) will be considered as non-responders. No imputation of missing values will 
be made for the efficacy analysis.
10.4.4
Supportive analyses
Additional supportive analysis may be conducted if appropriate.
10.5
Secondary objectives
The following secondary objectives will be performed (Table 10-2).
Table 10-2
The analysis for the list of secondary objectives
Objective
Analysis
Phase Ib
To evaluate the safety of the co-administration of LDE225 and INC424 in 
patients with MF
Refer to Section 10.5.
To characterize the single and multiple dose pharmacokinetics following the 
co-administration of LDE225 and INC424
Refer to Section 10.5.2.
Phase II
To assess the effect of the co-administration of LDE225 and INC424 on 
bone marrow fibrosis by central review and on disease-specific 
pharmacodynamic biomarkers as a function of the molecular disease 
characterization of MF
Refer to Section 10.5.3.1.
To evaluate the safety of the co-administration of LDE225 and INC424 in 
patients with MF
Refer to Section 10.5.1.
To characterize pharmacokinetics following the co-administration of LDE225 
and INC424
Refer to Section 10.5.2.
To assess the effect of the co-administration of LDE225 and INC424 on MF-
associated symptoms burden
Refer to Section 10.5.4.
10.5.1
Safety
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) will be considered as appropriate. The safety summary tables 


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will include only assessments collected no later than 30 days after study treatment 
discontinuation. All safety data will be listed.
10.5.1.1 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, i.e. the treatment-emergent AEs. On-treatment assessment is 
defined as any assessment reported in the time interval from the start date of study treatment 
to 30 days following the last date of study treatment. However, all safety data will be listed 
and data collected outside the on-treatment period will be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE 4.03 
grades), type of adverse event, relation to each treatment schedule and by study phase.
Deaths and serious adverse events will be listed by patient and tabulated by type of adverse 
event and each treatment schedule by study phase.
10.5.1.2 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, laboratory data will be graded accordingly. All laboratory values will 
be converted into SI units. For laboratory tests where grades are not defined by CTCAE, 
results will be graded by the low/normal/high classifications based on laboratory normal 
ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests by study phase:

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value.

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high).

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other exploratory analyses may be 
performed as appropriate.
10.5.1.3 Other safety data
Summary statistics for data from other tests will be provided, notable values will be flagged, 
and any other information collected will be listed as appropriate by study phase. Descriptive 
summary statistics will be provided for electrocardiogram (ECG) and vital sign data, as 
follows:

ECG: Changes from baseline to end of study, and new or worsening abnormalities.

Vital signs: Summary statistics of raw data and change from baseline values (means, 
medians, standard deviations) plus newly occurring or worsening abnormalities.
Listings with flagged notable values and any other information collected will be provided as 
appropriate.


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10.5.2
Pharmacokinetics
Plasma concentrations of LDE225 and INC424 will be summarized at each scheduled time 
point by dose level. Descriptive graphical plots of individual plasma concentrations over time 
will be generated, along with mean concentration time profiles and trough for LDE225 and 
INC424. A list of individual concentrations will be provided using FAS.
For Phase Ib and Phase II Stage 1 only, PK parameters listed in Table 10-3 and Table 10-4
will be determined for all PK-evaluable patients using non-compartmental method(s) using 
WinNonlin or Phoenix WinNonlin (Pharsight, Mountain View, CA). PK parameters will be 
estimated for Week 1 and Week 9 and reported, when feasible. PK parameters in Table 10-3
and Table 10-4 for LDE225 and INC424 will be descriptively summarized for Week 1 and 
Week 9 by dose level. For Phase II Stage 2, Ctrough will be descriptively summarized at each 
scheduled time point and by means of graphical display.
Descriptive statistics (n, mean, SD, CV%, median [range], and geometric mean and CV%) 
will be presented for all parameters with the exception of Tmax for which median values and 
ranges will be presented. When a geometric mean is presented, it will be stated as such.
 
 
Table 10-3
Noncompartmental pharmacokinetic parameters for LDE225 (Phase Ib 
and Phase II Stage 1 only)
Term
Definition
Cmax
Maximum observed plasma concentration after drug administration [mass x volume-1]
Tmax
Time to reach Cmax [time]
AUC0-24h
Area under the concentration-time curve from time zero to 24 hours [mass x time x volume-1]
Table 10-4
Noncompartmental pharmacokinetic parameters for INC424 (Phase Ib 
and Phase II Stage 1 only)
Term
Definition
Cmax
Maximum observed plasma concentration after drug administration [mass x volume-1]
Tmax
Time to reach Cmax [time]
AUClast
Area under the concentration-time curve from time zero to the time of last measurable concentration 
[mass x time x volume-1]
AUC0-12h
Area under the concentration-time curve from time zero to 12 hours extrapolate from AUClast[mass 
x time x volume-1]
AUCinf
Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal 
phase [mass x time x volume-1]
T1/2
Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic 
concentration-time curve [time]
CL/F
Apparent total plasma clearance of drug after oral administration [volume x time-1]
Racc
Accumulation ratio calculated as AUC on Week 9 Day 1 divided by AUC on Week 1 Day 1 [fold]
Vss/F
Apparent volume of distribution at steady state after oral administration [volume]


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10.5.2.1 Data handling principles
All concentrations below the limit of quantitation or missing data will be reported as such in 
the concentration data listings. Concentrations below the limit of quantitation will be treated 
as zero in summary statistics.
10.5.3
Biomarkers
This study is not adequately powered to assess specific biomarker-related hypotheses, thus 
statistical analyses of these data should be considered exploratory in nature. Analytical results 
from such analyses may be used to generate additional hypotheses that must then be verified 
with data derived from subsequent clinical trials.
Summary tables, listings and visual displays will be created in order to describe the data, 
detect trends and draw preliminary conclusions. If sample size permits, advanced analyses 
may be carried out to better understand the data, refine interpretation and generate more 
robust hypotheses. Furthermore, additional post hoc exploratory assessments are expected and 
may be performed. The data analysis will be described in the biomarker analysis plan (BAP).
There may be circumstances when a decision is made to stop sample collection, or not 
perform or discontinue the analysis of biomarker samples due to either practical or strategic 
reasons (e.g. issues related to the quality and or quantity of samples, or issues related to the 
assay that preclude the analysis of samples). Under such circumstances, the number of 
samples may be inadequate to perform a rigorous data analysis and the available data will 
only be listed.
10.5.3.1 Outline of the data analysis
The proposed data analysis is aligned with the exploratory biomarker objective of the study 
protocol. The analysis of biomarker data collected at baseline will include basic descriptive 
statistics for all enrolled patients and by dosing schedule and/or treatment group and for the 
full population. If post baseline biomarker data are collected, distribution of change from 
baseline data will also be described. Where appropriate; baseline values and/or change from 
baseline values of biomarker and mutational status will be described with respect to clinical 
endpoints of interest. Exploratory subgroup analysis according to some of the baseline 
biomarker data may be performed. In addition, the association between biomarker levels or 
change in biomarker levels with PK, efficacy or safety endpoints may also be explored via 
suitable statistical analysis or graphical aids. For instance scatter plots/strip plots of 
biomarkers at baseline versus response may be created. Results from these exploratory 
analyses may be summarized in the clinical study report or in a separate document.
10.5.3.2 Data handling principles for biomarkers
Detailed data handling methods will be addressed in the RAP or in a stand-alone analysis plan 
document, as appropriate. These details may include (but are not limited to) descriptions of 
data transformations, approach to handle measures below the lower limit of quantification 
(LLOQ), thresholds and algorithms used to categorize and combine biomarkers etc.


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10.5.3.3 Data analysis principles
10.5.3.3.1
Analysis sets
The standard analysis sets will be used instead according to the purpose of a given analysis 
(e.g. FAS to describe biomarkers, safety/per-protocol set to assess the relationship between 
biomarkers and selected safety/efficacy endpoints). Note that since no imputation is usually 
planned, the number of patients included in a given analysis will reflect the number of patients 
in the chosen analysis set which have a valid biomarker assessment.
10.5.3.3.2
Basic tables, figures and listings
Mutations involved in the molecular disease characterization of MF will be listed by patient 
and summarized using frequency tables by dose cohort. Association with efficacy endpoints 
(spleen volume reduction) and mutation status will be assessed graphically via strip plots or 
frequency tables of mutational status group and response categories (≥ 35% reduction and < 
35% reduction in spleen volume) by dose cohorts.
The expression levels of Hh pathway related biomarkers (such as Gli1), cytokine levels and 
allele burden (reported as percent mutated) will be reported and summarized as follows:
All data will be listed by dosing schedule, patient and time point. Summary tables of the 
expression levels will be created at each measured time point by doing schedule and all 
dosing groups combined. Summary tables will include number of samples (n), % of those 
samples below LLOQ, mean, standard deviation, median, %CV, minimum and maximum. For 
all post-baseline time-points; fold change in biomarker expression levels will also be 
summarized. The summary statistics will include, number of samples, mean, geometric 
mean, %CV of geometric mean, minimum, maximum etc. Additionally frequency tables 
(number and percentage of subjects) for JAK2 mutation status (positive/negative) at baseline 
will be reported.
Longitudinal plots of the mean fold-change from baseline along with 95% CI’s or standard 
error bars will be created to explore the trend over time. Additionally, a mixed model analysis 
of log2 (fold change from baseline) ~ log2 (baseline level) + dose schedule + time + dose 
schedule*time may be carried out. In that case, longitudinal plots of model adjusted means for 
each dose schedule over time, together with the 95% confidence intervals will be may be 
created to view trends over time. Strip plots or scatter plots of baseline or change from 
baseline in biomarker levels versus end-point of interest (spleen volume reduction) may also 
be produced to explore the association with efficacy.
The associations between biomarkers and efficacy outcomes may also be explored via more 
sophisticated statistical models if sufficient data are available.
10.5.3.3.3
Advanced analysis methods
Advanced statistical analysis may be carried out to explore the data in a post-hoc fashion.
These methods will typically be used to build a model to estimate, classify or predict the 
relationship between the explanatory variable(s) and the dependent variables (e.g. linear 
mixed models fitted on longitudinal data to quantify time-related changes or models to predict 


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response based on baseline gene expression levels) or to identify patterns and similarities in 
the data by establishing relationship among all variables (e.g. hierarchical clustering of 
patients into subgroups according to their biomarker profile). Variable selection, predictive 
modeling and surrogacy methodologies may be applied to explain and predict response to 
treatment.
Details of such methodology if applied to the data will be described in a separate Biomarker 
Analysis Plan document.
10.5.4
Patient Reported Outcomes (Seven-day modified MFSAF v2.0 and 
EORTC QLQ-C30)
The Seven-day Total Symptom Score (TSS) and individual item scores from MFSAF will be 
summarized descriptively along with changes from baseline to each visit where the variable is 
measured. At week 24 the proportion of patients who have a ≥50% reduction from baseline in 
total symptom score based on the Seven-day modified MFSAF v2.0 will be determined as 
follows.
The Seven-day TSS will be defined as the sum of 6 individual symptom scores (each scored 
on a 0-10 point scale) collected on the same day. The score will be missing if there are any 
missing individual scores and inactivity will not be included.
The percent change will be calculated by:

% change=100x(Week 24 Total Score-Baseline Total Score)/Baseline Total Score
The percent of patients who have a ≥50% reduction in TSS at week 24 will be estimated with 
a two-sided 95% confidence interval. Similar summary will be presented for each of the 
individual symptom scores. A waterfall graph will be presented to display the percent change 
from baseline in Total Symptom Score for each patient at Week 24.
The EORTC QLQ-C30 subscales and individual item scores will be summarized descriptively 
along with changes from baseline to each visit where the variable is measured.


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10.7
Interim analysis
There will be an interim analysis for both safety and efficacy after 18 patients are enrolled in 
the phase II study. After the first 18 patients are enrolled and observed over a minimum of 24 
weeks or until death, documented disease progression, intolerable toxicity, withdrawal of 
consent, discontinuation at the discretion of the investigator or lost to follow-up, whichever 
comes first, further enrollment can be stopped for futility if there are less than 8 responders 
(i.e., spleen volumetric reduction of at least 35% through MRI/CT). This corresponds to a 
decision threshold of >20% (Bayesian) predictive probability of success to continue 
enrollment (Table 10-6).
Review of safety data will include, but is not limited to, assessment of the nature and 
frequency of deaths during treatment, serious adverse events, Grade 3 or 4 adverse events, key 
laboratory abnormalities, abnormal results from electrocardiogram (ECG) assessments and 
distribution of safety-related reasons for discontinuation. The trial might be terminated at the 
interim if treatment is not well tolerated as determined by steering committee (Grade 3-4 
AEs >20% may result in termination).
It is possible to terminate the trial at the interim for lack of adequate efficacy, i.e. futility. 
Assessment of futility will be based on the calculated Bayesian predictive probabilities for the 
occurrence of the response rate in the FAS.
The efficacy outcome (response rate) is assumed to be binary, namely, response (achieving ≥ 
35% reduction of spleen volume from baseline by centralized reviewed MRI/CT, Yes vs. No), 
and the number of responders follow a binomial distribution.
Suppose the prior belief regarding the probability of response (π) is that it has a beta 
distribution with parameters α0 and β0. If there are x responders out of n patients, then the 
posterior distribution for π is beta distribution with parameters α1= α0+x and β1= β0+n-x. 
Now let Y represent the number of success from m future observations, then the posterior 
predictive distribution of Y conditional on the observed data at the interim (x responders out of 
n patients) is a betabinomial distribution described by
Where B(a,b) is the beta distribution with parameter a and b.
The prior for the response rate is assumed to follow a Beta(1,1) distribution, which 
corresponds to a priori expectation of 50%. If there are 8 or more responders, after the first 18 
patients have been observed for 24 weeks, then 28 additional patients will be enrolled into 
stage 2. Encouraging efficacy will be concluded if the observed ORR exceeds 50% (i.e. 
23/46) at the end of Phase II.
In this study, futility is equivalent to observe less than 8 responders in 18 patients (Table 10-
6). However, the cut-off for the number of responders needed will be determined at the time 
of interim analysis based on the actual number of patients enrolled in the study following the 
algorithm defined in the protocol.


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Table 10-6
Predictive probability of observing response rate of 50% (n=18) or 
greater in the FAS at the primary analysis (46 patients) under different 
interim results
Observed response at IA
Predictive probability of observing response rate ≥50%
# of response
%
4
22.2
0.002
5
27.8
0.011
6
33.3
0.047
7
38.9
0.143
8
44.4
0.318
9
50.0
0.548
10
55.6
0.762
11
61.1
0.905
12
66.7
0.972
13
72.2
0.994
10.8
Sample size calculation
The total sample-size for the study will be approximately 82.
Phase Ib: Approximately 36 patients are expected to be enrolled into dose escalation cohorts. 
Cohorts of 3 to 6 evaluable patients per dose level will typically be enrolled in the dose 
escalation part including at least 6 evaluable patients at the MTD level. Assuming a total of 5 
cohorts, the number of patients during dose escalation is expected to be approximately 30. An 
additional 6 patients will be treated at the MTD/RPIID during the safety expansion. If two 
MTDs/RPIIDs are established, each MTD/RPIID will enroll additional 6 patients in the safety 
expansion.
Phase II: Following the determination of an MTD or RPIID in phase Ib, 18 patients will be 
enrolled in the first stage and if the criterion is met to continue to stage 2, an additional 28 
patients will be enrolled.
Operating Characteristics
Phase Ib: The operating characteristics of the BLRM guided by EWOC used in the study is 
provided in Appendix 7 (Section 14.7).
Phase II: In terms of the frequentist operating characteristics, based on the sample size of 46 
patients in phase II, the design has a false-positive rate (type I error) of 9.5% when the true 
ORR is 40% (representing no benefit) and a true-positive rate (power) of 90% when the true 
ORR is 60%. The operating characteristics in this study are in Table 10-7.
Table 10-7
Decision of operating characteristics for the primary endpoint of 
CLDE225X2216 study design
True ORR
Probability of observing an ORR ≥ 50%
0.30
0.003
0.35
0.022
0.40
0.095
0.45
0.263


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True ORR
Probability of observing an ORR ≥ 50%
0.50
0.508
0.55
0.745
0.60
0.900
0.65
0.970
0.70
0.993
0.75
0.999
10.9
Power for analysis of key secondary variables
Not applicable.
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. 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 the eCRF.
Novartis will provide investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and 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 and sexually active males should be informed that taking 
the study medication may involve unknown risks to the fetus if pregnancy were to occur 


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during the study and agree that in order to participate in the study they must adhere to the 
contraception requirement for the duration of the study. If there is any question that the patient 
will not reliably comply, they should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
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.
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 


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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.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon 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. 


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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. United Kingdom requires the 
notification of urgent safety measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stat Med; 17(10):1103-20.
Ballen K (2012) How to manage the transplant question in myelofibrosis. Blood Cancer J;
2(3):e59.
Barbui T, Barosi G, Birgegard G, et al (2011) Philadelphia-negative classical 
myeloproliferative neoplasms: critical concepts and management recommendations from 
European LeukemiaNet. J Clin Oncol; 29(6):761-70.
Barosi G, Mesa RA, Thiele J, et al (2008) Proposed criteria for the diagnosis of post-
polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement 
from the International Working Group for Myelofibrosis Research and Treatment. Leukemia; 
22(2):437-8.
Cervantes F, Dupriez B, Pereira A, et al (2009) A new prognostic scoring system for primary
myelofibrosis based on a study of the International Working Group for Myelofibrosis 
Research and Treatment. Blood; 113:2895-2901.
Elliott M, Verstovsek S, Dingli D, et al (2007) Monocytosis is an adverse prognostic factor 
for survival in younger patients with primary myelofibrosis. Leuk Res. 31(11):1503-9.
Ferenci P, Lockwood A, Mullen K, et al (2002) Hepatic encephalopathy—definition, 
nomenclature, diagnosis, and quantification: final report of the working party at the 11th 
World Congress of Gastroenterology, Vienna, 1998. Hepatology; 35:716-721.
Gale RP, Barosi G, Barbui T, et al (2011) What are RBC-transfusion-dependence and -
independence? Leuk Res; 35(1):8-11.
Irvine DA, Copland M (2012) Targeting hedgehog in hematologic malignancy. Blood; 
119(10):2196-204.
Jamieson (2011) Phase 1 Dose-Escalation Study of PF-04449913, An Oral Hedgehog (Hh) 
Inhibitor, in Patients with Select Hematologic Malignancies (Abstract) Clin. Res; 118:424A.
Jung SH, Kim KM (2004) On the estimation of the binomial probability in multistage clinical 
trials. Statistics in Medicine; 23: 881-896.
Levine R, Pardanani A, Tefferi A, et al (2007) Role of JAK2 in the pathogenesis and therapy 
of myeloproliferative disorders. Cancer; 7: 673-683.
McMahon AP, Ingham PW, Tabin CJ (2003) Developmental roles and clinical significance of 
hedgehog signaling. Curr Top Dev Biol; 53:1-114.
Mesa R (2008) New insights into the pathogenesis and treatment of chronic 
myeloproliferative disorders. Curr Opin Hematol; 15: 121-126.
Mesa R (2010) New drugs for the treatment of myelofibrosis. Curr Hematol Malig Rep; 5:15-
21.


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Mesa R, Silverstein M, Jacobsen S, et al (1999) Population based incidence and survival 
figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County 
study,1975-1995. Am J Hematol; 61:10-15.
Oken MM, Creech RH, Tormey DC, et al (1982) Toxicity and Response Criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol; 5(6); 649-655.
Pasca di Magliano M, Hebrok M (2003) Hedgehog signaling in cancer formation and 
maintenance. Nat Rev Cancer; 3(12):903-11.
Pikman Y, Lee BH, Mercher T, et al (2006) MPLW515L is a novel somatic activating 
mutation in myelofibrosis with myeloid metaplasia. PLoS Med;3(7):1140-1151.
Quintas-Cardama A, Vaddi K, Liu P, et al (2010) Preclinical characterization of the selective 
JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of 
myeloproliferative neoplasms. Blood; 115(15):3109-17.
Rambaldi A, Barbui T, Barosi G (2008) From palliation to epigenetic therapy in 
myelofibrosis. Hematology; 83-91.
Reya T, Morrison SJ, Clarke MF, et al (2001) Stem cells, cancer, and cancer stem cells.
Nature; 414(6859):105-11.
Rollison DE, Howlader N, Smith MT, et al (2008) Epidemiology of myelodysplastic 
syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using 
data from the NAACCR and SEER programs. Blood; 112(1):45-52.
Scales SJ, de Sauvage FJ (2009) Mechanisms of Hedgehog pathway activation in cancer and 
implications for therapy. Trends Pharmacol Sci; 30(6):303-12.
Scherber R, Dueck A, Johansson P, et al (2011) The myeloproliferative neoplasm symptom 
assessment form (MPN-SAF): International prospective validation and reliability trial in 402 
patients. Blood; 118: 401-408.
Scott LM, Tong W, Levine RL, et al (2007) JAK2 Exon 12 mutations in polycythemia vera 
and idiopathic erythrocytosis. N Engl J Med; 356:459-468.
Shelton CA, Gilmartin AG (2009) Novel receptor antagonists for cancer therapy: hedgehog 
pathway inhibitors. Drug Discovery Today: Therapeutic Strategies; 6; 63-69.
Tefferi A, Barosi G, Mesa RA, et al (2006) International Working Group (IWG) consensus 
criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for 
Myelofibrosis Research and Treatment (IWG-MRT). Blood; 108:1497-1503.
Tefferi A, Vardiman JW (2008) Classification and diagnosis of myeloproliferative neoplasms: 
The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. 
Leukemia; 22:14-22.
Teglund S, Toftgard R (2010) Hedgehog beyond medulloblastoma and basal cell carcinoma. 
Biochim Biophys Acta; 1805(2):181-208.
Thall PF, Millikan R, Mueller P (2003) Dose-finding with two agents in Phase I oncology 
trials. Biometrics; 59(3):487-96.


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Thiele J, Kvasnicka HM, Facchetti F, et al (2005) European consensus on grading bone 
marrow fibrosis and assessment of cellularity. Haematologica; 90(8):1128-32.
Verstovsek S, Kantarjian H, Mesa RA, et al (2010) Safety and efficacy of INCB018424, a 
JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med; 363(12):1117-27.


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14
Appendices
14.1
Appendix 1: List of prohibited concomitant medications and 
concomitant medications requiring caution
14.1.1
Concomitant medications requiring caution
Table 14-1
Medications that are known substrates of BCRP to be used with 
caution
BCRP substrates
Nitrofuratoin
Pantoprazole
sulfasalazine
zidovudine
Table 14-2
List of weak CYP3A inducers or inhibitors to be used with caution
Weak CYP3A inducers
armodafinil (R-modafinil)
bexarotene
clobazam
danshen
dexamethasone
Echinacea
garlic (allium sativum)
glycyrrhizin
methylprednisolone
nevirapine
oxcarbazepine
pioglitazone
pleconaril (not available in 
US market)
prednisone
primidone
raltegravir
rufinamide
terbinafine
topiramate
troglitazone (not available in 
US market)
Weak CYP3A inhibitors
alprazolam
amlodipine
azithromycin
bicalutamide
chlorzoxazone
cilostazol
clotrimazole
cranberry juice
cyclosporine
delavirdine
drospirenone
ethinyl estradiol
fluvoxamine
fosaprepitant
isoniazid
lacidipine
linagliptin
norgestimate
peppermint oil
pravastatin*
propiverine
ranitidine
ranolazine
resveratrol
roxithromycin (not available 
in US market)
seville orange juice
sitaxentan
tabimorelin
tacrolimus
tolvaptan
*If it is essential that the patient takes a statin to control hyperlididemia, then only pravastatin may be used with 
extra caution.
Table 14-3
List of CYP2B6 and 2C9 substrates to be used with caution
CYP2B6 substrates
bupropion
CYP2C9 substrates
celecoxib
diclofenac
flurbiprofen
glipizide
glyburide
gliclazide
glimepiride
lornoxicam
indomethacin
irbesartan
ketobemidone
nateglinide
losartan
meloxicam
naproxen
piroxicam
S-iIbuprofen
sulfamethoxazole
tenoxicam
tolbutamide
torasemide
valdecoxib


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Table 14-4
List of permitted antifungal and antibiotic agents to be used with 
caution
Permitted antifungal and antibiotic agents to be used with caution
amphotericin B
anidulafungin
azithromycin
candicidin (not available in US 
market)
caspofungin
clotrimazole
flucytosine
griseofulvin
isoniazid
micafungin
nystatin
roxithromycin (not available in 
US market)
terbinafine
14.1.2
Prohibited co-medications
Table 14-5
List of prohibited CYP3A inducers or inhibitors
Moderate/Strong CYP3A inhibitors
amprenavir
aprepitant
atazanavir
boceprevir
casopitant
cimetidine
ciprofloxacin
clarithromycin
cobicistat
conivaptan
darunavir
diltiazem
dronedarone
elvitegravir
erythromycin
FK1706
fluconazole
fosamprenavir
grapefruit juice
imatinib
indinavir
itraconazole
ketoconazole
lopinavir
mibefradil
nefazodone
nelfinavir
posaconazole
ritonavir
saquinavir
schisandra sphenanthera
telaprevir
telithromycin
tipranavir
tofisopam
troleandomycin
verapamil
voriconazole
Moderate/Strong CYP3A4 inducers
avasimibe
bosentan
carbamazepine
efavirenz
etravirine
genistein
mitotane
modafenil
nafcillin
phenobarbital
phenytoin
rifabutin
rifampin (rifampicin)
ritonavir
St. John's wort
talviraline (not available in US 
market)
thioridazine
tipranavir
Table 14-6
List of prohibited CYP2B6 and CYP2C9 substrates with narrow 
therapeutic index
CYP2B6 substrates with narrow therapeutic index
cyclophosphamide*
efavirenz
ifosfamide*
methadone
thiotepa*
procarbazine*
CYP2C9 substrates with narrow therapeutic index
warfarin
acenocoumarol
*Chemotherapeutic agents are generally prohibited.
Table 14-7
List of prohibited antifungal and antibiotic agents
Prohibited antifungal and antibiotic agents
ciprofloxacin
clarithromycin
erythromycin
fluconazole
Itraconazole
ketoconazole
miconazole
posaconazole
telithromycin
troleandomycin
voriconazole


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14.2
Appendix 2: Eastern Cooperative Group Performance Scale
Table 14-8
ECOG (WHO) Performance Status
Grade
Performance Status
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, eg, 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
Source: Oken et al (1982).
14.3
Appendix 3: Seven-Day Modified Myelofibrosis Symptom 
Assessment Form v2.0
Instruction to patients:
Please answer all questions to the best of your ability, based on your memory over the past 7 
days (1 week). There is no right or wrong answer.
Symptoms
Intensity Scale
1. During the past 7 days, how severe were your worst 
night sweats (or feeling hot or flushed) due to MF?
0 (Absent)
1
2
3
4
5
6
7
8
9
10 
(Worst Imaginable)
2. During the past 7 days, how severe was your worst 
itchiness due to MF?
0 (Absent)
1
2
3
4
5
6
7
8
9
10 
(Worst Imaginable)
3. During the past 7 days, how severe was your worst 
abdominal discomfort (feel uncomfortable, pressure or 
bloating) due to MF?
0 (Absent)
1
2
3
4
5
6
7
8
9
10 
(Worst Imaginable)
4. During the past 7 days, how severe was your worst 
pain under the ribs on the left side due to MF?
0 (Absent)
1
2
3
4
5
6
7
8
9
10 
(Worst Imaginable)
5. During the past 7 days, what was the worst feeling of 
fullness (early satiety) you had after beginning to eat, 
due to MF?
0 (Absent)
1
2
3
4
5
6
7
8
9
10 
(Worst Imaginable)
6. During the past 7 days, how severe was your worst 
bone or muscle pain due to MF (diffuse, not joint or 
arthritis pain)?
0 (Absent)
1
2
3
4
5
6
7
8
9
10 
(Worst Imaginable)
7. During the past 7 days, what was the worst degree 
of inactivity (including work and social activities) you 
had due to MF?
0 (Absent)
1
2
3
4
5
6
7
8
9
10 
(Worst Imaginable)
Note: The questionnaire provided here is a sample for information purposes only. Paper 
questionnaires for patient completion in the study will be provided by Novartis to be used as 
source documents.


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14.4
Appendix 4: EORTC QLQ C-30


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14.5
Appendix 5: MDRD-eGFR Formula
14.6
Appendix 6: Hepatic encephalopathy grading according to West 
Haven Criteria
Grade
Symptoms
1
Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impaired performance of 
addition or subtraction
2
Lethargy or apathy; Minimal disorientation for time or place; Subtle personality change; Inappropriate 
behavior
3
Somnolence to semi-stupor, but responsive to verbal stimuli; Confusion; Gross disorientation
4
Coma (unresponsive to verbal or noxious stimuli)
Source: Ferenci et al (2002).


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SAP_000.pdf: 
Clinical Development
LDE225/Sonidegib
Protocol CLDE225X2116 / NCT01787552
A Phase Ib/II, open-label, multi-center, dose-finding study 
to assess the safety and efficacy of the oral combination of 
LDE225(Sonidegib) and INC424(Ruxolitinib) in Patients with 
myelofibrosis
RAP Module 3 – Detailed Statistical Methodology
Author(s):
 
 
Document type:
RAP Module 3
Document status:
Final V 3.0
Release date:
9 August 2016
Number of pages:
46
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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LDE225X2116


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Table of contents
Table of contents .................................................................................................................3
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Primary Objectives ................................................................................................10
1.3
Secondary objectives .............................................................................................10
10
11
1.6
Patient population..................................................................................................11
2
Definitions and general methodology ...............................................................................12
2.1
Definitions .............................................................................................................12
2.1.1
Study drug and study treatment...............................................................12
2.1.2
Monotherapy vs. combination studies.....................................................12
2.1.3
Date of first administration of study treatment .......................................12
2.1.4
Date of last administration of study treatment ........................................12
2.1.5
Study day.................................................................................................12
2.1.6
Baseline...................................................................................................13
2.1.7
On-treatment assessment or event...........................................................13
2.1.8
Last contact date......................................................................................13
2.1.9
Screening failure .....................................................................................14
2.1.10
Month ......................................................................................................14
2.1.11
Handling of missing values.....................................................................14
2.2
Analysis sets ..........................................................................................................17


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2.2.1
Full analysis set (FAS)............................................................................17
2.2.2
Safety analysis set (SAS) ........................................................................17
2.2.3
Dose Determining set (DDS) ..................................................................18
2.2.4
Pharmacokinetic analysis set (PAS)........................................................18
2.2.5
Biomarker analysis set (BAS).................................................................18
2.3
Protocol deviations ................................................................................................18
2.3.1
Anti-neoplastic therapy administered after start of study treatment .......18
3
Data analysis methods .......................................................................................................19
3.1
General presentation of descriptive summaries and listings..................................19
3.1.1
Multiple assessments within post-baseline visits....................................19
3.1.2
Center pooling.........................................................................................19
3.2
Subject disposition, protocol deviations, demographics and other baseline 
characteristics ........................................................................................................19
3.2.1
Subject disposition ..................................................................................19
3.2.2
Protocol deviations..................................................................................20
3.2.3
Protocol eligibility criteria ......................................................................20
3.2.4
Analysis sets............................................................................................20
3.2.5
Demographics..........................................................................................20
3.2.6
Other baseline characteristics..................................................................20
3.2.7
Medical history / current medical conditions..........................................21
3.2.8
Prior Anti-neoplastic therapy ..................................................................21
3.3
Study drug..............................................................................................................21
3.3.1
Duration of exposure...............................................................................21
3.3.2
Cumulative dose......................................................................................22
3.3.3
Average daily dose..................................................................................22
3.3.4
Actual dose intensity and relative dose intensity....................................23
3.3.5
Dose reduced, dose interrupted and dose discontinued permanently......23
3.4
Concomitant therapy..............................................................................................24


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3.5
Primary analysis and primary variables.................................................................24
3.5.1
Phase Ib ...................................................................................................24
3.5.2
Phase II....................................................................................................26
3.5.3
Handling of missing values/censoring/discontinuations.........................30
3.6
Secondary analysis.................................................................................................30
3.6.1
Bone marrow assessment ........................................................................30
3.7
Exploratory analysis ..............................................................................................31
31
3.7.2
Spleen length by manual palpation .........................................................31
3.8
Safety evaluation ...................................................................................................32
3.8.1
Adverse events data.................................................................................32
3.8.2
Laboratory data .......................................................................................34
3.8.3
Vital signs................................................................................................35
3.8.4
Cardiac assessments................................................................................36
3.9
Patient reported outcomes (PRO)..........................................................................37
3.9.1
EORTC Quality of Life Questionnaire (QLQ-C30) ...............................38
3.9.2
Seven-day modified MFSAF v2.0 ..........................................................38
3.9.3
Compliance..............................................................................................38
3.9.4
Descriptive statistics................................................................................39
3.9.5
Waterfall graphs......................................................................................39
3.10
Chest X-ray............................................................................................................39
3.11
Biomarkers.............................................................................................................39
3.11.1
Data handling and pre-processing...........................................................40
3.11.2
Statistical methods for Biomarker...........................................................42
3.12
Pharmacokinetic analyses......................................................................................42
3.12.1
Trough and profile concentration data ....................................................43
3.12.2
Pharmacokinetic parameters ...................................................................43


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3.12.3
Analysis of relationship between LDE225/INC424 and 
efficacy/safety endpoints.........................................................................44
3.13
Sample size and power considerations ..................................................................44
4
References .........................................................................................................................45
List of figures
Figure 1-1
Study design of CLDE225X2116 .............................................................9
List of tables
Table 2-1
AE/Treatment date abbreviations..........................................................15
Table 2-2
Imputation algorithm.............................................................................15
Table 2-3
Imputation algorithm legends ...............................................................15
Table 2-4
Example scenarios................................................................................16
Table 3-1
Prior parameters obtained for CLDE225X2116 ...................................25
Table 3-2
Predictive probability of observing response rate of 50% (n=18) or 
greater at the primary analysis (46 patients) under different interim 
results ....................................................................................................28
Table 3-3
Predictive probability of observing a response rate >= 50% at the 
final analysis with 46 patients under different interim results with 
20 patients .............................................................................................29
Table 3-3
Predictive probability of observing a response rate >= 50% at the 
final analysis with 53 patients under different interim results with 
27 patients .............................................................................................29
Table 3-2
Clinically notable elevated values.........................................................35
Table 3-3
Clinically notable below normal values................................................35
Table 3-5
Data pre-processing and handling of biomarkers in LDE225 and 
INC424..................................................................................................40
Table 3-6
Non-compartmental pharmacokinetic parameters for LDE225 
(Phase Ib and Phase II Stage 1 only).....................................................43
Table 3-7
Non-compartmental pharmacokinetic parameters for INC424 
(Phase Ib and Phase II Stage 1 only).....................................................44


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List of abbreviations
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
BAS
Biomarker Analysis Set
bpm
Beats per minute
Bw
Body Weight
CDR&R
Clinical Data Review & Reporting
CRF
Case Report Form
CSP
Clinical Study Protocol
CT
Computer Tomography
CTCAE/CTC
Common Terminology Criteria for Adverse Events
CTD
Common Technical Document
DDS
Dose-determining Set
DI
Actual Dose Intensity
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
EOS
End Of Study
FAS
Full Analysis Set
GCP
Good Clinical Practice
IA
Interim Analysis 
IQR
InterQuartile Range
IRT
Interactive Response Technology
ITT
Intention To Treat
JAK2
Janus kinase 2
LLOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
MF
Myelofibrosis
MRI
Magnetic Resonance Imaging
ms
Millisecond 
NCDS
Novartis Clinical Data Standards
NCI
National Cancer Institute
PAS
Pharmacokinetic Analysis Set
PDI
Planned Dose Intensity
PK
Pharmacokinetics
PPS
Per Protocol Set
PRO
Patient Reported Outcomes
RDI
Relative Dose Intensity
RAP
Report and Analysis Plan
RT-PCR
Reverse Transcription-Polymerase Chain Reaction
SAE
Serious Adverse Event
QoL
Quality of Life


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SPP
Safety Profiling Plot
SSD
Study Specification Document
UNK
Unknown
WHO
World Health Organization
1
Introduction
This document describes the detailed statistical methodology of the Report and Analysis Plan 
(RAP) of the study CLDE225X2116. The CLDE225X2116 is a phase Ib/II, an open-label, 
multi-center, dose-finding study to assess the safety and efficacy of the oral combination of 
Sonidegib (LDE225) and Ruxolitinib (INC424) in patients with myelofibrosis (MF) (primary 
myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential 
thrombocythemia myelofibrosis (post-ET MF).
This RAP describes the primary and final analysis of the data as specified in the protocol. The 
primary analysis of study data will be performed when all patients (Phase Ib and Phase II) 
have been treated for one year or discontinued treatment. The final analysis of study data for 
the purposes of generating CSR will be based on all patient data from phase Ib and phase II 
when all patients have completed at least two years of treatment or discontinued the study. 
1.1
Study design 
This study consists of an open-label, multi-center, dose-finding phase Ib including dose 
escalation and expansion followed by a phase II in patients with MF.  
The study has 3 parts:
(1) Screening: 21 days screening assessment period prior to receiving the first study treatment. 
(2) Treatment: it includes the dose escalation and dose expansion in phase Ib and stage 1 and 
stage 2 in phase II. The stage 2 enrollment in phase II depends on the result for the interim 
analysis (IA). The treatment period is from Day 1 for up to 2 years or until death, documented 
disease progression, initiation of a new MF therapy, intolerable toxicity, withdrawal of 
content, discontinuation at the discretion of the investigator, lost to follow-up or premature 
termination of the study, whichever comes first. Based on the recommendation from SC and 
internal decision, there will be no enrollment to Phase II Stage 2.
(3) Follow up: 30 days following up after the last day of treatment. 
The flow chart of the study design is in Figure 1-1.


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Figure 1-1
Study design of CLDE225X2116
Note: Patients who complete 2 years of treatment and are deriving clinical benefit in the 
opinion of the investigator will be allowed to continue receiving treatment (LDE225 and 
INC424) in an extension phase of this study, until discontinuation reasons are met or an 
alternative setting to receive study treatment (e.g., in form of another protocol) becomes 
available.


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1.2
Primary Objectives
The primary objective of Phase Ib is to establish the MTD and/or RPIID of the combination of 
LDE225 (QD) and INC424 (BID) when administered orally to patients with myelofibrosis 
who have not previously received therapy with a JAK inhibitor. 
The primary objective of Phase II is to assess the efficacy of the co-administration of LDE225 
and INC424 on spleen volume reduction as determined by centrally reviewed MRI/CT.
1.3
Secondary objectives
Phase Ib:

To evaluate the safety of the co-administration of LDE225 and INC424 in patients 
with MF

To characterize the single and multiple dose pharmacokinetics following the co-
administration of LDE225 and INC424
Phase II:

To assess the effect of the co-administration of LDE225 and INC424 on bone marrow 
fibrosis by central review and on disease-specific pharmacodynamic biomarkers as a 
function of the molecular disease characterization of MF

To evaluate the safety of the co-administration of LDE225 and INC424 in patients 
with MF

To characterize pharmacokinetics following the co-administration of LDE225 and 
INC424 

To assess the effect of the co-administration of LDE225 and INC424 on MF-
associated symptoms burden


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1.6
Patient population 
The patient population will consist of adult patients, aged ≥ 18 years who have been 
diagnosed with PMF, post-PV MF, or post-ET MF without previous treatment with JAK 
inhibitor, meet intermediate or high risk prognostic criteria and exhibit palpable splenomegaly 
≥ 5cm below the costal margin, and exhibit platelet counts of ≥ 75⨯109/L without the aid of 
transfusions. 
In the CSR, patients will be reported in one of the following patient groups:
Phase Ib group (All the Phase Ib escalation and expansion patients)
Phase Ib expansion and Phase II stage 1 group (All the Phase Ib expansion and Phase II 
stage 1 patients)
Phase Ib and Phase II stage 1 group (All the Phase Ib escalation, Phase Ib expansion and 
Phase II stage 1 patients)


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according to the corresponding outputs and parameters analyzed.
2
Definitions and general methodology
2.1
Definitions
2.1.1
Study drug and study treatment
Study drug refers to LDE225 and INC424. Study treatment refers to LDE225 XXmg + 
INC424 XXmg, for example, LDE225 400mg + INC424 10mg.
2.1.2
Monotherapy vs. combination studies
This is a combination study. 
The combination therapy administered is LDE225 jointly with the study treatment partner   
INC424.
2.1.3
Date of first administration of study treatment
The date of first administration of study drug is derived as the first date when a nonzero dose 
of study treatment was administered and recorded on LDE225 or INC424 DAR eCRF. The 
date of first administration of study treatment will also be referred as the start date of study 
treatment.
2.1.4
Date of last administration of study treatment
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug was administered and recorded on LDE225 or INC424 DAR eCRF. This date of 
last administration of study treatment will also be referred as the last date of study treatment.
2.1.5
Study day
The term assessment will be used to represent an evaluation, a measurement or an event (e.g. 
AE onset, laboratory abnormality occurrence, tumor assessment, disease progression, etc)
The study day for all assessments (efficacy, safety, QoL, etc.) will be calculated as follows:
Study day  =  date of assessment – start date of study treatment + 1 
if date of assessment is after the start date of study treatment. 
Study day  =  date of assessment – start date of study treatment
if date of assessment is before the start date of study treatment.
For any assessment or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease) that is supposed to occur prior to the start date of the study 
treatment, study day will be negative. There is no Day 0 defined. 


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2.1.6
Baseline
Baseline values for safety and non-safety evaluations are defined as below unless specified 
otherwise in the RAP. 
For safety evaluations (e.g. laboratory and vital signs), the last assessment available before or 
on the start date of study treatment (only if such assessment is pre-dose) is taken as a 
“baseline” assessment, except for the definition of ECG baseline (see Section 3.8.4.1). If there 
are multiple assessments on the same day and it is not possible to distinguish the last one for 
baseline assessment, then the average of these multiple assessments will be used with 
exception that if those assessments are from both central lab and local lab, the assessment(s) 
from central lab will be used.  
For efficacy and other non-safety evaluations (e.g. MRI scan or photograph), the last 
available assessment before or on the start of study treatment date and is taken as the 
“baseline” value or “baseline” assessment. Multiple assessments on the same day are not 
expected.
If patients have no assessments as defined above, the baseline result will be missing.
2.1.7
On-treatment assessment or event
The overall observation period will be divided into three mutually exclusive segments:
pre-treatment period: from day of patient’s informed consent to the prior start date of study 
treatment
on-treatment period: from day of start of study treatment to 30 days following the last date of 
study treatment:
[Start date of study treatment; last date of study treatment  + 30 days]. 
post-treatment period: starting at day 31 after last dose of study medication.
On-treatment assessment is defined as any assessment reported in the on-treatment period.
2.1.8
Last contact date
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the latest complete date among the following:

All assessment dates (e.g. vital signs assessment, performance status assessment, and 
also assessment date in third-party data such as tumor imaging, central laboratory, 
ECG etc.)

Medication dates including study medication, concomitant medications, antineoplastic 
therapies administered after study treatment discontinuation.

Adverse events dates including the start and stop date of AEs

Date of treatment assignment or start/last date of study treatment

Date of discontinuation from ‘End of Treatment’ eCRF


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Only dates associated with patient visits or actual examinations of the patient will be used in 
the derivation. Dates associated with a technical operation unrelated to patient status such as 
the date a blood sample was processed, will not be used. An imputed partial date will not be 
used to derive the last contact date. The assessment dates after the cutoff date will not be 
applied to derive the last contact date. 
2.1.9
Screening failure
The purpose of providing screening failures is to ensure that there was no bias in choosing 
patients who were enrolled into the study. 
Screening failures are potential subjects who did not meet one or more screening criteria 
required for participation into the study.  These patients are never treated.
Patients who met inclusion and exclusion criteria but they were never treated will be 
considered enrolled and will be listed separately.
2.1.10
Month
A month will be calculated as (365.25 / 12) = 30.4375 days. If duration is to be reported in 
months, duration in days will be divided by 30.4375. 
2.1.11
Handling of missing values
2.1.11.1 Adverse events data imputation
Date imputation is the creation of a new, complete date from a partial one according to an
agreed and acceptable algorithm. 
A partial date is simply an incomplete date e.g.,
ddOCT2001 the days are missing from this DDMMMYYYY date
Partial adverse event start dates, if left partial, would ultimately mean the following

It would not be possible to place the adverse event in time.

Therefore the treatment/dosage at the time of the event would be unknown.

Therefore the event could not be reported/summarized appropriately – if at all.
Therefore it is important to perform date imputation to ensure that as many data events are
represented as correctly as possible. Of course partial and/or missing dates should also be 
caught as edit checks and passed back to the investigator for resolution. 
There will be no attempt to impute the following:

Missing AE start dates

AE start dates missing the year

Missing AE end dates


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Table 2-1 explains the abbreviations used.
Table 2-1
AE/Treatment date abbreviations
Day
Month
Year
Partial adverse event start date
<not used>
AEM
AEY
Treatment start date (TRTSTD)
<not used>
TRTM
TRTY
Table 2-2 describes the possible combinations and their associated imputations. In the light 
grey boxes the upper text indicates the imputation (NC, A, B, C, etc.) and the lower text the 
relationship of the AE start date to the treatment start date (TRTSTD).
Table 2-2
Imputation algorithm
AEM 
MISSING
AEM 
< 
TRTM
AEM 
= 
TRTM
AEM 
> 
TRTM
AEY MISSING
NC
NC
NC
NC
Uncertain
Uncertain
Uncertain
Uncertain
AEY < TRTY
( D )
( C )
( C )
( C )
Before TRTSTD
Before TRTSTD
Before TRTSTD
Before TRTSTD
AEY = TRTY
( B )
( C )
( B )
( A )
Uncertain
Before TRTSTD
Uncertain
After TRTSTD
AEY > TRTY
( E )
( A )
( A )
( A )
After TRTSTD
After TRTSTD
After TRTSTD
After TRTSTD
The legend to the above table is shown in Table 2-3.
Table 2-3
Imputation algorithm legends
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date to 
Treatment Start Date
Imputation calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
Few examples are shown in Table 2-4.


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Table 2-4
Example scenarios
Partial
AE start date
Treatment
start date
Relationship 
with TRTSTD
Imputation 
calculation
Imputed date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001
ddNOV2001
20OCT2001
After
( A )
01NOV2001
2.1.11.2 Incomplete date of concomitant medication Diagnosis
The imputation of the start date of concomitant medication will follow the same convention 
for AE date. Partial concomitant medication end date will not be imputed. 
2.1.11.3 Incomplete date of initial diagnosis of myeloproliferative disorder
For incomplete date of initial diagnosis of myeloproliferative disorder, missing day is 
defaulted to 15 and missing month and day is defaulted to Jan 01 respectively.
2.1.11.4 Incomplete date of anti-neoplastic therapies
(myeloproliferative 
neoplasm directed therapy)
Prior therapies
Start date: The same rule which is applied to the imputation of AE/concomitant
medication start date will be used with the exception that: for scenario (B) will be replaced to 
be  start date treatment-1.
End date:
oImputed date = min(reference end date, DEC 31) , if month and day are
missing.
oImputed date = min(reference end date, last day of the Month) , if day is
missing.
oReference end date will be the start date of treatment.
If the end date is not missing and the imputed start date is after the end date, use the end 
date as the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date
Post therapies
Start date:
oIf Day is missing, then impute to the max (reference start date, first day of the
month).
oDay and month are missing then impute to the max(reference start date, Jan 1)
oReference start date will be last date of study treatment administration + 1.
End date: No imputation


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2.1.11.5 Incomplete dates for last contact or death
All dates must be completed with day, month and year. If the day is missing, the 1st of the
month will be used for incomplete death dates or dates of last contact.
2.1.11.6 Incomplete dates for last treatment administration
Scenario 1: If the last treatment administration date is completely missing and there is no EOT
page and no death date:
The patient should be treated as on-going and use the cutoff date as the last dosing date up to 
date.
Scenario 2: If the last treatment administration date is completely or partially missing and
there is either EOT page or death date available:
If only Year is available and Year < Year of min(EOT date, death date);
Imputed date= Dec31yyyy
If both Year and Month are available, Year = Year of min(EOT date, death date) and Month
< the month of min(EOT date, death date);
Imputed date= last day of the Month
All other cases imputed date= min(EOT date, death date).
The imputed date will be compared with start date of treatment. If the imputed date is < start
date of treatment, set the last treatment administration date to be the treatment start date;
otherwise use the imputed date.
2.2
Analysis sets
This section defines standard analysis sets and their use for statistical analyses.
2.2.1
Full analysis set (FAS)
Phase Ib and Phase II:
The Full Analysis Set (FAS) comprises all patients in Phase Ib and Phase II who received at 
least one dose of LDE225 and/or INC424. 
Patients will be classified according to the assigned treatment combination.  Unless otherwise 
specified the FAS will be the default analysis set used for all analyses. 
2.2.2
Safety analysis set (SAS)
Phase Ib and Phase II:
The Safety Analysis Set (SAS) includes all patients in Phase Ib and Phase II who received at 
least one dose of LDE225 and/or INC424, and had at least one valid post-baseline safety 
assessment.


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Patients will be analyzed according to the study treatment (regimen) they actually received, 
where treatment received for each drug is defined as (i) the treatment assigned if it was 
received at least once, or else (ii) the first treatment received when starting study medication. 
Each patient will be classified into and analyzed consistently within one (and only one) 
treatment group.
2.2.3
Dose Determining set (DDS)
The dose Determining set (DDS) consists of all patients from the safety set of Phase Ib who 
either meet the following minimum exposure criterion and have sufficient safety evaluations 
(as determined by the investigators and Novartis), or discontinue earlier due to DLT. This 
constitutes an evaluable patient for the determination of the MTD. 
A patient is considered to have met the minimum exposure criterion at treatment group if the 
patient receives at least 75% of the planned doses of LDE225 and INC424 within 6 weeks (42 
days) following the first dose (i.e., no more than 10 missed doses of LDE225 and no more 
than 20 missed doses of INC424 in 6 weeks are permitted). Patients who do not meet these 
minimum exposure and safety evaluation requirements will be regarded as ineligible for 
inclusion into the DDS. Patients in the DDS will be identified before database lock.
2.2.4
Pharmacokinetic analysis set (PAS)
Phase Ib and Phase II:
The pharmacokinetic analysis set (PAS) consists of all patients in Phase Ib and Phase II who 
receive at least one (full or partial) dose of LDE225 and/or INC424 and provide at least one 
evaluable PK blood sample for LDE225 and/or INC424.
2.2.5
Biomarker analysis set (BAS)
The Biomarker Analysis Set (BAS) consists of all patients in Phase Ib and Phase II who 
receive at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one 
evaluable biomarker sample.
2.3
Protocol deviations
2.3.1
Anti-neoplastic therapy administered after start of study treatment 
Patients who take any 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 intake of an anti-
neoplastic drug will not be included in analyses. 


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3
Data analysis methods
3.1
General presentation of descriptive summaries and listings
Categorical data or qualitative characteristics of a subject (e.g., gender, race, subject 
disposition, etc.) will be summarized by frequency count (number of subjects) and 
percentages. Percentages will be calculated using the number of subjects in the relevant 
population or subgroup as the denominator.
Continuous data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (mean, standard deviation, median, minimum, and maximum).
Summary of data will be presented by patient group, treatment and overall. 
3.1.1
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 analyses 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.
3.1.2
Center pooling 
All study centers will be combined for the analysis unless otherwise specified.  In general, no 
center effect will be assessed due to expected small size of centers.  
3.2
Subject disposition, protocol deviations, demographics and 
other baseline characteristics
The FAS will be used for all baseline and demographic summaries and listings.
3.2.1
Subject disposition
FAS will be used for the patient disposition summary tables and listings. The following
information will be summarized.
1. Number (%) of patients who are still on-treatment (based on the absence of the ‘End of 
Treatment’ page); 
2. Number (%) of patients who discontinued the study treatment (based on the ‘End of 
Treatment’ page) 
3. Reasons for study treatment discontinuation (based on ‘End of Treatment’ page).


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3.2.2
Protocol deviations
The number and percentage of patients in the FAS with any protocol deviation will be 
tabulated by the deviation category (as specified in the data handling plan) and by treatment
group and overall.  
Protocol deviations will also be listed by center. 
3.2.3
Protocol eligibility criteria
Protocol eligibility criteria will be provided as follows:
1. A list of screen failures along with their failed inclusion/exclusion criteria,
2. A list of informed consent signature dates,
3. A list of enrolled patients but not-treated along with the primary reason for not continuing 
into the study. The reason for not continuing in the study will be obtained from the end of 
treatment page. Additional details, if included in the comments domain or in the end of 
study CRF page, will be included.
4. Patients’ eligibility to analysis sets defined in section 2.2 and their allocation to treatment.
3.2.4
Analysis sets
The number and percentage of patients in each analysis set (definitions are provided in section 
2.2) will be summarized by treatment groups. Patients’ eligibility to analysis sets will also be 
listed.
3.2.5
Demographics
The following demographic variables will be summarized by study phase following the 
general presentation specified in section 3.1:
Continuous variables:
•Age (years)
•BMI (kg/m2)
Categorical variables: 
•gender (male/ female)
•race (Caucasian/Black/ Asian/ Native American/ Pacific Islander/unknown/other)
•ECOG performance status at screening (0/ 1/ 2)
3.2.6
Other baseline characteristics 
The following baseline characteristics will be summarized:
International Prognostic Scoring System (IPSS) Risk factors at the time of diagnosis, MF 
classification, prior PRBC transfusion status, and JAK2V617F status, bone marrow fibrosis 
grade (most recent result prior to study entry).


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3.2.7
Medical history / current medical conditions
Medical history and ongoing conditions will be summarized and listed by the redefined study 
treatment groups (details can be found in RAP M7.1 section 1.2.1). Separate summaries will 
be presented for ongoing and historical medical conditions. The summaries will be presented 
by primary system organ class and preferred term. Medical history/current medical conditions 
are coded using the medical dictionary for regulatory activities (MedDRA) terminology. 
3.2.8
Prior Anti-neoplastic therapy
Prior anti-cancer therapy will be listed in three separate listings: myeloproliferative Neoplasm 
Directed Therapy – Medication, anti-neoplastic radiotherapy and surgery.  
The number and percentage of patients recording any prior anti-neoplastic medications
(myeloproliferative neoplasm directed therapy-medication), prior anti-cancer radiotherapy and 
prior anti-cancer surgery will be summarized.
Prior anti-neoplastic medications will be classified and summarized by therapy type
(chemotherapy, hormonal therapy, immunotherapy, targeted therapy, and other), ATC class
(if appropriate), preferred term and treatment.
Any indication-specific significant prior anti-neoplastic medications will be identified in the 
summaries mentioned above.
Anti-neoplastic therapies since discontinuation of study drug will be listed and summarized by 
ATC class, preferred term and treatment and overall by means of frequency counts and 
percentages in separate summaries.
Partial dates will be imputed according to the algorithm specified in section 2.1.11.4.
3.3
Study drug
Summaries of study drug administration characteristics will be provided for both LDE225 and 
INC424 separately as indicated: duration of exposure to study drug; exposure to study drug 
measured by cumulative dose, average daily dose, actual dose intensity (DI), and relative dose 
intensity (RDI); and dose reductions and interruptions, which are defined in the following 
sections.
Listings of study drug administration records for LDE225 and INC424, as recorded in CRFs, 
along with dose reductions and dose interruptions will be provided.
The safety set will be used for all summaries and listings of study treatment. 
3.3.1
Duration of exposure
The number and percentage of patients treated with each study treatment will be summarized
by study phase. The following formula will be used to calculate duration of study drug 
exposure for patients who took at least one dose of any of the components of the study 
treatment. Duration of exposure includes the periods of temporary interruption of study drug 
for any reason.


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For patients who discontinued permanently from the study as of the data cut-off date:
Duration of exposure (days) = last dosing date of any study treatment component – first 
dosing date of any study treatment component + 1
For patients who are still on-treatment as of data cut-off date:
Duration of exposure (days) = data cut-off date – (first dosing date of any study treatment 
component) + 1.
Date of first administration of study treatment and date of last administration of study 
treatment are defined in section 2.1.3 and section 2.1.4.
In addition, duration of exposure will be categorized in intervals defined in RAP M7. The 
number and percentage of patients with duration of exposure per category will be summarized.
Cumulative duration of exposure will also be summarized. For patients who did not take any 
study treatment the duration of exposure is defined as zero. The following categories for 
exposure to study treatment will be analyzed:
•< 2 weeks
•≥ 2 weeks to < 4 weeks
•≥ 4 weeks to < 8 weeks
•≥ 8 weeks to < 12 weeks
•≥ 12 weeks to < 24 weeks
•≥ 24 weeks to < 48 weeks
•≥ 48 weeks to < 106 weeks
•≥ 106 weeks 
3.3.2
Cumulative dose
Cumulative dose (mg) is defined as the total dose given during the study treatment exposure
and will be summarized by study phase, treatment components separately. 
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
Cumulative dose will be calculated from the dose administration pages of LDE225 and 
INC424.
3.3.3
Average daily dose
Average daily dose is defined as follows:
Average daily dose (mg/day) = cumulative dose / number of dosing days.
Drug free day(s) are not counted in the number of dosing days.


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3.3.4
Actual dose intensity and relative dose intensity
Dose intensity (DI) [mg/day], planned dose intensity (PDI) [mg/day], and relative dose 
intensity (RDI) [%] will be summarized by study phase, overall (while on-treatment).
Frequencies for RDI will also be categorized in intervals for LDE225 and INC424 as follows: 
<70%, ≥70% - ≤90% and > 90%. The number and proportion of patients within each category 
will be presented.
Actual DI for patients with non-zero duration of exposure is defined as follows:
DI (mg/day) = Cumulative dose (mg)/(Duration of exposure (days)).
For patients who did not take any drug, DI will be zero.
Planned dose intensity (PDI) for patients with non-zero duration of exposure is defined as 
following:
PDI (mg/day) = Cumulative planned dose (mg)/(Duration of exposure (days)).
The calculation of planned dose is based on the initial assigned dose regardless the dose 
interruption.  Cumulative planned dose is the per-protocol planned dose cumulated over the 
actual duration on study treatment. For patients who did not take any drug the PDI is by 
definition equal to zero mg/day.
Relative dose intensity (RDI) is defined as following:
RDI (%) = DI (mg/day)/PDI (mg/day)*100.
3.3.5
Dose reduced, dose interrupted and dose discontinued permanently
Reduction: A reduction is defined as a decrease in dose from the protocol planned starting 
dose or a decrease from the previous non-zero dose for either INC424 or LDE225, even if this 
decrease has been directly preceded by an interruption.  For example, in the sequence 20mg –
0mg – 10mg, the 10mg dose will be counted as a reduction.  
Interruption: An interruption is defined as a zero dose on one or more days between two 
non-zero doses, for either INC424 or LDE225.
If, due to a dosing error, a patient receives higher than protocol planned starting dose and 
moves down to the planned starting dose then this is not be counted as a reduction, however if 
they move directly from a higher than planned starting dose down to a lower than protocol 
planned starting dose, then this is counted as a reduction.
Note: The last zero dose of INC424 and LDE225 (followed by permanent discontinuation) is 
not considered as a dose interruption. Additionally, two consecutive zero doses of INC424
(e.g. in the sequence 20 mg daily, 0 mg, 0 mg, 10 mg daily) will be counted as one
interruption if the reasons for these two consecutive dose interruption are the same.
The numbers and percentage of patients who have the dose reduction, dose interruption or 
dose permanent discontinuation will be summarized by redefined study treatment group. For 
patients who had dose reductions/interruptions, counts of reductions or interruptions, 


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reductions only and interruptions only will be categorized and presented as specified in RAP 
M7.1.
3.4
Concomitant therapy
The FAS will be used for all concomitant medication tables and listings.
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a subject preceding or coinciding 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 and using MedDRA for the 
procedures. 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. 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drug(s) will be listed and summarized by ATC class, preferred term and treatment arm 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. 
3.5
Primary analysis and primary variables
3.5.1
Phase Ib
3.5.1.1
Primary variable in phase Ib
The primary variable is the incidence of dose limiting toxicities (DLTs) in the first 6 weeks of 
treatment associated with continuous daily administration of LDE225 in combination of 
INC424. Estimation of the MTD of the combination treatment will be based upon the 
estimation of the probability of DLT in 6 weeks for patients in the dose-determining set using 
BLRM and guided by EWOC. This probability is estimated by the model in section 3.5.1.2.
3.5.1.2
Statistical model, and method of analysis
Statistical model:
The model is formulated in the following way: let π1(d1) be the probability of a DLT if 
INC424 is given as a single agent as dose d1, and let π2(d2) the probability of a DLT if 
LDE225 is given as a single agent at dose d2, further let π12(d1,d2) be the probability of a DLT 
when LDE225 and INC424 are given in combination at doses d1 and d2 respectively. The 
dose-DLT relationship is then modeled as:


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For a single-agent INC424: 
For a single-agent LDE225: 
For the combination of LDE225 and INC424:
Where I is the indicator function, logit(π(d))=log[π(d)/{1- π(d)}], d1*=30 mg total daily dose 
(15 mg bid) and d2*=700 mg (qd) are the reference doses of INC424 and LDE225 
respectively, α1, α2, β1, β2, η and γ>0 are model parameters. 
The parameter γ is related to the binary baseline covariate that indicates whether a patient’s 
platelet count at baseline is ≤ 200X109/L or not, and η is an interaction term between the two 
drugs. 
Prior Specification:
The priors used in this study are in Table 3-1. The further details on prior derivations and 
simulated operation characteristics can be found in the study protocol (Section 14.7, Appendix 
7).
Table 3-1
Prior parameters obtained for CLDE225X2116
Parameter
Means
Standard deviations
Correlation
INC424 log(α1),log(β1) 
(-2.141,-0.180)
0.602,0.634
0.085
LDE225 log(α2),log(β2)
(-2.291,0.721)
0.894,0.773
-0.117
η (normal)
0.250
2.028
n/a
γ (log-normal)
-1.426
1.61
n/a
Dose recommendation
Dose recommendation will be based on summaries of the posterior distribution of model 
parameters and the posterior distribution of DLT rates, including the mean, median, standard 


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deviation, 95%-credibility interval, and the probability that the true DLT rate for each dose 
combination lies in one of the following categories:

[0%, 16%) under dosing

[16%, 35%) targeted toxicity

[35%, 100] excessive 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 
[16%, 35%) among the doses fulfilling the overdose-control criterion that there is less than 
25% (posterior probability) chance of excessive toxicity. In addition, the maximum inter-
cohort dose escalation is limited to 100% (i.e. up to 100% and 0% increase for LDE225 and 
INC424 respectively or 0% and up to 100% increase for LDE225 and INC424 respectively). 
The proposed combination meets the EWOC criteria (i.e. less than 25% chance that the true 
rate of DLTs lies within the interval [35% - 100%].  A clinical synthesis of the available 
toxicity information (including AEs that are not DLTs), PK, PD, and efficacy information as 
well as the recommendations from the BLRM will be used to determine the dose combination 
for the next cohort at a dose escalation teleconference. 
Safety Expansion
After declaration of MTD and/or RPIID, the dose will be expanded by an additional 6 patients 
in order to further assess tolerability, safety and early efficacy. If two MTDs/RPIIDs are 
established, each MTD/RPIID will enroll an additional 6 patients in the safety expansion. 
Listing of DLTs
DLTs will be listed and their incidence summarized by primary system organ class, worst 
grade based on the CTCAE version 4.03, type of adverse event by treatment. The dose-
determining set will be used for these summaries.
3.5.2
Phase II 
3.5.2.1
Primary endpoints in phase II
The primary endpoint in phase II is the proportion of subjects achieving ≥ 35% reduction in 
spleen volume from baseline by centrally reviewed MRI/CT at the end of week 24 and week 
48.
The percent change from baseline at week 24 or week 48 will be calculated by:
35% Reduction at Week 24 or Week 48: A subject (responder) will be considered as having 
achieved 35% reduction of the spleen volume from baseline to Week 24 or Week 48 if the 
subject had evaluable baseline and Week 24 or Week 48 spleen volume assessments, the 
subject did not experience a protocol-defined progression event prior to the Week 24 or Week 
48 visit, and the calculated percent change was less than or equal to –35%.


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Listing of the data on response variables as assessed by the investigator will be provided. 
Recalculated response based on raw measurements will be listed additionally and 
discrepancies will be identified. Based on this approach, investigator’s assessment is 
considered to be validated and will be used for the primary efficacy analysis. 
The uniformly minimum variance unbiased estimator (UMVUE) (Jung and Kim, 2004) for 
patients achieving 35% spleen volume reduction from baseline as measured by MRI/CT with 
the exact two-sided 95% confidence interval will be provided in phase II. 
Let K be the number of stages, and nk and Xk denote the number of patients accrued and the 
number of responders(i.e. subjects achieve ≥35% spleen volume reduction), respectively, 
during stage k, 1≤k≤K. And let 
denote the cumulative number of responders by 
stage k. 
The ̂ = / is an unbiased estimator of the response rate p (i.e. achieving 35% spleen 
volume reduction), where and  denote the number of responders and the number patients 
accrued at stage 1, respectively.  
The UMVUE of the response rate () is obtained by 
 = {̂|(#, %)}
In a two-stage design,
 =
⎩
⎪
⎨
⎪
⎧
%

# = 1
∑
-./0
1/02 - .3
401/2
4^(6/0)
1/7(8/9)˅(40.3)
∑
-./
1/2 - .3
401/2
4^(6/0)
1/7(8/9)˅(40.3)
# = 2
Where <^= =min(a,b) and <˅= =max(a,b). <and =is the lower and upper boundaries for 
stage 1. As there is only a lower boundary in the study, the upper boundary = in this case is
= =  + 1.
Let M denote the stopping stage and let S=SM denote the total number of responders 
accumulated up to the stopping stage. The probability mass function of (M, S) in a two-stage 
design with lower stopping boundaries only is given as
@(#, %|) = A
4(1 −)./04 -
% 2
# = 1, 0 ≤% ≤<
4(1 −)./9.304 D
E
F
G E H
% −F
G
./^4
1/78/9
# = 2, < + 1 ≤% ≤ + H
Exact confidence intervals of the UMVUE are obtained as follows:
Pr((J, K) ≥(#, %)| = M) = N/2
and 


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Pr((J, K) ≥(#, %)| = O) = 1 −N/2
The transition from Stage 1 to Stage 2 in phase II study will be based on the response rate in 
the phase II stage 1 patients in FAS. The response rate will be calculated for the final analysis 
in patients with phase II.
Update: since a no-go decision has been made and Phase II Stage 2 was not started, the 
UMVUE estimator of  would be equivalent to the simple proportion 
4
./.
3.5.2.1.1 IA design as presented in protocol section 10.7
The IA decision based on originally enrolled 18 patients is presented in Table 3-1. It is 
possible to terminate the trial at the interim for lack of adequate efficacy, i.e. futility. In this 
study, futility is equivalent to observe less than 8 responders in 18 patients (Table 3-2). 
Table 3-2
Predictive probability of observing response rate of 50% (n=18) or 
greater at the primary analysis (46 patients) under different interim 
results
Observed response at IA
Predictive probability of observing 
response rate ≥50%
# of response
%
4
22.2
0.002
5
27.8
0.011
6
33.3
0.047
7
38.9
0.143
8
44.4
0.318
9
50.0
0.548
10
55.6
0.762
11
61.1
0.905
12
66.7
0.972
13
72.2
0.994
3.5.2.1.2 IA design based on actual enrolled patients in phase II stage 1
Since 20 patients instead of the protocol planned 18 patients enrolled in the phase II stage 1, 
the calculation is updated to provide a new threshold for ‘go’ decision based on phase II stage 
1 data (Table 3-3). 


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Table 3-3
Predictive probability of observing a response rate >= 50% at the final 
analysis with 46 patients under different interim results with 20 
patients
Observed response at IA
among 20 patients
Predictive probability of observing a 
response rate ≥50% in 46 patients 
# of response
%
5
25
0.002
6
30
0.013
7
35
0.051
8
40
0.149
9
45
0.325
10
50
0.552
11
55
0.763
12
60
0.904
13
65
0.971
14
70
0.994
15
75
0.999
If 9 or more responders are observed in IA, then 26 additional patients will be enrolled into 
this study. 
3.5.2.1.3 Exploratory analysis based on all patients with MRI/CT assessed spleen 
volume
Seven patients in phase Ib expansion underwent the exact same efficacy analysis as those in 
phase II. This exploratory analysis includes them in the ‘go’ criterion calculation. As such, 27 
patients will be used in IA analysis, and 53 patients (i.e. 7 patients from phase Ib expansion 
and 46 patients from phase II) will be used for final analysis (Table 3-3). 
Table 3-3
Predictive probability of observing a response rate >= 50% at the final 
analysis with 53 patients under different interim results with 27 
patients
Observed response at IA
among 27 patients
Predictive probability of observing a 
response rate ≥50% in 53 patients 
# of response
%
8
29.6
0.001
9
33.3
0.007
10
37.0
0.028
11
40.7
0.086
12
44.4
0.207
13
48.1
0.393


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14
51.9
0.607
15
55.6
0.793
16
59.3
0.914
17
63.0
0.972
18
66.7
0.993
19
70.4
0.999
If 12 or more responders are observed in IA, then 26 additional patients will be enrolled into 
this study. 
3.5.3
Handling of missing values/censoring/discontinuations
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study treatment, duration of exposure to study treatment and date of 
discontinuation for each patient. Other missing data will simply be noted as missing on the 
appropriate tables/listings. 
Phase Ib:
Patients in the dose escalation phase are ineligible for the dose-determining set will not be 
replaced. 
Phase II:
Patients with unknown clinical response (e.g. patients with missing assessments at the end of 
24 or 48 weeks) will be considered as non-responders. No imputation of missing values will 
be made for the efficacy analysis.
A subject must have a baseline spleen volume in order to be included in the primary efficacy 
analysis. Subjects who drop out of the study due to any reason, such as lack of efficacy or 
treatment-related adverse events (AEs), or who have a protocol-defined event of disease 
progression prior to Week 24 or Week 48 visit will all be considered as having not achieved 
the ≥ 35% reduction at Week 24 or Week 48 respectively.
3.6
Secondary analysis
3.6.1
Bone marrow assessment
Bone marrow variables as assessed by aspirate and/or biopsy will be listed. Fibrosis grade 
assessed by bone marrow histomorphology will be summarized by the collection time points
(week 1, week 25 and every 24 weeks thereafter). 
The following variables will be listed: 
Bone marrow aspirate
•Was the specimen adequate for assessment (yes/no), 


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•Specimen quality: dry tap/hemodiluted/other
•Blast cell (%)
Bone marrow biopsy
•Was the specimen adequate for assessment? (yes/no)
•Percentage of cellularity
•Cellularity: Hypocellular/Normocellular/Hypercellular/Not assessable/Aplastic
•Blast cell (%)
•Bone marrow fibrosis grade
3.7
Exploratory analysis
3.7.2
Spleen length by manual palpation
Frequency of patients who have palpable spleen measurement will be provided. Spleen 
measurement by manual palpation at week 24 will be compared to the week 1 day 1
measurement. Descriptive statistics will be provided for the spleen length and percent change 
from baseline over time by the redefined treatment groups (details can be found in RAP M7.1 
section 1.2.1) and overall. The maximum likelihood estimate and 95% exact binomial 
confidence interval will be also provided for patient who has ≥50% spleen length reduction by 
manual palpation.


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Data will be summarized for the set of patients from the FAS who have a valid corresponding 
baseline assessment.
The percentage change in spleen length is defined as:
% Change = (Post-baseline spleen length – Baseline spleen length) ×100 / Baseline spleen 
length.
3.8
Safety evaluation
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) will be considered as appropriate. 
All safety outputs will be provided by study phase, treatment and overall by using the safety 
set. The safety summary tables will include only assessments collected no later than 30 days 
after study treatment discontinuation. All safety assessments will be listed and those collected 
later than 30 days after study treatment discontinuation will be flagged. 
Adverse events of special interest will be summarized according to Section 3.8.1.5. 
3.8.1
Adverse events data
3.8.1.1
Coding of AEs
AEs will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. The latest version of MedDRA prior to the database lock will be used for 
reporting. 
3.8.1.2
Grading of AEs
AEs will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, grades 1 – 4 corresponding to the 
severity of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) 
will not be used in this study; rather, this information will be collected on the “End of 
Treatment” eCRF pages. In addition, information related to the death of a patient while in the 
study or within the follow-up period specified in the protocol will be collected in “Death” 
CRF page.
3.8.1.3
General rules for AE Reporting
AE summaries will include all 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 30 days after the end of treatment. 
All AEs will be listed. AEs starting prior to study day 1 and AEs starting later than 30 days 
after the last treatment date will be flagged in the listings.


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AEs will be summarized by dose level for the number and percentage of patients having at 
least one AE, in each primary system organ class and for each preferred term (using MedDRA 
coding). A subject with multiple occurrences of an AE will be counted only once in the 
corresponding AE category. Separate AE summaries will be presented by the maximum 
CTCAE grade. A patient with multiple CTCAE grades for an AE will be summarized under 
the maximum CTCAE grade recorded for the event.
In addition, a summary of serious and non-serious adverse events with number of occurrences 
will be produced (an occurrence is defined as >1 day between start and prior end date of 
record of same preferred term) as per EudraCT requirements.
3.8.1.4
AE summaries
The following AE summaries will be produced. Overall category will be included:

Number (%) of  patients who died, had AEs, had SAEs, discontinued, had concomitant 
medication or had a dose reduction or interruption, by treatment group

AEs, regardless of study drug relationship by primary system organ class, preferred term,
maximum CTC grade and treatment group

AEs suspected to be related to the study drug by primary system organ class, preferred 
term, maximum CTC grade and treatment group

Deaths by primary system organ class, preferred term and treatment group

Serious adverse events (SAE), regardless of study drug relationship, by primary system 
organ class, preferred term, maximum CTC grade and treatment group

AEs leading to study drug discontinuation, regardless of study drug relationship, by 
primary system organ class, preferred term, maximum CTC grade and treatment group

AEs requiring dose adjustment or study-drug interruption, regardless of study drug 
relationship, by primary system organ class, preferred term, maximum CTC grade and 
treatment group 

AEs which are not serious adverse events, regardless of study drug relationship, by 
primary system organ class, preferred term and treatment group

AEs, regardless of study drug relationship, by preferred term and treatment group 

On-treatment deaths and serious adverse events by primary system organ class, preferred 
term and treatment group
3.8.1.5
Adverse events of special interest
Specific groupings of AEs, referred as AEs of special interest, will be considered and the 
number of patients with at least one event in each grouping will be reported by the redefined 
study treatment. Such groups consist of AEs for which there is a specific clinical interest in 
connection with LDE225 or INC424 treatment (i.e. compound and class related risks linked to 
the drug structure, mechanism of action, formulation and mode of administration). 
Muscle-related events, including CK elevation 


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Nausea and/or Vomiting
Diarrhea
Fatigue
Dysgeusia
Alopecia
Weight decreased
Decreased Appetite
Thrombocytopenia
The classification and definition of AEs of special interest reflects the current version of the 
Safety Profiling Plan (SPP) and might be updated at the time of the data base lock for the 
analyses based on the latest approved version of the SPP. 
The following summaries will be provided for the AEs of special interest: 
AEs of special interest, by group, preferred term and treatment group. This includes all 
CTC grades, suspected AEs to be related to study drug, SAEs, AEs requiring dose 
adjustment and AEs leading to discontinuation from study treatment.
3.8.2
Laboratory data
The summaries will include all laboratory assessments collected no later than 30 days after 
study treatment discontinuation. All laboratory assessments will be listed and those collected
later than 30 days after study treatment discontinuation will be flagged in the listings.
The laboratory data will be classified into CTC grades according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03. If value within normal limits is 
assigned grade 0 as well as assigned a non-zero grade by the NCI Toxicity Criteria, the 
severity will be assigned to grade 0. These values are not counted in the frequency distribution
of the highest NCI toxicity grade even if the value met the criteria of a nonzero grade. This 
resolves cases where a laboratory value could simultaneously fall in the normal range and in 
the range of a non-zero grade under NCI toxicity Criteria.
3.8.2.1
Descriptive analyses
The following summaries will be produced for the hematology and biochemistry laboratory 
data (by laboratory parameter):

Shift tables using CTC grades to compare baseline to the worst post-baseline value, by 
treatment and overall

For laboratory parameters without CTC grade: shift tables using normal ranges to compare 
baseline to the worst post-baseline value, by treatment and overall
The following listings will be produced for laboratory data:


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
Listing of laboratory data, with values flagged to show the corresponding CTC grades and 
the classifications relative to the laboratory reference ranges by treatment. This listing will 
be provided for hematology, biochemistry and urinalysis lab data.

Listing of patients with laboratory abnormalities of CTC grade 3 or 4 by treatment with 
values flagged to show the corresponding CTC grades and the classifications relative to 
the laboratory reference ranges by treatment. This listing will be provided for hematology, 
biochemistry and urinalysis lab data combined.

A listing of patients with grade ¾ CK elevation with values flagged to show the 
corresponding CTC grades
and the classifications relative to the laboratory reference 
ranges by treatment. 

Listing of pregnancy test results by treatment
3.8.3
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
parameters collected in this study are: weight (kg or lb), height (cm or inches), body 
temperature (°C), heart rate (beats per minute), systolic and diastolic blood pressure (mmHg).
The criteria for clinically notable abnormalities are depicted in Table 3-2 and Table 3-3.
Table 3-2
Clinically notable elevated values
Variable
Criteria
Systolic BP
150 mmHg and an increase 20 mmHg from baseline
Diastolic BP
90 mmHg and an increase 20 mmHg from baseline
Body temperature
38°C
Weight
increase from baseline of 10%
Heart rate
100 bpm with increase from baseline of 20 bpm
Table 3-3
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


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Weight
decrease from baseline of 10%
Heart rate
50 bpm with decrease from baseline of 15 bpm
The following summary will be produced for heart rate, diastolic BP and systolic BP, body 
temperature and weight change by study phase, dose cohort and overall:

Number and percentage of patients with at least one post-baseline vital sign abnormality 
(in both directions, i.e. both elevated and below normal values)
The following listing will be produced by study treatment and overall:

Patients with clinically notable vital sign abnormalities

All vital sign assessments will be listed by patient and vital sign parameter
In both listings, the clinically notable values will be flagged and also the assessments 
collected later than 30 days after the last treatment/exposure date will be flagged.
3.8.4
Cardiac assessments
3.8.4.1
Electrocardiogram (ECG) Analyses
ECG data are collected from the site. The summaries will include all ECG assessment 
collected no later than 30 days after the last date of study treatment.  All ECG assessments
will be listed, and those collected later than 30 days after the study treatment discontinuation 
will be flagged in the listing.
Single ECGs are collected at pre-dose for the following visits: Screening, Week 1 Day 1, then 
every 4 weeks and EOT visit. 
All ECG analyses will be performed using the Safety set.
For all subjects, ECG baseline is defined as the average of all ECG measurements taken prior 
to the first dose as confirmed by date and time. 
The number and percentage of patients having notable ECG interval values will be 
summarized by study treatment and overall. The percentages will be calculated based on the 
total number of patients who are at risk for a specific category.
Quantitative abnormal prolongation as determined by central review of ECG will be provided 
via summary of worst change from baseline in ECG intervals by dosing schedule and overall. 
The following categories for QT, QTcB and QTcF [ms] will be used to identify notable 
values:

New >450 msec 

New >480 msec 

New >500 msec


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The following categories will be used to identify patients with notable ECG changes from 
baseline:
QT, QTcB and QTcF [ms]
(1) >30 and <= 60 ms increase from baseline 
(2) >60 ms increase from baseline 
PR [ms]
(1) An increase ≥25% from baseline resulting in PR >200 at any post-baseline assessment
QRS [ms]
(1) An increase ≥25% from baseline resulting in QRS >110 at any post-baseline 
assessment
HR [bpm]
(1) A decrease >25% from baseline resulting in HR <50 at any post-baseline assessment
(2) An increase >25% from baseline resulting in HR >100 at any post-baseline assessment
The following summaries will be produced:

A shift Table for QTcB and QTcF based on notable values. The patient’s baseline value is 
compared to the worst post-baseline value,

The number and percentage of patients with notable ECG change from baseline using the 
categories described above.
The percentage of patients having notable ECG interval values is based on the total number of 
patients who are at risk for a specific category.
Assessments collected later than 30 days after the study treatment discontinuation will be 
flagged in the listings. The following listings will be produced:

A listing of patients with abnormal ECG intervals,

All ECG intervals with corresponding baseline values and notable values flagged. 
Patients with abnormal ECG intervals will be listed and the corresponding notable values will 
be flagged in the listings. An overall listing of ECG data with notable values flagged will also 
be provided.
Patients will be considered evaluable (included in “Total”) for absolute QT/QTc outliner 
analysis if they have at least 1 post-drug ECG measurement. For change from baseline 
analyses they have to have at least 1 baseline ECG measurement and 1 post-baseline 
measurement. 
3.9
Patient reported outcomes (PRO)
The FAS will be used for all PRO summaries and listings.


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3.9.1
EORTC Quality of Life Questionnaire (QLQ-C30)
The EORTC QLQ-C30 includes 5 functional scales (physical, role, emotional, cognitive and 
social), global health status/quality-of-life scale and 9 symptom scale/items (fatigue, nausea 
and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties).  For functional and global health status/Qol scales, higher scores indicate better 
QoL and level of functioning; for symptom scales, higher scores indicate greater level of 
symptoms or difficulties. 
The EORTC QLQ-C30 will be collected at Week 1 Day 1, then every 4 weeks and at the EOT 
visit. 
3.9.1.1
Score generation
EORTC QLQ-C30 scale scores will be generated according to the scoring procedures and 
SAS code guidelines for version 3.0 provided in The EORTC QLQ-C30 Scoring Manual (3rd
Edition). Scores for each functional scale range from 0 to 100. As a general rule, scores values 
are set to missing when more than half of the items for that scale are missing. If the functional 
scale consists of one item and that item is missing, the score is automatically missing.
Change from baseline scores is defined as:
score value of given visit or time-point − baseline score,
where baseline scores are those obtained from Week 1visit assessments.
3.9.2
Seven-day modified MFSAF v2.0
The Seven-day Total Symptom Score (TSS) and individual item scores will be summarized 
descriptively along with changes from baseline to each visit where the variable is measured. 
At week 24 and week 48 the proportion of patients who have a ≥50% reduction from baseline 
in TSS based on the Seven-day modified MFSAF v2.0 will be determined as follows.
The Seven-day TSS will be defined as the sum of 6 individual symptom scores (each with a 0-
10 point scale) collected on the same day; the score will be missing if there are any missing 
individual scores and inactivity will not be included. 
The percent change will be calculated by:
% change=100⨯(Week 24 or Week 48 total score- baseline total score)/ baseline total score
The percent of patients who have ≥50% reduction in total symptom score at week 24 and 
week 48 will be estimated with a two-sided 95% confidence intervals.
3.9.3
Compliance
Compliance rate calculated as the number of patients who filled out the questionnaire will be 
summarized for each visit for EORTC QLQ-C30 by study treatment.


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3.9.4
Descriptive statistics
PRO scaled scores and change from baseline scores will be summarized by study treatment 
and by visit for patients in the FAS. All scores will be listed, and those assessments performed 
later than 30 days after the last date of study treatment will be flagged in the listings but not 
included in the summaries. Unscheduled assessments will not be included in the summaries.
The following listings will be produced:

A listing of individual responses to questionnaires.
3.9.5
Waterfall graphs
Waterfall graphs to display the change from baseline at Week 24 and 48 in Phase Ib dose 
expansion and Phase II Stage 1 will be constructed for the following scores: 
EORTC QLQ-C30
oPhysical functioning
oSocial functioning
oFatigue
oPain
MFSAF Total Symptom Score
3.10
Chest X-ray
All chest X-ray variables will be listed. 
3.11
Biomarkers
Since the study is not adequately powered to assess specific biomarker-related hypotheses, the 
statistical analyses of these data should be considered exploratory in nature. Analytical results 
from such analyses may be used to generate additional hypotheses that must then be verified 
with data derived from subsequent clinical trials. Furthermore, additional post hoc exploratory 
assessments are expected and may be performed. Such analyses may include, but are not 
limited to i) the meta – analysis of data from this study combined with data from other studies, 
ii) the analysis of pharmacogenetic biomarkers etc. Details of additional exploratory analysis 
will be described in separate Biomarker analysis plans and the results of such assessments 
may also be documented in separate biomarker reports.
The standard analysis sets will be used instead according to the purpose of a given analysis 
(e.g. FAS to describe biomarkers, safety/per-protocol set to assess the relationship between 
biomarkers and selected safety/efficacy endpoints). The purpose of the proposed data analysis 
is:
To describe the distribution of biomarkers at baseline and changes from baseline


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To assess the relationship between biomarkers and selected efficacy endpoints, if applicable:
•Response: achieving 35% spleen volume reduction (Yes/No)
•Bone marrow: blast count (%), blast count change from baseline (%)
•Gene expression signature at baseline correlated with efficacy endpoints
The following categories of biomarkers will be analyzed:
•Gene expression markers
•Gene mutation markers
3.11.1
Data handling and pre-processing
Gene expression data will be normalized to remove systematic bias. Values below the lower 
limit of quantification (LLOQ) will be handled as follows. If the proportion of such measures 
is below 15%, different imputation rule will be used depending on assay as specified below. 
Standard summary statistics will be used. Summary measures of changes in biomarkers 
collected longitudinally (if available) during the study will be derived as the difference from 
baseline at the time of response assessments. 
Unscheduled and missing measurements will be handled in a similar way as laboratory data. 
Table 3-4
Data pre-processing and handling of biomarkers in LDE225 and 
INC424
Biomarker 
type / assay
Assay and measurement
Data pre-processing and handling
RT-PCR
Measures the relative RNA expression 
of a particular gene
Assay output is the number of cycles 
(CT) to reach detection threshold 
(where 
the 
amplification 
becomes 
linear) Raw or normalized CT values 
will be reported.
The greater the starting amount of 
RNA, the fewer number of cycles to 
reach threshold
The higher the raw CT for a target 
gene, 
the 
weaker 
the 
level 
of 
expression for this gene.  
Raw CT results will be normalized1. ΔCT
is in general the average CT of the control 
genes minus the raw CT of the target 
gene.  
ΔCT is, by definition, on the log-2 scale. 
No transformation will be applied to this 
data. 
Values below LLOQ will be imputed as 
the maximum reliable CT, in general 36 
(contact BTH or GCSL to confirm this 
information).
Somatic 
mutation
(SMU)
Qualitative data
-  Usually 2 categories: wild type and 
mutant
Mutant may refers to several forms of 
mutations of the same gene (e.g. exon 20 
and exon 9 for PIK3CA gene) and may be 
reported together and separately.
1. Algorithms and formulas for normalization depend on the sample type will be defined in consultation with the 
RT-PCR Lab Scientist or BTH.
The mean of all pre dose assessments will be used as the baseline value.


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When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analysis.
Except for RT-PCR biomarkers, measures below the LLOQ will be handled according to the 
following algorithm:
1. Numerical values that are below the LLOQ for the assay will need to be imputed as 
LLOQ/2, except for RT-PCR biomarkers values which will be imputed following rules 
provided in Table 3-5. Sometimes numerical values for the biomarker are reported, even if 
the values are below LLOQ. In this case, the imputation is still needed.
2. If both baseline and post baseline values are below LLOQ, then change from baseline is 
not imputed and considered missing.
3. If <15% of the values (at a given time point/ change from baseline at a given time point) 
are below LLOQ then these will be summarized.
4. If the proportion of such measures below LLOQ is  >15% but <50% then only percentiles 
are reported as summary statistics
5. If >50% of such values are below LLOQ then data is only listed for this measure. 
3.11.1.1 RT-PCR biomarkers
RT-PCR data will be reported as cycle time (CT) values or delta CT (CT). ΔCT is, by 
definition, on the log2 scale and no transformation will be applied to this data. Values below 
the LLOQ will be imputed as the maximum reliable CT, in general 36. Maximum reliable CT 
values must be confirmed with the BTH or GCSL.
Change from baseline is defined as:
Diff= log2 (ΔCT)post - log2 (ΔCT)pre= log2 { (ΔCT)post / (ΔCT)pre }
Where (ΔCT)pre is the value at baseline and  (ΔCT)post is the value post-baseline.
Fold-change from baseline is defined as:
Fold-change = 2^(Diff) ; if Diff ≥0 i.e. Fold-change is { (ΔCT)post / (ΔCT)pre }
Fold-change = -1×{2^(-1×Diff) }; if Diff < 0 i.e. Fold-change is -1×{ (ΔCT)pre / (ΔCT)post}
Percent inhibition is defined as:
% inhibition = 100×(1−2^(Diff) )
Example:  If D_28 is the log2 ΔCT of day 28, and D_0 is the log2 ΔCT at baseline, then Diff = 
D_28 −D_0 (in this case it is the log2 fold change):
data lde_diff; 
set lde_diff; 
diff = D_28 - D_0; 
if diff < 0 then fold = -1*(2**(-1*diff)); 
else fold = (2**(diff)); 
run;


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New categorical variables will be derived for RT-PCR biomarkers using the median levels as 
the threshold or based on the post hoc analysis of the distribution of the data. For percent 
inhibition of Gli1, the following thresholds will be used: <80%, [80% - 90%], > 90%.
3.11.2
Statistical methods for Biomarker
Mutations involved in the molecular disease characterization of MF will be listed by patient 
and summarized using frequency tables by study treatment. 
The expression levels of Hh pathway related biomarkers (such as Gli1) and JAK signaling 
pathway related biomarkers (such as JAK2V617F allele burden; reported as percent mutated)
and cytokine levels will be reported and summarized as follows:
All data will be listed by patient in each cohort and time point. Summary tables of the 
expression levels will be created at each measured time point by study treatment in Phase Ib
and Phase II Stage 1. Summary tables will include number of samples (n), % of those samples 
below LLOQ, mean, standard deviation, median, %CV, minimum and maximum. For all post-
baseline time-points; fold change in biomarker expression levels will also be summarized. 
The summary statistics will include, number of samples, mean, geometric mean, %CV of 
geometric mean, minimum, maximum etc. Additionally frequency tables (number and 
percentage of subjects) for JAK2 mutation status (positive/negative) at baseline will be 
reported. 
Longitudinal plots of the mean fold-change from baseline along with 95% CI’s or standard 
error bars will be created to explore the trend over time.  
The associations between biomarkers and efficacy outcomes may also be explored via more 
sophisticated statistical models if sufficient data are available. Advanced statistical analysis 
may be carried out to explore the data in a post-hoc fashion. Details of such methodology if 
applied to the data will be described in a separate Biomarker Analysis Plan document.
3.12
Pharmacokinetic analyses
The pharmacokinetic analyses will be based on the PAS described in section 2.2.4, unless 
otherwise specified.
Listings will be presented by study treatment using FAS and ordered according to instructions 
detailed in the general guidance section of RAP M7. 
As convention, a PK sample should be excluded from analyses if the patient vomited within 
the first 4 hours following the last oral dose of study drug. Other PK samples will be excluded 
as deemed appropriate by the Pharmacokineticist. The excluded concentrations will be 
flagged in the listings.
All concentrations below the limit of quantification or missing data will be labeled as such in 
the concentration data listings. Concentrations below the limit of quantification will be treated 
as zero in summary statistics and for the calculation of pharmacokinetic parameters.


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3.12.1
Trough and profile concentration data
Plasma concentrations of LDE225 and INC424 will be summarized at each scheduled time 
point by study phase and dose cohort. Profile concentration data for LDE225 refers to the data 
collected on week 1 day 1 (also include pre-dose and week 1 day2) and week 9 day 1 (also 
include pre-dose and week 9 day 2). Profile concentration data for INC424 refers to the data 
collected on week 1 day 1 within the 12 hours after the first dose and before the second dose, 
and week 9 day 1 within the 12 hours after the first dose and before the second dose. Trough 
concentration data refers to pre-dose samples eg week 3 day1, week 5 day 1, week 7 day1, 
week 13 day1, etc. Descriptive graphical plots of individual plasma concentration time 
profiles with median will be generated, along with geometric mean and mean (SD)
concentrations time profiles trough concentrations for LDE225 and INC424. Individual plots 
of trough concentrations for LDE225 and INC424 will also be produced. A list of individual 
concentrations will be provided using FAS. Concentrations excluded from analyses will be 
flagged. Descriptive statistics will include n (number of patients), m (number of non-zero 
concentrations), arithmetic mean, geometric mean, median, SD, coefficient of variation CV 
(%), geometric CV (%), minimum and maximum. 
Coefficient of variation CV (%) is calculated as follows: 100×(SD/arithmetic mean).
Geometric CV (%) is calculated as follows: 100×sqrt(exp[Var(log(x))]-1), where Var(X) 
denotes the variance of X. 
3.12.2
Pharmacokinetic parameters
For Phase Ib and Phase II Stage 1 only, PK parameters listed in Table 3-6 and Table 3-7 will 
be determined for all PK-evaluable patients using non-compartmental method(s) using 
WinNonlin or Phoenix WinNonlin (Pharsight, Mountain View, CA). PK parameters will be 
estimated for Week 1 and Week 9 and reported, when feasible. PK parameters in Table 3-6
and Table 3-7 for LDE225 and INC424 will be descriptively summarized for Week 1 and 
Week 9 by dose level. 
Descriptive statistics (n, mean, SD, CV% or median [range], and geometric mean and CV%) 
will be presented for all parameters with the exception of Tmax for which median values and 
ranges will be presented. When a geometric mean is presented, it will be stated as such.
The following pharmacokinetic parameters
are determined using non-compartmental
method(s) (Table 3-6 and Table 3-7). 
Table 3-5
Non-compartmental pharmacokinetic parameters for LDE225 (Phase 
Ib and Phase II Stage 1 only)
Term
Definition
Cmax
Maximum observed plasma concentration after drug administration [mass x volume-1]
Tmax
Time to reach Cmax [time]
AUC0-24h
Area under the concentration-time curve from time zero to 24 hours [mass x time x 
volume-1]
CL/F
Apparent total plasma clearance of drug after oral administration [volume x time-1]


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Term
Definition
Racc
Accumulation ratio calculated as AUC0-24h on Week 9 Day 1 divided by AUC0-24h 
on Week 1 Day1 [fold]
Table 3-6
Non-compartmental pharmacokinetic parameters for INC424 (Phase Ib 
and Phase II Stage 1 only)
Term
Definition
Cmax
Maximum observed plasma concentration after drug administration [mass x volume-1]
Tmax
Time to reach Cmax [time]
AUClast
Area under the concentration-time curve from time zero to the time of last measurable 
concentration [mass x time x volume-1]
AUC0-12h
Area under the concentration-time curve from time zero to 12 hours extrapolate from 
AUClast[mass x time x volume-1]
AUCinf
Area under the concentration-time curve from time zero to infinity with extrapolation of 
the terminal phase [mass x time x volume-1]
T1/2
Elimination half-life associated with the terminal slope (lambda_z) of a semi 
logarithmic concentration-time curve [time]
CL/F
Apparent total plasma clearance of drug after oral administration [volume x time-1]
Racc
Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h
on Week 1 Day 1 [fold]
Vss/F
Apparent volume of distribution at steady state after oral administration [volume]
3.12.3
Analysis of relationship between LDE225/INC424 and efficacy/safety 
endpoints
3.12.3.1 Exposure-response relationship 
Box plots for LDE225 and INC424 AUC and Cmax will be presented by responders and non-
responders.  
3.12.3.2 Exposure-safety relationship 
Box plots for on-treatment LDE225 AUC and Cmax will be presented separately by worst 
CTC grade for CK. 
3.13
Sample size and power considerations
The total sample-size for the study will be approximately 82.
Phase Ib: Approximately 36 patients are expected to be enrolled into dose escalation cohorts. 
Cohorts of 3 to 6 evaluable patients per dose level will typically be enrolled in the dose 
escalation part including at least 6 evaluable patients at the MTD level. Assuming a total of 5 
cohorts, the number of patients during dose escalation is expected to be approximately 30. An 
additional 6 patients will be treated at the MTD/RPIID during the safety expansion. If two 


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MTDs/RPIIDs are established, each MTD/RPIID will enroll additional 6 patients in the safety 
expansion. 
Phase II: Following the determination of an MTD or RPIID in Phase Ib, 18 patients will be 
enrolled in the first stage and if the criterion is met to continue to stage 2, an additional 28 
patients will be enrolled.
4
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