Clinical trial NCT04097821
Conditions: Myelofibrosis
Keywords: myelofibrosis ruxolitinib INC424 siremadlin HDM201 crizanlizumab SEG101 sabatolimab MBG453 rineterkib LTT462 NIS793 platform study
Sponsor: Novartis Pharmaceuticals
Start date: 2019-09-26; Completion date: 2024-08-28
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to investigate the safety, pharmacokinetics and preliminary efficacy of combination treatment of ruxolitinib with 5 novel compounds: siremadlin, crizanlizumab, sabatolimab, rineterkib and NIS793 in myelofibrosis (MF) subjects.

Detailed description:
This open-label, multi-center, Phase Ib/II platform study design consisted of 3 parts. Part 1 was a Phase Ib dose escalation and safety run-in for the 5 novel agents in combination with ruxolitinib to assess safety, tolerability and to confirm a recommended Phase II dose. Dose escalation cohorts were treated with ruxoltinib + siremadlin or ruxolitinib + rineterkib. Safety run-in cohorts were treated with either ruxolitinb + sabatolimab, ruxolitinb + crizanlizumab or ruxolitinib + NIS7913.

Parts 2 and 3 were Phase II selection and expansion, respectively, to assess preliminary efficacy of the combination treatments from Part 1 that were evaluated as safe and tolerable. The number of combination treatment arms opening in Part 2 depended on the results of Part 1. In Part 2, an interim analysis was planned to determine if combination treatment(s) could be expanded in Part 3.

In June 2022, Novartis decided to permanently halt the study enrollment in all ongoing parts (Part 1 and Part 2), and Part 3 (expansion) was not initiated. With Protocol Amendment 8, an extension treatment phase of 12 cycles was added in Part 1 to allow access to the combination treatment for ongoing subjects deriving clinical benefit. In consideration of the enrollment halt, Parts 2 and 3 objectives were not pursued, and Part 1 objectives were updated accordingly.

Arms: arm 1: Dose escalation of siremadlin added to existing stable dose of ruxolitinib arm 2: Dose escalation of siremadlin added to existing stable dose of ruxolitinib arm 3: Dose escalation of siremadlin added to existing stable dose of ruxolitinib arm 4: Dose escalation of rineterkib added to existing stable dose of ruxolitinib arm 5: Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib arm 6: Safety run-in of sabatolimab added to existing stable dose of ruxolitinib arm 7: Safety run-in of NIS793 added to existing stable dose of ruxolitinib arm 8: Existing stable dose of ruxolitinib as control for Part 2
Interventions: intervention 1: Ruxolitinib intervention 2: Siremadlin intervention 3: Crizanlizumab intervention 4: Sabatolimab intervention 5: Rineterkib intervention 6: NIS793
Intervention descriptions: intervention 1: 5 mg tablets for oral use intervention 2: 10 mg, 20 mg, or 40 mg capsules for oral use intervention 3: 100 mg/10 mL concentrate for infusion for intravenous use intervention 4: 100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use intervention 5: 100 mg capsule for oral use intervention 6: 700 mg/7 mL concentrate for infusion for intravenous use

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
Ruxolitinib (INC424), siremadlin (HDM201), crizanlizumab 
(SEG101), sabatolimab (MBG453), rineterkib (LTT462), NIS793 
Clinical Trial Protocol CINC424H12201 / NCT04097821 
A randomized, open-label, phase I/II open platform study 
evaluating safety and efficacy of novel ruxolitinib 
combinations in myelofibrosis patients 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2019-000373-23 
Version number: 
09 (Clean)  
Clinical Trial Phase: 
I/II 
Release date: 
05-Dec-2023 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018 


Novartis 
Confidential 
Page 2 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 9 
List of abbreviations .......................................................................................................... 10 
Glossary of terms ............................................................................................................... 14 
Amendment 9 (05-Dec-2023) ............................................................................................ 15 
Amendment 8 (05-Oct-2022) ............................................................................................ 17 
Local Protocol Amendment 7-US.01 (08-Apr-2022) ........................................................ 22 
Amendment 7 (11-Jan-2022) ............................................................................................. 23 
Amendment 6 (20-Jul-2021) ............................................................................................. 26 
Amendment 5 (23-Feb-2021) ............................................................................................ 30 
Amendment 4 (25-Aug-2020) ........................................................................................... 35 
Amendment 3 (28-Apr-2020) ............................................................................................ 40 
Amendment 2 (17-Feb-2020) ............................................................................................ 42 
Amendment 1 (18-Jul-2019) ............................................................................................. 46 
Protocol summary .............................................................................................................. 49 
1 
Introduction ....................................................................................................................... 54 
1.1 
Background ........................................................................................... 54 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment ................................................................................................ 54 
1.1.2 
Introduction to Investigational treatments ............................................ 55 
1.2 
Purpose .................................................................................................. 61 
2 
Objectives and endpoints ................................................................................................... 62 
3 
Study design ...................................................................................................................... 65 
4 
Rationale ............................................................................................................................ 74 
4.1 
Rationale for study design ..................................................................... 74 
 
 77 
 
 77 
 
 78 
 
 79 
 
 79 
 
 80 
4.2.6 
Extension Treatment Phase ................................................................... 80 
 
 81 
 
 81 
 
 81 


Novartis 
Confidential 
Page 3 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 81 
 
 82 
 
 83 
 
 84 
4.4 
Purpose and timing of interim analyses/design adaptations (Not 
applicable) ............................................................................................ 85 
4.5 
Risks and benefits ................................................................................. 86 
4.6 
Rationale for Public Health emergency mitigation procedures ............ 88 
5 
Population .......................................................................................................................... 88 
5.1 
Inclusion criteria .................................................................................... 89 
5.2 
Exclusion criteria .................................................................................. 89 
5.3 
Eligibility for extension treatment phase .............................................. 93 
6 
Treatment ........................................................................................................................... 94 
6.1 
Study treatment ..................................................................................... 94 
6.1.1 
Investigational and control drugs .......................................................... 94 
6.1.2 
Additional study treatments .................................................................. 95 
6.1.3 
Treatment arms/group ........................................................................... 96 
6.1.4 
Guidelines for continuation of treatment .............................................. 97 
6.1.5 
Treatment duration ................................................................................ 97 
6.2 
Other treatment(s) ................................................................................. 98 
6.2.1 
Concomitant therapy ............................................................................. 98 
6.2.2 
Prohibited medication ......................................................................... 100 
6.3 
Subject numbering, treatment assignment, randomization ................. 103 
6.3.1 
Subject numbering .............................................................................. 103 
6.3.2 
Treatment assignment, randomization ................................................ 104 
6.4 
Treatment blinding .............................................................................. 104 
6.5 
Dose escalation and dose modification ............................................... 105 
6.5.1 
Dose escalation guidelines .................................................................. 105 
6.5.2 
Guidelines for dose escalation and determination of RP2D ............... 106 
6.5.3 
Definitions of dose limiting toxicities (DLTs) .................................... 108 
6.5.4 
Dose modifications .............................................................................. 109 
6.5.5 
Follow-up for toxicities ....................................................................... 128 
6.6 
Additional treatment guidance ............................................................ 131 
6.6.1 
Treatment compliance ......................................................................... 133 
6.6.2 
Emergency breaking of assigned treatment code ................................ 133 
6.7 
Preparation and dispensation............................................................... 133 


Novartis 
Confidential 
Page 4 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
6.7.1 
Handling of study treatment and additional treatment ........................ 134 
6.7.2 
Instruction for prescribing and taking study treatment ....................... 134 
7 
Informed consent procedures .......................................................................................... 137 
8 
Visit schedule and assessments ....................................................................................... 138 
8.1 
Screening ............................................................................................. 172 
8.1.1 
Eligibility screening ............................................................................ 172 
8.1.2 
Information to be collected on screening failures ............................... 172 
8.2 
Subject demographics/other baseline characteristics .......................... 173 
8.3 
Efficacy ............................................................................................... 174 
8.3.1 
Response rate for the composite primary efficacy endpoint ............... 174 
8.3.2 
Secondary efficacy endpoints ............................................................. 176 
8.3.3 
Appropriateness of efficacy assessments ............................................ 180 
8.3.4 
Extension treatment phase Efficacy Assessment ................................ 180 
8.4 
Safety and tolerability ......................................................................... 180 
8.4.1 
Laboratory evaluations ........................................................................ 181 
8.4.2 
Electrocardiogram (ECG) ................................................................... 183 
8.4.3 
Cardiac markers .................................................................................. 186 
8.4.4 
Cardiac imaging - MUGA scan or ECHO or cardiac MRI ................. 186 
8.4.5 
Ophthalmologic assessment ................................................................ 187 
8.4.6 
Pregnancy and assessments of fertility ............................................... 187 
8.4.7 
Appropriateness of safety measurements ............................................ 188 
8.5 
Additional assessments ....................................................................... 188 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................. 188 
8.5.2 
Pharmacokinetics ................................................................................ 190 
 
 204 
9 
Study discontinuation and completion ............................................................................ 206 
9.1 
Discontinuation ................................................................................... 206 
9.1.1 
Discontinuation of study treatment ..................................................... 206 
9.1.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples ....................................................................... 208 
9.1.3 
Lost to follow-up ................................................................................. 209 
9.1.4 
Early study termination by the sponsor ............................................... 209 
9.2 
Study completion ................................................................................ 209 
10 Safety monitoring and reporting ...................................................................................... 210 
10.1 
Definition of adverse events and reporting requirements ................... 210 
10.1.1 
Adverse events .................................................................................... 210 


Novartis 
Confidential 
Page 5 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
10.1.2 
Serious adverse events ........................................................................ 213 
10.1.3 
SAE reporting...................................................................................... 214 
10.1.4 
Pregnancy reporting ............................................................................ 215 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 216 
10.2 
Additional Safety Monitoring ............................................................. 216 
10.2.1 
Data Monitoring Committee ............................................................... 216 
10.2.2 
Steering Committee ............................................................................. 217 
11 Data Collection and Database management .................................................................... 217 
11.1 
Data collection .................................................................................... 217 
11.2 
Database management and quality control ......................................... 217 
11.3 
Site monitoring .................................................................................... 218 
12 Data analysis and statistical methods .............................................................................. 219 
12.1 
Analysis sets ........................................................................................ 220 
12.1.1 
Full Analysis Set ................................................................................. 220 
12.1.2 
Safety Set ............................................................................................ 220 
12.1.3 
Dose-Determining Set ......................................................................... 220 
12.1.4 
Pharmacokinetic analysis set ............................................................... 220 
12.2 
Subject demographics and other baseline characteristics ................... 221 
12.3 
Treatments ........................................................................................... 221 
12.4 
Analysis of the primary endpoint(s) .................................................... 221 
12.4.1 
Definition of primary endpoint(s) ....................................................... 222 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 222 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 226 
12.4.4 
Sensitivity and Supportive analyses (Not applicable) ......................... 226 
12.5 
Analysis of secondary endpoints ......................................................... 226 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 226 
12.5.2 
Safety endpoints .................................................................................. 229 
12.5.3 
Pharmacokinetics ................................................................................ 231 
 
 232 
 
 232 
 
 232 
 
 234 
 
 234 
 
 235 
 
 235 
 
 235 


Novartis 
Confidential 
Page 6 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 235 
12.7 
Interim analyses (Not applicable) ....................................................... 235 
12.8 
Sample size calculation ....................................................................... 236 
12.8.1 
Primary endpoint(s) ............................................................................. 236 
13 Ethical considerations and administrative procedures .................................................... 242 
13.1 
Regulatory and ethical compliance ..................................................... 242 
13.2 
Responsibilities of the investigator and IRB/IEC ............................... 242 
13.3 
Publication of study protocol and results ............................................ 242 
13.4 
Quality Control and Quality Assurance .............................................. 243 
14 Protocol adherence .......................................................................................................... 243 
14.1 
Protocol amendments .......................................................................... 243 
15 References ....................................................................................................................... 244 
16 Appendices ...................................................................................................................... 251 
16.1 
Appendix 1: Medications to be used with caution .............................. 251 
16.2 
Appendix 2: Prohibited medications ................................................... 252 
16.3 
Appendix 3: MFSAF v4.0 PRO .......................................................... 254 
16.4 
Appendix 4: EORTC QLQ-C30 PRO ................................................. 255 
 
 257 
16.6 
Appendix 6: Statistical considerations for dose-escalation ................. 257 
 
 257 
16.6.2 
Statistical model .................................................................................. 257 
16.6.3 
Prior specifications for logistic parameters ......................................... 258 
16.6.4 
Hypothetical on-study data scenarios .................................................. 262 
16.7 
Appendix 7: Simulation for hypothetical Part 2 and Part 3 study 
scenarios (Not applicable) ...................................................................................................... 264 
16.8 
Appendix 8: Hypothetical example to illustrate Part 2 and Part 3 
study design (Not applicable) ................................................................................................. 266 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 63 
Table 6-1 
Investigational drugs ............................................................................. 94 
Table 6-2 
Provisional dose levels for siremadlin ................................................ 106 
Table 6-3 
Provisional dose levels for rineterkib .................................................. 106 
Table 6-4 
Criteria for defining dose-limiting toxicities (related to study 
treatment) ............................................................................................ 109 


Novartis 
Confidential 
Page 7 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 111 
 
 114 
 
 117 
 
 
 118 
 
 
 123 
Table 6-10 
Follow-up evaluations for selected toxicities ...................................... 128 
Table 6-11 
Guidance to rule out possible alternative causes of observed LFT 
abnormalities ....................................................................................... 131 
Table 8-1 
Allowable visit windows ..................................................................... 140 
Table 8-2 
Assessment Schedule, Part 1 (for all arms with 28-day cycles) ......... 141 
Table 8-3 
Assessment Schedule, Part 2 & 3 (for all arms with 28-day cycles) 
(Not applicable) ................................................................................... 150 
Table 8-4 
Assessment Schedule, Part 1 Ruxolitinib + NIS793 arm (21-day 
cycles) ................................................................................................. 159 
Table 8-5 
Assessment Schedule, Part 2 & 3 Ruxolitinib + NIS793 or NIS793 
monotherapy arm (21-day cycles) (Not applicable) ............................ 165 
Table 8-6 
MRI/CT Assessment Collection Plan ................................................. 177 
Table 8-7 
Bone Marrow Assessment Collection Plan ......................................... 179 
Table 8-8 
Grading of myelofibrosis .................................................................... 179 
Table 8-9 
Safety & tolerability assessments & specifications ............................ 181 
Table 8-10 
ECOG Performance Status .................................................................. 181 
Table 8-11 
Clinical laboratory parameters collection plan ................................... 183 
Table 8-12 
ECG timepoints for ruxolitinib + siremadlin (or siremadlin 
monotherapy) treatment ...................................................................... 184 
Table 8-13 
ECG timepoints for ruxolitinib single agent, ruxolitinib + 
crizanlizumab (or crizanlizumab monotherapy), ruxolitinib + 
sabatolimab (or sabatolimab monotherapy) ........................................ 185 
Table 8-14 
ECG timepoints for ruxolitinib + rineterkib treatment (or rineterkib 
monotherapy) ...................................................................................... 185 
Table 8-15 
ECG timepoints for ruxolitinib + NIS793 treatment (or NIS793 
monotherapy) ...................................................................................... 185 
Table 8-16 
PK blood collection log for siremadlin and ruxolitinib combination 
arm (Part 1, 2 and 3*) .......................................................................... 191 
Table 8-17 
PK blood collection log for crizanlizumab and IG in combination 
arm with ruxolitinib (Part 1, 2 and 3*) ................................................ 193 


Novartis 
Confidential 
Page 8 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Table 8-18 
PK blood collection log for sabatolimab, soluble TIM-3 and IG in 
combination arm with ruxolitinib (Part 1, 2 and 3*) ........................... 195 
Table 8-19 
PK blood collection log for ruxolitinib in combination arm with 
crizanlizumab (Part 1, 2 and 3*) ......................................................... 196 
Table 8-20 
PK blood collection log for ruxolitinib in combination arm with 
sabatolimab (Part 1, 2 and 3*)............................................................. 197 
Table 8-21 
PK blood collection log for ruxolitinib (single agent control arm) in 
Part 2 ONLY ....................................................................................... 198 
Table 8-22 
PK blood collection log for rineterkib and ruxolitinib combination 
arm (Part 1, 2 and 3*) .......................................................................... 198 
Table 8-23 
PK blood collection log for NIS793 and IG in combination arm 
with ruxolitinib (Part 1, 2 and 3*) ....................................................... 199 
Table 8-24 
PK blood collection log for ruxolitinib in combination arm with 
NIS793 (Part 1, 2 and 3*) ................................................................... 201 
 
 205 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 216 
Table 12-1 
Toxicity levels ..................................................................................... 223 
Table 12-2 
1st interim look (seamless expansion to Part 3) efficacy threshold ..... 224 
Table 12-3 
1st Interim look efficacy regions for a given sample size .................... 224 
Table 12-4 
Futility threshold ................................................................................. 225 
Table 12-5 
Futility regions for a given sample size .............................................. 225 
Table 12-6 
Non compartmental pharmacokinetic parameters ............................... 231 
Table 12-7 
Probability of any arm to meet 1st interim look criterion for n = 10 
and various true RRs ........................................................................... 237 
Table 12-8 
Probability of arm(s) to fulfill futility criterion for n = 25 and 
various true RRs .................................................................................. 238 
Table 12-9 
Probability for each possible trial outcome of a combination 
treatment with N combo=45 and N rux=30 ........................................ 239 
Table 12-10 
Probability for each possible trial outcome of a combination 
treatment with N combo=45 and N rux=35 ........................................ 239 
Table 12-11 
Probability for each possible trial outcome of a combination 
treatment with N combo=45 and N rux=40 ........................................ 240 
Table 12-12 
Probability that the difference in the posterior distributions of the 
RRs is larger than zero ........................................................................ 241 
Table 16-1 
List of medications to be used with caution during study drug 
treatment .............................................................................................. 251 
Table 16-2 
List of prohibited medications during study drug treatment ............... 252 
Table 16-3 
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single-agent model parameters ...................... 259 


Novartis 
Confidential 
Page 9 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Table 16-4 
Regimens and doses from study CHDM201X2101 ............................ 260 
Table 16-5 
Prior distribution for the siremadlin model parameters ...................... 260 
Table 16-6 
Summary of prior distribution of DLT rates for the combination of 
siremadlin and ruxolitinib ................................................................... 261 
Table 16-7 
Prior distributions for the parameters of the MAP model used to 
derive the prior for the rineterkib model parameters .......................... 261 
Table 16-8 
Historical DLT data from Study LTT462X2101 ................................ 262 
Table 16-9 
Prior distribution for the model parameters ........................................ 262 
Table 16-10 
Summary of prior distribution of DLT rates for the combination of 
rineterkib and ruxolitinib ..................................................................... 262 
Table 16-11 
Hypothetical dose escalation scenarios for a cohort size of n=6 
subjects receiving a dose of 20 mg siremadlin .................................... 263 
Table 16-12 
Hypothetical dose escalation scenarios for a cohort size of n=6 
subjects receiving a dose of 200 mg rineterkib ................................... 264 
Table 16-13 
Hypothetical true RR for each treatment arm ..................................... 264 
Table 16-14 
Probabilities for a list of operating characteristic parameters for 
hypothetical scenarios of the study ..................................................... 265 
 
List of figures 
Figure 3-1 
Overview of study design...................................................................... 66 
Figure 3-2 
Overview of study design at subject level in Part 1 .............................. 69 
Figure 3-3 
Overview of study design at subject level in Part 2 .............................. 71 
Figure 3-4 
Pre-specified criteria for decision making in Part 2 for expansion 
into Part 3 .............................................................................................. 72 
Figure 3-5 
Overview of study design at subject level in Part 3 (Not applicable) ... 74 
Figure 12-1 
Success criterion for primary endpoint. .............................................. 225 
Figure 16-1 
Logistic DLT model. ........................................................................... 257 
Figure 16-2 
Hypothetical example for Part 2 and Part 3 study design ................... 266 
 


Novartis 
Confidential 
Page 10 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
List of abbreviations 
Ab 
antibody 
ADR 
adverse drug reactions 
AE 
adverse event 
AF 
atrial fibrillation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count  
ASCO 
American Society of Clinical Oncology 
ASCT 
allogeneic hematopoietic stem cell transplantation 
ART 
antiretroviral therapy 
AST 
aspartate aminotransferase 
AUC 
Area under curve 
BID 
twice a day 
BLRM 
Bayesian logistic regression model 
BM 
bone marrow 
C1D1 
Cycle 1 Day 1 (and sequentially for other cycles and days, eg C1D2, C2D1 etc.) 
CFR 
Code of Federal Regulation 
COVID-19 
coronavirus disease 2019 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRS 
Cytokine Release Syndrome 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P-450 
DDI  
Drug-drug interaction 
DDS 
Dose-Determining Set 
DILI 
Drug-Induced Liver Injury 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DOACs 
Direct oral anticoagulants 
DUSP6 
Dual specificity phosphatase 6 
DVT 
Deep vein thrombosis 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOI 
End of infusion 
EORTC 
European Organization for Research and Treatment of Cancer  


Novartis 
Confidential 
Page 11 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
EOS 
End of study 
EOT 
End of treatment 
ePRO 
electronic patient reported outcome 
ERK 
Extracellular signal-regulated kinase 
ESA 
Erythropoiesis-stimulating agents 
ESMO 
European Society for Medical Oncology 
ET 
essential thrombocythemia 
EWOC 
escalation with overdose control 
FDA 
Food and Drug Administration 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GCP 
Good Clinical Practice 
GDF15 
Growth Differentiation Factor 15 
GLDH 
Glutamate Dehydrogenase 
GLP 
Good Laboratory Practice 
GGT 
gamma-glutamyl-transferase 
GvHD 
Graft versus Host Disease 
Hb 
hemoglobin 
HBV 
Hepatitis B 
HCV 
Hepatitis C 
HDM2 
Human Double Minute-2 
HEV 
Hepatitis E 
HIV 
human immunodeficiency virus 
HSC 
hematopoietic stem cell 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IG 
immunogenicity 
INR 
International normalized ratio 
irAE 
Immune-Related Adverse Events 
IRB 
Institutional Review Board 
IRR 
Infusion-related reactions 
IRT 
Interactive Response Technology 
IV 
Intravenous 
IWG-MRT 
International Working Group-Myeloproliferative Neoplasms Research and Treatment 
JAK 
Janus kinase 
LCM 
left costal margin 
LFT 
Liver function test 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
LMWH 
low molecular weight heparin 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MAP 
meta-analytic-predictive 
MAPK 
Mitogen-activated protein kinase 
MDS 
Myelodysplastic syndrome 


Novartis 
Confidential 
Page 12 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
MedDRA 
Medical dictionary for regulatory activities 
MEK 
Mitogen-activated protein kinase kinase 
MF 
myelofibrosis 
MFSAF 
Myelofibrosis Symptom Assessment Form 
MK 
megakaryocyte 
mPDAC 
Metastatic pancreatic ductal adenocarcinoma 
MPN 
myeloproliferative neoplasm 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NGS 
next generation sequencing 
NK 
Natural Killer 
NTproBNP 
N-terminal pro b-type natriuetic peptide 
OATP 
organic-anion-transporting polypeptide 
PD 
pharmacodynamic(s) 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PET-MF 
post-essential thrombocythemia myelofibrosis 
PFS 
progression free survival 
 
 
PK 
pharmacokinetic(s) 
PLT 
platelets 
PMF 
primary myelofibrosis 
PML 
progressive multifocal leuko-encephalopathy 
PO 
Oral 
PPV-MF 
post-polycythemia vera myelofibrosis 
PRBC 
packed red blood cells 
PRO 
patient reported outcome 
PSDS 
post-study drug supply 
PTA 
Post-Trial Access 
PtdSer 
phosphatidylserine 
PV 
polycythemia vera 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QD 
once a day 
QLQ-C30 
Quality of Life Questionnaire-Core 30 
QoL 
quality of life 
RBC 
red blood cell(s) 
REB 
Research Ethics Board 
RP2D 
recommended phase 2 dose 
RR 
Response rate 
R/R 
relapsed/refractory 
RVO 
retinal vein occlusion 


Novartis 
Confidential 
Page 13 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
SAE 
serious adverse event 
SAF 
symptom assessment form 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
Steering Committee 
SCD 
sickle cell disease 
sCR 
serum creatinine 
SD 
standard deviation 
SJS 
Stevens-Johnson syndrome 
SmPC 
Summary of Product Characteristics 
SOC 
Standard of care 
STAT 
signal transducer and activator of transcription 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEN 
toxic epidermal necrolysis 
TBC 
to be confirmed 
TBIL 
Total bilirubin 
TFQ 
Trial Feedback Questionnaire 
TGFβ 
transforming growth factor beta 
TIM-3 
T Cell Immunoglobulin Mucin 3 
TLS 
Tumor lysis syndrome 
TNF-α 
Tumor necrosis factor alpha 
TReg 
Regulatory T cells 
TSS 
total symptom score 
ULN 
upper limit of normal 
USA 
United States of America 
VOC 
vaso-occlusive crises 
WHO 
World Health Organization 
WOCBP 
Women of child-bearing potential 
YBX1 
Y-box binding protein 1 


Novartis 
Confidential 
Page 14 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Control drug 
A study drug used as a comparator to reduce assessment bias, preserve blinding 
of investigational drug, assess internal study validity, and/or evaluate comparative 
effects of the investigational drug. 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day) 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a study 
participant  
Investigational drug 
The study drug 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” or “investigational medicinal product”. 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the study as well as 
their associated treatment controls. This includes any placebos, any active controls, 
as well as approved drugs used outside of their indication/approved dosage or 
tested in a fixed combination. Investigational treatment generally does not include 
other treatments administered as concomitant background therapy required or 
allowed by the protocol when used within approved indication/dosage. 
Part 
A single component of a study which contains different objectives or populations 
within that single study. 
Patient 
An individual with the condition of interest 
Period 
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Randomization number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A subject who is screened but is not treated or randomized 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later. 
Study drug/treatment 
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy. 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date 
Subject 
An individual who has consented to participate in this study 
Subject number 
A number assigned to each subject who enrolls in the study. When combined with 
the center number, a unique identifier is created for each subject in the study. 
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples 
Withdrawal of consent from the study occurs when the participant explicitly requests 
to stop use of their data and biological samples (opposition to use data and 
biological samples) AND no longer wishes to receive study treatment, AND does 
not agree to further protocol required assessments. This request should be in 
writing (depending on local regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries where collection 
and processing of personal data is justified by a different legal reason than consent. 
 


Novartis 
Confidential 
Page 15 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 9 (05-Dec-2023)  
Amendment rationale 
The main purpose of this amendment is to increase the duration of the extension treatment phase 
for the remaining patients to a maximum of 21 cycles. The enrollment remains halted as per 
protocol amendment 08. 
Changes to the protocol 
The following changes are implemented: 
• Update to the study design to increase the duration of the extension phase from 12 cycles 
to 21 cycles. 
• Updates to the investigational treatments (Table 6-1). Only the investigational drug 
strengths intended to be used during the extension phase, with ongoing patients receiving 
treatment, will be submitted to Health Authorities (i.e. ruxolitinib, siremadlin, rineterkib) 
as applicable, unless otherwise required from a local regulatory compliance perspective in 
any participating country. Siremadlin 40 mg is not applicable as it will no longer be 
investigated due to enrollment halt, and there are no ongoing subjects receiving such drug 
strength. 
• Updates to the study assessment to reduce the burden for ongoing subjects. 
• Updates in protocol summary related to the amendment 09. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Figure 3-1 and Figure 3-2: Planned duration of extension treatment phase have been 
updated to reflect the addition of 9 cycles. 
• Section 4.1: The extension treatment phase has been updated to reflect the addition of 9 
cycles. 
• Section 6.1.5: The extension treatment phase has been updated to reflect the addition of 9 
cycles. 
• Section 6.6.1: The availability of a patient diary for oral treatment compliance has been 
removed. 
• Table 6-1: Investigational drugs has been updated to indicate that siremadlin (HDM201) 
40 mg is not applicable. 
• Table 8-2: The study assessments of coagulation, urinalysis, and thyroid function have 
been removed from Cycle 2 and subsequent cycles in the extension treatment phase to 
reduce the burden for ongoing subjects. 
• Section 9.2: Study completion has been updated to reflect the addition of 9 cycles of the 
extension treatment phase. 
• Section 10.1.2: Definition and recording of Hy's Law has been added to ensure 
compliance with FDA request for expedited reporting of potential Hy’s Law cases. 
• Section 12: Data analysis has been updated to reflect the addition of 9 cycles of the 
extension treatment phase. 


Novartis 
Confidential 
Page 16 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 17 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 8 (05-Oct-2022)  
Amendment rationale  
The main purpose of this amendment is to reflect the changes in study conduct which are a 
result of the permanent enrollment halt decision by Novartis. These changes include adding an 
extension treatment phase and reduction of study assessments to decrease subject’s burden in 
Part 1. 
At the time of this amendment: 
• 46 subjects have been enrolled in the study in Part 1 and Part 2 with the last patient first 
visit occurring on 15-Jun-2022.  
• As of the 05-Oct-2022, 4 subjects are ongoing in Part 1. Four subjects are receiving 
treatment in the ruxolitinib+siremadlin and ruxolitinib+rineterkib arms and all of them 
have completed at least six treatment cycles. 3 subjects are in the safety follow-up period 
(1 subject in the 30 days after last dose in the ruxolitinib+siremadlin arm and, 2 subjects in 
the 30 and 90 days after last dose in the ruxolitinib+NIS793 arm).  
• No subject is ongoing in Part 2, and Part 3 will not be initiated. 
• Recruitment of subjects has been halted since 17-Jun-2022.  
Due to the rapidly evolving competitive landscape in drug development for myelofibrosis, with 
multiple ongoing trials and continued challenges with recruitment, Novartis decided to 
discontinue the development program for INC424H1. Therefore the CINC424H12201 study 
recruitment was terminated. This decision was not triggered by any patient safety signals or 
measures. 
Novartis is committed to providing access to the investigational drug combination when a 
subject is benefitting from the treatment. Therefore, this amendment defines a core treatment 
phase and introduces an extension treatment phase in Part 1 to provide study treatment until the 
subject no longer derives clinical benefit, meets one of the defined discontinuation criteria or 
until subject completes extension treatment phase, whichever occurs first. 
In consideration of the enrollment halt, a number of preplanned study objectives will not be 
pursued. Following the communication of permanent enrollment halt, investigators were 
instructed to halt unnecessary study procedures, such as pharmacokinetics (PK) 
 
, to reduce the burden for ongoing subjects. This will be summarized in the clinical 
study report. 
Changes to the protocol 
The following changes are implemented:  
• Update to the study design to define the core treatment phase for Part 1 and introduce the 
extension treatment phase for Part 1 subjects (after completion of the core treatment phase). 
The extension treatment phase is not applicable for Parts 2 and 3 as no subject is ongoing 
in these parts at the time of this amendment. 
• Addition of inclusion and exclusion criteria for the extension treatment phase.  


Novartis 
Confidential 
Page 18 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Addition of objectives and endpoints, to evaluate safety and tolerability during the extension 
treatment phase (Table 2-1) and the corresponding visits and evaluations schedule  
(Table 8-1, Table 8-2).  
• Updates to the investigational treatments (Table 6-1). Only the investigational drugs 
intended to be used during the extension phase, with ongoing patients receiving treatment, 
will be submitted to Health Authorities (i.e. ruxolitinib, siremadlin, rineterkib) as 
applicable, unless otherwise required from a local regulatory compliance perspective in any 
participating country. 
• Updates to the definition and timing of the primary and final analyses.  
• Updates in protocol summary related to the amendment 08 and updates in the list of 
abbreviations. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Section 1.1.2.1: Updated information about ruxolitinib and GvHD.  
• Section 1.1.2.2: Updated information about siremadlin. 
• Section 1.1.2.5: Updated information about rineterkib in combination therapy.  
• Section 1.1.2.6: Updated information about NIS793 in combination therapy.  
• Section 1.2: Definition of Part 1 includes now a core and extension treatment phase. The 
purpose of the extension treatment phase was added. 
• Section 2: Objectives have been updated to reflect the enrollment halt and the addition of 
extension treatment phase 
• Section 3: The study design has been adapted to include an extension treatment phase. Part 
1 includes now as core and an extension treatment phase. Part 2 remains unchanged as the 
only randomized subject was discontinued. Part 3 is not applicable anymore. Study design 
figures have been updated. 
• Section 4.1: The core treatment phase end and the extension treatment phase have been 
described in this section 
• Section 4.2.6: This is a new section and it was added to describe the extension treatment 
phase. 
• Section 4.4: Information about the applicability of Part 2 and Part 3 was added. 
• Section 4.5: Enrollment halt rationale was added 
• Section 5: Information about the applicability of Part 2 and Part 3 was added. 
• Section 5.3: This is a new section included to describe the inclusion and exclusion criteria 
for the extension treatment phase. 
• Section 6.1.1: Information about the applicability of investigational drugs was added. 
Investigational Drug supply for core and extension treatment phase specified. 
• Section 6.1.3: The possibility for subjects in Part 1 to continue in an extension treatment 
phase was added. Information about the applicability of Part 2 and Part 3 was added.  
• Section 6.1.5: The maximum treatment duration of the core and extension treatment phase 
is defined in this section. Information about the applicability of Part 2 and Part 3 was 
added.  


Novartis 
Confidential 
Page 19 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 6.2.1.1: Applicability of the section specified for the extension treatment phase. 
• Section 6.2.1.1.2: Applicability of the section specified for the extension treatment phase. 
• Section 6.2.1.1.3: Applicability of the section specified for the extension treatment phase. 
• Section 6.2.2: The list of prohibited medication has been specified to the extension 
treatment phase as well. The information about fluconazole (prohibited medication) has 
been updated. Fendratinib added to the prohibited medications. 
• Section 6.2.2.1 Applicability of the section specified for the extension treatment phase. 
• Section 6.2.2.2 Applicability of the section specified for the extension treatment phase. 
• Section 6.2.2.3 Applicability of the section specified for the extension treatment phase. 
• 
 
• Section 6.5.4.1: Information about the applicability during the extension treatment phase 
was added. 
• Section 6.5.5: Confirmation that the guidelines apply to extension treatment phase as well.  
• Section 6.6: Information about the applicability during the extension treatment phase was 
added. 
• Section 6.6.1: The availability of a patient diary for oral treatment compliance has been 
added. 
• Section 7: Re-consent for patients entering the extension treatment phase has been added. 
• Section 8: Revisions to text and visit schedule tables have been made to this section to 
include the core and extension treatment phase. Addition of the recommendation on cycle 
length for subjects on siremadlin combination. Information about the applicability of Part 
2 and Part 3 was added. Allowable visit window table was updated. Appendix of  
Table 8-2 updated. 
• Section 8.3: Information about the applicability of Part 2 and Part 3 was added. 
• Section 8.3.2: Information on secondary endpoints added to Part 1 was added.  
• Section 8.3.2.1: This section if not applicable anymore. 
• Section 8.3.2.2: Assessment of spleen volume by MRI or CT scan when clinically 
indicated was added in the extension treatment phase. 
• Section 8.3.2.4 Progression Free Survival is not applicable anymore. 
• Section 8.3.2.5: This is a new section heading for disease progression. 
• Section 8.3.2.6 This section if not applicable anymore. 
• Section 8.3.3: Extension treatment phase efficacy assessment section was added. 
• Section 8.4.2: Applicability of ECG assessments for core and extension phases has been 
added in the section and tables. 
• Section 8.4.4: Cardiac imaging assessments for core and extension treatment have been 
added. 
• Section 8.5.1: The applicability of COAs during the extension treatment phase is added. 
Table 8-18 and Table 8-23  were updated. 


Novartis 
Confidential 
Page 20 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 8.5.2: The collection of PK samples has been halted for the ongoing patients in the 
core treatment phase. No PK sample collection will be done during the extension 
treatment phase. 
• Section 8.5.2.1: Applicability of sample collection is specified. 
• 
 
 
 
• Section 9.1.1: Criteria for the discontinuation of patients in the extension treatment phase 
have been added. 
• Section 9.2: Information about study completion has been updated. 
• Section 10.2.1: Information about the applicability of Part 2 and Part 3 was added. 
• Section 10.2.2: Information about the applicability of Part 2 and Part 3 was added. 
• Section 12: Updates to specify the applicability of Part 2 and Part 3 data analysis has been 
made. Updates to the timing and the data to be included for both the primary analysis and 
the final analysis respectively. 
• Section 12.4: Information about the applicability of Part 2 and Part 3 was added. 
• Section 12.5: Information about the applicability of Part 2 and Part 3 was added. 
• Section 12.5.1.2: Specified the core treatment phase and the extension treatment phase 
analyses for change in spleen size (length and volume). 
• Section 12.5.1.3 Information about the applicability of EORTC QLQ-C30 in Part 1, Part 2 
and Part 3 was added.  
• Section 12.5.2: Defined ”on-extension treatment period” and clarified the analysis for the 
core treatment phase and the extension treatment phase safety endpoints. 
• Section 12.5.3 Descriptive statistics paragraph has been updated. 
• Section 12.5.3.2 and Section 12.5.4: Information about the applicability of 
immunogenicity 
 endpoints was added. 
• 
 
• 
 
  
• Section 12.6.5 Information about the applicability during the extension treatment phase 
was added. 
• 
 
• Section 12.7: Information about the applicability of interim analysis was added. 
• Section 14.1: Impact of the enrollment halt on decision to reduce assessments is 
summarized. 
• Appendix 16.7 and Appendix 16.8: Updated applicability of scenarios for Part 2 and Part 
3. 


Novartis 
Confidential 
Page 21 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. As a result of the permanent enrollment halt, a number of preplanned study 
objectives from the core treatment phase (Parts 1, 2, and 3) could not be pursued and 
investigators were instructed not to perform some of the planned procedures to reduce the 
burden on ongoing subjects in Part 1 prior to amended protocol version 08 approval. The 
assessments not performed in the core treatment phase because of the enrollment halt prior to 
protocol amendment’s IRB/IEC approval will be documented for transparency in the clinical 
study report. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 22 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Local Protocol Amendment 7-US.01 (08-Apr-2022) 
Amendment rationale 
At the time of this amendment, 43 subjects have been enrolled in Part 1 of this study. 
The main purpose of this local amendment for USA is to include additional strengths of 
ruxolitinib tablets beyond the strength of 5 mg currently allowed per study protocol version 07.  
Considering that ruxolitinib will be supplied locally as commercially available for USA only, 
the purpose of this amendment is to allow the use of all available ruxolitinib strengths (per US 
FDA approved label) including 5 mg, 10 mg, 15 mg, 20 mg and 25 mg for US patients enrolling 
in the study.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
The following sections of the protocol have been changed: 
• Section 6.1.1 Investigational and control drugs: Table 6-1 Investigational drugs: clarified 
that provision of ruxolinitib 5mg strength will be global and local for USA only, and 
updated to add new strengths (10 mg, 15 mg, 20 mg and 25 mg) of ruxolitinib for USA. 
• Section 6.3.2 Treatment assignment, randomization: updated to clarify that no medication 
number will be provided for local supply of ruxolitinib in USA. 
• Section 6.7.1.1 Handling of study treatment: clarified that medication number is not 
applicable for the local supply of ruxolitinib in USA. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein do NOT affect the Informed Consent. 


Novartis 
Confidential 
Page 23 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 7 (11-Jan-2022) 
Amendment rationale  
At the time of the amendment, 38 subjects have received study treatment in this study in Part 1. 
The purpose of this global amendment is to:  
• Allow patients requiring packed red blood cell (PRBC) transfusions at any timepoint prior 
to first dose of study treatment to participate in all parts of the study (currently only eligible 
for Part 1 of the study). Nearly 40% of MF patients have hemoglobin (Hb) levels < 10 g/dL 
at diagnosis, and nearly one-quarter of MF patients at time of initial diagnosis already need 
red blood cell transfusions. The etiology of anemia in patients with myelofibrosis is 
multifactorial in origin, and the frequency with which patients who have myelofibrosis 
require PRBC transfusions varies. Restricting inclusion in Parts 2 and 3 (inclusion 
criteria#11) to Subjects who do not require packed red blood cells (PRBC) transfusion at 
screening and will not require any PRBC transfusions within 4 weeks prior to first dose of 
study treatment limits enrollment of patients who may require more frequent transfusions, 
and the timing of when transfusions are required may not be easy to predict. These patients 
would also potentially benefit from study treatment, and the current composite endpoint 
remains clinically relevant.  
Therefore, this inclusion criteria is being removed with this protocol amendment.  
This change is anticipated to primarily improve enrollment in Parts 2 and 3, and there is no 
impact on overall patient safety profile expected. The implementation of this change will 
allow a consistent patient population in Parts 2 and 3 as it is currently in Part 1. 
• 
Add details on the endpoints definitions to assess the following secondary objectives (i) 
changes in symptoms of myelofibrosis using MFSAF v4.0 scale and (ii) changes in spleen 
volume to include pre-defined threshold of improvement to make the secondary efficacy 
evaluation endpoints more transparent.  
• 
Add a new strength of rineterkib to allow additional doses of rineterkib to be tested if ever 
required. 
• 
Updated exclusion criteria #17 to provide a more comprehensive guidance on the time gap 
between administration of monoclonal antibody or immunoglobulin-based agent for 
NIS793, crizanlizumab or sabatolimab arms (within 1 year) and rineterkib or siremadlin 
arms (within ≤4 weeks of screening or ≤5 half-lives whichever is shorter). 
• 
 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol Summary has been updated with key changes. 
• Section 1.1.2.1: Ruxolitinib background updated with the fact that it is now also approved 
for chronic GvHD in the USA. 


Novartis 
Confidential 
Page 24 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 2: Endpoints definitions for two secondary efficacy objectives were clarified as 
outlined under rationale. 
• Section 3: Study design clarification of the condition to allow a subject to participate in 
more than one part of the study was added. 
• Section 4.1: Clarification of the condition to allow a subject to participate in more than one 
part of the study was added. 
• 
 
 
• Section 5: Inclusion and exclusion criteria were updated as follows:  
• To remove the inclusion 11 as outlined under rationale 
• To update the exclusion criteria 17 for respective compounds  
• To clarify that exclusion 25 restricts the use of platelet transfusion while PRBC is 
allowed. 
• Section 6.1.1: Updated Table 6-1 to add a new strength of rineterkib. 
• Section 6.2.1.1.2: Clarification that vaccination against COVID-19 is allowed unless these 
are attenuated vaccines but should not be administered on the day of the study treatment 
administration. 
• Section 6.2.2: Clarification that all live vaccines are prohibited for all treatment arms was 
added as it was outlined already in the Section 6.2.1.1.2. Clarification of the alternative 
names of Hydroxyurea (Hydrea and Hydroxycarbamide) added. 
• Section 6.2.2.2: Ruxolitinib single arm removed as it was listed by mistake. Monoclonal 
antibody is not a prohibited medication for ruxolitinib single agent. 
• Section 6.5.4:
 
 
 
 
 
• 
 
 
 
• Section 8: Table 8-3: the frequencies of the thyroid function and hepatitis test were updated 
to be consistent across all parts and all arms of the study. 
• Section 8.2: Rationale for the collection of race and ethnicity when allowed by local 
authorities was added. 
• Section 8.5.1: Clarification that TFQ is not considered study data and will be received 
electronically outside of the clinical database added.  
• 
 
 
• Section 10.1.3: Terminology around SAE reporting time updated to say that if more 
stringent, local regulations regarding reporting timelines prevail. 
• Section 12.5.1.2: Clarification added on the change in spleen length. 


Novartis 
Confidential 
Page 25 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 12.5.1.3: Clarification added on the change in symptoms assessed by MFSAF. 
• Section 15: Additional reference has been added. 
• In addition, clarifications and corrections were made throughout the protocol to improve 
consistency and understanding. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 26 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 6 (20-Jul-2021) 
Amendment rationale  
At the time of the amendment, 27 subjects have received study treatment in this study in Part 1. 
The purpose of this global amendment is to:  
• Update the eligibility criteria to reduce the time required for patients to be treated with 
ruxolitinib from “at least 24 weeks” to “at least 12 weeks” prior to first dose of study 
treatment, and also to reduce the time required for patients to be on a stable prescribed dose 
of ruxolitinib (no dose adjustments) prior to first dose of study treatment from “≥ 8 weeks” 
to “≥ 4 weeks”. While this change is anticipated to primarily improve patient’s enrolment, 
no impact on overall patient safety profile is expected. The implementation of this change 
at this stage of the study will allow a consistent patient population in the randomized Part2 
and Part3. 
• Provide more detailed guidance regarding dose modifications of siremadlin, rineterkib and 
NIS793 in case of toxicity including to allow patients to continue on study treatment at a 
reduced dose level for siremadlin or rineterkib or, at a reduced frequency for NIS793 if 
patients derive clinical benefits as per investigator’s judgement.  
• Additional precautionary measures have been implemented based on emerging new 
NIS793-related preclinical safety findings including update of exclusion criteria for 
impaired cardiac function, addition of cardiac imaging and cardiac enzymes safety 
assessments during treatment to enhance cardio-vascular mitigation as outlined in latest 
investigator brochure Edition 6. 
• Additional guidance on dose discontinuation for NIS793 in case of Drug-induced liver 
injury (DILI). 
• 
 
 
 
 
 
 
  
• Update the withdrawal of consent language as per the latest Novartis protocol template. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol Summary has been updated with key changes. 
• Study treatment LTT462 has been updated to rineterkib throughout the protocol including 
in Figure 3-1, Figure 3-2 and Figure 3-3.  
• Section 1.1.2.6: Section was updated to include new NIS793 preclincial safety findings of 
vascular inflammation, tubulo-interstitial nephritis observed in non-clinical toxicology 
studies and cardiac valvulopathy in pharmacology study.  


Novartis 
Confidential 
Page 27 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• 
 
• Section 3: Added the loading dose of crizanlizumab at C1D15 to the description of 
ruxolitinib +crizanlizumab arm in Part 1 and Part 2 for completeness. 
• Section 4.1: Updated to reduce the time required for patients to be treated with ruxolitinib 
to “at least 12 weeks” and a stable dose for “at least 4 weeks” prior to first dose of study 
treatment. 
• Section 4.3.4: Updated section to include preclinical evidence supporting the choice of 
Rineterkib as a treatment in patients with myelofibrosis for completeness.  
• Section 4.3.6: Removed the rationale and reference to collection of bone marrow aspirate 
for megakaryocyte characterization. 
• Section 4.5: Added rationale to monitor cardiac and renal functions for subjects receiving 
NIS793. 
• Section 5: Updated the patient population to be patients treated with ruxolitinib for “at least 
12 weeks” prior to first dose of study treatment, and for patients to be on a stable prescribed 
dose of ruxolitinib to “at least 4 weeks” prior to first dose of study treatment. 
• Section 5.1: Inclusion criteria #5 has been updated to reduce the number of weeks required 
for patients to be treated with ruxolitinib from “at least 24 weeks” to “at least 12 weeks” 
prior to first dose of study treatment. 
• Section 5.1: Inclusion criteria #6 has been updated to reduce the number of weeks required 
for patients to be on a stable prescribed dose of ruxolitinib (no dose adjustments) prior to 
first dose of study treatment from “≥ 8 weeks” to “≥ 4 weeks”.  
• Section 5.2: Exclusion Criteria #12 has been updated to further clarify cardiac exclusion 
criteria, including exclusion of patients who have had coronary stenting, or bypass surgery 
within 6 months. Additionally, for NIS793 arms in Part 1 and all arms in Parts 2 and 3 if 
NIS793 is open for enrollment, additional exclusion criteria have been added including 
Cardiac valvulopathy ≥ Grade 2, elevated cardiac enzymes (troponin I) elevation > x2 ULN, 
and medical history or current diagnosis of myocarditis. 
• Section 5.2: Exclusion Criteria #13 has been updated to include uncontrolled atrial flutter / 
fibrillation as part of significant cardiac arrhythmias.  
• Section 6.1.3: Added the loading dose of crizanlizumab at C1D15 to the description of 
ruxolitinib +crizanlizumab arm for completeness.  
• Section 6.1.5: Added wording that ongoing patients will continue to receive study treatment 
in all parts as long as they derive benefits from the treatment to align with the other protocol 
sections that were updated in protocol amendment 2. 
• Section 6.2.1: Reduced the requirement of prior ruxolitinib treatment to be recorded in the 
eCRF to “at least 12 weeks” prior to the first dose of study treatment, including the dosing 
information “up to 4 weeks” prior to study treatment.  
• Section 6.5.1.1: Reduced the stable dose of ruxolitinib prior to first dose of study treatment 
to 4 weeks and clarified that the dose of ruxolitinib could be modified due to toxicity as 
outlined in Section 6.5.4.  


Novartis 
Confidential 
Page 28 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• 
 
 
 
 
• Section 6.5.5.1: Updated the follow up for toxicity for siremadlin (Table 6-10) 
 
 
• Section 6.5.5.3: Table 6-11 and additional guidance on potential drug-induced liver injury 
(DILI) added. 
• Section 6.6: Additional guidance and clarification added for the management of TLS. 
• Section 8 Table 8.1: Visit windows for the different assessments and parts of the study were 
clarified. The window for cardiac imaging and ophthalmologic exams is -3 days for C1D1 
visit in Part 2 and 3 of the study and was increased to -7 days for the Day 1 visit of all 
subsequent cycles in all parts. 
• 
 
 
• Section 8: Updated assessment schedules in Tables 8-4 and 8-5 to reflect additional cardiac 
assessments for NIS793 arms, including ECG, cardiac imaging and cardiac enzyme 
assessments at baseline and during treatment cycles. Table 8-3 was also updated to include 
cardiac markers at screening for all treatment arms in Parts 2 and 3 if NIS793 is open for 
enrollment. 
• Section 8.2: Updated the prior ruxolitinib treatment to “≥ 12 weeks” and on a stable dose 
“≥ 4 weeks”. 
 
the collection of Troponin I and NTproBNP and 
Cardiac imaging at screening were added when applicable. 
• Section 8.4.2: Modified frequency of ECG monitoring as well as need for triplicate ECG at 
all timepoints for subjects receiving NIS793, and outlined in new table 8-15 added  
• Section 8.4.3: Added new section regarding cardiac enzyme monitoring for all arms 
containing NIS793. 
• Section 8.4.4: Updated cardiac imaging section to include assessments for patients receiving 
NIS793. 
• Section 8.5.2: Deleted “Note c” in Table 8-16 as it is no longer needed. 
• 
 
 
• Section 9.1.2: Updated Withdrawal of consent language per Novartis template to include 
the opposition to use of data/biological samples wording. 
• Section 10.1.3: Terminology around SAE reporting time updated to say immediately, 
without undue delay, under no circumstances later than within 24 hours. 
• 
 
 


Novartis 
Confidential 
Page 29 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 15: Additional reference has been added. 
• Section 16.6.1: Updated to patients must have been on ruxolitinib for “at least 12 weeks” 
and must have been on a stable dose for “at least 4 weeks”. 
• In addition, clarifications and corrections were made throughout the protocol to improve 
consistency and understanding. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 30 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 5 (23-Feb-2021) 
Amendment rationale  
At the time of the amendment, 20 subjects have received study treatment in this study in Part 1. 
The purpose of this global amendment is to: 
• Update the study design to allow 1) Part 2 (Selection) to be conducted for each combination 
treatment once the combination treatment is determined to be safe and tolerable in Part 1, 
and 2) to allow more than one combination treatment selected in Part 2 to enter Part 3 
(Expansion). 
• Add an interim analysis per combination treatment after at least 10 subjects completed 24 
weeks of study treatment in Part 2 to allow for a seamless transition into Part 3 if an efficacy 
threshold is reached. 
• Reduce the number of PK and PD samples collected, including removal of a few assessment 
visits in Part 2 and Part 3 of the study. 
• Include specific requirements for conducting the study in China, Japan and USA. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol Summary has been updated with key changes. 
• Section 3: Study design has been updated to allow Part 2 to be conducted in one or more 
groups that will consists of one or more combination treatments and a common ruxolitinib 
monotherapy arm and that combination treatments may enter Part 2 in a staggered manner. 
Part 3 has been updated to allow for more than one combination treatment to be expanded. 
The expected number of subjects in the study has been increased to approximately 240 if all 
5 combination treatments enter Part 2 and then only one combination treatment enters  
Part 3. If all 5 combination treatments are expanded in Part 3, then there will be a maximum 
of approximately 380 subjects in all 3 parts of the study. Figures 3-1, 3-3 and 3-4 have been 
updated, accordingly. Two interim analyses are now planned for each treatment 
combination arm in Part 2. 
• Section 4.1: Added two interim analyses per combination treatment in Part 2; and clarified 
that subjects are not allowed to participate again within the same part of the study, however 
subjects can participate in other parts of the study provided that all inclusion criteria and 
none of the exclusion criteria are met. 
• Section 4.3.4: Additional rationale for the LTT462 and ruxolitinib combination and 
corresponding references have been added. 
• Section 4.4: A second interim analysis for each combination treatment has been added in 
Part 2. 
• Section 4.5: The sentence on TLS was updated with the current information that one grade 
4 TLS was observed in subjects administered siremadlin in study CHDM201X2101. Japan-
specific requirements for hospitalization has been added for ruxolitinib + crizanlizumab 
treatment in Part 1 Arm 2 of the study.  


Novartis 
Confidential 
Page 31 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 4.6: Rationale for public health emergency mitigation procedures has been added. 
• Section 5: Added wording to state that assuming all five combination treatments enter Part 2 
and one combination treatment is expanded in Part 3, a total of approximately 240 subjects 
are expected to be enrolled in all three parts of the study, and up to approximately 380 if all 
5 combination treatments enter Part 3. 
• Section 5.1: Inclusion criteria #1 has been updated to add Japan-specific requirements for 
written consent for subject under the age of 20 years. 
• Section 5.2: Exclusion criteria #23 has been updated to reduce the duration between the use 
of erythropoietin stimulating agents (ESA) and the first dose of study treatment from  
3 months to 4 weeks. 
• Section 6.1: Added statement in the text and in Table 6-1 that ruxolitinib in USA will be 
supplied locally as commercially available either by Novartis of the site pharmacy. 
• Section 6.1.3: Description of the groups for Part 2 of the study has been added and the 
number of patients in each treatment arm has been updated accordingly, and to remove 
reference to any randomization ratio. The same was done for part 3 of the study. 
• Section 6.2.2.4: Ruxolitinib + LTT462 was removed from one of the titles as it was not 
applicable.  
• Section 6.3.1: Clarified that subjects will receive a new subject ID if they participate in 
another part of the study. 
• Section 6.3.2: Treatment assignment has been updated to state that Part 2 will be conducted 
in groups based on the update to the study design; to remove reference to any randomization 
ratio; that medication numbers will not be provided for the local supply of ruxolitinib in 
USA; to add randomization numbers in place of a randomization list; and that details of the 
randomization requirements will be documented in randomization requirement 
specification document. 
• Section 6.5.2: Added a statement that for Japan only, further subjects can be added after the 
RP2D has been determined to further characterize safety.  
• 
 
• Section 6.6: Updated the additional treatment guidance for Tumor Lysis Syndrome with the 
latest available information. 
• Section 6.7: Added wording that medication numbers will not be provided for the local 
supply of ruxolitinib in USA. Also added a statement that during a public health emergency 
declared by local or regional authorities, delivery of the study treatment directly to a 
subject’s home may be permitted. In such cases regular phone calls or virtual contacts with 
the subject will also be required.  
• Section 6.7.2: Added wording that the assignment of study medication kits by IRT is not 
applicable for the local supply of ruxolitinib in USA. 
• Section 6.7.2.2: Clarification added for the administration of siremadlin in a fasted state. 
• Section 7: Statement added that during a public health emergency declared by local or 
regional authorities, informed consent may be collected remotely as per local guidance. 
• Section 8: Japan-specific requirements for hospitalization has been added for ruxolitinib + 
crizanlizumab treatment in Part 1 Arm 2 of the study. Statement also added that during a 


Novartis 
Confidential 
Page 32 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
public health emergency declared by local or regional authorities, if allowed by local Health 
Authority and depending on operational capabilities, phone calls, virtual contacts (e.g. tele 
consult) or visits by site staff/ home nursing staff to the participant´s home, can replace on-
site study visits, for the duration of the disruption until it is safe for the participant to visit 
the site again. 
• Section 8: Table 8-1 has been updated to clarify that during the C1D1 visit, the IRT 
dispensation transaction, the MUGA and the ophthalmologic exam can be performed up to 
3 days prior to the first dose. Table 8-2, Table 8-3, Table 8-4 and Table 8-5 have been 
updated to align with the updated protocol sections. 
  
 
 
• Section 8.3.2.2 and Section 8.3.2.4: Appearance of a new splenomegaly that is palpable at 
least 5cm below the LCM has been added as one of the criteria for progressive spleen size 
requiring a new MRI/CT scan to confirm spleen size progression. 
• Section 8.3.2.5: Footnote added to Table 8-7 that bone marrow aspirates collected within  
8 weeks of C1D1 for re-screened subjects are acceptable. 
• Section 8.4: Statement added that during a public health emergency declared by local or 
regional authorities that limits or prevents on-site study visits, regular phone or virtual calls 
can occur for safety monitoring and discussion of the participant´s health status until it is 
safe for the subject to visit the site again. 
• Section 8.4.1: Free T3 has been removed from Table 8-11 as a thyroid function parameter 
to be analyzed. 
• Section 8.4.5: Added statement that if subjects cannot visit the site to have serum pregnancy 
tests, urine pregnancy test kits may be used. A communication process should be established 
with the subject so that the site is informed and can verify the pregnancy test results as per 
country specific requirements. 
• 
 
 
 
 
• Section 8.5.1: Added statement that during a public health emergency as declared by local 
or regional authorities that limits or prevents on-site study visits, PROs may be collected 
remotely depending on local regulations, technical capabilities, and following any 
applicable training in the required process. 
• Section 8.5.2: Added statement that during a public health emergency as declared by local 
or regional authorities that limits or prevents on-site study visits, changes in PK assessments 
can be listed as one of the risk mitigation procedures. 
• Section 8.5.2: Updated the collection of IG samples, where applicable, to be limited to only 
the first 10 subjects in Arm 1 (the combination treatment arm) in Part 3. 
• Section 8.5.2: Table 8-15, Table 8-18, Table 8-20 and Table 8-21 have been updated to 
decrease the number of PK and IG samples collected during Part 2 and Part 3 of the study. 


Novartis 
Confidential 
Page 33 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 8.5.2: Some of the dose reference IDs in Table 8-15, Table 8-21 and Table 8-22 
have been updated. 
• Section 8.5.2: Table 8-15, Table 8-18, Table 8-19, Table 8-21 and Table 8-22 have been 
updated to add a new “Part” column to clarify which Part of the study the PK and IG samples 
are collected. 
• Section 8.5.2: The footnotes in Table 8-16 and Table 8-17 have been updated to limit the 
collection of IG samples to the first 10 enrolled subjects in Part 3, similar to the PK 
collection. 
• Section 8.5.2: Table 8-22 has been updated to collect PK and IG samples for the Day 30 
and Day 90 Safety Follow-up visits for subjects on treatment arms containing NIS793. 
• Section 8.5.2.1: Clarified that additional PD samples will not be collected at the 90-day 
safety follow up visit from subjects treated with sabatolimab, or at the 105-day safety follow 
up visit from subjects treated with crizanlizumab; and added statement that additional PK, 
PD and IG samples will be collected at the 30-day and 90-day safety follow up visits for 
subjects treated with NIS793. 
• Section 8.5.2.2: Corrected the LLOQ for the sabatolimab analytical assay to 5.0 µg/mL. 
• Section 8.5.3: Added statement that during a public health emergency as declared by local 
or regional authorities that limits or prevents on-site study visits, 
 
 can be listed as one of the risk mitigation procedures. 
• 
 
 
 
 
 
• 
 
 
• Section 9.2: Clarification added that for NIS793 treatment arm, PK, PD and IG samples will 
be collected at the 30-day and 90-day Safety Follow-up visits. 
• Section 10.1.2: Add the word new in reference to “all new malignant neoplasms” in the 3rd 
last paragraph. 
• Section 10.1.4: Updated as per latest protocol guidance. 
• Section 12: Added a statement that subjects from the common ruxolitinib monotherapy 
control arm will be pooled and analyzed jointly; updated the description of the interim 
analyses to include two interim analyses per combination treatment and that an additional 
interim analysis for Part 2 will be conducted when at least 10 subjects in the combination 
treatment arms completed 8 cycles (arms with NIS793) or 6 cycles (all other arms) of 
treatment; and added a statement that the second interim analysis is not required if a 
combination treatment is advanced in Part 3 based on the first interim analysis.  
• Section 12.1.3: Added a statement that subjects enrolled in Japan after the dose 
determination for a combination treatment will not be included in the DDS. 
• Section 12.4.2.2: Added and explained the efficacy threshold for the first interim analysis. 


Novartis 
Confidential 
Page 34 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 12.5.1.2: Added secondary analysis for the proportion of subjects achieving at least 
25% and 35% reduction in spleen volume from baseline. 
• Section 12.7: Described the two interim analyses for Part 2 and the primary analysis for  
Part 3. 
• Section 12.8.1.2: Added the sample size calculation with operating characteristics for 
supporting the 1st interim analysis in Part 2. 
• Section 12.8.1.3: Updated the probability for possible trial outcome tables in Part 3 for 
supporting the trial sample size calculation. 
• Section 15: Additional references have been added. 
• Section 16.7: Added an appendix with simulation for hypothetical study scenarios in Part 2 
and Part 3. 
• Section 16.8: Added an appendix with a hypothetical example to illustrate enrollment, 
interim analyses and expansion decision rules for the randomization parts (Parts 2 and 3) of 
the study design. 
• In addition, clarifications and corrections were made throughout the protocol to improve 
consistency and understanding. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 35 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 4 (25-Aug-2020)  
Amendment rationale  
At the time of the amendment, 13 subjects have received study treatment in this study in Part 1. 
The purpose of this global amendment is to: 
• Add two novel compounds to Part 1 of the protocol: LTT462, which is a potent, selective, 
inhibitor of extracellular signal-regulated kinase 1 (ERK1) and extracellular signal-
regulated kinase 2 (ERK2), and NIS793, which is an anti-transforming growth factor 
beta (anti-TGFβ) monoclonal antibody (mAb). 
• Add the additional cycles throughout the protocol, where applicable, for NIS793 since the 
dosing regimen of NIS793 is once every 3 weeks (Q3W) in comparison to all other treatment 
combinations, which are 28-day cycles. A separate visit assessment schedule for study 
treatment arms with NIS793 has been added for clarity. 
• Increase the number of subjects required for Part 2 from 15 subjects per arm to 25 subjects 
per arm to ensure the acceptable futility probability for applying the futility rule in multiple 
arms. The overall number of subjects in the study increases from approximately 130 to 
approximately 240 in total due to the additional arms for the 2 new compounds in Parts 1 
and 2 and the increased number of subjects required per arm for Part 2. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol Summary has been updated with key changes. 
• Section 1: Added background information on LTT462 and NIS793.  
• Section 2: Updated the primary endpoint for Parts 2 and 3 to clarify that the response rate 
(RR) is evaluated at the end of 6 cycles or 8 cycles in order to cater for the different cycles 
lengths with the addition of ruxolitinib + NIS793. The secondary objectives have also been 
updated for the addition of LTT462 and NIS793. 
• Section 3: Added the new combination arms with LTT462 and NIS793, Figure 3-1,  
Figure 3-2, Figure 3-3 and Figure 3-5 have been updated accordingly. Total number of 
subjects expected to be enrolled in the study updated to take into account the new treatment 
arms and the number of subjects in Part 2. 
• Section 4.1: Study rationale updated with LTT462 and NIS793.  
• Section 4.2.1: Added ruxolitinib is also metabolized by CYP2C9.  
• 
  
• 
 
• 
 
 
• 
 
. 
• 
 


Novartis 
Confidential 
Page 36 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 4.5: Added risks and benefits associated with the addition of LTT462 and NIS793, 
including an update to the guidance for immune-related events in subjects treated with 
immunomodulatory therapies such as NIS793 and sabatolimab, and careful monitoring for 
the possibility of cardiac events and ophthalmological toxicities with LTT462. 
• Section 4.5: Added information and guidance for infusion-related reactions (IRRs), 
particularly for the potential of IRRs such as pain events associated with administration of 
crizanlizumab in sickle-cell disease (SCD) patients. 
• Section 4.5: Added a statement that no substantial additional risk for subject safety due to 
the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the coronavirus 
disease 2019 (COVID-19) pandemic has been identified at this time and therefore the 
benefit risk remains unchanged. 
• Section 5: Updated the inclusionary Hb value (now < 11 g/dL (≤ 6.8 mmol/L)) and increased 
the total number patients to be enrolled (approximately 240). 
• Section 5.1: Inclusion criteria #7 has been updated to increase the hemoglobin level for 
study eligibility to < 11 g/dL (≤ 6.8 mmol/L).  
• Section 5.2: Exclusion criteria #3 has been updated to remove the reference to any studies 
as this exlusion criteria refers to cancer vaccine and immunotherapy treatment within  
6 months of starting study treatment. 
• Section 5.2: Updated the definition of severely impaired renal function for exclusion criteria 
#6 to remove reference to serum creatinine.  
• Section 5.2: Exclusion criteria #8 has been updated to clarify that immunodeficiency 
syndromes are exclusionary if in the opinion of the investigator they are clinically 
significant.  
• Section 5.2: Exclusion criteria #12 has been updated with more details related to 
uncontrolled congestive heart failure. 
• Section 5.2: Exclusion criteria #13 has been updated to clarify that subjects with risk factors 
for Torsades de Pointe including uncorrected hypokalemia or hypomagnesemia, history of 
cardiac failure, or history of clinically significant/symptomatic bradycardia or for whom 
there is an inability to determine the QTcF interval are also excluded from the study. 
• Section 5.2: Exclusion criteria #20 has been updated for the safety follow up periods of 
treatments with LTT462 and NIS793. 
• Section 5.2: Exclusion criteria #21 has been updated to include male subjects who are 
receiving LTT462. 
• Section 5.2: Exclusion criteria #31 has been updated to allow the use of anticoagulant and 
anti-platelet therapy but exclude subjects with any clinically significant bleeding events 
within 6 months.  
• Section 5.2: Exclusion criteria #32 has been added to exclude subjects with pre-existing 
retinal vein occlusion (RVO) or current risk factors (apart from the underlying MF) for 
RVO. 
• Section 6.1: Added LTT462 and NIS793 as investigational drugs, and as part of the 
combination treatment. 


Novartis 
Confidential 
Page 37 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 6.1.1: Updated Table 6-1 to add the packaging description of the new investigational 
drugs: LTT462 and NIS793. 
• Section 6.1.2: Consideration for pre medication for subjects receiving crizanlizumab has 
been added. 
• Section 6.1.3: Added LTT462 and NIS793 treatment arms. 
• Section 6.1.5: Clarified the duration of treatment in cycles rather than weeks, which is 
dependent on the treatment arm since NIS793 has 21-day cycles, and all other arms have 
28-day cycles. 
• Section 6.2.1.1: Added any other anti-coagulant, and anti-platelet (including aspirin ≤ 150 
mg/day) drugs to the list of permitted medications that have restrictions. 
• Section 6.2.1.1.2: Added ruxolitinib + NIS793 to the list of permitted concomitant therapy 
requiring caution and/or action. 
• Section 6.2.1.1.3: Added the list of permitted concomitant therapy requiring caution and/or 
action specific to combination arm ruxolitinib + LTT462. 
• Section 6.2.2: References to LTT462 and NIS793 added, as appropriate. Drugs that interfere 
with coagulation or inhibit platelets function removed from the list of prohibited 
medications for all arms of the study except for aspirin > 150 mg/day. 
• Section 6.2.2.1: Added strong inducers of CYP3A4/5 are prohibited within 14 days prior to 
starting and at any time during the study treatment period for all arms of treatment since 
ruxolitinib, siremadlin and LTT462 are CYP3A4 substrate (moved from Section 6.2.2.2). 
• Section 6.2.2.2: Added ruxolitinib + NIS793 to the list of prohibited medications. Removed 
strong inducers of CYP3A4/5 to Section 6.2.2.1 (as noted above). 
• Section 6.2.2.3: Added the prohibited medications specific to combination arm ruxolitinib 
+ LTT462. 
• Section 6.3: Updated the subject numbering and treatment assignment for LTT462 and 
NIS793. 
• Section 6.5.1: Added the rationale for the dose chosen for LTT462 and NIS793. Table 6-3 
has been added to define the provisional dose levels for LTT462. 
• Section 6.5.2: Added LTT462 and NIS793 to the guidelines for dose escalation and 
determination of RP2D. 
• Section 6.5.3: Added LTT462 and NIS793. Table 6-4 updated with DLT criteria specific to 
LTT462 and NIS793. 
• 
 
 
 
• Section 6.5.5: Added LTT462 and NIS793 to the follow-up for toxicities, including 
guidance for immune-related AEs (irAEs) for NIS793. 
• Section 6.7.2.5: Added the description of the mode of administration of LTT462. 
• Section 6.7.2.6: Added the description of the mode of administration of NIS793. 
• Section 8: Tables 8-2 and 8-3 have been updated to align with the updated protocol sections. 
There are now applicable only for arms with 28-day cycles. 


Novartis 
Confidential 
Page 38 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 8: Table 8-4 and 8-5 have been added to present the assessment schedules for 
Ruxolitinib + NIS793 arm for Part 1 and Part 2 and 3, respectively. 
• Section 8.2: Added ECOG and ECG to the list of screening assessments required, as well 
as clarified the PROs and bone marrow aspirate and biopsy samples required at screening. 
• Section 8.3.1.2: Clarified that the MRI/CT scans required for the primary efficacy endpoint 
of change in spleen volume are the screening (baseline) and the cycle 8 (NIS793 arms) or 
cycle 6 (all other arms) timepoints. Table 8-6 moved to Section 8.3.2.2.  
• Section 8.3.2.2: Added the various MRI/CT scan timepoints required for the secondary 
efficacy endpoint of change in spleen volume, including Table 8-6 (as noted above). 
• Section 8.4.2: Table 8-14 added to list the ECG timepoints for ruxolitinib + LTT462 
treatment arm  
• Section 8.4.3 added to describe cardiac imaging 
• Section 8.4.4 added to describe ophthalmologic assessment 
• Section 8.5.2: Table 8-21 added to define the PK blood collection timepoints for LTT462 
in combination with ruxolitinib. 
• Section 8.5.2: Table 8-22 and 8-23 have been added to define the PK and IG blood collection 
timepoints for NIS793 in combination with ruxolitinib. 
• Section 8.5.2.1: Added the PK, 
 and IG blood sampling required for LTT462 and 
NIS793. 
• Section 8.5.2.2: Added bioanalytical methods for the analysis of serum concentrations of 
NIS793 and anti-NIS793 antibodies. 
• 
 
 
 
• Sections 9 and 10: Safety follow-up periods for LTT462 and NIS793 treatment combination 
arms added. 
• Section 12.1.3: Minimum exposure required definition clarified for each treatment arm. 
• Section 12.1.4: Added LTT462 to the evaluable profile for the Pharmacokinetic Analysis 
Set (PAS). 
• Section 12.4.3: Added clarification of evaluation of primary endpoint for subjects who 
withdraw from study treatment before assessments at the end of Cycle 8 (NIS793 arms) or 
Cycle 6 (all the other arms). 
• 
 
• Section 12.7: Added LTT462 to the bayesian logistic regression model (BLRM) for dose 
decisions and escalations. 
• Section 12.8: Updated with the new sample size of 25 subjects (instead of 15) in Part 2 
including Table 12-5, Table 12-6 and Table 12-7. 
• Section 15: Added references for LTT462 and NIS793.  
• Appendices 1 and 2 updated for LTT462 and NIS793. 


Novartis 
Confidential 
Page 39 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Updates were made throughout the protocol to clarify the timepoints for the different 
treatment arms since ruxolitinib + NIS793 is administered in 21-day cycles, whereas the 
other treatment combinations of ruxolitinib + siremadlin, ruxolitinib + crizanlizumab, 
ruxolitinib + sabatolimab and ruxolitinib + LTT462 are administered in 28-day cycles. 
• MBG453 has been updated to sabatolimab throughout the protocol. 
• In addition, clarifications and corrections were made throughout the protocol to improve 
consistency and understanding. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 40 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 3 (28-Apr-2020)  
Amendment rationale  
At the time of the amendment, 7 subjects have received study treatment in this study in Part 1 
and none of them have been treated with sabatolimab. 
The purpose of this global amendment is to implement updates following requests from Health 
Authorities: 
• Update Exclusion Criteria #8 to exclude any patients with known history of HIV as an 
overall positive benefit risk ratio to include HIV patients with the various novel combination 
treatments cannot be determined at this stage. In addition, antiretroviral therapy (ART) 
regimen including strong CYP3A4 inhibitors may lead to the potential drug-drug interaction 
of one or more study medications. 
• Extend the restrictions on the use of live vaccines until the end of the follow-up period after 
the last dose of crizanlizumab and sabatolimab, which is within 5 half-lives of the study 
treatment.  
• Guidance has been added on the criteria for sabatolimab dose management for 
dermatological adverse drug reactions (ADRs) and non-immune related toxicities to align 
with the sabatolimab (MBG453) Investigator’s Brochure. 
• Guidance has been added that subjects should be monitored carefully for any skin toxicity 
or mucositis, and that study treatment should be discontinued for any suspected case of 
Stevens-Johnson syndrome (SJS), or Lyell syndrome/toxic epidermal necrolysis (TEN) to 
align with the sabatolimab (MBG453) Investigator’s Brochure. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Section 5.2: Exclusion Criteria #8 was updated to exclude any subjects with known history 
of HIV. 
• Section 6.2.2.2: The restriction of the use of live vaccines has been extended to 105 days 
after the last dose of crizanlizumab and to 150 days after the last dose of sabatolimab.  
• 
 
 
 
• Section 6.5.5: Guidance has been added for subjects on sabatolimab that subjects should be 
monitored carefully for any skin toxicity or mucositis, and that study treatment should be 
discontinued for any suspected SJS/TEN. 
• In addition, corrections have been made throughout the protocol for any typographical 
errors. 


Novartis 
Confidential 
Page 41 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 42 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 2 (17-Feb-2020)  
Amendment rationale  
At the time of the amendment, 3 subjects have received study treatment in this study in Part 1. 
The purpose of the amendment is to: 
• Clarify the definition of accelerated phase for progression free survival (PFS) as there was 
a discrepancy between Section 2 (Table 2-1) and Section 8.3.2.4. 
• Clarify that subjects who previously participated in the CINC424H12201 study can 
participate in a subsequent part of the study. 
• Remove the exclusion of subjects who have been treated with hematopoietic colony-
stimulating growth factors (CSFs) to align with Section 6.2.1.1, where it states that 
granulocyte growth factors are permitted concomitant therapy requiring caution and/or 
action. 
• Exclude any subjects that have used live vaccines within 30 days of starting any study 
treatment, and to add live vaccines as prohibited medication for study treatment arms 
containing crizanlizumab or sabatolimab. This is added considering the safety profile of 
crizanlizumab and sabatolimab, both of which have immunoregulatory functions. 
• Exclude any subjects that have used systemic steroid therapy and other immunosuppressive 
drugs (> 10 mg/day prednisone or equivalent) within 14 days prior to first dose of study 
treatment (Topical, inhaled, nasal, and ophthalmic steroids are allowed. Replacement 
therapy, steroids given in the context of a transfusion are allowed and not considered a form 
of systemic treatment). The use of systemic steroid therapy was also added as prohibited 
medication except for treatment of infusion reaction, treatment of immune-related AEs 
(irAEs), prophylaxis against imaging contrast dye allergy, replacement-dose steroids in the 
setting of adrenal insufficiency (providing this is ≤ 10 mg/day prednisone or equivalent) or 
treatment of transient exacerbation of other underlying diseases such as chronic obstructive 
pulmonary disease requiring treatment for ≤ 3 weeks. This is added considering the safety 
profile of sabatolimab as a checkpoint inhibitor.  
• Exclude any subjects that have used anticoagulation or antiplatelet therapy within 10 days 
of prior to first dose of study treatment, as well as any subjects that have had any bleeding 
events within 6 months prior to first dose of study treatment. This aligns with the prohibited 
concomitant medications in Section 6.2.2. 
• Update the prohibition of anticoagulation therapy to allow the use of low molecular weight 
heparin (LMWH) or Direct Oral Anti-coagulants (DOACs) if used at sub-therapeutic doses, 
to prevent deep vein thrombosis (DVT) or atrial fibrillation (AF). 
• Add erythropoietin stimulating agents (ESAs) as prohibited medication to align with 
exclusion criteria #23, since ESAs could improve anemia and interfere with the study 
endpoints.  
• Add a new fill volume vial of sabatolimab that will be used in the study. 
• Update the dose modification table’s specific to the novel agents to remove any reference 
to ruxolitinib, as the dose modification of ruxolitinib will be guided by the Summary of 
Product Characteristics (SmPC) for ruxolitinib. 


Novartis 
Confidential 
Page 43 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Allow subjects in Part 1 to continue on study treatment after the planned 6 cycles if, in the 
opinion of the Investigator, the subject is still deriving clinical benefit. 
• Define an ‘overall safety period’ that is from the date of first administration of study 
treatment to 30 days after the date of the last administration of ruxolitinib or siremadlin, or 
105 days after the date of the last administration of crizanlizumab, or 150 days after the date 
of the last actual administration of sabatolimab, whichever is later. This is for reporting the 
safety data within the long safety follow-up period. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol Summary has been updated with key changes. 
• Section 1.1.2: Added the trade names for ruxolitinib (Jakavi) and crizanlizumab (Adakveo), 
and that Adakveo was recently approved in the USA to reduce the frequency of vaso-
occlusive crises (VOCs), or pain crises, in adult and pediatric patients aged 16 years and 
older with sickle cell disease (SCD). 
• Section 3: The paragraph on Post-Trial Access (PTA) to study treatment has been deleted 
as it is already outlined in Section 6.1.5; Footnotes have been added to Figure 3-1 and  
Figure 3-3 clarifying the number of treatment arms and total subjects in Part 2. 
• Section 5: Statement that subjects who were enrolled in one part of the study cannot 
participate in another part of the study has been removed 
• Section 5.1: Inclusion criteria #7 has been updated to add the equivalent mmol/L units for 
hemoglobin < 10 g/dL, which is ≤ 6.2 mmol/L. 
• Section 5.2: Exclusion criteria #3 has been updated to clarify that subjects who previously 
participated in the protocol are not excluded from participating again in a further part of the 
study. 
• Section 5.2: Exclusion criteria #5 has been updated to add the levels of total bilirubin that 
are exlcusionary. 
• Section 5.2: Exclusion criteria #6 has been updated with conditions on the estimated 
creatinine clearance. 
• Section 5.2: Exclusion criteria #8 has been updated to change known ‘confirmed diagnosis’ 
to known ‘history’ and to clarify that subjects with known HIV infection are excluded only 
if the infection is not controlled by standard therapy, or have known history of opportunistic 
infection within the past 12 months, or are receiving an antiretroviral therapy (ART) 
regimen including strong CYP3A4 inhibitors. 
• Section 5.2: Exclusion criteria #23 has been updated to delete the exclusion of subjects that 
have used G-CSFs. 
• Section 5.2: Exclusion criteria #29 has been added to exclude any subjects who have used 
live vaccines within 30 days of starting study treatment. 
• Section 5.2: Exclusion criteria #30 has been added to exclude any subjects who use systemic 
steroid therapy and other immunosuppressive drugs within 14 days prior to first dose of 
study treatment (> 10 mg/day prednisone or equivalent), noting that topical, inhaled, nasal, 


Novartis 
Confidential 
Page 44 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
and ophthalmic steroids are allowed, and that replacement therapy, steroids given in the 
context of a transfusion are allowed and not considered a form of systemic treatment. 
• Section 5.2: Exclusion criteria #31 has been added to exclude any subjects who use 
anticoagulation (prophylactic doses permitted) or antiplatelet therapy (other than aspirin) 
within 10 days of starting study treatment, or any bleeding events within 6 months prior to 
first dose of study treatment. 
• Section 6.1.1: Updated Table 6-1 to add a new formulation of sabatolimab. 
• Section 6.1.5: Post-Trial Access (PTA) wording has been updated in accordance with the 
latest guidelines. 
• Section 6.2.1.1: The condition pertaining to G-CSF not being allowed while study 
medication is being administered has been deleted. 
• Section 6.2.2: Use of systemic steroid therapy and other immunosuppressive drugs within 
14 days prior starting treatment and at any time during the study treatment was added to the 
list of prohibited medications; The prohibition of anticoagulation therapy was updated to 
allow the use of LMWH or DOACs if used at sub-therapeutic doses; Restrictions on the use 
of live vaccines after starting treatment were added for certain treatment arms. 
• Section 6.5.4: Instructions added for the occurrence of potentially overlapping toxicity or if 
it cannot be distinguished which of the study drugs within the combination treatment is 
suspected to be related to an adverse event; Table 6-4,
 
• Section 8: Wording has been added to state that the planned duration of Part 1 is 6 cycles of 
study treatment. 
• Section 8: Table 8-1 has been updated to clarify that only C1D1 does not have a visit 
window for assessments and administration of study drugs, and that all D1 visits of 
subsequent cycles have a ± 3-day window; Table 8-2 and Table 8-3 have been updated to 
align with the updated protocol sections.  
• Section 8.2: The screening assessments have been updated to remove the assessment of 
serology and cytokines (moved to Cycle 1 Day 1) as these two analyses are dependent on 
the combination treatment arm. 
• Section 8.3.1.2: Reference to measuring spleen volume by the least squares method has been 
deleted. 
• Section 8.3.2.4: Corrected the definition of accelerated phase for PFS to align with the 
definition in Section 2 (Objectives and endpoints). 
• Section 8.4.1: Table 8-9 has been updated to clarify that: Bands will no longer be collected 
as part of the white blood cell differential. Direct Bilirubin will now only be collected if 
Total Bilirubin is ≥ Grade 2; Indirect Bilirubin will now only be collected if Total Bilirubin 
is out of range; and the urinalysis microscopic panel will be required only if clinically 
indicated based on the results of the macroscopic panel analysis. A note was added to clarify 
that serology is only required for patients in treatment combination arms with sabatolimab 
and cytokines is only required for patients in treatment combination arms with 
crizanlizumab or sabatolimab, and that these two assessments will now be performed pre-
dose at C1D1 instead of at baseline. 


Novartis 
Confidential 
Page 45 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 8.4.3: Clarification added that pregnancy assessment at the beginning of each cycle 
could be performed via urine or serum testing, however serum testing is the preferred 
method. 
• Section 8.5.1: Updated the calculation of the Total Symptom Score (TSS) to match the user 
manual for the MFSAF ePRO, and updated the wording in the paragraph describing the 
Trial Feedback Questionnaire. 
• Section 8.5.2: Removed sample 233 in Table 8-12, as it is not applicable at this visit; Note 
added in Table 8-13 and Table 8-14 to clarify that when there are two Dose Reference ID 
the first number is for the current dose, while the second is for the last (previous) dose 
received prior to the collection of the PK sample. 
• 
 
 
• Section 9.2: Post-study treatment paragraph deleted as PTA is already described in  
section 6.1.5. 
• Sections 9.2 and 10.1: Added instructions on the collection of new AEs and SAEs for 
subjects who begin new antineoplastic medication (other than study treatment) before the 
end of the safety follow-up period. 
• Section 12.1.4: Clarification added that a PK profile is evaluable if the subject does not 
vomit within 2 hours after oral dosing of ruxolitinib in treatment arms that do not contain 
siremadlin. 
• Section 12.5.2: Updated the definition for on-treatment period and post-treatment period 
following the protocol standard language and defined the ‘overall safety period’ for 
reporting the safety data within the long safety follow-up period; Updated the corresponding 
AE analysis for the defined safety periods; eleted the provision of the ECG summary 
statistics by visit/time. 
• In addition, clarifications and corrections were made throughout the protocol to improve 
consistency and understanding. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 46 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Amendment 1 (18-Jul-2019)  
Amendment rationale  
At the time of the amendment, the study has not started in any of the participating 
countries/sites. 
The purpose of the amendment is to: 
• Exclude any subjects from the study that are eligible for allogeneic hematopoeitic stem cell 
treatment (ASCT). Patients eligible for ASCT should not be prevented from such curative 
treatment by participating in the clinical trial. 
• Clarify that any subjects that are scheduled for ASCT during the study must be discontinued 
to ensure that eligible patients for ASCT are not prevented from curative ASCT treatment. 
• Align updated information available from the sabatolimab (MBG453) Investigator’s 
Brochure to use highly effective forms of contraception for women of child-bearing 
potential (WOCBP) for up to 150 days for subjects on study treatment that includes 
sabatolimab. 
• Clarify that the safety follow-up for subjects on study treatment that includes sabatolimab 
is up to 150 days in accordance with the sabatolimab (MBG453) Investigator’s Brochure. 
Safety Follow-up visits are now conducted at 30 days, 90 days and 150 days. 
• Exclude all forms of hormonal contraception for WOCBP since the effectiveness of 
hormonal contraception can potentially be reduced with the possible induction of CYP3A4 
by siremadlin. For consistency, hormonal contraception has been excluded from all arms of 
the study. 
• Exclude any subjects that cannot discontinue drugs that strongly induce or inhibit CYP2C9 
since ruxolitinib is metabolised by CYP2C9 
• Add strong inducers or inhibitors of CYP2C9 as prohibited medications, and to advise 
caution on the use of moderate inducers or inhibitors of CYP2C9 since ruxolitinib is 
metabolised by CYP2C9. 
• Clarify the safety run-in of crizanlizumab and sabatolimab arms of the study in Part 1, that 
if 2 subjects experience a DLT in either arm, then further enrolment into that arm will stop, 
and the treatment combination will not open in Part 2. 
• Clarify that intra-subject dose escalation is not allowed in this study. This was left out of 
the original protocol.  
• Add additional ECG safety monitoring for any QTc interval prolongation > 60 msecs from 
baseline per the ICH E14 guidelines.  
• Add a recommendation for all subjects to protect their skin from solar UV radiation if they 
are on study treatment that contains siremadlin as there is a potential for phototoxicity with 
siremadlin (in vitro findings). 
• Clarify that soft centimeter rulers will not be provided to investigators to measure the 
palpable spleen length as this can be acquired by the site. 
• 
 
 


Novartis 
Confidential 
Page 47 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
• Clarify that urine pregnancy tests will be performed monthly for all pre-menopausal women 
who are not surgically sterile to ensure appropriate pregnancy monitoring for all WOCBP. 
• Add further hypothetical on-study data scenarios to the Bayesian model used to guide dose 
escalation in Part 1 for siremadlin in combination with ruxolitinib to further demonstrate 
the performance of the Bayesian Logistic Regression Model (BLRM).  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Section 3: Figure 3-2, Figure 3-3, and Figure 3-5 have been updated for the extended safety 
follow-up of up to 150 days for sabatolimab. 
• Section 5.2: Exclusion criteria #20 has been updated to clarify that WOCBP should use 
highly effective methods of contraception for up to 150 days after the last dose of 
sabatolimab. 
• Section 5.2: Exclusion criteria #20 has been updated to exclude all forms of hormonal 
contraception for WOCBP.  
• Section 5.2: Exclusion criteria #27 has been updated to exclude any subjects that cannot 
discontinue drugs that strongly induce or inhibit CYP2C9. 
• Section 5.2: Exclusion criteria #28 has been added to exclude any patient that is eligible for 
ASCT from entering the study. 
• Section 6.2.1.1: Added statement to advise that the use of moderate inducers or inhibitors 
of CYP2C9 requires caution. 
• Section 6.2.2: Added statement that strong inhibitors or inducers of CYP2C9 are prohibited 
medications. 
• Section 6.5.2: Updated sentence to clarify that if 2 subjects in either arm with crizanlizumab 
(Arm 2) or sabatolimab (Arm 3) experience a DLT, further enrollment into that arm will 
stop and that combination treatment will not open in Part 2.  
• Section 6.5.2.2: Added a sentence to state that intra-subject dose escalation is not allowed 
in the study. 
• Section 6.5.4: Added a sentence as a footnote to rash/photosensitivity that it is 
recommended that subjects should protect their skin from solar UV radiation while on any 
study treatment that includes siremadlin. 
• Section 6.5.4.1: Increased ECG safety monitoring has been added for QTc prolongation > 
60 msec from baseline. 
• Section 6.5.5, Section 9.2, Section 10.1.1, Section 10.1.3 and Section 12.5.2: Updates have 
been made throughout the protocol for the extended safety follow-up of up to 150 days for 
sabatolimab. 
• Section 8.3.2.2: Removed the sentence that states investigators will be provided with a soft 
centimeter ruler to measure the length of the palpable spleen. 


Novartis 
Confidential 
Page 48 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Section 8.4.3: Clarified that additional urine pregnancy testing will be performed at the 
beginning of every cycle for all pre-menopausal women who are not surgically sterile. 
• 
  
• Tables 8-1, 8-2 and 8-3: Updates made to the tables to be in alignment with the updated 
protocol sections. 
• Section 9.1.1: Added a sentence to clarify that any subject that is scheduled for ASCT during 
the course of the study must be discontinued from the study treatment. 
• Section 16.1 (Appendix 1): Updated Table 16-1 to add moderate inhibitors and inducers of 
CYP2C9. 
• Section 16.2 (Appendix 2): Updated Table 16-2 to add strong inhibitors and inducers of 
CYP2C9. 
• Section 16.6.4 and Table 16-7: Additional wording and scenarios have been added to the 
hypothetical dose escalations scenarios for siremadlin 
• In addition, clarifications and corrections were made throughout the protocol to improve 
consistency and understanding. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


Novartis 
Confidential 
Page 49 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Protocol summary 
Protocol number 
CINC424H12201 
Full Title 
A randomized, open-label, phase I/II open platform study evaluating safety and efficacy 
of novel ruxolitinib combinations in myelofibrosis patients 
Brief title 
A safety, pharmacokinetics and preliminary efficacy study of novel ruxolitinib 
combination treatments in patients with myelofibrosis 
Sponsor and 
Clinical phase 
Novartis, phase Ib/II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
Myelofibrosis (MF) is defined by progressive bone marrow (BM) fibrosis and a consecutive 
reduction of blood cells. The disruption of the medullary erythropoietic niche is the primary 
mechanism governing the bone marrow failure and anemia, which typify MF. Nearly 40% 
of MF patients have hemoglobin (Hb) levels < 10 g/dL at diagnosis. Furthermore, anemia 
is the disease feature most consistently associated with poor prognosis in MF. Ruxolitinib 
demonstrates improvements in splenomegaly and constitutional symptoms, however, 
does not improve anemia. 
The purpose of this study is to investigate the safety, pharmacokinetics (PK) and 
preliminary efficacy of combinations treatment of ruxolitinib with 5 novel compounds: 
siremadlin, crizanlizumab, sabatolimab, rineterkib and NIS793 in MF subjects. These 
combination therapies may deliver transformational clinical benefits such as improvement 
of progression free survival (PFS) as a consequence of superior disease control or 
reduction of the malignant clone, associated with an improvement of cytopenia and in 
particular anemia, as well as improvement in quality of life (QoL) as captured by relevant 
patient reported outcomes measurements (PROs).  
Novartis decided to permanently halt the enrollment of CINC424H12201. An extension 
treatment phase was introduced in Part 1 with amended protocol version 08 to allow 
access to the investigational drug combination to ongoing subjects deriving clinical 
benefit. The duration of the extension treatment phase was increased to a maximum of 
21 cycles with amended protocol version 09. 
Primary 
Objective(s) 
The primary objective of Part 1 of this study is to characterize the safety, tolerability, and 
the recommended Phase 2 dose (RP2D) of each combination partner used with ruxolitinib 
in subjects with myelofibrosis. This is assessed by the incidence and severity of dose-
limiting toxicity (DLTs) within the first 2 treatment cycles in Part 1 of the study.  
The primary objective of Parts 2 and 3 of the study is to evaluate the preliminary efficacy 
of the novel ruxolitinib combination treatments in subjects with myelofibrosis. This is 
based on the assessment of the response rate (RR) at the end of Cycle 8 for all arms 
containing NIS793 or Cycle 6 for all other arms. The RR is the composite of anemia 
improvement of ≥ 1.5 g/dL, no spleen volume progression and no symptom worsening.  
As the enrollment was permanently halted, not all planned study objectives for Parts 1, 2, 
and 3 could be completed. All Parts 2 and 3 objectives will not be pursued. 
 
 
Secondary 
Objectives 
• 
To assess the proportion of subjects in each treatment arm who achieve an Hb 
improvement of ≥ 2.0 g/dL or ≥ 1.5 g/dL from baseline (Parts 2 & 3) 
• 
To evaluate changes in symptoms of myelofibrosis in each treatment arm using 
Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 and European Organization 
for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 
30 (QLQ-C30) patient reported outcomes (PROs) from baseline (Parts 2 & 3) 
• 
To characterize the pharmacokinetic profile of ruxolitinib administered in combination 
with siremadlin, crizanlizumab, sabatolimab, rineterkib and NIS793 respectively 
(Parts 1, 2 & 3)  
• 
To assess emergence of anti-crizanlizumab, anti-sabatolimab or anti-NIS793 
antibodies following one or more IV infusions (Parts 1, 2 & 3) 
• 
To evaluate the changes in spleen size in each treatment arm measured by change 
in spleen length (by palpation) and spleen volume (by magnetic resonance imaging 
(MRI)/computed tomography (CT)) from baseline (Parts 2 & 3) 


Novartis 
Confidential 
Page 50 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• 
To evaluate the effect of each ruxolitinib combination treatment in delaying 
progression of MF and estimate time to progression free survival (PFS) event (Parts 
2 & 3)  
• 
To evaluate the effect on bone marrow fibrosis in each treatment arm by determining 
the proportion of subjects achieving improvement in bone marrow fibrosis of ≥ 1 
grade from baseline (Parts 2 & 3) 
• 
To evaluate long-term safety and tolerability of ruxolitinib combination treatments in 
each arm based on frequency, duration and severity of adverse events (AE), 
abnormalities in vital signs and laboratory test values, 
including electrocardiogram (ECG) data (Parts 1, 2 & 3) 
In consideration of the enrollment halt, a number of preplanned study objectives will not 
be pursued. All Parts 2 and 3 objectives will not be pursued. 
 
 The following objectives 
were added or edited as secondary objectives: 
• 
To evaluate the changes in spleen size in each treatment arm (Part 1 core and 
extension, Part 2 & 3) 
• 
To evaluate changes in symptoms of myelofibrosis in each treatment arm using 
MFSAF v4.0 (Part 1) 
• 
To evaluate safety and tolerability of ruxolitinib combination treatments in each arm 
(Part 1 core and extension, Part 2 & 3) 
Study design 
This is an open-label, multi-center, phase Ib/II platform study consisting of 3 parts that will 
enroll approximately 240 subjects in total, assuming that 5 novel combination treatments 
from Part 1 are selected for Part 2, and that 1 of the 5 novel combination treatments is 
expanded in Part 3. If all 5 combination treatments enter Part 3, then there will be a 
maximum of approximately 380 subjects in total in all 3 parts of the study. Part 1 is a 
phase Ib dose escalation and safety run-in for the 5 novel agents in combination with 
ruxolitinib to assess safety, tolerability and to confirm recommended Phase II dose. 
Approximately 18 subjects in total will be enrolled in 3 dose escalation cohorts for 
ruxolitinib + siremadlin treatment, and approximately 12 subjects in total will be enrolled 
in 2 dose escalation cohorts for ruxolitinib + rineterkib treatment. In the safety run-in, 
approximately 6 subjects will be enrolled for each arm of ruxolitinib + crizanlizumab, 
ruxolitinib + sabatolimab, and ruxolitinib + NIS793. Eligible subjects in Part 1 will be 
treated for a planned duration of 8 cycles (arms with NIS793) or 6 cycles (all other arms), 
where a cycle consists of 21 or 28 days, depending on the treatment arm (24 weeks), 
however a minimal of 2 cycles of treatment will be used to evaluate whether the 
combination treatment is eligible for Part 2.  
In the context of the permanent enrollment halt, the 3 parts study design has been revised 
with Part 1: Dose escalation and safety-run-in to include a core treatment phase and an 
extension treatment phase, Part 2: Selection remained unchanged as the only 
randomized subject has discontinued prior to amended protocol version 08 and Part 3: 
Expansion will not be applicable as it will never be initiated.  
Parts 2 and 3 are a phase II selection and expansion, respectively, to assess preliminary 
efficacy of the combination treatments from Part 1 that are evaluated as safe and 
tolerable. Part 2 will be conducted in groups and will consist of a maximum of 6 arms of 
treatment, one arm for each of the 5 novel combinations plus a common ruxolitinib 
monotherapy control arm. The number of arms will depend on the results of the Part 1 
dose escalation and safety run-in phase in Part 1. A maximum of 155 subjects will be 
randomized to combination treatments and ruxolitinib monotherapy for a planned duration 
of 12 cycles or 16 cycles of treatment (48 weeks), depending on the treatment arm. Each 
combination treatment arm will enroll approximately 25 subjects, and the common 
ruxolitinib monotherapy control arm will enroll approximately 30 subjects assuming 3 
groups in Part 2. Two interim analyses are planned in Part 2 for each combination 
treatment arm. The two interim analyses will be performed after respectively at least 10 
and 25 subjects in the combination treatment arms have completed 6 cycles or 8 cycles 
of treatment, depending on the treatment arm (24 weeks), to determine whether the 
combination treatment is expanded in Part 3. For each selected combination treatment, 
Part 3 of study is expected to consist of the combination treatment(s) chosen from Part 2, 
the ruxolitinib cessation arm(s) (novel agent monotherapy), and a common ruxolitinib 
monotherapy control arm. Subjects will be randomized with a planned enrollment of 


Novartis 
Confidential 
Page 51 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
approximately 20 subjects for a combination treatment arm, 10 subjects for a ruxolitinib 
cessation arm (novel agent monotherapy) for Part 3, and maximum 50 subjects for the 
ruxolitinib monotherapy arm for Part 2 and Part 3 in total. 
Part 1 is updated to include a core treatment phase and an extension treatment phase. 
The end of core treatment phase will occur when amended Protocol version 08 is 
implemented, after a minimum of 24 weeks of treatment in the core phase. The planned 
duration for the extension treatment phase is maximum 21 cycles (84 weeks) when 
amended protocol version 09 is implemented. Core treatment phase and extension 
treatment phase are not applicable to Parts 2 and 3.  
Population 
The patient population will include male or female adults (age 18 or over) with a 
confirmed diagnosis of PMF or PPV- MF, or PET- MF. 
Key Inclusion 
criteria 
Key inclusion criteria are listed below, please refer to the protocol for the full list of 
inclusion criteria: 
• 
Subjects have diagnosis of primary myelofibrosis (PMF) according to the 2016 World 
Health Organization (WHO) criteria, or diagnosis of post-essential thrombocythemia 
(ET) (PET-MF) or post-polycythemia vera (PV) myelofibrosis (PPV-MF) according to 
the International Working Group for Myelofibrosis Research and Treatment (IWG-
MRT) 2007 criteria. 
• 
Palpable spleen of at least 5 cm from the left costal margin (LCM) to the point of 
greatest splenic protrusion or enlarged spleen volume of at least 450 cm3 per MRI or 
CT scan at baseline (a MRI/CT scan up to 8 weeks prior to first dose of study 
treatment can be accepted). 
• 
Have been treated with ruxolitinib for at least 12 weeks prior to first dose of study 
treatment. 
• 
Are stable (no dose adjustments) on the prescribed ruxolitinib dose (between 5 and 
25 mg twice a day (BID)) for ≥ 4 weeks prior to first dose of study treatment.  
• 
Hemoglobin < 11 g/dL (≤ 6.8 mmol/L). 
• 
Part 1: Platelet counts ≥ 75,000/μL. 
• 
Part 2 and Part 3: Platelet counts ≥ 50,000/μL. 
Key inclusion criteria for the extension treatment phase are listed below, please refer to 
the protocol for the full list of inclusion criteria: 
• 
Signed informed consent form prior to participation 
• 
Ongoing in the core treatment phase 
• 
Demonstrated clinical benefit in the core treatment phase per investigator’s 
assessment. 
Key Exclusion 
criteria 
Key exclusion criteria are listed below, please refer to the protocol for the full list of 
exclusion criteria: 
• 
Not able to understand and to comply with study instructions and requirements.  
• 
Received any investigational agent for the treatment of MF (except ruxolitinib) within 
30 days of first dose of study treatment or within 5 half-lives of the study treatment, 
whichever is greater. 
• 
Peripheral blood blasts count of > 10%.  
• 
Had documented severe hypersensitivity reactions/immunogenicity (IG) to a prior 
biologic product in any treatment arm OR received a monoclonal antibody or 
immunoglobulin-based agent: 
• 
For treatment arms with NIS793, crizanlizumab or sabatolimab within 1 year of 
screening,  
• 
For treatment arms with rineterkib or siremadlin arms within <=4 weeks of 
screening or <=5 half lives whichever is shorter for rineterkib or siremadlin arms 
• 
For Part 2 and Part 3, the longest window will apply based on the compounds 
opened for randomization. 
• 
Splenic irradiation within 6 months prior to the first dose of study drug. 
• 
Received blood platelet transfusion within 28 days prior to first dose of study 
treatment. (Note: PRBC transfusions are permitted) 


Novartis 
Confidential 
Page 52 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• 
Subjects with known TP53 mutation or deletion of TP53. 
• 
Use of systemic steroid therapy and other immunosuppressive drugs within 14 days 
prior to first dose of study treatment (> 10 mg/day prednisone or equivalent). Topical, 
inhaled, nasal, and ophthalmic steroids are allowed. Replacement therapy, steroids 
given in the context of a transfusion are allowed and not considered a form of systemic 
treatment. 
• 
Occurrence of any clinically significant bleeding events within 6 months prior to first 
dose of study treatment. 
• 
For patients treated with rineterkib in Part 1 and for all patients in Part 2 and Part 3 (if 
an rineterkib arm is included in the randomization for Part 2 or Part 3): Pre-existing 
retinal vein occlusion (RVO) or current risk factors (apart from the underlying MF) for 
RVO. 
Key exclusion criteria for the extension treatment phase are listed below, please refer to 
the protocol for the full list of exclusion criteria: 
• 
Subject meeting the list of discontinuation criteria 
• 
Evidence of treatment failure 
• 
Enrollment in another interventional study 
• 
Subject has evidence of non-compliance to study procedures or withdrew consent in 
core treatment phase 
• 
Unresolved toxicities for which treatment has been interrupted in the core treatment 
phase 
• 
Subject has local access to alternative myelofibrosis treatment as assessed suitable 
in the opinion of the investigator.  
Study treatment 
Ruxolitinib (INC424), siremadlin (HDM201), crizanlizumab (SEG101), sabatolimab 
(MBG453), rineterkib (LTT462), NIS793  
Efficacy 
assessments 
The efficacy assessments for the primary objectives are: 
• 
Laboratory hemoglobin assessments taken at the end of Cycle 8 for all arms 
containing NIS793 or Cycle 6 for all other arms compared to baseline  
• 
MRI or CT imaging of the spleen performed at the end of Cycle 8 (for NIS793) or 
Cycle 6 (for all other arms) compared to baseline 
• 
Total symptom score (TSS) assessed by MFSAF v4.0 at baseline and at the end of. 
Cycle 8 (for NIS793) or Cycle 6 (for all other arms) 
The efficacy assessments for the secondary objectives are: 
• 
Laboratory hemoglobin assessments 
• 
Manual palpation and MRI/CT imaging of the spleen 
• 
MFSAF v4.0 and EORTC QLQ-C30 patient reported outcomes (PROs) 
• 
Disease progression events assessed by progressive splenomegaly, accelerated 
phase, deteriorating cytopenia, leukemic transformation or death 
• 
Bone marrow fibrosis and histomorphology assessment of bone marrow biopsy and 
aspirate 
• 
Clinical benefit assessment per investigator’s opinion for extension treatment phase 
Pharmacokinetic 
assessments  
• 
PK parameters (e.g., AUC, Cmax, Tmax) and concentration vs. time profiles of each 
investigational drug within combination regimens 
• 
IG samples to monitor appearance of antidrug antibodies (ADAs) directed against 
crizanlizumab, sabatolimab or NIS793 
• 
PK assessments are not applicable for the extension treatment phase 
• 
The investigators were instructed prior to the implementation of the amended protocol 
version 08 to not collect pharmacokinetic, immunogenicity 
 
samples from subjects in Part 1 all treatment arms to reduce subject burden. 
Key safety 
assessments 
• 
Physical examination 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
• 
Weight and vital signs 
• 
12-lead ECG 


Novartis 
Confidential 
Page 53 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• 
Laboratory assessments including hematology, chemistry, urinalysis, coagulation, 
thyroid function, serology, safety cytokines 
• 
Pregnancy testing for women of childbearing potential 
• 
Adverse events (AEs): severity, relationship to study treatment and seriousness 
• 
For LTT462 arms: cardiac imaging and ophthalmological assessments 
• 
For NIS793 arms: cardiac imaging and cardiac assessments (troponin I, NTproBNP) 
Other 
assessments  
Data analysis 
Part 1 primary analysis 
Identification of the RP2D of siremadlin in combination with ruxolitinib or rineterkib in 
combination with ruxolitinib will be based upon the estimation of the probability of DLT 
within the first 2 cycles for patients in the respective Dose-Determining Set (DDS). The 
dose escalation will be guided by a Bayesian analysis of dose-limiting toxicity (DLT) data 
from Cycle 1 and Cycle 2. For the crizanlizumab arm, the sabatolimab arm, and the 
NIS793 arm the DLT probability is determined as the number of patients in the DDS who 
experienced a DLT divided by the number of patients in the DDS. 
Part 2 and Part 3 primary analysis. Analysis on the protocol defined primary endpoint is 
not applicable for Part 2 and Part 3 due to enrollment halt. Data collected for Part 2 will 
be reported.  
The primary clinical study report (CSR) will include  analyses on all subject data at the 
time when the last subject completed the end of treatment visit for core treatment phase 
(Part 1) and after all subjects have completed at least, 8 cycles (arms with NIS793) or 6 
cycles (all other arms) of treatment (24 weeks), or discontinued earlier (Part 1 and Part 
2). All extension treatment phase data will be reported in the final CSR after all subjects 
discontinue from the study or complete the extension treatment phase (maximum 21 
cycles) whichever comes last. Due to the permanent enrollment halt, the description for 
Part 2 and Part 3, including interim analysis are no longer applicable. 
Key words 
Myelofibrosis, ruxolitinib (INC424), siremadlin (HDM201), crizanlizumab (SEG101), 
sabatolimab (MBG453), rineterkib (LTT462), NIS793, platform study. 
 


Novartis 
Confidential 
Page 54 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
1 
Introduction 
1.1 
Background 
1.1.1 
Overview of disease pathogenesis, epidemiology and current treatment 
Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm 
(MPN) characterized by the presence of megakaryocyte proliferation and atypia, usually 
accompanied by either reticulin and/or collagen fibrosis (Tefferi and Vardiman 2008). 
Additional clinical features include splenomegaly (due to extramedullary hematopoiesis), 
anemia (due to bone marrow failure and splenic sequestration), and debilitating constitutional 
symptoms (due to overexpression of inflammatory cytokines) that include fatigue, weight loss, 
pruritus, night sweats, fever, and bone, muscle, or abdominal pain (Naymagon and  
Mascarenhas 2017, Abdel Wahab and Levine 2009, Mesa et al 2007). 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 median age at diagnosis of 65 years (Mehta et al 2014, Rollison et al 2008). 
MF can develop de novo, as a primary hematologic malignancy, primary myelofibrosis (PMF) 
or 
arise 
from 
the 
progression 
of 
preexisting 
myeloproliferative 
neoplasms, 
namely: polycythemia vera (PV) or essential thrombocythemia (ET) (Naymagon and 
Mascarenhas 2017, Mesa et al 2007). The World Health Organization (WHO) classification 
system for hematopoietic tumors was recently revised and the 2016 document recognizes 
several major categories of myeloid malignancies including MPN. Within the WHO MPN 
category, PMF, PV and ET are operationally grouped together as “ JAK2 MPN ”. Furthermore, 
some patients with ET or PV develop a PMF-like phenotype over time, referred to as post-ET 
(PET-MF) or post-PV MF (PPV-MF), with similar treatment and outcome (Tefferi and Barbui 
2019). 
Patients with MF have shortened survival (median survival is 6.5 years) and greatly 
compromised quality of life (QoL). Contributing factors for shortened survival include 
leukemic transformation and thrombohemorrhagic complications and for the compromised 
quality of life severe anemia (often requiring red blood cell (RBC) transfusions), symptomatic 
enlargement of the spleen and liver, substantial MF-associated symptoms burden (MF-SB), and 
cachexia (Tefferi and Barbui 2019). 
The only potential curative treatment for MF is allogeneic hematopoietic stem cell 
transplantation (ASCT), for which the great majority of patients are ineligible. Therefore, 
treatment options remain primarily palliative and aimed at controlling disease symptoms, 
complications and improving the patient's QoL. The therapeutic landscape of MF has changed 
with the discovery of the V617F mutation of the Janus kinase JAK2 gene present in 60% of 
patients with PMF or PET-MF and in 95% of patients with PPV-MF, triggering the 
development of molecular targeted therapy for MF (Cervantes 2014). JAKs play an important 
role in signal transduction following cytokine and growth factor binding to their receptors. 
Aberrant activation of JAKs has been associated with increased malignant cell proliferation and 
survival (Valentino and Pierre 2006). JAKs activate a number of downstream signaling 
pathways implicated in the proliferation and survival of malignant cells including members of 
the Signal Transducer and Activator of Transcriptions (STAT) family of transcription factors. 


Novartis 
Confidential 
Page 55 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
JAK inhibitors were developed to target JAK2 thereby inhibiting JAK signaling. Ruxolitinib, 
as all agents of this class, mainly inhibits dysregulated JAK-STAT signaling present in all 
MF patients irrespective of their JAK2 mutational status, but is not selective for the mutated 
JAK2, which explains its efficacy in both JAK2-positive and -negative MF. Ruxolitinib is 
highly effective in reducing the spleen size and controlling the symptoms of MF, with this 
resulting in a marked improvement in the patient's QoL (Cervantes et al 2016). Ruxolitinib is 
the only JAK inhibitor that has been granted a marketing authorization, as a single agent, for 
the treatment of patients with PMF, PPV-MF or PET-MF and for the treatment of patients with 
PV who are resistant to or intolerant to hydroxyurea. Ruxolitinib is the only approved 
pharmacological treatment for MF patients with splenomegaly and/or clinical symptoms and is 
considered standard of care (SoC). Although ruxolitinib has changed the treatment paradigm of 
MF patients, there is no clear indication of its disease-modifying effect (Cervantes 2014) and 
therapy-related anemia is often an anticipated downside (Naymagon and Mascarenhas 2017, 
Mead et al 2015). Combination therapies of ruxolitinib with novel agents may deliver 
transformational clinical benefits such as improvement of anemia and progression free survival 
(PFS) by better controlling or even reducing the malignant clone. 
1.1.2 
Introduction to Investigational treatments 
The investigational treatment for this trial is the combination of ruxolitinib with one of five 
novel compounds: siremadlin, crizanlizumab, sabatolimab, rineterkib or NIS793. 
1.1.2.1 
Ruxolitinib: an inhibitor of JAK1, JAK2 and mutated JAK2V617 
signaling 
Ruxolitinib (INC424, Jakavi®, Jakafi®) is a potent inhibitor of Janus Kinase (JAK) 1 and JAK2 
with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3. Ruxolitinib 
interferes with the signaling of a number of cytokines and growth factors that are important for 
hematopoiesis and immune function. Dysregulated JAK-STAT signaling, via upregulation of 
JAK1 and JAK2 or gain of function mutations such as JAK2V617F, has been implicated as a 
driver of BCR-ABL (breakpoint cluster region abelson)-negative MPNs, namely MF, PV and 
ET. Ruxolitinib through binding to and inhibiting of JAK1, JAK2 and mutated JAK2V617F, 
leads to inhibition of growth factor-mediated cell signaling and tumor cell proliferation. 
Ruxolitinib is currently approved under the trade name of ‘Jakavi®’ in over 100 countries for 
the treatment of disease-related splenomegaly or symptoms in adult patients with PMF, PPV-
MF and PET-MF. The use of ruxolitinib to treat PV patients who are resistant to or intolerant 
of hydroxyurea is currently approved in more than 60 countries worldwide including Europe. 
Ruxolitinib is also approved in the United States of America (USA) under the trade name of 
‘Jakafi®’ and is indicated for the treatment of patients with intermediate- or high- risk 
myelofibrosis, including PMF, PPV-MF and PET-MF, for the treatment of PV patients who 
have had an inadequate response to or are intolerant of hydroxyurea . 
Ruxolitinib is also approved for the treatment of patients aged 12 and older with acute or chronic 
graft versus host disease (GvHD) in several countries, including the USA, the European Union, 
United Kingdom, Australia and Brazil. 


Novartis 
Confidential 
Page 56 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Detailed information about the safety and efficacy of ruxolitinib is provided in the Investigator's 
Brochure. 
1.1.2.2 
Siremadlin: an inhibitor of HDM2 and modulator of p53 activation 
Siremadlin (HDM201) is a novel small molecule inhibitor that targets Human Double Minute-
2 (HDM2) by inhibiting its interaction with p53, an intracellular tumor suppressor protein that 
regulates the cell cycle. The p53 function is frequently compromised in tumor cells (Levine and 
Oren 2009, Vogelstein et al 2000). 
Under physiological conditions, activation of p53 pathway is tightly controlled 
(Millard et al 2011, Xiao et al 2000), however p53 can be induced and activated by a variety of 
potentially tumorigenic stress factors, including aberrant growth signals, DNA damage, a range 
of chemotherapeutic drugs, ultraviolet light, and protein-kinase inhibitors (Millard et al 2011). 
These pathways maintain a high concentration of intracellular p53, which modulates the 
expression of genes controlling cell growth arrest, DNA repair, and induces apoptosis of DNA 
damaged or mutated cells and new blood vessel formation (Vogelstein et al 2010, Bullock and 
Fersht 2001). 
Inactivating mutations in the TP53 gene are found in approximately 50% of all human cancers. 
In cancers in which the TP53 gene is not mutated, the function of the p53 pathway is often 
suppressed. This is owing to perturbation of its associated pathways through mechanisms that 
affect its stability and activity, with overexpression of HDM2 or silencing of p14 ARF (alternate 
reading frame) being two clinically important mechanisms (Eischen and Lozano 2009, 
Van Maerken et al 2009, Zhang et al 1998). 
Different strategies to restore the p53 function in tumors have been attempted, e.g. the design 
of antagonists for negative regulators of p53 in tumors carrying wild-type (WT) p53 
(Vassilev LT 2007), reactivation of mutant p53 (Joerger and Fersht 2008, Bullock and Fersht 
2001), and exogenous p53 expression, e.g., via adenovirus-mediated gene transfer 
(Roth JA 2006). Two studies on transgenic mice, in which p53 expression was reversibly 
switched on and off, have independently shown that restoration of the p53 function can lead to 
tumor regression in vivo, indicating that reactivating p53 is a promising therapeutic strategy 
(Ventura et al 2007, Martins et al 2006). 
HDM2 is one of the most important negative regulators of p53. Inhibition of the p53-HDM2 
protein-protein interaction using small molecules as a means to antagonize negative regulators 
of p53 and thus activate p53, has been focused on the p53 binding pocket of HDM2. As such, 
inhibiting the interaction between HDM2 and p53 represents an attractive and promising 
therapeutic approach against multiple types of solid and hematological cancers (Saha et al 2013, 
Capdevila et al 2012, Millard et al 2011). 
Siremadlin, by preventing HDM2-p53 interaction, inhibits the proteasome–mediated enzymatic 
degradation of p53, which may result in the restoration of both p53 signaling and p53-mediated 
induction of tumor cell apoptosis (Levine and Oren 2009). The goal of treatment with 
siremadlin is to increase the levels of intracellular p53 through antagonism of HDM2 and 
thereby activate downstream effector pathways that decrease cell proliferative events. Thus, the 
efficacy of siremadlin depends on the presence of wild-type p53. As almost all MF patients 


Novartis 
Confidential 
Page 57 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
have non-mutated p53WT, therefore Siremadlin may offer enhanced clinical benefit in these 
patients. 
Siremadlin is being evaluated as a treatment for several oncology indications including solid 
and hematological tumors characterized by wild-type TP53 (CHDM201X2101), liposarcoma 
(CHDM201X2103C), and acute myeloid leukemia (AML). Detailed information about 
siremadlin safety and efficacy is provided in the Investigator's Brochure. 
1.1.2.3 
Crizanlizumab: an anti-P-selectin monoclonal antibody 
Crizanlizumab (SEG101, Adakveo®) is a recombinant humanized IgG2 kappa anti-P-selectin 
monoclonal antibody (Ab). The target of crizanlizumab is P-selectin, an adhesion receptor 
expressed on the surface of activated endothelial cells and platelets. P-selectin plays a role in 
the initial adhesion and rolling of platelets and leukocytes to areas of injury and inflammation 
via its ligand P-selectin glycoprotein ligand 1 (PSGL-1) (Frenette et al 2000). By binding to P-
selectin on the surface of endothelial cells and platelets, crizanlizumab has been shown to 
effectively block interactions between endothelial cells, platelets, sickled red blood cells and 
leukocytes. The pharmacological effect of interfering with P-selectin/PSGL-1 interactions is 
anti-inflammatory. Considering the cell-cell interactions that are mediated by P-selectin binding, 
crizanlizumab may have immunosuppressant properties. 
The rationale for investigating crizanlizumab in MF patients is based on studies demonstrating 
a potential role for P-selectin in MF pathophysiology. PMF has a unique cellular signature: both 
bone marrow (BM) and the spleen contain numerous megakaryocytes (MK) exhibiting 
distinctive abnormalities that include reduced expression of the transcription factor Gata1 
(Vannucchi et al 2005), increased proliferation with delayed maturation (Centurione et al 2004, 
Schmitt et al 2000) and PMF MKs also express increased levels of P-selectin (Schmitt et al 
2000). 
PMF MK engage in emperipolesis with neutrophils, which in the case of PMF, may lead to MK 
para-apoptosis (Centurione et al 2004, Thiele et al 1997) that may cause release of 
transforming growth factor beta (TGFβ) to the microenvironment (Zingariello et al 2013). In 
agreement with this hypothesis, it has been found that plasma from PMF patients contains 
significantly increased levels of total and bioactive TGFβ than normal (Zingariello et al 2013). 
The relevance of these MKs and TGFβ abnormalities in the pathogenesis of PMF was shown 
in mice where the reduction of Gata1 expression in MK by ablation of its lineage-specific 
enhancer (hypomorphic Gata1low mutation Shivdasani et al 1997) induced MK abnormalities 
similar to those observed in PMF (Centurione et al 2004, Vannucchi et al 2002, Vyas et al 1999). 
This included an increase of the plasma levels of TGFβ, and the formation of a myelofibrosis 
phenotype. In addition, deleting the P-selectin gene in the myelofibrosis mouse model carrying 
the hypomorphic Gata1low mutation that induces megakaryocyte abnormalities, resulted in 
substantial reduction of MF disease burden in mice. P-selnullGata1low mice survived 
splenectomy and lived 3 months longer than P-selWTGata1low littermates, and they expressed 
only limited fibrosis in the bone marrow or splenomegaly (Spangrude et al 2016). Deletion of 
P-selectin also disrupted megakaryocyte/neutrophil interactions in the spleen, reduced TGF-β 
content, and corrected the hematopoietic stem cells (HSC) distribution that in Gata1low mice, 
as in PMF patients, is abnormally expanded in the spleen. 


Novartis 
Confidential 
Page 58 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
A recent study demonstrated that P-selectin expression is increased in JAK2V617F endothelial 
cells from Pdgfb-iCreERT2; JAK2V617F/WT mice (Guy et al 2019). The increased P-selectin 
expression at the endothelial cell (EC) surface are a pro-adhesive phenotype of JAK2V617F EC. 
Pre-treatment of mice with the P-selectin blocking antibody completely abrogated thrombus 
formation in Pdgfb-iCreERT2; JAK2V617F/WT mice, but had no effect in control mice. 
Furthermore, JAK2V617F human umbilical vein endothelial cells (HUVEC) when treated in vitro 
in the presence of a P-selectin blocking antibody, showed a complete reversion of the hyper-
adhesive properties of JAK2V617F HUVEC. The results of this study demonstrated that the pro-
thrombotic phenotype of JAK2V617F EC is primarily the consequence of increased adhesive 
properties, due to overexpression of membrane P-selectin. 
Conversely, pharmacological inhibition of TGFβ reduced P-selectin expression in MKs and 
corrected HSC distribution. Spleens, but not marrow of Gata1low mice contained numerous 
cKITpos activated fibrocytes, probably of dendritic cell origin, whose membrane protrusions 
interacted with MKs establishing niches hosting immature cKITpos hematopoietic cells. These 
activated fibrocytes were not detected in spleens from P-selnullGata1low or TGFβ-inhibited 
Gata1low littermates but were observed in spleen, but not in marrow, from PMF patients. 
Therefore, in Gata1low mice, and possibly in PMF, abnormal P-selectin expression in MKs 
may mediate the pathological cell interactions that increase TGFβ content in MKs and favor the 
establishment of a microenvironment that supports myelofibrosis-related HSC in spleen 
(Spangrude et al 2016).Based on these findings, pharmacologic neutralization of P-selectin on 
MKs via a monoclonal antibody holds promise to prevent progression and bone marrow fibrosis 
in MF patients. 
P-selectin also plays a pivotal role in the pathophysiology of sickle cell disease (SCD) and 
crizanlizumab was recently approved in the USA as Adakveo® to reduce the frequency of vaso-
occlusive crises (VOCs), or pain crises, in adult and pediatric patients aged 16 years and older 
with SCD. Additional studies in SCD patients (CSEG101A2201 and CSEG101A2202) have 
helped identify an important feature of crizanlizumab in vitro.  
It was found that there was interference with laboratory tests that measure the amount of 
platelets in blood in SCD patients treated with crizanlizumab. Clinical and pre-clinical data 
suggest this is an ex vivo phenomenon (laboratory test interference), that is ETDA- and time-
dependent, without indication of platelet clumping in vivo, and has no influence on the safety 
of crizanlizumab. Further information and recommendations that may mitigate this laboratory 
test interference are provided in Section 8.4.1. 
Detailed information about crizanlizumab safety and efficacy is provided in the Investigator's 
Brochure. 
1.1.2.4 
Sabatolimab: an inhibitor of a negative immune regulator, TIM-3 
Sabatolimab (MBG453) is a high-affinity, ligand-blocking, humanized anti-T-cell 
immunoglobulin domain and mucin domain-3 (TIM-3) IgG4 antibody. It is a novel checkpoint 
inhibitor that blocks the binding of an immune checkpoint receptor TIM-3 to phosphatidylserine 
(PtdSer). 


Novartis 
Confidential 
Page 59 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining 
self-tolerance and modulating the duration and amplitude of physiological immune responses 
in peripheral tissues in order to minimize collateral tissue damage (Shin and Ribas 2015). 
Checkpoint inhibitors, such as ipilimumab targeting CTLA-4, pembrolizumab and nivolumab 
targeting programmed cell death protein 1 (PD-1), have been approved for numerous cancer 
indications including hematologic malignancies. 
TIM-3 is expressed on the majority of CD34+CD38- leukemic stem cells (LSCs) and 
CD34+CD38+ leukemic progenitors in Acute Myeloid Leukemia (AML), but not on 
CD34+CD38- normal HSCs (Jan et al 2011, Kikushige et al 2010). Functional evidence for a 
key role for TIM-3 in AML was established by use of an anti-TIM-3 antibody which inhibited 
engraftment and development of human AML in immunodeficient murine hosts 
(Kikushige et al 2010). Upregulation of TIM-3 is also associated with leukemic transformation 
of pre-leukemic disease, include myelodysplastic syndromes (MDSs) and myeloproliferative 
neoplasms (MPNs), such as chronic myelogenous leukemia (CML) (Kikushige et al 2015). 
TIM-3 expression on MDS blasts was also found to correlate with disease progression 
(Asayama et al 2017). 
In addition to its cell-autonomous role on pre-leukemic and leukemic stem cells, TIM-3 has a 
widespread and complex role in immune system regulation, with published roles in both the 
adaptive immune response (CD4+ and CD8+ T effector cells, regulatory T cells) and innate 
immune responses (macrophages, dendritic cells, natural killer cells) (Ndhlovu et al 2012, 
Anderson et al 2007). TIM-3 has a critical role in tumor-induced immune suppression as it 
marks the most suppressed or dysfunctional populations of CD8+ T cells in animal models of 
solid and hematologic malignancies (Yang et al 2012, Zhou et al 2011, Sakuishi et al 2010) 
and is expressed on FoxP3+ regulatory T cells (Tregs), which correlate with disease severity in 
many cancer indications (Yan et al 2013, Gao et al 2012). Blockade of TIM-3 on macrophages 
and antigen cross-presenting dendritic cells enhances activation and inflammatory 
cytokine/chemokine production (de Mingo Pulido et al 2018, Zhang et al 2012, Chiba et al 2012, 
Zhang et al 2011), ultimately leading to enhanced effector T cells responses. 
Sabatolimab has been evaluated as a single agent or in combination with PDR001 (an anti-PD 
IgG4 Ab currently in the clinic) in a first in human (CMBG453X2101) clinical trial in solid 
tumors. It is also being investigated in a phase Ib study (CPDR001X2105) as a single agent or 
in combination with PDR001 and/or decitabine in patients with AML and patients with high 
risk MDS.  
Detailed information about sabatolimab safety and efficacy is provided in the Investigator’s 
Brochure. 
1.1.2.5 
Rineterkib: a potent and selective ERK1/2 kinase inhibitor 
Rineterkib is a potent, selective, orally bioavailable, adenosine triphosphate (ATP)-competitive, 
inhibitor of Extracellular signal-regulated kinase 1 (ERK1) and Extracellular signal-regulated 
kinase 2 (ERK2).  
In vitro, rineterkib demonstrated potent anti-proliferative activity (with sub-µM half maximum 
inhibitory concentration (IC50)) in cell lines containing mutations that activate mitogen-
activated protein kinase (MAPK) pathway signaling, including mutations of v-raf Murine 


N o v arti s  
C o nfi d e nti al  
P a g e 6 0  of 2 6 7  
A m e n d e d Pr ot o c ol V er si o n  N o  0 9 (Cl e a n )  
 
Pr ot o c ol N o. CI N C 4 2 4 H 1 2 2 0 1  
 
Sarc o ma Viral O nc o ge ne H o m ol o g B 1 ( B R A F ), Kirste n rat sarc o ma viral o nc o ge ne h o m ol o g 
(K R A S ), Ne ur o blast o ma R A S viral ( v-ras) o nc o ge ne h o m ol o g (N R A S ) a n d mit o ge n-acti vate d 
pr otei n ki nase ki nase 1 ( M E K 1 ). Ri neter ki b als o effecti vel y i n hi bite d t he pr oliferati o n of t he A-
3 7 5 mela n o ma cell li ne a n d its e n gi neere d deri vati ves e x pressi n g m ulti ple k n o w n m olec ular 
dri vers  of  B R A F  a n d/ or  M E K  i n hi bit or  resista nce,  i ncl u di n g  B R A F V 6 0 0 E , B R A F p 6 1 V 6 0 0 E, 
N R A S Q 6 1 K , M E K 1
C 1 2 1 S , M E K 1
E 2 0 3 K , M E K 1
P 1 2 4 L , M E K 1
Q 5 6 P  a n d M E K 2
Q 6 0 P .  
I n i n  viv o h u ma n  t u m or  xe n o graft  m o dels,  ri neter ki b  de m o nstrates  a  p har mac o ki netic  
( P K)/ p har mac o d y na mics ( P D)/efficac y relati o ns hi p, lea di n g t o d ose-de pe n de nt t u m or gr o wt h 
i n hi biti o n a n d re gressi o n w he n d ose d eit her dail y or i nter mitte ntl y i n h u ma n N o n-S mall Cell 
L u n g Carci n o ma ( N S C L C) Cal u -6 ( K R A S Q 6 1 K ), o varia n He y-A 8 ( K R A S G 1 2 D /B R A F G 4 6 4 E ) a n d 
mela n o ma A -3 7 5 ( B R A F V 6 0 0 E ) xe n o graft m o dels. Ri neter ki b has bee n e val uate d as a si n gle 
a ge nt i n a first i n h u ma n st u d y ( C L T T 4 6 2 X 2 1 0 1), t o esta blis h t he safet y a n d t ol era bilit y of 
ri neter ki b i n a d ult patie nts wit h a d va nce d s oli d t u m ors har b ori n g M A P K pat h wa y alterati o ns. 
It is c urre ntl y bei n g i n vesti gate d i n a P hase I b st u d y ( C L X H 2 5 4 X 2 1 0 2) i n c o m bi nati o n wit h 
L X H 2 5 4 ( B R A F a n d C R A F i n hi bit or) i n a d ult patie nts wit h a d va n ce d or metastatic K R A S or 
B R A F m uta nt N o n -S mall Cell L u n g Ca ncer or N R A S m uta nt mela n o ma. It is als o bei n g 
i n vesti gate d i n c o m bi nati o n wit h da brafe ni b ( D R B 4 3 6) as part of a platf or m st u d y i n a d ult 
patie nts  wit h  a d va nce d  or  metastatic  B R A F  V 6 0 0  c ol orectal  c a ncer  ( A D P T 0 1 C 1 2 1 0 1).  
Detaile d  i nf or mati o n  a b o ut  ri neter ki b  safet y  a n d  efficac y  is  pr o vi de d  i n  t he  I n vesti gat or's 
Br oc h ure. 
1. 1. 2. 6  
NI S 7 9 3: a n a nti -T G F β m o n o cl o n al a nti b o d y  
NI S 7 9 3 is a rec o m bi na nt h u ma n i m m u n o gl o b uli n G 2 (I g G 2) m o n ocl o nal a nti b o d y  ( m A b) t hat 
bi n ds t o T G F β 1 a n d T G F β 2 wit h hi g h affi nit y a n d t o T G F β 3 wit h l o wer affi nit y . C o nsiste nt 
wit h t he bi n di n g affi nities, NI S 7 9 3 dis pla ye d p ote nt T G F 1- a n d T G F2- ne utralizi n g acti vit y, 
w hile less effect was o bser ve d a gai nst T G F β 3. A d mi nistrati o n of NI S 7 9 3 si g nifica ntl y re d uce d 
t u m or gr o wt h i n i m m u n o deficie nt m o use m o dels. 
Precli nical  st u dies  s u p p ort  a  pat h o bi ol o gical  r ole  of  T G F β  i n  M F  ( Sc h mitt  et  al  2 0 0 2 ,  
Va n n ucc hi et al 2 0 0 5 , Wa n g et al 2 0 0 6 ). A d diti o nall y, Va n n ucc hi et al. 2 0 0 5  s h o we d t hat i n 
b ot h T P O hi g h mice a n d G A T A - 1l o w mice de vel o p me nt of m yel ofi br osis was ass ociate d wit h hi g h 
T G F β 1 c o nte nt i n e xtracell ular fl ui ds of marr o w a n d s plee n.  
F or t he n o n -cli nical t o xic ol o g y of NI S 7 9 3, refer t o NI S 7 9 3 I n vesti gat or’s Br oc h ure. Briefl y, 
bef ore t he first e ntr y i n h u ma ns, NI S 7 9 3 was i n vesti gate d i n tiss ue cr oss -reacti vit y st u dies a n d 
i n a 1 3-wee k rat t o xicit y st u d y u p t o 1 0 m g/ k g/ w k i. v. as well as i n a 4 -wee k c y n o m ol g us 
m o n ke y t o xicit y st u d y u p t o 1 6 m g/ k g/ w k i. v. b ot h f oll o we d b y 4 -wee k rec o ver y peri o d. I n t he 
rat, mi ni mal t o mil d n o n-a d verse effects were o bser ve d i n li ver, ki d ne y, b o ne, a n d e yeli ds, 
w hic h c o ul d reflect i n hi biti o n of t he tiss ue h o me o static effects of T G F β wit h NI S 7 9 3 ( b o ne, 
e yeli ds). F or t he effects i n li ver a n d ki d ne y, t he relati o n t o treat me nt a n d i n hi biti o n of T G F β is 
n ot clear a n d c o ul d i n dicate i nci de ntal fi n di n gs or a n i ncrease i n n or mal rat s pecific bac k gr o u n d 
fi n di n gs. I n t he m o n ke y st u d y, assess me nts of safet y p har mac ol o g y e n d p oi nts were i ncl u de d. 
N o a d verse effects o n car di o vasc ular, ce ntral ner v o us s yste m or res pirat or y f u ncti o n were 
o bser ve d. O verall, n o o bser ve d a d verse e ve nt le vel ( N O A E L) were set t o 1 0 m g/ k g i n t he rat 
stu d y a n d t o 1 6 m g/ k g i n t he c y n o m ol g us st u d y. 


Novartis 
Confidential 
Page 61 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
In a rat non-GLP pharmacology model of lung fibrosis, valvulopathy in the heart was found at 
NIS793 at 30mg/kg intraperitoneal, every second day (IP, Q2D) after 14 days. The exposure 
levels in these animals were in the clinically relevant range. In currently evaluated 8-week dose 
range finding and tolerability studies in rats and monkeys, adverse findings were observed in 
the kidney (tubulo-interstitial nephritis with tubular hypertrophy/hyperplasia) and the vascular 
system (vascular inflammation, vascular necrosis and endothelial cell hyperplasia) of 
cynomolgus monkeys at 65 mg/kg/wk i.v., and in the heart (cardiac valvulopathy) of rats at 30 
and 90 mg/kg/wk i.v. Toxicokinetic and anti-drug antibody data are not yet available. Based on 
modeling and simulation projections of exposure in rats and monkeys, these findings likely 
occurred at exposure comparable to those achieved in participants in current oncology and 
hematology trials. 
An investigator-initiated study (registered at www ClinicalTrials gov under NCT01291784) to 
investigate the tolerability and safety of GC1008 (Fresolimumab; Genzyme) a human 
immunoglobulin (IgG4) kappa monoclonal antibody capable of neutralizing TGFβ1, TGFβ2 
and TGFβ3 in patients with PMF or post-PV/ET MF showed evidence of a clinical response 
based on standard criteria and thus indicates the likelihood that targeting TGFβ with monoclonal 
antibodies or small molecule inhibitors is a promising strategy for treating patients with MF 
(Mascarenhas et al 2014). Another phase I/Ib study is currently ongoing to assess the safety and 
tolerability of another compound (AVID200) that targets TGFβ1 and TGFβ3 in patients with 
PMF or post-PV/ET MF (registered at www ClinicalTrials gov under NCT03895112). 
TGFβ1 is the best characterized pro-fibrotic factor within the family. TGFβ2 also displays 
potent fibrotic activity, whereas TGFβ3 appears to have anti-fibrotic activity in some tissues 
(Walton et al 2017). The selectivity of NIS793 for TGFβ1 and TGFβ2 over TGFβ3 could be a 
great advantage to inhibit fibrosis especially when combined with ruxolitinib. 
NIS793 has been evaluated in one clinical study to date, this first in human study 
(CNIS793X2101) is a dose escalation study of NIS793 in combination with PDR001 in adult 
patients with advanced malignancies. It is also being investigated in combination with SOC 
chemotherapy in first line metastatic pancreatic ductal adenocarcinoma (mPDAC), metastatic 
colorectal adenocarcinoma and lower risk myelodysplastic syndrome. 
Detailed information about NIS793 safety and efficacy is provided in the Investigator's 
Brochure. 
1.2 
Purpose 
MF is defined by progressive bone marrow fibrosis, the result of a nonclonal fibroblastic 
response to inflammatory and fibrogenic cytokines produced by aberrant clonal myeloid cells, 
most prominently megakaryocytes. This disruption of the medullary erythropoietic niche is the 
primary mechanism governing the bone marrow failure and anemia, which typify MF. Anemia 
is among the cardinal features of MF. Nearly 40% of MF patients have hemoglobin (Hb) levels 
< 10 g/dL at diagnosis, and nearly one-quarter already need red blood cell (RBC) transfusions. 
All patients with MF will eventually develop anemia, which has consistently been associated 
with inferior QoL measures. Furthermore, anemia is the disease feature most consistently 
associated with poor prognosis in MF (Naymagon and Mascarenhas 2017).  


Novartis 
Confidential 
Page 62 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Ruxolitinib demonstrated improvements in splenomegaly and constitutional symptoms, 
presumed to be mediated by its anti-proliferative effects, and through normalization of cytokine 
signaling, as abnormal cytokine levels have been associated with MF symptoms. However, not 
all patients respond to ruxolitinib, with some losing response while on treatment, and some 
having to discontinue treatment owing to toxicities (Verstovsek et al 2017). 
Ruxolitinib does not improve cytopenias but may aggravate anemia due to transient suppression 
of the erythropoiesis, which at least partially resolves over time on continuous therapy. Current 
treatment options for these patients are limited in their efficacy, durability and tolerability. 
Anemia and thrombocytopenia have remained challenges in the management of MF and 
represent a high unmet medical need.  
Combination therapies of ruxolitinib with novel agents may deliver transformational clinical 
benefits such as improvement of PFS as a consequence of superior disease control or reduction 
of the malignant clone, associated with an improvement of cytopenia and in particular anemia, 
as well as improvement in QoL as captured by relevant patient reported outcomes 
measurements (PROs).  
The purpose of this study is to investigate the safety, pharmacokinetics and preliminary efficacy 
of combinations treatment of ruxolitinib with five novel compounds: siremadlin, crizanlizumab, 
sabatolimab, rineterkib and NIS793 in MF subjects. The study was planned in three parts, as 
described in Section 3: 
• Part 1: Dose escalation and safety run-in (recommended Phase II dose confirmation) 
o Core treatment phase 
o Extension treatment phase 
Part 1 refers now to the core treatment phase unless specified.  
• Part 2: Selection 
• Part 3: Expansion 
Part 1 corresponds to phase Ib and Parts 2 and 3 correspond to phase II. 
The purpose of the extension treatment phase is to provide continued drug access to ongoing 
subjects who are deriving clinical benefit.  
2 Objectives and endpoints 
Please refer to Section 8.3 for details on the endpoint and to Section 12 for details on the 
analysis. 
As the enrollment was permanently halted, not all planned study objectives for Parts 1, 2, and 
3 could be completed. All Parts 2 and 3 objectives will not be pursued. 
 
 


Novartis 
Confidential 
Page 63 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the preliminary efficacy of 
each novel ruxolitinib combination 
treatment arm (Parts 2 & 3) 
• 
Response rate (RR) for the composite endpoint (anemia 
improvement of ≥ 1.5 g/dL and no spleen volume 
progression and no symptom worsening) at the end of Cycle 
8 for all arms containing NIS793 or Cycle 6 for all other 
arms.  
• 
To characterize the safety, tolerability, 
and 
recommended 
phase 
2 
dose 
(RP2D) of each combination partner 
used with ruxolitinib (Part 1) 
• 
Incidence and severity of dose limiting toxicity (DLTs) within 
the first 2 treatment cycles in Part 1 of the study 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the proportion of subjects in 
each treatment arm who achieve an Hb 
improvement of ≥ 2.0 g/dL or ≥ 1.5 g/dL 
(Parts 2 & 3) 
• 
Proportion of subjects achieving improvement of Hb level of 
≥ 1.5 g/dL from baseline 
• 
Proportion of subjects achieving improvement of Hb level 
of ≥ 2.0 g/dL from baseline 
• 
To evaluate changes in symptoms of 
myelofibrosis in each treatment arm 
using MFSAF v4.0 and EORTC QLQ-
C30 patient reported outcomes (PROs) 
(Parts 2 & 3) 
• 
Change in MFSAF v4.0 and EORTC QLQ-C30 from 
baseline, including proportion of subjects who achieved at 
least 50% 
reduction from baseline in MFSAF v4.0 Total Symptom 
Score (TSS) at the end of Cycle 4 (NIS793 arms) or Cycle 3 
(all other arms), of Cycle 8 (NIS793 arms) or Cycle 6 (all 
other arms) and of Cycle 16 (NIS793 arms) or Cycle 12 (all 
other arms) from baseline. 
• 
To evaluate changes in symptoms of 
myelofibrosis in each treatment arm 
using MFSAF v4.0 (Part 1) 
• 
Change in MFSAF v4.0 from baseline, including proportion 
of subjects who achieved at least 50% reduction from 
baseline in MFSAF v4.0 Total Symptom Score (TSS) at the 
end of Cycle 4 (NIS793 arms) or Cycle 3 (all other arms), of 
Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) and of 
Cycle 16 (NIS793 arms) or Cycle 12 (all other arms) from 
baseline. 
• 
To characterize the pharmacokinetic 
profile of ruxolitinib administered in 
combination with siremadlin, 
crizanlizumab, sabatolimab, rineterkib 
and NIS793, respectively (Parts 1, 2 & 
3) 
• 
PK parameters (e.g., AUC, Cmax, Tmax) and concentration 
vs. time profiles of each investigational drug with in 
combination regimens 
• 
To 
assess 
emergence 
of 
anti-
crizanlizumab, anti-sabatolimab, or anti-
NIS793 antibodies following one or more 
IV infusions (Parts 1, 2 & 3) 
• 
Presence and/or concentration of anti-crizanlizumab, anti-
sabatolimab or anti-NIS793 antibodies 
• 
To evaluate the changes in spleen size 
in each treatment arm (Part 1 core and 
extension, Parts 2 & 3) 
• 
Change in spleen length (by palpation) from baseline. 
• 
Change in spleen volume (by MRI/CT) from baseline, 
including 
proportions of subjects who achieved (i) at least 35% spleen 
volume reduction and (ii) at least 25% spleen volume 
reduction at the end of Cycle 8 (NIS793 arms) or Cycle 6 (all 
other arms) from baseline and, at the end of Cycle 16 
(NIS793 arms) or Cycle 12 (all other arms) from baseline 
respectively. 
• 
To evaluate the effect of each ruxolitinib 
combination 
treatment 
in 
delaying 
progression of MF and estimate time to 
• 
Estimate of progression free survival (PFS) where events 
are defined as follows:  
• 
Progressive splenomegaly as assessed by increasing 
spleen volume (by MRI/CT) of ≥ 25% from baseline. 


Novartis 
Confidential 
Page 64 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Objective(s) 
Endpoint(s) 
progression 
free 
survival 
(PFS) event (Parts 2 & 3) 
The progression date will be the date of MRI/CT 
assessment confirming spleen volume increase of ≥ 
25% from baseline 
• 
Accelerated phase defined by a circulating peripheral 
blood blast content of > 10% but < 20% confirmed after 
2 weeks. The progression date will be the date of first 
increase in peripheral blood blast content of > 10% 
• 
Deteriorating cytopenia (dCP) independent from 
treatment defined for all patients by platelet count < 35 
x10^9/L or neutrophil count < 0.75 x 10^9/L that lasts 
for at least 4 weeks. The progression date will be the 
date of first decrease of platelets < 35 x10^9/L or 
neutrophils < 0.75 x 10^9/L confirmed after 4 weeks 
• 
Leukemic transformation defined by a peripheral blood 
blast content of ≥ 20% associated with an absolute 
blast count of ≥ 1x10^9/L that lasts for at least 2 weeks 
or a bone marrow blast count of ≥ 20%. The 
progression date will be the date of first increase in 
peripheral blood blast content of ≥ 20% associated with 
an absolute blast count of ≥ 1x10^9/L OR the date of 
the bone marrow blast count of ≥ 20% 
• 
Death from any cause 
• 
To evaluate the effect on bone marrow 
fibrosis in each treatment arm (Parts 2 
& 3) 
• 
Proportion of subjects achieving improvement in bone 
marrow fibrosis of ≥ 1 grade from baseline 
• 
To 
evaluate 
long-term 
safety 
and 
tolerability of ruxolitinib combination 
treatments in each arm (Part 1 coreand 
extension, Parts 2 & 3) 
• 
Frequency, duration and severity of adverse events, 
abnormalities in vital signs and laboratory test values, 
including ECG data 


Novartis 
Confidential 
Page 65 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
3 
Study design 
This is an open-label, multi-center, three-part, phase Ib/II open platform study to assess safety 
and efficacy of ruxolitinib in combination with novel compounds in myelofibrosis patients 
followed by an extension treatment phase in Part 1. 
The study was planned in three parts. In the context of the permanent enrollment halt, the study 
design has been revised as follows: 
• Part 1: Dose escalation and safety-run-in (recommended Phase II dose confirmation) 
including a core and an extension treatment phase 
• Part 2: Selection (unchanged as the only randomized subject has discontinued prior to 
amended protocol version 08) 
• Part 3: Expansion (not applicable as it will never be initiated)  
After a screening period of up to 28 days (Day -28 to Day -1), eligible subjects will begin 
treatment on Cycle 1 Day 1 (C1D1) and will be treated for a planned duration of 24 weeks, 
which is 8 cycles for all treatment arms containing NIS793 or 6 cycles for all other treatment 
arms in Part 1, or for a planned duration of 48 weeks, which is 16 cycles for all arms containing 
NIS793 and 12 cycles for all other arms in Parts 2 and 3, per the treatment arms outlined below 
for each part of the study. Subjects may be discontinued from treatment earlier due to 
unacceptable toxicity, disease progression or treatment is discontinued at the discretion of the 
investigator or the subject. Refer to Section 8 for details on the screening period, treatment 
period and assessments, and to Section 9 for details on-study discontinuation and completion. 
Assuming all five combination treatments enter Part 2 and one combination treatment is 
expanded in Part 3, a total of approximately 240 subjects are expected to be enrolled in all three 
parts of the study: approximately 50 subjects in Part 1; approximately 155 subjects in Part 2; 
and approximately 35 subjects in Part 3. If additional combination treatments are expanded in 
Part 3, then the sample size will increase by approximately 35 subjects per treatment 
combination, to a maximum of approximately 175 subjects in Part 3, resulting in a maximum 
of approximately 380 subjects in all 3 parts of the study.  
Crossover, re-allocation or re-randomization of subjects to other combination arms including 
better performing arms within the same Part of the study is not permitted. Subjects are permitted 
to participate in another Part of the study, if all corresponding inclusion and none of the 
exclusion criteria are met, provided they are not randomized twice. This means that Part 1 
subjects could join Part 2 or Part 3 of the study and Part 2 and Part 3 subjects could participate 
in Part 1 of the study only. However, Part 2 subjects are not allowed to join Part 3 and vice 
versa. 
An overview of the study design is shown in Figure 3-1. A hypothetical example illustrating 
interim analyses in Part 2 and primary analysis of Part 3 is shown in Section 16.8 (Appendix 8). 
In the context of the permanent enrollment halt, the study design is revised as follows:  
• Part 1 is updated to define a core treatment phase and add an extension treatment phase. 
The end of core treatment phase will occur when amended protocol version 08 is 
implemented, after a minimum of 24 weeks in the core treatment phase. The extension 
treatment phase will occur (for ongoing subjects meeting eligibility criteria who are re-


Novartis 
Confidential 
Page 66 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
consented) from the time when amended protocol version 08 is implemented until the end 
of extension study treatment. 
• Part 2 is not updated.  
• Part 3 is not applicable as it will never be initiated. 
Figure 3-1 
Overview of study design 
 
*Rineterkib and NIS793 added in amendment 4 of the protocol 
TBC: To be confirmed 
Notes: 
Part 2 will be conducted in groups and will consist of a maximum of 5 arms of combination 
treatment plus a ruxolitinib monotherapy control arm. Each group consists of 1 or more 
combination treatments. A ruxolitinib monotherapy arm will open with the start of Part 2. The 
number of arms will depend on the results of the Part 1 dose escalation and safety run-in phase. 
There will be a maximum of approximately 155 subjects in total in Part 2 if all 5 combination 
treatments enter Part 2. Part 3 will consist of 3 arms per treatment combination that is expanded 


Novartis 
Confidential 
Page 67 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
with approximately 35 subjects in total per treatment combination. If additional treatment 
combinations are continued to be investigated in Part 3, then there will be up to a maximum of 
175 subjects in Part 3 (i.e., 35 subjects x 5 combination treatments). 
Assuming all 5 combination treatments enter Part 2 and one combination treatment enters  
Part 3, then there will be approximately 240 subjects enrolled in all three parts of the study. 
As the enrollment was permanently halted, the only randomized subject in Part 2 has 
discontinued prior to amended protocol version 08, and Part 3 will not be initiated, therefore 
the description below for Parts 2 and 3 are not applicable. 
Part 1: Dose escalation and safety run-in 
The primary objective of the first part of the study is to characterize safety, tolerability, and the 
recommended Phase 2 dose (RP2D) of novel agents given in combination with ruxolitinib in 
subjects with myelofibrosis.  
For siremadlin, since there are overlapping toxicities with ruxolitinib, a dose escalation will be 
performed to determine the RP2D of the combination treatment with ruxolitinib. It is estimated 
that approximately 18 subjects will be included in the dose escalation part for the combination 
of ruxolitinib and siremadlin. 
For rineterkib a dose escalation will also be performed to determine the RP2D of the 
combination treatment with ruxolitinib. It is estimated that approximately 12 subjects will be 
included in the dose escalation part of the combination of ruxolitinib with rineterkib. For 
crizanlizumab, sabatolimab, and NIS793 the proposed RP2D is known prior to the study start 
and based on previous single agent phase I and phase II studies in solid and hematologic 
malignancies. These compounds are monoclonal antibodies and no overlapping toxicities with 
ruxolitinib are expected (see Section 4.2.2, Section 4.2.3, and Section 4.2.5). However, since it 
is the first time these compounds will be given in combination with ruxolitinib and also the first 
time in an MF patient population, a safety run-in based on approximately 6 subjects will be 
conducted for these combination arms. The safety run-in is performed to assess the risk of 
unexpected toxicities, to confirm 
 pharmacokinetic properties, and to 
assess potential drug-drug interactions (DDI). In case of unexpected toxicities, administration 
of crizanlizumab, sabatolimab or NIS793 will be interrupted or terminated. 
The core treatment phase of Part 1 will include the following five combination arms, one novel 
agent per arm in combination with stable ruxolitinib.  
• Arm 1: Ruxolitinib 5-25 mg PO BID and siremadlin at various dose levels (either 10 mg, 
20 mg (starting dose), 30 mg or 40 mg) PO QD on Days 1 to 5 of a 28-day cycle 
• Arm 2: Ruxolitinib 5-25 mg PO BID and crizanlizumab 5 mg/kg IV once every 4 weeks 
(Q4W) with an additional loading dose administered at Cycle 1 Day 15 (C1D15) 
• Arm 3: Ruxolitinib 5-25 mg PO BID and sabatolimab 800 mg IV Q4W 
• Arm 4: Ruxolitinib 5-25 mg PO BID and rineterkib at various dose levels (either 100 mg, 
200 mg (starting dose) or 300 mg) PO QD in 28-day cycles 
• Arm 5: Ruxolitinib 5-25 mg PO BID and NIS793 2100 mg IV Q3W 


Novartis 
Confidential 
Page 68 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
The dose of ruxolitinib for all subjects should not change from the stable dose used prior to first 
dose of study treatment. As the combination arm of ruxolitinib and siremadlin in Part 1 is likely 
to enroll more subjects overall to evaluate various dose levels of siremadlin with ruxolitinib, 
eligible subjects will initially be allocated to the first dosing cohort of the ruxolitinib 
and siremadlin arm until enrolment of the first cohort is complete. Eligible subjects will then 
be allocated to either the ruxolitinib + crizanlizumab arm, the ruxolitinib + sabatolimab arm, 
the first cohort of the ruxolitinib + rineterkib arm, the ruxolitinib + NIS793 arm or subsequent 
cohorts of the ruxolitinib + siremadlin arms, and the ruxolitinib + rineterkib arm, as 
appropriate. The assignment of a subject to a particular treatment arm and dose cohort will 
be using the interactive response technology (IRT) system and coordinated by Novartis.  
Patients who have received study treatment in the Part 1 core treatment phase for a minimum 
of 24 weeks and are benefitting from the combination treatment may be eligible to enter the 
extension treatment phase after amended protocol version 08 is implemented (see Section 5.3). 
An overview of the study design at the subject level in Part 1 is shown in Figure 3-2. 


Novartis 
Confidential 
Page 69 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Figure 3-2 
Overview of study design at subject level in Part 1 
 
*Rineterkib and NIS793 added in amendment 4 of the protocol  
TBC: To be confirmed  
The combination treatment arms eligible for Part 2 will be determined after the Data Monitoring 
Committee (DMC) and Novartis study personnel have reviewed all of the available relevant 
data. This will include, but not limited to, safety information, DLTs, available 
, 
PK and PD data from evaluable subjects in Part 1 who have completed a minimum of 2 cycles 
of treatment or discontinued from the study in each treatment arm. 
This study is an open platform design as outlined in Section 4.1. Thus, new suitable combination 
treatments with ruxolitinib may be added to the protocol by amending the protocol. The 
potential adjustments to the design triggered by adding new treatments will be discussed in a 
protocol amendment. 


Novartis 
Confidential 
Page 70 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Part 2: Selection 
Part 2 of the study for each combination treatment will start once sufficient information has 
been collected in Part 1 of the study to assess the safety and tolerability of the novel agents in 
combination with ruxolitinib and to make an informed decision on which arms will be studied 
in Part 2. Combination treatment arms may enter Part 2 in a staggered manner. The primary 
objective of Part 2 is to evaluate the preliminary efficacy of ruxolitinib in combination with 
novel agents in subjects with myelofibrosis. Eligible subjects will be randomized to one or more 
combination treatment arm(s) or a ruxolitinib monotherapy arm within one or more groups. The 
combination arms will be selected based on the results from Part 1, as follows: 
• Arm 1: Ruxolitinib 5-25 mg PO BID and siremadlin at the RP2D from Part 1 PO on Days 
1 to 5 of a 28-day cycle 
• Arm 2: Ruxolitinib 5-25 mg PO BID and crizanlizumab 5 mg/kg IV Q4W with addition of 
a loading dose administered at C1D15 
• Arm 3: Ruxolitinib 5-25 mg PO BID and sabatolimab 800 mg IV Q4W 
• Arm 4: Ruxolitinib 5-25 mg PO BID and rineterkib at the RP2D from Part 1 PO QD in 28-
day cycles  
• Arm 5: Ruxolitinib 5-25 mg PO BID and NIS793 2100 mg IV Q3W  
• Arm 6: Ruxolitinib 5-25 mg PO BID monotherapy control 
The dose of ruxolitinib for all subjects should not change from the stable dose used prior to 
enrolment into the study.  
As the enrollment was permanently halted, the only randomized subject in Part 2 has 
discontinued prior to amended protocol version 08, therefore the description below for Part 2 is 
not applicable. 
Approximately 25 subjects will be randomized to each combination treatment arm, and 
approximately 30 subjects will be randomized to the common ruxolitinib monotherapy control 
arm assuming 3 groups are opened. Subjects will be randomized using the IRT system and 
treatment will continue for at least 16 cycles for treatment arms with NIS793 or 12 cycles for 
all other treatment arms (48 weeks). An overview of the study design at the subject level in Part 
2 is shown in Figure 3-3.  


Novartis 
Confidential 
Page 71 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Figure 3-3 
Overview of study design at subject level in Part 2 
 
  
Notes:  
Part 2 will consist of a maximum of 5 arms of combination treatment plus a ruxolitinib 
monotherapy control arm. The number of combination treatment arms will depend on the results 
of the Part 1 dose escalation and safety run-in phase. There will be up to approximately 155 
subjects in total in Part 2, including the ruxolitinib comparator arm. 
Part 2 will be conducted in one or more groups. Each group consists of one or more combination 
treatments along with a common ruxolitinib monotherapy control arm. 
Two interim analyses are planned for each combination treatment in Part 2 to expand into 
Part 3. The first interim analysis will be conducted after at least 10 subjects per combination 
treatment arm in Part 2 have completed 8 cycles (arms with NIS793) or 6 cycles (all other arms) 
of treatment. A threshold for outstanding preliminary efficacy will be applied to the 
combination treatments in this interim analysis. An arm that crosses the first interim analysis 
efficacy threshold and is considered safe (Figure 3-4), will be advanced to Part 3 seamlessly 
upon completion of enrollment of the Part 2 subjects in that arm (approximately 25 subjects). 


Novartis 
Confidential 
Page 72 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
The threshold has been chosen based on the probability that an observed response rate (RR) of 
the primary efficacy endpoint will be of clinical interest (i.e. 5 or more responders out of 10 
subjects) for subjects with myelofibrosis.  
The second interim analysis will be conducted after at least 25 subjects of each combination 
treatment arm in Part 2 have completed 8 cycles (arms with NIS793) or 6 cycles (all other arms) 
of treatment. A futility threshold will be applied to the combination treatments in the second 
interim analysis. The threshold has been chosen based on the probability that an observed RR 
of the primary efficacy endpoint will be of clinical interest (i.e. 5 or more responders out of 25 
subjects) for subjects with myelofibrosis. Arms that fulfill the futility criteria shown in  
Figure 3-4 are declared futile and will not be eligible for Part 3. For arms that are not considered 
futile, i.e. arms that show preliminary efficacy, all available efficacy, safety, PK 
 data 
will be assessed and combination arms that do not have a manageable safety profile or have an 
unpredictable PK/PD profile will not be considered for Part 3. The second interim analysis is 
not required if a combination treatment is advanced in Part 3 based on the first interim analysis. 
Further details are provided in Section 12. 
Figure 3-4 
Pre-specified criteria for decision making in Part 2 for expansion into 
Part 3 
 


Novartis 
Confidential 
Page 73 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Part 3: Expansion (Not applicable) 
As the enrollment was permanently halted, the Part 3 will not be initiated, therefore the 
description below for Part 3 is not applicable. 
The primary objective for Part 3 is to further characterize the efficacy of the combination 
treatment arms carried forward from Part 2. Only combination treatment arms that show 
preliminary efficacy, have a manageable safety profile, and a predictable PK/PD profile will be 
considered for expansion. A maximum of 5 combination treatments can be expanded in Part 3. 
The efficacy of ruxolitinib combination treatment(s) chosen for expansion will be compared to 
ruxolitinib monotherapy. In addition to the ruxolitinib monotherapy arm and the combination 
treatment arm(s), Part 3 will contain an arm in which subjects receive 3 or 4 cycles of 
combination treatment followed by combination partner only i.e. stopping ruxolitinib 
(“ruxolitinib cessation arm”). The Part 3 subjects will be treated for at least 16 cycles (arms 
with NIS793) or 12 cycles (all other arms). In the ruxolitinib cessation arm, during cycle 4 for 
the ruxolitinib+NIS793 combination treatment and cycle 3 for all other combination treatments 
(depending on which combination treatment is chosen), ruxolitinib will be gradually tapered 
off at the investigator's discretion to 0 mg dose. Tapering ruxolitinib treatment should be done 
within at least 14 days. At Cycle 5 Day 1 (C5D1; for NIS793) or C4D1 (for other treatments) 
in the ruxolitinib cessation arm, the dose of ruxolitinib must be reduced to 0 mg. Following 
interruption of ruxolitinib, symptoms of myelofibrosis may return over a period of 
approximately one week. In case of any withdrawal symptoms reported, investigators may 
decide to re-start ruxolitinib treatment immediately based on the clinical judgement and the 
safety assessment of the subject. 
The ruxolitinib cessation arm is included to observe the effect of monotherapy of the 
combination partner. By comparing the primary endpoint RR of the combination treatment arm 
with the RRs in the ruxolitinib cessation arm and the ruxolitinib monotherapy arm, the 
contribution of each combination partner to the efficacy of the combination treatment can be 
assessed. Four cycles (arms with NIS793) or three cycles (all other arms) of combined treatment 
is deemed necessary to establish the effect of combined treatment on disease activity, based on 
experience with single agent ruxolitinib (COMFORT-I and COMFORT-II). 
For each combination treatment chosen to be expanded in Part 3, subjects will be randomized 
to the chosen combination treatment arm, or a compound monotherapy arm (ruxolitinib 
cessation arm) or a ruxolitinib monotherapy arm, with a planned enrollment of approximately 
20 subjects for the combination treatment arm, 10 subjects for the ruxolitinib cessation arm, and 
approximately 5 subjects for the ruxolitinib monotherapy control arm. There will be maximum 
number of 50 subjects in total for the common ruxolitinib monotherapy control arm in Part 2 
and Part 3. 
• Arm 1: Ruxolitinib 5-25 mg PO BID and novel compound from Part 2 (TBC) 
• Arm 2: Ruxolitinib 5-25 mg PO BID and novel compound from Part 2 (TBC) for 3 or 4 
cycles of treatment (depending on the combination treatment), followed by ruxolitinib 
cessation treatment (i.e. novel agent monotherapy control) 
• Arm 3: Ruxolitinib 5-25 mg PO BID monotherapy control 


Novartis 
Confidential 
Page 74 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
An overview of the study design at the subject level in Part 3 is shown in Figure 3-5. A 
hypothetical example illustrating the randomization parts of the overall study design is shown 
in Section 16.8 (Appendix 8). 
Figure 3-5 
Overview of study design at subject level in Part 3 (Not applicable)  
 
TBC: To be confirmed 
4 
Rationale 
4.1 
Rationale for study design 
This is a phase Ib/II open-label, multi-center platform study in MF patients on ruxolitinib 
treatment for at least 12 weeks prior to first dose of study treatment, evaluating the safety, 
tolerability and preliminary efficacy of each novel ruxolitinib combination treatment. Using 
ruxolitinib as the backbone, this study will evaluate the combined effect of novel compounds 
that impact the hematopoietic environment through different mechanisms, which may deliver 


Novartis 
Confidential 
Page 75 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
transformational clinical benefits such as superior disease control or even reduction of the 
malignant clone.  
Considering the number of potential targets and available compounds, an open platform design 
is applied for this study. In general, platform designs allow for simultaneous assessment of 
multiple 
treatments 
within 
a 
single 
disease 
under 
one 
master 
protocol 
(Ventz et al 2017, Saville and Berry 2016). An open platform design starts with a pre-defined 
fixed number of treatment arms but as new suitable treatments become available during the 
course of the trial, new treatment arms can be added. Those new arms are added based on 
evolving scientific rationale (e.g. mechanism of action), preclinical data and if an acceptable 
safety profile has been established. Furthermore, platform designs offer adaptive features such 
as dropping treatment arms for futility and declaring one or more treatments efficacious. The 
protocol will be amended if a new arm is added to the study in Part 1. 
The platform study design methodology has been successfully applied as an accelerated 
mechanism to evaluate multiple compounds in various diseases, and has been implemented in 
recent clinical studies (e.g. I-SPY2, STAMPEDE, AML15, AML16) (Renfro and Mandrekar 
2018, Ventz et al 2017, Woodcock and LaVange 2017, Saville and Berry 2016,  
Berry et al 2015). 
The first 3 novel compounds chosen for inclusion in this study are siremadlin, crizanlizumab, 
and sabatolimab. Rineterkib and NIS793 were added in Amendment 4 of the protocol. At the 
time of the amendment, none of these compounds have been tested in MF patients previously, 
however a trial to investigate sabatolimab and NIS793 in MF patients who have had a sub-
optimal response to a JAK inhibitor (including ruxolitinib) is planned (NCT04283526; 
CMBG453D1201). The specific rationale for the combinations selected is provided 
in Section 4.3. 
The study was planned in three parts. In the context of the permanent enrollment halt, the study 
design has been revised revised as follows: 
• Part 1: Dose escalation and safety run-in (recommended Phase II dose confirmation) 
including a core treatment phase and an extension treatment phase 
• Part 2: Selection (unchanged as the only randomized subject has discontinued prior to 
amended protocol version 08) 
• Part 3: Expansion (not applicable as it will never be initiated)  
Part 1 of the study focuses on safety and tolerability, while Parts 2 and 3 assess the (preliminary) 
efficacy of siremadlin, crizanlizumab sabatolimab, rineterkib and NIS793 in combination 
with ruxolitinib, respectively.  
Part 1 includes five separate arms (core treatment phase): two dose escalation arms to determine 
the RP2D for ruxolitinib in combination with siremadlin or rineterkib, and three safety run-in 
arms to confirm the selected doses of ruxolitinib in combination with crizanlizumab, 
sabatolimab or NIS793. The end of the core treatment phase will occur when amended protocol 
version 08 is implemented and after subjects have completed a minimum of 24 weeks of 
treatment.  
As the enrollment was permanently halted, an extension treatment phase is added to the Part 1 
design as a mechanism to provide access of ruxolitinib in combination for eligible and 


Novartis 
Confidential 
Page 76 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
benefitting subjects from Part 1 until the subjects complete 21 cycles in the extension treatment 
phase or until treatment discontinuation criteria is met, whichever occurs first (see Section 9.1).  
This study will utilize a Bayesian Logistic Regression Model (BLRM) to identify the maximum 
tolerated dose (MTD) and/or RP2D for siremadlin in combination with ruxolitinib, and 
rineterkib in combination with ruxolitinib. The use of BLRMs is a well-established method to 
identify the MTD and/or RP2D. The adaptive BLRM will be guided by the escalation with 
overdose control (EWOC) principle to control the risk of DLT in future subjects on the study. 
The use of Bayesian response adaptive models for small datasets is widely accepted and 
endorsed by numerous publications (Neuenschwander et al 2008, Babb et al 1998) with its 
development and appropriate use one aspect of the Food and Drug Administration's (FDA) 
Critical Path Initiative. The decisions on new dose levels are made by the Investigators and 
Novartis study personnel in a dose escalation meeting based upon the review of patient 
tolerability and safety information (including the BLRM summaries of DLT risk) along with 
PK, PD and preliminary activity information available at the time of the decision. 
While Part 1 of the study focuses on safety and tolerability, Parts 2 and 3 assess the preliminary 
efficacy of siremadlin, crizanlizumab, sabatolimab, rineterkib, and NIS793 in combination 
with ruxolitinib, respectively.  
As the enrollment was permanently halted, the only randomized patient in Part 2 has 
discontinued prior to this amendment 08, and Part 3 will not be initiated, therefore the 
description for Parts 2 and 3 are not applicable. 
Part 2 of the study includes combination arms and a ruxolitinib single agent arm. The single 
agent arm is included as no prior information for ruxolitinib in a clinical trial setting is available 
in the population considered in this study, i.e. subjects with a prior treatment of ruxolitinib for 
at least 12 weeks and a stable dose for at least four weeks prior to study entry. The size of Part 
2 with a planned randomization of approximately 25 subjects per treatment combination arm is 
sufficient to identify treatments that show an activity that warrants further development.  
Two interim analyses are planned for each treatment combination arm in Part 2. The first interim 
analysis is planned when at least 10 subjects in each combination treatment arm have completed 
Cycle 8 (treatment arms with NIS793) or Cycle 6 (all other treatment arms), or discontinued 
earlier. The second interim analysis is planned when at least 25 subjects in each combination 
treatment arm have completed Cycle 8 (treatment arms with NIS793) or Cycle 6 (all other 
treatment arms), or discontinued earlier. If a combination treatment is advanced in Part 3 based 
on the first interim analysis, the second interim analysis is not required. All available efficacy, 
safety, PK 
 data will be assessed to determine if a particular ruxolitinib 
combination treatment will be dropped due to futility based on pre-specified criteria (see 
Section 3) or if it demonstrates preliminary efficacy and should be considered for expansion in 
Part 3. 
Part 3 is the expansion part of the study in the event that a combination treatment is deemed to 
be of interest for further development. New subjects will be randomized into this part of the 
study. The expansion part allows collection of additional data for the combination treatment 
and ruxolitinib single agent control, such that the combination treatment and ruxolitinib single 
agent can be compared. Part 3 will also include a combination partner single agent arm, where 
after an initial three months of combination therapy, ruxolitinib will be stopped to assess the 


Novartis 
Confidential 
Page 77 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
efficacy of the combination partner alone. This arm is called the ruxolitinib cessation arm. The 
expansion part of the study increases confidence in the ruxolitinib combination treatment 
selected after Part 2, prior to the start of a potential phase III trial. 
This study design will allow for assessment of safety, tolerability, and preliminary efficacy 
of siremadlin, crizanlizumab, sabatolimab, rineterkib, and NIS793 in combination 
with ruxolitinib, respectively, while reducing subjects exposure to futile treatments. 
Crossover or re-randomization of subjects to other combination arms, including better 
performing arms within a part of the study is not allowed. However, subjects are allowed to 
participate in another part of the study provided that all inclusion and none of the exclusion 
criteria are met and that they are not randomized twice. This means that Part 1 subjects could 
join Part 2 or Part 3 of the study and Part 2 and Part 3 subjects could participate in Part 1 of the 
study only. However, Part 2 subjects are not allowed to join Part 3 and vice versa.”. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 78 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 79 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 80 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
4.2.6 
Extension Treatment Phase 
Subjects eligible for the extension treatment phase will be assessed at the end of the core 
treatment phase by investigators (after the amended protocol version 08 is implemented), to 
ensure the regimen and dose subjects have been receiving is safe, tolerable and provides clinical 
benefit prior to continuation of the study treatment in the extension treatment phase.  


Novartis 
Confidential 
Page 81 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 


Novartis 
Confidential 
Page 82 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 


Novartis 
Confidential 
Page 83 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 


Novartis 
Confidential 
Page 84 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 


Novartis 
Confidential 
Page 85 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
4.4 
Purpose and timing of interim analyses/design adaptations (Not 
applicable) 
As the enrollment was permanently halted, the only randomized subject in Part 2 has 
discontinued prior to this amendment, and Part 3 will not be initiated therefore the description 
below for Parts 2 and 3 are not applicable as there will be no interim analyses for Parts 2 and 3. 
Two interim analyses are planned for each combination treatment in Part 2. The first interim 
analysis will be conducted when at least 10 subjects of each combination treatment arm in Part 
2 have completed 8 cycles (for all arms containing NIS793) or 6 cycles (all other arms) of 
treatment or discontinued from the study prior to completing Cycle 8 or Cycle 6, respectively. 
This is to determine whether combination treatment arms will be expanded in Part 3 seamlessly 
after the enrollment of the 25 subjects of the arm in Part 2 is completed, or whether the 
enrollment into Part 3 will only start once the second interim analysis is completed at the end 
of Part 2 (i.e. once all 25 subjects have completed 8 cycles (for all arms containing NIS793) or 
6 cycles (all other arms) of treatment or discontinued from the study prior to completing Cycle 
8 or Cycle 6, respectively). A threshold for outstanding preliminary efficacy will be applied to 
the combination treatments in the first interim analysis. An arm that crosses the threshold and 
is considered safe (see Figure 3-4), will continue to enroll into Part 3 seamlessly after enrollment 
of the Part 2 subjects in that arm is completed (approximately 25 subjects). The threshold has 


Novartis 
Confidential 
Page 86 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
been chosen based on the probability that an observed RR of the primary efficacy endpoint will 
be of clinical interest (i.e., 5 or more responders out of 10 subjects) for subjects with 
myelofibrosis. 
The second interim analysis is planned after at least 25 subjects of each combination treatment 
arm in Part 2 have completed 8 cycles of treatment (for all arms containing NIS793) or 6 cycles 
of treatment (all other arms), or discontinued from the study prior to completing Cycle 8 or 
Cycle 6, to determine whether combination treatment arms will be dropped for futility or be 
considered for expansion in Part 3 based on pre-specified criteria shown in Figure 3-4. See 
Section 3 and Section 12.1 for further details. 
4.5 
Risks and benefits 
Subjects enrolled in this study with a confirmed diagnosis of MF have experienced reduction 
in splenomegaly and improved QoL from clinical symptoms improvement as a result of 
ruxolitinib treatment. However, some of those subjects will present with sub-optimal treatment 
response through potential loss of the therapeutic effect of ruxolitinib in controlling clinical 
symptoms of MF or spleen size reduction. Other subjects may lose their response to ruxolitinib 
over time as inhibition of JAK-STAT signaling alone is not a curative strategy for MF. In 
addition, enrolled subjects also may experience cytopenia which cannot be controlled by 
ruxolitinib monotherapy. As such, there are limited treatment options for this population, which 
represents an unmet medical need in this disease setting. Therefore, the combinations of 
ruxolitinib with agents targeting other signaling pathways dysregulated in MF, tested in this 
study, may improve or reverse myelosuppression and provide disease-modifying effect. 
Potential risks for each combination treatment are discussed in Section 4.2. The risk to subjects 
in this trial is minimized by compliance with the eligibility criteria and adherence to the study 
procedures, as well as, close clinical monitoring and implementation of the protocol defined 
dose-modifications guidelines and treatment discontinuation criteria and appropriate adverse 
event management. 
Occurrence of an immune-related event is an anticipated risk in subjects treated with 
immunomodulatory therapies, such as NIS793 and sabatolimab. In the case of an immune-
related event, there are dose modification and management guidelines, including for follow-up 
of toxicities, proposed by the protocol in relation consensus guidelines, such as those from the 
American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network 
(NCCN) and the European Society for Medical Oncology (ESMO) (Brahmer et al 2018; 
Haanen et al 2017; see Section 6.5.4 and Section 6.5.5). 
Administration of monoclonal antibodies (mAbs) can be associated with infusion-related 
reactions (IRRs). Management and dose modification guidelines for IRRs are provided in 
Section 6.5.4 for crizanlizumab, sabatolimab, and NIS793. 
A focused search for potentially severe IRRs (i.e. indicative of hypersensitivity/anaphylaxis or 
cytokine-release syndrome) identified 2 (1.8%) patients treated with crizanlizumab at 5 mg/kg 
in the pooled data set in SCD; the reported term was infusion-related reaction, none of which 
was serious. However, severe IRRs including cases requiring hospitalization have been 
described in ongoing clinical trials and the post-marketing setting. Additionally, a broad search 
for IRRs using an extensive list of potential signs and symptoms related to infusion reactions in 


Novartis 
Confidential 
Page 87 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
SCD patients treated with crizanlizumab, and occurring within 24 hours of the infusion, 
identified 28.8% of patients in the safety pool with at least one event. Most of these events were 
reported in 1 or 2 patients only, except for nausea (9.0%), headache (8.1%), arthralgia and back 
pain (4.5%), and fatigue and myalgia (2.7%). In the SUSTAIN study [clinicaltrials.gov number 
NCT01895361], IRRs using this broader search were more frequent in the 5 mg/kg arm (34.8%) 
compared to the placebo arm (21.0%). However, except for nausea, none of the events were 
reported with an absolute differences of more than 5% in the crizanlizumab 5 mg/kg vs. the 
placebo arm. 
In summary, current data suggest that administration of crizanlizumab can be commonly 
associated with infusion related reactions, including pain events in patients with SCD, some of 
which can be severe and/or require hospitalization. Subjects should be monitored for potential 
signs and symptoms of IRRs, and participants instructed to contact the investigator/site when 
experiencing such events. In case of severe IRRs (eg. hypersensitivity/anaphylactic reaction), 
study treatment should be discontinued. For Japan only, subjects enrolled in the crizanlizumab 
arm of Part 1 (Arm 2) are required to be hospitalized in the first 7 days of study treatment. 
Grade 4 tumor lysis syndrome (TLS) was observed in one subject administered siremadlin in 
study CHDM201X2101. During this study, subjects receiving siremadlin will be closely 
monitored for signs and symptoms of TLS before initiation and during a treatment cycle as per 
guidance in Section 6.6. 
Cardiac events (AV block, atrial fibrillation, QT prolongation) associated with siremadlin 
treatment were observed in phase I and II monotherapy and combination trials. In this study, 
considering the potential cardiac risk of siremadlin, subjects treated with ruxolitinib and 
siremadlin combination will be monitored frequently in this study. See Section 8.4.2. 
No 
cardiac 
events 
have 
been 
observed 
so 
far 
in 
studies 
with 
rineterkib  
(Janku et al 2020), however considering the potential cardiac risk for MEK inhibitors, subjects 
treated with ruxolitinib and rineterkib will be frequently monitored for cardiac events as 
outlined in Section 8.4.2. In addition, since left ventricular ejection fraction (LVEF) decrease 
is a class effect of MEK inhibitors, close monitoring with a multigated acquisition (MUGA) 
scan or echocardiogram (ECHO) is recommended. See Section 8.4.3. 
Ocular events have been observed with MAPK pathway inhibitors such as MEK inhibitors, and 
in studies with rineterkib (Janku et al 2020). Therefore, in this study, subjects treated with 
ruxolitinib and rineterkib will undergo thorough ophthalmological assessments and be carefully 
monitored throughout the study, as outlined in Section 8.4.4.  
For NIS793, based on currently available data, tubulointerstitial nephritis, vascular 
inflammation, endothelial hyperplasia, and cardiac valvulopathy have been observed in NIS793 
animal studies but not in ongoing clinical studies. Cardiac and renal functions will be regularly 
monitored to minimize these risks.  
No substantial additional risk for subject safety due to the SARS-CoV-2 virus and the COVID-
19 pandemic has been identified at this time and therefore the benefit risk remains unchanged. 
In case of active COVID-19 infection, a careful benefit risk evaluation should be performed to 
determine whether a subject can remain on study treatment. 


Novartis 
Confidential 
Page 88 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
As in any clinical study, there may be unforeseen risks with ruxolitinib treatment alone or in 
combination with siremadlin, crizanlizumab, sabatolimab, rineterkib and NIS793, which could 
be serious.  
Recommended guidelines for prophylactic or supportive management of study-drug induced 
adverse events are provided in Section 6.1.4 and in the most recent version of the Investigator's 
Brochure. 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study and must agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
subject will not reliably comply, they should not be entered or continue in the study. 
Periodic review of safety data will be performed by an independent DMC. 
The enrollment halt decision was neither triggered by any safety signals nor safety concerns 
related to subjects receiving the study treatment, but due to the rapidly evolving competitive 
landscape in drug development for myelofibrosis, with multiple ongoing trials and continued 
challenges with recruitment. 
4.6 
Rationale for Public Health emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Population 
As the enrollment was permanently halted, the only randomized patient in Part 2 has 
discontinued prior to this amendment, and Part 3 will not be initiated therefore the description 
below for Parts 2 and 3 are not applicable as there will be no further subjects enrolled in Parts 
2 and 3. 
The patient population will include male or female adults (age 18 or over) with a confirmed 
diagnosis of PMF as defined by the World Health Organization 2016 criteria (Arber et al 2016) 
or PPV-MF, or PET-MF according to International Working Group for Myelofibrosis Research 
and Treatment (IWG-MRT) 2007 (Barosi et al 2008) criteria and in addition at baseline: 
• Have Hb < 11g/dL (≤ 6.8 mmol/L), and 
• Are on ruxolitinib therapy for at least 12 weeks with an unchanged ruxolitinib dose (range 
5-25 mg BID) for the previous ≥ 4 weeks prior to first dose of study treatment, and 
• Exhibit measurable splenomegaly demonstrated by spleen volume of ≥ 450 cm3 by MRI or 
CT scan assessment or by palpable spleen measuring of ≥ 5 cm below left costal margin 
(LCM). MRI/CT scan up to 8 weeks prior to first dose of study treatment can be accepted. 
The total number of subjects expected to enroll into the entire study, allowing for dropouts and 
non-evaluable patients, is approximately 240 assuming that 5 combination treatments from Part 


Novartis 
Confidential 
Page 89 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
1 are selected for Part 2, and that 1 of the 5 combination treatments is expanded in Part 3. The 
actual number of patients recruited will depend upon the number of dose levels tested in the 
dose escalation Part 1 and the number of combination arms carried into Parts 2 and 3. If all 5 
combination treatments enter Part 3, then there will be a maximum of approximately 380 
subjects in total in all 3 parts of the study 
The investigator or designee must ensure that only patients who meet all of the following 
inclusion and none of the exclusion criteria at screening are assigned treatment in the study. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Male or female subjects are at least 18 years of age at the time of signing the informed 
consent form (ICF). For Japan only: written consent is necessary both from the subject and 
his/her legal representative if he/she is under the age of 20 years. 
2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2. 
3. Subjects have diagnosis of primary myelofibrosis (PMF) according to the 2016 World 
Health Organization (WHO) criteria, or diagnosis of post-ET (PET-MF) or post-PV 
myelofibrosis (PPV-MF) according to the International Working Group for Myelofibrosis 
Research and Treatment (IWG-MRT) 2007 criteria. 
4. Palpable spleen of at least 5 cm from the left costal margin (LCM) to the point of greatest 
splenic protrusion or enlarged spleen volume of at least 450 cm3 per MRI or CT scan at 
baseline (a MRI/CT scan up to 8 weeks prior to first dose of study treatment can be accepted). 
5. Have been treated with ruxolitinib for at least 12 weeks prior to first dose of study treatment. 
6. Are stable (no dose adjustments) on the prescribed ruxolitinib dose (between 5 and 25 mg 
BID) for ≥ 4 weeks prior to first dose of study treatment. 
7. Hemoglobin < 11 g/dL (≤ 6.8 mmol/L). 
8. Absolute neutrophil count (ANC) ≥ 1000/μL. 
9. Part 1: Platelet counts ≥ 75,000/μL 
10. Part 2 and Part 3: Platelet counts ≥ 50,000/μL. 
11. Subjects must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Not able to understand and to comply with study instructions and requirements. 
2. Received any investigational agent for the treatment of MF (except ruxolitinib) within 30 
days of first dose of study treatment or within 5 half-lives of the study treatment, whichever 
is greater. 
3. Received any investigational cancer vaccine or immunotherapy within 6 months prior to 
first dose of study treatment.  
4. Peripheral blood blasts count of > 10%. 


Novartis 
Confidential 
Page 90 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
5. Inadequate liver function defined by any of these: Total bilirubin ≥ 2.5 x ULN and 
subsequent determination of direct bilirubin ≥ 2.5 x upper limit of normal (ULN); Alanine 
aminotransferase (ALT) > 2.5 x ULN; Aspartate aminotransferase (AST) > 2.5 x ULN. 
6. Severely impaired renal function defined by: Estimated creatinine clearance < 30mL/min.  
7. Active bacterial (including active and latent tuberculosis), fungal, parasitic, or viral 
infection that requires therapy. 
8. Known history of human immunodeficiency virus (HIV) infection or in the opinion of the 
investigator other clinically significant immunodeficiency syndromes such as X-linked 
agammaglobulinemia and common variable immune deficiency. 
9. Evidence of active HBV or HCV viral infection (HBsAg in the absence of HBsAb OR HCV 
Ab positive with HCV RNA positive). Subjects whose disease is controlled under antiviral 
therapy should not be excluded. 
10. History of progressive multifocal leuko-encephalopathy (PML). 
11. History of a second primary malignancy in the past 3 years in need of systemic treatment. 
12. History or current diagnosis of uncontrolled or significant cardiac disease including any of 
the following: 
• Acute Myocardial infarction, coronary stenting, or bypass surgery within the last 6 
months 
• Uncontrolled congestive heart failure requiring treatment (New York Heart Association 
Grade ≥ 2), LVEF < 50% as determined by multigated acquisition (MUGA) scan or 
echocardiogram (ECHO), or uncontrolled hypertension defined by blood pressure ≥ 
140 (systolic) /90 (diastolic) mmHg at rest (average of 3 consecutive readings) despite 
medical treatment 
• Unstable angina pectoris within the last 6 months 
• For NIS793 arms only in Part 1 and all arms in Part 2 and 3 if NIS793 is open for 
enrollment: 
• Cardiac valvulopathy ≥ Grade 2 
• Elevated cardiac enzymes (troponin I) elevation > 2x ULN 
• Medical history or current diagnosis of myocarditis 
13. History or current diagnosis of ECG abnormalities indicating significant risk of cardiac 
disease such as:  
• Resting QTcF ≥ 470 msec at pretreatment (baseline) for both male and female or 
impossibility to determine QTc 
• Concomitant clinically significant cardiac arrhythmias (e.g. uncontrolled atrial flutter / 
fibrillation, ventricular tachycardia), and clinically significant second or third degree 
AV block without a pacemaker 
• History of familial long QT syndrome or know family history of Torsades de Pointe or 
any of the following: 
• Risk factors for Torsades de Pointe including uncorrected hypokalemia or 
hypomagnesemia, 
history 
of 
cardiac 
failure, 
or 
history 
of 
clinically 
significant/symptomatic bradycardia 
• Inability to determine the QTcF interval 


Novartis 
Confidential 
Page 91 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
14. Any condition which, in the opinion of the investigator, is likely to interfere with the 
successful collection of the measurements required for the study 
15. Contraindication or hypersensitivity to any drug or metabolites from similar class as study 
drug or to any excipients of the study drug formulation. 
16. Any other known disease that could compromise participation in the study including 
gastrointestinal (GI) disorders impacting absorption of ruxolitinib or siremadlin (e.g., 
ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, 
small bowel resection), evidence of major active bleeding or history of bleeding diathesis 
or major coagulopathy. 
17. Had history of documented severe hypersensitivity reactions/immunogenicity to a prior 
biologic product in any treatment arm OR received a monoclonal antibody or 
immunoglobulin-based agent: 
• For treatment arms with NIS793, crizanlizumab or sabatolimab within 1 year of 
screening,  
• For treatment arms with rineterkib or siremadlin arms within <=4 weeks of screening 
or <=5 half-lives whichever is shorter for rineterkib or siremadlin arms.  
• For Part 2 and Part 3, the longest window will apply based on the compounds opened 
for randomization. 
18. Significant immune deficiency (including chronic use of immunosuppressive drugs) in the 
opinion of the investigator.  
19. Pregnant females or females who have given birth within the past 90 days or who are 
breastfeeding.  
20. Women of child-bearing potential (WOCBP), defined as all women physiologically capable 
of becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 30 days after the last dose of single-agent ruxolitinib 
(control/monotherapy), for 30 days after the last dose of siremadlin for subjects on 
ruxolitinib + siremadlin (or siremadlin monotherapy), for 30 days after the last dose of 
rineterkib for subjects on ruxolitinib + rineterkib (or rineterkib monotherapy), for 90 days 
after the last dose of NIS793 for subjects on ruxolitinib + NIS793 (or NIS793 monotherapy), 
105 days after the last dose of crizanlizumab for subjects on ruxolitinib + crizanlizumab (or 
crizanlizumab monotherapy), and for 150 days after the last dose of sabatolimab for subjects 
on ruxolitinib + sabatolimab (or sabatolimab monotherapy). 
Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral 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 sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 


Novartis 
Confidential 
Page 92 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Use of an intrauterine device (IUD) or intrauterine system (IUS). Any forms of 
hormonal contraception for example oral, injectable, implanted, transdermal hormonal 
patch or hormonal vaginal ring are excluded from use 
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six 
weeks prior to start of study treatment. 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. 
If local regulations deviate from the contraception methods listed above (for women of 
child-bearing potential or male) to prevent pregnancy, local regulations apply and will be 
described in the ICF. 
21. Sexually active males unless they use a condom during intercourse while taking siremadlin 
or rineterkib and for 2 weeks after siremadlin or rineterkib discontinuation, and thus do not 
attempt to father a child in this period. A condom is required to be used also by vasectomized 
men in order to prevent delivery of the drug via seminal fluid. 
22. History of drug-induced pneumonitis or current pneumonitis. 
23. Use of erythropoietin stimulating agents (ESA) ≤ 4 weeks prior to first dose of study 
treatment. 
24. Splenic irradiation within 6 months prior to the first dose of study drug. 
25. Received blood platelet transfusion within 28 days prior to first dose of study treatment. 
Note: PRBC transfusions are permitted. 
26. Subjects with known TP53 mutation or deletion of TP53. 
27. Currently receiving treatment with drug or herbal medications that meet any of the 
following criteria: 
• Require the use of herbal preparations/medications and dietary supplements (except for 
vitamins) within 7 days prior to first dose of study treatment or are expected to use such 
products during the entire study. 
• Receiving fluconazole at doses higher than 200 mg daily. 
• Require treatment with moderate or strong CYP3A4/5 inducers within 14 days 
prior to first dose of study treatment, and cannot be discontinued or switched to 
alternative medication prior to first dose of study treatment. 
• Require treatment with strong CYP2C9 inducers within 14 days prior to first dose of 
study treatment, and cannot be discontinued or switched to alternative medication prior 
to first dose of study treatment. 
• Require treatment with moderate or strong CYP3A4/5 inhibitors within 48 hours prior 
to first dose of study treatment, and cannot be discontinued or switched to alternative 
medication prior to first dose of study treatment. 
• Require treatment with strong CYP2C9 inhibitors within 48 hours prior to first dose of 
study treatment, and cannot be discontinued or switched to alternative medication prior 
to first dose of study treatment. 


Novartis 
Confidential 
Page 93 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Require treatment with substrates of CYP3A4/5 with a narrow therapeutic index within 
24 hours prior to first dose of study treatment. 
(NOTE: the above criteria is consolidated across ALL treatment arms to accommodate for 
subject randomization process. For 'treatment arm' specific restrictions related to 
concomitant medication while on 'study treatment’, please refer to Section 6.2.2) 
28. Eligible for allogeneic hematopoietic stem cell transplantation (ASCT) at the time of 
enrollment. 
29. Use of live vaccines within 30 days prior to first dose of study treatment. 
30. Use of systemic steroid therapy and other immunosuppressive drugs within 14 days prior to 
first dose of study treatment (> 10 mg/day prednisone or equivalent). Topical, inhaled, nasal, 
ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a 
transfusion are allowed and not considered a form of systemic treatment. 
31. Occurrence of any clinically significant bleeding events within 6 months prior to first dose 
of study treatment. 
32. For patients treated with rineterkib in Part 1 and for all patients in Part 2 and Part 3 (if an 
rineterkib arm is included in the randomization for Part 2 or Part 3): Pre-existing retinal vein 
occlusion (RVO) or current risk factors (apart from the underlying MF) for RVO (e.g. 
uncontrolled 
glaucoma 
or ocular 
hypertension, 
history 
of 
hyperviscosity or 
hypercoagulability syndromes). 
5.3 
Eligibility for extension treatment phase 
Subjects eligible for inclusion in the extension treatment phase must meet all 
the following criteria:Inclusion criteria 
1. Signed informed consent for the extension treatment phase must be obtained ect who is 
ongoing in the core treatment phase. 
2. Subject who demonstrates clinical benefit of treatment in core treatment phase per 
investigator’s assessment. 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for the extension treatment phase:  
1. Subject meets any of study treatment discontinuation criteria outlined in Section 9.1 
2. Subject currently has evidence of treatment failure as determined by the investigator, 
following treatment in core treatment phase. 
3. Subject enrolled in another interventional study. 
4. Subject has evidence of non-compliance to study procedures or withdrew consent in core 
treatment phase. 
5. Subject currently has unresolved toxicities for which study treatment has been interrupted 
in the core treatment phase. 
6. Subject has local access to alternative myelofibrosis treatment including those currently 
under investigation in clinical trials as assessed suitable in the opinion of the investigator. 


Novartis 
Confidential 
Page 94 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
6 
Treatment 
6.1 
Study treatment 
For this study, the term 'investigational drug' refers to ruxolitinib, siremadlin, crizanlizumab 
sabatolimab, rineterkib, or NIS793 labelled and supplied by Novartis as listed in Table 6-1. For 
USA only, ruxolitinib will be supplied locally as commercially available either by Novartis or 
by the site pharmacy. The term 'combination treatment' refers to ruxolitinib administered in 
combination with siremadlin (HDM201), crizanlizumab (SEG101), sabatolimab (MBG453), 
rineterkib (LTT462) or NIS793. The term 'study treatment' refers to any single agent treatment 
(investigational drug) or combination treatment that a subject has been allocated to in Part 1 or 
randomized to in Parts 2 and 3 of the study. 
6.1.1 Investigational and control drugs 
Table 6-1 
Investigational drugs 
Investigational 
Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global or local) 
Ruxolitinib 
(INC424) 5 mg 
Tablet 
Oral use 
open-label 
supply; bottles 
Sponsor (global and local 
for USA only) 
Ruxolitinib 
(INC424) 10 mg 
(not applicable*) 
Tablet 
Oral use 
open-label 
supply; bottles 
Sponsor (local, USA only) 
Ruxolitinib 
(INC424) 15 mg 
(not applicable*) 
Tablet 
Oral use 
open-label 
supply; bottles 
Sponsor (local, USA only) 
Ruxolitinib 
(INC424) 20 mg 
(not applicable*) 
Tablet 
Oral use 
open-label 
supply; bottles 
Sponsor (local, USA only) 
Ruxolitinib 
(INC424) 25 mg 
(not applicable*) 
Tablet 
Oral use 
open-label 
supply; bottles 
Sponsor (local, USA only) 
Siremadlin 
(HDM201) 10 mg 
Capsule 
Oral use 
open-label 
subject packs; 
bottles 
Sponsor (global) 
Siremadlin 
(HDM201) 20 mg  
Capsule 
Oral use 
open-label 
subject packs; 
bottles 
Sponsor (global) 
Siremadlin 
(HDM201) 40 mg 
(not applicable#) 
Capsule 
Oral use 
open-label 
subject packs; 
bottles 
Sponsor (global) 
Crizanlizumab 
(SEG101) 100 mg / 
10 mL (not 
applicable**) 
Concentrate for 
solution for infusion 
Intravenous 
use  
open-label 
subject packs; 
vials 
Sponsor (global) 
Sabatolimab 
(MBG453) 100 mg 
/ 1 mL (not 
applicable**) 
Concentrate for 
solution for infusion 
Intravenous 
use  
open-label 
subject packs; 
vials 
Sponsor (global) 


Novartis 
Confidential 
Page 95 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Investigational 
Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global or local) 
Sabatolimab 
(MBG453) 400 mg 
/ 4 mL (not 
applicable**) 
Concentrate for 
solution for infusion 
Intravenous 
use  
open-label 
subject packs; 
vials 
Sponsor (global) 
Rineterkib 
(LTT462) 100 mg 
Capsule 
Oral use 
open-label 
subject packs; 
bottles 
Sponsor (global) 
Rineterkib 
(LTT462) 50 mg 
(not applicable**) 
Capsule 
Oral use 
open-label 
subject packs; 
bottles 
Sponsor (global) 
NIS793 700mg / 
7mL (not 
applicable**) 
Concentrate for 
solution infusion 
(Liquid in vial) 
Intravenous 
use  
open-label 
subject packs; 
vials 
Sponsor (global) 
From amended protocol version 08: 
* Investigational Drug provided locally by the sponsor in USA is not applicable as USA will not be initiated due 
to enrollment halt. 
** Investigational Drugs which are not applicable as they will no longer be investigated due to enrollment halt, 
and there are no ongoing subjects receiving such drug.  
From amended protocol version 09: 
# Investigational Drug strengths which are not applicable as they will no longer be investigated due to 
enrollment halt, and there are no ongoing subjects receiving such drug strength. 
A dose of 30 mg siremadlin will also be used in the study as a combination of the 10 mg and 
20 mg capsules. 
The Part 1 extension treatment phase will use similar clinical supplies as the Part 1 core 
treatment phase. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
Ancillary treatments for potential infusion reactions with crizanlizumab, 
sabatolimab and NIS793 
 
  
 
 
 
 
 
 
 
 If a subject experiences an infusion reaction, he/she may receive pre-medication on 
subsequent dosing days. The pre-medication should be chosen per institutional standard of care, 


Novartis 
Confidential 
Page 96 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
at the discretion of the treating physician. If a subject experiences a Grade 3 or Grade 4 infusion 
reaction, the investigational drug should be discontinued. 
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. 
 
 
 
 
  
 
 
 
 
 
6.1.3 Treatment arms/group 
This is an open-label, three-part study. The dose of ruxolitinib used for all subjects in any part 
of the study (5-25 mg PO BID), whether taken as a single agent control or in combination with 
one of the 5 novel compounds, should not change from the stable dose used prior to first dose 
of study treatment. This applies also to the extension treatment phase. 
Part 1: Dose escalation and safety run-in 
In Part 1 of the study, subjects will be allocated to one of the following 5 treatment arms (core 
treatment phase): 
• Arm 1: Ruxolitinib 5-25 mg PO BID and siremadlin at various dose levels (either 10 mg, 
20 mg (starting dose), 30 mg or 40 mg) PO QD on Days 1 to 5 of a 28-day cycle 
• Arm 2: Ruxolitinib 5-25 mg PO BID and crizanlizumab 5 mg/kg IV Q4W with a loading 
dose administered at C1D15 
• Arm 3: Ruxolitinib 5-25 mg PO BID and sabatolimab 800 mg IV Q4W 
• Arm 4: Ruxolitinib 5-25 mg PO BID and rineterkib at various dose levels (either 100 mg, 
200 mg (starting dose) or 300 mg) PO QD in 28-day cycles 
• Arm 5: Ruxolitinib 5-25 mg PO BID and NIS793 2100 mg IV Q3W 
For Arm 1 and Arm 4, a dose escalation will be performed to determine the RP2D of the 
combination treatment of siremadlin with ruxolitinib and rineterkib with ruxolitinib, 
respectively. It is estimated that approximately 18 subjects will be included in the dose 
escalation part for the combination of ruxolitinib and siremadlin in Arm 1, approximately 6 
subjects in each of 3 proposed cohorts. Approximately 12 subjects will be included in the dose 
escalation part for the combination or ruxolitinib and rineterkib in Arm 4. For Arm 2 (ruxolitinib 
+ crizanlizumab), Arm 3 (ruxolitinib + sabatolimab) and Arm 5 (ruxolitinib + NIS793), a safety 
run-in based on approximately 6 subjects per treatment arm will be conducted.  


Novartis 
Confidential 
Page 97 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
From the time of implementation of the amended protocol version 08, subjects who have 
received the combination treatment for a minimum of 24 weeks in the core treatment phase of 
Part 1 and are benefitting from the allocated combination treatment may be eligible to continue 
the same combination treatment in the extension treatment phase. 
As the enrollment was permanently halted, the only Part 2 subject who was randomized to Arm 
6 has been prematurely discontinued, and Part 3 will not be initiated, therefore the descriptions 
below for Parts 2 and 3 are not applicable. 
Part 2: Selection (not applicable) 
In Part 2 of the study, subjects will be randomized to one of the following 6 treatment arms in 
groups with approximately 25 subjects per combination treatment arm and up to approximately 
30 subjects per ruxolitinib monotherapy control arm (no (0) subjects will be allocated to each 
non-selected arm if a combination treatment does not enter Part 2): 
• Arm 1: Ruxolitinib 5-25 mg PO BID and siremadlin at the RP2D from Part 1 PO QD on 
Days 1 to 5 of a 28-day cycle 
• Arm 2: Ruxolitinib 5-25 mg PO BID and crizanlizumab 5 mg/kg IV Q4W 
• Arm 3: Ruxolitinib 5-25 mg PO BID and sabatolimab 800 mg IV Q4W 
• Arm 4: Ruxolitinib 5-25 mg PO BID and rineterkib at the RP2D from Part 1 PO QD in 28-
day cycles  
• Arm 5: Ruxolitinib 5-25 mg PO BID and NIS793 2100 mg IV Q3W 
• Arm 6: Ruxolitinib 5-25 mg PO BID monotherapy control 
Part 3: Expansion (not applicable) 
In Part 3 of the study, subjects will be randomized to combination treatment arms or 
monotherapy arms with a planned enrollment of approximately 20 subjects for the combination 
treatment arms, 10 subjects for the cessation arms (novel agent monotherapy arm), and a 
common ruxolitinib monotherapy control arm. There will be maximum number of 50 subjects 
in total for the common ruxolitinib monotherapy control arm in Part 2 and Part 3: 
• Arm 1: Ruxolitinib 5-25 mg PO BID and novel compound from Part 2 (TBC) 
• Arm 2: Ruxolitinib 5-25 mg PO BID and novel compound from Part 2 (TBC) for 3 or 4 
cycles of study treatment (depending on the combination treatment), followed by ruxolitinib 
cessation treatment (i.e. novel agent monotherapy control) 
• Arm 3: Ruxolitinib 5-25 mg PO BID monotherapy control 
6.1.4 
Guidelines for continuation of treatment 
For continuation of study treatment, please refer to Section 6.5.4 dose modifications and 
Section 6.5.5 follow-up for toxicities. 
6.1.5 
Treatment duration 
The duration of core treatment phase in Part 1 (Dose escalation and safety run-in) is planned 
for 6 or 8 cycles depending on the treatment arm (24 weeks). For all arms containing NIS793, 


Novartis 
Confidential 
Page 98 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
which has a 21-day cycle (Q3W), the duration of treatment is 8 cycles. For all other arms, which 
have 28-day cycles the duration of treatment is 6 cycles.  
As of amended protocol version 08 implementation, subjects who are in the core treatment 
phase of Part 1 and are benefitting from the allocated combination treatment may be eligible to 
continue the same combination treatment in the extension treatment phase. The duration of the 
extension treatment phase is planned for a maximum of 21 cycles and will continue until all 
subjects have reached the planned duration or have discontinued treatment earlier (see  
Section 9.1). As the enrollment was permanently halted, the only Part 2 patient who was 
randomized to Arm 6 has been prematurely discontinued, and Part 3 will not be initiated, 
therefore the descriptions below for Parts 2 and 3 are not applicable. 
In Part 2 (Selection) and Part 3 (Expansion) the planned duration of treatment is 12 or 16 cycles 
depending on the study treatment arm (48 weeks), as noted above for Part 1.  
The subject will start study treatment on Cycle 1 Day 1 (C1D1) and each cycle is either 21 days 
(all arms containing NIS793) or 28 days (all other arms).  
Subjects may be discontinued from treatment earlier due to unacceptable toxicity, disease 
progression or treatment is discontinued at the discretion of the investigator or the subject. 
Subjects who complete participation in this trial and continue to derive clinical benefit from the 
treatment based on the investigator’s evaluation may receive post-trial access. Post Trial Access 
(PTA) means the provision of treatment to trial participants following their completion of trial 
participation. PTA will be provided until one of the following is met: participant no longer 
derives clinical benefit, investigator discontinues treatment, launch or reimbursement (where 
applicable), treatment fails to achieve registration in the trial participant’s country, or the 
clinical program is discontinued for any other reason. Mechanisms for provision of PTA may 
include an extension phase to this study, a separate extension protocol, a rollover protocol, 
provision of the Novartis investigational product in a non-trial setting (known as post-study 
drug supply [PSDS]) when no further safety or efficacy data are required, or any other 
mechanism appropriate for the country.  
Following the enrollment halt decision, the post-trial access solution for this study is the 
extension treatment phase introduced with amended protocol version 08.  
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
Prior ruxolitinib treatment of at least 12 weeks prior to the first dose of study treatment must be 
recorded in the eCRF, including the dosing information up to 4 weeks prior to study treatment. 
The subject must be told to notify the investigational site about any new medications he/she 
takes within 30 days prior to initial dosing until the completion of end of study (EOS) visit. 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) taken within 30 days prior to first dose of study treatment must be recorded 
on the appropriate case report forms (CRFs). 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 


Novartis 
Confidential 
Page 99 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
enrolling a subject or allowing a new medication to be started. If the subject is already enrolled, 
contact Novartis to determine if the subject should continue participation in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
The following medications have restrictions on their use during the study, including the 
extension treatment phase: 
• In patients for whom low molecular weight heparin or any other anti-coagulant, and anti-
platelet (including aspirin ≤ 150 mg/day) drug use will be initiated, the degree of 
thrombocytopenia should be considered, coagulation parameters monitored, and dose of 
anti-coagulant adjusted accordingly. 
• Granulocyte growth factors (G-CSF) may be used for severe neutropenia at the 
Investigator’s discretion while study medication is being withheld. 
• The drug label for ruxolitinib should be consulted for guidance on concomitant therapies 
and in consideration of the below cautionary use under Section 6.2.1.1.1 and 
Section 6.2.1.1.2 for the respective combinations arms. 
• Concomitant use of moderate CYP2C9 inducers are to be used with caution. 
• Concomitant use of moderate CYP2C9 inhibitors are to be used with caution 
6.2.1.1.1 Permitted concomitant therapy requiring caution and/or action: Specific to 
combination arm ruxolitinib + siremadlin 
In addition to the permitted medications requiring cautionary use listed under Section 6.2.1.1, 
the following applies to treatment arm ruxolitinib + siremadlin: 
• CYP3A4 sensitive substrates are to be used with caution 24 hours before, during and 48 
hours after siremadlin administration 
• OATP1B1 substrates are to be used with caution 24 hours before, during and 48 hours after 
siremadlin administration 
• MATE1 substrates are to be used with caution 24 hours before, during and 48 hours after 
siremadlin administration 
• P-gp inhibitors are to be used with caution on all days of siremadlin administration 
Refer to Table 16-1 in Section 16.1 (Appendix 1) for a detailed list on concomitant medications 
to be used with caution. 
6.2.1.1.2 Permitted concomitant therapy requiring caution and/or action: Specific to 
ruxolitinib single agent arm, or combination arm ruxolitinib + crizanlizumab, 
or ruxolitinib + sabatolimab, or ruxolitinib + NIS793 
In addition to the permitted medications requiring cautionary use listed under Section 6.2.1.1, 
the following applies for treatment arms ruxolitinib + crizanlizumab, ruxolitinib + sabatolimab, 
ruxolitinib + NIS793, and ruxolitinib single agent, including during the extension treatment 
phase: 
• Concomitant use of moderate CYP3A4 inducers is discouraged during the study, and 
investigators should seek alternatives where possible. No dose adjustments are needed when 


Novartis 
Confidential 
Page 100 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
moderate CYP3A4 inducers are co-administered with study treatment. However, any 
concomitant use of moderate CYP3A4 inducers must be documented (Section 16.1). 
• Vaccination against COVID-19 is allowed, unless these are attenuated vaccines, but should 
not be administered on the same day of study treatment administration to avoid potential 
overlapping adverse events. (Note: Use of COVID-19 live vaccine is prohibited during the 
study (Section 6.2.2)). 
Refer to Table 16-1 in Appendix 1 (Section 16.1) for a detailed list on concomitant medications 
to be used with caution. 
6.2.1.1.3 Permitted concomitant therapy requiring caution and/or action: Specific to 
combination arm ruxolitinib + rineterkib 
In addition to the permitted medications requiring cautionary use listed under Section 6.2.1.1, 
the following applies to treatment arm ruxolitinib + rineterkib, including during the extension 
treatment phase: 
• Substrates of CYP3A4 with narrow therapeutic index 
• Sensitive substrates of CYP3A 
• Moderate CYP3A inhibitors or inducers. 
• Moderate CYP2C8 inhibitors or inducers. 
• Proton pump inhibitors and agents that modify gastric pH. If antacids and/or H2 receptor 
antagonists are indicated, follow the guideline provided in Appendix 1 regarding timing of 
administration of these agents relative to rineterkib dosing. 
• Drugs with known risk of Torsades de Pointes. 
6.2.2 Prohibited medication 
The following medications, herbal remedies or foods are prohibited during the study, including 
during the extension treatment phase: 
• Any investigational medication (other than ruxolitinib, siremadlin, crizanlizumab, 
sabatolimab, rineterkib, or NIS793) that is not approved for any indication. Use of such 
medications within 30 days, prior to the first dose of study treatment, or within 5 half-lives 
of the study treatment, whichever is greater, and during the study through the Safety Follow-
up Visit is prohibited. 
• Aspirin > 150 mg/day  
• Any use of ESAs. 
• Any other medication for the treatment of myelofibrosis, including but not limited to: 
• Hydroxyurea (Hydrea, Hydroxycarbamide) 
• Busulfan 
• Interferon 
• Lenalidomide 
• Thalidomide 
• Anagrelide 
• Fedratinib 


Novartis 
Confidential 
Page 101 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Use of systemic steroid therapy and other immunosuppressive drugs is prohibited within 14 
days prior to starting study treatment (> 10 mg/day prednisone or equivalent) and during 
the study treatment period except for the treatment of infusion reaction, treatment of 
immune-related AEs (irAEs), for prophylaxis against imaging contrast dye allergy, 
replacement-dose steroids in the setting of adrenal insufficiency (provided this is ≤ 
10 mg/day prednisone or equivalent) or treatment of transient exacerbation of other 
underlying diseases such as chronic obstructive pulmonary disease requiring treatment for 
≤ 3 weeks.  
• Systemic corticosteroids required for control of infusion reactions or irAEs must be tapered 
and be at non-immunosuppressive doses (≤ 10 mg/day prednisone or equivalent) before the 
next study treatment administration. If more than 10 mg/day prednisone is used, study 
treatment should be interrupted until the subject receives 10 mg/day or less of prednisone.  
• Topical, inhaled, nasal, ophthalmic steroids are allowed.  
• Replacement therapy, steroids given in the context of a transfusion are allowed and not 
considered a form of systemic treatment. 
• Use of live vaccines within 30 days prior to starting treatment and at any time during 
treatment period. Refer to Section 6.2.2.2 for the restriction of vaccines for the respective 
combination arms during study treatment. 
• Use of strong CYP3A4/5 inhibitors are prohibited within 48 hours prior to starting treatment. 
When such a concomitant administration of a strong CYP3A4 inhibitor (see Table 16-2 in 
Appendix 2 (Section 16.2) for a listing of these medications) is required for patient 
management, the dose of ruxolitinib must be adjusted as described in Section 6.2.2.4 in 
accordance with the respective treatment arm. Note for Part 1, use of strong CYP3A4/5 
inhibitors are strictly prohibited up to end of Cycle 2, as a dose adjustment for 
ruxolitinib is not permitted within this period. 
• Herbal preparations/medications and dietary supplements (except for vitamins) are not 
allowed throughout the study. 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. Subjects should stop using these herbal medications 
7 days prior to first dose of study drug. 
• Subjects should be instructed to avoid consumption of grapefruit, grapefruit hybrids, 
pummelos, star-fruit, Seville oranges or products containing the juice of each during the 
entire study, due to potential CYP3A4 interaction with the study medications. 
• Fluconazole doses greater than 200 mg daily are prohibited in all combination arms. In 
addition, all doses of fluconazole are prohibited in combination arm ruxolitinib + siremadlin 
(see Section 6.2.2.1). The drug label for ruxolitinib should be consulted for guidance on 
concomitant therapies, however, it must be in consideration of the restrictions under 
Section 6.2.2, Section 6.2.1.1 and Section 6.2.2.2 for the respective combinations arms. 
• Use of strong inducers of CYP3A4/5 are prohibited within 14 days prior to starting and at 
any time during the study treatment period as ruxolitinib, siremadlin and rineterkib are 
CYP3A4 substrate. 


Novartis 
Confidential 
Page 102 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Use of strong inducers of CYP2C9 are prohibited within 14 days prior to starting treatment 
and at any time during the study treatment period as CYP2C9 is a major contributor to 
ruxolitinib metabolism. 
• Use of strong inhibitors of CYP2C9 are prohibited within 48 hours prior to starting 
treatment and at any time during the study treatment period. 
6.2.2.1 
Prohibited medication specific to combination arm ruxolitinib + 
siremadlin 
In addition to the prohibited medications listed under Section 6.2.2, the following medications 
are prohibited during the study, including the extension treatment phase, or prohibited within a 
defined time window:  
• Use of moderate inducers of CYP3A4/5 are prohibited within 14 days prior to starting and 
at any time during the study treatment period as both ruxolitinib and siremadlin are primarily 
metabolized by CYP3A4 
• Moderate or strong inhibitors of CYP3A4/5 are prohibited during 48 hours before and 48 
hours after siremadlin administration 
• Use of CYP3A4/5 substrates with a narrow therapeutic index (NTI) are prohibited 24 hours 
before and 48 hours after siremadlin administration as in vitro experiments have shown 
siremadlin to be both a time-dependent and reversible inhibitor of CYP3A4/5 
Refer to Table 16-2 in Appendix 2 (Section 16.2) for a detailed list on prohibited concomitant 
medications 
6.2.2.2 
Prohibited medication specific to combination arm ruxolitinib + 
crizanlizumab or ruxolitinib + sabatolimab, or ruxolitinib +NIS793) 
In addition to the prohibited medications listed under Section 6.2.2, the following medications 
are prohibited during the study, including the extension treatment phase for the treatment arms 
ruxolitinib + crizanlizumab, ruxolitinib + sabatolimab, and ruxolitinib + NIS793:  
• Administration of monoclonal antibodies other than crizanlizumab, sabatolimab or NIS793. 
• Use of live vaccines after administration of NIS793, crizanlizumab or sabatolimab at any 
time during the study treatment period until 90 days, 105 days and 150 days after the last 
dose of NIS793, crizanlizumab and sabatolimab, respectively.  
Refer to Table 16-2 in Appendix 2 (Section 16.2) for a detailed list on prohibited concomitant 
medications. 
6.2.2.3 
Prohibited medication specific to combination arm ruxolitinib + 
rineterkib 
In addition to the prohibited medications listed under Section 6.2.2, the following medications 
are prohibited during the study, including the extension treatment phase, or prohibited within a 
defined time window for the treatment arm ruxolitinib + rineterkib:  
• Medication, herbs or supplements that are strong inhibitors of CYP3A4 as rineterkib is 
metabolized mainly by CYP3A4  
• Strong inducers and inhibitors of CYP2C8 as rineterkib is partly metabolized by CYP2C8. 


Novartis 
Confidential 
Page 103 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
6.2.2.4 
Dose reduction of ruxolitinib with concomitant strong CYP3A4 
inhibitors or fluconazole 
The drug label for ruxolitinib should be consulted for guidance on ruxolitinib dose adjustment 
requirement when coadministered with strong inhibitors of CYP3A4 or dual inhibitors of 
CYP2C9 and CYP3A4 (e.g. fluconazole). See Table 16-2 in Appendix 2 (Section 16.2) for a 
listing of strong CYP3A4 inhibitors. Ruxolitinib is eliminated through metabolism by CYP3A4 
and CYP2C9. With concomitant strong CYP3A4 inhibitors such as, but not limited to, 
ketoconazole, clarithromycin, itraconazole, nefazodone and telithromycin (see Appendix 2, 
Section 16.2), plasma exposure of ruxolitinib increases approximately 2-fold. Therefore, when 
the concomitant administration of a strong systemic CYP3A4 inhibitor or a dual inhibitor of 
CYP2C9 and CYP3A4 is required for patient management the dose of ruxolitinib must be 
adjusted as follows according to the respective treatment arm. 
For ruxolitinib single agent, ruxolitinib + crizanlizumab, ruxolitinib + sabatolimab, or 
ruxolitinib + NIS793 (Part 1 from start of cycle 3 and parts 2 and 3): Use of strong CYP3A4 
inhibitors or fluconazole is strongly discouraged, and investigators should consider alternative 
therapies wherever possible. However, if the use of a strong CYP3A4 inhibitor is necessary for 
patient management, then a dose reduction of ~ 50% for ruxolitinib is appropriate, to be 
administered twice daily.  
For ruxolitinib + siremadlin (Part 1 from start of cycle 3 and parts 2 and 3): Concomitant 
use of strong or moderate inhibitors of CYP3A4/5 are strictly prohibited 48 hours before, 
during and 48 hours after siremadlin administration, as concomitant strong CYP3A4 inhibitors 
such as itraconazole increase plasma exposure of siremadlin by approximately 6-fold. If the use 
of a strong CYP3A4 inhibitor is necessary for patient management, the use of a strong 
CYP3A4/5 inhibitor or fluconazole can only be concomitantly administered outside the 
aforementioned restriction window (between day 7 and day 26 of a 28 day treatment cycle), and 
will require a ruxolitinib dose reduction of ~50% to be administered twice daily.NOTE: once 
the course of therapy using a strong CYP3A4 inhibitor or fluconazole has been completed, the 
patient may resume his/her prior dose level of ruxolitinib beginning the next day. 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (As assigned by Novartis to the investigative site) with a sequential 
subject number suffixed to it, so that each subject is numbered uniquely across the entire 
database. Upon signing the ICF, the subject is assigned to the next sequential Subject No. 
available. 
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information for the patient to register them into the IRT. Once 
assigned, the Subject No. must not be reused for any other subject. A new ICF will need to be 
signed if the investigator chooses to re-screen the subject after a subject has screen failed. If a 
subject is re-screened or participates again in another part of the study, a new subject ID will 


Novartis 
Confidential 
Page 104 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
be generated, however, the original subject ID must be added in the respective eCRF to link the 
two subjects for reporting and validation purposes. All required screening activities must be 
performed when the subject is re-screened for participation in the study. An individual subject 
may only be re-screened once for the study. Once the number of subjects screened and 
allocated/randomized has been reached to ensure the target number of enrolled subjects for the 
study, Novartis may close the study to further screening. In this case, the subjects who screen 
failed will not be permitted to re-screen. If the subject fails to be allocated to a treatment (Part 
1 subjects) or to be randomized (Part 2 or Part 3) for any reason, the reason will be entered into 
the appropriate Disposition eCRF. 
6.3.2 Treatment assignment, randomization 
No randomization will be performed in Part 1 of this study. The assignment of a subject to a 
particular treatment arm (ruxolitinib + siremadlin, ruxolitinib + crizanlizumab, ruxolitinib + 
sabatolimab, ruxolitinib + rineterkib or ruxolitinib + NIS793) and dose cohort within the 
ruxolitinib + siremadlin and ruxolitinib + rineterkib arms will be using the IRT system and 
coordinated by Novartis. 
For Part 2 and Part 3 (randomization parts of the study), following screening and prior to 
dosing, all eligible subjects will be randomized via IRT to one of the treatment arms open to 
enrollment (Section 3). The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the subject. A medication number will not be provided for the local supply of 
ruxolitinib in USA. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. The 
randomization numbers will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers (except for the local supply of ruxolitinib in USA). A separate medication 
list will be produced by Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment with the exception of local supply of ruxolitinib in USA for which no medication 
number will be provided. 
Details of the randomization requirements will be documented in randomization requirement 
specification document. The randomization scheme for subjects will be reviewed and approved 
by a member of the Randomization Office.  
6.4 
Treatment blinding 
Treatment will be open to subjects, investigator staff, persons performing the assessments, and 
the clinical trial team (CTT). 


Novartis 
Confidential 
Page 105 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
6.5 
Dose escalation and dose modification 
As outlined in Section 3, the proposed RP2D of siremadlin and rineterkib for the combination 
treatments are not known. Therefore, a dose escalation approach will be used in Part 1 to 
determine the RP2D as outlined in Section 6.5.1and Section 6.5.2. 
For the ruxolitinib + crizanlizumab, the ruxolitinib + sabatolimab, and the ruxolitinib + NIS793 
combination treatments the proposed RP2Ds will be confirmed in a safety-run-in rather than 
using the dose escalation approach.  
DLT definitions and dose modification guidelines for all three combinations are provided in 
Section 6.5.3 and Section 6.5.4, respectively. 
6.5.1 Dose escalation guidelines 
6.5.1.1 
Starting dose 
Ruxolitinib as a single agent has been tolerated up to doses of 25 mg BID 
(Verstovsek et al 2010). From the INCB018424-251 trial and supported by results from the 
CINC424A2352 study, 15 mg BID and 20 mg BID was established as the most effective and 
safest starting dose, followed by individualized dose titration. In patients with moderate 
thrombocytopenia, data show the feasibility of starting with 5 mg BID and then escalating to 
10 mg and occasionally to 15 mg BID, without causing severe thrombocytopenia 
(Cervantes 2014). 
As outlined in Section 5  patients must be on a stable ruxolitinib dose for at least 4 weeks prior 
to first dose of study treatment. A subject's ruxolitinib dose can vary between 5 mg BID and 25 
mg BID and it is neither escalated nor de-escalated and will remain fixed at the stable dose 
during the dose escalation/safety run-in part (Part 1) of the study unless dose modification is 
required due to toxicity as outlined in Section 6.5.4. 
The rationale for the regimen for siremadlin in combination with ruxolitinib is discussed 
in Section 4.2.1. To mitigate the risk of adverse events, the starting dose of siremadlin is  
20 mg/day (day 1-5 each of a 28-day cycle). This dose was chosen based on prior single agent 
safety data in subjects with solid and hematological malignancies and it is supported by 
population PK/PD modeling of thrombocytopenia and bone marrow blast (AML subjects) data 
(CHDM201X2101). The starting dose corresponds to ~3.15-fold reduction compared to the 
cumulative dose of siremadlin single agent RD, as evaluated in CHDM201X2101 at 45 mg/day 
(day 1-7 of a 28-day cycle), or 315 mg/cycle. At the starting dose level, limited target 
myelosuppression is predicted, while clinical activity is already expected. Additionally, PBPK 
SimCyp modeling of siremadlin in combination with ruxolitinib, at their respective dose and 
treatment schedules, did not predict any clinically relevant PK DDI (see Section 4.2.1). For 
crizanlizumab the dose level chosen to be evaluated in this trial is 5 mg/kg IV infusion (with a 
second loading dose after 14 days of initial dosing for Cycle 1 only), every 4 weeks cycle. This 
dose based on p-Selectin inhibition of SelG1 evaluated in healthy subjects, as well as the 
acceptable safety data observed in the Phase I CSEG101A2101 study. This dose was also 
evaluated in the Phase II CSEG101A2201 study, with 67 patients receiving SelG1 at  
5 mg/kg (Ataga et al 2017).  


Novartis 
Confidential 
Page 106 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
For sabatolimab the dose level chosen to be evaluated in this trial is 800 mg IV infusion Q4W. 
This dose is based on acceptable safety, as well as efficacy, PK and target (TIM-3) occupancy 
evaluated in CMBG453X2101 and CPDR001X2105 trials for sabatolimab. 
The rationale for the regimen for rineterkib in combination with ruxolitinib is discussed in 
Section 4.2.4. The starting dose of rineterkib is 200 mg QD and was chosen based on prior 
single agent safety data in subjects with solid malignancies (CLTT462X2101). The starting 
dose corresponds to ~2-fold reduction compared to the MTD (400 mg QD) of rineterkib single 
agent, as evaluated in CLTT462X2101. Additionally, PBPK SimCyp modeling of rineterkib in 
combination with ruxolitinib, at their respective dose and treatment schedules, did not predict 
any clinically relevant PK DDI. 
For NIS793 the dose level chosen to be evaluated in this trial is 2100 mg IV infusion Q3W. 
This dose is based on acceptable safety, as well as efficacy and PK/PD modeling information 
from the CNIS793X2101 study investigating NIS793 in combination with PDR001 
(spartalizumab) in advanced solid tumors. 
6.5.1.2 
Provisional dose levels 
Table 6-2 and Table 6-3 describes the starting dose and the dose levels that may be evaluated 
during this trial for siremadlin and rineterkib, respectively. 
Table 6-2 
Provisional dose levels for siremadlin 
Dose Level 
Proposed Daily Dose* 
Increment From Previous Dose 
- 1** 
10 mg 
- 50% 
1 
20 mg 
(starting dose) 
2 
30 mg 
50% 
3 
40 mg 
33% 
*Additional and/or intermediate dose levels may be added during the course of the study. Cohorts may be added 
at any dose level below the MTD in order to better understand safety, PK, or PD. 
**Dose level -1 represents a dose that may be evaluated if de-escalation from the starting dose is required due 
to toxicity 
Table 6-3 
Provisional dose levels for rineterkib 
Dose Level 
Proposed Daily Dose* 
Increment From Previous Dose 
- 1** 
100 mg 
- 50% 
1 
200 mg 
(starting dose) 
2 
300 mg 
50% 
*Additional and/or intermediate dose levels may be added during the course of the study. Cohorts may be added 
at any dose level below the MTD in order to better understand safety, PK, or PD. 
**Dose level -1 represents a dose that may be evaluated if de-escalation from the starting dose is required due 
to toxicity. 
6.5.2 Guidelines for dose escalation and determination of RP2D 
The maximum tolerated dose (MTD) is the highest drug dosage that is not expected to cause 
dose-limiting toxicity (DLT) in more than 33% of the treated subjects during the DLT 
evaluation period. The recommended Phase 2 dose (RP2D) may be chosen with fewer subjects, 
prior to identification of the MTD and may be lower than the MTD. 


Novartis 
Confidential 
Page 107 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Siremadlin and rineterkib 
For the purpose of dose escalation decisions and determination of RP2D, each cohort in Part 1 
of the study will consist of 3 to 6 newly enrolled subjects who will be treated at the specified 
dose levels. Subjects in the first cohort of siremadlin combined with ruxolitinib will be treated 
with the starting dose of siremadlin 20 mg QD (Day 1-5 of each 28-day cycle). Subjects in the 
first cohort of rineterkib combined with ruxolitinib will be treated with the starting dose of 
rineterkib 200 mg QD. 
Subjects must complete a minimum of two cycles of treatment with the minimum safety 
evaluation and drug exposure (see Section 12.1.3 for details) or have had a DLT within the DLT 
period to be considered evaluable for dose escalation decisions. Dose escalation decisions and 
RP2D will occur when the cohort of subjects has met these criteria. If a minimum of 3 subjects 
are required in a cohort and only 2 of these subjects are evaluable and neither subject has 
experienced a treatment-related toxicity > CTCAE grade 1, dose escalation decisions may be 
considered. 
Dose escalation decisions will be made by Investigators and Novartis study personnel. 
Decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study including safety information, DLTs, all CTCAE Grade ≥ 2 
toxicity data during Cycle 1 or 2, PK, and PD data from evaluable subjects. The recommended 
dose for the next cohort of subjects will be guided by the Bayesian logistic regression model 
(BLRM) with EWOC principle. A subject's ruxolitinib dose is neither escalated nor de-escalated 
and will remain fixed at the stable dose during the dose-escalation/safety run-in part (Part 1) of 
the study. 
The adaptive Bayesian methodology provides an estimate of all dose levels of the combination 
agent, which is escalated, that do not exceed the MTD and incorporates all DLT information at 
all dose levels for this estimation. In general, the next dose will have the highest chance that the 
DLT rate will fall in the target interval (16-33%) and will always satisfy the EWOC principle. 
In all cases, the dose for the next cohort will not exceed a 100% increase from the previous 
dose. Smaller increases in dose may be recommended by the investigators and sponsor upon 
consideration of all of the available clinical data. 
If the first 2 subjects in a cohort experience a DLT, further enrollment to that cohort will stop 
and the BLRM will be updated with this new information. Re-evaluation of the available safety, 
PK, and PD data will occur. By incorporating information gained at the preceding dose levels, 
additional subjects may be enrolled at this dose level or a lower dose level as agreed by 
Investigators and Novartis personnel and if the BLRM predicts that the risk that this dose 
exceeds the MTD remains below 25% (EWOC). 
Dose escalation will continue until identification of the MTD or a suitable lower RP2D. This 
will occur when the following conditions are met: 
• at least 6 subjects have been treated at this dose and observed for two cycles 
• this dose satisfies one of the following conditions:  
1. the posterior probability of targeted toxicity at this dose exceeds 50% and is the highest 
among potential doses, or 
2. Minimum of 12 subjects have already been treated on the trial. 


Novartis 
Confidential 
Page 108 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• It is the dose recommended for subjects, either per the model or by review of all clinical 
data by Novartis and investigators in a dose escalation teleconference, see Section 6.5.2.1. 
To better understand the safety, tolerability and PK of siremadlin or rineterkib in combination 
with ruxolitinib, additional cohorts of subjects may be enrolled at preceding dose levels, or to 
intermediate dose levels before or while proceeding with further dose escalation. 
If a decision is made to escalate to a higher dose level but one or more additional subject(s) 
treated at the preceding dose level experiences a DLT during the first cycle of treatment, then 
the BLRM will be updated with this new information before any additional subjects are enrolled 
at that higher dose level. Subjects ongoing will continue treatment at their assigned dose levels. 
Crizanlizumab, sabatolimab and NIS793 
For crizanlizumab, the dose level chosen to be evaluated in Arm 2 will be 5 mg/kg IV infusion 
Q4W (with the 2nd loading dose after 14 days of initial dosing for Cycle 1 only). For 
sabatolimab, the dose level chosen to be evaluated in Arm 3 will be 800 mg IV Q4W. For 
NIS793, the dose level chosen to be evaluated in Arm 5 will be 2100 mg IV Q3W. If 2 subjects 
in any safety run-in arm (either Arm 2, Arm 3, or Arm 5) in Part 1 of the study experience a 
DLT within the first 2 cycles of study treatment, further enrollment into that arm will stop and 
that combination treatment will not open in Part 2. 
A decision may be made to include further subjects into the combination arm or conduct 
additional dose cohorts within the arm based on a synthesis of all relevant data available in the 
ongoing study including safety information, DLTs, all CTCAE Grade ≥ 2 toxicity data during 
Cycle 1 or 2, PK, and PD data from evaluable subjects. Any decisions will be made by 
Investigators and Novartis study personnel. 
For Japan only: Further subjects can be added after the RP2D has been determined to further 
characterize safety. 
6.5.2.1 
Implementation of dose escalation decisions 
To implement dose escalation decisions for siremadlin and rineterkib in combination with 
ruxolitinib, 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. 
6.5.2.2 
Intra-Subject dose escalation 
Intra-subject dose escalation is not allowed in this study. 
6.5.3 Definitions of dose limiting toxicities (DLTs) 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as clinically significant and considered by the Investigator to be related to siremadlin, 


Novartis 
Confidential 
Page 109 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
crizanlizumab, sabatolimab, rineterkib, NIS793 as single contributors or in combination with 
ruxolitinib, that occurs within the first two cycles of treatment (C1D1 through to C3D1) of Part 
1 and meets any of the criteria included in Table 6-4. Toxicities that are related to MF, MF 
progression, inter-current illness, or concomitant medications that occurs within the first two 
cycles of treatment (C1D1 through to C3D1) with ruxolitinib + siremadlin or ruxolitinib + 
crizanlizumab or ruxolitinib + sabatolimab or ruxolitinib + rineterkib or ruxolitinib + NIS793 
will not be considered a DLT. The National Cancer Institute Common Terminology Criteria for 
Adverse events (NCI CTCAE) version 5.0 will be used for all grading. For the purpose of dose 
escalation decisions for the ruxolitinib + siremadlin and ruxolitinib + rineterkib combination 
treatments, DLTs will be considered and included in the BLRM. 
The investigator must notify the sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling subjects into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all subjects at the current dose level. 
Table 6-4 
Criteria for defining dose-limiting toxicities (related to study 
treatment) 
Toxicity 
DLT Criteria 
Hematologic toxicities  
Acute severe myelosuppression in absence of leukemic transformation: 
Neutropenia G4* 
Febrile neutropenia G ≥ 3 (ANC < 1.0 x 10^9/L + Fever ≥ 38.5 degrees C) 
Thrombocytopenia G4* (platelets < 25 x 10^9/L) persisting ≥ 3 days 
Prolonged myelosuppression in absence of leukemic transformation: 
Thrombocytopenia G3 (platelets < 50 x 10^9/L) persisting ≥ 21 days 
Thrombocytopenia G3 (platelets < 50 x 10^9/L) prior to dosing on C2D1 and 
C3D1 ** 
Non-hematologic toxicities  
All toxicity ≥ Grade 3 not due to underlying MF or complications of the 
disease (for all arms) 
Other Toxicity < Grade 3 considered as DLTs for subjects on arms 
containing rineterkib: 
• Retinal vein occlusion of any CTCAE Grade confirmed by 
ophthalmologic evaluation 
• Newly emerging grade 2 total bilirubin with ≥ CTCAE Grade 2 AST/ALT 
Other Toxicity < Grade 3 considered as DLTs for subjects on arms 
containing NIS793: 
• Grade 2 bullous disease that does not resolve to ≤ Grade 1 within 7 days 
of starting corticosteroids  
* in two consecutive assessments within 24 hours (the second assessment will be considered valid and final) 
**in case of platelets count of 40-50 x 10^9/L, the assessment has to be repeated within 24 hours. The second 
assessment will be considered valid and final 
CTCAE version 5.0 will be used for all grading 
6.5.4 
Dose modifications 
For subjects who do not tolerate the protocol-specified dosing schedule due to DLT or other 
toxicities, dose adjustments are permitted in order to allow subjects to continue the study 
treatment. Similar guidelines also apply to the extension treatment phase. All dose 
modifications should be based on the worst preceding toxicity and AEs are to be graded 


Novartis 
Confidential 
Page 110 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
according to NCI CTCAE v5.0. If the investigational study treatment is being held due to 
toxicity, planned visits and all assessments should continue as scheduled, except without dosing.  
For Part 1, dose modifications for toxicities occurring during the DLT-definition period (i.e. 
first 2 cycles of treatment C1D1 through C3D1), and considered as treatment-related, will not 
be allowed unless the toxicity qualifies as DLT. After a toxicity has been characterized as a 
DLT, a subject can resume therapy with a modified dose according to the guidelines.  
During part 2 and 3, investigator should follow the dose modifications for toxicities during any 
cycle of the treatment period.  
These dose changes must be recorded on the appropriate eCRF. 
  
 
  
For clinical management of suspected immune-related events for sabatolimab and NIS793, 
reference to consensus management guidelines is recommended, such as those provided in the 
NCCN Guidelines for the Management of Immunotherapy-Related Toxicities (NCCN 
Guidelines for specific populations), ASCO clinical practice guideline for Management of 
Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor 
Therapy (Brahmer et al 2018) or the ESMO Clinical Practice Guidelines for Management of 
Toxicities from Immunotherapy (Haanen et al 2017). Note that in general, sabatolimab or 
NIS793 should be interrupted for grade 3 and 4 toxicities and for a subset of lower grade 
toxicities. If the specific adverse event is not listed, the guideline for "Other adverse 
events" must be followed. Deviations to mandatory dose interruptions and/or reductions are not 
allowed. Permanent treatment discontinuation is mandatory for specific events
 
 
  
The investigator should follow the dose modifications for the study drug suspected to be related 
to the event: 
• 
If the event is suspected to be related to ruxolitinib, the investigator should follow the dose 
modification specific to ruxolitinib as per current label. If the event is suspected to be related 
to siremadlin, crizanlizumab, sabatolimab, rineterkib or NIS793, the investigator should 
follow the dose modifications specific for the suspected study drug.
 
 
  
• 
In the occurrence of potentially overlapping toxicity or if it cannot be distinguished which 
of the study drugs within the combination is suspected to be related to the event, the 
investigator should first modify the dose of siremadlin, crizanlizumab, sabatolimab, 
rineterkib or NIS793 before changing the ruxolitinib dose. If the toxicity does not resolve 
until the next planned dose of siremadlin, crizanlizumab, sabatolimab, rineterkib or NIS793, 
the investigator should follow the dose modifications specific to both study drugs within the 
combination treatment. 
Additionally, the following guidelines need to be considered for patients on siremadlin and 
rineterkib:  


Novartis 
Confidential 
Page 111 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• 
 
 
All dose modifications 
should be based on the worse preceding toxicity (CTCAE v 5.0).  
• 
A patient must discontinue treatment with siremadlin or rineterkib if, after treatment is 
resumed at a lower dose, the toxicity recurs with the same or worse severity, unless in the 
opinion of the investigator it is in the patient’s best interest to continue siremadlin or 
rineterkib, and upon documented agreement with Novartis. 
• 
For each patient, once a dose reduction has occurred, the dose level must not be re-escalated 
during subsequent treatment cycles with siremadlin or rineterkib. 
Finally, the following guidelines should be followed for patients on NIS793: 
• 
No dose reductions are allowed for NIS793. Reducing dosing frequency is allowed under 
circumstances 
 
• 
Dose interruption due to toxicities is permitted. Dosing of study treatment may resume once 
the AE has resolved, 
 
 
 
 


Novartis 
Confidential 
Page 112 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 113 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 114 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 


Novartis 
Confidential 
Page 115 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 116 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 117 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 


Novartis 
Confidential 
Page 118 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
. 
 
 


Novartis 
Confidential 
Page 119 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 120 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 121 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 122 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 123 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 


Novartis 
Confidential 
Page 124 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 125 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 


Novartis 
Confidential 
Page 126 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 


Novartis 
Confidential 
Page 127 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
6.5.4.1 
Dose adjustments for QTcF prolongation 
In case QTcF prolongation > 500 msec (or QTcF prolongation > 60 msec from baseline) is 
observed at any time point during study treatment, and confirmed, increased ECG safety 
monitoring is mandatory during or in-between subsequent visits (e.g. collecting ECGs at 
following treatments at predose and at Cmax), as follows: 


Novartis 
Confidential 
Page 128 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
• Collect triplicate ECG and confirm QTc assessment (by site cardiologist or Novartis 
cardiologist)  
• Correct any serum electrolyte abnormalities (in particular hypokalemia, hypomagnesemia) 
before continuing study treatment. 
• Review concomitant medication use for other causes for QT prolongation (refer to 
qtdrugs.org for known QT prolonging drugs) and for drugs with the potential to increase 
the risk of drug exposure related QT prolongation (e.g. concomitant use of CYP3A4 
inhibitors, if the study treatment is a CYP3A4 substrate) 
• Check the dosing schedule and treatment compliance 
• Consider collecting a time-matched PK sample (Refer to PK sampling section for correct 
procedures) and record time and date of last study treatment intake. Not applicable during 
the extension treatment phase. 
6.5.5 Follow-up for toxicities 
Subjects 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 
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. Similar guidelines apply during the extension treatment phase. 
Appropriate clinical experts such as cardiologist, dermatologist, psychiatrists, etc., should be 
consulted as deemed necessary. All subjects must be followed up for adverse events and serious 
adverse events (SAEs) for 30 days after the last dose of single-agent ruxolitinib 
(control/monotherapy), for 30 days after the last dose of ruxolitinib or siremadlin for subjects 
on ruxolitinib + siremadlin (or siremadlin monotherapy in Part 3), for 30 days after the last 
dose of ruxolitinib or rineterkib for subjects on ruxolitinib + rineterkib (or rineterkib 
monotherapy in Part 3), for 90 days after the last dose of NIS793 for subjects on ruxolitinib + 
NIS793 (or NIS793 monotherapy in Part 3), for 105 days after the last dose of 
crizanlizumab for subjects on ruxolitinib + crizanlizumab (or crizanlizumab monotherapy in 
Part 3), and for 150 days after the last dose of sabatolimab for subjects on ruxolitinib + 
sabatolimab (or sabatolimab monotherapy in Part 3). 
6.5.5.1 
Follow up for Siremadlin 
For subjects receiving siremadlin, Table 6-10 outlines the follow-up evaluations recommended 
for toxicities of specific types and CTCAE grades. 
Table 6-10 
Follow-up evaluations for selected toxicities 
Toxicity 
Follow-up Evaluation 
Blood and lymphatic 
system disorders 
Test twice weekly until ≤ CTCAE grade 2, then restart treatment 
 
 
Continue to test weekly until resolution to baseline or stabilization. 
Investigations 
(hematologic) 
Neutropenia ≥ CTCAE 
grade 3 
Test twice weekly until ≤ CTCAE grade 2, then restart treatment 
 
 
Continue to test weekly until resolution to baseline or stabilization. 
Perform physical examination for check on bruising in case of major 
thrombocytopenia. 


Novartis 
Confidential 
Page 129 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Toxicity 
Follow-up Evaluation 
Thrombocytopenia ≥ 
CTCAE grade 3 
Investigations 
(metabolic) 
Amylase or lipase ≥ 
CTCAE grade 3 
Test twice weekly until ≤ CTCAE grade 2, then restart treatment 
 
 
Continue to test weekly until resolution to ≤ CTCAE grade 1 or stabilization. 
A CT scan or equivalent imaging procedure to assess the pancreas, liver, and 
gallbladder is recommended within 7 days of the first occurrence of any ≥ CTCAE 
grade 3 result, to exclude disease progression or potential other liver disease. 
In subjects with serum triglycerides ≥ 500 mg/dL, urine amylase also needs to be 
tested. 
Cardiac disorders 
QT and ECG 
ECG changes indicative 
of ischemic event 
Refer to ECG and QTc Clinical Safety Standards Guidelines  
Twice weekly ECGs until normalization or stabilization of ECG findings then restart 
treatment refer to section 6.5.4.1. 
6.5.5.2 
Follow up for sabatolimab & NIS793 
The emergence of Immune-Related AE (irAE) may be anticipated based on general experience 
in clinical studies with similar class of compounds that block the negative immune regulators. 
An irAE is a clinically significant AE affecting any organ that is associated with study drug 
exposure, is consistent with an immune-mediated mechanism, and where alternative 
explanations have been investigated and ruled out or are considered unlikely. 
Subjects should be monitored carefully for any skin toxicity or mucositis and study treatment 
should be discontinued for any suspected case of SJS/TEN. 
Serologic, histologic and immunological assessments should be performed as deemed 
appropriate by the Investigator, to verify the immune-related nature of the AE. 
All subjects with signs or symptoms of irAEs should be monitored and managed following the 
consensus guidelines from NCCN, ASCO or ESMO for the management of immune-related 
adverse events as outlined in Section 6.5.4  
Patients whose treatment is interrupted or permanently discontinued due to an irAE, AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
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 experts should be consulted as deemed necessary. 
In case of a suspected irAE, the relevant immunological assessments (e.g. rheumatoid factor, 
anti-DNA Ab, etc.) should be performed. In case of a toxicity suspected to be a cytokine release 
syndrome, the assessments outlined in Section 8 (Table 8-2, Table 8-3, Table 8-4 & Table 8-5) 
must be performed. All patients must be followed up for irAEs, AEs and SAEs for 90 days 
following the last dose of NIS793 in combination with ruxolitinib, and for 105 days following 
the last dose of sabatolimab in combination with ruxolitinib. 
 
For any AE/AEs Grade 1 and/or Grade 2, treatment with sabatolimab should be 
maintained at the determined dose and schedule, unless otherwise specified in Table 6-7. 
Similarly, 
 


Novartis 
Confidential 
Page 130 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 For any AE/AEs Grade 1 and/or Grade 2, treatment with NIS793 should be maintained 
at the determined dose and schedule, unless otherwise specified in 
 
6.5.5.3 
Follow up on potential drug-induced liver injury (DILI) cases 
Subjects with transaminase increase combined with TBIL increase may be indicative of 
potential DILI and should be considered as clinically important events. 
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below: 
• For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in subjects without bone metastasis, or elevation 
of ALP liver fraction in subjects with bone metastasis. 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. 
In the absence of cholestasis, these subjects should be immediately discontinued from study 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment, and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR, and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing 
liver conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” (Table 6-11) and thus, meet the definition of SAE and should reported as SAE 
using the term “potential drug-induced liver injury.” All events should be followed up with the 
outcome clearly documented. 


Novartis 
Confidential 
Page 131 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Table 6-11 
Guidance to rule out possible alternative causes of observed LFT 
abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
• 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
• 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-
EBV 
Autoimmune hepatitis 
• 
Antinuclear Antibodies (ANA) & Anti-Smooth Muscle 
Antibody (ASMA) titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
• 
Ethanol history, GGT, Mean Corpuscular Volume (MCV), CD-
transferrin 
Nonalcoholic steatohepatitis 
• 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• 
Medical history: acute or chronic congestive heart failure, 
hypotension, hypoxia, hepatic venous occlusion. Ultrasound 
or MRI. 
Biliary tract disease 
• 
Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
cholangiopancreatography (ERCP) as appropriate. 
Wilson disease (if <40 yrs old) 
• 
Caeruloplasmin 
Hemochromatosis 
• 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• 
Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes / glycogenic hepatitis). 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented. 
6.6 
Additional treatment guidance 
Tumor Lysis Syndrome (TLS) TLS was observed in subjects diagnosed with hematological 
malignancies (AML) and administered siremadlin in study CHDM201X2101 with siremadlin. 
One subject, who had grade 4 TLS, was treated according to regimen 2C (daily dosing Day 1-
7, Q4W) at 45 mg siremadlin dose. During this study, including the extension treatment phase, 
subjects receiving siremadlin should be closely monitored (including relevant laboratory tests) 
for signs and symptoms of TLS before initiation and during a treatment cycle. Risk assessment 
of TLS, prophylaxis and events should be managed according to the institutional guidelines. 
Before initiation of a treatment cycle and during a treatment cycle, the following measures 
should be followed: 


Novartis 
Confidential 
Page 132 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Before initiation of a treatment cycle: 
• Prophylaxis (i.e. allopurinol) for TLS should be administered. 
• Oral fluids are recommended 
• Prompt supportive care in case of acute TLS (IV fluids and rasburicase as clinically 
indicated, when uric acid continues to rise despite allopurinol/febuxostat and fluids) 
During a treatment cycle: 
• Frequent monitoring of the following laboratory tests (per Table 8-2 and Table 8-3 and as 
clinically indicated): potassium, phosphorus, calcium, creatinine, and uric acid 
• Encourage oral hydration 
Based on laboratory and clinical TLS criteria (modified from Cairo and Bishop 2004), the 
following measures for TLS should be also followed 
Laboratory tumor lysis syndrome 
Defined as two or more of the following values within three days before or in the days following 
initiation of a treatment cycle: 
• Uric acid ≥ 8 mg/dL or 25% increase from baseline 
• Potassium ≥ 6 mEq/L or 25% increase from baseline 
• Phosphorus or ≥ 4.5 mg/dL or 25% increase from baseline 
• Calcium ≤ 7 mg/dL or 25% decrease from baseline 
Regimen: 
• If none or one of the laboratory values above is abnormal, continue to manage with 
allopurinol or a non-allopurinol alternative (e.g. febuxostat) and oral fluids. If uric acid 
remains elevated, consider IV fluids, rasburicase, and hospital monitoring. 
• Laboratory TLS should be managed with IV fluids, laboratory blood tests every 6 to 8 hours 
and inpatient care. Cardiac monitoring and rasburicase should be considered if uric acid 
remain elevated. 
Clinical tumor lysis syndrome 
Defined as the presence of laboratory TLS and ≥ 1 of the following criteria that cannot be 
explained by other causes: 
• Serum creatinine ≥ 1.5 times the upper limit of the age-adjusted normal range 
• Symptomatic hypocalcemia 
• Cardiac arrhythmia 
Regimen: Clinical TLS should be managed with IV fluids, laboratory blood tests every 6 to 8 
hours, cardiac monitoring, rasburicase/allopurinol/febuxostat and inpatient care (consider ICU). 
Subjects who have been treated for TLS with favorable outcome (defined as return to within 
10% of baseline value or within limit of normal of relevant laboratory parameters) may re-start 
study treatment upon discussion between the sponsor and the investigator. 


Novartis 
Confidential 
Page 133 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
6.6.1 Treatment compliance 
Study medication will be dispensed and/or administered at the site/clinic under the supervision 
of the investigator and/or study personnel during the study, including the extension treatment 
phase. This information should be captured in the source document and the eCRF at each visit. 
All study treatment administered must be recorded in the Drug Accountability Log.  
For any study medication administered at home (such as ruxolitinib, siremadlin and rineterkib), 
the investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. A Patient Diary is available for use to support patient documentation 
of oral treatment compliance for those study medications administered at home. Patient Diary 
is no longer applicable in the extension treatment phase post amended protocol version 09 
implementation. The subject must also be instructed to contact the investigator if he/she is 
unable for any reason to take the study treatment as prescribed. Compliance will be assessed by 
the investigator and/or study personnel at each visit using pill counts (if applicable) and 
information provided by the subject. This information should be captured in the source 
document at each visit. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
as detailed in pharmacokinetics section, see Section 8.5.2. 
6.6.2 
Emergency breaking of assigned treatment code 
Not applicable 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described in the investigational 
and control drugs Section 6.1.1. 
A unique medication number is printed on the study medication label. This is not applicable for 
the local supply of ruxolitinib in USA. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). This is not applicable for the local supply of 
ruxolitinib in USA. The study medication has a 2-part label (base plus tear-off label). 
Immediately before dispensing the medication kit to the subject, site personnel will detach the 
outer part of the label from the packaging and affix it to the source document. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of investigational drug directly to a participant’s home may be permitted (if allowed 
by Local or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant’s health to administer the study treatment 
even without performing an on-site visit. The dispatch of investigational drug from the site to 
the participant’s home remains under the accountability of the Investigator. Each 
shipment/provisioning will be for a maximum of 2-months’ supply. In this case, regular phone 


Novartis 
Confidential 
Page 134 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
calls or virtual contacts (every 4 weeks or more frequently if needed) will occur between the 
site and the participant for instructional purposes, safety monitoring, drug accountability, 
investigation of any adverse events, ensuring the participant continues to benefit from treatment 
and discussion of the participant´s health status until the participant can resume visits at the 
study site. 
6.7.1 Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure (IB). Clinical supplies are 
to be dispensed only in accordance with the protocol. Technical complaints are to be reported 
to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number (medication number not applicable for the local 
supply of ruxolitinib in USA). 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all 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. 
6.7.1.2 
Handling of additional treatment 
Not applicable 
6.7.2 
Instruction for prescribing and taking study treatment 
All kits of study treatment will be assigned by the IRT and will be recorded in the IRT system. 
This is not applicable for the local supply of ruxolitinib in USA. 
6.7.2.1 
Ruxolitinib 
Ruxolitinib will be administered orally (PO) at 5-25 mg twice a day (BID) every day in a  
28-day treatment cycle with or without food at the stable dose at the time of study entry. The 
subject should take the tablets at approximately the same time each day, with a glass of water. 
If the subject forgets to take a dose, then he/she should take ruxolitinib within 3 hours after the 
missed dose. If more than 3 hours have passed, then that missed dose should be omitted and the 


Novartis 
Confidential 
Page 135 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
patient should continue treatment with the next scheduled dose. Any missed study medication 
should be reported to the Investigator at the next study visit.  
If vomiting occurs during the course of treatment, subjects should not take ruxolitinib again 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted in the adverse events section of the eCRF. 
On the days that PK samples are obtained the subject should take the ruxolitinib tablets during 
the clinic visit after the pre-dose PK samples and prior to post-dose PK samples, when 
instructed by the study staff. 
6.7.2.2 
Siremadlin 
Siremadlin (HDM201) capsules will be administered orally (PO) once daily (QD) on day 1 to 
5 of every 28-day cycle at the indicated dose level (10 mg, 20 mg, 30 mg or 40 mg) on an empty 
stomach at least 1 hour before or 2 hours after a meal. The subject should take the capsules at 
approximately the same time each day of dosing, with a glass of water, swallowing whole 
without chewing the capsules, preferably with the morning dose of ruxolitinib. On days when 
siremadlin and ruxolitinib are administered at the same time, the dose of ruxolitinib should be 
taken in the fasted state together with siremadlin. If the subject is assigned to a siremadlin dose 
level where multiple capsules are to be taken, the capsules should be taken consecutively, within 
as short an interval as possible. If the subject forgets to take his/her daily dose, then he/she 
should restart the dose on the next scheduled dosing day without compensating for missed doses. 
Subjects should be instructed not to make up missed doses. A missed dose is defined when the 
full dose is not taken within 8 hours after the approximate time of the usually daily dosing. That 
day's dose should be omitted and the subject should continue treatment with the next scheduled 
dose. Any missed study medication should be reported to the Investigator at the next study visit. 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before 
the next scheduled dose. The occurrence and frequency of any vomiting during a treatment 
cycle must be noted in the adverse events section of the eCRF. 
On the days that PK samples are obtained the subject should take the siremadlin and ruxolitinib 
tablets during the clinic visit after the pre-dose PK samples and prior to post-dose PK samples, 
when instructed by the study staff. The exact time for dose administration and breakfast (if 
applicable) intake must be recorded in the source documents and eCRF. In addition, on the days 
of full PK sampling, if a subject vomits within the first 4 hours after dose administration on that 
day, then the exact time of the first episode of vomiting should be recorded on the CRF and the 
dose should not be re-administered. 
6.7.2.3 
Crizanlizumab 
Crizanlizumab (SEG101) will be administered at 5 mg/kg Q4W on Day 1 of every 28-day cycle 
with an additional loading dose administered at Cycle 1 Day 15 via IV infusion over 30 minutes 
(up to 2 hours, if clinically indicated) as described in the pharmacy manual starting 
approximately within the next hour after ruxolitinib administration, if and when administered. 
There should be a period of at least 1 hour after the infusion whereby the subject requires close 
observation.  


Novartis 
Confidential 
Page 136 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
6.7.2.4 
Sabatolimab 
Sabatolimab (MBG453) will be administered at 800 mg dose level Q4W on Day 1 of every  
28-day cycle via IV infusion over 30 minutes (up to 2 hours, if clinically indicated) as described 
in the pharmacy manual starting approximately within the next hour after ruxolitinib 
administration, if and when administered. There should be a period of at least 1 hour after the 
infusion whereby the subject requires close observation. 
6.7.2.5 
Rineterkib 
Rineterkib (LTT462) capsules will be administered orally (PO) once daily (QD) every day in a 
28-day treatment cycle at the indicated dose level (100 mg, 200 mg or 300 mg) on an empty 
stomach at least 1 hour before or 2 hours after a meal. The subject should take the capsules at 
approximately the same time each day of dosing with a glass of water, swallowing whole 
without chewing the capsules, preferably with the morning dose of ruxolitinib. When rineterkib 
and ruxolitinib are administered at the same time, the dose of ruxolitinib should be taken in the 
fasted state together with rineterkib. If the subject is assigned to a rineterkib dose level where 
multiple capsules are to be taken, the capsules should be taken consecutively, within as short 
an interval as possible. If the subject forgets to take his/her daily dose, then he/she should restart 
the dose on the next scheduled dosing day without compensating for missed doses. 
Subjects should be instructed not to make up missed doses. A missed dose is defined when the 
full dose is not taken within 8 hours after the approximate time of the usually daily dosing. That 
day's dose should be omitted and the subject should continue treatment with the next scheduled 
dose. Any missed study medication should be reported to the Investigator at the next study visit. 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before 
the next scheduled dose. The occurrence and frequency of any vomiting during a treatment 
cycle must be noted in the adverse events section of the eCRF. 
On the days that PK samples are obtained the subject should take the rineterkib capsules and 
ruxolitinib tablets during the clinic visit after the pre-dose PK samples and prior to post-dose 
PK samples, when instructed by the study staff. The exact time for dose administration and 
breakfast (if applicable) intake must be recorded in the source documents and eCRF. In addition, 
on the days of full PK sampling, if a subject vomits within the first 4 hours after dose 
administration on that day, then the exact time of the first episode of vomiting should be 
recorded on the CRF and the dose should not be re-administered. 
6.7.2.6 
NIS793 
NIS793 will be administered at 2100 mg dose level Q3W on Day 1 of every 21-day cycle via 
IV infusion over at least 30-60 minutes as described in the pharmacy manual starting 
approximately within the next hour after ruxolitinib administration, if and when administered. 
The subject should be observed closely for a period of at least 2 hour after the infusion. 


Novartis 
Confidential 
Page 137 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. In addition to the informed consent obtained 
before the screening procedures, subjects must be re-consented prior to entering the extension 
treatment phase. 
Novartis will provide to investigators in a separate document a proposed ICF that complies with 
the ICH GCP guidelines and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be agreed 
by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) of each investigational drug. This information will be 
included in the subject informed consent and should be discussed with the subject during the 
study as needed. Any new information regarding the safety profile of the investigational drug 
that is identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the subject. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. 
 
 
 
 
 
 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 


Novartis 
Confidential 
Page 138 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
As per Section 4.6, during a Public Health Emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, the Investigator 
may conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Heath Authority. Guidance issued by local regulatory bodies on this aspect 
prevail and must be implemented and appropriately documented (e.g. the presence of an 
impartial witness, sign/dating separate ICFs by trial subject and person obtaining informed 
consent, etc.). 
8 
Visit schedule and assessments 
The assessment schedules in Table 8-2 and Table 8-4 for Part 1 of the study (Dose escalation 
and safety run-in) and Table 8-3 and Table 8-5 for Part 2 (Selection) and Part 3 (Expansion) of 
the study list all of the assessments and indicates with an "X" or "S" when they are to be 
performed. The assessment schedule used is dependent upon which study treatment 
combination the subject is assigned to. All data obtained from these assessments must be 
supported in the subject’s source documentation, however an "S" on the assessment schedule 
indicates that the data can remain in the source documentation and will not be collected in the 
database. No CRF will be used as a source document. Additional assessments may be performed 
as clinically indicated. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final End of Treatment (EOT) visit will be performed. At this final visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications recorded on the CRF. 
Study treatment will begin on Cycle 1 Day 1 (C1D1) with the first administration of the assigned 
study treatment, depending on the arm into which the subject has been allocated (Part 1) or 
randomized (Parts 2 and 3). C1D1 should occur on the same day as the allocation/randomization 
to study treatment, however if this is not logistically possible, it should not be more than 3 days 
after allocation/randomization in IRT. Each treatment cycle is 21 days for all treatment arms 
containing NIS793 or 28 days for all other treatment arms. It is recommended that a 28-day gap 
between Cycle (X) Day 1 and Cycle (X+1) Day 1 is maintained in ruxolitinib + siremadlin 
combination arm. The duration between cycles should not be shortened to < 28 days due to 
potential for additive hematotoxicity and adequate time for bone marrow recovery between 
cycles.  
All study visits, assessments and study treatment administration are to be scheduled according 
to the appropriate number of calendar days from the day of first study treatment administration 
on C1D1 (whenever possible as per the allowable visit window specified in Table 8-1 below). 
If one of the investigational drugs is interrupted or permanently discontinued, at any time during 
the study, all study visits and safety assessments should continue according to the appropriate 
number of calendar days from C1D1 as per the schedule of assessments, and efficacy 
assessments must continue as per the scheduled number of weeks from C1D1 as described in 


Novartis 
Confidential 
Page 139 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
Table 8-2 (Part 1) and Table 8-3 (Parts 2 and 3) for treatment arms with 28-day cycles (all 
treatment arms not containing NIS793 except the monotherapy arm in Part 3 if ruxolitinib + 
NIS793 is chosen for Part 3), and Table 8-4 (Part 1) and Table 8-5 (Parts 2 and 3) for treatment 
arms containing NIS793. 
Subjects will be treated for a planned duration of 8 cycles for arms with NIS793 or 6 cycles for 
all other arms in Part 1 (24 weeks), or for a planned duration of 16 cycles for NIS793 or 12 
cycles for all other arms in Parts 2 and 3 (48 weeks).  
In the context of enrollment halt, ongoing subjects from Part 1 who are benefitting from study 
treatment may continue to receive study treatment in the core treatment phase of Part 1 and be 
followed as per the schedule of assessments, as long as subjects derive benefit until the amended 
protocol version 08 is implemented. From the time of implementation of the amended protocol 
version 08, subjects who have received the combination treatment in the core treatment phase 
of Part 1 and benefitting from the allocated combination treatment may be eligible to continue 
on the same combination treatment in the extension treatment phase. These subjects will 
perform an End of Treatment visit for the core treatment phase to enter in the extension phase. 
The EOT (core treatment phase) visit is treated as Cycle 1 Day 1 of extension treatment phase 
and should occur on the same day, once the current cycle is completed i.e. on day 1 of next 
planned cycle to maintain treatment regimen. 
The assessments schedule for Part 1 core and extension treatment phase are outlined in  
Table 8-2. Extension treatment phase is not applicable for the ruxolitinib+NIS793 arm  
(Table 8-4) as no subject was ongoing at time of the amended protocol version 08.  
Subjects may be discontinued from treatment earlier due to unacceptable toxicity, disease 
progression or treatment is discontinued at the discretion of the investigator or the subject. 
Following treatment discontinuation, an EOT core visit will be performed for all subjects, after 
which safety follow-up visits are to be scheduled for subjects not entering the extension 
treatment phase.  
For those subjects who enter the extension treatment phase and complete or discontinue earlier 
the extension treatment phase for any reason, an EOT extension visit will be performed for all 
subjects and after which safety follow-up visits are to be scheduled according to the appropriate 
number of calendar days after the last dose of study drug treatment administered depending on 
the investigational drug (refer to Section 9.2).  
In addition, subjects in Part 2 and Part 3 will have a survival follow-up call every 3 months until 
the end of the study (Section 9.2). (Not applicable from amended protocol version 08).  
Every effort must be made to follow the schedule of assessments within the windows outlined 
in the protocol. 
Study visits with scheduled PK sampling should be scheduled in the morning so that a pre-dose 
PK blood sample can be collected. 
The preferred sequence for assessments during study visits is ECG collection first, followed by 
vital signs, and blood sampling. 
For Japan only, subjects enrolled in the crizanlizumab arm of Part 1 (Arm 2) are required to be 
hospitalized in the first 7 days of study treatment. 


Novartis 
Confidential 
Page 140 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 
Table 8-1 
Allowable visit windows 
Visit name 
Assessments 
Window allowed 
Screening  
MRI/CT scan of abdomen (all parts)  
within 8 weeks prior to first dose of 
study treatment 
Cardiac 
imaging 
(MUGA 
or 
echocardiogram or cardiac MRI) and 
ophthalmologic exams (Part1 only) 
≤ 28 days before C1D1  
Bone marrow biopsy (part 2 and 3) 
within 8 weeks prior to first dose of 
study treatment 
All other assessments 
≤ 28 days before C1D1  
C1D1 
(Core Phase) 
IRT dispensing call  
-3 days 
Cardiac 
imaging 
(MUGA 
or 
echocardiogram or cardiac MRI) and 
ophthalmologic exams (Part 2 and Part 3) 
-3 days 
All 
other 
visit 
assessments 
and 
administration of study drugs 
NA 
Day 1 visit of all 
subsequent cycles  
(Core and extension)  
Cardiac 
imaging 
and 
ophthalmologic 
exams 
-7 days 
All 
other 
visit 
assessments 
and 
administration of study drugs 
± 3 days 
During Treatment and 
Safety Follow-up 
periods 
PK sampling 
Refer 
to 
PK 
sample 
tables 
in  
Section 8.5.2 
EOT Core Phase for 
subjects not entering in 
extension; 
EOT extension  
All assessments 
+ 7 days after last dose of study 
treatment (except for MRI/CT scan or 
bone marrow biopsy if completed in 
the past 12 weeks) 
EOT core for subjects 
entering in extension 
and C1 D1 (extension) 
All assessments  
± 3 days  
(EOT core and C1D1 extension visits 
must be performed on the same day)  
30-, 90-, and 105-day 
Safety Follow-up visit 
All assessments 
+ 7 days 
150-day Safety Follow-
up visit 
All assessments 
+ 14 days 
Survival follow-up 
All assessments 
± 14 days 


Novartis 
Confidential 
Page 141 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 8-2 
Assessment Schedule, Part 1 (for all arms with 28-day cycles) 
Period 
Screening 
Core Treatment1 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Days 
-28 to -1 
1 2 5 
6 8 15 16 1 
2 
5 
6 15 1 
2 
5 8 15 1 2 5 
1 2 5 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT screening call 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT eligibility checklist and allocation call 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior ruxolitinib therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior anti-neoplastic therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X (at every clinic visit) 
Non-drug therapies and procedures 
X 
X (at every clinic visit) 
Transfusion record (PRBC and platelets) 
X 
X (at every clinic visit) 
Physical examination 
S 
S 
 
 
 
 
 
 
S 
 
 
 
 
S 
 
 
 
 
S 
 
 
S 
 
 
ECOG performance status 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 X2 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Vital signs 
X 
X (at every clinic visit) 
Spleen length measurement by palpation 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
X X 
 
 
 X X 
 
 
X 
 
 
Laboratory assessments 
- 
Hematology 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
X X 
 
 
 X X 
 
 
X 
 
 
Chemistry 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Additional chemistry for siremadlin safety 
monitoring3 
 
 
X X 
X 
 
 
 
 
X 
X 
X 
 
 
X 
X 
 
 
 
X X 
 
X X 


Novartis 
Confidential 
Page 142 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
Core Treatment1 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Days 
-28 to -1 
1 2 5 
6 8 15 16 1 
2 
5 
6 15 1 
2 
5 8 15 1 2 5 
1 2 5 
Coagulation 
X 
X (as clinically indicated) 
Urinalysis 
X 
X (as clinically indicated) 
Thyroid function 
X 
X (as clinically indicated) 
Pregnancy test - serum 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test - urine or serum 
 
S 
 
 
 
 
 
 
S 
 
 
 
 
S 
 
 
 
 
S 
 
 
S 
 
 
Hepatitis test 
X5 
X (as clinically indicated) 
HIV screen 
S4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology exam 
 
X6 
X (as clinically indicated) 
Cytokines 
 
X7 
X (anytime if suspected cytokine release syndrome, immediately after the AE, and one week after 
the AE) 
Safety 
- 
Adverse events 
X 
X (at every clinic visit) 
ECG8 
X 
X 
 X8 
 
 X8 
 
X8 
 
X8 
 
 
X8 
 
 
 
 
X8  
 
X8  
 
Cardiac imaging (MUGA scan or ECHO) 
 
X19  
 
 
 
 
 
 
 
 
 
 X19 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic assessments19 
X19 
 
 
 
 
 
 
 X19 
 
 
 
 X19 
 
 
 
 X19  
 
X19  
 
ePROs  
- 
MFSAF v4.0 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
EORTC QLQ-C30 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
TFQ (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Imaging 
- 
MRI/CT of abdomen 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 143 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
Core Treatment1 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Days 
-28 to -1 
1 2 5 
6 8 15 16 1 
2 
5 
6 15 1 
2 
5 8 15 1 2 5 
1 2 5 
Disease progression assessment  
(Section 8.3.2.5) 
 
X (at every clinic visit) 
Confirmation of clinical benefit 
assessment (Section 8.3.3) 
 
 
Study Drug Administration 
- 
IRT drug dispensation call 
 
  
  
  
  
  X2  
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
X 
 
 
Ruxolitinib 
 
 
X (BID - twice a day) 
Siremadlin 
 
X (Day 1-
5) 
  
  
  
 X (Day 1-5) 
  
  
X (Day 1-5) 
  
  X (Day 1-
5) 
X (Day 1-
5) 
Crizanlizumab infusion 
 
X 
  
  
  
  X 
 
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
X 
 
 
Sabatolimab infusion 
 
X 
  
  
  
  
  
 
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
X 
 
 
Rineterkib 
 
X (QD – once a day) 
PK sampling 
- 
Ruxolitinib10 
 
X X X10 X10  
X 
 
X X10 X10 X10 X X 
 
X10  X X 
 X10 X 
 X10 
Siremadlin  
 
X X X 
X 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
X X 
 
X X 
Crizanlizumab 
 
X X 
 
 
X X 
 
X 
 
 
 
 
X 
X 
 
X X X 
 
 
X 
 
 
Sabatolimab 
 
X X 
 
 
X X 
 
X 
 
 
 
 
X 
X 
 
X X X 
 
 
X 
 
 
Blood sample for sTIM-3 (sabatolimab) 
 
X X 
 
 
X X 
 
X 
 
 
 
 
X 
X 
 
X X X 
 
 
X 
 
 
Rineterkib 
 
X X 
 
 
 
X X X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Immunogenicity 
- 
Crizanlizumab 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 


Novartis 
Confidential 
Page 144 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
Core Treatment1 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Days 
-28 to -1 
1 2 5 
6 8 15 16 1 
2 
5 
6 15 1 
2 
5 8 15 1 2 5 
1 2 5 
Sabatolimab 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Anti-neoplastic therapy after discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT discontinuation call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disposition11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Period 
Core Treatment1 
End of 
Treatment 
(Core)22 
Extension Treatment 
End of 
Treatment 
(Extension) 
Safety Follow-up12 
Cycle 
Cycle 6 
Cycle 7 and 
subsequent 
cycles* 
 
Cycle 122 
Cycle 2 and 
subsequent 
cycles 
 
 
Days 
1 2 5 
1 
 
1 
1 
 
30 Days 
(All) 
90 & 150 Days 
(sabatolimab) 
105 Days 
(Crizanlizumab) 
Informed consent 
 
 
 
 
 
X 
 
 
 
 
 
IRT screening call 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
X 
 
 
 
 
 
IRT eligibility checklist and 
allocation call 
 
 
 
 
 
X 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
 
 
Disease diagnosis 
 
 
 
 
 
 
 
 
 
 
 
Prior ruxolitinib therapy 
 
 
 
 
 
 
 
 
 
 
 
Prior anti-neoplastic 
therapy 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X (at every clinic visit) 
X 
X 
X 
X 
X 
X 
X 


Novartis 
Confidential 
Page 145 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment1 
End of 
Treatment 
(Core)22 
Extension Treatment 
End of 
Treatment 
(Extension) 
Safety Follow-up12 
Cycle 
Cycle 6 
Cycle 7 and 
subsequent 
cycles* 
 
Cycle 122 
Cycle 2 and 
subsequent 
cycles 
 
 
Days 
1 2 5 
1 
 
1 
1 
 
30 Days 
(All) 
90 & 150 Days 
(sabatolimab) 
105 Days 
(Crizanlizumab) 
Non-drug therapies and 
procedures 
X (at every clinic visit) 
X 
X 
X 
X 
X 
X 
X 
Transfusion record (PRBC 
and platelets) 
X (at every clinic visit) 
X 
X22 
X 
X 
X 
X 
X 
Physical examination 
S 
 
 
S 
S 
S 
S 
S 
S 
S 
S 
ECOG performance status X 
 
 
X 
X 
X22 
X 
X 
 
 
 
Height 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
X22 
X 
X 
 
 
 
Vital signs 
X (at every clinic visit) 
X 
X22 
X (at every clinic 
visit) 
X 
X 
X 
X 
Spleen length 
measurement by palpation X 
 
 
X 
X 
X22 
X 
X 
 
 
 
Laboratory assessments 
- 
Hematology 
X 
 
 
X 
X 
X22 
X 
X 
X 
X 
X 
Chemistry 
X 
 
 
X 
X 
X22 
X 
X 
X 
X 
X 
Additional chemistry for 
siremadlin safety 
monitoring3 
 
X X 
 
 
 
 
 
 
 
 
Coagulation 
X (as clinically indicated) 
 
 X (as clinically 
indicated) 
 
 
 
 
 
Urinalysis 
X (as clinically indicated) 
X 
X22 
 
X 
 
 
 
Thyroid function 
X (as clinically indicated) 
X 
X22 
 
X 
 
 
 
Pregnancy test - serum 
 
 
 
 
S 
 
 
S 
S 
S 
S 


Novartis 
Confidential 
Page 146 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment1 
End of 
Treatment 
(Core)22 
Extension Treatment 
End of 
Treatment 
(Extension) 
Safety Follow-up12 
Cycle 
Cycle 6 
Cycle 7 and 
subsequent 
cycles* 
 
Cycle 122 
Cycle 2 and 
subsequent 
cycles 
 
 
Days 
1 2 5 
1 
 
1 
1 
 
30 Days 
(All) 
90 & 150 Days 
(sabatolimab) 
105 Days 
(Crizanlizumab) 
Pregnancy test - urine or 
serum 
S 
 
 
S 
 
S 
S 
 
 
 
 
Hepatitis test 
X (as clinically 
indicated) 
X 
 
X (as clinically 
indicated) 
X 
 
 
 
HIV screen 
 
 
 
 
 
 
 
 
 
 
 
Serology exam 
X (as clinically 
indicated) 
 
X (as clinically 
indicated) 
X (as clinically 
indicated) 
 
 
 
 
Cytokines 
X (anytime if suspected 
cytokine release 
syndrome, immediately 
after the AE, and one 
week after the AE) 
 
X (anytime if 
suspected 
cytokine release 
syndrome, 
immediately 
after the AE, 
and one week 
after the AE) 
X (anytime if 
suspected 
cytokine release 
syndrome, 
immediately after 
the AE, and one 
week after the AE) 
 
 
 
 
Safety 
- 
Adverse events 
X (at every clinic visit) 
X 
X 
X 
X 
X 
X 
X 
ECG8 
X8 
 
 
X8 
X 
X22 
X (as clinically 
indicated) 
X 
 
 
 
Cardiac imaging (MUGA or 
ECHO) 
 
 
 
X20 
 
 
X20 
 
 
 
Ophthalmologic 
assessments19 
X19  
 
X19 
X19 
X22 
X19 
X19 
 
 
 
ePROs  
- 
MFSAF v4.0 
X 
 
 
X 
X 
 
 
 
 
 
 
EORTC QLQ-C30 
X 
 
 
X 
X 
 
 
 
 
 
 


Novartis 
Confidential 
Page 147 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment1 
End of 
Treatment 
(Core)22 
Extension Treatment 
End of 
Treatment 
(Extension) 
Safety Follow-up12 
Cycle 
Cycle 6 
Cycle 7 and 
subsequent 
cycles* 
 
Cycle 122 
Cycle 2 and 
subsequent 
cycles 
 
 
Days 
1 2 5 
1 
 
1 
1 
 
30 Days 
(All) 
90 & 150 Days 
(sabatolimab) 
105 Days 
(Crizanlizumab) 
TFQ (optional) 
 
 
 
 
X 
 
 
 
 
 
 
Imaging 
- 
MRI/CT of abdomen 
 
 
 
X17 
X13 
X22 
X (as clinically 
indicated) 
X13 
 
 
 
Disease progression 
assessment  
(Section 8.3.2.5) 
X (at every clinic visit) 
 
 
X (at every clinic 
visit) 
 
 
 
 


Novartis 
Confidential 
Page 148 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment1 
End of 
Treatment 
(Core)22 
Extension Treatment 
End of 
Treatment 
(Extension) 
Safety Follow-up12 
Cycle 
Cycle 6 
Cycle 7 and 
subsequent 
cycles* 
 
Cycle 122 
Cycle 2 and 
subsequent 
cycles 
 
 
Days 
1 2 5 
1 
 
1 
1 
 
30 Days 
(All) 
90 & 150 Days 
(sabatolimab) 
105 Days 
(Crizanlizumab) 
Confirmation of clinical 
benefit assessment 
(Section 8.3.4) 
 
 
 
X 
 
 
 
 
Study Drug 
Administration 
- 
IRT drug dispensation call 
X 
 
 
X 
 
X 
X 
 
 
 
 
Ruxolitinib 
X (BID - twice a day) 
 
X 
X 
 
 
 
 
Siremadlin 
X (Day 1-
5) 
X (Day 1-5) 
 
X (Day 1-5) 
X (Day 1-5) 
 
 
 
 
Crizanlizumab infusion 
X 
 
 
X 
 
 
 
 
 
 
 
Sabatolimab infusion 
X 
 
 
X 
 
 
 
 
 
 
 
Rineterkib 
X (QD – once a day) 
 
X 
X 
 
 
 
 
PK sampling 
- 
Ruxolitinib10 
X 
 X10 
 
 
 
 
 
 
 
 
Siremadlin  
 
X X 
 
 
 
 
 
 
 
 
Crizanlizumab 
X 
 
 
X18 
X 
 
 
 
 
 
X 
Sabatolimab 
X 
 
 
X18 
X 
 
 
 
 
X14 
 
Blood sample for sTIM-3 
(sabatolimab) 
X 
 
 
X18 
X 
 
 
 
 
 
 
Rineterkib 
X 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
- 
Crizanlizumab 
X 
 
 
X18 
X 
 
 
 
 
 
X 
Sabatolimab 
X 
 
 
X18 
X 
 
 
 
 
X14 
 


Novartis 
Confidential 
Page 149 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment1 
End of 
Treatment 
(Core)22 
Extension Treatment 
End of 
Treatment 
(Extension) 
Safety Follow-up12 
Cycle 
Cycle 6 
Cycle 7 and 
subsequent 
cycles* 
 
Cycle 122 
Cycle 2 and 
subsequent 
cycles 
 
 
Days 
1 2 5 
1 
 
1 
1 
 
30 Days 
(All) 
90 & 150 Days 
(sabatolimab) 
105 Days 
(Crizanlizumab) 
Anti-neoplastic therapy 
after discontinuation 
 
 
 
 
 
 
 
 
X 
X 
X 
IRT discontinuation call 
 
 
 
 
X 
 
 
X 
 
 
 
Disposition11 
 
 
 
 
X 
 
 
X 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
* Only for subjects for which the investigator has confirmed continued clinical benefit after the first 6 planned cycles. 
1 Actual clinic visit days will depend on the treatment arm for PK, PD 
 collection: For all subjects = Day 1 & 2 of Cycle 1, Day 1 of all subsequent cycles, 
and Day 15 of Cycles 1, 2 & 3; For subjects on ruxolitinib + siremadlin = also Days 2 & 5 for any Cycle, and Day 6 of Cycle 1 & 2; For subjects on ruxolitinib + 
crizanlizumab and ruxolitinib + sabatolimab = also Day 8 of Cycle 1 & 3 
3 Additional chemistry only for subjects on ruxolitinib + siremadlin = phosphorus, calcium, uric acid, potassium, and creatinine 
4 As per country and local regulations 
5 Subjects that have a positive test for hepatitis should be re-tested pre-dose at the beginning of every cycle or as clinically indicated to monitor for hepatitis reactivation 
6 Only for subjects on the ruxolitinib + sabatolimab arm. Sample to be collected pre-dose. 
7 Only for subjects on the ruxolitinib + crizanlizumab and ruxolitinib + sabatolimab arms. Sample to be collected pre-dose. 
8 All subjects at screening, predose C1D1, and EOT. Also only for subjects on ruxolitinib + siremadlin = predose at C1D1, C1D5, C2D1, C2D5 and at 4h post-dose 
(Cmax) of C2D5, then pre-dose on Day 1 of Cycles 3-6 and then only if clinically relevant after Cycle 6. For subjects on ruxolitinib + rineterkib = predose at C1D1, 
predose and at 2h post-dose at C1D15, then pre-dose on Day 1 of Cycles 2-6 and then only if clinically relevant after Cycle 6. 
9 Previously completed scans can be considered for baseline if obtained within 8 weeks prior to first dose 
10 Refer to PK log tables for specific PK sampling depending on the combination treatment 
11 Subject disposition to be recorded in the eCRF 
12 Safety follow-up visits as follows: +30 days after last dose of all investigational drugs for all subjects; also +90 days and +150 days post last dose of sabatolimab for 
subjects on ruxolitinib + sabatolimab; and also +105 days post last dose of crizanlizumab for subjects on ruxolitinib + crizanlizumab 
13 If not performed in the past 12 weeks 
14 Only collected at the 90-day safety follow-up visit (not at the 150-day safety follow-up visit) 
16 Every 3 cycles after C6D1 until study treatment discontinuation (C9D1, C12D1 etc.) for subjects on ruxolitinib + crizanlizumab treatment 
17 At the end of every 6 cycles (± 7 days) for all subjects 


Novartis 
Confidential 
Page 150 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment1 
End of 
Treatment 
(Core)22 
Extension Treatment 
End of 
Treatment 
(Extension) 
Safety Follow-up12 
Cycle 
Cycle 6 
Cycle 7 and 
subsequent 
cycles* 
 
Cycle 122 
Cycle 2 and 
subsequent 
cycles 
 
 
Days 
1 2 5 
1 
 
1 
1 
 
30 Days 
(All) 
90 & 150 Days 
(sabatolimab) 
105 Days 
(Crizanlizumab) 
18 Every 3 cycles until study treatment discontinuation (C9D1, C12D1 etc.) 
19 Only for subjects on ruxolitinib + rineterkib treatment 
20 Only for subjects on ruxolitinib + rineterkib treatment and if not performed within the last 14 days 
21 Every 6 cycles after C1D1 until study treatment discontinuation (C7D1, C13D1 etc.) for subjects on ruxolitinib + sabatolimab treatment 
22 Assessments performed for Core End of Treatment visit are not to be repeated for Extension Cycle 1 Day 1 as these two visits should occur on the same day. 
Corresponding data will be recorded only once in the CRF under Core Phase EOT visit.  
Table 8-3 
Assessment Schedule, Part 2 & 3 (for all arms with 28-day cycles) (Not applicable)  
Period 
Screening 
Treatment1 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Days 
-28 to -1 
1 
2 
5 
6 
8 
15 
1 
5 
6 
1 
2 
5 
8 
15 
1 
2 
5 
1 
2 
5 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT screening call 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT eligibility checklist and 
randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior ruxolitinib therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior anti-neoplastic therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X (at every clinic visit) 
Non-drug therapies and procedures 
X 
X (at every clinic visit) 


Novartis 
Confidential 
Page 151 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
Treatment1 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Days 
-28 to -1 
1 
2 
5 
6 
8 
15 
1 
5 
6 
1 
2 
5 
8 
15 
1 
2 
5 
1 
2 
5 
Transfusion record (PRBC and 
platelets) 
X 
X (at every clinic visit) 
Physical examination 
S 
S 
 
 
 
 
 
S 
 
 
S 
 
 
 
 
S 
 
 
S 
 
 
ECOG performance status 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X2 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Vital signs 
X 
X (at every clinic visit) 
Spleen length measurement by 
palpation 
X 
X 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
Laboratory assessments 
- 
Hematology 
X 
X 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
Chemistry 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Additional chemistry for siremadlin 
safety monitoring3 
 
 
X 
X 
X 
 
 
 
X 
X 
 
X 
X 
 
 
 
X 
X 
 
X 
X 
Coagulation 
X 
X (as clinically indicated) 
Urinalysis 
X 
X (as clinically indicated) 
Thyroid function 
X 
X (as clinically indicated) 
Cardiac markers (Troponin I, 
NTproBNP) 
X21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test - serum 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test - urine 
 
S 
 
 
 
 
 
S 
 
 
S 
 
 
 
 
S 
 
 
S 
 
 
Hepatitis test 
X5 
X (as clinically indicated) 
HIV screen 
S4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology exam 
 
X6 
 
X (as clinically indicated) 
Cytokines 
 
X7 
 
X (anytime if suspected cytokine release syndrome, immediately after the AE, and one week after the AE) 
Safety 
- 
Adverse events 
X 
 
X (at every clinic visit) 


Novartis 
Confidential 
Page 152 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
Treatment1 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Days 
-28 to -1 
1 
2 
5 
6 
8 
15 
1 
5 
6 
1 
2 
5 
8 
15 
1 
2 
5 
1 
2 
5 
ECG8 
X 
X 
 
 
 
 
 
X8 
 
 
X8 
 
 
 
 
X8 
 
 
X8 
 
 
Cardiac imaging (MUGA or ECHO) 
19 
 
X19 
 
 
 
 
 
 
 
 
X19 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic assessments19 
 
X19 
 
 
 
 
 
X19 
 
 
X19 
 
 
 
 
X19 
 
 
X19 
 
 
Imaging 
- 
MRI/CT of abdomen 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ePROs 
- 
MFSAF v4.0 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
EORTC QLQ-C30 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
TFQ (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease progression assessment 
 
X (at every clinic visit) 
Study Drug Administration 
- 
IRT drug dispensation call 
 
 
 
 
 
 
X2 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Ruxolitinib 
 
X (BID - twice a day) 
Siremadlin 
 
X (Day 1-5) 
 
 
 
X (Day 1-5) 
 
X (Day 1-5) 
 
 
X (Day 1-5) 
X (Day 1-5) 


Novartis 
Confidential 
Page 153 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
Treatment1 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Days 
-28 to -1 
1 
2 
5 
6 
8 
15 
1 
5 
6 
1 
2 
5 
8 
15 
1 
2 
5 
1 
2 
5 
Crizanlizumab infusion 
 
X 
 
 
 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Sabatolimab infusion 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Rineterkib 
 
X (QD – once a day) 
PK sampling 
- 
Ruxolitinib10 
 
X 
X10 
X10 
X10 
 
X10 
X10 
X10 
X10 
X 
 
X10 
 
X10 
X 
 
X10 
X 
 
X10 
Siremadlin 
 
X 
X 
X 
X 
 
 
 
X10 
X 
 
X 
X 
 
 
 
X 
X 
 
X 
X 
Crizanlizumab 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Sabatolimab 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Blood sample for sTIM-3 
(sabatolimab)# 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Rineterkib 
 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Immunogenicity 
- 
Crizanlizumab 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Sabatolimab 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
IRT discontinuation call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-neoplastic therapy after 
discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukemic transformation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disposition11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 154 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
 
End of 
Treatment 
Safety Follow-up12 
Survival Follow-
up 
Cycle 
Cycle 6 
Cycle 7 (and subsequent cycles)* 
 
 
 
Days 
1 
2 
5 
1 
EOT 
+30 Days 
(All) 
+90 & +150 Days 
(sabatolimab) 
+105 Days 
(crizanlizumab) 
Every 3 months 
(All) 
Informed consent 
 
 
 
 
 
 
 
 
 
IRT screening call 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
IRT eligibility checklist and 
randomization 
 
 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
Disease diagnosis 
 
 
 
 
 
 
 
 
 
Prior ruxolitinib therapy 
 
 
 
 
 
 
 
 
 
Prior anti-neoplastic therapy 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X (at every 
clinic visit) 
X 
X 
X 
X 
X 
 
Non-drug therapies and procedures X (at every 
clinic visit) 
X 
X 
X 
X 
X 
 
Transfusion record (PRBC and 
platelets) 
X (at every 
clinic visit) 
X 
X 
X 
X 
X 
 
Physical examination 
S 
 
 
S 
S 
S 
S 
S 
 
ECOG performance status 
X 
 
 
X 
X 
 
 
 
 
Height 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
 
 
 
 
Vital signs 
X (at every 
clinic visit) 
X 
X 
X 
X 
 
 
Spleen length measurement by 
palpation 
X 
 
 
X 
X 
 
 
 
 


Novartis 
Confidential 
Page 155 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
 
End of 
Treatment 
Safety Follow-up12 
Survival Follow-
up 
Cycle 
Cycle 6 
Cycle 7 (and subsequent cycles)* 
 
 
 
Days 
1 
2 
5 
1 
EOT 
+30 Days 
(All) 
+90 & +150 Days 
(sabatolimab) 
+105 Days 
(crizanlizumab) 
Every 3 months 
(All) 
Laboratory assessments 
- 
 
Hematology 
X 
 
 
X 
X 
X 
X 
X 
 
Chemistry 
X 
 
 
X 
X 
X 
X 
X 
 
Additional chemistry for Siremadlin 
safety monitoring3 
 
X 
X 
 
 
 
 
 
 
Coagulation 
X (as clinically indicated) 
 
 
 
 
 
Urinalysis 
X (as clinically indicated) 
 
 
 
 
 
Thyroid function 
X (as clinically indicated) 
 
X 
 
 
 
 
 
Cardiac markers (Troponin I, 
NTproBNP) 
 
 
 
 
 
 
 
 
 
Pregnancy test - serum 
 
 
 
 
S 
S 
S 
S 
 
Pregnancy test - urine 
S 
 
 
S 
 
 
 
 
 
Hepatitis test 
X (as clinically indicated) 
 
X 
 
 
 
 
HIV screen 
 
 
 
 
 
 
 
 
 
Serology exam 
X (as clinically indicated) 
X 
 
 
 
 
Cytokines 
X (anytime if suspected cytokine release 
syndrome, immediately after the AE, and one 
week after the AE) 
 
 
 
 
 
Safety 
 
Adverse events 
X (at every 
clinic visit) 
X 
X 
X 
X 
X 
 
ECG8 
X8 
 
X8 
X8 
X 
 
 
 
 
Cardiac imaging (MUGA or ECHO) 
19 
 
 
 
 
X20 
 
 
 
 


Novartis 
Confidential 
Page 156 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
 
End of 
Treatment 
Safety Follow-up12 
Survival Follow-
up 
Cycle 
Cycle 6 
Cycle 7 (and subsequent cycles)* 
 
 
 
Days 
1 
2 
5 
1 
EOT 
+30 Days 
(All) 
+90 & +150 Days 
(sabatolimab) 
+105 Days 
(crizanlizumab) 
Every 3 months 
(All) 
Ophthalmologic assessments19 
X19 
 
 
X19 
X19 
 
 
 
 
Imaging 
 
MRI/CT of abdomen 
 
 
 
X13 
X14 
 
 
 
 
ePROs  
 
MFSAF v4.0 
X 
 
 
X 
X 
 
 
 
 
EORTC QLQ-C30 
X 
 
 
X 
X 
 
 
 
 
TFQ (optional) 
 
 
 
X23 
X 
 
 
 
 
Disease progression assessment 
X (at every clinic visit) 
 
 
 
 
 
Study Drug Administration 
 
IRT drug dispensation call 
X 
 
 
X 
 
 
 
 
 
Ruxolitinib 
X (BID - twice a day) 
 
 
 
 
 
Siremadlin 
X (Day 1-5) 
X (Day 1-5) 
 
 
 
 
 
Crizanlizumab infusion 
X 
 
 
X 
 
 
 
 
 


Novartis 
Confidential 
Page 157 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
 
End of 
Treatment 
Safety Follow-up12 
Survival Follow-
up 
Cycle 
Cycle 6 
Cycle 7 (and subsequent cycles)* 
 
 
 
Days 
1 
2 
5 
1 
EOT 
+30 Days 
(All) 
+90 & +150 Days 
(sabatolimab) 
+105 Days 
(crizanlizumab) 
Every 3 months 
(All) 
Sabatolimab infusion 
X 
 
 
X 
 
 
 
 
 
Rineterkib 
X (QD – once a day) 
 
 
 
 
 
PK sampling 
 
Ruxolitinib10 
X 
 
X10 
 
 
 
 
 
 
Siremadlin 
 
X 
X 
 
 
 
 
 
 
Crizanlizumab 
X15 
 
 
 
X 
 
 
X 
 
Sabatolimab 
X15 
 
 
 
X 
 
X16 
 
 
Blood sample for sTIM-3 
(sabatolimab)# 
X15 
 
 
 
X 
 
 
 
 
Rineterkib 
X 
 
 
 
 
 
 
 
Immunogenicity 
 
Crizanlizumab 
X15 
 
 
 
X 
 
 
X 
 
Sabatolimab 
X15 
 
 
 
X 
 
X16 
 
 
IRT discontinuation call 
 
 
 
 
X 
 
 
 
 
Anti-neoplastic therapy after 
discontinuation 
 
 
 
 
 
X 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
 
X 
Leukemic transformation  
 
 
 
 
 
 
 
 
X 
Disposition11 
 
 
 
 
X 
 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
* Investigator will need to confirm continued clinical benefit for the subjects to continue beyond the first 12 planned cycles. 
1 Actual clinic visit days will depend on the treatment arm for PK, PD 
 collection: For all subjects = Day 1 & 2 of Cycle 1, Day 1 of all subsequent cycles, 
and Day 15 of Cycles 1, 2 & 3; For subjects on ruxolitinib + siremadlin = also Days 2 & 5 for any Cycle, and Day 6 of Cycle 1 & 2; For subjects on ruxolitinib + 
crizanlizumab and ruxolitinib + sabatolimab = also Day 8 of Cycle 1 & 3 
3 Additional chemistry for ruxolitinib + siremadlin subjects only (or siremadlin monotherapy arm in Part 3) = phosphorus, calcium, uric acid, potassium, and creatinine 


Novartis 
Confidential 
Page 158 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
 
End of 
Treatment 
Safety Follow-up12 
Survival Follow-
up 
Cycle 
Cycle 6 
Cycle 7 (and subsequent cycles)* 
 
 
 
Days 
1 
2 
5 
1 
EOT 
+30 Days 
(All) 
+90 & +150 Days 
(sabatolimab) 
+105 Days 
(crizanlizumab) 
Every 3 months 
(All) 
4 If required per As per country and local regulations 
5 Subjects that have a positive test for hepatitis should be re-tested pre-dose at the beginning of every cycle or as clinically indicated to monitor for hepatitis reactivation 
7 Only for subjects on the ruxolitinib + crizanlizumab and ruxolitinib + sabatolimab arms (or crizanlizumab or sabatolimab monotherapy arms in Part 3, as applicable), 
sample to be collected pre-dose. 
8 All subjects at screening, predose C1D1, and EOT in Part 2 and 3. For ruxolitinib + siremadlin subjects only, as follows: Part 2 = also predose on Day 1 of cycles 2-6, 
and 4h postdose (Cmax) on C6D5, and then only if clinically relevant after Cycle 6; Part 3 = also predose on Day 1 of cycles 2, 4 & 6, and 4h postdose (Cmax) on C6D5, 
and then only if clinically relevant after Cycle 6. For subjects on ruxolitinib + rineterkib only, as follows: Part 2 = also pre-dose on Day 1 of Cycles 2-6 and then only if 
clinically relevant after Cycle 6, Part 3 = also pre-dose on Day 1 of Cycles 2, 4 & 6 and then only if clinically relevant after Cycle 6. Please see Section 8.4.2 for the list of 
requirements. 
9 Previously completed MRI/CT scans and bone marrow biopsies can be considered for baseline if obtained within 8 weeks prior to first dose of study treatment.  
10 Refer to PK log tables for specific PK sampling depending on the combination treatment 
11 Subject disposition to be recorded in the eCRF 
12 Safety follow-up visits as follows: +30 days after last dose of all investigational drugs for all subjects; also +90 days and +150 days post last dose of sabatolimab for 
subjects on ruxolitinib + sabatolimab (or sabatolimab monotherapy in Part 3); and also +105 days post last dose of crizanlizumab for subjects on ruxolitinib + 
crizanlizumab (or crizanlizumab monotherapy in Part 3) 
13 At the end of every 6 cycles (± 7 days) for all subjects. 
14 If not performed in the past 12 weeks 
15 C6D1 then every 3 cycles until study treatment discontinuation (ie C9D1, C12D1 etc.) 
16 Only collected at the 90-day safety follow-up visit (not at the 150-day visit) 
 
18 C6D1 then every 3 cycles until study treatment discontinuation (C9D1, C12D1 etc.) for subjects on ruxolitinib + crizanlizumab treatment 
19 Only for subjects on ruxolitinib + rineterkib treatment 
20 Only for subjects on ruxolitinib + rineterkib treatment and if not performed within the last 14 days 
21 Only when NIS793 is open for enrollment in Part 2 or 3.  
22 Every 6 cycles after C1D1 until study treatment discontinuation (C7D1, C13D1 etc.) for subjects on ruxolitinib + sabatolimab treatment 
 


Novartis 
Confidential 
Page 159 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 8-4 
Assessment Schedule, Part 1 Ruxolitinib + NIS793 arm (21-day cycles) 
Period 
Screening 
 Core Treatment 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Days 
-28 to -1 
1 
2 
4 
8 
11 15 
1 
15 
1 
2 
4 
8 
11 15 
1 
1 
1 
1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT screening call 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT eligibility checklist and 
allocation call 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior ruxolitinib therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior anti-neoplastic therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X (at every clinic visit) 
Non-drug therapies and 
procedures 
X 
X (at every clinic visit) 
Transfusion record (PRBC and 
platelets) 
X 
X (at every clinic visit) 
Physical examination 
S 
S 
 
 
 
 
 
S 
 
S 
 
 
 
 
 
S 
S 
S 
S 
ECOG performance status 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Vital signs 
X 
X (at every clinic visit) 
Spleen length measurement by 
palpation 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
Laboratory assessments 
- 
Hematology 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 


Novartis 
Confidential 
Page 160 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
 Core Treatment 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Days 
-28 to -1 
1 
2 
4 
8 
11 15 
1 
15 
1 
2 
4 
8 
11 15 
1 
1 
1 
1 
Coagulation 
X 
X (as clinically indicated) 
Urinalysis 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Thyroid function 
X 
X (as clinically indicated) 
Cardiac markers (Troponin 
I,NTproBNP) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy test - serum 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test - urine or serum 
 
S 
 
 
 
 
 
S 
 
S 
 
 
 
 
 
S 
S 
S 
S 
Hepatitis test 
X1 
X (as clinically indicated) 
HIV screen 
S2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology exam 
 
X3 
X (as clinically indicated) 
Cytokines 
 
X3 
X (anytime if suspected cytokine release syndrome, immediately after the AE, and one week after the AE) 
Safety 
- 
Adverse events 
X 
X (at every clinic visit) 
ECG 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
ePROs  
- 
MFSAF v4.0 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
EORTC QLQ-C30 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
TFQ (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Imaging 
- 
MRI/CT of abdomen 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Imaging: 
Echocardiogram (or if not 
available, Cardiac MRI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 161 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
 Core Treatment 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Days 
-28 to -1 
1 
2 
4 
8 
11 15 
1 
15 
1 
2 
4 
8 
11 15 
1 
1 
1 
1 
Disease progression 
assessment 
 
X (at every clinic visit) 
Study Drug Administration 
- 
IRT drug dispensation call 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Ruxolitinib 
 
X (BID - twice a day) 
NIS793 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
PK sampling 
- 
Ruxolitinib5 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
NIS793 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
- 
NIS793 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Anti-neoplastic therapy after 
discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT discontinuation call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disposition6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 162 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment 
End of Treatment  
(Core)  
Safety Follow-up 
Cycle 
Cycle 8 
Cycle 9 and subsequent cycles* 
 
 
Days 
1 
1 
EOT 
30 Days 
90 Days 
Informed consent 
 
 
 
 
 
IRT screening call 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
IRT eligibility checklist and allocation call 
 
 
 
 
 
Demography 
 
 
 
 
 
Medical history 
 
 
 
 
 
Disease diagnosis 
 
 
 
 
 
Prior ruxolitinib therapy 
 
 
 
 
 
Prior anti-neoplastic therapy 
 
 
 
 
 
Prior/concomitant medications 
X (at every clinic visit) 
X 
X 
X 
Non-drug therapies and procedures 
X (at every clinic visit) 
X 
X 
X 
Transfusion record (PRBC and platelets) 
X (at every clinic visit) 
X 
X 
X 
Physical examination 
S 
S 
S 
S 
S 
ECOG performance status 
X 
X 
X 
 
 
Height 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
Vital signs 
X (at every clinic visit) 
X 
X 
X 
Spleen length measurement by palpation 
X 
X 
X 
 
 
Laboratory assessments 
Hematology 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
Coagulation 
X (as clinically indicated) 
 
 
 
Urinalysis 
X 
X 
X 
 
 
Thyroid function 
X (as clinically indicated) 
X 
 
 
Cardiac markers (Troponin I, NTproBNP) 
 
X10 
 
X10 
 
Pregnancy test - serum 
 
 
S 
S 
S 


Novartis 
Confidential 
Page 163 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment 
End of Treatment  
(Core)  
Safety Follow-up 
Cycle 
Cycle 8 
Cycle 9 and subsequent cycles* 
 
 
Days 
1 
1 
EOT 
30 Days 
90 Days 
Pregnancy test - urine or serum 
S 
S 
 
 
 
Hepatitis test 
X (as clinically indicated) 
X 
 
 
HIV screen 
 
 
 
 
 
Serology exam 
X (as clinically indicated) 
 
 
 
Cytokines 
X (anytime if suspected cytokine release 
syndrome, immediately after the AE, and one 
week after the AE) 
 
 
 
Safety 
Adverse events 
X (at every clinic visit) 
X 
X 
X 
ECG 
X 
X 
X 
 
 
ePROs  
MFSAF v4.0 
X 
X 
X 
 
 
EORTC QLQ-C30 
X 
X 
X 
 
 
TFQ (optional) 
 
 
X 
 
 
Imaging 
MRI/CT of abdomen 
 
X7 
X8 
 
 
Cardiac Imaging Echocardiogram (or if not 
available, Cardiac MRI) 
 
X11 
 
X 
 


Novartis 
Confidential 
Page 164 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Core Treatment 
End of Treatment  
(Core)  
Safety Follow-up 
Cycle 
Cycle 8 
Cycle 9 and subsequent cycles* 
 
 
Days 
1 
1 
EOT 
30 Days 
90 Days 
Disease progression assessment 
X (at every clinic visit) 
 
 
 
Study Drug Administration 
IRT drug dispensation call 
X 
X 
 
 
 
Ruxolitinib 
X (BID - twice a day) 
 
 
 
NIS793 
X 
X 
 
 
 
PK sampling 
Ruxolitinib5 
X 
 
 
 
 
NIS793 
X 
X9 
X 
X 
X 
Immunogenicity 
NIS793 
X 
X9 
X 
X 
X 
Anti-neoplastic therapy after 
discontinuation 
 
 
 
X 
X 
IRT discontinuation call 
 
 
X 
 
 
Disposition6 
 
 
X 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
 S Assessment to be recorded in the source documentation only 
* Only for subjects for which the investigator has confirmed continued clinical benefit after the first 6 planned cycles. 
1 Subjects that have a positive test for hepatitis should be re-tested pre-dose at the beginning of every cycle or as clinically indicated to monitor for hepatitis reactivation 
 2 As per country and local regulations 
3 Sample to be collected pre-dose. 
 4 Previously completed scans can be considered for baseline if obtained within 8 weeks prior to first dose 
 5 Refer to PK log tables for specific PK sampling depending on the combination treatment 
 6 Subject disposition to be recorded in the eCRF 
 7 At the end of every 8 cycles (± 7 days)  
8 If not performed in the past 12 weeks 
9 Every 4 cycles after C8D1 until study treatment discontinuation, pre-dose at the beginning of the next cycle (C12D1, C16D1 etc.) 
10 Every 3 cycles after C3D1 until study treatment discontinuation, pre-dose at the beginning of the cycle (C6D1, C9D1...) also as clinically indicated.  
11 If a patient continued beyond planned duration of 8 cycles, pre-dose at the beginning of the cycle at C9D1 (at 24 weeks) also as clinically indicated and/or if cardiac 
enzyme increase ≥ 2x ULN (if normal at screening), or ≥ 2x baseline (if baseline value was elevated).  


Novartis 
Confidential 
Page 165 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 8-5 
Assessment Schedule, Part 2 & 3 Ruxolitinib + NIS793 or NIS793 monotherapy arm (21-day cycles) (Not applicable) 
Period 
Screening 
Treatment 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Days 
-28 to -1 
1 
2 
8 
15 
1 
15 
1 
2 
8 
15 
1 
1 
1 
1 
Informed consent 
X 
  
  
  
  
 
  
  
  
  
  
  
  
 
 
IRT screening call 
X 
  
  
  
 
  
  
  
 
  
  
  
  
 
 
Inclusion/exclusion criteria 
X 
 
  
  
  
 
  
  
 
  
  
  
  
 
 
IRT eligibility checklist and 
allocation call 
 
X 
  
  
 
  
  
  
  
 
  
  
  
  
 
 
Demography 
X 
  
  
  
  
  
  
  
 
  
  
  
  
 
 
Medical history 
X 
  
 
  
  
  
  
  
  
  
  
  
  
 
 
Disease diagnosis 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Prior ruxolitinib therapy 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Prior anti-neoplastic therapy 
X 
  
 
  
 
 
  
  
  
  
  
  
  
 
 
Prior/concomitant medications 
X 
X (at every clinic visit) 
Non-drug therapies and 
procedures 
X 
X (at every clinic visit) 
Transfusion record (PRBC and 
platelets) 
X 
X (at every clinic visit) 
Physical examination 
S 
S 
 
 
 
S 
 
S 
 
 
 
S 
S 
S 
S 
ECOG performance status 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Height 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Vital signs 
X 
X (at every clinic visit) 
Spleen length measurement by 
palpation 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Laboratory assessments 
- 
Hematology 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 


Novartis 
Confidential 
Page 166 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
Treatment 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Days 
-28 to -1 
1 
2 
8 
15 
1 
15 
1 
2 
8 
15 
1 
1 
1 
1 
Coagulation 
X 
X (as clinically indicated) 
Urinalysis 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Thyroid function 
X 
X (as clinically indicated) 
Cardiac markers (Troponin I, 
NTproBNP) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Pregnancy test - serum 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test - urine or serum 
 
S 
 
 
 
S 
 
S 
 
 
 
S 
S 
S 
S 
Hepatitis test 
X1 
X (as clinically indicated) 
HIV screen 
S2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology exam 
 
X3 
X (as clinically indicated) 
Cytokines 
 
X3 
X (anytime if suspected cytokine release syndrome, immediately after the AE, and one week after the AE) 
Safety 
- 
Adverse events 
X 
X (at every clinic visit) 
ECG 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
ePROs  
- 
MFSAF v4.0 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
EORTC QLQ-C30 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
TFQ (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging 
- 
MRI/CT of abdomen 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Imaging: 
Echocardiogram (or if not 
available, Cardiac MRI) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 167 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Screening 
Treatment 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Days 
-28 to -1 
1 
2 
8 
15 
1 
15 
1 
2 
8 
15 
1 
1 
1 
1 
Disease progression assessment  
X (at every clinic visit) 
Study Drug Administration 
- 
IRT drug dispensation call 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Ruxolitinib 
 
X (BID - twice a day) 
NIS793 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
PK sampling 
- 
Ruxolitinib5 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
NIS793 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
- 
NIS793 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Anti-neoplastic therapy after 
discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT discontinuation call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukemic transformation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disposition6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 168 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
End of Treatment 
Safety Follow-up 
Survival Follow-up 
Cycle 
Cycle 8 
Cycle 9 and subsequent cycles* 
 
 
 
Days 
1 
1 
EOT 
30 Days 
90 Days 
Every 3 months 
Informed consent 
 
 
 
 
 
 
IRT screening call 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
IRT eligibility checklist and allocation 
call 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
Disease diagnosis 
 
 
 
 
 
 
Prior ruxolitinib therapy 
 
 
 
 
 
 
Prior anti-neoplastic therapy 
 
 
 
 
 
 
Prior/concomitant medications 
X (at every clinic visit) 
X 
X 
X 
 
Non-drug therapies and procedures 
X (at every clinic visit) 
X 
X 
X 
 
Transfusion record (PRBC and 
platelets) 
X (at every clinic visit) 
X 
X 
X 
 
Physical examination 
S 
S 
S 
S 
S 
 
ECOG performance status 
X 
X 
X 
 
 
 
Height 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
 
Vital signs 
X (at every clinic visit) 
X 
X 
X 
 
Spleen length measurement by 
palpation 
X 
X 
X 
 
 
 
Laboratory assessments 
- 
 
Hematology 
X 
X 
X 
X 
X 
 
Chemistry 
X 
X 
X 
X 
X 
 
Coagulation 
X (as clinically indicated) 
 
 
 
 
Urinalysis 
X 
X 
X 
 
 
 


Novartis 
Confidential 
Page 169 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
End of Treatment 
Safety Follow-up 
Survival Follow-up 
Cycle 
Cycle 8 
Cycle 9 and subsequent cycles* 
 
 
 
Days 
1 
1 
EOT 
30 Days 
90 Days 
Every 3 months 
Thyroid function 
X (as clinically indicated) 
X 
 
 
 
Cardiac markers (Troponin I, 
NTproBNP) 
 
X10 
 
X 
 
 
Pregnancy test - serum 
 
 
S 
S 
S 
 
Pregnancy test - urine or serum 
S 
S 
 
 
 
 
Hepatitis test 
X (as clinically indicated) 
X 
 
 
 
HIV screen 
 
 
 
 
 
 
Serology exam 
X (as clinically indicated) 
 
 
 
 
Cytokines 
X (anytime if suspected cytokine release 
syndrome, immediately after the AE, and one 
week after the AE) 
 
 
 
 
Safety 
- 
 
Adverse events 
X (at every clinic visit) 
X 
X 
X 
 
ECG 
X 
X 
X 
 
 
 
ePROs  
- 
 
MFSAF v4.0 
X 
X 
X 
 
 
 
EORTC QLQ-C30 
X 
X 
X 
 
 
 
TFQ (optional) 
X 
 
X 
 
 
 
Imaging 
- 
 
MRI/CT of abdomen 
 
X7 
X8 
 
 
 
Cardiac imaging: Echocardiogram (or if 
not available, Cardiac MRI) 
 
X11 
 
X 
 
 


Novartis 
Confidential 
Page 170 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
End of Treatment 
Safety Follow-up 
Survival Follow-up 
Cycle 
Cycle 8 
Cycle 9 and subsequent cycles* 
 
 
 
Days 
1 
1 
EOT 
30 Days 
90 Days 
Every 3 months 
Disease progression 
 
 
 
 
 
 
Disease progression assessment 
X (at every clinic visit) 
 
 
 
 
Study Drug Administration 
- 
 
IRT drug dispensation call 
X 
X 
 
 
 
 
Ruxolitinib 
X (BID - twice a day) 
 
 
 
 
NIS793 
X 
X 
 
 
 
 
PK sampling 
- 
 
Ruxolitinib6 
X 
 
 
 
 
 
NIS793 
X 
X9 
X 
X 
X 
 
Immunogenicity 
- 
 
NIS793 
X 
X9 
X 
X 
X 
 
Anti-neoplastic therapy after 
discontinuation 
 
 
 
X 
X 
X 
IRT discontinuation call 
 
 
X 
 
 
 
Survival status 
 
 
 
 
 
X 
Leukemia transformation 
 
 
 
 
 
X 
Disposition11 
 
 
X 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
* Only for subjects for which the investigator has confirmed continued clinical benefit after the first 6 planned cycles. 
1 Subjects that have a positive test for hepatitis should be re-tested pre-dose at the beginning of every cycle or as clinically indicated to monitor for hepatitis reactivation 
2As per country and local regulations 


Novartis 
Confidential 
Page 171 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Period 
Treatment 
End of Treatment 
Safety Follow-up 
Survival Follow-up 
Cycle 
Cycle 8 
Cycle 9 and subsequent cycles* 
 
 
 
Days 
1 
1 
EOT 
30 Days 
90 Days 
Every 3 months 
3 Sample to be collected pre-dose. 
4 Previously completed MRI/CT scans and bone marrow biopsies can be considered for baseline if obtained within 8 weeks prior to first dose of study treatment. For re-
screened subjects. 
5 Refer to PK log tables for specific PK sampling depending on the combination treatment 
6 Subject disposition to be recorded in the eCRF 
7 At the end of every 8 cycles (± 7 days)  
8 If not performed in the past 12 weeks 
9 Every 4 cycles after C8D1 until study treatment discontinuation, pre-dose at the beginning of the next cycle (C12D1, C16D1 etc.) 
10 Every 3 cycles after C3D1 until study treatment discontinuation, pre-dose at the beginning of the cycle (C6D1, C9D1...) also as clinically indicated.  
11 At C9D1 (24 weeks) and also as clinically indicated and/or if cardiac enzyme increase ≥ 2x ULN (if normal at screening), or ≥ 2x baseline (if baseline value was 
elevated). 
 


Novartis 
Confidential 
Page 172 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
8.1 
Screening 
The screening period begins once written informed consent is provided and ends after 28 days 
or when subject is allocated (Part 1) /randomized (Parts 2 and 3) to study treatment, whichever 
comes first. 
Screening assessments to confirm eligibility into the study, as described in Table 8-2 and  
Table 8-3, Table 8-4 and Table 8-5 should be performed within 1 to 28 days prior to the first 
dose of study treatment, unless otherwise specified in Table 8-1. 
A serum pregnancy test, where applicable, must be confirmed negative prior to the first dose of 
study treatment. 
A subject who has a laboratory test result(s) that does not satisfy the entrance criteria may have 
the test(s) repeated once, prior to randomization. These test(s) may be repeated as soon as the 
investigator believes the re-test result(s) is/are likely to be within the acceptable range to satisfy 
the entrance criteria, but should be completed within approximately 3 weeks of the original 
screening visit date. In this case, the subject will not be required to sign another ICF, and the 
original subject ID number assigned by the investigator will be used. In the event that the 
laboratory test(s) cannot be performed within 3 weeks of the original screening visit, or the re-
test(s) do not meet the entrance criteria, or other eligibility criteria have changed and are not 
met anymore, the subject is considered a screen failure. 
A new ICF will need to be signed if the investigator chooses to re-screen the subject after a 
subject has screen failed. A new subject ID number will be used. All required screening 
activities must be performed when the subject is re-screened for participation in the study to 
satisfy eligibility requirements. An individual subject may only be re-screened once for the 
study. Once the number of subjects screened and enrolled is likely to ensure target enrollment, 
Novartis may close the study to further screening. In this case, the subjects who screen failed 
will not be permitted to re-screen. 
8.1.1 Eligibility screening 
Following registering in the IRT for screening, subject eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual. 
8.1.2 Information to be collected on screening failures 
Part 1 subjects who sign an ICF and subsequently found to be ineligible will be considered a 
screen failure. The reason for screen failure should be entered on the applicable CRF. The 
demographic information, informed consent, disease diagnosis, prior ruxolitinib treatment, 
Inclusion/Exclusion pages and study disposition must also be completed for screen failure 
subjects. No other data will be entered into the clinical database for subjects who are screen 
failures, unless the subject experienced a serious adverse event during the screening phase (see 
SAE Section 10.1.2 for reporting details). 


Novartis 
Confidential 
Page 173 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Part 1 subjects who sign an informed consent and are considered eligible but fail to be started 
on treatment for any reason will be considered an early terminator. The reason for early 
termination should be captured on the appropriate disposition CRF. 
Part 2 and Part 3 subjects who sign the study ICF but are subsequently found to be ineligible 
prior to randomization will be considered a screen failure. The demographic information, 
informed consent, and Inclusion/Exclusion and study disposition pages must also be completed 
for screen failure subjects. No other data will be entered into the clinical database for subjects 
who are screen failures, unless the subject experienced a serious adverse event during the 
screening phase (see SAE Section 10.1.2 for reporting details). If the subject fails to be 
randomized, the IRT must be notified within 2 days of the screen fail that the subject was not 
randomized. 
Part 2 and Part 3 subjects who are randomized and fail to start study treatment for any reason 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate CRF. 
8.2 
Subject demographics/other baseline characteristics 
The following data on subject characteristics will be collected at screening for all Parts of the 
study as listed in Table 8-2, Table 8-3, Table 8-4 and Table 8-5: 
• Demographic information: age at consent, gender, ethnicity and race (if permitted) 
• Participant race/ethnicity data are collected and analyzed to identify any difference in the 
safety and/or efficacy profile of the treatment due to these characteristics. In addition, the 
diversity of the study population should be taken into consideration to support subgroup 
analysis as required by some Health Authorities. Relevant medical history (including 
medical conditions present at time of ICF signature) 
• Diagnosis of disease 
• Prior ruxolitinib treatment (≥ 12 weeks and on a stable dose ≥ 4 weeks) 
• All prior anti-neoplastic therapies (medications, surgeries, radiation) 
• Prior and concomitant medications: All medications and significant non-drug therapies 
taken within 30 days prior to the first dose of study treatment must be recorded in the CRF. 
They will be updated on a continuous basis if there are any new changes to the medications. 
• HIV history (If mandated per local requirements, a local HIV testing is to be done during 
screening) 
• Transfusion record for PRBC and platelets 
Subjects will have the following screening assessments performed before the start of study 
treatment in all Parts of the study as listed in Table 8-2, Table 8-3, Table 8-4 and Table 8-5: 
• Physical examination 
• Height 
• Weight 
• Vital signs 


Novartis 
Confidential 
Page 174 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
• Laboratory assessments - Hematology, chemistry, coagulation, urinalysis, thyroid function, 
Troponin I and NTproBNP for NIS793 patients in Part 1 and all patients in part 2 and 3 if 
NIS793 is open for enrollment. 
• Hepatitis test 
• HIV screen (if required per local regulations) 
• Serum pregnancy test 
• Spleen measurement by palpation 
• Baseline MRI/CT (if not already performed within 8 weeks prior to first dose of study 
treatment) 
• PRO questionnaires (MFSAF v4.0 and EORTC QLQ-C30) 
• Bone marrow biopsy and aspirate for measuring bone marrow fibrosis changes (Parts 2 and 
3) 
• 
 
• ECOG performance status 
• ECG 
• Cardiac imaging as required based on the allocated study treatment. 
8.3 
Efficacy 
As the enrollment was permanently halted, the only randomized subject in Part 2 has 
discontinued prior to this amendment, and Part 3 will not be initiated, therefore the descriptions 
of endpoints for Parts 2 and 3 are not applicable. Secondary efficacy endpoints for Part 1 are 
outlined in Table 2-1. 
8.3.1 Response rate for the composite primary efficacy endpoint  
The primary efficacy endpoint for Part 2 and Part 3 is the response rate (RR) of the composite 
of the following, assessed at the end of Cycle 8 (for treatment arms with NIS793) or Cycle 6 
(for all other treatment arms) Section 12.4.1: 
• Improvement in anemia of ≥ 1.5 g/dL, and 
• No spleen volume progression, and 
• No symptoms worsening 
The composite criteria are defined as follows:  
• Anemia improvement requires an increase of hemoglobin from baseline of at least 1.5 g/dL 
• Spleen volume progression is defined as a spleen volume increase of 25% or more from 
baseline as determined by MRI/CT 
• Symptoms worsening is defined as a total symptom score (TSS) increase of 10 or more from 
baseline assessed by MFSAF version 4.0 
The following assessments will be utilized to determine the 3 components for the RR  


Novartis 
Confidential 
Page 175 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
8.3.1.1 
Improvement in Anemia 
Anemia improvement requires an increase of hemoglobin from baseline of at least 1.5 g/dL as 
measured at the end of Cycle 8 (arms with NIS793) or Cycle 6 (all other arms). The increase in 
hemoglobin should be confirmed at least 2 weeks later. Anemia improvement requires the 
absence of any PRBC transfusion in the 12 weeks prior to achieving an increase of 1.5 g/dL. 
Laboratory Hb assessments (as outlined in Section 8.4.1) taken at the end of Cycle 8 (arms with 
NIS793) or Cycle 6 (all other arms) in comparison to C1D1 will be used to determine those 
subjects that achieved an improvement of ≥ 1.5 g/dL. 
8.3.1.2 
Spleen volume progression 
Evaluation of spleen volume will be performed by Magnetic Resonance Imaging (MRI) or 
Computed Tomography (CT) scan. MRI of the spleen (or CT if MRI is contraindicated) will be 
performed as regular assessment at screening, and at the end of Cycle 8 (arms with NIS793) or 
Cycle 6 (all other arms) in comparison to the screening assessment (baseline). Previously 
completed scans can be considered for baseline if obtained within 8 weeks prior to first dose of 
study treatment (C1D1). 
Volumetric spleen size progression is defined as a spleen volume increase of at least 25% from 
baseline, as per IWG-MRT revised criteria (Tefferi et al 2013). 
MRI will be performed with a body coil because the objective is to measure organ volume, not 
to find very small lesions. MRIs will be performed and assessed by local radiologists who will 
be instructed to provide a quantitative and a qualitative assessment of spleen volume (as 
enlarged, smaller, larger, etc.). The MRI will not determine spleen length below the costal 
margin, as there are no validated approaches for determining this measurement. The site 
radiologist will provide the read-out and the results from the local evaluations will be used for 
the endpoints analyses. 
MRI is the preferred method for obtaining spleen volume data. However, CT scans may be 
performed at the visits where MRI would be conducted if the subject is not a candidate for MRI 
(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. 
Generally, the same method (MRI or CT) should be consistently used for all visits for a given 
subject unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurs. 
Any imaging assessments already completed during the regular work-up of the subject within 
8 weeks prior to start of study treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after 
allocation (Part 1)/randomization (Part 2 and Part 3) cannot be considered baseline images.  
Imaging assessments during the study should be scheduled using the allocation/randomization 
date as the reference date and should be respected regardless of whether study treatment is 
temporarily withheld or unscheduled assessments performed. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 


Novartis 
Confidential 
Page 176 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment. 
8.3.1.3 
Total symptom score (TSS) worsening 
Symptom worsening occurs when the total symptom score (TSS) assessed by MFSAF v4.0 
increases 10 or more scores from baseline (C1D1) at the end of Cycle 8 (arms with NIS793) or 
Cycle 6 (all other arms). Refer to Section 8.5.1 for a description of the MFSAF v4.0 PRO. The 
TSS absolute increase of 10 or more from baseline is considered as a clinical meaningful 
symptom worsening based on the COMFORT I trial data using a combination of distribution- 
and anchor- based approaches (Dueck et al 2017). An absolute score change, rather than a 
percentage change, is the criterion as the latter would either require not enough change in 
magnitude for a lower baseline or too much change in magnitude for a higher baseline. 
8.3.2 Secondary efficacy endpoints 
The following assessments will be performed for each treatment arm as secondary efficacy 
endpoints in Parts 2 and 3. 
Changes in spleen size and volume and MFSAF v4.0 Total Symptoms Score will be assessed 
as secondary endpoints for Part 1 (core and/or extension) as outlined in Table 2-1: 
• Hb measurement to assess proportion of subjects who achieved improvement in Hb level of 
≥ 1.5 g/dL or ≥ 2.0 g/dL 
• Evaluation of a change in spleen length by palpation and spleen volume by MRI/CT 
• Changes in MFSAF v4.0 and EORTC QLQ-C30 
• Estimation of time to PFS events 
• Evaluation of the effect on bone marrow fibrosis 
8.3.2.1 
Proportion of subjects achieving improvement of Hb level (Not 
applicable) 
The improvement in anemia based on an increase of hemoglobin from baseline of at least ≥  
1.5 g/dL or ≥ 2.0 g/dL is assessed at the end of Cycle 8 (for arms with NIS793) or Cycle 6 (all 
other arms) and at the end of Cycle 16 (arms with NIS793) or Cycle 12 (all other arms). The 
increase in hemoglobin should be confirmed at least 2 weeks later.  
Anemia improvement requires the absence of any PRBC transfusion in the 12 weeks prior to 
achieving an increase of 1.5 g/dL or 2.0 g/dL. 
Laboratory Hb assessments (as outlined in Section 8.4.1) taken at the end of Cycle 8 (for arms 
with NIS793) or Cycle 6 (all other arms) and at the end of Cycle 16 (arms with NIS793) or 
Cycle 12 (all other arms) will be compared to baseline (C1D1) to determine the proportion of 
those subjects that have achieved an improvement of ≥ 1.5 g/dL or ≥ 2.0 g/dL from baseline. 
8.3.2.2 
Changes in spleen length and spleen volume 
Evaluation of spleen size changes for secondary endpoint will be assessed by performing 
manual palpation and MRI/CT imaging as outlined below. 


Novartis 
Confidential 
Page 177 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Spleen length assessment by manual palpation 
Spleen length measurements will be conducted by manual palpation at regular 
intervals during the study in order to evaluate changes in spleen length in each treatment arm. 
Manual palpation will be performed on days 1 and 15 of cycles 1 to 3, and day 1 of subsequent 
cycles, as noted in the schedule of assessments in Table 8-2 to Table 8-5. 
The edge of the spleen shall be determined by palpation, and measured in centimeters (not 
fingerbreadths), from the lower costal margin (LCM) to the point of greatest splenic protrusion.  
In case of spleen length increase that meets any of the criteria for progressive spleen size as 
described below are met, an MRI/CT scan will be conducted to confirm spleen size progression. 
• Appearance of a new splenomegaly that is palpable at least 5cm below the LCM, or 
• A ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 
cm, or 
• A 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm, 
as per IWG-MRT revised criteria (Tefferi et al 2013). 
In case any of the criteria for progressive spleen size as described above are met, MRI/CT scan 
will be conducted to confirm spleen size progression. 
Spleen volume assessment by MRI or CT scan 
Assessment of spleen volume by MRI (or CT if MRI is contraindicated) will be performed as 
described in Section 8.3.1.2 at screening (baseline), at the end of Cycle 8 (arms with NIS793) 
or Cycle 6 (all other arms), then every 8 cycles (arms with NIS793) or 6 cycles (all other arms), 
and at EOT (if not performed in the past 12 weeks) as noted in Table 8-6. Previously completed 
scans can be considered for baseline if obtained within 8 weeks prior to first dose of study 
treatment. 
During the extension treatment phase, assessment of spleen volume by MRI or CT scan should 
be performed as needed by investigator to assess subject spleen response and clinical benefit of 
study treatment.  
Table 8-6 
MRI/CT Assessment Collection Plan 
Procedure 
Timepoints 
Abdomen MRI or CT 
• 
Screening/baseline (Day -28 to day-1) 
• 
At the end of every 8 cycles for arms with NIS793 or 6 cycles for all other 
arms ( ± 7 days) 
• 
EOT (if not performed in last 12 weeks) 
• 
Treatment extension phase – as needed by investigator 
• 
Unscheduled – at the discretion of investigator 
8.3.2.3 
Change in MFSAF v4.0 and EORTC QLQ-C30 
The changes in symptoms of myelofibrosis in each treatment arm using MFSAF v4.0 and 
EORTC QLQ-C30 patient reported outcomes (PROs) from baseline will be evaluated. Refer to 
Section 8.5.1 for details of these PROs. 


Novartis 
Confidential 
Page 178 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
8.3.2.4 
Progression Free Survival 
Progression free survival endpoint is not applicable as Part 2 and 3 endpoints will not be pursued.  
Progression free survival (PFS) is defined as the time from randomization until earliest time for 
one of the following progression events. 
• Progressive splenomegaly as assessed by increasing spleen volume (by MRI/CT) of ≥ 25% 
from baseline 
• Accelerated phase defined by an increase in circulating peripheral blood blast content of > 
10% but < 20% confirmed after 2 weeks. The progression date will be the date of first 
increase in peripheral blood blast content of > 10% 
• Deteriorating cytopenia (dCP) independent from treatment defined for all patients by 
platelet count < 35 x10^9/L or neutrophil count < 0.75 x 10^9/L that lasts for at least 4 
weeks. The progression date will be the date of first decrease of platelets < 35 x10^9/L or 
neutrophils < 0.75 x 10^9/L confirmed after 4 weeks 
• Leukemic transformation defined by an increase in peripheral blood blast content of ≥ 20% 
associated with an absolute blast count of ≥ 1x10^9/L that lasts for at least 2 weeks or a 
bone marrow blast count of ≥ 20%. The progression date will be the date of first increase in 
peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 
1x10^9/L OR the date of the bone marrow blast count of ≥ 20% as per IWG-MRT revise 
criteria (Tefferi et al 2013). 
• Death from any cause.  
Progressive splenomegaly: 
For the PFS assessment progressive splenomegaly is defined as an increased spleen volume 
from baseline of at least 25% as measured by MRI/CT. 
The spleen length regular assessment done by palpation will be used to trigger splenomegaly 
progression. 
In case of spleen length increase that meet any of the criteria for progressive spleen size as 
described below are met, MRI/CT will be conducted to confirm spleen size progression. 
• Appearance of a new splenomegaly that is palpable at least 5cm below the LCM, or 
• A ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 
cm, or 
• A 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm 
The progression date will be the date of MRI/CT assessment confirming spleen volume increase 
of at least 25% from baseline 
For patients meeting the progressive disease criteria the Investigator must review according to 
the guidance below, and confirm the relevant criterion. The data should be entered in the 
appropriate CRF and IRT notified. 
8.3.2.5 
Disease progression  
The progression events as defined in Section 8.3.2.4 bullets will be assessed as one of the 
criteria for leading to discontinuation of study treatment (Section 9.1.1). 


Novartis 
Confidential 
Page 179 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Guidance for progressive disease criterion assessment is as follows: 
• Earliest confirmed single disease progression criterion should be entered. 
• If more than one criterion are confirmed on the same date, time or visit; progressive disease 
should be assessed using the single criterion based on the hierarchy below: 
1. Death 
2. Leukemic transformation 
3. Accelerated phase  
4. Progressive splenomegaly 
5. Deteriorating cytopenia 
8.3.2.6 
Change in bone marrow fibrosis and histomorphology (Not applicable) 
In Part 2 and Part 3 of the study, bone marrow fibrosis will be measured in grades from samples 
obtained from subjects at screening and at the end of Cycle 8 (for arms with NIS793) or Cycle 
6 (for all other arms), then every six cycles and at EOT per Table 8-7. 
Table 8-7 
Bone Marrow Assessment Collection Plan 
Procedure 
Timepoints 
Bone marrow 
biopsy and 
aspirate 
• 
Screening* 
• 
At the end of every 8 cycles for arms with NIS793 or at the end of every 6 cycles for all 
other arms (pre-dose at the beginning of the next cycle, e.g. C7D1 or C9D1 etc.) 
• 
EOT (if not performed in the last 12 weeks) 
* Bone marrow biopsies collected within 8 weeks of C1D1 are acceptable for baseline assessment. Bone marrow 
aspirates should be collected at screening (within 28 days of C1D1), however for re-screened subjects, aspirates 
collected within 8 weeks of C1D1 are acceptable.  
Collection, processing and staining of bone marrow aspirations and paraffin embedded bone 
marrow core biopsy block samples for local analysis will be done in accordance with standard 
procedures at the investigative site. The bone marrow aspirate should be assessed at local 
investigative site by an experienced hematopathologist using his/her standard examination. 
Bone marrow fibrosis should be graded using the grading system as applied by European 
consensus according to "The 2016 revision to the World Health Organization 
(WHO) classification of myeloid neoplasms and acute leukemia" (Arber et al 2016), as 
presented in Table 8-8.  
Table 8-8 
Grading of myelofibrosis 
Myelofibrosis grading 
MF - 0 
Scattered linear reticulin with no intersections (crossovers) corresponding to normal BM 
MF - 1 
Loose network of reticulin with many intersections, especially in perivascular areas 
MF - 2 
Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles 
of thick fibers mostly consistent with collagen, and/or focal osteosclerosis* 
MF - 3 
Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick 
fibers consistent with collagen, usually associated with osteosclerosis* 
Note: Semiquantitative grading of BM fibrosis (MF) with minor modifications concerning collagen and 
osteosclerosis. Fiber density should be assessed only in hematopoietic areas. 
* In grades MF-2 or MF-3 an additional trichrome stain is recommended. 


Novartis 
Confidential 
Page 180 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Changes in bone marrow fibrosis of at least 1 grade will be assessed as a secondary endpoint in 
Part 2 and Part 3. The following assessments 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 
granulomatous process. 
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. 
8.3.3 
Appropriateness of efficacy assessments 
Not applicable  
8.3.4 
Extension treatment phase Efficacy Assessment 
For subjects entering the extension treatment phase, the investigator is required to confirm that 
the subject continues to derive clinical benefit and may continue receiving study treatment at 
every visit during extension treatment phase. This includes an assessment of disease progression 
as per definition of disease progression in Section 8.3.2.5. 
8.4 
Safety and tolerability 
Safety assessments are specified below in Table 8-9 and Table 8-10 and with the assessment 
schedule in Table 8-2, Table 8-3, Table 8-4 and Table 8-5 detailing when each assessment is to 
be performed during the study. These include a physical examination, vital signs, weight, 
laboratory assessments, ECOG performance status and ECGs, as well as the collection of AEs 
at every clinic visit. For details on AE collection and reporting, refer to Section 10.1 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every 4 weeks or more frequently if needed) for safety 
monitoring and discussion of the subject´s health status until it is safe for the subject to visit the 
site again. 
Additional safety monitoring for Tumor Lysis Syndrome (TLS) 
TLS is a known risk for patients with hematological malignancies, and was observed in two 
subjects diagnosed with AML and administered siremadlin in study CHDM201X2101. 
Therefore, additional safety assessments will be collected for subjects on the ruxolitinib and 


Novartis 
Confidential 
Page 181 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
siremadlin arm in this study to monitor for signs and symptoms of TLS. In addition to the full 
chemistry panel collected as outlined in Table 8-2 and Table 8-3, phosphorus, calcium, uric 
acid, potassium, and creatinine will also be measured on Days 2, 5 and 6 of Cycle 1 and Cycle 
2, and Days 2 and 5 for Cycles 3-6, and then only when clinically indicated. Refer to Section 6.6 
for additional information.  
Table 8-9 
Safety & tolerability assessments & specifications 
Assessment 
Specification 
Physical 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. A complete physical examination should be 
conducted at screening and baseline (pre-dose C1D1) for Parts 1, 2 and 3 of the study. If 
indicated, based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic examinations will be performed. 
A short physical examination will include the examination of general appearance along with 
vital signs. A short physical examination may be conducted in Part 1, 2 and 3 of the study 
starting from for all visits after baseline (C1D1) except where a complete physical examination 
is required when clinically indicated or based on symptoms. 
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be recorded on the appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature. 
Height and 
weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) 
Performance 
status 
ECOG Performance status scale will be used as described in Table 8-10. 
Table 8-10 
ECOG Performance Status 
  
ECOG 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 (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
8.4.1 Laboratory evaluations 
A local laboratory will be used for all planned laboratory assessments listed in Table 8-2,  
Table 8-3, Table 8-4 and Table 8-5, except cytokines and serology, which will be evaluated by 
a central laboratory. Refer to Table 8-11 for a summary of the parameters to be evaluated. The 
laboratory parameters must be performed as per the schedule in Table 8-2, Table 8-3,  
Table 8-4 and Table 8-5.  
The laboratory assessments listed are for all subjects in the study except as follows. Serology 
examination for anti-drug antibodies (ADAs) will be evaluated pre-dose at Cycle 1 Day 1 and 


Novartis 
Confidential 
Page 182 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
then when clinically indicated for subjects on the ruxolitinib + sabatolimab combination 
treatment arm (and the sabatolimab monotherapy arm in Part 3, if applicable) and the ruxolitinib 
+ NIS793 combination treatment arm (and the NIS793 monotherapy arm in Part 3, if applicable). 
This is based on potential AEs of immune-mediated etiology reported in sabatolimab 
monotherapy and combination studies and NIS793 combination studies, respectively. 
Cytokines will be evaluated pre-dose at Cycle 1 Day 1 and then when clinically indicated for 
suspected cytokine release syndrome for subjects on ruxolitinib + crizanlizumab combination 
treatment (and crizanlizumab monotherapy in Part 3, if applicable), for subjects on ruxolitinib 
+ sabatolimab combination treatment (and sabatolimab monotherapy in Part 3, if applicable) 
and for subjects on ruxolitinib + NIS793 combination treatment (and NIS793 monotherapy in 
Part 3, if applicable).  
There are no specific notable range criteria for this study; however, the local and central 
laboratory will flag laboratory values falling outside of the normal range on the local and central 
laboratory report (as applicable) as per local practice, and the Investigator will report any values 
considered clinically significant in the eCRF. Clinically significant abnormalities must be 
recorded as either medical history/current medical conditions or adverse events as appropriate. 
Sites will be requested to provide the local laboratory reference ranges and a copy of the 
laboratory certification to Novartis for all local laboratory results recorded in the eCRF. 
Crizanlizumab laboratory test interference - automated platelet counts 
Interference with automated platelet counts (i.e. unevaluable result) for SCD patients treated 
with crizanlizumab have been observed in clinical studies when blood samples are drawn in 
tubes containing ethylenediaminetetraacetic acid (EDTA) and analyzed by a central laboratory. 
Platelet clumping has been reported by the central lab in approximately half of the blood 
samples collected in EDTA-tubes. This observation led to an ex vivo study to assess the impact 
of time and anti-coagulant used (i.e. EDTA vs citrate) on the interference with automated 
platelet counts. 
This observation led to an ex vivo study to assess the impact of time and anti-coagulant used 
(i.e. EDTA vs citrate) on the interference with automated platelet counts. 
Blood was collected from healthy volunteer donors using either EDTA or citrate as 
anticoagulant. The results of this study indicated that crizanlizumab induced EDTA- and time-
dependent platelet clumping ex vivo in serum anticoagulated with EDTA, resulting in an 
interference with the automated platelet count. This effect was not observed when using citrate 
tubes, or when EDTA-samples were analyzed within 4 hours post blood collection, and was 
enhanced when blood samples were primed with thrombin in order to pre-activate platelets, 
thereby increasing platelet surface P-selectin expression. 
There is no evidence that crizanlizumab causes a reduction in circulating platelets or has a pro-
aggregant effect in vivo. Recommendations that may mitigate this laboratory interference are: 
1. 
Collect the sample for platelet count in a tube with citrate as anticoagulant 
2. 
Analyze platelet count in a local lab as soon as possible. Based on in vitro data, platelet 
clumping was observed in some donor samples as early as 4 hours following the addition 
of crizanlizumab. 


Novartis 
Confidential 
Page 183 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
3. Review peripheral smear for platelet clumping and manual platelet estimation, if necessary. 
Table 8-11 
Clinical laboratory parameters collection plan 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells differential - Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils (absolute value preferred, %s are 
acceptable), Circulating peripheral blasts 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus (inorganic 
phosphorus) , Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Total Bilirubin, 
Direct Bilirubin (only if Total Bilirubin is ≥ Grade 2), Indirect Bilirubin (only if Total Bilirubin is 
out of range), Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (fasting) 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) (unless local institution policies 
dictate otherwise) 
Microscopic Panel if clinically indicated (Red Blood Cells, White Blood Cells, Casts, Crystals, 
Bacteria, Epithelial cells) 
Coagulation 
International normalized ratio [INR]), Activated partial thromboplastin time (APTT)  
Thyroid function 
T4 [free], TSH 
Hepatitis 
markers 
HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR  
HIV screen 
If required per local regulations 
Serology 
examination* 
Anti-DNA antibodies (Abs), Anti-nuclear Abs, Anti-phospho lipid Abs, Anti-mitochondrial Abs, 
c-Reactive protein (CRP), Rheumatoid factor (RF) 
Cytokines* 
IFN-γ, IL-6, IL-1, TNF-α  
Pregnancy Test 
Serum or urine pregnancy test only for women of child-bearing potential depending on the 
timepoint (refer to 'Pregnancy and assessments of fertility' Section 8.4.5) 
* To be performed by a central laboratory: Serology for all treatment combinations with sabatolimab or NIS793; 
Cytokines for all treatment combinations with crizanlizumab, sabatolimab or NIS793. 
8.4.2 Electrocardiogram (ECG) 
Standard 12 lead ECGs are to be collected locally with ECG machines available at the site. 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. 
At baseline, a minimum of 3 sequential, individual ECGs should be recorded at least 5 minutes 
apart. The mean QTcF value will be calculated from the triplicate ECGs for each subject. The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions. Refer to section 
Dose adjustments in the case of QTcF prolongation (Section 6.5.4.1). 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. For any ECGs with subject 
safety concerns, two additional ECGs must be performed to confirm the safety finding. A 
monitoring or review process should be in place for clinically significant ECG findings 
throughout the study and especially at baseline before administration of study treatment. 
Clinically significant ECG findings at baseline must be discussed with the sponsor before 
administration of any study treatment. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the Adverse Events CRF page.  


Novartis 
Confidential 
Page 184 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
The ECG collection plan for ruxolitinib + siremadlin (or siremadlin monotherapy in Part 3) is 
noted in Table 8-12. Considering the potential cardiac risks (AV block, atrial fibrillation, QT 
prolongation) associated with siremadlin observed in phase I and II monotherapy and 
combination trials, cardiac risk is being monitored frequently. The ECG collection plan for 
subjects on ruxolitinib single agent, ruxolitinib + crizanlizumab (or crizanlizumab monotherapy 
in Part 3), ruxolitinib + sabatolimab (or sabatolimab monotherapy in Part 3 is less frequent and 
is listed in Table 8-13. Cardiac toxicity is a known risk for MAPK pathway inhibitors such as 
MEK inhibitors, therefore the cardiac risk will be more frequently monitored for subjects on 
ruxolitinib + rineterkib (or rineterkib monotherapy in Part 3) even though no drug related 
cardiac toxicity event has been reported so far in rineterkib studies (Janku et al 2020). The ECG 
collection plan for ruxolitinib + rineterkib (or rineterkib monotherapy in Part 3) is noted in 
Table 8-14. For NIS793, given the preclinical findings outlined in Section 1.1.2.6 of vascular 
inflammation, ECGs will be performed every cycle as noted in Table 8-15 .  
As there is a potential food effect related to siremadlin, it is recommended a fixed food-drug 
schedule for all patients, preferably drug intake 2 hours after a meal, as this can affect the QTc 
findings by almost 10 msec. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate CRF. Each ECG tracing should be labeled with the study number, subject initials 
(where regulations permit), subject number, date, and kept in the source documents at the study 
site. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. 
Table 8-12 
ECG timepoints for ruxolitinib + siremadlin (or siremadlin 
monotherapy) treatment  
Visit /Cycle 
Timepoint for ruxolitinib + siremadlin 
ECG Type 
 Part 1 
Part 2 
Part 3 
Screening 
Any time 
Any time 
Any time 
Single 
C1D1 
Pre-dose 
Pre-dose 
Pre-dose 
Triplicate 
C1D5 
Pre-dose 
Not applicable 
Not applicable 
Single 
C2D1 
Pre-dose 
Pre-dose 
Pre-dose 
Single 
C2D5 
Pre-dose 
Not applicable 
Not applicable 
Single 
4h post dose after 
administration of 
siremadlin 
Not applicable 
Not applicable 
Single 
C3D1 
Pre-dose 
Pre-dose 
Not applicable 
Single 
C4D1 
Pre-dose 
Pre-dose 
Pre-dose 
Single 
C5D1 
Pre-dose 
Pre-dose 
Not applicable 
Single 
C6D1 
Pre-dose 
Pre-dose 
Pre-dose 
Single 
C6D5 
Not applicable 
4h post dose after 
administration of 
siremadlin 
4h post dose after 
administration of 
siremadlin 
Single 
Subsequent cycles 
Only if clinically 
relevant 
Only if clinically 
relevant 
Only if clinically 
relevant 
Single 


Novartis 
Confidential 
Page 185 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Visit /Cycle 
Timepoint for ruxolitinib + siremadlin 
ECG Type 
 Part 1 
Part 2 
Part 3 
(Core and 
Extension phase) 
EOT (Core and 
Extension phase) 
Any time 
Any time 
Any time 
Single 
Unscheduled 
Any time 
Any time 
Any time 
Triplicate 
Table 8-13 
ECG timepoints for ruxolitinib single agent, ruxolitinib + crizanlizumab 
(or crizanlizumab monotherapy), ruxolitinib + sabatolimab (or 
sabatolimab monotherapy) 
Visit /Cycle 
ECG Time-points 
ECG Type 
Screening 
Any time 
Single 
C1D1 
Pre-dose 
Triplicate 
EOT 
Any time 
Single 
Unscheduled 
Any time 
Triplicate 
Table 8-14 
ECG timepoints for ruxolitinib + rineterkib treatment (or rineterkib 
monotherapy) 
Visit /Cycle 
Timepoint for ruxolitinib + rineterkib 
ECG Type 
 Part 1 
Part 2 
Part 3 
Screening 
Any time 
Any time 
Any time 
Single 
C1D1 
Pre-dose 
Pre-dose 
Pre-dose 
Triplicate 
C1D15 
Pre-dose 
Not applicable 
Not applicable 
Single 
C1D15 
2h post-dose after 
administration of 
rineterkib 
Not applicable 
Not applicable 
Single 
C2D1 
Pre-dose 
Pre-dose 
Pre-dose 
Single 
C3D1 
Pre-dose 
Pre-dose 
Not applicable 
Single 
C4D1 
Pre-dose 
Pre-dose 
Pre-dose 
Single 
C5D1 
Pre-dose 
Pre-dose 
Not applicable 
Single 
C6D1 
Pre-dose 
Pre-dose 
Pre-dose 
Single 
Subsequent cycles 
(Core and 
Extension phase) 
Only if clinically 
relevant 
Only if clinically 
relevant 
Only if clinically 
relevant 
Single 
EOT 
(Core and 
Extension phase) 
Any time 
Any time 
Any time 
Single 
Unscheduled 
Any time 
Any time 
Any time 
Triplicate 
Table 8-15 
ECG timepoints for ruxolitinib + NIS793 treatment (or NIS793 
monotherapy) 
Visit /Cycle 
ECG Time-points 
ECG Type 
Screening 
Any time 
Triplicate 
C1D1 
Pre-dose 
Triplicate 
C2D1 and all other cycles  
(Core phase) 
Pre-dose 
Triplicate 


Novartis 
Confidential 
Page 186 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Visit /Cycle 
ECG Time-points 
ECG Type 
EOT 
(Core phase) 
Any time 
Triplicate 
Unscheduled 
Any time 
Triplicate 
8.4.3 Cardiac markers 
For patients to be enrolled to NIS793 arm cardiac specific markers Troponin I and NTproBNP 
will be performed at the following timepoints:  
• at screening for all patients in part 1 and all patients in Part 2 and 3 if NIS793 is open for 
enrollment 
• at C3D1 pre-dose, and at every third cycle thereafter, and as clinically indicated during 
treatment duration and at the 30-day safety follow-up visit after EOT for patients allocated 
to NIS793.  
• patients with elevated cardiac enzymes ≥ 2xULN (if normal at screening), or ≥ 2x baseline 
(if baseline value was elevated) will have cardiac imaging (echocardiogram) performed 
8.4.4 Cardiac imaging - MUGA scan or ECHO or cardiac MRI 
Left ventricular ejection fraction (LVEF) decrease is a class effect of MEK inhibitors, therefore 
subjects treated with rineterkib will be closely monitored with a multigated acquisition (MUGA) 
scan or echocardiogram (ECHO).  
Subjects allocated to arms containing rineterkib in Part 1 and subjects randomized to arms 
containing rineterkib in Part 2 and Part 3 (if applicable), will have a MUGA scan or ECHO to 
assess LVEF prior to dosing on C1D1 (i.e. within 28days from C1D1 for part 1, and within 3 
days from C1D1 for part 2 and 3), at C3D1 and Core and Extension Treatment EOT, as outlined 
in Table 8-2 and Table 8-3 within the windows outlined in Table 8-1. 
Additional assessments may be performed if clinically indicated. A MUGA scan or ECHO will 
be performed at EOT core and extension only if an assessment of LVEF has not been performed 
≤ 14 days prior to EoT. 
Cardiac imaging i.e. echocardiogram or cardiac MRI if echocardiogram is not available or 
otherwise indicated will also be performed prior to dosing at screening for Part 1 within ≤ 28 
days before C1D1 and, for parts 2 and 3 at C1D1, to determine cardiac function and morphology 
at baseline for all patients receiving NIS793 in light of the preclinical findings outlined in 
Section 1.1.2.6.  
Thereafter, the cardiac imaging will be performed for patients enrolled to NIS793 arm during 
the treatment period as described below:  
• 
in Part 1: 30-day safety follow-up visit after core treatment EOT and at anytime as clinically 
indicated and/or if Troponin I is elevated > 2x ULN. If patients continue beyond planned 
duration of 8 cycles in part 1, then cardiac imaging should be done also at C9D1 as 
applicable.  
• 
in Parts 2 and 3: at C9D1 and 30-day safety follow-up after EOT and at anytime as clinically 
indicated and/or if Troponin I is elevated > 2x ULN.  


Novartis 
Confidential 
Page 187 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cardiac imaging assessments for patients receiving NIS 793 are outlined in Table 8-4 and  
Table 8-5 and within the windows outlined in Table 8-1. 
The same assessment method will be used throughout the study for each patient. When possible, 
the same cardiologist or radiologist should read and report the outcome to minimize the 
variability in results.  
8.4.5 Ophthalmologic assessment 
Since ocular AEs has been observed but resolved over time in other rineterkib studies  
(Janku et al 2020), subjects on ruxolitinib + rineterkib (or rineterkib monotherapy in Part 3) will 
be monitored for ocular toxicity at the beginning of each cycle and as clinically indicated. 
A full ophthalmologic examination including slit lamp examination, visual acuity testing 
(preferably Snellen or Early Treatment Diabetic Retinopathy Study (ETDRS)), visual field 
testing, tonometry (Intra Ocular Pressure (IOP)), and indirect fundoscopy (with dilation) with 
attention to retinal abnormalities (especially signs of central serous retinopathy and RVO), 
should be performed by an ophthalmologist at screening for Part 1 subjects who are allocated 
to receive rineterkib and for subjects randomized to arms with rineterkib in Part 2 and Part 3, if 
applicable, prior to dosing on C1D1. Similar assessments will then be performed and the 
beginning of every cycle only for subjects in arms with rineterkib, as outlined in Table 8-2 and 
Table 8-3 within the windows outlined in Table 8-1.  
Optical coherence tomography (OCT) will be performed at baseline prior to dosing on C1D1 
together with the above ophthalmologic assessments, then as clinically indicated for subjects in 
arms with rineterkib. 
For patients with clinical suspicion of retinal changes, additional assessments of fluorescein 
angiography and/or OCT should be performed upon the discretion of the treating physician. 
Any observed abnormalities and/or changes to Screening/baseline must be documented in the 
Adverse Events eCRF. 
In addition to the assessments performed by the ophthalmologist, subjective ophthalmic 
examination will be done by the investigator during each physical examination to monitor 
potential eye toxicity only for subjects in arms with rineterkib. During this subjective 
ophthalmic evaluation, the investigator will check for any new sign of visual disturbance, ocular 
discomfort, or any new abnormal ocular appearance. 
For patients with new ocular symptoms or findings that are considered clinically relevant by 
the investigator, an ophthalmologist should be consulted within 72 hours. 
8.4.6 Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have serum pregnancy testing at 
screening, the end of treatment and at the safety follow-up visits. Additional serum (preferred) 
or urine pregnancy testing will be performed at the beginning of every cycle. 
Local pregnancy tests and associated results will not be collected on the CRF. 
If subjects cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may be 
used. Subjects can perform the urine pregnancy test at home and report the result to the site. It 


Novartis 
Confidential 
Page 188 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
is important that subjects are instructed to perform the urine pregnancy test first and only if the 
test result is negative proceed with the administration of the study treatment. A communication 
process should be established with the subject so that the site is informed and can verify the 
pregnancy test results (e.g. following Country specific measures). 
Assessments of Fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
subject regardless of reported reproductive/menopausal status at screening/baseline. 
8.4.7 Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/subject population. 
 
 
 
 
 
 
 
8.5.1 Clinical Outcome Assessments (COAs) 
Collection of COAs will not apply to subjects entering the Part 1 extension treatment phase. 
Patient reported outcomes (PRO) 
Subjects with MF often experience significant symptoms that interfere with their quality of life 
(QoL) including fatigue, early satiety, pruritus, weight loss, weakness and night sweats. The 
effect of ruxolitinib combination treatment on subject symptoms and QoL will be measured 
using three PRO assessment tools: the MF Symptom Assessment Form version 4.0  
(MFSAF v4.0); the European Organisation for the Research and Treatment of Cancer Quality 
of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the
 
 
The PRO questionnaires will be provided electronically (ePRO) to the subject at the clinic visit 
and collected according to the visit schedules outlined in Table 8-2, Table 8-3, Table 8-4 and 
Table 8-5 before any clinical assessments are conducted. The ePRO measures should be 
completed by the subject in the language most familiar to the subject. The subject should be 
given sufficient space and time to complete the ePRO measures. The ePRO measures should be 
completed in the same order at each visit to ensure the subject is answering them as consistently 


Novartis 
Confidential 
Page 189 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
as possible. The measures should be given in the following order: MFSAF v4.0, EORTC QLQ-
C30, 
 
Subject’s refusal to complete all or any part of an ePRO measure should be documented in the 
study data capture system and should not be captured as a protocol deviation. Handling of 
protocol deviations can be modified if needed per study protocol. 
The site personnel should check the ePRO measures for completeness and ask the subject to 
complete any missing responses. The responses stored electronically on the database will be 
considered the source file. 
Completed measures and any unsolicited comments written by the subject should be reviewed 
and assessed by the investigator for responses which may indicate potential AEs or SAEs before 
any clinical study examinations. This assessment should be documented in study source records. 
If AEs or SAEs are confirmed, study investigators should not encourage the subject to change 
responses reported in the completed questionnaires. Study investigators must follow reporting 
instructions outlined in Section 10 (e.g. reference “Adverse Events” section) of the study 
protocol. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
PROs may be collected remotely (e.g. web portal, telephone interviews) depending on local 
regulations, technical capabilities, and following any applicable training in the required process. 
MFSAF v4.0 
MFSAF v4.0 (Section 16.3 in Appendix 3) is a harmonized, consensus-based 
PRO questionnaire recently developed for use in MF trials by a PRO Consortium Working 
Goup (Gwaltney et al 2017), which focuses on the 7 core symptoms of MF: fatigue, night sweats, 
pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety and bone pain.  
Subjects record symptom severity at it worst for each of the 7 symptoms on an 11-point numeric 
rating scale, from 0 (absent) to 10 (worst imaginable). The Total Symptom Score (TSS) is 
calculated as the average of the observed individual item responses on the 0 to 10 scale 
multiplied by 7. The MFSAF v4.0 has two formats, 24-h recall and 7-day recall. The 7-day 
recall format will be used in this study.  
MFSAF v4.0 will be collected at Screening, C1D1, Day 1 of all subsequent cycles of treatment, 
as well as the EOT visit, as shown in Table 8-2, Table 8-3, Table 8-4 and Table 8-5. 
EORTC QLQ-C30 
The EORTC QLQ-C30 PRO (Section 16.4 in Appendix 4) is one of the most widely used and 
validated instruments to measure health-related quality of life (QoL) in subjects with cancer 
(Aaronson et al 1993). The core questionnaire, the QLQ-C30 version 3.0, is the current standard. 
The EORTC QLQ-C30 includes 5 functional scales (physical, emotional, social, role, cognitive), 
eight symptom scales (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, 
and appetite loss), as well as global health/quality-of-life and financial impact. This instrument 
asks the subject to respond according to the past week recall period, with the exception of the 
first 5 questions that represent physical functioning and capture the subject’s current status. 


Novartis 
Confidential 
Page 190 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Raw scores are linearly converted to a 0–100 scale. 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. 
As indicated in Table 8-2, Table 8-3, Table 8-4 and Table 8-5, the EORTC QLQ-C30 will be 
collected at Screening, C1D1, Day 1 of all subsequent cycles of treatment, as well as the 
EOT visit. 
 
 
 
 
 
 
 
Trial Feedback 
This study is including an optional questionnaire, the ‘Trial Feedback Questionnaire’ (TFQ) for 
trial subjects to provide feedback on their clinical trial experience. Individual trial subject 
responses will not be reviewed by investigators. Responses may be used by the sponsor 
(Novartis) to understand where improvements can be made in the clinical trial process. This 
questionnaire does not ask question about the subject's disease, symptoms, treatment effect, or 
adverse events, and, therefore is not considered as trial data. The TFQ is not considered study 
data and will be received electronically outside of the clinical database. 
8.5.2 Pharmacokinetics 
Blood samples for Pharmacokinetic (PK), immunogenicity (IG) or pharmacodynamics (PD) 
will be obtained from all subjects who receive at least one dose of ruxolitinib, siremadlin, 
crizanlizumab, sabatolimab, rineterkib and NIS793. IG samples will also be collected to 
monitor appearance of anti-drug antibodies (ADAs) directed against crizanlizumab, 
sabatolimab and NIS793. The time points of blood collection for each respective investigational 
drug are outlined in Table 8-16 to Table 8-24 . As a result of the permanent enrollment halt and 
decision to no longer pursue the planned study objectives for Parts 1, 2, and 3:  
• The investigators were instructed prior to the implementation of the amended protocol 
version 08 to not collect pharmacokinetic, immunogenicity and pharmacodynamic 
samples from subjects in core Part 1 in all treatment arms to reduce subject burden. The 
assessments not performed in the Part 1 core study treatment phase because of the 
enrollment halt prior to the amended protocol version 08 will be reported in the clinical 
study report. No pharmacokinetic sample collection will be scheduled in the Part 1 
extension treatment phase, including those subjects who complete Safety Follow-up visits 
following the extension treatment phase EOT.  
• There is no change in collection of samples in Part 2 as the only randomized patient in 
Part 2 has discontinued prior to this amendment.  


Novartis 
Confidential 
Page 191 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
• Part 3 description in Table 8-16 to Table 8-24  is not applicable as Part 3 will not be 
initiated. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
changes in PK assessments can be listed as one of the risk mitigation procedures. 
Note for subjects that will be randomized to the expansion monotherapy Arm 2 (ruxolitinib 
cessation) in Part 3, the PK, PD and IG sampling (if applicable) will follow the sampling scheme 
for the respective investigational drug of the chosen study treatment that enters Part 3. In Part 
3 of the study, PK/IG collection (and where applicable, PD samples for sabatolimab) is limited 
to the first 10 subjects in Arm 1, PK samples will be collected for all 10 subjects in Arm 2 
(ruxolitinib cessation), however PK samples will not be collected from subjects randomized to 
the ruxolitinib control Arm 3.  
PK parameters will be estimated from individual plasma concentration-time profiles using 
appropriate methods and software. A detailed description of the planned PK analyses is given 
in Section 12.5.3. 
Table 8-16 
PK blood collection log for siremadlin and ruxolitinib combination arm 
(Part 1, 2 and 3*) 
Cycle 
Day 
Scheduled 
Time Point 
(sampling 
window) 
Dose Reference ID 
PK Sample No.  
Analytes 
Part 
siremadlin 
ruxolitinib 
siremadlin 
ruxolitinib 
 
 
1 
1 
Pre-dose/0 h a 
11 
101 
101 
201 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
1 
0.5 h (± 10 
min) 
11 
101 
102 
202 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
1 
1 h (± 10 min) 
11 
101 
103 
203 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
1 
2 h (± 10 min) 
11 
101 
104 
204 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
1 
3 h (± 15 min) 
11 
101 
105 
205 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
1 
4 h (± 15 min) 
11 
101 
106 
206 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
1 
8 h (± 1h) 
11 
101 
107 
207 
siremadlin, 
ruxolitinib 
1 
1 
2 
24 h (± 2h) 
post 
siremadlin/ 
pre-AM C1D2 
ruxolitinib 
dose a 
11 
102 
108 
208 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
5 
Pre-AM 
dose/0 h a 
12 
103 
109 
209 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
5 
1 h (± 10 min) 
12 
103 
110 
210 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
5 
2 h (± 10 min) 
12 
103 
111 
211 
siremadlin, 
ruxolitinib 
1, 2, 
3 


Novartis 
Confidential 
Page 192 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled 
Time Point 
(sampling 
window) 
Dose Reference ID 
PK Sample No.  
Analytes 
Part 
siremadlin 
ruxolitinib 
siremadlin 
ruxolitinib 
 
 
1 
5 
3 h (± 15 min) 
12 
103 
112 
212 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
5 
4 h (± 15 min) 
12 
103 
113 
213 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
5 
8 h (± 1h) 
12 
103 
114 
214 
siremadlin, 
ruxolitinib 
1 
1 
6 
24 h (± 2h) 
post 
siremadlin/ 
pre-AM C1D6 
ruxolitinib 
dose a 
12 
104 
115 
215 
siremadlin, 
ruxolitinib 
1, 2, 
3 
1 
15 
Pre-AM 
dose/0 h a 
  
105 
  
216 
ruxolitinib 
1 
2 
1 
Pre-AM 
dose/0 h a, 
13 
106 
116 
217 
siremadlin, 
ruxolitinib 
1 
2 
1 
1 h (± 10 min) 
13 
106 
117 
218 
siremadlin, 
ruxolitinib 
1 
2 
1 
2 h (± 10 min) 
13 
106 
118 
219 
siremadlin, 
ruxolitinib 
1 
2 
1 
3 h (± 15 min) 
13 
106 
119 
220 
siremadlin, 
ruxolitinib 
1 
2 
1 
4 h (± 15 min 
13 
106 
120 
221 
siremadlin, 
ruxolitinib 
1 
2 
1 
8 h (± 1h) 
13 
106 
121 
222 
siremadlin, 
ruxolitinib 
1 
2 
2 
24 h (± 2h) 
post 
siremadlin/ 
pre-AM C2D2 
ruxolitinib 
dose a 
13 
107 
122 
223 
siremadlin, 
ruxolitinib 
1 
2 
5 
Pre-AM 
dose/0 h a 
14 
108 
123 
224 
siremadlin, 
ruxolitinib 
1, 2 
2 
5 
3 h (± 15 min) 
14 
  
124 
  
siremadlin 
1, 2 
2 
6 
24 h (± 2h) 
post 
siremadlin/ 
pre-AM C1D6 
ruxolitinib 
dosea 
14 
109 
125 
225 
siremadlin, 
ruxolitinib 
1, 2 
2 
15 
Pre-AM 
dose/0 h a, 
  
110 
  
226 
ruxolitinib 
1 
3 
1 
Pre-AM 
dose/0 h a 
  
111 
  
227 
ruxolitinib 
1, 2, 
3 
3 
2 
Pre-AM 
dose/0 h a 
15 
  
126 
  
siremadlin 
1, 2, 
3 
3 
5 
Pre-AM 
dose/0 h a 
16 
112 
127 
228 
siremadlin, 
ruxolitinib 
1, 2, 
3 


Novartis 
Confidential 
Page 193 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled 
Time Point 
(sampling 
window) 
Dose Reference ID 
PK Sample No.  
Analytes 
Part 
siremadlin 
ruxolitinib 
siremadlin 
ruxolitinib 
 
 
3 
15 
Pre-AM 
dose/0 h a, 
  
113 
  
229 
ruxolitinib 
1 
4 
1 
Pre-AM 
dose/0 h a 
  
114 
  
230 
ruxolitinib 
1, 2, 
3 
4 
2 
Pre-AM 
dose/0 h a 
17 
  
128 
  
siremadlin 
1, 2, 
3 
4 
5 
Pre-AM 
dose/0 h a 
18 
115 
129 
231 
siremadlin, 
ruxolitinib 
1, 2, 
3 
5 
1 
Pre-AM 
dose/0 h a 
  
116 
  
232 
ruxolitinib 
1, 2, 
3 
5 
2 
Pre-AM 
dose/0 h a 
19 
  
130 
 
siremadlin 
1, 2, 
3 
5 
5 
Pre-AM 
dose/0 h a 
20 
117 
131 
234 
siremadlin, 
ruxolitinib 
1, 2, 
3 
6 
1 
Pre-AM 
dose/0 h a 
  
118 
  
235 
ruxolitinib 
1, 2, 
3 
6 
2 
Pre-AM 
dose/0 h a 
21 
  
132 
  
siremadlin 
1, 2, 
3 
6 
5 
Pre-AM 
dose/0 h a 
22 
119 
133 
236 
siremadlin, 
ruxolitinib 
1, 2, 
3 
NA 
NA 
Unscheduled 
Anytime b 
NA 
NA 
1001+ 
2001+ 
siremadlin, 
ruxolitinib 
1, 2, 
3 
a Collect PK sample immediately prior to administration 
b Unscheduled PK blood samples may be collected at any time for measurement of plasma drug concentrations 
if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
* For Part 3, PK collection limited to first 10 enrolled subjects 
Table 8-17 
PK blood collection log for crizanlizumab and IG in combination arm 
with ruxolitinib (Part 1, 2 and 3*) 
Cycle 
Day 
Scheduled Time 
Point (sampling 
window) 
Dose 
Reference 
ID 
PK Sample No. 
(crizanlizumab) 
IG 
Sample 
No.  
(IG) 
Analytes 
1 
1 
0 h / Pre-infusion a 
301 
601 
701 
crizanlizumab, 
IG d 
1 
1 
1h post EOI (± 
15min) b 
301 
602 
  
crizanlizumab, 
1 
2 
24h post start of 
infusion (± 2h) c 
301 
603 
  
crizanlizumab, 
1 
8 
168h post start of 
infusion (± 8h) c 
301 
604 
  
crizanlizumab, 
1 
15 
Pre-infusion of next 
dose a /336h (day 
15) post start of 
infusion (± 24h) 
322/301** 
605 
  
crizanlizumab, 
1 
15 
1h post EOI (± 
15min) b 
322 
606 
  
crizanlizumab, 


Novartis 
Confidential 
Page 194 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled Time 
Point (sampling 
window) 
Dose 
Reference 
ID 
PK Sample No. 
(crizanlizumab) 
IG 
Sample 
No.  
(IG) 
Analytes 
2 
1 
0 h / Pre-infusion a 
302/322** 
607 
702 
crizanlizumab, 
IG d 
2 
1 
1h post EOI (± 
15min) b 
302 
608 
  
crizanlizumab 
3 
1 
0 h / Pre-infusion a 
303/302** 
609 
703 
crizanlizumab, 
IG d 
3 
1 
1h post EOI (± 
5min) b 
303 
610 
  
crizanlizumab, 
3 
2 
24h post start of 
infusion (± 2h) c 
303 
611 
  
crizanlizumab, 
3 
8 
168h post start of 
infusion (± 8h) c 
303 
612 
  
crizanlizumab, 
3 
15 
336h post start of 
infusion (±24h) c 
303 
613 
  
crizanlizumab, 
4 
1 
0 h / Pre-infusion a 
304/303** 
614 
704 
crizanlizumab, 
IG d 
4 
1 
1h post EOI (± 
15min) b 
304 
615 
  
crizanlizumab 
5 
1 
0 h / Pre-infusion a 
305/304** 
616 
705 
crizanlizumab, 
IG d 
5 
1 
1h post EOI (± 
15min) b 
305 
617 
  
crizanlizumab 
6 
1 
0 h / Pre-infusion a 
306/305** 
618 
706 
crizanlizumab, 
IG d 
6 
1 
1h post EOI (± 
15min) b 
306 
619 
  
crizanlizumab 
Every 3 Cycles 
after C6D1 
until 
discontinuation 
of study 
treatment 
1 
0 h / Pre-infusion a 
307e 
620f 
707g 
crizanlizumab, 
IG d 
EOT Core treatment 
phase 
Anytime 
NA  
6000 
7000 
crizanlizumab, 
IG d 
105-day safety follow-up 
period 
Anytime 
NA 
6001 
7001 
crizanlizumab, 
IG d 
Unscheduled h 
Anytime 
 NA 
6002+ 
7002+ 
crizanlizumab, 
IG d 
EOI = end of infusion 
.** The first Dose Reference ID (for e.g. 302) is for the current dose, while the second Dose Reference ID (for 
e.g. 301) is for the last (previous) dose received prior to the collection of the PK sample 
a Pre-dose: blood samples should be collected prior to the start of the infusion 
b Post-dose: sampling time is relative to the end of the infusion; and blood samples should be taken after 
completion of the infusion 
c Post-dose: sampling time is relative to the start of the infusion 
d IG samples are to be collected together with PK samples at the same time 
e Dose reference ID will be labeled sequentially from 307, 308, 309.....before EOT 


Novartis 
Confidential 
Page 195 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled Time 
Point (sampling 
window) 
Dose 
Reference 
ID 
PK Sample No. 
(crizanlizumab) 
IG 
Sample 
No.  
(IG) 
Analytes 
f PK sample will be labeled sequentially from 620, 621, 622.....before EOT 
g IG sample will be labeled sequentially from 707, 708, 709.....before EOT 
h Unscheduled PK blood samples may be collected at any time for measurement of plasma drug concentrations 
if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
* For Part 3, PK/IG collection limited to first 10 enrolled subjects 
Note: PK and IG blood samples are collected from the opposite arm of infusion site. Alternatively, infusion site 
will need to be flushed with 10 mL of saline. 
Table 8-18 
PK blood collection log for sabatolimab, soluble TIM-3 and IG in 
combination arm with ruxolitinib (Part 1, 2 and 3*) 
Cycle 
Day 
Scheduled 
Time Point 
(sampling 
window) 
Dose 
Reference 
ID 
PK Sample 
No. ( 
sabatolimab) 
PD 
Sample 
No.  
(TIM-3) 
IG 
Sample 
No.  
(IG) 
Analyte 
1 
1 
0 h / Pre-
infusion a 
201 
301 
401 
501 
sabatolimab, 
TIM-3, IG d 
1 
1 
1h post EOI (± 
15min) b 
201 
302 
402 
  
sabatolimab, 
TIM-3 d 
1 
2 
24h post start of 
infusion (± 2h) c 
201 
303 
403 
  
sabatolimab, 
TIM-3 d 
1 
8 
168h post start 
of infusion (± 8h) 
c 
201 
304 
404 
  
sabatolimab, 
TIM-3 d 
1 
15 
336h post start 
of infusion (± 
24h) c 
201 
305 
405 
  
sabatolimab, 
TIM-3 d 
2 
1 
0 h / Pre-
infusion a 
202/201** 
306 
406 
502 
sabatolimab, 
TIM-3, IG d 
2 
1 
1h post EO 
(± 15min) b 
202 
307 
  
  
sabatolimab 
3 
1 
0 h / Pre-
infusion a 
203/202** 
308 
407 
503 
sabatolimab, 
TIM-3, IG d 
3 
1 
1h post EOI (± 
15min) b 
203 
309 
408 
  
sabatolimab, 
TIM-3 d 
3 
2 
24h post start of 
infusion (± 2h) c 
203 
310 
409 
  
sabatolimab, 
TIM-3 d 
3 
8 
168h post start 
of infusion (± 8h) 
c 
203 
311 
410 
  
sabatolimab, 
TIM-3 d 
3 
15 
336h post start 
of infusion (± 
24h) c 
203 
312 
411 
  
sabatolimab, 
TIM-3 d 
4 
1 
0 h / Pre-
infusion a 
204/203** 
313 
412 
504 
sabatolimab, 
TIM-3, IG d 
4 
1 
1h post EOI  
(± 15min) b 
204 
314 
  
  
sabatolimab 
5 
1 
0 h / Pre-
infusion a 
205/204** 
315 
413 
505 
sabatolimab, 
TIM-3, IG d 


Novartis 
Confidential 
Page 196 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled 
Time Point 
(sampling 
window) 
Dose 
Reference 
ID 
PK Sample 
No. ( 
sabatolimab) 
PD 
Sample 
No.  
(TIM-3) 
IG 
Sample 
No.  
(IG) 
Analyte 
5 
1 
1h post EOI (± 
15min) b 
205 
316 
  
  
sabatolimab 
6 
1 
0 h / Pre-
infusion a 
206/205** 
317 
414 
506 
sabatolimab, 
TIM-3, IG d 
6 
1 
1h post EOI (± 
15min) b 
206 
318 
  
  
sabatolimab 
Every 3 Cycles 
after C6D1 
until 
discontinuation 
of study 
treatment 
1 
0 h / Pre-
infusion a 
207e 
319f 
415g 
507h 
sabatolimab, 
TIM-3, IG d 
EOT Core treatment 
phase 
Anytime 
NA 
3000 
4000 
5000 
sabatolimab, 
TIM-3, IG d 
90-day safety follow-
up period 
Anytime 
NA 
3001 
  
5001 
sabatolimab, 
IG d 
Unscheduled i 
Anytime 
NA 
3002+ 
4001+ 
5002+ 
sabatolimab, 
TIM-3, IG d 
EOI = end of infusion 
** The first Dose Reference ID (for e.g. 202) is for the current dose, while the second Dose Reference ID (for 
e.g. 201) is for the last (previous) dose received prior to the collection of the PK sample. 
a Pre-dose: blood samples should be collected prior to the start of the infusion 
b Post-dose: sampling time is relative to the end of the infusion; and blood samples should be taken after 
completion of the infusion 
c Post-dose: sampling time is relative to the start of the infusion 
d IG and/or TIM-3 samples are to be collected together with PK samples at the same time 
e Dose reference ID will be labeled sequentially from 207, 208, 209.....before EOT 
f PK sample will be labeled sequentially from 319, 320, 221.....before EOT 
g PD sample will be labeled sequentially from 415, 416, 417.....before EOT 
h IG sample will be labeled sequentially from 507, 508, 509.....before EOT 
i Unscheduled PK blood samples may be collected at any time for measurement of plasma drug concentrations 
if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
* For Part 3, PK, PD and IG collection limited to first 10 enrolled subjects 
Note: PK/IG/TIM-3 blood samples are collected from the opposite arm of infusion site. Alternatively, infusion 
site will need to be flushed with 10 mL of saline. 
Table 8-19 
PK blood collection log for ruxolitinib in combination arm with 
crizanlizumab (Part 1, 2 and 3*) 
Cycle 
Day 
Scheduled Time Point 
(sampling window) 
Dose 
Reference ID 
PK Sample 
No. 
Analytes 
Part 
1 
1 
Pre-dose/0 h a 
501 
1501 
ruxolitinib 
1, 2, 3 
1 
1 
0.5 h (± 10 min) 
501 
1502 
ruxolitinib 
1, 2, 3 
1 
1 
1 h (± 10 min) 
501 
1503 
ruxolitinib 
1, 2, 3 
1 
1 
2 h (± 10 min) 
501 
1504 
ruxolitinib 
1, 2, 3 
1 
1 
3 h (± 15 min) 
501 
1505 
ruxolitinib 
1, 2, 3 
1 
1 
4 h (± 15 min) 
501 
1506 
ruxolitinib 
1, 2, 3 


Novartis 
Confidential 
Page 197 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled Time Point 
(sampling window) 
Dose 
Reference ID 
PK Sample 
No. 
Analytes 
Part 
1 
1 
8 h (± 1h) 
501 
1507 
ruxolitinib 
1, 2, 3 
1 
2 
 Pre-AM dose/0 h a 
502 
1508 
ruxolitinib 
1, 2, 3 
1 
15 
Pre-AM dose/0 h a 
503 
1509 
ruxolitinib 
1 
2 
1 
 Pre-AM dose/0 h a 
504 
1510 
ruxolitinib 
1, 2, 3 
2 
15 
Pre-AM dose/0 h a 
505 
1511 
ruxolitinib 
1 
3 
1 
 Pre-AM dose/0 h a 
506 
1512 
ruxolitinib 
1, 2, 3 
3 
15 
Pre-AM dose/0 h a 
507 
1513 
ruxolitinib 
1 
4 
1 
Pre-AM dose/0 h a 
508 
1514 
ruxolitinib 
1, 2, 3 
5 
1 
Pre-AM dose/0 h a 
509 
1515 
ruxolitinib 
1, 2, 3 
6 
1 
Pre-AM dose/0 h a 
510 
1516 
ruxolitinib 
1, 2, 3 
NA 
NA 
Unscheduled Anytime b 
NA 
1601+ 
ruxolitinib 
1, 2, 3 
a Collect PK sample immediately prior to administration 
b Unscheduled PK blood samples may be collected at any time for measurement of plasma drug concentrations 
if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
* For part 3, PK collection limited to first 10 enrolled subjects 
Table 8-20 
PK blood collection log for ruxolitinib in combination arm with 
sabatolimab (Part 1, 2 and 3*) 
Cycle 
Day 
Scheduled Time Point 
(sampling window) 
Dose 
Reference ID 
PK Sample 
No. 
Analytes 
Part 
1 
1 
Pre-dose/0 h a 
401 
801 
ruxolitinib 
1, 2, 3 
1 
1 
0.5 h (± 10 min) 
401 
802 
ruxolitinib 
1, 2, 3 
1 
1 
1 h (± 10 min) 
401 
803 
ruxolitinib 
1, 2, 3 
1 
1 
2 h (± 10 min) 
401 
804 
ruxolitinib 
1, 2, 3 
1 
1 
3 h (± 15 min) 
401 
805 
ruxolitinib 
1, 2, 3 
1 
1 
4 h (± 15 min) 
401 
806 
ruxolitinib 
1, 2, 3 
1 
1 
8 h (± 1h) 
401 
807 
ruxolitinib 
1, 2, 3 
1 
2 
 Pre-AM dose/0 h a 
402 
808 
ruxolitinib 
1, 2, 3 
1 
15 
Pre-AM dose/0 h a 
403 
809 
ruxolitinib 
1 
2 
1 
 Pre-AM dose/0 h a 
404 
810 
ruxolitinib 
1, 2, 3 
2 
15 
Pre-AM dose/0 h a 
405 
811 
ruxolitinib 
1 
3 
1 
 Pre-AM dose/0 h a 
406 
812 
ruxolitinib 
1, 2, 3 
3 
15 
Pre-AM dose/0 h a 
407 
813 
ruxolitinib 
1 
4 
1 
Pre-AM dose/0 h a 
408 
814 
ruxolitinib 
1, 2, 3 
5 
1 
Pre-AM dose/0 h a 
409 
815 
ruxolitinib 
1, 2, 3 
6 
1 
Pre-AM dose/0 h a 
410 
816 
ruxolitinib 
1, 2, 3 
NA 
NA 
Unscheduled Anytime b 
NA 
8001+ 
ruxolitinib 
1, 2, 3 
a Collect PK sample immediately prior to administration 
b Unscheduled PK blood samples may be collected at any time for measurement of plasma drug concentrations 
if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
* For part 3, PK collection limited to first 10 enrolled subjects 


Novartis 
Confidential 
Page 198 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 8-21 
PK blood collection log for ruxolitinib (single agent control arm) in 
Part 2 ONLY 
Cycle 
Day 
Scheduled Time Point 
(sampling window) 
Dose 
Reference ID 
PK Sample No. 
Analytes 
1 
1 
Pre-dose/0 h a 
601 
901 
ruxolitinib 
1 
1 
0.5 h (± 10 min) 
601 
902 
ruxolitinib 
1 
1 
1 h (± 10 min) 
601 
903 
ruxolitinib 
1 
1 
2 h (± 10 min) 
601 
904 
ruxolitinib 
1 
1 
3 h (± 15 min) 
601 
905 
ruxolitinib 
1 
1 
4 h (± 15 min) 
601 
906 
ruxolitinib 
1 
1 
8 h (± 1h) 
601 
907 
ruxolitinib 
2 
1 
Pre-AM dose/0 h a 
604 
910 
ruxolitinib 
3 
1 
 Pre-AM dose/0 h a 
606 
912 
ruxolitinib 
4 
1 
Pre-AM dose/0 h a 
608 
914 
ruxolitinib 
5 
1 
Pre-AM dose/0 h a 
609 
915 
ruxolitinib 
6 
1 
Pre-AM dose/0 h a 
610 
916 
ruxolitinib 
NA 
NA 
Unscheduled Anytime b 
 NA 
9001+ 
ruxolitinib 
a Collect PK sample immediately prior to administration 
b Unscheduled PK blood samples may be collected at any time for measurement of plasma drug concentrations 
if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
Table 8-22 
PK blood collection log for rineterkib and ruxolitinib combination arm 
(Part 1, 2 and 3*) 
Cycle 
Day 
Scheduled 
Time Point 
(sampling 
window) 
Dose Reference ID 
PK Sample No.  
Analytes 
Part 
rineterkib 
ruxolitinib 
rineterkib 
ruxolitinib 
 
 
1 
1 
Pre-dose/0 h a 
701 
801 
2501 
3501 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
1 
0.5 h (± 10 
min) 
701 
801 
2502 
3502 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
1 
1 h (± 10 min) 
701 
801 
2503 
3503 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
1 
2 h (± 10 min) 
701 
801 
2504 
3504 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
1 
3 h (± 15 min) 
701 
801 
2505 
3505 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
1 
4 h (± 15 min) 
701 
801 
2506 
3506 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
1 
8 h (± 1h) c 
701 
801 
2507 
3507 
rineterkib, 
ruxolitinib 
1 
1 
2 
24 h (± 2h) 
post LTT462 / 
pre-AM C1D2 a 
701/702 
802 
2508 
3508 
rineterkib, 
ruxolitinib 
1 
1 
15 
Pre-AM dose/0 
h a 
703 
803 
2509 
3509 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
15 
0.5 h (± 10 
min) 
703 
803 
2510 
3510 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
15 
1 h (± 10 min) 
703 
803 
2511 
3511 
rineterkib, 
ruxolitinib 
1, 2, 
3 


Novartis 
Confidential 
Page 199 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled 
Time Point 
(sampling 
window) 
Dose Reference ID 
PK Sample No.  
Analytes 
Part 
rineterkib 
ruxolitinib 
rineterkib 
ruxolitinib 
 
 
1 
15 
2 h (± 10 min) 
703 
803 
2512 
3512 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
15 
3 h (± 15 min) 
703 
803 
2513 
3513 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
15 
4 h (± 15 min) 
703 
803 
2514 
3514 
rineterkib, 
ruxolitinib 
1, 2, 
3 
1 
15 
8 h (± 1h) c 
703 
803 
2515 
3515 
rineterkib, 
ruxolitinib 
1 
1 
16 
24 h (± 2h) 
post LTT462 / 
pre-AM C1D16 
a,c 
703/704 
 
804 
2516 
3516 
rineterkib, 
ruxolitinib 
1 
2 
1 
Pre-AM dose/0 
h a 
705 
805 
2517 
3517 
rineterkib, 
ruxolitinib 
1, 2, 
3 
3 
1 
Pre-AM dose/0 
h a 
706 
806 
2518 
3518 
rineterkib, 
ruxolitinib 
1, 2, 
3 
4 
1 
Pre-AM dose/0 
h a 
707 
807 
2519 
3519 
rineterkib, 
ruxolitinib 
1, 2, 
3 
5 
1 
Pre-AM dose/0 
h a 
708 
808 
2520 
3520 
rineterkib, 
ruxolitinib 
1, 2, 
3 
6 
1 
Pre-AM dose/0 
h a 
709 
809 
2521 
3521 
rineterkib, 
ruxolitinib 
1, 2, 
3 
NA 
NA 
Unscheduled 
Anytime b 
NA 
NA 
2601+ 
3601+ 
rineterkib, 
ruxolitinib 
1, 2, 
3 
a Collect PK sample immediately prior to administration 
b Unscheduled PK blood samples may be collected at any time for measurement of plasma drug concentrations 
if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
c PK sampling time point not collected for Part 2 and 3 
* For Part 3, PK collection limited to first 10 enrolled subjects 
Table 8-23 
PK blood collection log for NIS793 and IG in combination arm with 
ruxolitinib (Part 1, 2 and 3*) 
Cycle 
Day 
Scheduled Time 
Point (h)** 
Dose 
Reference 
ID 
PK 
Sample 
No. 
IG Sample 
No.* 
Analyte 
Part 
1 
1 
0 h / Pre-infusion 
a 
901 
4501 
5501 
NIS793, IG d 
1, 2, 
3 
1 
1 
1h post EOI (± 
15min) b 
901 
4502 
  
NIS793 
1, 2, 
3 
1 
2  
24 h post start of 
infusion (+ 2h) c 
901 
4503 
  
NIS793 
1, 2, 
3 
1 
4 
72h post start of 
infusion (± 8h) c 
901 
4504 
  
NIS793 
1 
1 
8 
168h post start of 
infusion (± 8h) c 
901 
4505 
  
NIS793 
1, 2, 
3 
1 
11 
240h post start of 
infusion (± 24h) c 
901 
4506 
  
NIS793 
1 


Novartis 
Confidential 
Page 200 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled Time 
Point (h)** 
Dose 
Reference 
ID 
PK 
Sample 
No. 
IG Sample 
No.* 
Analyte 
Part 
1 
15 
336h post start of 
infusion (± 24h) c 
901 
4507 
  
NIS793 
1, 2, 
3 
2 
1 
504h post start of 
infusion (± 48h) 
(Pre-infusion of 
cycle 2) 
901/902 
4508 
5502 
NIS793, IG d 
1, 2, 
3 
3 
1 
0 h / Pre-infusion 
a 
903 
4509 
5503 
NIS793, IG d 
1, 2, 
3 
3 
1 
1h post EOI (± 15 
min) b 
903 
4510 
  
NIS793 
1, 2, 
3 
3 
2  
24 h post start of 
infusion (+ 2h) c 
903 
4511 
 
NIS793 
1, 2, 
3 
3 
4 
72h post start of 
infusion (± 8h) c 
903 
4512 
 
NIS793 
1 
3 
8 
168h post start of 
infusion (± 8h) c 
903 
4513 
 
NIS793 
1, 2, 
3 
3 
11 
240h post start of 
infusion (± 24h) c 
903 
4514 
 
NIS793 
1 
3 
15 
336h post start of 
infusion (± 24h) c 
903 
4515 
 
NIS793 
1, 2, 
3 
4 
1 
504h post start of 
infusion (± 48h) 
(Pre-infusion of 
cycle 4) 
903/904 
4516 
5504 
NIS793, IG d 
1, 2, 
3 
5 
1 
0 h / Pre-infusion 
a 
905 
4517 
5505 
NIS793, IG d 
1, 2, 
3 
6 
1 
0 h / Pre-infusion 
a 
906 
4518 
5506 
NIS793, IG d 
1, 2, 
3 
6 
1 
1h post EOI (± 15 
min) b  
906 
4519 
- 
NIS793 
1, 2, 
3 
7 
1 
0 h / Pre-infusion 
a 
907 
4520 
5507 
NIS793, IG d 
1, 2, 
3 
8 
1 
0 h / Pre-infusion 
a 
908 
4521 
5508 
NIS793, IG d 
1, 2, 
3 
Every 4 Cycles 
after C8D1 
until 
discontinuation 
of study 
treatment 
1 
0 h / Pre-infusion 
a 
909 e 
4522 f 
5509 g 
NIS793, IG d 
1, 2, 
3 
EOT Core treatment 
phase 
Anytime 
NA 
10000 
20000 
NIS793, IG d 
1, 2, 
3 
Safety follow-up Day 
30 
Anytime 
NA 
10001 
20001 
NIS793, IG d 
1, 2, 
3 
Safety follow-up Day 
90 
Anytime 
NA 
10002 
20002 
NIS793, IG d 
1, 2, 
3 
Unscheduled h  
Anytime  
NA 
10003+ 
20003+ 
NIS793, IG d 
1, 2, 
3 
EOI = end of infusion 


Novartis 
Confidential 
Page 201 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Cycle 
Day 
Scheduled Time 
Point (h)** 
Dose 
Reference 
ID 
PK 
Sample 
No. 
IG Sample 
No.* 
Analyte 
Part 
** The first Dose Reference ID (for e.g. 902) is for the current dose, while the second Dose Reference ID (for 
e.g. 901) is for the last (previous) dose received prior to the collection of the PK sample 
a Pre-dose: blood samples should be collected prior to the start of the infusion 
b Post-dose: sampling time is relative to the end of the infusion; and blood samples should be taken after 
completion of the infusion 
c Post-dose: sampling time is relative to the start of the infusion 
d IG samples are to be collected together with PK samples at the same time 
e Dose reference ID will be labeled sequentially from 910, 911, 912.....before EOT 
f PK sample will be labeled sequentially from 4523, 4524, 4525.....before EOT 
g IG sample will be labeled sequentially from 5510, 5511, 5512.....before EOT 
h Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
* For Part 3, IG/PK collection limited to first 10 enrolled subjects 
Note: PK and IG blood samples are collected from the opposite arm of infusion site. Alternatively, infusion site 
will need to be flushed with 10 mL of saline. 
Table 8-24 
PK blood collection log for ruxolitinib in combination arm with NIS793 (Part 1, 
2 and 3*) 
Cycle 
Day 
Scheduled Time Point 
(sampling window) 
Dose 
Reference ID 
PK Sample No. 
Analyte 
1 
1 
Pre-dose/0 h a 
1001 
6501 
ruxolitinib 
1 
1 
0.5 h (± 10 min) 
1001 
6502 
ruxolitinib 
1 
1 
1 h (± 10 min) 
1001 
6503 
ruxolitinib 
1 
1 
2 h (± 10 min) 
1001 
6504 
ruxolitinib 
1 
1 
3 h (± 15 min) 
1001 
6505 
ruxolitinib 
1 
1 
4 h (± 15 min) 
1001 
6506 
ruxolitinib 
1 
1 
8 h (± 1h) 
1001 
6507 
ruxolitinib 
2 
1 
Pre-AM dose/0 h a 
1002 
6508 
ruxolitinib 
3 
1 
Pre-AM dose/0 h a 
1003 
6509 
ruxolitinib 
4 
1 
Pre-AM dose/0 h a 
1004 
6510 
ruxolitinib 
5 
1 
Pre-AM dose/0 h a 
1005 
6511 
ruxolitinib 
6 
1 
Pre-AM dose/0 h a 
1006 
6512 
ruxolitinib 
7 
1 
Pre-AM dose/0 h a 
1007 
6513 
ruxolitinib 
8 
1 
Pre-AM dose/0 h a 
1008 
6514 
ruxolitinib 
NA 
NA 
Unscheduled Anytime b 
NA 
30001+ 
ruxolitinib 
a Collect PK sample immediately prior to administration 
b Unscheduled PK blood samples may be collected at any time for measurement of plasma drug concentrations 
if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
* For part 3, PK collection limited to first 10 enrolled subjects 
8.5.2.1 
Pharmacokinetic, 
 immunogenicity blood 
collection and handling 
Blood samples for ruxolitinib PK evaluation will be collected from all subjects who receive at 
least one dose of ruxolitinib, except as follows: PK samples will only be collected from the first 
10 subjects of the 20 subjects randomized into the combination treatment arm (Arm 1) of  


Novartis 
Confidential 
Page 202 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Part 3 (d), and no PK samples will be collected from the ruxolitinib control arm (Arm 3) of  
Part 3 of the study. The time points of blood collection for ruxolitinib PK are outlined in  
Table 8-16, Table 8-19, Table 8-20, Table 8-21, Table 8-22 and Table 8-24 . 
Blood samples for siremadlin PK evaluation will be collected from all subjects who receive at 
least one dose of siremadlin. Time points of blood collection for siremadlin PK are outlined 
in Table 8-16, along with the time points of blood collection for ruxolitinib PK in combination 
with siremadlin.  
Blood samples for crizanlizumab PK and IG will be collected from all subjects who receive at 
least one dose of crizanlizumab. Time points of blood collection for crizanlizumab PK and IG 
are outlined in Table 8-17. The time points of blood collection for ruxolitinib PK in combination 
with crizanlizumab are outlined in Table 8-19. 
Blood samples for sabatolimab PK, IG and PD (TIM-3) will be collected from all subjects who 
receive at least one dose of sabatolimab. Time points of blood collection for sabatolimab PK, 
IG and TIM-3 are outlined in Table 8-18. The time points of blood collection for ruxolitinib PK 
in combination with sabatolimab are outlined in Table 8-20.  
Blood samples for rineterkib PK evaluation will be collected from all subjects who receive at 
least one dose of rineterkib. Time points of blood collection for rineterkib PK are outlined in 
Table 8-22 , along with the the time points of blood collection for ruxolitinib PK in combination 
with rineterkib. 
Blood samples for NIS793 PK and IG will be collected from all subjects who receive at least 
one dose of NIS793. Time points of blood collection for NIS793 PK and IG are outlined in 
Table 8-23 . The time points of blood collection for ruxolitinib PK in combination with NIS793 
are outlined in Table 8-24 . 
On days of sample blood collection, subjects should take their medication at the clinic 
immediately after the first blood sample (e.g., pre-dose/0 hr sample). The exact dates and clock 
times of study drug administration and sample blood collection will be recorded on the 
appropriate CRF. Any sampling issues should be noted on the CRF and on appropriate source 
documentation. 
Blood samples will be collected by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein opposite to the arm used for study drug infusion (in the case of sabatolimab 
crizanlizumab or NIS793). For ruxolitinib, a total of 2.5 mL of blood will be collected for PK 
analysis in plasma. For siremadlin and rineterkib, a total of 2 mL of blood will be collected for 
PK analysis in plasma. For crizanlizumab, a total of 2.5 and 3.5 mL of blood will be collected 
for PK and IG analysis in serum, respectively. For sabatolimab, a total of 1 mL of blood will 
each be collected for PK and TIM-3 analysis in serum, while a total of 2 mL of blood will be 
collected for IG analysis in serum. For NIS793, a total of 6 mL of blood will each be collected 
for PK and IG analysis in serum. For time points when sampling of mAb (sabatolimab, 
crizanlizumab or NIS793) PD or IG coincide with PK, a single blood sample of the appropriate 
volume will be collected for PD or IG and PK. 
Additional PK, PD and IG samples will be collected at EOT from subjects treated with 
crizanlizumab, sabatolimab, and NIS793. Additional PK and IG samples will be collected at 
the 90-day safety follow up visit from subjects treated with sabatolimab, or at the 105-day safety 


Novartis 
Confidential 
Page 203 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
follow up visit from subjects treated with crizanlizumab. Additional PK, PD and IG samples 
will be collected at the 30-day and 90-day safety follow up visits for subjects treated with 
NIS793. Not applicable from amended protocol version 08. The assessments not performed in 
the study treatment phase because of the enrollment halt prior to the implementation of amended 
protocol version 08 will be documented for transparency in the clinical study report. 
If subjects experience a DLT, SAE or an AE leading to the discontinuation of the study 
treatment, an unscheduled PK blood sample should be obtained as close as possible to the event 
occurrence. If patients experience a suspected immune-related AE such as infusion-related 
reaction, hypersensitivity, cytokine release syndrome and anaphylaxis, an unscheduled IG 
blood sample should be obtained as close as possible to the event occurrence. The date and time 
of the last dose and the time of PK blood draw should be recorded. 
 
 
 
 
 
 
Refer to the study [Laboratory Manual] for detailed instructions for the collection, handling, 
and shipment of PK, IG and PD samples. 
8.5.2.2 
Analytical method 
Bioanalysis for PK, IG or PD samples will employ the following validated assays: 
1. Plasma concentrations of rineterkib, siremadlin and ruxolitinib will be determined using a 
validated LC-MS/MS assay, with a current LLOQ of 1 ng/mL, 1 ng/mL and  
0.5 ng/mL, respectively. 
2. Serum concentrations of crizanlizumab will be determined using a validated target capture 
enzyme-linked immunosorbent assay (ELISA). 
3. Serum concentrations of sabatolimab will be determined using a validated LC-MS assay, 
with a current LLOQ of 5.0 µg/mL. 
4. Anti-crizanlizumab antibodies will be evaluated in serum using a validated Meso Scale 
Discovery (MSD) electrochemiluminescence assay and anti-sabatolimab antibodies will 
evaluated in serum using a validated ELISA.  
5. Serum concentrations of total TIM-3 will be determined using a validated ELISA.  
6. The assay to quantify NIS793 will be a validated sandwich ELISA.  
7. The assay to quantify and assess the IG against NIS793 will be a validated Meso Scale 
Discovery (MSD) electrochemiluminescence assay. 
Details of each analytical method will be documented in the bioanalytical data reports. 


Novartis 
Confidential 
Page 204 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
• 
 
  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 205 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 206 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
 
 
 
 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator. 


Novartis 
Confidential 
Page 207 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Subject/guardian decision 
• Pregnancy 
• Investigator decision, including lack of clinical benefit 
• Disease progression (refer to definition in Section 8.3.2.5) 
• Adverse events leading to study treatment discontinuation 
• Protocol deviations that result in a significant risk to the subject's safety including the use 
of prohibited treatment and any dose holds greater than 21 days for arms containing NIS793 
or 28 days for all other arms 
• New anti-neoplastic therapy for study indication 
• Subjects who are scheduled for ASCT at any time during the course of the study 
In addition to the above, study treatment should be discontinued under the following 
circumstances during the extension treatment phase:  
• Subject is no longer deriving clinical benefit from study treatment in the opinion of the 
investigator.  
• Subject has local access to alternative treatment for study indication including those 
currently under investigation in clinical trials as assessed suitable in the opinion of the 
investigator.  
• Subject withdraws consent. 
Subject enrolls in another interventional study.If discontinuation of study treatment occurs, the 
Investigator should make a reasonable effort to understand the primary reason for the subject’s 
premature discontinuation of study treatment and record this information. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, all subjects 
should return for and End of Treatment (EOT) visit within 7 days after discontinuation of 
permanent study treatment (all investigational drugs), at which time all of the assessments for 
EOT indicated in Table 8-2, Table 8-3, Table 8-4, or Table 8-5 should be performed, including 
a physical examination, vital signs, height, weight, ECOG performance status, ECG, 
concomitant medications, non-drug therapy and procedures, collection of AEs and any 
transfusions, laboratory assessments, spleen palpation (CT or MRI imaging, blood sampling for 
PK/PD 
, bone marrow biopsy or aspirate, and, if applicable, immunogenicity for 
crizanlizumab, sabatolimab or NIS793. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in the lost to follow-up Section 9.1.3. This contact should 
preferably be done according to the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 


Novartis 
Confidential 
Page 208 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
After study treatment discontinuation, all subjects must have a Safety Follow-up visit 30 days 
after permanent study treatment discontinuation as described in Section 9.2. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
9.1.1.1 
Replacement policy 
Part 1 (Dose escalation and safety run-in) 
Subjects will not be replaced on study. However, if a subject is considered as non-evaluable for 
the DDS, enrollment of a new subject to the current cohort will be considered if there is less 
than the required number of evaluable subjects. 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 the cohort. Minimum and maximum numbers of evaluable subjects per 
cohort are defined in the guidelines for dose escalation and determination section 
(Section 6.5.2). 
Part 2 and Part 3 (Selection and expansion) 
During the selection and expansion parts of the study no replacements will be needed. 
9.1.2 
Withdrawal of informed consent/Opposition to use data/biological 
samples 
Withdrawal of consent/opposition to use data/biological samples occurs when a subject: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data.Study treatment must be 
discontinued and no further assessments conducted, and the data that would have been collected 
at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 


Novartis 
Confidential 
Page 209 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
If the subject agrees, a final evaluation at the time of the subject’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.1.3 Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed. 
Subjects considered to be lost to follow-up should be recorded as such on the appropriate 
Disposition eCRF. 
9.1.4 Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate the 
study, Novartis will always consider the subject welfare and safety. Should early termination 
be necessary, subjects must be contacted and seen as soon as possible to stop study treatment, 
and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion  
All subjects receiving combination treatment must have a Safety Follow-up visit at least 30 
days (+7 days) after the last dose of study treatment (all investigational drugs) to have 
hematology, chemistry, vital signs and serum pregnancy assessments and to collect information 
on any AEs, concomitant medications, transfusions, non-drug therapies and procedures, and 
anti-neoplastic therapies. Additional Safety Follow-up visits should also occur, as follows: 
• 105 days (+7 days) after the last dose of crizanlizumab for subjects on ruxolitinib + 
crizanlizumab (or crizanlizumab monotherapy in Part 3)  
• 90 days (+7 days), and 150 days (+14 days) after the last dose of sabatolimab for subjects 
on ruxolitinib + sabatolimab (or sabatolimab monotherapy in Part 3).  
• 90 days (+7 days) after the last dose of NIS793 for subjects on ruxolitinib + NIS793 (or 
NIS793 monotherapy in Part 3). 
The timing of the final Safety Follow-up visit is based on a period of at least 5 times the half-
life of crizanlizumab, sabatolimab, and NIS792 after the last dose when the serum level of 


Novartis 
Confidential 
Page 210 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
crizanlizumab, sabatolimab, and NIS793 in all subjects should be negligible or below the 
LLOQ.  
At the 90-, 105-, and 150-day Safety Follow-up visits, the same assessments will be performed 
as per the 30-day Safety Follow-up visit. The planned PK sample and IG sample will not be 
collected at the 90-day Safety Follow-up visit for sabatolimab, and at the 105-day Safety 
Follow-up visit for crizanlizumab, due to enrollment halt. For NIS793, the planned PK, PD and 
IG samples will not be collected at the 30-day and 90-day Safety Follow-up visits, due to 
enrollment halt. However, if the subject begins new antineoplastic medication (other than study 
treatment) before the end of the safety follow-up period, the collection of new SAEs and AEs 
unrelated to study medication will stop and thereafter only suspected AEs and suspected SAEs 
will continue to be collected up to the end of the safety follow-up period. 
Refer to Table 8-2, Table 8-3, Table 8-4 and Table 8-5 for a complete list of the assessments to 
be completed at the Safety Follow-up visits. The information collected is kept as source 
documentation. All SAEs reported during this time period must be reported as described in 
Section 10.1.3. Documentation of attempts to contact the subject should be recorded in the 
source documentation. 
Subjects in Part 2 and Part 3 of the study will also be contacted by telephone every 3 months 
(12 weeks +/- 14 days) after study treatment discontinuation to follow-up on the survival status, 
any new anti-neoplastic therapies (including transfusions), and leukemic transformation. See 
Table 8-3 and Table 8-5 for details.  
Due to enrollment halt, the primary analysis will be conducted after the last subject performed 
the eEOT for core treatment phase in Part 1 and after Part 1 and 2 subjects have received at 
least 8 cycles (for arms with NIS793) or 6 cycles of treatment (for all other arms) or 
discontinued earlier. The primary analysis data will be summarized in the primary clinical study 
report (CSR). Following the cut-off date for the analysis reported in the primary CSR, the study 
will remain open until the end of the study. Ongoing subjects may continue to receive study 
treatment in the extension treatment phase and be followed as per the schedule of assessments, 
as long as subjects derive benefit from the study treatment. 
The end of study (study completion) will occur after the last subject has completed the extension 
treatment phase (21 cycles of extension treatment), or earlier if all subjects have died or 
discontinued from the study (provided that all required safety follow-up visits have occurred). 
The final analysis will occur at the end of the study. All available extension treatment phase 
data up to this cut-off date will be analyzed and reported in a final CSR. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 


Novartis 
Confidential 
Page 211 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 
2. Its relationship to the study treatments. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose reduced 
• Drug interrupted/withdrawn 
6. Its outcome (i.e. recovery status or whether it was fatal) 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least: 


Novartis 
Confidential 
Page 212 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
• 30 days after the last dose of single-agent ruxolitinib (control/monotherapy) 
• 30 days after the last dose of ruxolitinib or siremadlin for subjects on ruxolitinib + 
siremadlin (or siremadlin monotherapy in Part 3) 
• 30 days after the last dose of ruxolitinib or rineterkib for subjects on ruxolitinib + rineterkib 
(or rineterkib monotherapy in Part 3) 
• 90 days after the last dose of NIS793 for subjects on ruxolitinib + NIS793 (or NIS793 
monotherapy in Part 3) 
• 105 days after the last dose of crizanlizumab for subjects on ruxolitinib + crizanlizumab (or 
crizanlizumab monotherapy in Part 3) 
• 150 days after the last dose of sabatolimab for subjects on ruxolitinib + sabatolimab (or 
sabatolimab monotherapy in Part 3). 
OR 
• until the start of a new post treatment anti-neoplastic medication if sooner than the end of 
the safety follow-up period mentioned above, depending on the study treatment. If a subject 
starts post treatment antineoplastic medication, then only adverse events suspected to be 
related to study treatment should be collected, up to the end of the safety follow-up period 
noted above. 
Progression of the underlying disease (myelofibrosis) (including fatal outcomes) based on the 
criteria described in Section 8.3.2.3 (ie. progressive splenomegaly, increase in peripheral blood 
blast content of > 10% (accelerated phase), deteriorating cytopenia, leukemic transformation) 
should not be reported as a serious adverse event. These disease progression events will be 
reported on specific CRF pages other than the AE CRF. 
Adverse events separate from the progression of malignancy (i.e. 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. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
1. they induce clinical signs or symptoms 
2. they are considered clinically significant 
3. they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values, which are considered to be non-typical in subjects with 
the underlying disease. 


Novartis 
Confidential 
Page 213 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
10.1.2 Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
1. fatal 
2. life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• 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 
• 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 subject’s 
general 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 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred (Section 10.1.5). 
Treatment-emergent elevations in AST or ALT (>3x ULN) in combination with total 
bilirubin >2x ULN or jaundice in the absence of cholestasis (defined as ALP < 2 ULN) or other 
causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s Law). 


Novartis 
Confidential 
Page 214 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
For this reason, a potential Hy’s Law case requires expedited reporting, and will be handled as 
a serious unexpected adverse event (assessing it as medically significant in the absence of any 
other seriousness criteria). It must be reported as an SAE to the sponsor promptly (i.e., even 
before all other possible causes of liver injury have been excluded). Reporting should include 
all available information, especially that needed for evaluating the diagnosis, severity and 
likelihood that the study treatment caused the reaction. For patient monitoring and to better 
understand potential etiologies, the investigator must initiate a close follow-up until complete 
resolution of the problem and completion of all attempts to obtain supplementary data. 
10.1.3 SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent must be reported to Novartis safety immediately, without undue 
delay, but under no circumstances later than within 24 hours of obtaining knowledge of the 
events (Note: If more stringent, local regulations regarding reporting timelines prevail) until the 
end of the safety follow-up period, as follows: 
• 30 days after the last dose of single-agent ruxolitinib (control/monotherapy) 
• 30 days after the last dose of ruxolitinib or siremadlin for subjects on ruxolitinib + 
siremadlin (or siremadlin monotherapy in Part 3) 
• 30 days after the last dose of ruxolitinib or rineterkib for subjects on ruxolitinib + rineterkib 
(or rineterkib monotherapy in Part 3) 
• 90 days after the last dose of NIS793 for subjects on ruxolitinib + NIS793 (or NIS793 
monotherapy in Part 3) 
• 105 days after the last dose of crizanlizumab for subjects on ruxolitinib + crizanlizumab (or 
crizanlizumab monotherapy in Part 3),  
• 150 days after the last dose of sabatolimab for subjects on ruxolitinib + sabatolimab (or 
sabatolimab monotherapy in Part 3). 
If a subject starts post treatment anti-neoplastic medication then only SAEs suspected to be 
related to study treatment should be collected, up to the time frame noted above depending on 
the study treatment (30 days for ruxolitinib, siremadlin or rineterkib, 90 days for NIS793, 105 
days for crizanlizumab or 150 days for sabatolimab). 
For Screen Failure subjects, SAEs occurring after the subject has provided informed consent 
until the time the subject is deemed a Screen Failure must be reported to Novartis. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 


Novartis 
Confidential 
Page 215 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
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 study treatment, a CMO & PS 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 study treatment 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 EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Progression of the underlying disease (myelofibrosis) (including fatal outcomes) based on the 
criteria described in Section 8.3.2.4 (ie. progressive splenomegaly, increase in peripheral blood 
blast content of > 10% (accelerated phase), deteriorating cytopenia, leukemic 
transformation) should not be reported as a SAE. As noted in Section 10.1.1, these disease 
progression events will be reported on specific CRF pages other than the AE CRF. 
Any SAEs experienced more than 30 days after the last dose of single-agent 
ruxolitinib (control/monotherapy), 30 days after the last dose of ruxolitinib + siremadlin, 30 
days after the last dose of ruxolitinib + rineterkib, 90 days after the last dose of ruxolitinib + 
NIS793, 105 days for ruxolitinib + crizanlizumab (or crizanlizumab monotherapy in Part 3), 
and 150 days after the last dose of ruxolitinib + sabatolimab (or sabatolimab monotherapy in 
Part 3) should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment. 
10.1.4 Pregnancy reporting 
Pregnancies 
If a female subject becomes pregnant, the study treatment should be stopped, and the subject 
must be asked to read and sign pregnancy consent form to allow the investigator ask about her 
pregnancy. To ensure subject safety, each pregnancy occurring after signing the informed 
consent 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. 
If the pregnancy results in a live birth, the baby will have regular check-ups and the investigator 
will need to know the outcomes of these check-ups until one year after the baby was due to be 
born. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
Pregnancy outcomes should 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. 


Novartis 
Confidential 
Page 216 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
10.1.5 Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment Error Type 
Document in Dosing 
CRF (Yes/No) 
Document in AE eCRF 
Complete SAE Form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will be responsible to review safety, PK/PD, 
DLT and critical efficacy variables data approximately every 6 months (or as needed) during 
the treatment period (after the first subject has started Part 1 study treatment) and recommend 
to Novartis whether to continue, modify, or terminate a trial. The DMC will also provide 
recommendation to the Novartis study team which ruxolitinib treatment combination arm(s) 
should be further developed in Part 2 and Part 3. As the enrollment was permanently halted, the 
Part 2 has been prematurely discontinued with one randomized patient, and Part 3 will not be 
initiated, therefore the descriptions above for Parts 2 and 3 are not applicable. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate DMC Charter that is established between Novartis and the DMC. 


Novartis 
Confidential 
Page 217 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
10.2.2 Steering Committee 
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being members of the DMC and not Novartis representatives from the Clinical 
Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will provide 
recommendation to the study team about which ruxolitinib combination treatment arm 
(s) should be further developed in Part 2 and Part 3. As the enrollment was permanently halted, 
the Part 2 has been prematurely discontinued with one randomized patient, and Part 3 will not 
be initiated, therefore the descriptions above for Parts 2 and 3 are not applicable. 
The SC will also review protocol amendments as appropriate. Together with the Clinical Trial 
Team, the SC will also develop recommendations for publications of study results including 
authorship rules. The details of the role of the steering committee will be defined in the SC 
Charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
This study will use Electronic Data Capture (EDC). 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, allow 
modification and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entries and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
Blood samples for some laboratory assessments, 
 and PK samples and/or data will 
be processed centrally and the results will be sent electronically to Novartis as described in the 
Data Transfer Specifications. 
11.2 
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. 


Novartis 
Confidential 
Page 218 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Randomization codes and data about all study treatment(s) dispensed to the subject and all 
dosage changes will be tracked using an IRT. The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis/moved to restricted 
area to be accessed by independent programmer and statistician. Any changes to the database 
after that time can only be made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/delegated CRO/CRA organization. Additionally, a central 
analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original ICF signed by the subject (a signed 
copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 


Novartis 
Confidential 
Page 219 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
12 
Data analysis and statistical methods 
All statistical analyses will be performed under the direction of Novartis personnel. Any data 
analysis carried out independently by the investigator should be submitted to Novartis prior to 
publication or presentation. 
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized with 
respect to demographic and baseline characteristics, efficacy and safety observations and 
measurements, and all relevant PK and PD measurements using descriptive statistics 
(quantitative data) and contingency tables (qualitative data) as appropriate. 
Subjects treated at different dose levels of ruxolitinib will be pooled into a single treatment 
group for each dose level of the combination partners. A treatment group is defined by both 
combination partner and the dose level of the combination partner (siremadlin arm and 
rineterkib arm) for Part 1 subjects. A treatment group is defined by the combination partner for 
Part 2 and Part 3 subjects. 
Enrollment was permanently halted and Part 2 was prematurely discontinued with one 
randomized subject; Part 3 will not be initiated. The primary CSR will include analyses on all 
subject data at the time when the last subject completed the end of treatment visit for core 
treatment phase (Part1), and after all subjects have completed at least 8 cycles (arms with 
NIS793) or 6 cycles (all other arms) of treatment or discontinued earlier (Part 1 and Part 2). All 
extension treatment phase data will be reported in the final CSR once all subjects are 
discontinued from the study or completed the extension treatment phase (maximum 21 cycles) 
whichever comes last. Subjects in Part 1 will be analyzed separately from subjects in Part 2. 
Data from Part 2 will be listed but not summarized.  
Two interim analyses are planned for each combination treatment in Part 2. The first interim 
analysis is planned when at least 10 subjects have been randomized into each of the treatment 
and have completed at least 8 cycles (arms with NIS793) or 6 cycles (all other arms) of treatment 
or discontinued earlier for a seamless transition into Part 3 expansion in the presence of 
outstanding preliminary efficacy. The second interim analysis is planned when all Part 2 
subjects (at least 25 subjects) of each combination treatment arm have completed at least 8 
cycles (arms with NIS793) or 6 cycles (all other arms) of treatment or discontinued earlier for 
advancing the combination treatment in Part 3 that are not futile or stopped for safety. The 
second interim analysis is not required if a combination treatment is advanced in Part 3 based 
on the first interim analysis.  
Due to the permanent enrollment halt, the description for Parts 2 and 3, including interim 
analyses are not applicable as outlined in amended protocol version 08.  
The primary analysis will be performed on all subjects after the last subject performed the end 
of treatment visit (EOT) for core treatment phase (Part 1), and after all subjects have completed 
at least 8 cycles (arms with NIS793) or 6 cycles (all other arms) of treatment or discontinued 
earlier (Part 1 and Part 2). The final analysis for the extension phase data will be performed at 
the end of the study. 


Novartis 
Confidential 
Page 220 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
12.1 
Analysis sets 
12.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all subjects that received any study drug. Subjects will 
be analyzed according to the treatment(s) received. 
12.1.2 
Safety Set 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized/assigned treatment if the subject took at least one dose of that treatment or 
the first treatment received if the randomized/assigned treatment was never received.  
12.1.3 
Dose-Determining Set 
The Dose-Determining Set (DDS) includes all subjects from the safety run-in and dose 
escalation part (Part 1) of the study who met the minimum exposure criterion and had sufficient 
safety evaluations, or experienced a dose-limiting toxicity (DLT) between C1D1 and C3D1. 
The minimum exposure required for combination treatments defined as follows:  
• For ruxolitinib + rineterkib study treatment arm, a subject has met the minimum exposure 
criterion if the subject takes at least 75% of the planned daily rineterkib and ruxolitinib 
combination doses during the first two treatment cycles of dosing, i.e. at least 21 full dosing 
days out of the planned 28 days for the rineterkib and ruxolitinib combination, and the 
subject takes at least 80% of the planned daily doses of ruxolitinib i.e. at least 23 full dosing 
days out of the planned 28 days for ruxolitinib. 
• For all other study treatment arms, a subject has met the minimum exposure criterion if the 
subject takes all planned doses of the combination agent during the first two treatment cycles 
of dosing, and at least 80% of the planned daily doses of ruxolitinib i.e. at least 23 full 
dosing days (17 days for NIS793) out of the planned 28 days (21 days for NIS793) for 
ruxolitinib. 
Subjects who do not experience a DLT between C1D1 and C3D1 are considered to have 
sufficient safety evaluations if they have been observed until C2D28, or C2D21 for the 
ruxolitinib + NIS793 study treatment arm, and are considered by both the sponsor and 
investigators to have enough safety data to conclude that a DLT did not occur.  
For Japan only: subjects enrolled after the dose determination for a combination treatment will 
not be included in the DDS. 
12.1.4 Pharmacokinetic analysis set 
The Pharmacokinetic Analysis Set (PAS) includes all enrolled subjects who have an evaluable 
PK profile. A profile is considered evaluable if all of the following conditions are satisfied: 
• Subject receives the planned treatments 
• Subject takes the dose of study treatments as described in Section 6.7.2 
• Subject provides at least one primary PK parameter as defined in Section 12.5.3 


Novartis 
Confidential 
Page 221 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
• Subject ingests siremadlin or rineterkib at least 1 h before or 2 h after a meal (only applicable 
for treatment arm ruxolitinib + siremadlin or treatment arm ruxolitinib + rineterkib) 
• Subject does not vomit within 4 hours after oral dosing of siremadlin, rineterkib or 
ruxolitinib (only applicable for treatment arm ruxolitinib + siremadlin or treatment arm 
ruxolitinib + rineterkib). 
• Subject does not vomit within 2 hours after oral dosing of ruxolitinib (all other treatment 
arms). 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented.  
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, and by treatment group. This will include baseline 
JAK2V617F mutational status and review of Packed Red Blood Cell (PRBC) transfusion 
history for the last 12 weeks prior to baseline. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in days to ruxolitinib, siremadlin, crizanlizumab, sabatolimab, 
rineterkib, and NIS793 as well as the dose intensity (computed as the ratio of actual cumulative 
dose received and actual duration of exposure) and the relative dose intensity will be 
summarized by means of descriptive statistics using the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system by treatment group. 
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group and all dosing data 
will be listed. 
12.4 
Analysis of the primary endpoint(s) 
The primary objective of Part 1 of the study is to characterize the safety, tolerability, and the 
recommended Phase 2 dose (RP2D) of each combination partner used with ruxolitinib in 
subjects with myelofibrosis.  
The primary objective of Parts 2 and 3 of the study is to evaluate the preliminary efficacy of the 
ruxolitinib combination treatments in subjects with myelofibrosis. 
Due to permanent enrollment halt, the objectives for Parts 2 and 3 are no longer applicable. 


Novartis 
Confidential 
Page 222 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
12.4.1 
Definition of primary endpoint(s) 
Part 1  
The primary endpoint in Part 1 is the incidence of dose-limiting toxicities (DLTs) within the 
first two treatment cycles.  
Part 2 and Part 3 (Not applicable) 
The primary endpoint in Parts 2 and 3 is the response rate (RR) at the end of Cycle 8 (for arms 
with NIS793) or Cycle 6 (all other arms). 
The RR is the composite of anemia improvement and no spleen volume progression and no 
symptom worsening. For a subject to be considered a responder, all three components of the 
composite endpoint have to be fulfilled. The components of the composite endpoint are defined 
as follows: 
• Anemia improvement is defined as an increase of hemoglobin from baseline of at least 1.5 
g/dL. Anemia improvement requires absence of any PRBC transfusion in 12 weeks prior to 
achieving an increase of 1.5 g/dL. The increase in hemoglobin should be confirmed at least 
2 weeks later. 
• No spleen volume progression with progression defined as a spleen volume increase of 25% 
or more from baseline as measured by MRI/CT. 
• No symptoms worsening as measured by the MFSAF version 4 patient reported outcome 
(PRO). An increase in total symptom score (TSS) of 10 or more from baseline is considered 
worsening of symptoms. 
12.4.2 Statistical model, hypothesis, and method of analysis 
12.4.2.1 Part 1 
Identification of a recommended dose for siremadlin and rineterkib 
Identification of the RP2D of the combination treatment will be based upon the estimation of 
the probability of DLT within the first two cycles for patients in the DDS. A recommended dose 
below the MTD may be identified based on other safety, clinical, PK, and PD data 
(Section 6.5.2). The dose escalation will be guided by a Bayesian analysis of dose-limiting 
toxicity (DLT) data from Cycle 1 and Cycle 2. The relationship between dose and the 
probability of DLT is modelled using logistic regression. Details of the model are given in 
Section 16.6. 
Assessment of patient risk 
After each cohort of patients that have been followed for two cycles, the BLRM will be updated 
and the posterior distribution for the risk of DLTs for patients at dose levels of siremadlin of 
interest will be evaluated. The posterior distributions will be summarized to provide the 
posterior probability that the risk of a DLT within the first two cycles lies within the following 
intervals: 


Novartis 
Confidential 
Page 223 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 12-1 
Toxicity levels 
Under-dosing: 
[0 , 0.16) 
Targeted toxicity: 
[0.16 , 0.33) 
Excessive toxicity: 
[0.33 , 1] 
The escalation with overdose control (EWOC) principle 
Dosing decisions are guided by the escalation with overdose control principal. A dose of the 
combination agent may only be used for newly enrolled patients if the risk of excessive toxicity 
at that dose is less than 25%. 
Prior distributions 
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
model parameters. The MAP prior for the logistic model parameters for this study is the 
conditional 
distribution 
of 
the 
parameters 
given 
the 
historical 
data 
(see 
Neuenschwander et al 2014, Neuenschwander et al 2010, 
Spiegelhalter et al 2004). 
MAP 
priors are derived from hierarchical models, which take into account possible differences 
between the studies. 
A full description of the application of the MAP approach to derive the prior distributions of 
the model parameters is given in Section 16.6. 
Starting dose 
The starting dose for siremadlin in combination with ruxolitinib is 20 mg (Section 6.5.1.1). For 
this dose the prior risk of excessive toxicity is 15.42% (see Section 16.6), which satisfies the 
EWOC criterion. Any dose lower than 20 mg also fulfills the EWOC criterion. A full 
assessment of the prior risk to patients is given in Section 16.6. 
The starting dose for rineterkib in combination with ruxolitinib is 200 mg (Section 6.5.1.1). For 
this dose the prior risk of excessive toxicity is 18.85% (see Section 16.6), which satisfies the 
EWOC criterion. Any dose lower than 200 mg also fulfills the EWOC criterion. A full 
assessment of the prior risk to patients is given in Section 16.6. 
Listing of DLTs 
DLTs will be listed, and their incidence summarized by primary system organ class and worst 
grade (CTCAE version 5.0). Listings and summaries will be based on the DDS. 
Identification of DLT probability for crizanlizumab, sabatolimab, and NIS793 
For each combination treatment, the DLT probability is determined as the number of patients 
in the DDS who experienced a DLT divided by the number of patients in the DDS.  
Any DLTs occurring will be listed, and their incidence summarized by primary system organ 
class and worst grade (CTCAE version 5.0). Listings and summaries will be based on the DDS.  
12.4.2.2 Part 2 (Not applicable) 
No formal hypothesis testing or between arm comparison will be conducted in Part 2. The 
objective of this part of the study is to explore the disease-modifying activity of the combination 
treatments, and to drop the arm(s) which lack promising activity.  


Novartis 
Confidential 
Page 224 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
The arms that will advance into Part 3 will be selected based on the totality of the data. That 
includes, among other data, efficacy, safety, PK/PD, 
 data as appropriate, and 
also data from the ruxolitinib single agent arm.  
To determine whether a combination treatment has the potential to be disease-modifying and, 
as such, be eligible to advance into Part 3, the combination must not cross a specified futility 
boundary defined for the RR with respect to the primary composite endpoint. 
A combination treatment arm that shows an early sign of outstanding efficacy by crossing a 
specific efficacy boundary (i.e. when at least 10 subjects of a combination treatment are 
evaluable) at the first interim look may expand into Part 3 seamlessly, without stopping at the 
second interim look. 
At the second interim look, the combination treatment arm must not cross a specified futility 
boundary (i.e. when at least 25 subjects of a combination treatment are evaluable) defined for 
the RR with respect to the primary composite endpoint.  
The threshold for the first interim look is shown in Table 12-2. 
Table 12-2 
1st interim look (seamless expansion to Part 3) efficacy threshold 
Decision rule 
Action 
P (RR>0.3|D) > 80% 
Preliminary efficacy declared 
According to the first interim threshold, an arm is considered of clinical interest and will be 
advanced to Part 3 expansion if the posterior probability of the RR for the primary composite 
endpoint being greater than 0.3 is more than 80%. This first interim decision rule was 
determined such that arms with outstanding efficacy that warrant further development (i.e. True 
RR > 50%) will be advanced with higher probability, see Section 12.8.1.2 for details. 
Concerning the posterior probability of the RR, let i index the study arm, let pi be the 
corresponding responder rate with respect to the primary endpoint, let ni be the number of 
subjects of arm i, and let ri be the number of responders in arm i. The number of responders ri 
in arm i is modelled by a binomial distribution with parameters ni and pi. With the assumptions 
of a vague prior, beta(1/2, 1/2), the posterior probability distribution of pi is given by 
 
For a given sample size ni, the first interim threshold shown in Table 12-4 can be transformed 
into a number of responders with respect to the primary endpoints for which preliminary 
efficacy would be declared, as shown in Table 12-3. 
Table 12-3 
1st Interim look efficacy regions for a given sample size 
ni 
Region 
9 
≥ 4 
10 
≥ 5 
11 
≥ 5 
12 
≥ 5 
The futility threshold is shown in Table 12-4. 


Novartis 
Confidential 
Page 225 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 12-4 
Futility threshold 
Decision rule 
Action 
P (RR≤0.2|D) > 50% 
Declare combination arm futile 
According to the futility threshold, an arm is dropped for futility if the posterior distribution of 
the RR for the primary composite endpoint is less than or equal to 0.2 with a probability of more 
than 50%. This futility decision rule was determined such that arms with a RR which are not of 
interest for further development, that are RRs of 10% or less, are likely to cross the futility 
threshold and would therefore be dropped at the end of Part 2, see Section 12.8.1.2 for details.  
For a given sample size ni, the futility threshold shown in Table 12-4 can be transformed into a 
number of responders with respect to the primary endpoints for which futility would be declared, 
see Table 12-5. 
Table 12-5 
Futility regions for a given sample size 
ni 
Futility region 
24 
≤ 4 
25 
≤ 4 
26 
≤ 5 
27 
≤ 5 
Due to the discrete nature of the binomial distribution, the futility region does not necessarily 
change in the sample size ni. 
12.4.2.3 Part 3 (Not applicable) 
Part 3 of the study aims to further assess the efficacy of the combination by comparing them to 
ruxolitinib using the FAS.  
The comparison of each combination arm with ruxolitinib will be performed separately based 
on a Bayesian model and include data from both Part 2 and Part 3.  
In detail, let nrux and rrux be the sample size and the number of responders with respect to the 
primary composite endpoint in the ruxolitinib arm, respectively. Analogously, ncomb and rcomb 
denote the sample size and the number of responders in the combination arm to be compared 
with ruxolitinib. The number of responders within each arm is modelled by a binomial 
distribution with RR pi (i = rux, comb). As in Section 12.4.2.2, a vague prior, beta(1/2, 1/2), is 
assumed for pi. This results in the beta-distributed posterior distribution for the RR, 
see Section 12.4.2.2. The study is considered to be successful with respect to the primary 
endpoint when the difference in RRs between combination arm and ruxolitinib arm is greater 
than zero with a probability of greater than or equal to 90%:  
Figure 12-1 
Success criterion for primary endpoint. 
 
In addition to the comparison of the combination arm(s) with the ruxolitinib arm, the efficacy 
of the monotherapy of the agent combined with ruxolitinib will be evaluated in Part 3.  


Novartis 
Confidential 
Page 226 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
12.4.3 
Handling of missing values/censoring/discontinuations 
Subjects with missing assessments of hemoglobin, spleen volume or MF SAF TSS at the end 
of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) that prevent the evaluation of the primary 
endpoint will be considered non-responders to that treatment. Subjects who withdraw from 
treatment before assessment of hemoglobin, spleen volume or MF SAF TSS at the end of Cycle 
8 (NIS793 arms) or Cycle 6 (all other arms) will be considered non-responders to that treatment 
as the primary endpoint cannot be evaluated for these subjects. Further details about visit 
windows considered when defining what constitutes a missing value will be provided in the 
SAP. 
12.4.4 
Sensitivity and Supportive analyses (Not applicable) 
Sensitivity analyses 
As sensitivity analyses, the primary endpoint will be evaluated with different prior distributions 
for the responder rates: 
3. The prior distribution for the responder rate in the combination arm is the same prior as in 
the primary analysis, i.e., a vague prior. The prior distribution for the responder rate in the 
ruxolitinib arm is the robustified MAP prior based on historical data from INCB18424-351 
(Comfort I) and CINC424A2352 (Comfort II). The detailed prior distribution will be 
specified in the SAP. 
4. The prior distribution for the responder rate in the combination arm is obtained by updating 
the vague prior, beta(1/2, 1/2), using the number of responders from Part 1. The prior 
distribution for the responder rate in the ruxolitinib arm is not changed compared to the 
primary analysis. The detailed prior distribution will be specified in the SAP. 
Supportive analyses 
As supportive analyses, the definition of 'responders' will be changed compared to the primary 
endpoint by only considering the hemoglobin and spleen volume measurement. Thus, a subject 
is considered a responder if the following two criteria are fulfilled: 
• Anemia improvement is defined as an increase of hemoglobin from baseline of at least  
1.5 g/dL at the end of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) after randomization. 
Anemia improvement requires absence of any PRBC transfusion in the 12 weeks prior to 
achieving an increase of 1.5 g/dL and a confirmation of Hb increase at least 2 weeks later. 
• No spleen volume progression is given when the spleen volume increase is smaller than 25% 
between baseline and the end of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) measured 
by MRI/CT.  
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy 
 endpoint(s) 
All secondary efficacy endpoint analyses will be analyzed using the Full Analysis Set (FAS). 


Novartis 
Confidential 
Page 227 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
12.5.1.1 Proportion of subjects achieving improvement of hemoglobin level 
(Not applicable) 
Hemoglobin is measured at baseline and at least once per cycle. The change from baseline will 
be summarized by treatment group using descriptive statistics. 
The proportion of subjects achieving improvement in hemoglobin ≥ 1.5 g/dL and ≥ 2.0 g/dL, 
respectively, from baseline to the end of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms), and 
the end of Cycle 16 (NIS793 arms) or Cycle 12 (all other arms) will be estimated with 95% 
confidence intervals (Clopper-Pearson interval). 
12.5.1.2 Change in spleen volume and spleen length  
Spleen volume will be measured by MRI/CT at baseline, the end of Cycle 8 (NIS793 arms) or 
Cycle 6 (all other arms), the end of Cycle 16 (NIS793 arms) or Cycle 12 (all other arms) and at 
EOT (if not performed in the past 12 weeks) as noted in Table 8-6. The change from baseline 
will be summarized at each scheduled assessment time point during the core treatment phase 
using descriptive statistics. 
The proportion of subjects with a spleen volume progression from baseline to the end of Cycle 
8 (NIS793 arms) or Cycle 6 (all other arms) and the end of Cycle 16 (NIS793 arms) or Cycle 
12 (all other arms) during the core treatment phase will be summarized descriptively. A spleen 
progression requires confirmation by MRI or CT showing a spleen volume increase of at least 
25%. 
The proportion of subjects achieving at least 25% and 35% reduction in spleen volume from 
Baseline to the end of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) and the end of Cycle 
16 (NIS793 arms) or Cycle 12 (all other arms) during the core treatment phase as measured by 
MRI or by CT will be summarized descriptively. 
Spleen length measurement will be conducted by manual palpation. Manual palpation will be 
performed on days 1 and 15 of cycles 1 to 3, and day 1 of subsequent cycles, as noted in the 
schedule of assessments in Table 8-3 and Table 8-5. The change from baseline at each planned 
scheduled point during the core treatment phase will be summarized using descriptive statistics. 
The proportion of subjects who achieved at least 50% spleen length reduction at the end of 
Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) from baseline during the core treatment phase 
for subjects with baseline splenomegaly that is palpable at greater than 10 cm, or became not 
palpable for subjects with baseline splenomegaly that is palpable at ≥5-≤10 cm will be estimated. 
The proportion of subjects who achieved at least 50% spleen length reduction at the end of 
Cycle 4 (NIS793 arms) or Cycle 3 (all other arms) from baseline during the core treatment phase 
for subjects with baseline splenomegaly that is palpable at greater than 10 cm, or became not 
palpable for subjects with baseline splenomegaly that is palpable at ≥5-≤10 cm will be estimated. 
The proportion of subjects who achieved at least 50% spleen length reduction at the end of 
Cycle 16 (NIS793 arms) or Cycle 12 (all other arms) from baseline during the core treatment 
phase for subjects with baseline splenomegaly that is palpable at greater than 10 cm, or became 
not palpable for subjects with baseline splenomegaly that is palpable at ≥5-≤10 cm will be 
estimated. 


Novartis 
Confidential 
Page 228 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Spleen volume and spleen length data including change from baseline from both the core and 
extension treatment phases will be reported. 
12.5.1.3 Change in symptoms assessed by MFSAF and EORTC 
Symptoms of myelofibrosis will be measured by MFSAF v4.0 for the core treatment phase of 
the study.  
The change from baseline in MFSAF total symptom score and individual symptoms will be 
summarized with descriptive statistics by cycle and treatment group. The proportion of subjects 
has no worsening in symptom at the end of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) 
and Cycle 16 (NIS793 arms) or Cycle 12 (all other arms) will be summarized. The symptom 
worsening is defined as an increase in TSS of 10 or more from baseline. 
The proportion of subjects who achieved at least 50% reduction in MFSAF v4.0 Total Symptom 
Score (TSS) at the end of Cycle 4 (NIS793 arms) or Cycle 3 (all other arms), at the end of Cycle 
8 (NIS793 arms) or Cycle 6 (all other arms) and at the end of Cycle 16 (NIS793 arms) or Cycle 
12 (all other arms) respectively from baseline will be estimated.  
Due to enrollment halt, EORTC data is not available for Parts 2 and 3 of the study.
 
  
12.5.1.4 Progression free survival (Not applicable) 
PFS is defined as the time from the date of randomization to the date of the first documented 
progressive splenomegaly, or accelerated phase, or deteriorating cytopenia, or leukemic 
transformation or death due to any cause (See Section 8.3.2.4). 
PFS will be analyzed in the FAS population according to the randomized treatment group 
assigned at randomization. The PFS distribution will be estimated using the Kaplan-Meier 
method, and the Kaplan-Meier curves, medians and 95% confidence intervals of the medians 
will be presented for each treatment group. The hazard ratio for PFS comparing a combination 
treatment with ruxolitinib single agent will be calculated, along with its 95% confidence interval, 
using a Cox model. 
PFS will be censored if no PFS event is observed before the cut-off date or the date when a new 
anti-neoplastic therapy or another investigational treatment is started, whichever occurs earlier. 
The censoring date will be the date of last adequate assessment before either of these two dates. 
12.5.1.5 Proportion of subjects achieving improvement in bone marrow 
fibrosis (Not applicable) 
The grade of bone marrow fibrosis will be measured at baseline, the end of Cycle 8 (NIS793 
arms) or Cycle 6 (all other arms), and every subsequent six cycles per Table 8-7. The grade of 
bone marrow fibrosis will be summarized descriptively for each scheduled point by treatment 
group. The proportion of patients achieving improvement in bone marrow fibrosis of ≥ 1 grade 
from baseline to the end of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms), and the end of 
Cycle 16 (NIS793 arms) or Cycle 12 (all other arms) will be summarized.  


Novartis 
Confidential 
Page 229 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
12.5.2 Safety endpoints 
For all safety analyses, the safety set will be used, except for summaries of DLTs, for which the 
DDS will be used in addition to the safety set. All listings and tables will be presented by 
treatment group. Safety summaries (tables, figures) include only data from the on-treatment 
period with the exception of baseline data which will also be summarized where 
appropriate (e.g. change from baseline summaries). In addition, a separate summary for death 
including on treatment and post treatment deaths will be provided. In particular, summary tables 
for adverse events (AEs) will summarize only on-treatment events, with a start date during the 
on-treatment period (treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of subject’s informed consent to the day before first dose 
of study treatment. 
2. On-treatment period: from date of first dose of study treatment to 30 days after the date 
of the last administration of study treatment. 
3. On-extension treatment period: from day of first dose of extension treatment to 
30 days after the date of the last administration of study treatment. 
4. Post-treatment period: starting at 31 days after the date of the last administration of study 
treatment. 
In addition, the overall safety period is defined from date of first administration of study 
treatment to 30 days after the date of the last administration of ruxolitinib, siremadlin or 
rineterkib, 90 days after the date of the last administration of NIS793, or 105 days after the date 
of the last administration of crizanlizumab, or 150 days after the date of the last actual 
administration of sabatolimab, whichever is later. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group for all subjects 
on Safety Set. Summary tables for adverse events (AEs) will include only AEs that started or 
worsened during the on-treatment period. The number (and percentage) of subjects with 
treatment emergent AEs will be summarized by primary system organ class, preferred term and 
maximum severity (based on CTCAE grades). Separate summaries will be provided for study 
medication related adverse events, deaths, serious adverse events, other significant adverse 
events leading to discontinuation and adverse events leading to dose adjustment. 
In addition, all AEs and SAEs which started during the overall safety period will be summarized. 
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
All AEs, deaths and serious adverse events (including those from the pre, on-extension 
treatment period and post-treatment periods) will be listed and those started during the pre-
treatment period, post-treatment period, and post-treatment/overall safety overlapping period 
will be flagged. 


Novartis 
Confidential 
Page 230 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Vital signs 
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment group for core treatment phase.  
12-lead ECG 
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment group for core treatment phase. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time for core treatment phase. Shift tables using the low/normal/high/ (low and high) 
classification will be used to compare baseline to the worst on-treatment value for core 
treatment phase. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
5. Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades if applicable and the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE v5.0: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value 
For laboratory tests where grades are not defined by CTCAE v5.0: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value. 
 
 


Novartis 
Confidential 
Page 231 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
12.5.3 Pharmacokinetics 
Pharmacokinetic parameters will be derived from the individual concentration versus time 
profile using a non-compartmental method as implemented in Phoenix WinNonlin (Pharsight, 
Mountain View, CA). The pharmacokinetic parameters described in Table 12-6 will be 
determined for each investigational drug, as deemed appropriate. Additional PK parameters 
may be estimated as needed.  
Table 12-6 
Non compartmental pharmacokinetic parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (Tlast) 
AUCinf 
The AUC from time zero extrapolated to infinity 
AUC0-t 
The AUC from zero to specified time points (amount x time x volume-1) for example 12, 24, 336 
or 504h 
Cmax 
The maximum (peak) observed plasma drug concentration 
Tlast 
Time at which the last measurable concentration was observed (time) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (Lambda_z) of a semi logarithmic 
concentration-time curve 
CL (CL/F) 
The total body clearance (or apparent clearance) of drug from the plasma or serum 
Vz (Vz/F) 
The volume (or apparent volume) of distribution during terminal phase (associated with 
Lambda_z) 
AR 
Accumulation Ratio = AUC0-t (multiple Dose)/AUC0-t (single dose) 
The PAS will be used in all pharmacokinetic data analysis and summary statistics Section 8.5.2. 
Descriptive statistics of PK parameters for ruxolitinib, siremadlin, crizanlizumab, sabatolimab 
and rineterkib will be listed by treatment arm for PAS. Due to enrollment halt, PK parameters 
for NIS793 will be listed. Descriptive statistics will include arithmetic and geometric mean, 
median, SD, and coefficient of variance (CV), geometric CV, minimum and maximum. Zero 
concentrations will not be included in the geometric mean calculation. Since Tmax is generally 
evaluated by a nonparametric method, median values and ranges will be given for this parameter. 
The parameters that require terminal phase determination (AUCinf, T1/2, CL or CL/F and Vz 
or Vz/F) may not be adequately calculated by non-compartmental methods. All individual PK 
parameters will be listed using FAS. In Part 1, siremadlin PK data will be listed and summarized 
by dose level. 
Plasma concentration data for ruxolitinib, siremadlin, crizanlizumab, sabatolimab, rineterkib 
and NIS793 will be listed by treatment arm for FAS. Descriptive summary statistics will be 
provided by treatment arm at each scheduled time point for PAS. Summary statistics will 
include n (number of subjects with non-missing values), mean (arithmetic and geometric), SD, 
CV% (arithmetic and geometric), median, minimum and maximum. Individual profiles with 
median by treatment as well as arithmetic mean with SD and geometric mean plasma 
concentration versus time profiles by treatment will be displayed graphically. Further graphical 
exploratory analyses will be carried out if deemed appropriate 


Novartis 
Confidential 
Page 232 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
12.5.3.1 Data handling principles 
The subjects in the PAS will be used in the pharmacokinetic data analysis and PK summary 
statistics. 
Bio-fluid concentrations will be expressed in mass per volume units. All Plasma concentration 
values below the limit of quantification (LLOQ) will be set to zero by the Bioanalyst, and will 
be displayed as zero in the listings and flagged. LLOQ values will be treated as zero in any 
calculations of summary statistics, and treated as missing for the calculation of the geometric 
means and their coefficient of variation (CV%). Any missing PK parameter or concentration 
will not be imputed. 
12.5.3.2 Immunogenicity (only applicable to ruxolitinib combination arms with 
crizanlizumab, sabatolimab or NIS793) (Not applicable) 
The presence and titer of anti-crizanlizumab, anti-sabatolimab antibodies, or anti-NIS793 (IG) 
will be listed by subject and summarized (when sample size is sufficient) using descriptive 
statistics to assess IG following one or more intravenous infusions of crizanlizumab, 
sabatolimab or NIS793. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 233 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 234 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 235 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
12.7 
Interim analyses (Not applicable) 
No interim analysis is planned for Part 1. For the combination of ruxolitinib and siremadlin and 
ruxolitinib plus rineterkib, a BLRM will be used to assist assigning subjects to treatment dose 
levels, and to guide dose escalation decisions. 
As the enrollment was permanently halted, the Part 2 has been prematurely discontinued with 
one randomized patient, and Part 3 will not be initiated, therefore the descriptions below for 
Parts 2 and 3 are not applicable. 


Novartis 
Confidential 
Page 236 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
In Part 2, two interim analyses are planned for each combination treatment arm. The first interim 
analysis will be conducted after at least 10 subjects of each combination treatment arm in Part 
2 have completed Cycle 8 (arms with NIS793) or Cycle 6 (all other arms) or discontinued earlier. 
An arm that crosses the threshold for the first interim look and is considered safe, will be 
advanced to Part 3 seamlessly after enrollment of the arm in Part 2 (approximately 25 subjects) 
is completed, without stopping for the second interim look. The second interim analysis is 
planned after at least 25 subjects in each randomized arm have completed Cycle 8 (arms with 
NIS793) or Cycle 6 (all other arms) or discontinued earlier. As described in Section 3, in the 
second interim analysis, futile arms are dropped and not considered further for Part 3. The 
second interim analysis is not required if a combination treatment is advanced in Part 3 based 
on the first interim analysis. In Part 2, the criterion for the first interim look and the futility 
criterion are evaluated for each combination treatment arm based on the primary endpoint 
(Section 12.4.2.2) and no formal comparison between combination treatment arms and 
ruxolitinib will be performed.  
In Part 3, no formal interim analysis is planned for this part of the trial. The first primary analysis 
will be performed once the first expanded Part 3 arms (combination treatment arm, compound 
monotherapy arm (ruxolitinib cessation arm), and monotherapy arm) have fully enrolled and 
have completed Cycle 8 (arms with NIS793) or Cycle 6 (all other arms) or discontinued earlier. 
Comparison of the primary endpoint between combination treatment arm(s) and ruxolitinib will 
be performed at the primary analysis with respect to the success criterion described in  
Section 12.4.2.3. 
If the planned analyses are very close in time, multiple analyses will be performed at the same 
time to ensure timely operational feasibility for executing analyses and actions. 
12.8 
Sample size calculation 
12.8.1 Primary endpoint(s) 
12.8.1.1 Part 1 
No formal statistical power calculations were performed to determine sample size for this part 
of the study. 
Cohorts of 3 to 6 evaluable subjects will be enrolled in the dose escalation part including at 
least six subjects at the RP2D, as described in Section 6.5. Multiple cohorts may be sequentially 
enrolled to the same dose level. Additional cohorts of 1 to 6 subjects may be enrolled at any 
dose level below the estimated MTD for further elaboration of safety and pharmacokinetic 
parameters as required. At least 12 subjects are expected to be treated in the dose escalation 
part, for the model to have reasonable operating characteristics relating to its RP2D 
recommendation. 
12.8.1.2 Part 2 
The primary objective of Part 2 is to evaluate the preliminary efficacy of the combination 
treatments as outlined in Section 12.4.2.2. No formal hypothesis testing will be performed. 
While the totality of the data will be considered when deciding whether an arm will advance to 


Novartis 
Confidential 
Page 237 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Part 3, the decision whether an arm showing preliminarily efficacy or is futile will be based on 
the posterior probability distribution for the responder rate within each arm.  
Based on historical data from the COMFORT I and II studies, a primary endpoint RR of less 
than 10% is expected for the ruxolitinib single agent arm. A treatment with a true RR of 
• less than 10% generally does not warrant further investigation,  
• around 20% is potentially interesting,  
• more than 30% is of interest.  
Therefore, the criterion for the first interim look is defined as  
𝑃𝑃(𝑝𝑝i > 0.3|𝑛𝑛i, 𝑟𝑟i) > 0.8 
For a sample size of ni = 10 with a vague prior distribution, beta(1/2, 1/2), for the RR, an arm 
will be considered showing preliminary efficacy and advanced into Part 3 expansion seamlessly 
if ≥ 5 subjects are responders. Table 12-7 lists related operating characteristics for various true 
RRs. 
Table 12-7 
Probability of any arm to meet 1st interim look criterion for n = 10 and 
various true RRs 
True RR  
Single arm  
Two arms 
Four arms 
0.35 
0.2485 
0.4352 
0.6811 
0.4 
0.3669 
0.5992 
0.8393 
0.45 
0.4956 
0.7456 
0.9353 
0.5 
0.6230 
0.8579 
0.9798 
0.55 
0.7384 
0.9316 
0.9953 
0.6 
0.8338 
0.9724 
0.9992 
The table indicates that with the planned sample size of ni = 10, an arm with outstanding 
efficacy, i.e. a true RR of 0.5 or higher, has more than 60% probability to meet the criterion for 
the first interim look. If 2 arms each with true RR of 0.4, the probability of either arm meeting 
the criterion is close to 60%.  
The futility decision will be guided by the criterion 
 
For a sample size of ni = 25 with a vague prior distribution, beta(1/2, 1/2), for the RR, an arm 
fulfills the futility criterion if ≤ 4 subjects are responders. Table 12-8 lists futility related 
operating characteristics for various true RRs. 


Novartis 
Confidential 
Page 238 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 12-8 
Probability of arm(s) to fulfill futility criterion for n = 25 and various 
true RRs 
True RR 
Probability of declaring 
futility for a single arm  
Total probability of 
declaring futility for both 
arms when there are two 
arms in Part 2 
Total probability of 
declaring futility for all 4 
arms 
0.05 
0.9928 
0.9857 
0.9716 
0.1 
0.9020 
0.8136 
0.6620 
0.15 
0.6821 
0.4653 
0.2165 
0.2 
0.4207 
0.1770 
0.0313 
0.25 
0.2137 
0.0457 
0.0021 
0.3 
0.0905 
0.0082 
0.0001 
The table shows that with the planned sample size of ni = 25, an arm with low activity, i.e. a 
true RR of 0.1 or smaller, will fulfill the futility criterion with a probability of larger than 90%. 
For potentially interesting true RRs of pi = 0.2, there is an approximately 40% chance that the 
arm fulfills the futility criterion. For arms with a true RR of more than 30%, the probability to 
fulfill the futility criterion is less than 10%. If two combination arms are advanced in Part 2 and 
both arms have low activity, i.e. the true RR of 0.1 or smaller, the overall probability that both 
arms are considered futile is larger than 80%. If four combination arms are advanced in Part 2 
and all four arms have low activity, i.e. the true RR of 0.1 or smaller, the overall probability 
that all four arms are considered futile is approximately 66% or higher.  
12.8.1.3 Part 3 
Combination treatments not stopped for futility or safety after Part 2 will be considered for 
expansion into Part 3. After Part 3, each combination treatment will be compared to the 
ruxolitinib monotherapy arm by evaluating whether the difference in the posterior distributions 
of the RRs for the primary endpoint is larger than zero with a probability of 90%, i.e. 
  
To determine the posterior distributions, data from both Part 2 and Part 3 is considered. In the 
following, the sample size considerations for the efficacy evaluation of one combination arm 
(combo) is illustrated. Table 12-9, Table 12-10 and Table 12-11 show the probability of possible 
outcomes for various true RRs in the ruxolitinib monotherapy arm (rux) for ncombo = 45 and nrux 
= 30, 35 and 40 respectively, at the primary analysis (PA). Calculations assume the interim 
analysis (IA) is conducted with 25 subjects The four possible outcomes are based on the futility 
at interim analysis (Yes/No) and the treatment meet the success criterion at primary analysis 
(Yes/No). The first interim look boundary is in line with the second interim look boundary in 
respect of the require number of responders. In the first interim look, the arm can be expanded, 
when there are 5 or more responders out of 10 subjects. Similarly, the arm can be expanded 


Novartis 
Confidential 
Page 239 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
when there are 5 or more responders out of 25 subjects because the arm is not futile. In  
Table 12-9, assuming a true RR of 0.1 for ruxolitinib monotherapy, and a true RR of 0.35 for 
combination treatment, the probability that the primary analysis is successful when the interim 
is not futile, is 0.8933. 
Table 12-9 
Probability for each possible trial outcome of a combination treatment 
with N combo=45 and N rux=30  
True RR for 
ruxolitinib 
monotherapy 
True RR for 
combination 
treatment 
IA Not Futile 
PA Fail 
IA Not Futile  
PA Success 
IA Futile  
PA Fail 
IA Futile  
PA Success 
0.05 
0.05 
0.0037 
0.0035 
0.9036 
0.0893 
0.15 
0.0678 
0.2501 
0.3800 
0.3021 
0.2 
0.0692 
0.5101 
0.1659 
0.2547 
0.25 
0.0467 
0.7396 
0.0568 
0.1570 
0.3 
0.0233 
0.8863 
0.0155 
0.0750 
0.1 
0.1 
0.0686 
0.0294 
0.8342 
0.0678 
0.2 
0.2328 
0.3466 
0.3025 
0.1182 
0.25 
0.2080 
0.5783 
0.1278 
0.0860 
0.3 
0.1400 
0.7695 
0.0435 
0.0470 
0.35 
0.0746 
0.8933 
0.0120 
0.0201 
0.15 
0.15 
0.2533 
0.0646 
0.6454 
0.0367 
0.25 
0.4143 
0.3719 
0.1759 
0.0379 
0.3 
0.3375 
0.5720 
0.0670 
0.0235 
0.35 
0.2214 
0.7465 
0.0208 
0.0112 
0.4 
0.1196 
0.8709 
0.0053 
0.0042 
0.2 
0.2 
0.4935 
0.0858 
0.4060 
0.0146 
0.3 
0.5442 
0.3654 
0.0808 
0.0097 
0.35 
0.4176 
0.5504 
0.0269 
0.0052 
0.4 
0.2709 
0.7196 
0.0073 
0.0021 
0.45 
0.1505 
0.8472 
0.0016 
0.0007  
Notes: IA = Interim Analysis; PA = Primary Analysis 
Table 12-10 
Probability for each possible trial outcome of a combination treatment 
with N combo=45 and N rux=35  
True RR for 
ruxolitinib 
monotherapy 
True RR for 
combination 
treatment 
IA Not Futile 
PA Fail 
IA Not Futile  
PA Success 
IA Futile  
PA Fail 
IA Futile  
PA Success 
0.05 
0.05 
0.0031 
0.0041 
0.9076 
0.0853 
0.15 
0.0576 
0.2603 
0.3446 
0.3375 
0.2 
0.0580 
0.5214 
0.1455 
0.2752 
0.25 
0.0375 
0.7487 
0.0489 
0.1648 
0.3 
0.0173 
0.8922 
0.0132 
0.0773 
0.1 
0.1 
0.0672 
0.0308 
0.8284 
0.0736 
0.2 
0.2227 
0.3566 
0.2969 
0.1238 
0.25 
0.1890 
0.5972 
0.1251 
0.0886 


Novartis 
Confidential 
Page 240 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
0.3 
0.1174 
0.7921 
0.0421 
0.0483 
0.35 
0.0567 
0.9113 
0.0113 
0.0207 
0.15 
0.15 
0.2548 
0.0631 
0.6465 
0.0356 
0.25 
0.3955 
0.3908 
0.1768 
0.0369 
0.3 
0.3053 
0.6042 
0.0669 
0.0235 
0.35 
0.1883 
0.7796 
0.0205 
0.0116 
0.4 
0.0955 
0.8951 
0.0050 
0.0044 
0.2 
0.2 
0.4935 
0.0858 
0.4081 
0.0125 
0.3 
0.5190 
0.3905 
0.0811 
0.0093 
0.35 
0.3852 
0.5827 
0.0268 
0.0052 
0.4 
0.2403 
0.7502 
0.0072 
0.0023 
0.45 
0.1266 
0.8711 
0.0016 
0.0008 
Table 12-11 
Probability for each possible trial outcome of a combination treatment 
with N combo=45 and N rux=40  
True RR for 
ruxolitinib 
monotherapy 
True RR for 
combination 
treatment 
IA Not Futile 
PA Fail 
IA Not Futile  
PA Success 
IA Futile  
PA Fail 
IA Futile  
PA Success 
0.05 
0.05 
0.0027 
0.0044 
0.8851 
0.1077 
0.15 
0.0429 
0.2750 
0.3260 
0.3561 
0.2 
0.0386 
0.5407 
0.1281 
0.2925 
0.25 
0.0225 
0.7637 
0.0395 
0.1743 
0.3 
0.0096 
0.9000 
0.0097 
0.0808 
0.1 
0.1 
0.0631 
0.0349 
0.8277 
0.0743 
0.2 
0.1871 
0.3923 
0.2812 
0.1395 
0.25 
0.1522 
0.6341 
0.1134 
0.1003 
0.3 
0.0914 
0.8182 
0.0365 
0.0540 
0.35 
0.0425 
0.9254 
0.0094 
0.0226 
0.15 
0.15 
0.2447 
0.0732 
0.6434 
0.0387 
0.25 
0.3653 
0.4209 
0.1709 
0.0428 
0.3 
0.2760 
0.6335 
0.0636 
0.0268 
0.35 
0.1648 
0.8032 
0.0192 
0.0129 
0.4 
0.0796 
0.9109 
0.0047 
0.0048 
0.2 
0.2 
0.4860 
0.0933 
0.4066 
0.0141 
0.3 
0.5006 
0.4089 
0.0802 
0.0103 
0.35 
0.3626 
0.6054 
0.0264 
0.0057 
0.4 
0.2177 
0.7729 
0.0071 
0.0024 
0.45 
0.1085 
0.8892 
0.0015 
0.0008 
When the true RRs in the ruxolitinib monotherapy arm and the combination arm shown in  
Table 12-9, Table 12-10 and Table 12-11 are identical, the probabilities in the ‘IA Not Futile 
PA Success’ column can be considered to be the Bayesian equivalent to the type I error rate, 
i.e., the probability to wrongfully consider an inefficacious treatment as efficacious. This 
probability is smaller than 10% for all proposed sample sizes (ruxolitinib monotherapy sample 
size = 30, 35, 40), depending on the treatment arm and group. When the true RRs for the 


Novartis 
Confidential 
Page 241 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
ruxolitinib monotherapy arm is smaller than the combination arm, the probabilities in the ‘IA 
Not Futile PA Success’ column can be considered to be the Bayesian equivalent to the power. 
For a difference in RRs of 20%, the power is approximately 75% or higher for the considered 
ruxolitinib RRs for all proposed sample sizes. 
Next, the probability that the difference between the posterior distributions of the RRs is 
calculated for several potential trial outcomes and it is illustrated for which outcomes the trial 
would be considered successful with respect to the primary endpoint. The outcomes are shown 
in Table 12-12 for ncombo = 45 and nrux = 30, 35, and 40 respectively. The scenarios in which the 
trial would be considered successful are highlighted in bold. 
Finally, Section 16.7 (Appendix 7) shows the simulated probabilities for a list of operating 
characteristic parameters under three hypothetical Part 2 and Part 3 study scenarios. 
Table 12-12 
Probability that the difference in the posterior distributions of the RRs 
is larger than zero 
  
Number of responders in ruxolitinib monotherapy arm nrux = 30 
3 (10.0%) 
5 (16.7%) 
7 (23.3%) 
9 (30.0%) 
11 (36.7%) 
Number of 
responders in 
combination 
treatment arm 
ncombo = 45  
5(11.1%) 
0.5519 
0.2420 
0.0797 
0.0206 
0.0042 
7(15.6%) 
0.7519 
0.4432 
0.1978 
0.0683 
0.0186 
9(20.0%) 
0.8777 
0.6368 
0.3617 
0.1602 
0.0557 
11(24.4%) 
0.9456 
0.7881 
0.5399 
0.2953 
0.1277 
13(28.9%) 
0.9780 
0.8888 
0.7004 
0.4560 
0.2389 
15(33.3%) 
0.9919 
0.9473 
0.8239 
0.6167 
0.3816 
17(37.8%) 
0.9973 
0.9774 
0.9066 
0.7549 
0.5371 
19(42.2%) 
0.9992 
0.9913 
0.9554 
0.8583 
0.6837 
21(46.7%) 
0.9998 
0.9970 
0.9809 
0.9263 
0.8042 
23(51.1%) 
0.9999 
0.9990 
0.9927 
0.9658 
0.8911 
25(55.6%) 
1.0000 
0.9997 
0.9975 
0.9859 
0.9461 
27(60.0%) 
1.0000 
0.9999 
0.9993 
0.9949 
0.9765 
 
Number of responders in ruxolitinib monotherapy arm nrux = 35 
3 (8.6%) 
5 (14.3%) 
7 (20.0%) 
9 (25.7%) 
11 (31.4%) 
Number of 
responders in 
combination 
treatment arm  
ncombo = 45  
5(11.1%) 
0.6408 
0.3327 
0.1349 
0.0443 
0.0120 
7(15.6%) 
0.8247 
0.5586 
0.3004 
0.1301 
0.0461 
9(20.0%) 
0.9247 
0.7456 
0.4971 
0.2709 
0.1210 
11(24.4%) 
0.9710 
0.8706 
0.6794 
0.4462 
0.2433 
13(28.9%) 
0.9899 
0.9415 
0.8184 
0.6219 
0.4015 
15(33.3%) 
0.9968 
0.9763 
0.9083 
0.7688 
0.5701 
17(37.8%) 
0.9991 
0.9914 
0.9587 
0.8737 
0.7217 
19(42.2%) 
0.9998 
0.9972 
0.9835 
0.9386 
0.8387 
21(46.7%) 
0.9999 
0.9992 
0.9941 
0.9735 
0.9167 
23(51.1%) 
1.0000 
0.9998 
0.9981 
0.9899 
0.9620 
25(55.6%) 
1.0000 
1.0000 
0.9995 
0.9966 
0.9848 
27(60.0%) 
1.0000 
1.0000 
0.9999 
0.9990 
0.9947 
 
Number of responders in ruxolitinib monotherapy arm nrux = 40 
3 (7.5%) 
5 (12.5%) 
7 (17.5%) 
9 (22.5%) 
11 (27.5%) 


Novartis 
Confidential 
Page 242 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Number of 
responders in 
combination 
treatment arm  
ncombo = 45  
5(11.1%) 
0.7124 
0.4200 
0.1994 
0.0786 
0.0263 
7(15.6%) 
0.8756 
0.6546 
0.4036 
0.2068 
0.0892 
9(20.0%) 
0.9531 
0.8235 
0.6141 
0.3884 
0.2079 
11(24.4%) 
0.9842 
0.9213 
0.7822 
0.5823 
0.3735 
13(28.9%) 
0.9952 
0.9691 
0.8922 
0.7482 
0.5555 
15(33.3%) 
0.9987 
0.9892 
0.9530 
0.8661 
0.7192 
17(37.8%) 
0.9997 
0.9966 
0.9819 
0.9372 
0.8428 
19(42.2%) 
0.9999 
0.9991 
0.9938 
0.9740 
0.9223 
21(46.7%) 
1.0000 
0.9998 
0.9981 
0.9906 
0.9662 
23(51.1%) 
1.0000 
1.0000 
0.9995 
0.9970 
0.9872 
25(55.6%) 
1.0000 
1.0000 
0.9999 
0.9992 
0.9958 
27(60.0%) 
1.0000 
1.0000 
1.0000 
0.9998 
0.9988 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Council on Harmonisation (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written ICF, consent form updates, subject recruitment procedures (e.g. advertisements) and 
any other written information to be provided to subjects. 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 Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform Novartis immediately that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.)  
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


Novartis 
Confidential 
Page 243 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
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 and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
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 prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. In addition, as the result of enrollment halt, a number of 
preplanned study objectives will not be pursued, the investigators were instructed not to 
continue to perform some of the study procedures to reduce the burden on ongoing patients. 
The assessments or visits not performed in the core treatment phase because of the permanent 
enrollment halt prior to implementation of the amended protocol version 08 will be summarized 
in the clinical study report. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject 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. 


Novartis 
Confidential 
Page 244 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
15 
References 
References are available upon request 
Aaronson N. et Al (1993) The European Organization for Research and Treatment of Cancer 
QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical Trials in Oncology 
journal of National Cancer Institute, Vol. 85, No. 5 Marche 3. 1993 p. 365-76. 
Abdel-Wahab OI, Levine RL (2009) Primary myelofibrosis: update on definition, pathogenesis, 
and treatment. Annu. Rev. Med. p. 233-45. 
 
 
Akaike H (1974) A new look at the statistical model identification. Selected Papers of Hirotugu 
Akaike. Springer, New York, NY, p. 716-23. 
Akhurst RJ, Hata A (2012) Targeting the TGFβ signalling pathway in disease. Nat Rev Drug 
Discov. p.790–812. 
Anderson AC, Anderson DE, Bregoli L, et al (2007) Promotion of tissue inflammation by the 
immune receptor Tim-3 expressed on innate immune cells. Science p. 1141-3. 
Arber DA, Orazi A, Hasserjian R, et al (2016) The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia. Blood p. 2391-405. 
Asayama T, Tamura H, Ishibashi M, et al (2017) Functional expression of Tim-3 on blasts and 
clinical impact of its ligand galectin-9 in myelodysplastic syndromes. Oncotarget p. 88904-
88917. 
Ataga KI, Kutlar A, Kanter J, et al (2017) Crizanlizumab for the Prevention of Pain Crises in 
Sickle Cell Disease. N. Engl. J. Med. p. 429-39. 
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation with 
overdose control. Stat Med p. 1103-20. 
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 p. 
437-38. 
Berry SM, Connor JT, Lewis RJ (2015) The Platform Trial: An efficient strategy for evaluating 
multiple treatments. JAMA p. 1619-20. 
Brahmer JR, Lacchetti C, Schneider BJ, et al (2018) Management of Immune-Related Adverse 
Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of 
Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. p. 1714-68. 
 


Novartis 
Confidential 
Page 245 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Bullock AN, Fersht AR (2001) Rescuing the function of mutant p53. Nat. Rev. Cancer p. 68-
76. 
Cairo MS, Bishop M (2004) Tumour lysis syndrome: new therapeutic strategies and 
classification. Br. J. Haematol. p. 3-11. 
Capdevila J, Cervantes A and Tabernero J (2012) New players in cancer therapeutics: focus on 
inhibitors of MDM2-p53 protein-protein interaction. Drugs of the Future p. 273-81. 
Centurione L, Di Baldassarre A, Zingariello M, et al (2004) Increased and pathologic 
emperipolesis of neutrophils within megakaryocytes associated with marrow fibrosis in GATA-
1(low) mice. Blood p. 3573-80. 
Cervantes F (2014) How I treat myelofibrosis. Blood p. 2635-42. 
Cervantes F, Correa JG, Hernandez-Boluda JC (2016) Alleviating anemia and 
thrombocytopenia in myelofibrosis patients. Expert Rev Hematol p. 489-96. 
 
 
Chiba S, Baghdadi M, Akiba H, et al (2012) Tumor-infiltrating DCs suppress nucleic acid-
mediated innate immune responses through interactions between the receptor TIM-3 and the 
alarmin HMGB1. Nat. Immunol. p. 832-42. 
de Mingo Pulido Á, Gardner A, Hiebler S, et al (2018) TIM-3 Regulates CD103+ Dendritic 
Cell Function and Response to Chemotherapy in Breast Cancer. Cancer Cell p. 60-74. 
Dempster AP, Laird NM, Rubin DB (1977) Maximum likelihood from incomplete data via the 
EM algorithm. Journal of the Royal Statistical Society, Series B p. 39(1):1-38. 
Derynck R, Akhurst RJ (2007) Differentiation plasticity regulated by TGF-β family proteins in 
development and disease. Nature Cell Biol. p. 1000–1004. 
Dueck A, Scherber R, Kosiorek H, et al (2017) Determining Meaningful Change in the 
Myelofibrosis Symptom Assessment Form (MFSAF) V2.0 using a Combination of 
Distribution- and Anchor-based Approaches in the COMFORT-I Trial. Madrid 22nd congress 
(June 22 -25, 2017). 
Eischen CM, Lozano G (2009) p53 and MDM2: antagonists or partners in crime? Cancer Cell 
p. 161-62. 
 
 
Frenette PS, Denis CV, Weiss L, et al (2000) P-Selectin glycoprotein ligand 1 (PSGL-1) is 
expressed on platelets and can mediate platelet-endothelial interactions in vivo. J. Exp. Med. p. 
1413-22. 
Gao X, Zhu Y, Li G, et al (2012) TIM-3 expression characterizes regulatory T cells in tumor 
tissues and is associated with lung cancer progression. PLoS ONE p. e30676. 


Novartis 
Confidential 
Page 246 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Girish S, Martin SW, Peterson MC, et al (2011) AAPS workshop report: strategies to address 
therapeutic protein-drug interactions during clinical development. AAPS J p. 405-16. 
 
 
 
 
Guy A, Gourdou-Latyszenok V, Le Lay N, et al (2019) Vascular endothelial cell expression of 
JAK2V617F is sufficient to promote a pro-thrombotic state due to increased P-selectin 
expression. Haematologica p. 70-81. 
Gwaltney C, Paty J, Kwitkowski VE, et al (2017) Development of a harmonized patient-
reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials. Leuk. Res. 
p. 26-31. 
Haanen J, Carbonnel F, Robert C, Kerr K, Peters S, Larkin J, Jordan K on behalf of the ESMO 
Guidelines Committee (2017) Management of toxicities from immunotherapy: ESMO clinical 
practive guidelines for diagnosis, treatment and follow-up. Annals of Oncology p. 119-142. 
Huang SM, Zhao H, Lee JI, et al (2010) Therapeutic protein-drug interactions and implications 
for drug development. Clin. Pharmacol. Ther. p. 497-503. 
Jan M, Chao MP, Cha AC, et al (2011) Prospective separation of normal and leukemic stem 
cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell 
marker. Proc. Natl. Acad. Sci. U.S.A. p. 5009-14. 
 
 
 
 
 
  
Joerger AC, Fersht AR (2008) Structural biology of the tumor suppressor p53. Annu. Rev. 
Biochem. p. 557-82. 
Kikushige Y, Miyamoto T, Yuda J, et al (2015) A TIM-3/Gal-9 Autocrine Stimulatory Loop 
Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression. Cell 
Stem Cell p. 341-52. 
Kikushige Y, Shima T, Takayanagi S, et al (2010) TIM-3 is a promising target to selectively 
kill acute myeloid leukemia stem cells. Cell Stem Cell p. 708-17. 
 
 


Novartis 
Confidential 
Page 247 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Lee JI, Zhang L, Men AY, et al (2010) CYP-mediated therapeutic protein-drug interactions: 
clinical findings, proposed mechanisms and regulatory implications. Clin Pharmacokinet p. 
295-10. 
Levine AJ, Oren M (2009) The first 30 years of p53: growing ever more complex. Nat. Rev. 
Cancer p. 749-58. 
Martins CP, Brown-Swigart L, Evan GI (2006) Modeling the therapeutic efficacy of p53 
restoration in tumors. Cell p. 1323-34. 
 
Mascarenhas J, Lu M, Kosiorek H, Virtgaym E, Xia L, Sandy L, Mesa R, Petersen B, Farnoud 
N, Najfeld V, Rampal R, Dueck A, Hoffman R (2019) Oral idasanutlin in patients with 
polycythemia vera. Blood p. 525-533. 
Mead AJ, Milojkovic D, Knapper S, et al (2015) Response to ruxolitinib in patients with 
intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. 
Br. J. Haematol. p. 29-39. 
Mehta J, Wang H, Iqbal SU, et al (2014) Epidemiology of myeloproliferative neoplasms in the 
United States. Leuk. Lymphoma p. 595-600. 
 
 
 
 
  
Mesa RA, Niblack J, Wadleigh M, et al (2007) The burden of fatigue and quality of life in 
myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD 
patients. Cancer p. 68-76. 
Millard M, Pathania D, Grande F, et al (2011) Small-molecule inhibitors of p53-MDM2 
interaction: the 2006-2010 update. Curr. Pharm. Des. p. 536-59. 
Naymagon, L; Mascarenhas, J (2017) Myelofibrosis-Related Anemia. Current and Emerging 
Therapeutic Strategies. HemaSphere p. 1. 
NCCN guidelines for specific populations available from: https: www nccn 
org/professionals/physician gls/defaults aspx#immunotherapy (Accessed 20 August 2020). 
Ndhlovu LC, Lopez-Vergès S, Barbour JD, et al (2012) Tim-3 marks human natural killer cell 
maturation and suppresses cell-mediated cytotoxicity. Blood p. 3734-43. 
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med p. 2420-39. 
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials p. 5-18. 


Novartis 
Confidential 
Page 248 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Neuenschwander B, Matano A, Tang Z, et al (2014) A Bayesian Industry Approach to Phase I 
Combination Trials in Oncology. Statistical Methods in Drug Combination Studies p. 96 - 135. 
 
 
 
 
 
Renfro LA, Mandrekar SJ (2018) Definitions and statistical properties of master protocols for 
personalized medicine in oncology. J Biopharm Stat p. 217-28. 
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 p. 45-52. 
Roth JA (2006) Adenovirus p53 gene therapy. Expert Opin. Biol. Ther., p. 55–61. 
Saha MN, Qiu L, Chang H (2013) Targeting p53 by small molecules in hematological 
malignancies. J Hematol Oncol p. 23. 
 
 
Saville BR, Berry SM (2016) Efficiencies of platform clinical trials: A vision of the future. Clin 
Trials p. 358-66. 
Schmitt A, Drouin A, Masse JM, Guichard J, Shagraoui H, Cramer E (2002) 
Polymorphonuclear neutrophil and megakaryocyte mutual involvement in myelofibrosis 
pathogenesis . Leuk Lymphoma p. 719-724. 
Schmitt A, Jouault H, Guichard J, et al (2000) Pathologic interaction between megakaryocytes 
and polymorphonuclear leukocytes in myelofibrosis. Blood p. 1342-47. 
Shin DS, Ribas A (2015) The evolution of checkpoint blockade as a cancer therapy: what's here, 
what's next? Curr. Opin. Immunol. p. 23-35. 
Shivdasani RA, Fujiwara Y, McDevitt MA, et al (1997) A lineage-selective knockout 
establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and 
platelet development. EMBO J. p. 3965-73. 
 
 
Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation. Vol. 13. John Wiley & Sons. 
 
 


Novartis 
Confidential 
Page 249 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
Tefferi A, Barbui T (2019) Polycythemia vera and essential thrombocythemia: 2019 update on 
diagnosis, risk-stratification and management. Am. J. Hematol. p. 133-43. 
Tefferi A, Cervantes F, Mesa R, et al (2013) Revised response criteria for myelofibrosis: 
International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-
MRT) and European LeukemiaNet (ELN) consensus report. Blood p. 1395-8. 
Tefferi A, Vardiman JW (2008) Classification and diagnosis of myeloproliferative neoplasms: 
the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 
p. 14-22. 
Thiele J, Lorenzen J, Manich B, et al (1997) Apoptosis (programmed cell death) in idiopathic 
(primary) osteo-/myelofibrosis: naked nuclei in megakaryopoiesis reveal features of para-
apoptosis. Acta Haematol. p. 137-43. 
Valentino L, Pierre J (2006) JAK/STAT signal transduction: regulators and implication in 
hematological malignancies. Biochem. Pharmacol. p. 713-21. 
Van Maerken T, Vandesompele J, Rihani A, et al (2009) Escape from p53-mediated tumor 
surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis. Cell Death Differ. 
p. 1563-72. 
Vannucchi AM, Bianchi L, Cellai C, et al (2002) Development of myelofibrosis in mice 
genetically impaired for GATA-1 expression (GATA-1(low) mice). Blood p. 1123-32. 
Vannucchi AM, Pancrazzi A, Guglielmelli P, et al (2005) Abnormalities of GATA-1 in 
megakaryocytes from patients with idiopathic myelofibrosis. Am. J. Pathol. p. 849-58. 
Vannucchi AM , Bianchi L , Paoletti F , et al. (2005) A pathobiologic pathway linking 
thrombopoietin, GATA-1, and TGF-beta1 in the development of myelofibrosis . Blood p. 
3493-3501. 
Vassilev LT (2007) MDM2 inhibitors for cancer therapy. Trends Mol. Med. p. 23–31. 
 
 
 
Ventura A, Kirsch DG, McLaughlin ME, et al (2007) Restoration of p53 function leads to 
tumour regression in vivo. Nature p. 661-5. 
Ventz S, Alexander BM, Parmigiani G, et al (2017) Designing Clinical Trials That Accept New 
Arms: An Example in Metastatic Breast Cancer. J. Clin. Oncol. p. 3160-68. 
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. p. 1117-27. 
Verstovsek S, Talpaz M, Ritchie E, et al (2017) A phase I, open-label, dose-escalation, 
multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis. Leukemia p. 
393-02. 


Novartis 
Confidential 
Page 250 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature p. 307-10. 
Vogelstein B, Sur S, Prives C (2010) p53: the most frequently altered gene in human cancers. 
Nature Education p. 6. 
Vyas P, Ault K, Jackson CW, et al (1999) Consequences of GATA-1 deficiency in 
megakaryocytes and platelets. Blood p. 2867-75. 
Walton K, Johnson K, Harrison C (2017) Targeting TGF-β Mediated SMAD Signaling for the 
Prevention of Fibrosis. Front Pharmacol p. 1-11. 
Wang JC , Chang TH , Goldberg A , et al (2006) Quantitative analysis of growth factor 
production in the mechanism of fibrosis in agnogenic myeloid metaplasia. Exp. Hematol. p. 
1617-1623. 
Woodcock J, LaVange LM (2017) Master Protocols to Study Multiple Therapies, Multiple 
Diseases, or Both. N. Engl. J. Med. p. 62-70. 
 
 
Xiao G, Chicas A, Olivier M, et al (2000) A DNA damage signal is required for p53 to activate 
gadd45. Cancer Res. p. 1711-9. 
Yan J, Zhang Y, Zhang JP, et al (2013) Tim-3 expression defines regulatory T cells in human 
tumors. PLoS ONE p. e58006. 
Yang ZZ, Grote DM, Ziesmer SC, et al (2012) IL-12 upregulates TIM-3 expression and induces 
T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J. Clin. Invest. p. 
1271-82. 
Zhang Y, Ma CJ, Wang JM, et al (2011) Tim-3 negatively regulates IL-12 expression by 
monocytes in HCV infection. PLoS ONE p. e19664. 
Zhang Y, Ma CJ, Wang JM, et al (2012) Tim-3 regulates pro- and anti-inflammatory cytokine 
expression in human CD14+ monocytes. J. Leukoc. Biol. p. 189-96. 
Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes 
p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 
p. 725-34. 
Zhou Q, Munger ME, Veenstra RG, et al (2011) Coexpression of Tim-3 and PD-1 identifies a 
CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. 
Blood p. 4501-10. 
 
 


Novartis 
Confidential 
Page 251 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
16 
Appendices 
16.1 
Appendix 1: Medications to be used with caution 
Refer to Section 6.2.1.1 and in Table 16-1 below for guidance on cautionary use. For study 
treatment with siremadlin please refer to Section 6.2.1.1.1 for guidance on 'time window' to be 
applied. 
Table 16-1 
List of medications to be used with caution during study drug treatment 
Mechanism of Interaction 
Drug Names 
Sensitive substrates of CYP3A 
(for patients on siremadlin or 
rineterkib) 
abemaciclib, ABT-384, acalabrutinib, alisporivir, almorexant, aplaviroc, 
asunaprevir, avapritinib, AZD1305, BIRL 355, blonanserin, brecanavir, 
capravirine, eliglustat (in subjects CYP2D6 PM), entrectinib, L-771,688, 
terfenadine, 
ubrogepant, 
vilaprisan, 
zanubrutinib 
alpha-
dihydroergocryptine, 
atorvastatin, 
avanafil, 
bosutinib, 
brotizolam, 
budesonide, buspirone, cobimetinib, danoprevir, darifenacin, dasatinib, 
ebastine, eletriptan, elvitegravir, eplerenone, everolimus, felodipine, 
fluticasone, grazoprevir, ibrutinib, ivabradine, ivacaftor, levomethadyl 
(LAAM), lomitapide, lovastatin, lumefantrine, lurasidone, maraviroc, 
midazolam, midostaurin, naloxegol, neratinib, nisoldipine, paritaprevir, 
perospirone, quetiapine, ridaforolimus, saquinavir, sildenafil, simeprevir, 
simvastatin, ticagrelor, tilidine, tipranavir, tolvaptan, triazolam, ulipristal, 
vardenafil, venetoclax, vicriviroc, voclosporin 
Substrates of OATP1B1 
(for patients on siremadlin) 
aliskiren, ambrisentan, anacetrapib, atenolol, asunaprevir, atorvastatin, 
bromocriptine, caspofungin, celiprolol, danoprevir, digoxin, docetaxel, 
eliglustat, 
empangliflozin, 
ezetimibe, 
fimasartan, 
fexofenadine, 
fluvastatin, glyburide, maraviroc, methotrexate, rosuvastatin, saquinavir, 
simvastatin, paclitaxel, pirataprevir, pitavastatin, pravastatin, repaglinide, 
rosuvastatin, 
simvastatin, 
valsartan, 
olmesartan, 
montelukast, 
ticlopidine, thyroxine 
Substrates of MATE 1 
(for patients on siremadlin) 
acyclovir, ganciclovir, pindolol, pilsicainide, procainamide, ranitidine, 
topotecan, varenicline, Metformin, procainamide, glycopyrronium, 
cephalexin, cephadrine, fexofenadine, tetraethylammonium 
Inhibitors of P-gp 
(for patients on siremadlin) 
asian ginseng (Panax ginseng), asunaprevir, AZD5672, diosmin, five-
flavor berry (Schisandra chinensis), flibanserin, glecaprevir/pibrentasvir, 
ivacaftor, maribavir, milk thistle (silymarin, silibinin)a, neratinib, 
osimertinib, pexidartinib, piperine, rifampin, rucaparib, sarecycline, 
sofosbuvir / velpatasvir / voxilaprevir, surfactant TPGS, tezacaftor / 
ivacaftor, valbenazine, vemurafenib, verapamil, zanubrutinib, alogliptin, 
amiodarone, azithromycin, canaglifozin, captopril, carvedilol, clopidrogel, 
cremophor EL and RH40, curcumin, daclatasvir, eliglustat, felodipine, 
fluvoxamine, fostamatinib, ginkgo (Ginkgo biloba)a, green teaa, ivacaftor, 
lapatinib, milk thistle (silymarin, silibinin)a, mirabegron, nifedipine, 
nitrendipine, paroxetine, propafenone, quercetin, quinine, ranolazine, 
rolapitant, saquinavir , simeprevir, survorexant, talinolol, telmisartan, 
ticagrelor, tipranavir, tolvaptan, valspodar, vandetanib, velpatasvir, 
voclosporin, vorapaxar 
Moderate inhibitors of CYP2C9 
ataciguat, tienilic acid, oxandrolone, AZD1981, piperine, nitisinone, 
amiodarone, milk thistle (Silybum marianum)a, phenylbutazone, 
azapropazone, bucolome, benzbromarone 
Moderate inducers of CYP2C9 
refer to footnote b 
Moderate inhibitors of CYP2C8 
(for patients on rineterkib) 
deferasirox, letermovir, teriflunomide 
Moderate inducers of CYP2C8 
(for patients on rineterkib) 
hormonal contraceptives, rifampin 


Novartis 
Confidential 
Page 252 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Mechanism of Interaction 
Drug Names 
Proton pump inhibitors (PPIs) 
(for patients on rineterkib) 
omeprazole, lansoprazole, dexlansoprazole, esomeprazole, 
pantoprazol, rabeprazole 
Drugs which modify gastric pH 
(for patients on rineterkib) 
dAntacids (e.g. TUMS®, Maalox®), ecimetidine, efamotidine, enizatidine, 
eranitidine 
Drugs with known Torsade de 
Pointes riskc 
(for patients on rineterkib) 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US market), 
azithromycin, bepridil (off US market), chloroquine, chlorpromazine, 
cilostazol, ciprofloxacin, cisapride (off US market), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone (not on 
US 
market), 
donepezil, 
dronedarone, 
droperidol, 
erythromycin, 
escitalopram, flecainide, fluconazole, gatifloxacin (removed from 
market), grepafloxacin (off market worldwide), halofantrine, haloperidol, 
ibogaine 
(only 
on 
non 
US 
market), 
ibutilide, 
levofloxacin, 
levomepromazine (only on non US market), levomethadyl (off US 
market), levosulpiride (only on non US market), mesoridazine (off US 
market), methadone, moxifloxacin, ondansetron, oxaliplatin, papaverine 
HCl (intra-coronary), pentamidine, pimozide, probucol (off US market), 
procainamide (oral off US market), propofol, quinidine, roxithromycin 
(only on non US market), sevoflurane, sotalol, sparfloxacin (off US 
market), sultopride (only on non US market), sulpiride (not on US 
market), terfenadine (off US market), terlipressin (only on non US 
market), terodiline (only on non US market), thioridazine, vandetanib. 
a Herbal product 
b Moderate inducers of CYP2C9 (reported as of April 2019 database search of University of Washington’s Drug 
Interaction Database (druginteractioninfo.org)) listed as rifampin, enzalutamide, ritonavir and carbamazepine, 
are all excluded based on exclusion criteria as specified in Section 6.2.2 and Appendix 2, Table 16-2. Source: 
The list is adapted from the Novartis PK Sciences internal memorandum (v1, January, 2018): drug-drug 
interactions (DDI) database, which is compiled primarily from the Indiana University School of Medicine’s 
“Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s Drug 
Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”  
Note: Any drug mentioned in the above list should be contraindicated if they are excluded based on any other 
exclusion criteria as specified in Section 6.2.2 of the Study Protocol. 
CYP: cytochrome P-450; OATP: organic-anion-transporting polypeptide 
c Arizona Center for Education and Research on Therapeutics (CERT), Drugs that prolong the QT interval 
and/or induce Torsade de Pointes (wwwqtdrugs.org) 
d Rineterkib should be administered at least 1 hour before or 2 hours after an antacid 
e Rineterkib should be administered at least 3 hours before or 6 hours after an H2 receptor antagonist 
16.2 
Appendix 2: Prohibited medications 
In general, the use of any concomitant medication deemed necessary for the care of the subject 
is permitted in this study, except as specifically prohibited in Section 6.2.2 and in  
Table 16-2 below. Refer to Section 6.2.2 for guidance on restrictions (including time window) 
to be applied during study drug treatment. 
Table 16-2 
List of prohibited medications during study drug treatment 
Mechanism of Interaction 
Drug Names 
Narrow therapeutic index 
substrates of CYP3A5 
(for patients on siremadlin) 
alfentanil, 
astemizole, 
cisapride, 
cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus 
Strong inhibitors of CYP3A 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)4, 
indinavir/ritonavir4, tipranavir/ritonavir4, ritonavir, cobicistat, indinavir, 
ketoconazole, troleandomycin, telaprevir, danoprevir/ritonavir4, 
elvitegravir/ritonavir4, saquinavir/ritonavir4, lopinavir/ritonavir4, 


Novartis 
Confidential 
Page 253 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Mechanism of Interaction 
Drug Names 
itraconazole, voriconazole, mibefradil, clarithromycin, posaconazole, 
telithromycin, grapefruit juice3, conivaptan, nefazodone, nelfinavir, 
idelalisib, boceprevir, atazanavir/ritonavir4, darunavir/ritonavir4, ceritinib, 
LCL161, mifepristone, ribociclib, saquinavir 
Moderate inhibitors of CYP3A 
(for patients on combination: 
siremadlin+ruxolitinib) 
aprepitant, amprenavir, atazanavir, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, faldaprevir, 
fluconazole, grapefruit juice3, imatinib, isavuconazole, netupitant, nilotinib, 
tofisopam, Schisandra sphenanthera (nan wu wei zi)1, asafoetida resin 
(Ferula 
asafoetida)1, 
verapamil, 
duvelisib, 
fedratinib, 
letermovir, 
GSK2647544, lefamulin, casopitant, ravuconazole, istradefylline, ACT-
178882, voxelotor, FK1706 
Strong inducers of CYP3A 
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampicin, mitotane, St. John’s wort (Hypericum perforatum)1, 
avasimibe, rifapentine, apalutamide, ivosidenib 
Moderate inducers of CYP3A 
(for patients on siremadlin) 
bosentan, dabrafenib, efavirenz, etravirine, genistein2, modafinil, nafcillin, 
tipranavir/ritonavir, lopinavir, telotristat, thioridazine, 
semagacestat, 
cenobamate, lesinurad, rifabutin, lorlatinib, talviraline, daclatasvir and 
asunaprevir and beclabuvir, PF-06282999, elagolix, lersivirine 
Strong inhibitors of CYP2C9 
tasisulam, sulfaphenazole, miconazole 
Strong inducers of CYP2C9  
None reported6 
Strong inhibitors of CYP2C8 
(for patients on rineterkib) 
gemfibrozil, clopidogrel 
Strong inducers of CYP2C8 
(for patients on rineterkib) 
None reported6 
1 Herbal product 
2 Food product 
3 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g. low dose, single strength). 
4 Combination ritonavir-boosted regimens are listed here in the DDI memo as strong CYP3A inhibitors (to avoid 
potential confusion), even though some are considered moderate CYP3A inhibitors in the University of 
Washington’s Drug Interaction Database. 
5 Drugs whose exposure-response indicates that increases in their exposure levels by the concomitant use of 
potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes) 
6 No drugs under this category have been reported as of June 2020 database search of University of 
Washington’s Drug Interaction Database (druginteractioninfo.org). 
 
Source: The list is adapted from the Novartis PK Sciences internal memorandum (v1, January, 2018): drug-
drug interactions (DDI) database, which is compiled primarily from the Indiana University School of Medicine’s 
“Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s Drug 
Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”. 
These lists are not comprehensive and are only meant to be used as a guide. Please contact the medical 
monitor with any questions. If a medication appears on both the list of prohibited and the list of medications to 
be used with caution, the medication is prohibited. 


Novartis 
Confidential 
Page 254 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
16.3 
Appendix 3: MFSAF v4.0 PRO 
 


Novartis 
Confidential 
Page 255 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
16.4 
Appendix 4: EORTC QLQ-C30 PRO 


Novartis 
Confidential 
Page 256 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 


Novartis 
Confidential 
Page 257 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
 
 
16.6 
Appendix 6: Statistical considerations for dose-escalation 
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data, the results of the Bayesian analyses and respective dosing decisions for some 
hypothetical data scenarios, and a simulation study of the operating characteristics of the model. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16.6.2 
Statistical model 
Let π(d) be the risk of DLT for the combination of ruxolitinib given at dose combination agent 
(siremadlin or rineterkib) dose d, the dose-DLT model is logistic: 
Figure 16-1 
Logistic DLT model. 
 


Novartis 
Confidential 
Page 258 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
where d* is used to scale the doses. Hence, α>0 is the odds of a DLT at d*; and β>0 is the 
increase in the log-odds of a DLT by a unit increase in log-dose. 
16.6.3 
Prior specifications for logistic parameters 
The Bayesian approach requires the specification of prior distributions for the model parameters 
log(α) and log(β). A meta-analytic-predictive (MAP) approach was used to derive the prior 
distribution for these model parameters.  
16.6.3.1 Description of the meta-analytic-predictive (MAP) approach 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
(log(α*), log(β*)) of the new trial using DLT data from historical studies. 
Let rds and nds be the number of patients with a DLT, and the total number of patients at dose d in 
historical trial s (s = 1,...,S). The corresponding probability of a DLT is πds. The model 
specifications for the derivation of the MAP prior are as follows: 
 
Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution. This is implemented using JAGS version 4.2.0. The sample from this 
distribution is then approximated by a mixture of bivariate normal (BVN) distributions. BVN 
mixtures with increasing numbers of mixture components are fitted to the sample using the 
expectation-maximization (EM) algorithm (Dempster et al 1977). The optimal number of 
components of the mixture is then identified using the Akaike information criterion (AIC) 
(Akaike H 1974). 


Novartis 
Confidential 
Page 259 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
16.6.3.2 Single-agent siremadlin 
For the MAP model for siremadlin, reference dose d* = 50 mg is used, and data from one 
historical study with four regimens is available, so S = 4 is chosen. 
Weakly informative normal priors are assumed for μ1 and μ2, with means corresponding to a 
risk of DLT at the reference dose of 1/3, and a doubling in dose leading to a doubling in the 
odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such that (1) their 
medians correspond to substantial between trial heterogeneity, and (2) their uncertainty (95% 
prior interval) cover plausible between-trial standard deviations (Neuenschwander et al 2014).  
The prior distributions for the model used for deriving the MAP priors are specified in  
Table 16-3. 
Table 16-3 
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent model parameters 
Parameter 
Prior Distribution 
μ1 
N (mean = logit (1/3), sd = 2) 
μ2 
N (mean = 0, sd = 1) 
t1 
log-normal (mean = log (0.5), sd = log (2)/1.96) 
t2 
log-normal (mean = log (0.25), sd = log (2)/1.96) 
ρ 
uniform (-1,1) 
Historical data from study CHDM201X2101 
The prior is determined based on solid tumor data from study CHDM201X2101. 
In this study, four different regimens and dose-schedules where studied: 
• 1A: dose on day 1 of a three week cycle 
• 1B: dose on day 1 and on day 8 of a four week cycle 
• 2A: once dose daily for the first two weeks of a four week cycle 
• 2C: once daily dosing for the first week of a four week cycle 
The doses in the difference regimens are scaled to fit the schedule of siremadlin in the 
combination study, which is once daily for the first five days in a four-week cycle. 
In study CHDM201X2101, the original interest was in DLTs in cycle 1, however after 
observing cumulative toxicity DLTs within the first two cycles were considered for the 
recommended dose for expansion (document release date 28-Oct-2016). As the ruxolitinib 
combination study focuses on DLTs occurring in the first two cycles, the corresponding DLTs 
from the study CHDM201X2101 were considered. When building the MAP prior distribution 
for siremadlin, the different regimens from study CHDM201X2101 were considered as 
different studies. 


Novartis 
Confidential 
Page 260 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 16-4 
Regimens and doses from study CHDM201X2101 
Regimen 
Dose level 
Dose per 
cycle 
Dose per 
day in 5 
day 
schedule 
N 
DLTs 
(Cycle 1) 
HEM DLTs 
(Cycle 2) 
DLTs 
considered 
for MAP 
1A 
12.5 
12.5 
2.5 
1 
0 
0 
0 
25 
25 
5.0 
1 
0 
0 
0 
50 
50 
10.0 
4 
0 
1 
1 
100 
100 
20.0 
4 
0 
0 
0 
200 
200 
40.0 
5 
0 
1 
1 
250 
250 
50.0 
6 
0 
1 
1 
350 
350 
70.0 
5 
2 
2 
4 
1B 
120 
240 
48.0 
9 
0 
2 
2 
150 
300 
60.0 
8 
1 
1 
2 
200 
400 
80.0 
3 
0 
Data n/a at 
cutoff 
0 
2A 
1 
14 
2.8 
1 
0 
0 
0 
2 
28 
5.6 
2 
0 
0 
0 
4 
56 
11.2 
4 
0 
0 
0 
7.5 
105 
21.0 
4 
0 
0 
0 
15 
210 
42.0 
4 
0 
1 
1 
20 
280 
56.0 
5 
0 
4 
4 
2C 
15 
105 
21.0 
8 
0 
1 
1 
20 
140 
28.0 
6 
0 
0 
0 
25 
175 
35.0 
5 
2 
0 
2 
Summary of prior distributions for siremadlin 
To obtain the MAP prior for (log(α), log(β)), the predictive distribution obtained from data 
in Table 16-4 will be mixed with a vague prior assuming a weight of 0.5. This mixing takes into 
account the fact the that patient population from study CHDM201X2101 and this combination 
study are not identical and that in this combination study a single-agent model is used to account 
for both the effect of siremadlin and potential interaction with ruxolitinib. 
The MAP prior for (log(α), log(β)) is a mixture of three multivariate normal distributions and 
it is summarized in Table 16-5. 
Table 16-5 
Prior distribution for the siremadlin model parameters 
Prior for (log(α), log(β)) in the single agent DLT-model for the combination of siremadlin and ruxolitinib 
  
Mean 
Standard 
Deviations 
Correlation 
Weight 
MAP component 1 
(-0.771 ,0.492) 
(0.700, 0.435) 
0.221 
0.3255 
MAP component 2 
(-0.884, 0.051) 
(0.573, 0.643) 
0.237 
0.1745 
MAP component 3 
(logit(1/3), 0) 
(2, 1) 
0 
0.5 
Prior summaries for DLT rates for are summarized in Table 16-6. 


Novartis 
Confidential 
Page 261 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 16-6 
Summary of prior distribution of DLT rates for the combination of 
siremadlin and ruxolitinib 
Siremadlin 
Dose (mg) 
Prior Probabilities that P(DLT) is in 
the interval: 
Mean 
SD 
Quantiles 
(0, 0.16) 
(0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
10 
0.7982 
0.0967 
0.1051 
0.1191 
0.1895 
0.0001 
0.0443 
0.7679 
20 
0.6526 
0.1932 
0.1542 
0.1793 
0.2103 
0.0011 
0.1046 
0.8384 
30 
0.4687 
0.3077 
0.2235 
0.2392 
0.2217 
0.0050 
0.1713 
0.8792 
40 
0.3035 
0.3630 
0.3335 
0.2996 
0.2297 
0.0110 
0.2425 
0.9087 
16.6.3.3 Single-agent rineterkib 
For the MAP model for rineterkib, reference dose 𝑑𝑑∗= 300 mg is used, and data from 𝑆𝑆= 1 
historical studies (First in Human study) is available. 
Weakly informative normal priors are assumed for μ1 and μ2, with means corresponding to a 
10% risk of DLT at the reference dose of 300 mg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such that (1) their 
medians correspond to substantial between trial heterogeneity, and (2) their uncertainty (95% 
prior interval) cover plausible between-trial standard deviations (Neuenschwander et al 2014).  
The prior distributions for the model used for deriving the MAP priors are specified in  
Table 16-7. 
Table 16-7 
Prior distributions for the parameters of the MAP model used to derive 
the prior for the rineterkib model parameters 
Parameter 
Prior Distribution 
μ1 
N (mean = logit (0.1), sd = 2) 
μ2 
N (mean = 0, sd = 1) 
t1 
log-normal (mean = log (0.5), sd = log (2)/1.96) 
t2 
log-normal (mean = log (0.25), sd = log (2)/1.96) 
ρ 
uniform (-1,1) 
Historical data from Study LTT462X2101 
The dose-DLT data from rineterkib single agent from study LTT462X2101 are considered as 
the relevant information (Table 16-8) and used to derive the prior distribution for the BLRM 
parameters (log(α), log(β)). The clinical study LTT462X2101 is a phase I dose finding study of 
oral rineterkib in adult patients with advanced solid tumors harboring MAPK pathway 
alterations. 
The DLT observation window in the Phase I dose escalation part of this trial was 4 weeks. A 
review of AE records of the patients did not indicate any significant additional toxicity in the 
2nd cycle of treatment, suggesting data from the 1 cycle DLT evaluation period of study 
LTT462X2101 is also informative for a 2 cycle DLT evaluation period. 


Novartis 
Confidential 
Page 262 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 16-8 
Historical DLT data from Study LTT462X2101 
Dose (mg, daily/QD) 
Number of patients 
Number of DLTs 
45 
2 
0 
100 
3 
0 
150 
6 
1 
200 
4 
1 
300 
7 
0 
400 
4 
0 
450 
7 
2 
600 
3 
3 
Summary of prior distributions for rineterkib 
To obtain the MAP prior for (log(α), log(β)), the predictive distribution obtained from data 
in Table 16-9 will be mixed with a vague prior assuming a weight of 0.5. This mixing takes into 
account the fact the that patient population from study LTT462X2101 and this combination 
study are not identical and that in this combination study a single-agent model is used to account 
for both the effect of rineterkib and potential interaction with ruxolitinib. 
The MAP prior for (log(α), log(β)) is a mixture of four multivariate normal distributions and it 
is summarized in Table 16-9. 
Table 16-9 
Prior distribution for the model parameters 
Prior for (log(α), log(β)) in the single agent DLT-model for the combination of siremadlin and ruxolitinib 
  
Mean 
Standard 
Deviations 
Correlation 
Weight 
MAP component 1 
(-1.737, 0.330) 
(1.135, 0.685) 
-0.089 
0.190 
MAP component 2 
(-1.518, 0.571) 
(0.648, 0.478) 
-0.289 
0.163 
MAP component 3 
(-1.491, -0.211) 
( 0.764, 0.868) 
-0.018 
0.147 
MAP component 4 
(logit(1/4), 0) 
(2, 1) 
0 
0.5 
Prior summaries for DLT rates for are summarized in Table 16-10. 
Table 16-10 
Summary of prior distribution of DLT rates for the combination of 
rineterkib and ruxolitinib 
Rineterkib 
Dose (mg) 
Prior Probabilities that P(DLT) is in 
the interval: 
Mean 
SD 
Quantiles 
(0, 0.16) 
(0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
100 
0.7673 
0.1171 
0.1155 
0.1273 
0.1905 
0.0002 
0.0492 
0.7552 
200 
0.6126 
0.1989 
0.1885 
0.1966 
0.2183 
0.0040 
0.1142 
0.8444 
300 
0.4217 
0.2923 
0.2860 
0.2705 
0.2378 
0.0114 
0.1934 
0.8999 
16.6.4 
Hypothetical on-study data scenarios 
To illustrate the performance of the Bayesian model used to guide dose escalation, hypothetical 
dose escalations scenarios following the provisional dose levels specified in Section 6.5.1 are 
displayed. In each case, the maximum dose that can be used in the next cohort of subjects is 
shown. This recommended Phase 2 dose is determined using the model-based assessment of 


Novartis 
Confidential 
Page 263 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
the risk of DLT in future subjects and the dose escalation rules as described in Section 6.5.1. In 
practice, a dose below the maximum might be chosen based on additional safety, PK or PD 
information (Section 6.5). 
16.6.4.1 Scenarios for siremadlin 
The first three hypothetical dose escalation scenarios in Table 16-11 are for the case that the 
first cohort contains six subjects being administered a combination treatment with a siremadlin 
dose of 20 mg. Scenarios 4, 5, 6 and 7 are for the second cohort and the case that the first cohort 
contains six subjects receiving 20 mg siremadlin and two subjects having DLTs. Scenarios 8 
and 9 demonstrate if enrolling 2 and 3 subjects in Arm 1, the first 2 subjects experience a DLT, 
then further enrollment into Arm 1 will stop and the combination treatment will not open in  
Part 2.  
Table 16-11 
Hypothetical dose escalation scenarios for a cohort size of n=6 
subjects receiving a dose of 20 mg siremadlin 
Scenario 
Siremadlin 
Dose [mg] 
Number of 
Possible next dose levels 
patients 
DLTs 
Dose [mg] 
Median P(DLT) 
P(excessive 
toxicity) 
1 
20 
6 
0 
40 
0.162 
0.122 
2 
20 
6 
1 
30 
0.192 
0.148 
3 
20 
6 
2 
20 
0.206 
0.219 
4 
20 
6 
2 
 
 
 
 
20 
3 
0 
30 
0.233 
0.222 
5 
20 
6 
2 
 
 
 
 
20 
4 
0 
30 
0.221 
0.183 
6 
20 
6 
2 
 
 
 
 
20 
5 
0 
30 
0.212 
0.159 
7 
20 
6 
2 
 
 
 
 
20 
3 
1 
20 
0.233 
0.247 
8 
20 
2 
2 
10* 
0.554 
0.696 
9 
20 
3 
2 
10* 
0.275 
0.435 
*The possible next dose level is not available, as the probability of excessive toxicity of the lower dose does not 
satisfy EWOC criteria. The combination treatment will not open in Part 2. 
16.6.4.2 Scenarios for rineterkib 
The first three hypothetical dose escalation scenarios in Table 16-12 are for the case that the 
first cohort contains six subjects being administered a combination treatment with a rineterkib 
dose of 200 mg. Scenarios 4, 5, 6 and 7 are for the second cohort and the case that the first 
cohort contains six subjects receiving 200 mg rineterkib and different number of subjects having 
DLTs. Scenarios 8 and 9 demonstrate if enrolling 2 and 3 subjects in the rineterkib Arm (Arm 
4), the first 2 subjects experience a DLT, then further enrollment into the rineterkib Arm will 
stop and the combination treatment will not open in Part 2.  


Novartis 
Confidential 
Page 264 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 16-12 
Hypothetical dose escalation scenarios for a cohort size of n=6 
subjects receiving a dose of 200 mg rineterkib 
Scenario 
RineterkibDose 
[mg] 
Number of 
Possible next dose levels 
patients 
DLTs 
Dose [mg] 
Median P(DLT) 
P(excessive 
toxicity) 
1 
200 
6 
0 
300 
0.108 
0.064 
2 
200 
6 
1 
300 
0.203 
0.204 
3 
200 
6 
2 
100 
0.119 
0.100 
4 
200 
6 
0 
 
 
 
 
300 
6 
2 
300 
0.192 
0.124 
5 
200 
6 
1 
 
 
 
 
300 
6 
1 
300 
0.186 
0.099 
6 
200 
6 
1 
 
 
 
 
300 
6 
2 
200 
0.160 
0.070 
7 
200 
6 
2 
 
 
 
 
100 
3 
0 
200 
0.188 
0.157 
8 
200 
2 
2 
100* 
0.493 
0.656 
9 
200 
3 
2 
100* 
0.268 
0.418 
*The possible next dose level is not available, as the probability of excessive toxicity of the lower dose does not 
satisfy EWOC criteria. The combination treatment will not open in Part 2. 
16.7 
Appendix 7: Simulation for hypothetical Part 2 and Part 3 study 
scenarios (Not applicable)  
The simulation assumed three groups for Part 2 and Part 3 of the study. Group 1 included 
Combination 1, Combination 2 and Ruxolitinib monotherapy; Group 2 included Combination 
3, Combination 4 and Ruxolitinib monotherapy; Group 3 included Combination 5 and 
Ruxolitinib monotherapy. The three groups are assumed to be enrolled in a sequential manner 
within Part 2 and Part 3. Three scenarios are simulated with the true RR for each treatment arm 
shown in Table 16-13. The probabilities for a list of operating characteristic parameters for the 
three hypothetical scenarios are presented in Table 16-14. 
Table 16-13 
Hypothetical true RR for each treatment arm 
Scenarios 
True RR 
RUX 
COMB1 
COMB2 
COMB3 
COMB4 
COMB5 
Scenario1 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
Scenario2 
0.05 
0.3 
0.05 
0.05 
0.05 
0.05 
Scenario3 
0.05 
0.05 
0.2 
0.3 
0.05 
0.25 


Novartis 
Confidential 
Page 265 of 267 
Amended Protocol Version No 09 (Clean) 
 
Protocol No. CINC424H12201 
 
 
Table 16-14 
Probabilities for a list of operating characteristic parameters for 
hypothetical scenarios of the study 
Scenarios  
Probabilities 
All combo arms 
are futile 
All combo arms are 
futile at IA or not 
success at PA 
Any combo arm(s) is 
not futile at IA and 
success at PA 
Any combo arm(s) 
with true RR>0.2 is 
not futile at IA and 
success at PA 
Scenario1 
0.9651 
0.9800 
0.0200 
0.0000 
Scenario2 
0.0894 
0.1145 
0.8855 
0.8841 
Scenario3 
0.0100 
0.0177 
0.9823 
0.9713 
Scenario 1 assumed all treatment arms have equal true RR and do not warrant further 
development (RR=0.05). The column ‘All combo arms are futile at IA or not success at PA’ in 
Table 16-14 shows the probability to reject all inefficacious treatments at interim or primary 
analysis. Scenario 2 assumed one combination treatment in Group 1 has a true RR of interest 
(i.e. RR>0.2). Scenario 3 assumed one combination treatment in each Group has true RR of 
interest (i.e. RR>0.2). The column ‘Any combo arm(s) with true RR>0.2 is not futile at IA and 
success at PA’ shows the probability to select any combination arm or arms that are of interest 
for the study. 


Novartis 
Confidential 
Page 266 of 267 
Amended Protocol Version No 09 (Clean)  
 
Protocol No. CINC424H12201 
 
 
16.8 
Appendix 8: Hypothetical example to illustrate Part 2 and Part 3 study design (Not applicable)  
A hypothetical example below in Figure 16-2 aims to illustrate the randomization parts of the study design. Part 1 is not included in the 
diagram. The number of groups and the combination treatment arm(s) within each group are hypothetical. A ruxolitinib monotherapy arm is 
open in group 1 and remains open as additional groups start enrollment. In Figure 16-2, the results of the primary endpoint, i.e. Response Rate 
(RR), are assumed to illustrate possible actions at the 1st interim look and 2nd interim look. 
Figure 16-2 
Hypothetical example for Part 2 and Part 3 study design 
 
 


Novartis 
Confidential 
Page 267 of 267 
Amended Protocol Version No 09 (Clean)  
 
Protocol No. CINC424H12201 
 
 
a. Group 1: Part 2 randomization started with Combo 1 (combination treatment 1) and RUX mono (ruxolitinib monotherapy control). Combo 
1 meets criteria at 2nd interim analysis to expand enrollment to this arm in Part 3.  
b. The 1st Interim look will take place when the first 10 subjects of a combination treatment arm have completed 24 weeks of treatment. In 
the case of outstanding efficacy, the combination treatment arm may expand for seamless enrollment to Part 3. e.g. Outstanding efficacy 
boundary ≥5 responders out of 10 subjects (RR≥5/10). 
c. The 2nd Interim look will take place when the first 25 subjects of a combination treatment arm have completed 24 weeks of treatment. In 
the case of futility, further enrollment in the arm will be dropped from Part 3, e.g. Futility boundary ≤4 responders/25 subjects (RR≤4/25). 
Otherwise, further enrollment in the arm will be expanded in Part 3.  
d. The final look (Primary Analysis) for each arm will take place when 45 subjects have completed 24 weeks of treatment.  
e. Group 2: Combo 2 started randomization with other open arms after Part 1 safety evaluation. Combo 2 seamlessly expanded to Part 3 
based on results of the 1st interim analysis (RR=5/10). 
f. Group 3: Combo 3, Combo 4, and Combo 5 started randomization with other open arms after Part 1 safety evaluation. Combo 3 and 
Combo 4 completed Part 2 and declared futile at the 2nd interim analysis and not expand in Part 3 (RR=4/25 and RR=3/25, respectively). 
Combo 5 expanded to Part 3 after the 2nd interim analysis (RR=6/25). 
If the planned analyses are very close in time, multiple analyses will be performed at the same time to ensure timely operational feasibility 
for executing analyses and actions. 
Notes:  
The figure is not drawn for scale 
Combo/Combo Tx = combination treatment 
RUX mono = ruxolitinib monotherapy treatment 
Sub = subject(s) 
 

SAP_001.pdf: 
Clinical Development 
INC424 
CINC424H12201 / NCT04097821 
A randomized, open-label, phase I/II open platform study 
evaluating safety and efficacy of novel ruxolitinib 
combinations in myelofibrosis patients 
Statistical Analysis Plan (SAP) – Amendment 2 
Author: 
Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Final v2.0 
Release date: 
2-Jul-2024
Number of pages: 
71 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
SAP 
 
CINC424H12201 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason 
for update 
Outcome for update 
Section and title 
impacted 
(Current) 
12-
Mar-
2020 
In line with 
Protocol 
Amendment
#2 
Creation of 
final version 
N/A - First version 
NA 
30-
Nov-
2022 
In line with 
Protocol 
Amendment
#8 
Updated 
according to 
PA#8 and 
reflected the 
main 
changes 
made by PA 
#3 to 7 
Provided the background of the SAP 
amendment in the introduction section. 
Updated study design and, objectives and 
endpoints according to PA#8. 
Specified the timepoints and data included 
in the primary and final CSRs. 
Introduced extension treatment phase 
related concepts, including the date of first 
administration of extension treatment and 
on-extension treatment period. 
 
 
Modified the WOC description for third 
party data. 
For assessing COVID-19 impact, included 
additional analyses for protocol deviations 
and COVID infected AEs. 
Defined the exposure concepts for 
Rineterkib and NIS793 that were added in 
PA#4. 
Included the analyses for dose escalation 
and safety run-in for Rineterkib and NIS793 
respectively  
Noted the analyses that are no longer 
applicable due to the permanent enrollment 
halt, such as analyses for Parts2&3, 
. 
Updated the interim analyses and sample 
size according to PA#4 
Added summary for AEs of eye disorder for 
rineterkib and listing display for 
ophthalmology assessments. 
Removed overall safety period summaries 
for AESI and death cases.  
Added analyses for Part 1 SVR and change 
in TSS MFSAF following the updated 
secondary objectives from PA7.   
Section 1 
Introduction 
Section 2.1 Data 
analysis general 
definitions 
Section 2.3 patient 
disposition, 
demographics and 
other baseline 
characteristics 
Section 2.4 
Treatments 
Section 2.5 
Analysis of the 
primary objective 
Section 2.7 
Analysis of 
secondary efficacy 
objectives 
Section 2.8 Safety 
analyses 
Section 2.9 
Pharmacokinetic 
endpoints 
 
 
 
 
 
Section 3 Sample 
size calculation   


Novartis 
Confidential 
Page 3 
SAP 
 
CINC424H12201 
 
 
 
Date 
Time point 
Reason 
for update 
Outcome for update 
Section and title 
impacted 
(Current) 
2-Jul-
2024 
In line with 
Protocol 
Amendment   
#9 
Updated 
according to 
PA#9 
Provided the background of the SAP 
amendment in the introduction section. 
Updated study design and, objectives and 
endpoints according to PA#9. 
Add details about Hy’s law. 
 
 
Section 1 
Introduction 
Section 2.7 
Analysis of 
secondary 
objectives 
Section 2.8 
Safety Analysis 
 


Novartis 
Confidential 
Page 4 
SAP 
 
CINC424H12201 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 4 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design ............................................................................................................ 7 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 17 
2.2.1 
Subgroup of interest .............................................................................. 18 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 18 
2.3.1 
Patient disposition ................................................................................. 19 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 20 
2.4.1 
Study treatment / compliance ................................................................ 20 
2.4.2 
Prior, concomitant and post therapies ................................................... 24 
2.5 
Analysis of the primary objective .......................................................................... 25 
2.5.1 
Primary endpoint ................................................................................... 25 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 26 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 30 
2.5.4 
Supportive analyses (NOT applicable) ................................................. 30 
2.6 
Analysis of the key secondary objective ............................................................... 31 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 32 
2.7.1 
Secondary endpoints ............................................................................. 32 
2.8 
Safety analyses....................................................................................................... 34 
2.8.1 
Adverse events (AEs) ............................................................................ 35 
2.8.2 
Deaths .................................................................................................... 37 
2.8.3 
Laboratory data ..................................................................................... 37 
2.8.4 
Other safety data ................................................................................... 38 
2.9 
Pharmacokinetic endpoints .................................................................................... 40 
2.9.1 
PK parameters ....................................................................................... 40 
2.9.2 
PK concentrations ................................................................................. 41 
2.9.3 
Handling of PK data below LLOQ or missing...................................... 42 
2.9.4 
Immunogenicity (only applicable to ruxolitinib combination arms 
with crizanlizumab, sabatolimab and NIS793) ..................................... 42 
 
 42 


Novartis 
Confidential 
Page 5 
SAP 
 
CINC424H12201 
 
 
 
 
 42 
 
 43 
 
 44 
 
 44 
 
 45 
 
 45 
 
 45 
2.13 
Interim analysis (NOT applicable) ........................................................................ 46 
3 
Sample size calculation ..................................................................................................... 46 
3.1 
Primary analysis .................................................................................................... 46 
3.1.1 
Part 1 ..................................................................................................... 46 
3.1.2 
Part 2 ..................................................................................................... 47 
3.1.3 
Part 3 ..................................................................................................... 48 
4 
Change to protocol specified analyses .............................................................................. 52 
5 
Appendix ........................................................................................................................... 52 
5.1 
Imputation rules ..................................................................................................... 52 
5.1.1 
Study drug ............................................................................................. 52 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 53 
5.2 
AEs coding/grading ............................................................................................... 55 
5.3 
Laboratory parameters derivations ........................................................................ 55 
5.4 
Statistical considerations for siremadlin dose-escalation ...................................... 56 
 
 56 
5.4.2 
Statistical model .................................................................................... 56 
5.4.3 
Prior specifications for logistic parameters ........................................... 57 
5.4.4 
Hypothetical on-study data scenarios .................................................... 62 
5.5 
Statistical considerations for MAP prior in sensitivity analysis ............................ 63 
5.5.1 
Meta-analytic-predictive (MAP) approach hierarchical model ............ 63 
5.5.2 
Robustified MAP prior calculation for ruxolitinib monotherapy ......... 64 
5.6 
MFSAF v4.0 PRO ................................................................................................. 66 
5.7 
EORTC QLQ-C30 PRO ........................................................................................ 67 
5.8 
Scoring the QLQ-C30 ............................................................................................ 69 
5.9 
Simulation for hypothetical Part 2 and Part 3 study scenarios .............................. 70 
6 
Reference ........................................................................................................................... 71 
 


Novartis 
Confidential 
Page 6 
SAP 
 
CINC424H12201 
 
 
 
List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


Novartis 
Confidential 
Page 7 
SAP 
 
CINC424H12201 
 
 
 
1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report 
(CSR) of study CINC424H12201, a randomized, open-label, phase I/II open platform study 
evaluating safety and efficacy of novel ruxolitinib combinations in myelofibrosis patients. 
DMC analyses will refer to this study SAP as appropriate. 
SAP Amendment 2 
This SAP is an amendment of the SAP amendment 1 that was based on study protocol 
CINC424H12201 Amendment version 08. The content of this SAP is based on protocol 
Amendment version 09. The main purpose of this amended SAP is to implement the changes 
made by protocol amendment 9 with details specified in the following paragraph.  
The main purpose of the protocol amendment version 09 is to increase the duration of the 
extension treatment phase for the remaining patients to a maximum of 21 cycles. The enrollment 
remains halted as per protocol amendment 08. 
These changes include adding an extension treatment phase and reduction of study assessments 
to decrease subject’s burden in Part 1. The purpose of the extension phase is to allow access to 
the investigational drug for ongoing subjects deriving clinical benefit. In addition, definition 
and recording of Hy's Law has been added to ensure compliance with FDA request for expedited 
reporting of potential Hy’s Law cases. 
Notations are remaining in the contents that become not applicable due to permanent enrollment 
halt. All decisions regarding final analysis, as defined in the SAP document, will be made prior 
to the final database lock (DBL). 
 
SAP Amendment 1 
The SAP amendment 1 is an amendment of the original SAP that was based on study protocol 
CINC424H12201 Amendment version 01. The content of this SAP is based on protocol 
Amendment version 08. The main purpose of this amended SAP is to implement the changes 
made by protocol amendment 8 with details specified in the following paragraph. This SAP 
amendment also reflects the main changes made by protocol amendments 2 to 7, such as 
defining an ‘overall safety period’ for reporting safety data within the long safety follow-up 
period, adding two novel compounds (LTT462 and NIS793) to Part 1, increasing the number 
of subjects for Part 2 from 15 subjects to 25 subjects per arm, adding an interim analysis per 
combination treatment in Part 2, and clarifying the definition of secondary endpoints for 
evaluating change in MF symptoms and change in spleen size.  
1.1 
Study design 
This is an open-label, multi-center, three-part, phase Ib/II open platform study to assess safety 
and efficacy of ruxolitinib in combination with novel compounds in myelofibrosis patients. 
In the context of the permanent enrollment halt and protocol amendment 8 and 9, the study 
design is revised as follows:  


Novartis 
Confidential 
Page 8 
SAP 
 
CINC424H12201 
 
 
 
• Part 1: Dose escalation and safety-run-in (recommended Phase II dose confirmation) 
including a core and an extension treatment phase  
• The end of core treatment phase will occur when amended protocol version 08 is 
implemented, after a minimum of 24 weeks in the core treatment phase.  
• The extension treatment phase will occur (for ongoing subjects meeting eligibility 
criteria who are re-consented) from the time when amended protocol version 08 is 
implemented until the end of extension study treatment. 
• Part 2: Selection remained unchanged as the only randomized subject has discontinued 
prior to amended protocol version 08. 
• Part 3: Expansion will not be applicable as it will never be initiated. 
An overview of the study design is shown as Figure 1-1. 
Figure 1-1 
Overview of study design 
 
* Rineterkib and NIS793 added in amendment 4 of the protocol 


Novartis 
Confidential 
Page 9 
SAP 
 
CINC424H12201 
 
 
 
TBC: To be confirmed 
Subjects treated at different dose levels of ruxolitinib will be pooled into a single treatment 
group for each dose level of the combination partners. A treatment group is defined by both 
combination partner and the dose level of the combination partner for study subjects.  
The primary clinical study report (CSR) is the main primary  report of the study. It will include 
analyses on all subject data when the last subject end the core treatment phase (Part 1) and after 
all subjects have completed at least, 8 cycles (arms with NIS793) or 6 cycles (all other arms) of 
treatment (24 weeks) or discontinued earlier (Part 1 and Part 2).  
All extension treatment phase data will be reported in the final CSR after all subjects 
discontinue from the study or complete the extension treatment phase (maximum 21 cycles) 
whichever comes last. The purpose of the extension phase is to allow access to the 
investigational drug for ongoing subjects deriving clinical benefit. There will be a maximum of 
4 subjects entering extension treatment phase and these 4 subjects will be treated with different 
combination treatments and/or dose levels.   
Due to the permanent enrollment halt, formal analysis for Part 2 and Part 3, including interim 
analysis are no longer applicable. Subjects in Part 1 will be analyzed separately from the subject 
in Part 2. 
An independent safety Data Monitoring Committee (DMC) will monitor unblinded safety, 
, DLT and critical efficacy variables accruing during the trial. The analysis results for 
the DMC reviews will be provided by Novartis Personnel (Trial Statistician and Trial 
Programmer).  
1.2 
Study objectives and endpoints 
As the enrollment was permanently halted, not all planned study objectives for Parts 1, 2, and 
3 could be completed. All Parts 2 and 3 objectives will not be pursued. 
 
 Table 1-1 shows the applicable 
objectives and related endpoints following protocol amendment version 09 Table 2-1. The 
objectives that will not be pursued due to the permannent enrollment halt will not require any 
analysis, so these are not included in Table 1-1 of this document. 
Table 1 - 1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To characterize the safety, tolerability, 
and recommended phase 2 dose 
(RP2D) of each combination partner 
used with ruxolitinib (Part 1) 
• 
Incidence and severity of dose limiting toxicity (DLTs) within 
the first 2 treatment cycles in Part 1 of the study 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate changes in symptoms of 
myelofibrosis in each treatment arm 
using MFSAF v4.0 (Part 1 core) 
Change in MFSAF v4.0 from baseline, including proportion 
of subjects who achieved at least 50% reduction from 
baseline in MFSAF v4.0 Total Symptom Score (TSS) at the 
end of Cycle 4 (NIS793 arms) or Cycle 3 (all other arms), of 
Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) and of 


Novartis 
Confidential 
Page 10 
SAP 
 
CINC424H12201 
 
 
 
Objective(s) 
Endpoint(s) 
Cycle 16 (NIS793 arms) or Cycle 12 (all other arms) from 
baseline. 
• 
To characterize the pharmacokinetic 
profile of ruxolitinib administered in 
combination with siremadlin, 
crizanlizumab, sabatolimab, rineterkib 
and NIS793, respectively (Part 1 core) 
• 
PK parameters (e.g., AUC, Cmax, Tmax) and concentration 
vs. time profiles of each investigational drug with in 
combination regimens 
• 
To 
assess 
emergence 
of 
anti-
crizanlizumab, 
anti-sabatolimab, 
or 
anti-NIS793 antibodies following one or 
more IV infusions (Part 1 core) 
• 
Presence and/or concentration of anti-crizanlizumab, anti-
sabatolimab or anti-NIS793 antibodies 
• 
To evaluate the changes in spleen size 
in each treatment arm (Part 1 core and 
extension) 
• 
Change in spleen length (by palpation) from baseline. 
• 
Change in spleen volume (by MRI/CT) from baseline, 
including 
proportions of subjects who achieved (i) at least 35% spleen 
volume reduction and (ii) at least 25% spleen volume 
reduction at the end of Cycle 8 (NIS793 arms) or Cycle 6 (all 
other arms, and at the end of Cycle 16 (NIS793 arms) or 
Cycle 12 (all other arms), or Cycle 21 (extension phase) from 
baseline respectively. 
 
• 
To evaluate long-term safety and 
tolerability of ruxolitinib combination 
treatments in each arm (Part 1 core and 
extension) 
• 
Frequency, duration and severity of adverse events, 
abnormalities in vital signs and laboratory test values, 
including ECG data 
2 
Statistical methods 
2.1 
Data analysis general information 
The data analysis (including analysis for DMC reviews, primary analysis, and final analysis) 
will be performed by Novartis personnel, Biostatistics and Statistical Programming departments. 
SAS version 9.4 or later and/or R version 3.0.2 or later will be used to perform all data analyses 
and to generate tables, figures and listings. 


Novartis 
Confidential 
Page 11 
SAP 
 
CINC424H12201 
 
 
 
Data included in the analysis 
At the time of protocol amendment version 08 release, all subjects have completed at least 8 
cycles (arms with NIS793) or 6 cycles (all other arms) of treatment or discontinued earlier (Part 
1 and Part 2). If the last core treatment phase subject entered extension treatment phase, the cut-
off date for the primary analysis of study data will be established after the last subject performed 
the end of treatment visit (EOT) for core treatment phase (Part 1).If the last core treatment phase 
subject would not enter extension treatment phase, the cut-off date will be established after the 
last subject completed protocol defined safety follow up visit. All statistical analyses will be 
performed using all data collected in the database up to the data cut-off date. For clarification, 
Part 1 subjects might have entered extension treatment phase prior to the primary analysis cut-
off date. In this case, extension treatment phase data prior to the cut-off date will also be 
included for the primary CSR. All data with an assessment date or event start date (e.g. vital 
sign assessment date or start date of an adverse event) prior to or on the cut-off date will be 
included in the analysis. Any data collected beyond the cut-off date will not be included in the 
analysis and will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings. 
The final analysis for the extension phase data will be performed at the end of the study. The 
cut-off date for the final analysis of study data will be established when all subjects have 
completed the study. All extension treatment phase data will be reported in the final CSR. 
General analysis conventions 
Pooling of center: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of centers, no center effect will be assessed.  
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
by treatment group; a missing category will be included as applicable. Percentages will be 
calculated using the number of subjects in the relevant population or subgroup as the 
denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by 
treatment group. 
2.1.1 
General definitions  
Investigational drug and study treatment 
Investigational drug, will refer to either ruxolitinib (INC424) or any of the novel agents. 
Whereas, study treatment will refer to ruxolitinib single agent or in combination with any of 
the novel agents. 


Novartis 
Confidential 
Page 12 
SAP 
 
CINC424H12201 
 
 
 
Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a nonzero 
dose of investigational drug is administered and recorded on the Dosage Administration Record 
(DAR) (e)CRF. The date of first administration of study drug will also be referred as start of 
investigational drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on DAR eCRF. The date of 
last administration of investigational drug will also be referred as end of investigational drug. 
Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of study treatment was administered as per the Dosage Administration CRF. The date of 
first administration of study treatment will also be referred as start of study treatment. 
Date of first administration of extension phase study treatment 
The date of first administration of extension phase study treatment is derived as the first date 
when a nonzero dose of extension phase study treatment was administered as per the Dosage 
Administration CRF for subject who entered extension treatment phase.  
Date of last administration of study treatment  
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment was administered as per Dose Administration (e)CRF.  
Study day 
The study day describes the day of the event or assessment date, relative to the reference start 
date.  
The study day is defined as: 
 •   The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date; 
• The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date. 
The reference date for all assessments (safety, efficacy, PK, QoL, etc.) is the start of study 
treatment.  
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 


Novartis 
Confidential 
Page 13 
SAP 
 
CINC424H12201 
 
 
 
Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is reported in 
years, duration in days will be divided by 365.25. 
Baseline 
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment.  
In case time of assessment and time of treatment start is captured (e.g. pre-dose ECG), the last 
available assessment before the treatment start date/time is used for baseline.  
For safety parameters (e.g ECGs or vital signs), where study requires multiple replicates per 
time point, the average of these measurements would be calculated for baseline (if not already 
available in the database). 
If patients have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods 
The overall observation period will be divided into three mutually exclusive segments:  
1. pre-treatment period: from day of subject’s informed consent to the day before first 
administration of study treatment 
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date) 
3. post-treatment period: starting at day 31 after last administration of study treatment. 
Moreover, on-extension treatment period is defined from day of first administration of 
extension phase study treatment to 30 days after the date of the last administration of study 
treatment. 
In addition, the overall safety period is defined for this study as following: 
Overall safety period: from date of first administration of study treatment to 30 days after the 
date of the last administration of ruxolitinib, siremadlin or rineterkib, 90 days after the date of 
the last administration of NIS793, or 105 days after the date of the last administration of 
crizanlizumab, or 150 days after the date of the last administration of sabatolimab, whichever 
is later. 
Safety summaries (tables, figures) include data from the pre-treatment period (to display the 
baseline status e.g. for ECG) and the on-treatment period, i.e. data from the post-treatment 
period with the exception of deaths should not be included unless requested from Health 
Authorities or external committees.   
In particular, summary tables for adverse events (AEs) will summarize on-treatment events, 
with a start date during the on-treatment period, the so-called treatment-emergent AEs.  
Additionally, all (study treatment related/regardless) AEs and SAEs with a start date during the 
overall safety period will be summarized. 


Novartis 
Confidential 
Page 14 
SAP 
 
CINC424H12201 
 
 
 
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment, post-treatment overall safety period and post-treatment 
period are to be flagged.  
For the final analysis, all extension treatment phase safety data will be listed and those collected 
during post-treatment overall safety period and post-treatment period are to be flagged. The 
safety data in part 1 core and extension phase will be summarized in tables for the extension 
treatment phase clinical trial safety disclosure. 
Windows for multiple assessments  
In order to summarize data collected over time (including unscheduled visits), the assessments 
will be time slotted. The following general rule will be applied in creating the assessment 
windows: If more than one assessment is done within the same time window, the assessment 
performed closest to the target date will be used. If two assessments within a time window are 
equidistant from the target date, then the assessment that occurred later will be used. If multiple 
assessments occur on the same date then the worst case will be used.  Data from all assessments 
(scheduled and unscheduled), including multiple assessments, will be listed. 
The following time windows are defined for descriptive summary on spleen imaging, spleen 
length palpation, ePROs, laboratory assessments 
 (Tables 2-1, 2-2, and 2-3) by 
visit regardless of core or extension treatment phases. The end of treatment assessment will be 
mapped into the time points as needed.   
Table 2-1  
Time windows for imaging assessments (MRI/CT of abdomen) 
Time Point 
Planned Visit Timing  
Time Window Definition 
Screening/Baseline 
On or before Study Day 1* 
≤ Study Day 1 
Cycle 7 Day 1 
Study Day 168 
Study Days 140 – 196 
Cycle 13 Day 1 
Study Day 336 
Study Days 308 – 364 
Every 6 cycles thereafter 
Cycle y=13+6*k Day 1 
(with k = 1, 2, …) 
Study Day (13+6*k-1)*28 
Study Days  
(13+6*k-1)*28-28 to  
(13+6*k-1)*28+28 
* Study Day 1 = Date of first administration of study treatment (start of study treatment) 
EOT core and EOT extension assessments are mapped to the corresponding time points based 
on the defined time window. 
 
Table 2-2  
Time windows for ePROs, laboratory assessments (chemistry, 
coagulation, urinalysis and thyroid function) 
 
Time Point 
Planned Visit Timing  
Time Window Definition 
Baseline (Cycle 1 Day 1) 
On or before Study Day 1* 
≤ Study Day 1 
Cycle 2 Day 1 
Study Day 29 
Study Days 15 – 42 
Cycle 3 Day 1 
Study Day 57 
Study Days 43 – 70 
Cycle 4 Day 1 
Study Day 85 
Study Days 71 – 98 


Novartis 
Confidential 
Page 15 
SAP 
 
CINC424H12201 
 
 
 
Cycle 5 Day 1 
Study Day 113 
Study Days 99 – 126 
Cycle 6 Day 1 
Study Day 141 
Study Days 127– 154 
Cycle 6+k Day 1 
 (with k = 1, 2, …) 
Study Day (6+k-1)*28+1 
Study Day  
(6+k-1)*28+1-14 to  
(6+k-1)*28+14 
Post treatment 
 
 
30-day safety follow-up 
Post treatment study day 30 
Post treatment study days 23 – 37 
90-day safety follow-up 
Post treatment study day 90 
Post treatment study days 83 – 97 
105-day safety follow-up 
Post treatment study day 105 
Post treatment study days 98 – 112 
150-day safety follow-up 
Post treatment study day 150 
Post treatment study days 136 – 164 
* Study Day 1 = Date of first administration of study treatment (start of study treatment) 
EOT core and EOT extension assessments are mapped to the corresponding time points based on 
the defined time window. 
Post treatment study day 1 = end of study treatment date + 1 
Post treatment visits are for laboratory chemistry assessments only 
90-day safety follow-up visit for NIS7393 arm(s) 
90-day safety follow-up visit, and 150-day safety follow up visit are for sabatolimab arm(s)   
105-day safety follow-up visit is for crizanlizumab arm(s)  
 
 
Table 2-3  
Time windows for spleen length palpation assessments and 
hematology laboratory assessments 
Time Point 
Planned Visit Timing  
Time Window Definition 
Baseline (Cycle 1 Day 1) 
On or before Study Day 1* 
≤ Study Day 1 
Cycle 1 Day 15 
Study Day 15 
Study Days 8 – 21 
Cycle 2 Day 1 
Study Day 29 
Study Days 22 – 35 
Cycle 2 Day 15 
Study Day 43 
Study Days 36 – 49 
Cycle 3 Day 1 
Study Day 57 
Study Days 50 – 63 
Cycle 3 Day 15 
Study Day 71 
Study Days 64 – 77 
Cycle 4 Day 1 
Study Day 85 
Study Days 78 – 98 
Cycle 5 Day 1 
Study Day 113 
Study Days 99 – 126 
Cycle 6 Day 1 
Study Day 141 
Study Days 127– 154 
Cycle 6+k Day 1 
 (with k = 1, 2, …) 
Study Day (6+k-1)*28+1 
Study Day  
(6+k-1)*28+1-14 to  
(6+k-1)*28+14 
Post treatment 
 
 
30-day safety follow-up 
Post treatment study day 30 
Post treatment study days 23 – 37 
90-day safety follow-up 
Post treatment study day 90 
Post treatment study days 83 – 97 
105-day safety follow-up 
Post treatment study day 105 
Post treatment study days 98 – 112 
150-day safety follow-up 
Post treatment study day 150 
Post treatment study days 136 – 164 


Novartis 
Confidential 
Page 16 
SAP 
 
CINC424H12201 
 
 
 
* Study Day 1 = Date of first administration of study treatment (start of study treatment) 
EOT core and EOT extension assessments are mapped to the corresponding time points based on 
the defined time window. 
Post treatment study day 1 = end of study treatment date + 1 
Post treatment visits are for laboratory hematology assessments only 
90-day safety follow-up visit for NIS7393 arm(s) 
90-day safety follow-up visit, and 150-day safety follow up visit are for sabatolimab arm(s) 
105-day safety follow-up visit is for crizanlizumab arm(s) 
Last contact date  
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following: 
Source data 
Conditions 
Date of Randomization  
 
No Condition 
Last date patient was known to be alive from 
Survival Follow-up page  
 
Patient status is reported to be alive, lost to 
follow-up or unknown. 
Start/End dates from further antineoplastic 
therapy 
Non-missing medication/procedure term. 
Start/End* dates from drug administration record  
 
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from end of treatment page 
 
No condition. 
Efficacy assessment date if available (e.g., spleen 
imaging/palpation assessment, bone marrow  
assessment, ePRO assessment) 
Evaluation is marked as ‘done’. 
Laboratory/PK collection dates/
 
 
 
Sample collection marked as ‘done’.  
Vital signs date 
 
At least one non-missing parameter value 
Performance Status date 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
 
The last contact date is defined as the latest complete date from the above list or the cut-off 
date whichever comes first. The cut-off date will not be used for last contact date, unless the 
subject was seen or contacted on that date. No date post cut-off date will be used. 
Completely imputed dates (e.g. the analysis cut-off date programmatically imputed to replace 
the missing end date of a dose administration record) will not be used to derive the last contact 
date. Partial date imputation is allowed for event (death)/censoring is coming from ‘Survival 
information’ eCRF.  
The last contact date will be used for censoring of patients in the analysis of survival analysis. 


Novartis 
Confidential 
Page 17 
SAP 
 
CINC424H12201 
 
 
 
2.2 
Analysis sets 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all subjects that received any study drug. Subjects will 
be analyzed according to the treatment(s) received. 
Safety Set 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized/assigned treatment if the subject took at least one dose of that treatment or 
the first treatment received if the randomized/assigned treatment was never received.  
Dose-Determining Set 
The Dose-Determining Set (DDS) includes all subjects from the safety run-in and dose 
escalation part (Part 1) of the study who met the minimum exposure criterion and had sufficient 
safety evaluations, or experienced a dose-limiting toxicity (DLT) between C1D1 and C3D1. 
The minimum exposure required for combination treatments defined as follows:  
• For ruxolitinib + rineterkib study treatment arm, a subject has met the minimum exposure 
criterion if the subject takes at least 75% of the planned daily rineterkib and ruxolitinib 
combination doses during the first two treatment cycles of dosing, i.e. at least 21 full dosing 
days out of the planned 28 days for the rineterkib and ruxolitinib combination, and the 
subject takes at least 80% of the planned daily doses of ruxolitinib i.e. at least 23 full dosing 
days out of the planned 28 days for ruxolitinib. 
• For all other study treatment arms, a subject has met the minimum exposure criterion if the 
subject takes all planned doses of the combination agent during the first two treatment cycles 
of dosing, and at least 80% of the planned daily doses of ruxolitinib i.e. at least 23 full 
dosing days (17 days for NIS793) out of the planned 28 days (21 days for NIS793) for 
ruxolitinib. 
Subjects who do not experience a DLT between C1D1 and C3D1 are considered to have 
sufficient safety evaluations if they have been observed until C2D28, or C2D21 for the 
ruxolitinib + NIS793 study treatment arm, and are considered by both the sponsor and 
investigators to have enough safety data to conclude that a DLT did not occur.  
Pharmacokinetic analysis set (PAS) 
The Pharmacokinetic Analysis Set (PAS) includes all enrolled subjects who have an evaluable 
PK profile. A profile is considered evaluable if all of the following conditions are satisfied: 
• Subject receives the planned treatments 
• Subject takes the dose of study treatments  
• Subject provides at least one primary PK parameter 
• Subject ingests siremadlin at least 1 h before or 2 h after a meal (only applicable for 
treatment arm ruxolitinib + siremadlin) 


Novartis 
Confidential 
Page 18 
SAP 
 
CINC424H12201 
 
 
 
• Subject does not vomit within 4 hours after oral dosing of siremadlin or ruxolitinib (only 
applicable for treatment arm ruxolitinib + siremadlin). 
• Subject does not vomit within 2 hours after oral dosing of ruxolitinib (all other treatment 
arms). 
Patient Classification:  
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-4.  
Table 2-4 
Subject classification based on protocol deviations and non-PD 
criteria 
 
Analysis set 
Protocol deviations leading 
to exclusion 
Non 
protocol 
deviation 
leading to exclusion 
FAS  
No written inform consent 
Not applicable 
Safety set 
No written inform consent 
No dose of study medication  
Dose-Determining Set 
No written inform consent 
Not meeting the definition of 
inclusion in the DDS 
PK Analysis Set 
No written inform consent 
Not meeting the definition of 
inclusion in the PAS 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF.  
Third party data e.g. PK, 
 etc., collected in the clinical database after a subject 
withdraws the consent or analyzed after withdrawal of consent will not be included in the 
analysis. 
2.2.1 
Subgroup of interest 
The permanent enrollment halt led to limited data that are not sufficient for subgroup analysis. 
Subgroup analysis is not applicable for the primary and final analysis for this early terminated 
study. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by treatment group (defined in 
Section 1-1) and for all subjects and listings will be reported by treatment group to assess 
baseline comparability. Subjects in Part 1 will be analyzed separately from the subject in Part 
2. Data from Part 2 will be listed but not summarized. 


Novartis 
Confidential 
Page 19 
SAP 
 
CINC424H12201 
 
 
 
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment group. Categorical data (e.g. gender, age groups: <65 and ≥ 65 years, rac ethnicity, 
ECOG performance status etc.) will be summarized by frequency counts and percentages; the 
number and percentage of patients with missing data will be provided. Continuous data (e.g. 
age, weight, height etc.) will be summarized by descriptive statistics (N, mean, median, standard 
deviation, minimum and maximum). 
Diagnosis and other baseline characteristics 
Summary statistics will be tabulated for diagnosis and other baseline disease characteristics. 
This analysis will include the following: initial diagnosis of disease, most recent diagnosis of 
disease, time since initial diagnosis, time since most recent diagnosis, hemoglobin level (g/dL), 
absolute neutrophil count (ANC) (/μL), platelet count (/µL), spleen palpable (Yes/No), spleen 
length below left costal margin (cm), spleen volume (cm3), MFSAF Total Symptom Score, 
prior ruxolitinib duration (weeks).  
 
Note: Prior ruxolitinib administration is recorded on Prior/Concomitant Medications eCRF 
pages.  
Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on the (e) CRF will be summarized and listed by treatment group. Separate summaries 
will be presented for ongoing and historical medical conditions.  The summaries will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment arm. 
Medical history and current medical conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. The MedDRA version used for reporting will 
be specified in the CSR and as a footnote in the applicable tables/listings. 
2.3.1 
Patient disposition 
Enrollment by country and center will be summarized for all screened patients and also by 
treatment group using the FAS.  
The number (%) of treated patients included in the FAS will be presented overall and by 
treatment group. The number (%) of screened and not-treated patients and the reasons for 
screening failure will also be displayed. The number (%) of patients in the FAS who are still on 
treatment, who discontinued the study phases and the reason for discontinuation will be 
presented overall and by treatment group for core and extension treatment phase. 
The following summaries will be provided: % based on the total number of FAS patients: 
• Number (%) of patients who were treated (based on ‘DAR’ eCRF pages of each 
study treatment component completed with non-zero dose administered) 
• Number (%) of patients who are still on-treatment (core) (based on the Disposition 
page and Subject Status page);  


Novartis 
Confidential 
Page 20 
SAP 
 
CINC424H12201 
 
 
 
• Number (%) of patients who discontinued the core treatment phase (based on the 
Disposition page)  
• Primary reason for study core treatment phase discontinuation (based on the 
Disposition page) 
• Number (%) of patients who are still on-treatment (extension) (based on the 
Disposition page and Subject Status page);  
• Number (%) of patients who discontinued the extension treatment phase (based on 
the Disposition page)  
• Primary reason for study extension treatment phase discontinuation (based on the 
Disposition page) 
Protocol deviations 
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Quality Plan) overall and by treatment group 
for the FAS. All protocol deviations will be listed. 
Summarize PDs that are not pandemic related and those that are, separately and in total. 
For those related to the pandemic summarize “all COVID-19 pandemic related” together and 
by each specific relationship to COVID-19 if applicable/provided, following the COVID-19 
(Coronavirus) Guidance for Clinical Trial Teams and Trial Monitoring Associates-Protocol 
Deviations and Data Collection: Go Live after 01-Dec-2020 Relationship to COVID-19 via 
CRFs Version 2.0. Percentage is out of total patients in the FAS. 
Analysis sets 
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized by 
treatment group. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by treatment group, separately for each component of study treatment 
(Ruxolitinib and appropriate novel agent). The duration of exposure to study treatment will also 
be presented for each treatment group. Duration of exposure will be categorized into time 
intervals; frequency counts and percentages will be presented for the number (%) of subjects in 
each interval. The number (%) of subjects who have a dose change, and the reasons, will be 
summarized by treatment group. Data in this section is based on the study treatment CRF pages. 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.   
The Safety Set will be used for all summaries and listings of study treatment.  


Novartis 
Confidential 
Page 21 
SAP 
 
CINC424H12201 
 
 
 
Duration of exposure to study treatment 
Duration of exposure to study treatment is calculated by taking into account the duration of 
exposure to ruxolitinib and/or any novel agent partner for each treatment group: 
Duration of exposure to study treatment (days) for each treatment group = (last date of exposure 
to study treatment) – (date of first administration of study treatment) + 1.  
The first date of exposure to study treatment for each treatment group is the earliest of the first 
dates of exposure to ruxolitinib or any novel agent partner. 
The last date of exposure to study treatment for each treatment group is the latest of the last 
dates of exposure to ruxolitinib or any novel agent partner (see Table 2-5). 
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries and continuous summaries (i.e. mean, standard deviation etc.) using 
appropriate units of time. 
Duration of exposure to investigational drug (ruxolitinib or any novel agent 
partner) 
Duration of exposure to investigational drug (days) = (last date of exposure to investigational 
drug) – (date of first administration of investigational drug) + 1.  
Table 2-5 
Definition of last date of exposure of study drug 
Scenario 
Definition of last date of exposure 
of study drug  
Example 
Ruxolitinib (INC424) 
Rineterkib (LTT462) 
Date of last administration of a non -
zero dose of the study drug. 
Example 1: A patient had a 
permanent discontinuation of the 
study drug on 06Jan2013 after 
being 
put 
on 
a 
temporary 
interruption since 01Jan2013. In 
this case the last date of exposure 
is 31Dec2012.  
Siremadlin 
(HDM201) 
Crizanlizumab 
(SEG101)   
Sabatolimab 
(MBG453) 
NIS793 
 
The planned end date of the last cycle 
in which the last non-zero dose of the 
investigational 
drug 
was 
last 
administered. 
Note:  If the patient died or was lost to 
follow-up before the derived last date, 
the 
last 
date 
of 
exposure 
to 
investigational drug is the date of death 
or the date of last contact, respectively.  
If the derived last date of exposure goes 
beyond the data cut-off date, it should 
be truncated to the date of data cut-off. 
Example 2: Siremadlin is in a 28-
day cycle with once a day 
administration for Day 1-5 of each 
cycle. The last date of exposure is 
the date of administration in the 
last cycle + 23 days. 
Example 3: Crizanlizumab is in a 
28-day cycle with one iv infusion in 
the beginning of the cycle and with 
a 2nd loading dose after 14 days of 
initial dosing for Cycle1 only. The 
late dose of exposure is the date 
of last infusion in Cycle 1 + 13 
days if Cycle 1 is the last cycle. 


Novartis 
Confidential 
Page 22 
SAP 
 
CINC424H12201 
 
 
 
The last date of exposure is the 
date of first infusion in the last 
cycle + 27 days if the last cycle is 
post Cycle 1. 
Example 4:  Sabatolimab is in a 
28-day cycle with one iv infusion in 
the beginning of the cycle. The last 
date of exposure is the date of first 
infusion in the last cycle + 27 days 
Example 5:  NIS793 is in a 21-day 
cycle with one iv infusion in the 
beginning of the cycle. The last 
date of exposure is the date of first 
infusion in the last cycle + 20 days 
 
Summary of duration of exposure of an investigational drug will include categorical summaries 
based on 12 weeks intervals and using descriptive statistics (mean, standard deviation etc). The 
duration includes the periods of temporary interruption. 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components. The 
actual cumulative dose refers to the total actual dose administered, over the duration for which 
the subject is on the study treatment as documented in the Dose Administration eCRF. 
For subjects who did not take any drug the cumulative dose is by definition equal to zero. 
The planned cumulative dose for a study treatment component is the total planned dose as per 
the protocol up to the last date of investigational drug administration. The planned cumulative 
dose will not be summarized/listed. It will be used for relative dose intensity calculations.  
For each component of study treatment which is administered daily the planned cumulative 
dose is the planned starting dose summed over the duration of exposure for the component. For 
each component of study treatment that has cyclic administration, the planned cumulative dose 
is the sum of planned total starting dose in a cycle times the number of complete cycles the 
patient should have been over the duration exposure, plus the total dose expected in the last 
incomplete cycle. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for subjects with non-zero duration of exposure is defined as follows:  
For Ruxolitinib and Rineterkib: 
DI (mg/day) = Actual Cumulative dose (mg) / Duration of exposure to study drug (in days). 
For Siremadlin, sabatolimab and NIS793: 
DI (mg/week) = Actual Cumulative dose (mg) / Duration of exposure to study drug (in weeks). 


Novartis 
Confidential 
Page 23 
SAP 
 
CINC424H12201 
 
 
 
Example 1, the duration of exposure to siremadlin is 24 weeks (6 cycles) and the subject 
receives 20 mg siremadlin daily i.v. infusion on Days 1 to 5 of each cycle: 
DI (mg/week) = Actual Cumulative dose (mg) / Duration of exposure to study drug (in weeks) 
=20*5*6 (mg) / 24 (weeks) = 25 (mg/week). 
Example 2, the duration of exposure to sabatolimab is 24 weeks (6 cycles) and the subject 
receives 800 mg sabatolimab i.v. infusion on Day 1 of each cycle: 
DI (mg/week) = Actual Cumulative dose (mg) / Duration of exposure to study drug (in weeks) 
=800*6 (mg) / 24 (weeks) = 200 (mg/week). 
Example 3, the duration of exposure to NIS793 is 24 weeks (8 cycles) and the subject receives 
2100 mg NIS793 i.v. infusion on Day 1 of each cycle: 
DI (mg/week) = Actual Cumulative dose (mg) / Duration of exposure to study drug (in weeks) 
=2100*8 (mg) / 24 (weeks) = 700 (mg/week). 
For Crizanlizumab: 
DI (mg/kg/week) = Actual Cumulative dose (mg/kg) / Duration of exposure to study drug (in 
weeks). 
For example, the duration of exposure to crizanlizumab is 24 weeks (6 cycles) and the subject 
receives 5 mg/kg crizanlizumab IV infusion every 4 weeks with a second loading dose after 14 
days of the initial dose (7 IV infusion of crizanlizumab at 5 mg/kg): 
DI (mg/kg/week) = Actual Cumulative dose (mg/kg) / Duration of exposure to study drug (in 
weeks)=5*7 (mg/kg) / 24 (weeks) = 1.46 mg/kg/week. 
For subjects who did not take any drug the DI is by definition equal to zero.  
 
Planned dose intensity (PDI) is defined as follows: 
For Ruxolitinib and Rineterkib: 
PDI (mg/day) = Planned Cumulative dose (mg) / Duration of exposure (in days). 
For Siremadlin, Sabatolimab and NIS793: 
DI (mg/week) = Planned Cumulative dose (mg) / Duration of exposure (in weeks). 
For Crizanlizumab: 
DI (mg/kg/week) = Planned Cumulative dose (mg/kg) / Duration of exposure (in weeks). 
 
Relative dose intensity (RDI) is defined as follows: 
For Ruxolitinib and Rineterkib: 
RDI = DI (mg/day)  / PDI (mg/day).   
For Siremadlin, Sabatolimab and NIS793: 


Novartis 
Confidential 
Page 24 
SAP 
 
CINC424H12201 
 
 
 
RDI = DI (mg/week)  / PDI (mg/week).   
For Crizanlizumab: 
RDI = DI (mg/kg/week)  / PDI (mg/kg/week).   
DI and RDI will be summarized separately for each of the study treatment components 
(ruxolitinib and novel agent combination) using the duration of exposure of each of the 
components.  
Dose changes, interruptions or permanent discontinuations 
The number of subjects who have dose changes, permanent discontinuations or interruptions, 
and the reasons, will be summarized separately for each of the study treatment components.  
‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration CRF pages (DAR) will be used to determine the dose change, dose 
interruptions, and permanent discontinuations, respectively. 
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
Dose interruptions are captured in the eCRF following the Oncology Data standard Reference 
manual and CRF Completions Guidelines. Depending on the dosing administration schedule 
(e.g. continuous dosing, interval dosing), data would be collected in different fashion. For 
instance, for continuous dosing an interruption is defined as a dose of zero in a unit of time 
between two non-zero dosing records. In general any rest period as part of the regimen/schedule 
is not considered as an interruption.  
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this block of entries, then it will be 
counted as one interruption.  
2.4.2 
Prior, concomitant and post therapies 
Prior anti-neoplastic therapy 
The number and percentage of subjects who received any prior anti-neoplastic medications will 
be summarized by treatment group. Prior anti-neoplastic medications will be summarized by 
setting (e.g. adjuvant, metastatic, etc.) and also by lowest ATC class, preferred term and 
treatment. Summaries will include total number of regimens, indication, reason for 
discontinuation of therapy and best response hematological. Listings will be produced for prior 
anti-neoplastic medications. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD). 
Details regarding MedDRA and WHO-DD version will be included in the footnote in the 
tables/listings.  


Novartis 
Confidential 
Page 25 
SAP 
 
CINC424H12201 
 
 
 
The above analyses will be performed using the FAS. 
Post treatment anti-neoplastic therapy 
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by ATC class, preferred term, overall and by treatment group by means of frequency counts 
and percentages using FAS. 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a subject coinciding with the study treatment 
period. Concomitant therapy includes medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference  Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and preferred term 
using frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. These summaries will include: 
1. Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study treatment, 
or starting more than 30 days after the last date of study treatment and within the overall safety 
period will be flagged in the listing. The safety set will be used for all concomitant medication 
tables and listings. 
2.5 
Analysis of the primary objective 
The primary objective of Part 1 of the study is to characterize the safety, tolerability, and the 
recommended Phase 2 dose (RP2D) of each combination partner used with ruxolitinib in 
subjects with myelofibrosis.  
The primary objective of Parts 2 and 3 of the study is to evaluate the preliminary efficacy of the 
ruxolitinib combination treatments in subjects with myelofibrosis. Due to permanent enrollment 
halt, the Part 2 and Part 3 primary objective will not be pursued.  
2.5.1 
Primary endpoint 
Part 1  
The primary endpoint in Part 1 is the incidence of dose-limiting toxicities (DLTs) within the 
first two treatment cycles.  


Novartis 
Confidential 
Page 26 
SAP 
 
CINC424H12201 
 
 
 
Part 2 and Part 3 (NOT applicable) 
The primary endpoint in Parts 2 and 3 is the response rate (RR) at the end of Cycle 6. 
The RR is the composite of anemia improvement and no spleen volume progression and no 
symptom worsening. For a subject to be considered a responder, all three components of the 
composite endpoint have to be fulfilled. The components of the composite endpoint are defined 
as follows: 
• Anemia improvement is defined as an increase of hemoglobin from baseline of at least 1.5 
g/dL. Anemia improvement requires absence of any PRBC transfusion in 12 weeks prior 
to achieving an increase of 1.5 g/dL. The increase in hemoglobin should be confirmed at 
least 2 weeks later. 
• No spleen volume progression with progression defined as a spleen volume increase of 
25% or more from baseline as measured by MRI/CT. 
• No symptoms worsening as measured by the MFSAF version 4 patient reported outcome 
(PRO). An increase in total symptom score (TSS) of 10 or more from baseline is 
considered worsening of symptoms. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
2.5.2.1 
Part 1 
Identification of a recommended dose for siremadlin and rineterkib 
Identification of the recommended Phase 2 dose (RP2D) of the combination treatment will be 
based upon the estimation of the probability of dose-limiting toxicity (DLT) within the first two 
cycles for patients in the Dose-Determining Set (DDS). The maximum tolerated dose (MTD) is 
the highest drug dosage that is not expected to cause DLT in more than 33% of the treated 
subjects during the DLT evaluation period. The RP2D may be chosen prior to identification of 
the MTD and may be lower than the MTD. The decisions on new dose levels are made by the 
Investigators and Novartis study personnel in a dose escalation meeting based upon the review 
of patient tolerability and safety information (including the BLRM summaries of DLT risk) 
along with PK, PD and preliminary activity information available at the time of the decision. 
The dose escalation will be guided by a Bayesian analysis of dose-limiting toxicity (DLT) data 
from Cycle 1 and Cycle 2. The relationship between dose and the probability of DLT is 
modelled using logistic regression. Details of the model are as follows. 
Let π(d) be the risk of DLT for the combination of ruxolitinib given at dose siremadlin dose d, 
the dose-DLT model is logistic: 
Figure 2-1 
Logistic DLT model. 
 
where d* is used to scale the doses. Hence, α>0 is the odds of a DLT at d*; and β>0 is the 
increase in the log-odds of a DLT by a unit increase in log-dose. 


Novartis 
Confidential 
Page 27 
SAP 
 
CINC424H12201 
 
 
 
Assessment of patient risk 
After each subject within each cohort is followed for two cycles, the BLRM will be updated 
and the posterior distribution for the risk of DLTs for patients at dose levels of siremadlin will 
be evaluated. The posterior distributions will be summarized to provide the posterior probability 
that the risk of a DLT within the first two cycles lies within the following intervals (Table 2-
6):: 
Table 2-6 
Toxicity levels 
Under-dosing: 
[0 , 0.16) 
Targeted toxicity: 
[0.16 , 0.33) 
Excessive toxicity: 
[0.33 , 1] 
The escalation with overdose control (EWOC) principle 
Dosing decisions are guided by the escalation with overdose control principle. A dose of 
siremadlin may only be used for newly enrolled patients if the risk of excessive toxicity at that 
dose is less than 25%. 
Prior distributions 
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
model parameters. The MAP prior for the logistic model parameters for this study is the 
conditional 
distribution 
of 
the 
parameters 
given 
the 
historical 
data 
(see  
Neuenschwander et al 2014, Neuenschwander et al 2010, 
Spiegelhalter et al 2004). 
MAP 
priors are derived from hierarchical models, which take into account possible differences 
between multiple historical studies. 
A full description of the application of the MAP approach to derive the prior distributions of 
the model parameters is given in Section 5.4. 
Starting dose 
The starting dose for siremadlin in combination with ruxolitinib is 20 mg/day (day 1-5 each of 
a 28-day cycle). For this dose the prior risk of excessive toxicity is 15.42% (see Section 5.4), 
which satisfies the EWOC criterion. Any dose lower than 20 mg also fulfills the EWOC 
criterion. A full assessment of the prior risk of toxicity is given in Section 5.4. 
The starting dose for rineterkib in combination with ruxolitinib is 200 mg. For this dose the 
prior risk of excessive toxicity is 18.85% (see Section 5.4), which satisfies the EWOC criterion. 
Any dose lower than 200 mg also fulfills the EWOC criterion. A full assessment of the prior 
risk to patients is given in Section 5.4. 
Listing of DLTs 
DLTs will be listed, and their incidence summarized by primary system organ class and worst 
grade (CTCAE version 5.0). Listings and summaries (if data warrant) will be based on the DDS. 


Novartis 
Confidential 
Page 28 
SAP 
 
CINC424H12201 
 
 
 
DLT rate for crizanlizumab, sabatolimab and NIS793 
For crizanlizumab, sabatolimab, and NIS793 the proposed RP2D is known prior to the study 
start and based on previous single agent phase I and phase II studies in solid and hematologic 
malignancies. A safety run-in is performed to assess the risk of unexpected toxicities and a dose 
escalation procedure is not followed for these combination treatments.  
For each combination treatment, the DLT rate is determined as the observed number of patients 
in the DDS who experienced a DLT divided by the number of patients in the DDS.  
Any DLTs occurring will be listed, and their incidence summarized by primary system organ 
class and worst grade (CTCAE version 5.0). Listings and summaries (if data warrant) will be 
based on the DDS.  
2.5.2.2 
Part 2 (NOT applicable) 
No formal hypothesis testing or between arm comparison will be conducted in Part 2. The 
objective of this part of the study is to explore the disease-modifying activity of the combination 
treatments, and to drop the arm(s) that lack promising activity.  
The arms that advance into Part 3 will be selected based on the totality of the data. That includes, 
among other data, efficacy, safety, PK/PD, 
 data as appropriate, and also data 
from the ruxolitinib single agent arm.  
To determine whether a combination treatment has the potential to be disease-modifying and, 
as such, be eligible to advance into Part 3, the combination must not cross a specified futility 
boundary defined for the response rate with respect to the primary composite endpoint.  
A combination treatment arm that shows an early sign of outstanding efficacy by crossing a 
specific efficacy boundary (i.e. when at least 10 subjects of a combination treatment are 
evaluable) at the first interim look may expand into Part 3 seamlessly, without stopping at the 
second interim look. 
At the second interim look, the combination treatment arm must not cross a specified futility 
boundary (i.e. when at least 25 subjects of a combination treatment are evaluable) defined for 
the RR with respect to the prima ry composite endpoint.  
The threshold for the first interim look is shown in Table 2-7 
Table 2-7 
1st interim look (seamless expansion to Part 3) efficacy threshold 
Decision rule 
Action 
P (RR>0.3|D) > 80% 
Preliminary efficacy declared 
According to the first interim threshold, an arm is considered of clinical interest and will be 
advanced to Part 3 expansion if the posterior probability of the RR for the primary composite 
endpoint being greater than 0.3 is more than 80%. This first interim decision rule was 
determined such that arms with outstanding efficacy that warrant further development (i.e. True 
RR > 50%) will be advanced with higher probability, see Section 3.1.2 for details. 
Concerning the posterior probability of the response rate, let i index the study arm, let pi be the 
corresponding responder rate with respect to the primary endpoint, let ni be the number of 


Novartis 
Confidential 
Page 29 
SAP 
 
CINC424H12201 
 
 
 
subjects of arm i, and let ri be the number of responders in arm i. The number of responders ri 
in arm i is modelled by a binomial distribution with parameters ni and pi. With the assumptions 
of a vague prior, beta(1/2, 1/2), the posterior probability distribution of pi is given by 
 
For a given sample size ni, the first interim threshold shown in Table 2-7 can be transformed 
into a number of responders with respect to the primary endpoints for which preliminary 
efficacy would be declared, as shown in Table 2-8. 
Table 2-8 
1st Interim look efficacy regions for a given sample size 
ni 
Region 
9 
≥ 4 
10 
≥ 5 
11 
≥ 5 
12 
≥ 5 
The futility threshold of the 2nd interim look is shown in Table 2-9. 
Table 2-9 
Futility threshold 
Decision rule 
Action 
P (RR ≤ 0.2 | Data) > 50% 
Declare combination arm futile 
According to the futility threshold, an arm is dropped for futility if the posterior distribution of 
the response rate for the primary composite endpoint is less than or equal to 0.2 with a 
probability of more than 50%. This futility decision rule was determined such that arms with a 
response rate which are not of interest for further development, that are response rates of 10% 
or less, are likely to cross the futility threshold and would therefore be dropped at the end of 
Part 2, see Section 3.1.2 for details.  
For a given sample size ni, the futility threshold shown in Table 2-9 can be transformed into a 
number of responders with respect to the primary endpoints for which futility would be declared, 
see Table 2-10. 
Table 2-10 
Futility regions for a given sample size 
ni 
Futility region 
24 
≤ 4 
25 
≤ 4 
26 
≤ 5 
27 
≤ 5 
Due to the discrete nature of the binomial distribution, the futility region does not necessarily 
change in the sample size ni. 
The response rate (RR) as defined in Section 2.5.2.1 will be summarized using descriptive 
statistics (N, %) by treatment arm along with a 95% credible interval of the RR posterior 


Novartis 
Confidential 
Page 30 
SAP 
 
CINC424H12201 
 
 
 
distribution. In addition, the probability that RR is less than or equal to 0.2 will be derived from  
the posterior distribution of RR. 
2.5.2.3 
Part 3 (NOT applicable) 
Part 3 of the study aims to further assess the efficacy of the chosen treatment combination from 
Part 2 by comparing it to ruxolitinib using the FAS.  
The comparison of the combination arm to ruxolitinib will be performed separately based on a 
Bayesian model and include data from both Part 2 and Part 3.  
In detail, let nrux and rrux be the sample size and the number of responders with respect to the 
primary composite endpoint in the ruxolitinib arm, respectively. Analogously, ncomb and rcomb 
denote the sample size and the number of responders in the combination arm. The number of 
responders within each arm is modelled by a binomial distribution with response rate pi (i = rux, 
comb). As in Section 2.5.2.2, a vague prior, beta(1/2, 1/2), is assumed for pi. This results in a 
beta-distributed posterior distribution for the response rate, see Section 2.5.2.2. The study is 
considered to be successful with respect to the primary endpoint when the difference in response 
rates between combination arm and ruxolitinib arm is greater than zero with a probability of 
greater than or equal to 90%:  
Figure 2-2 
Success criterion for primary endpoint. 
 
The RR will be summarized using descriptive statistics (N, %) by treatment arm along with 95% 
creditable interval of the RR posterior distribution. The joint distribution of the posterior 
difference in response rates will be summarized using median and 95% credible interval. The 
probability that the posterior difference is greater than zero will also be presented.  
2.5.3 
Handling of missing values/censoring/discontinuations 
Subjects with missing assessments of hemoglobin, spleen volume or MF SAF TSS at the end 
of Week 24 that prevent the evaluation of the primary endpoint will be considered non-
responders to that treatment. The visit windows considered when defining what constitutes a 
missing value for hemoglobin level, spleen volume or MF SAF TSS is provided in Section 2.1.1. 
2.5.4 
Supportive analyses (NOT applicable) 
Sensitivity analyses (NOT applicable) 
As sensitivity analyses, the primary endpoint in Parts 2 and 3, i.e. the response rate (RR) at the 
end of Cycle 6 (Section 2.5.1), will be evaluated with different prior distributions for the 
response rates: 
1. The prior distribution for the response rate in the combination arm is the same prior as in 
the primary analysis, i.e., a vague prior. The prior distribution for the response rate in the 
ruxolitinib arm is the robustified MAP prior based on historical data from INCB18424-
351 (Comfort I) and CINC424A2352 (Comfort II). The historical data from Comfort I and 


Novartis 
Confidential 
Page 31 
SAP 
 
CINC424H12201 
 
 
 
Comfort II and the statistical methodological details and the summary of robustified MAP 
prior are described in Section 5.5.   
2. The prior distribution for the response rate in the combination arm is obtained by updating 
the vague prior, beta(1/2, 1/2), using the number of responders from Part 1.  Let i index 
the combination study arm, let niP1 be the number of subjects of Part 1 arm i, and let riP1 be 
the number of responders in Part 1 arm i. The updated prior distribution for the RR in the 
combination arm i is given by 
 
The prior distribution for the responder rate in the ruxolitinib arm is not changed 
compared to the primary analysis.  
For the two sensitivity analyses proposed above, the RR will be summarized using descriptive 
statistics (N, %) by treatment arm along with 95% creditable interval of the RR posterior 
distribution. The joint distribution of the posterior difference in response rates will be 
summarized using median and 95% credible interval. The probability that the posterior 
difference is greater than zero will also be presented.  
Supportive analyses (NOT applicable) 
As supportive analyses, the definition of 'responders' will be modified compared to the primary 
endpoint by only considering the hemoglobin and spleen volume measurement. Thus, for 
supportive analyses, a subject is considered a responder if the following two criteria are fulfilled: 
• Anemia improvement is defined as an increase of hemoglobin from baseline of at least 1.5 
g/dL at the end of 24 weeks after randomization. Anemia improvement requires absence 
of any PRBC transfusion in the 12 weeks prior to achieving an increase of 1.5 g/dL and a 
confirmation of Hb increase at least 2 weeks later. 
• No spleen volume progression is given when the spleen volume increase is smaller than 
25% between baseline and the end of Week 24 measured by MRI/CT.  
Subjects with missing assessment of hemoglobin or spleen volume at the end of Week 24 that 
prevent the evaluation of the analysis endpoint will be considered as non-responders to that 
treatment. 
The RR will be summarized using descriptive statistics (N, %) by treatment arm along with 
95% creditable interval of the RR posterior distribution. The joint distribution of the posterior 
difference in response rates will be summarized using median and 95% credible interval. The 
probability that the posterior difference is greater than zero will also be presented. 
2.6 
Analysis of the key secondary objective 
 
Not applicable 


Novartis 
Confidential 
Page 32 
SAP 
 
CINC424H12201 
 
 
 
2.7 
Analysis of secondary efficacy objective(s) 
Due to the enrollment halt, some of the secondary efficacy objectives are no longer applicable. 
The updated secondary efficacy objectives are listed as follows:  
• To evaluate changes in symptoms of myelofibrosis in each treatment arm using MFSAF 
v4.0 (Part 1 core) 
• To evaluate the changes in spleen size (spleen volume and spleen length) in each treatment 
arm (Part 1 core and extension) 
In final CSR, data collected in extension phase will be listed instead of summary tables. 
2.7.1 
Secondary endpoints 
All secondary efficacy endpoints will be analyzed using the Full Analysis Set (FAS). 
Proportion of subjects achieving improvement of hemoglobin level (NOT 
applicable) 
Hemoglobin is measured at baseline and at least once per cycle. The change from baseline will 
be summarized by treatment group using descriptive statistics. Individual hemoglobin level at 
different time points will be displayed graphically by treatment group. 
The proportion of subjects achieving improvement in hemoglobin ≥ 1.5 g/dL and ≥ 2.0 g/dL, 
respectively, from baseline to the end of Week 24, and the end of Week 48 will be summarized 
using descriptive statistics (N, %) by treatment arm along with two-sided exact binomial 95% 
CIs [Clopper and Pearson 1934]. The proportion will be calculated using FAS subjects as the 
denominator; the numerator will be based on the number of subjects with a baseline measure 
and a post-baseline measure of the corresponding time-point.   
Change in spleen volume and spleen length 
Spleen volume will be measured by MRI/CT at baseline, the end of every 24 weeks (8 cycles 
for NIS793 arms and 6 cycles for all other arms) and at EOT (if not performed in the past 12 
weeks) for Part 1 core treatment phase and extension phase. The change from baseline will be 
summarized at each scheduled assessment time point by treatment group using descriptive 
statistics. The change from baseline at the end of Week 24 will be displayed graphically for 
individual subjects by treatment groups. 
The proportion of patients with a spleen volume progression will be summarized using 
descriptive statistics (N, %) at the end of Week 24 and separately at the end of Week 48 by 
treatment group. 
The proportion of subjects achieving at least 25% and 35% reduction in spleen volume from 
Baseline to the end of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) and the end of Cycle 
16 (NIS793 arms) or Cycle 12 (all other arms) during the core treatment phase as measured by 
MRI or by CT will be summarized descriptively. 
Spleen length measurement will be conducted by manual palpation. Manual palpation will be 
performed on days 1 and 15 of cycles 1 to 3, and day 1 of subsequent cycles for Part 1 core 
treatment phase and extension treatment phase. The change from baseline at each planned 


Novartis 
Confidential 
Page 33 
SAP 
 
CINC424H12201 
 
 
 
scheduled point will be summarized by treatment group using descriptive statistics. The change 
from baseline at the end of Week 24 will be displayed graphically for individual subjects by 
treatment groups. 
The proportion of subjects who achieved at least 50% spleen length reduction from baseline for 
subjects with baseline splenomegaly that is palpable at greater than 10 cm, or became not 
palpable for subjects with baseline splenomegaly that is palpable at ≥5-≤10 cm will be 
calculated at the end of Cycle 4 (NIS793 arms) or Cycle 3 (all other arms), and at the end of 
Cycle 8 (NIS793 arms) or Cycle 6 (all other arms), and at the end of Cycle 16 (NIS793 arms) 
or Cycle 12 (all other arms). 
Change in symptoms assessed by MFSAF and EORTC 
Symptoms of myelofibrosis will be measured by MFSAF v4.0 and EORTC QLQ-C30 for the 
core treatment phase.  Due to enrollment halt, EORTC data is not available for Parts 2 and 3 of 
the study. 
 
MFSAF v4.0 
MFSAF v4.0 (Appendix 5.6) is a harmonized, consensus-based PRO questionnaire recently 
developed for use in MF trials by a PRO Consortium Working Group (Gwaltney et al 2017), 
which focuses on the 7 core symptoms of MF: fatigue, night sweats, pruritus, abdominal 
discomfort, pain under the ribs on the left side, early satiety and bone pain.  
Subjects record symptom severity at its worst for each of the 7 symptoms on an 11-point 
numeric rating scale, from 0 (absent) to 10 (worst imaginable). The 7-day recall format is used 
in this study. The Total Symptom Score (TSS) is calculated as the average of the observed 
individual item responses on the 0 to 10 scale multiplied by 7, resulting in a TSS ranging from 
0 to 70. At least four items must be completed to calculate the TSS from the 7-day recall format 
of the MFSAF v4.0. MFSAF v4.0 is collected at Screening, C1D1, Day 1 of all subsequent 
cycles of treatment, as well as the EOT visit. 
The change from baseline in MFSAF total symptom score and individual symptoms will be 
summarized with descriptive statistics by treatment group at each scheduled assessment time 
point for Part 1. The change from baseline at the end of Week 24 will be displayed graphically 
for individual subjects by treatment groups. The proportion of subjects with no worsening in 
symptom at the end of Week 24 and Week 48 will be summarized. The proportion will be 
calculated using FAS subjects as the denominator; the numerator will be based on the number 
of subjects with a baseline measure and a post-baseline measure of the corresponding time-
point. The symptom worsening is defined as an increase in TSS of 10 or more from baseline. 
The proportion of subjects who achieved at least 50% reduction in MFSAF v4.0 Total Symptom 
Score (TSS) at the end of Cycle 4 (NIS793 arms) or Cycle 3 (all other arms), at the end of Cycle 
8 (NIS793 arms) or Cycle 6 (all other arms) and at the end of Cycle 16 (NIS793 arms) or Cycle 
12 (all other arms) respectively from baseline will be calculated.  


Novartis 
Confidential 
Page 34 
SAP 
 
CINC424H12201 
 
 
 
Progression free survival (PFS) (NOT applicable) 
PFS is defined as the time from the date of randomization to the date of the first documented 
progressive splenomegaly, or accelerated phase, or deteriorating cytopenia, or leukemic 
transformation or death due to any cause. See Protocol Section 8.3.2.4 for the details of the PFS 
events definition. The PFS event and the corresponding date are taken from the Progressive 
Disease Assessment CRF page.  
PFS will be analyzed using the FAS population according to the randomized treatment group 
assigned at randomization. The PFS distribution will be estimated using the Kaplan-Meier 
method, and the Kaplan-Meier curves, medians and 95% confidence intervals of the medians 
will be presented for each treatment group. The hazard ratio for PFS comparing a combination 
treatment with ruxolitinib single agent will be calculated, along with its 95% confidence interval, 
using a Cox model. 
PFS will be censored if no PFS event is observed before the cut-off date or the date when a new 
anti-neoplastic therapy or another investigational treatment is started, whichever occurs earlier. 
The censoring date will be the date of last adequate assessment before a new anti-neoplastic 
therapy or another investigational treatment is started, if it occurred, else the date of last 
adequate assessment before the cut-off date. 
Disease Progression 
Disease progression will be assessed at every clinical visit. The date of assessment, date of 
confirmatory progressive disease, progressive disease criteria will be listed for core and 
extension treatment phases. 
Proportion of subjects achieving improvement in bone marrow fibrosis (NOT 
applicable) 
The grade of bone marrow fibrosis will be measured at baseline, the end of Week 24, and every 
subsequent 24 weeks. The grade of bone marrow fibrosis will be summarized descriptively for 
each scheduled point by treatment group. The proportion of patients achieving improvement in 
bone marrow fibrosis of ≥ 1 grade from baseline to the end of Week 24, and the end of Week 
48 will be summarized by treatment group. The proportion will be calculated using FAS 
subjects as the denominator; the numerator will be based on the number of subjects with a 
baseline measure and a post-baseline measure of the corresponding time-point. 
2.8 
Safety analyses 
For all safety analyses, the safety set will be used, except for summaries of DLTs, for which the 
dose-determining set will be used in addition to the safety set. All listings and tables will be 
presented by treatment group. Safety summaries (tables, figures) include only data from the on-
treatment period with the exception of baseline data which will also be summarized where 
appropriate (e.g. change from baseline summaries). In addition, a separate summary for death 
including on treatment and post treatment deaths will be provided. In particular, summary tables 
for adverse events (AEs) will summarize only on-treatment events, with a start date during the 
on-treatment period (treatment-emergent AEs). 


Novartis 
Confidential 
Page 35 
SAP 
 
CINC424H12201 
 
 
 
The overall observation period will be divided into three mutually exclusive segments (pre-, 
on-, post- treatment period) in addition to overall safety period and on-extension treatment 
period as defined in Section 2.1.1. 
In final CSR, patient safety information related to adverse events from the extension phase will 
be summarized together with data from phase I core.  
2.8.1 
Adverse events (AEs) 
AE summaries will include all AEs occurring (new or worsening) during the on treatment 
period. In addition, all AEs and SAEs which started during the overall safety period will be 
summarized.  AEs collected in the AE (e)CRF page will be listed along with the information 
collected on those AEs e.g. AE relationship to study drug, AE outcome etc. AEs with start date 
outside of on-treatment period (pre-treatment period, post-treatment period, and post-treatment 
overall safety period) will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. Grading of AEs is based on NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. A subject with multiple CTCAE grades for 
the same preferred term will be summarized under the maximum CTCAE grade recorded for 
the event . AE with missing CTCAE grade will be included in the ‘All grades’ column of the 
summary tables. 
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the total column.  
The following adverse event summaries will be produced by treatment arm; overview of 
adverse events and deaths (number and % of subjects who died, with any AE, any SAE, any 
dose reductions/interruptions, leading to treatment discontinuation, requiring additional 
therapy), AEs by SOC and PT, summarized by relationship (all AEs and AEs related to study 
treatment), seriousness (SAEs and non-SAEs), leading to treatment discontinuation, leading to 
dose interruption/adjustment, requiring additional therapy and leading to fatal outcome. In 
addition, a summary of 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 recommended in the COVID-19 (Coronavirus) Guidance for Clinical Trial Teams - 
Developing Clinical Study Reports (CSRs) for Studies Conducted During the COVID-19 
Pandemic, all suspected or confirmed SARS-CoV-2 infections will be listed for all patients and 
by treatment groups. The infected cases will be selected using specified criteria as detailed in 
the TFL shells document.  


Novartis 
Confidential 
Page 36 
SAP 
 
CINC424H12201 
 
 
 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Adverse events of special interest (AESI) during the on-treatment period will be tabulated. The 
list of AESI will also include relevant events for ruxolitinib, and the novel agents including but 
not limited to siremadlin, crizanlizumab, sabatolimab and NIS793, if deemed appropriate. 
Data analysis of AESIs 
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound ruxolitinib and the individual novel agents, if deemed 
appropriate. These groupings are defined using MedDRA terms, SMQs (standardized MedDRA 
queries), HGLTs (high level group terms), HLT (high level terms) and PTs (preferred terms). 
Customized SMQs (Novartis MedDRA queries, NMQ) may also be used. A NMQ is a 
customized group of search terms which defines a medical concept for which there is no official 
SMQ available or the available SMQ does not completely fit the need. It may include a 
combination of single terms and/or an existing SMQ, narrow or broad. All AESI terms for the 
individual compounds as well as for combination specific AESIs, if deemed appropriate, are 
captured in the case retrieval strategy/strategies (CRS).  
For each specified AESI, number and percentage of patients with at least one event of the AESI 
occurring during on treatment period will be summarized. Summaries of these AESIs will be 
provided by treatment arm, (specifying grade, SAE, relationship, action taken, medication or 
therapy taken, AE outcome). A listing of all grouping levels down to the MedDRA preferred 
terms used to define each AESI will be generated.  
2.8.1.2 
Adverse events of clinical trial safety disclosure  
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on adverse 
events which are not serious adverse events with an incidence greater than 5% and on serious 
adverse events and SAE suspected to be related to study treatment will be provided by system 
organ class and preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 


Novartis 
Confidential 
Page 37 
SAP 
 
CINC424H12201 
 
 
 
2.8.1.3 
Eye disorders for rineterkib 
To assess the eye toxicity of rineterkib, eye disorder AEs (SOC = ‘Eye disorders’) will be 
summarized by PT and listed for rineterkib combination treatment group. 
2.8.2 
Deaths 
Separate summaries for on-treatment and all deaths (on-treatment and post-treatment) will be 
produced by treatment arm, primary reason, system organ class and preferred term.  All deaths 
will be listed, post treatment deaths and deaths occurred in the post-treatment overall safety 
period will be flagged. A separate listing of deaths prior to starting treatment (i.e. during 
screening period) will be provided for all screened subjects as applicable. 
Note: “Study indication” as primary reason of death should be coded using MedDRA terms 
based on the diagnosis eCRF field at start of study. If not coded accordingly in the database, it 
still must be included in the summary table. Coded reasons for deaths will then be summarized 
by category ‘Study indication’ and ‘Other’ (as selected by the investigator). 
2.8.3 
Laboratory data 
Data from all sources (central and local laboratories) will be combined. The summaries will 
include all laboratory assessments collected no later than 30 days after the last study treatment 
administration date. Laboratory data will be listed by treatment group, subject, and visit/time 
and if normal ranges are available abnormalities will be flagged. Summary statistics will be 
provided by treatment and visit/time. Shift tables using the low/normal/high/ (low and high) 
classification will be used to compare baseline to the worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades if applicable and the classifications relative to the laboratory normal ranges. Lab 
data collected during the post-treatment period will be flagged. 
• Listing of all CTCAE grade 3 or 4 laboratory toxicities 
For laboratory tests where grades are defined by CTCAE v5.0: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value 


Novartis 
Confidential 
Page 38 
SAP 
 
CINC424H12201 
 
 
 
For laboratory tests where grades are not defined by CTCAE v5.0: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
 
 
 
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBIL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per 
Novartis Liver Toxicity guidelines will be summarized: 
The following summaries will be produced: 
• ALT or AST > 3xULN  
• ALT or AST > 5xULN 
• ALT or AST > 10xULN 
• ALT or AST > 20xULN 
• ALP > 1.5xULN 
• TBL > 2xULN 
• ALT or AST > 3xULN & TBL > 2xULN 
• ALT or AST > 3xULN & ALP < 2xULN 
• ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN   
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided for Notable ECG values by treatment group. 
Data handling 
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses. At baseline, a minimum of 3 sequential, 
individual ECGs should be recorded at least 5 minutes apart. The mean QTcF value will be 
calculated from the triplicate ECGs for each subject. 
Data analysis 
12-lead ECGs including HR, QT and QTcF will be obtained for each subject during the study. 
ECG data will be read and interpreted locally  


Novartis 
Confidential 
Page 39 
SAP 
 
CINC424H12201 
 
 
 
The number and percentage of subjects with notable ECG values will be presented by treatment 
group.  
• QT or QTcF 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from Baseline of > 30 ms to ≤  60ms 
- 
Increase from Baseline of > 60 ms 
• HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 50 bpm 
Cardiac imaging (rineterkib and NIS793) data will be listed for each assessment points for the 
corresponding treatment group (s), if deemed appropriate. 
2.8.4.2 
Vital signs 
The following parameters are being collected: height (cm), weight (kg), body temperature (°C), 
heart rate (beats per minute), and systolic and diastolic blood pressure (mmHg).  
Data handling 
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-11  
below. 
Table 2-11 
Clinically notable changes in vital signs 
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
Weight (kg) 
increase > 10% from Baseline 
decrease  > 10% from Baseline 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate 
(bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
 
Body 
temperature 
>= 39.1  
≤ 35.0 


Novartis 
Confidential 
Page 40 
SAP 
 
CINC424H12201 
 
 
 
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
(Celsius) 
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented  by treatment arm.          
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. A separate listing of only the subjects with notable vital sign values may also be 
produced. In the listing, the assessments collected outside of on-treatment period will be flagged.  
2.8.4.3 
Ophthalmologic assessment 
For rineterkib treatment group, ophthalmologic assessments will be listed, if deemed 
appropriate. The assessments include but not limited to slit lamp examination, visual acuity 
testing (preferably Snellen or Early Treatment Diabetic Retinopathy Study (ETDRS)), visual 
field testing, tonometry (Intra Ocular Pressure (IOP)), and indirect fundoscopy (with dilation) 
with attention to retinal abnormalities (especially signs of central serous retinopathy and RVO). 
2.9 
Pharmacokinetic endpoints   
Pharmacokinetic parameters will be derived from the individual concentration versus time 
profile using a non-compartmental method as implemented in Phoenix WinNonlin® (Pharsight, 
Mountain View, CA) software version 8.0. The pharmacokinetic parameters described in 
Table 2-12 will be determined for each investigational drug, as deemed appropriate. Additional 
PK parameters may be estimated as needed.  
2.9.1 
PK parameters 
The PK parameters that will be determined are shown in Table 2-12. A list of PK parameters 
will be estimated for individual drug (ruxolitinib, siremadlin, crizanlizumab, sabatolimab, 
rineterkib or NIS793 as appropriate. 


Novartis 
Confidential 
Page 41 
SAP 
 
CINC424H12201 
 
 
 
Table 2-12 
Non-compartmental PK parameters  
AUClast 
The AUC from time zero to the last measurable concentration sampling time 
(Tlast) 
AUCinf 
The AUC from time zero extrapolated to infinity 
AUC0-t 
The AUC from zero to specified time points (amount x time x volume-1) for 
example 12, 24, 336 or 504h 
Cmax 
The maximum (peak) observed plasma drug concentration 
Tlast 
Time at which the last measurable concentration was observed (time) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid 
drug concentration after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (Lambda_z) of 
a semi logarithmic concentration-time curve 
CL (CL/F) 
The total body clearance (or apparent clearance) of drug from the plasma or 
serum 
Vz (Vz/F) 
The volume (or apparent volume) of distribution during terminal phase 
(associated with Lambda_z) 
AR 
Accumulation Ratio = AUC0-t (multiple Dose)/AUC0-t (single dose) 
Descriptive statistics of PK parameters for ruxolitinib, siremadlin, crizanlizumab, sabatolimab 
and rineterkib will be presented by treatment group for PAS. Due to enrollment halt, PK 
parameters for NIS793 will be listed but not summarized. Descriptive statistics will include 
arithmetic and geometric mean, median, SD, and coefficient of variance (CV), geometric CV, 
minimum and maximum. Zero concentrations will not be included in the geometric mean 
calculation. Since Tmax is generally evaluated by a nonparametric method, median values and 
ranges will be given for this parameter. The parameters that require terminal phase 
determination (AUCinf, T1/2, CL or CL/F and Vz or Vz/F) may not be adequately calculated 
by non-compartmental methods. All individual PK parameters will be listed using FAS and 
summarized using PAS. 
2.9.2 
PK concentrations  
Descriptive summary statistics for ruxolitinib, siremadlin, crizanlizumab, sabatolimab, 
rineterkib and NIS793 concentrations will be provided by treatment group at each scheduled 
time point for the Pharmacokinetic analysis set. Summary statistics will include n (number of 
subjects with non-missing values), mean (arithmetic and geometric), SD, CV% (arithmetic and 
geometric), median, minimum and maximum. 
Plasma concentration data for ruxolitinib, siremadlin, crizanlizumab, sabatolimab, rineterkib 
and NIS793 will be listed by treatment group for Full analysis set.  
The mean (+/- SD)  concentration-time profiles for ruxolitinib, siremadlin, crizanlizumab, 
sabatolimab, rineterkib and NIS793 concentrations by treatment group over time will be 


Novartis 
Confidential 
Page 42 
SAP 
 
CINC424H12201 
 
 
 
displayed graphically for Pharmacokinetic analysis set on the linear view. Further graphical 
exploratory analyses will be carried out if deemed appropriate. 
2.9.3 
Handling of PK data below LLOQ or missing 
Bio-fluid concentrations will be expressed in mass per volume units.  
All concentration values below the lower limit of quantitation (LLOQ) (e.g.: ruxolitinib < 0.5 
ng/mL; siremadlin < 1 ng/mL; sabatolimab < 1 ug/mL; crizanlizumab 150 ng/mL; rineterkib 1 
ng/mL; NIS793 150 ng/mL) are set to zero by the Bioanalyst, and will be displayed in the 
listings as zero and flagged. LLOQ values will be treated as zero in any calculations of summary 
statistics, and treated as missing for the calculation of the geometric means and their CV%. The 
number of non-zero concentrations will also be reported in the summary statistics. 
Missing values for any PK data will not be imputed and will be treated as missing. 
2.9.4 
Immunogenicity (only applicable to ruxolitinib combination arms with 
crizanlizumab, sabatolimab and NIS793)  
The presence and titer of anti-crizanlizumab, anti-MBG453 and anti-NIS793 antibodies (IG) 
will be listed by subject for the corresponding treatment group, as appropriate. . 
. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 43 
SAP 
 
CINC424H12201 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 44 
SAP 
 
CINC424H12201 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 45 
SAP 
 
CINC424H12201 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


Novartis 
Confidential 
Page 46 
SAP 
 
CINC424H12201 
 
 
 
 
 
 
 
 
 
  
 
 
 
2.13 
Interim analysis (NOT applicable) 
No interim analysis is planned for Part 1. For the combination of ruxolitinib plus siremadlin 
and ruxolitinib plus LTT462, a BLRM will be used to guide dose escalation decisions. 
For Part 2, an interim analysis is planned after all subjects have completed Cycle 8 (arms with 
NIS793) or Cycle 6 (all other arms)of study treatment or discontinued earlier. As described in 
Section 1.1, in this interim analysis, futile arms are dropped and the arm(s) to be considered for 
Part 3 are selected. In this interim analysis, no formal testing of the primary endpoint with 
respect to the success criterion described in Section 2.5 will be performed, i.e., no formal 
comparison between combination treatment arms and ruxolitinib will be performed.  
No interim analysis is planned for Part 3. An efficacy analysis comparing combination treatment 
arms and ruxolitinib will only be performed at the end of Part 3 as described in Section 2.5. 
3 
Sample size calculation 
3.1 
Primary analysis 
3.1.1 
Part 1 
No formal statistical power calculations were performed to determine sample size for this part 
of the study. 
Cohorts of 3 to 6 evaluable subjects will be enrolled in the dose escalation part including at 
least six subjects at the RP2D, as described in Section 6.5 of the protocol. Multiple cohorts may 
be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 subjects may be 
enrolled at any dose level below the estimated MTD for further elaboration of safety and 
pharmacokinetic parameters as required. At least 12 subjects are expected to be treated in the 


Novartis 
Confidential 
Page 47 
SAP 
 
CINC424H12201 
 
 
 
dose escalation part, for the model to have reasonable operating characteristics relating to its 
RP2D recommendation. 
3.1.2 
Part 2 
The primary objective of Part 2 is to evaluate the preliminary efficacy of the combination 
treatments and as outlined in Section 2.5 no formal hypothesis testing will be performed. While 
the totality of the data will be considered when deciding whether an arm will advance to Part 3, 
the decision whether an arm is futile will be based on the posterior probability distribution for 
the responder rate within each arm.  
Based on historical data from the COMFORT I and II studies, a primary endpoint response rate 
of less than 10% is expected for the ruxolitinib single agent arm. A treatment with a true 
response rate of 
• less than 10% generally does not warrant further investigation,  
• around 20% is potentially interesting,  
• more than 30% is of interest.  
 
Therefore, the criterion for the first interim look is defined as  
𝑃𝑃(𝑝𝑝i > 0.3|𝑛𝑛i, 𝑟𝑟i) > 0.8 
For a sample size of ni = 10 with a vague prior distribution, beta(1/2, 1/2), for the RR, an arm 
will be considered showing preliminary efficacy and advanced into Part 3 expansion seamlessly 
if ≥ 5 subjects are responders. Table 3-1 lists related operating characteristics for various true 
RRs. 
Table 3-1 
Probability of any arm to meet 1st interim look criterion for n = 10 and 
various true RRs 
True RR  
Single arm  
Two arms 
Four arms 
0.35 
0.2485 
0.4352 
0.6811 
0.4 
0.3669 
0.5992 
0.8393 
0.45 
0.4956 
0.7456 
0.9353 
0.5 
0.6230 
0.8579 
0.9798 
0.55 
0.7384 
0.9316 
0.9953 
0.6 
0.8338 
0.9724 
0.9992 
The table indicates that with the planned sample size of ni = 10, an arm with outstanding 
efficacy, i.e. a true RR of 0.5 or higher, has more than 60% probability to meet the criterion for 


Novartis 
Confidential 
Page 48 
SAP 
 
CINC424H12201 
 
 
 
the first interim look. If 2 arms each with true RR of 0.4, the probability of either arm meeting 
the criterion is close to 60%.  
The futility decision will be guided by the criterion 
 
For a sample size of ni = 25 with a vague prior distribution, beta(1/2, 1/2), for the RR, an arm 
fulfills the futility criterion if ≤ 4 subjects are responders. Table 3-2 lists futility related 
operating characteristics for various true RRs. 
Table 3-2 
Probability of arm(s) to fulfill futility criterion for n = 25 and various 
true RRs 
True RR 
Probability of declaring 
futility for a single arm  
Total probability of 
declaring futility for both 
arms when there are two 
arms in Part 2 
Total probability of 
declaring futility for all 4 
arms 
0.05 
0.9928 
0.9857 
0.9716 
0.1 
0.9020 
0.8136 
0.6620 
0.15 
0.6821 
0.4653 
0.2165 
0.2 
0.4207 
0.1770 
0.0313 
0.25 
0.2137 
0.0457 
0.0021 
0.3 
0.0905 
0.0082 
0.0001 
The table shows that with the planned sample size of ni = 25, an arm with low activity, i.e. a 
true RR of 0.1 or smaller, will fulfill the futility criterion with a probability of larger than 90%. 
For potentially interesting true RRs of pi = 0.2, there is an approximately 40% chance that the 
arm fulfills the futility criterion. For arms with a true RR of more than 30%, the probability to 
fulfill the futility criterion is less than 10%. If two combination arms are advanced in Part 2 and 
both arms have low activity, i.e. the true RR of 0.1 or smaller, the overall probability that both 
arms are considered futile is larger than 80%. If four combination arms are advanced in Part 2 
and all four arms have low activity, i.e. the true RR of 0.1 or smaller, the overall probability 
that all four arms are considered futile is approximately 66% or higher.  
3.1.3 
Part 3 
Combination treatments not stopped for futility or safety after Part 2 will be considered for 
expansion into Part 3. After Part 3, each combination treatment will be compared to the 
ruxolitinib monotherapy arm by evaluating whether the difference in the posterior distributions 
of the response rates for the primary endpoint is larger than zero with a probability of 90%, i.e. 
  


Novartis 
Confidential 
Page 49 
SAP 
 
CINC424H12201 
 
 
 
Table 3-3, Table 3-4 and Table 3-5 show the probability of possible outcomes for various true 
RRs in the ruxolitinib monotherapy arm (rux) for ncombo = 45 and nrux = 30, 35 and 40 
respectively, at the primary analysis (PA). Calculations assume the interim analysis (IA) is 
conducted with 25 subjects. The four possible outcomes are based on the futility at interim 
analysis (Yes/No) and the treatment meet the success criterion at primary analysis (Yes/No). 
The first interim look boundary is in line with the second interim look boundary in respect of 
the require number of responders. In the first interim look, the arm can be expanded, when there 
are 5 or more responders out of 10 subjects. Similarly, the arm can be expanded when there are 
5 or more responders out of 25 subjects because the arm is not futile. In Table 3-3, assuming a 
true RR of 0.1 for ruxolitinib monotherapy, and a true RR of 0.35 for combination treatment, 
the probability that the primary analysis is successful when the interim is not futile, is 0.8933. 
Table 3-3 
Probability for each possible trial outcome of a combination treatment 
with N combo=45 and N rux=30  
True RR for 
ruxolitinib 
monotherapy 
True RR for 
combination 
treatment 
IA Not Futile 
PA Fail 
IA Not Futile  
PA Success 
IA Futile  
PA Fail 
IA Futile  
PA Success 
0.05 
0.05 
0.0037 
0.0035 
0.9036 
0.0893 
0.15 
0.0678 
0.2501 
0.3800 
0.3021 
0.2 
0.0692 
0.5101 
0.1659 
0.2547 
0.25 
0.0467 
0.7396 
0.0568 
0.1570 
0.3 
0.0233 
0.8863 
0.0155 
0.0750 
0.1 
0.1 
0.0686 
0.0294 
0.8342 
0.0678 
0.2 
0.2328 
0.3466 
0.3025 
0.1182 
0.25 
0.2080 
0.5783 
0.1278 
0.0860 
0.3 
0.1400 
0.7695 
0.0435 
0.0470 
0.35 
0.0746 
0.8933 
0.0120 
0.0201 
0.15 
0.15 
0.2533 
0.0646 
0.6454 
0.0367 
0.25 
0.4143 
0.3719 
0.1759 
0.0379 
0.3 
0.3375 
0.5720 
0.0670 
0.0235 
0.35 
0.2214 
0.7465 
0.0208 
0.0112 
0.4 
0.1196 
0.8709 
0.0053 
0.0042 
0.2 
0.2 
0.4935 
0.0858 
0.4060 
0.0146 
0.3 
0.5442 
0.3654 
0.0808 
0.0097 
0.35 
0.4176 
0.5504 
0.0269 
0.0052 
0.4 
0.2709 
0.7196 
0.0073 
0.0021 
0.45 
0.1505 
0.8472 
0.0016 
0.0007  
Notes: IA = Interim Analysis; PA = Primary Analysis 
Table 3-4 
Probability for each possible trial outcome of a combination treatment 
with N combo=45 and N rux=35  
True RR for 
ruxolitinib 
monotherapy 
True RR for 
combination 
treatment 
IA Not Futile 
PA Fail 
IA Not Futile  
PA Success 
IA Futile  
PA Fail 
IA Futile  
PA Success 


Novartis 
Confidential 
Page 50 
SAP 
 
CINC424H12201 
 
 
 
0.05 
0.05 
0.0031 
0.0041 
0.9076 
0.0853 
0.15 
0.0576 
0.2603 
0.3446 
0.3375 
0.2 
0.0580 
0.5214 
0.1455 
0.2752 
0.25 
0.0375 
0.7487 
0.0489 
0.1648 
0.3 
0.0173 
0.8922 
0.0132 
0.0773 
0.1 
0.1 
0.0672 
0.0308 
0.8284 
0.0736 
0.2 
0.2227 
0.3566 
0.2969 
0.1238 
0.25 
0.1890 
0.5972 
0.1251 
0.0886 
0.3 
0.1174 
0.7921 
0.0421 
0.0483 
0.35 
0.0567 
0.9113 
0.0113 
0.0207 
0.15 
0.15 
0.2548 
0.0631 
0.6465 
0.0356 
0.25 
0.3955 
0.3908 
0.1768 
0.0369 
0.3 
0.3053 
0.6042 
0.0669 
0.0235 
0.35 
0.1883 
0.7796 
0.0205 
0.0116 
0.4 
0.0955 
0.8951 
0.0050 
0.0044 
0.2 
0.2 
0.4935 
0.0858 
0.4081 
0.0125 
0.3 
0.5190 
0.3905 
0.0811 
0.0093 
0.35 
0.3852 
0.5827 
0.0268 
0.0052 
0.4 
0.2403 
0.7502 
0.0072 
0.0023 
0.45 
0.1266 
0.8711 
0.0016 
0.0008 
Table 3-5 
Probability for each possible trial outcome of a combination treatment 
with N combo=45 and N rux=40  
True RR for 
ruxolitinib 
monotherapy 
True RR for 
combination 
treatment 
IA Not Futile 
PA Fail 
IA Not Futile  
PA Success 
IA Futile  
PA Fail 
IA Futile  
PA Success 
0.05 
0.05 
0.0027 
0.0044 
0.8851 
0.1077 
0.15 
0.0429 
0.2750 
0.3260 
0.3561 
0.2 
0.0386 
0.5407 
0.1281 
0.2925 
0.25 
0.0225 
0.7637 
0.0395 
0.1743 
0.3 
0.0096 
0.9000 
0.0097 
0.0808 
0.1 
0.1 
0.0631 
0.0349 
0.8277 
0.0743 
0.2 
0.1871 
0.3923 
0.2812 
0.1395 
0.25 
0.1522 
0.6341 
0.1134 
0.1003 
0.3 
0.0914 
0.8182 
0.0365 
0.0540 
0.35 
0.0425 
0.9254 
0.0094 
0.0226 
0.15 
0.15 
0.2447 
0.0732 
0.6434 
0.0387 
0.25 
0.3653 
0.4209 
0.1709 
0.0428 
0.3 
0.2760 
0.6335 
0.0636 
0.0268 
0.35 
0.1648 
0.8032 
0.0192 
0.0129 
0.4 
0.0796 
0.9109 
0.0047 
0.0048 
0.2 
0.2 
0.4860 
0.0933 
0.4066 
0.0141 
0.3 
0.5006 
0.4089 
0.0802 
0.0103 


Novartis 
Confidential 
Page 51 
SAP 
 
CINC424H12201 
 
 
 
0.35 
0.3626 
0.6054 
0.0264 
0.0057 
0.4 
0.2177 
0.7729 
0.0071 
0.0024 
0.45 
0.1085 
0.8892 
0.0015 
0.0008 
When the true RRs in the ruxolitinib monotherapy arm and the combination arm shown in 
Table 3-3, Table 3-4 and Table 3-5 are identical, the probabilities in the ‘IA Not Futile PA 
Success’ column can be considered to be the Bayesian equivalent to the type I error rate, i.e., 
the probability to wrongfully consider an inefficacious treatment as efficacious. This probability 
is smaller than 10% for all proposed sample sizes (ruxolitinib monotherapy sample size = 30, 
35, 40), depending on the treatment arm and group. When the true RRs for the ruxolitinib 
monotherapy arm is smaller than the combination arm, the probabilities in the ‘IA Not Futile 
PA Success’ column can be considered to be the Bayesian equivalent to the power. For a 
difference in RRs of 20%, the power is approximately 75% or higher for the considered 
ruxolitinib RRs for all proposed sample sizes. 
Next, the probability that the difference between the posterior distributions of the RRs is 
calculated for several potential trial outcomes and it is illustrated for which outcomes the trial 
would be considered successful with respect to the primary endpoint. The outcomes are shown 
in Table 3-6 for ncombo = 45 and nrux = 30, 35, and 40 respectively. The scenarios in which the 
trial would be considered successful are highlighted in bold. 
Finally, Section 5.9 of the protocol shows the simulated probabilities for a list of operating 
characteristic parameters under three hypothetical Part 2 and Part 3 study scenarios. 
Table 3-6 
Probability that the difference in the posterior distributions of the RRs 
is larger than zero 
  
Number of responders in ruxolitinib monotherapy arm nrux = 30 
3 (10.0%) 
5 (16.7%) 
7 (23.3%) 
9 (30.0%) 
11 (36.7%) 
Number of 
responders in 
combination 
treatment arm 
ncombo = 45  
5(11.1%) 
0.5519 
0.2420 
0.0797 
0.0206 
0.0042 
7(15.6%) 
0.7519 
0.4432 
0.1978 
0.0683 
0.0186 
9(20.0%) 
0.8777 
0.6368 
0.3617 
0.1602 
0.0557 
11(24.4%) 
0.9456 
0.7881 
0.5399 
0.2953 
0.1277 
13(28.9%) 
0.9780 
0.8888 
0.7004 
0.4560 
0.2389 
15(33.3%) 
0.9919 
0.9473 
0.8239 
0.6167 
0.3816 
17(37.8%) 
0.9973 
0.9774 
0.9066 
0.7549 
0.5371 
19(42.2%) 
0.9992 
0.9913 
0.9554 
0.8583 
0.6837 
21(46.7%) 
0.9998 
0.9970 
0.9809 
0.9263 
0.8042 
23(51.1%) 
0.9999 
0.9990 
0.9927 
0.9658 
0.8911 
25(55.6%) 
1.0000 
0.9997 
0.9975 
0.9859 
0.9461 
27(60.0%) 
1.0000 
0.9999 
0.9993 
0.9949 
0.9765 
 
Number of responders in ruxolitinib monotherapy arm nrux = 35 
3 (8.6%) 
5 (14.3%) 
7 (20.0%) 
9 (25.7%) 
11 (31.4%) 
5(11.1%) 
0.6408 
0.3327 
0.1349 
0.0443 
0.0120 
7(15.6%) 
0.8247 
0.5586 
0.3004 
0.1301 
0.0461 
9(20.0%) 
0.9247 
0.7456 
0.4971 
0.2709 
0.1210 


Novartis 
Confidential 
Page 52 
SAP 
 
CINC424H12201 
 
 
 
Number of 
responders in 
combination 
treatment arm  
ncombo = 45  
11(24.4%) 
0.9710 
0.8706 
0.6794 
0.4462 
0.2433 
13(28.9%) 
0.9899 
0.9415 
0.8184 
0.6219 
0.4015 
15(33.3%) 
0.9968 
0.9763 
0.9083 
0.7688 
0.5701 
17(37.8%) 
0.9991 
0.9914 
0.9587 
0.8737 
0.7217 
19(42.2%) 
0.9998 
0.9972 
0.9835 
0.9386 
0.8387 
21(46.7%) 
0.9999 
0.9992 
0.9941 
0.9735 
0.9167 
23(51.1%) 
1.0000 
0.9998 
0.9981 
0.9899 
0.9620 
25(55.6%) 
1.0000 
1.0000 
0.9995 
0.9966 
0.9848 
27(60.0%) 
1.0000 
1.0000 
0.9999 
0.9990 
0.9947 
 
Number of responders in ruxolitinib monotherapy arm nrux = 40 
3 (7.5%) 
5 (12.5%) 
7 (17.5%) 
9 (22.5%) 
11 (27.5%) 
Number of 
responders in 
combination 
treatment arm  
ncombo = 45  
5(11.1%) 
0.7124 
0.4200 
0.1994 
0.0786 
0.0263 
7(15.6%) 
0.8756 
0.6546 
0.4036 
0.2068 
0.0892 
9(20.0%) 
0.9531 
0.8235 
0.6141 
0.3884 
0.2079 
11(24.4%) 
0.9842 
0.9213 
0.7822 
0.5823 
0.3735 
13(28.9%) 
0.9952 
0.9691 
0.8922 
0.7482 
0.5555 
15(33.3%) 
0.9987 
0.9892 
0.9530 
0.8661 
0.7192 
17(37.8%) 
0.9997 
0.9966 
0.9819 
0.9372 
0.8428 
19(42.2%) 
0.9999 
0.9991 
0.9938 
0.9740 
0.9223 
21(46.7%) 
1.0000 
0.9998 
0.9981 
0.9906 
0.9662 
23(51.1%) 
1.0000 
1.0000 
0.9995 
0.9970 
0.9872 
25(55.6%) 
1.0000 
1.0000 
0.9999 
0.9992 
0.9958 
27(60.0%) 
1.0000 
1.0000 
1.0000 
0.9998 
0.9988 
4 
Change to protocol specified analyses 
No change from protocol specified analysis was made according to protocol amendment 8 per 
Protocol section 12. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment component: 
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going:  
The patient should be treated as on-going and the cut-off date should be used as the last 
dosing date.  
Scenario 1 should not applicable for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR  


Novartis 
Confidential 
Page 53 
SAP 
 
CINC424H12201 
 
 
 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:  
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.   
Case 2: Only Year (yyyy) of the dose end date is available and yyyy < the year of EOT date:   
            Use Dec31yyyy 
Case 3: Only Year (yyyy) of the dose end date is available and yyyy = the year of EOT date:  
            Use EOT date 
Case 4: Both Year (yyyy) and Month (mm) are available for dose end date, and yyyy = the 
year of EOT date and mm < the month of  EOT date:  
            Use last day of the Month (mm) 
For the primary CSR, all patients should have completed EOT page for the Part1 core 
treatment phase or Part 2, or have entered Part 1 extension treatment phase. The on-going 
status is only applicable for patients entered extension treatment phase. 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:  
Use the treatment start date 
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed. 
 
5.1.2 
AE, ConMeds and safety assessment date imputation 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
Missing 
Element 
Rule 
day, month, 
and year 
• No imputation will be done for completely missing dates 
day, month 
• If available year = year of study treatment start date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY  
o Else set start date = study treatment start date.  
• If available year > year of study treatment start date then 01JanYYYY 
• If available year < year of study treatment start date then 01JulYYYY 


Novartis 
Confidential 
Page 54 
SAP 
 
CINC424H12201 
 
 
 
Missing 
Element 
Rule 
Day 
• If available month and year = month and year of study treatment start 
date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01MONYYYY.  
o Else set start date = study treatment start date. 
• If available month and year > month and year of study treatment start 
date then 01MONYYYY   
• If available month and year < month year of study treatment start date 
then 15MONYYYY   
Table 5-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*if end of the on-treatment period  not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
• 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period *  
Day 
• 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period* 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided.  
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications.  
5.1.2.1 
Other imputations 
Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence  
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan.  
Missing death date 
For cases when either day is missing or both month and day are missing for the date of death, 
the following imputation rules will be implemented: 
• If only day is missing, then impute max [(1 mmm-yyyy), min(last contact date+1 , cutoff 
date)].  


Novartis 
Confidential 
Page 55 
SAP 
 
CINC424H12201 
 
 
 
If both day and month are missing, then impute max [(1 Jan-yyyy, min (last contact date +1, 
cutoff date)]. 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
The latest available MedDRA version at the time of the analyses should be used. The MedDRA 
version used should be specified in the footnote of relevant tables.   
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0.  
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).  
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 5 at the time of analysis will be used. The Novartis 
internal CTCAE grading document should be added as appendix to the CSR. 
For laboratory tests where grades are not defined by CTCAE v 5, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
Imputation Rules   
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC.  
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.   
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 


Novartis 
Confidential 
Page 56 
SAP 
 
CINC424H12201 
 
 
 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for  derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading 
For missing normal ranges, please follow ‘Normal ranges (Merck manual, July 2015) and 
conversion factors’ (column 4 of the link: 
 LAB - CTC grades in Novartis Oncology update 
for CTC Grade 5(26 Jul 2018).pdf) 
5.4 
Statistical considerations for siremadlin dose-escalation 
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data, the results of the Bayesian analyses and respective dosing decisions for some 
hypothetical data scenarios, and a simulation study of the operating characteristics of the model. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.4.2 
Statistical model 
Let π(d) be the risk of DLT for the combination of ruxolitinib given at combination agent 
(siremadlin or rineterkib) dose d, the dose-DLT model is logistic: 


Novartis 
Confidential 
Page 57 
SAP 
 
CINC424H12201 
 
 
 
Figure 5-1 
Logistic DLT model. 
 
where d* is used to scale the doses. Hence, α>0 is the odds of a DLT at d*; and β>0 is the 
increase in the log-odds of a DLT by a unit increase in log-dose. 
5.4.3 
Prior specifications for logistic parameters 
The Bayesian approach requires the specification of prior distributions for the model parameters 
log(α) and log(β). A meta-analytic-predictive (MAP) approach was used to derive the prior 
distribution for these model parameters.  
5.4.3.1 
Description of the meta-analytic-predictive (MAP) approach 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
(log(α*), log(β*)) of the new trial using DLT data from historical studies. 
Let rds and nds be the number of patients with a DLT, and the total number of patients at dose d in 
historical trial s (s = 1,...,S). The corresponding probability of a DLT is πds. The model 
specifications for the derivation of the MAP prior are as follows: 
 
Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution. This is implemented using JAGS version 4.2.0. The sample from this 
distribution is then approximated by a mixture of bivariate normal (BVN) distributions. BVN 


Novartis 
Confidential 
Page 58 
SAP 
 
CINC424H12201 
 
 
 
mixtures with increasing numbers of mixture components are fitted to the sample using the 
expectation-maximization (EM) algorithm (Dempster et al 1977). The optimal number of 
components of the mixture is then identified using the Akaike information criterion (AIC) 
(Akaike H 1974). 
5.4.3.2 
Single-agent siremadlin 
For the MAP model for siremadlin, reference dose d* = 50 mg is used, and data from one 
historical study with four regimens is available, so S = 4 is chosen. 
Weakly informative normal priors are assumed for μ1 and μ2, with means corresponding to a 
risk of DLT at the reference dose of 1/3, and a doubling in dose leading to a doubling in the 
odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such that (1) their 
medians correspond to substantial between trial heterogeneity, and (2) their uncertainty (95% 
prior interval) cover plausible between-trial standard deviations (Neuenschwander et al 2014).  
The prior distributions for the model used for deriving the MAP priors are specified in Table 5-3. 
Table 5-3 
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent model parameters 
Parameter 
Prior Distribution 
μ1 
N (mean = logit (1/3), sd = 2) 
μ2 
N (mean = 0, sd = 1) 
t1 
log-normal (mean = log (0.5), sd = log (2)/1.96) 
t2 
log-normal (mean = log (0.25), sd = log (2)/1.96) 
ρ 
uniform (-1,1) 
Historical data from study HDM201X2101 
The prior is determined based on solid tumor data from study HDM201X2101. 
In this study, four different regimens and dose-schedules where studied: 
• 1A: dose on day 1 of a three week cycle 
• 1B: dose on day 1 and on day 8 of a four week cycle 
• 2A: once dose daily for the first two weeks of a four week cycle 
• 2C: once daily dosing for the first week of a four week cycle 
The doses in the difference regimens are scaled to fit the schedule of siremadlin in the 
combination study, which is once daily for the first five days in a four-week cycle. 
In study HDM201X2101, the original interest was in DLTs in cycle 1, however after observing 
cumulative toxicity DLTs within the first two cycles were considered for the recommended 
dose for expansion (document release date 28-Oct-2016). As the ruxolitinib combination study 
focuses on DLTs occurring in the first two cycles, the corresponding DLTs from the study 
HDM201X2101 were considered. When building the MAP prior distribution for siremadlin, the 
different regimens from study HDM201X2101 were considered as different studies (see Table 
5-4). 


Novartis 
Confidential 
Page 59 
SAP 
 
CINC424H12201 
 
 
 
Table 5-4 
Regimens and doses from study HDM201X2101 
Regimen 
Dose 
level 
Dose per 
cycle 
Dose per 
day in  
5 day 
schedule 
N 
DLTs 
(CYCLE 1) 
Hematologic 
DLTs  
(CYCLE 2) 
DLTs 
considered 
for MAP 
1A 
12.5 
12.5 
2.5 
1 
0 
0 
0 
25 
25 
5.0 
1 
0 
0 
0 
50 
50 
10.0 
4 
0 
1 
1 
100 
100 
20.0 
4 
0 
0 
0 
200 
200 
40.0 
5 
0 
1 
1 
250 
250 
50.0 
6 
0 
1 
1 
350 
350 
70.0 
5 
2 
2 
4 
1B 
120 
240 
48.0 
9 
0 
2 
2 
150 
300 
60.0 
8 
1 
1 
2 
200 
400 
80.0 
3 
0 
Data n/a at 
cutoff 
0 
2A 
1 
14 
2.8 
1 
0 
0 
0 
2 
28 
5.6 
2 
0 
0 
0 
4 
56 
11.2 
4 
0 
0 
0 
7.5 
105 
21.0 
4 
0 
0 
0 
15 
210 
42.0 
4 
0 
1 
1 
20 
280 
56.0 
5 
0 
4 
4 
2C 
15 
105 
21.0 
8 
0 
1 
1 
20 
140 
28.0 
6 
0 
0 
0 
25 
175 
35.0 
5 
2 
0 
2 
5.4.3.3 
Summary of prior distributions 
To obtain the MAP prior for (log(α), log(β)), the predictive distribution obtained from data 
in Table 5-4 will be mixed with a vague prior assuming a weight of 0.5. This mixing takes into 
account the fact the that patient population from study HDM201X2101 and this combination 
study are not identical and that in this combination study a single-agent model is used to account 
for both the effect of siremadlin and potential interaction with ruxolitinib. 
The MAP prior for (log(α), log(β)) is a mixture of three multivariate normal distributions and 
it is summarized in Table 5-5. 
Table 5-5 
Prior distribution for the model parameters 
Prior for (log(α), log(β)) in the single agent DLT-model for the combination of siremadlin and 
ruxolitinib 
  
Mean 
Standard 
Deviations 
Correlation 
Weight 
MAP component 1 
(-0.771 ,0.492) 
(0.700, 0.435) 
0.221 
0.3255 
MAP component 2 
(-0.884, 0.051) 
(0.573, 0.643) 
0.237 
0.1745 


Novartis 
Confidential 
Page 60 
SAP 
 
CINC424H12201 
 
 
 
Prior for (log(α), log(β)) in the single agent DLT-model for the combination of siremadlin and 
ruxolitinib 
  
Mean 
Standard 
Deviations 
Correlation 
Weight 
MAP component 3 
(logit(1/2), 0) 
(2, 1) 
0 
0.5 
Prior summaries for DLT rates for are summarized in Table 5-6. 
Table 5-6 
Summary of prior distribution of DLT rates for the combination of 
siremadlin and ruxolitinib 
Siremadlin 
Dose (mg) 
Prior Probabilities that P(DLT) 
is in the interval: 
Mean 
SD 
Quantiles 
(0, 0.16) 
(0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
10 
0.7982 
0.0967 
0.1051 
0.1191 
0.1895 
0.0001 
0.0443 
0.7679 
20 
0.6526 
0.1932 
0.1542 
0.1793 
0.2103 
0.0011 
0.1046 
0.8384 
30 
0.4687 
0.3077 
0.2235 
0.2392 
0.2217 
0.0050 
0.1713 
0.8792 
40 
0.3035 
0.3630 
0.3335 
0.2996 
0.2297 
0.0110 
0.2425 
0.9087 
5.4.3.4 
Single-agent rineterkib 
For the MAP model for rineterkib, reference dose 𝑑𝑑∗= 300 mg is used, and data from 𝑆𝑆= 1 
historical studies (First in Human study) is available. 
Weakly informative normal priors are assumed for μ1 and μ2, with means corresponding to a 
10% risk of DLT at the reference dose of 300 mg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such that (1) their 
medians correspond to substantial between trial heterogeneity, and (2) their uncertainty (95% 
prior interval) cover plausible between-trial standard deviations (Neuenschwander et al 2014).  
The prior distributions for the model used for deriving the MAP priors are specified in  
Table 5-7. 
Table 5-7 
Prior distributions for the parameters of the MAP model used to derive 
the prior for the rineterkib model parameters 
Parameter 
Prior Distribution 
μ1 
N (mean = logit (0.1), sd = 2) 
μ2 
N (mean = 0, sd = 1) 
t1 
log-normal (mean = log (0.5), sd = log (2)/1.96) 
t2 
log-normal (mean = log (0.25), sd = log (2)/1.96) 
ρ 
uniform (-1,1) 
Historical data from Study LTT462X2101 
The dose-DLT data from rineterkib single agent from study LTT462X2101 are considered as 
the relevant information (Table 5-8) and used to derive the prior distribution for the BLRM 
parameters (log(α), log(β)). The clinical study LTT462X2101 is a phase I dose finding study of 


Novartis 
Confidential 
Page 61 
SAP 
 
CINC424H12201 
 
 
 
oral rineterkib in adult patients with advanced solid tumors harboring MAPK pathway 
alterations. 
The DLT observation window in the Phase I dose escalation part of this trial was 4 weeks. A 
review of AE records of the patients did not indicate any significant additional toxicity in the 
2nd cycle of treatment, suggesting data from the 1 cycle DLT evaluation period of study 
LTT462X2101 is also informative for a 2 cycle DLT evaluation period. 
Table 5-8 
Historical DLT data from Study LTT462X2101 
Dose (mg, daily/QD) 
Number of patients 
Number of DLTs 
45 
2 
0 
100 
3 
0 
150 
6 
1 
200 
4 
1 
300 
7 
0 
400 
4 
0 
450 
7 
2 
600 
3 
3 
Summary of prior distributions for rineterkib 
To obtain the MAP prior for (log(α), log(β)), the predictive distribution obtained from data 
in Table 5-9 will be mixed with a vague prior assuming a weight of 0.5. This mixing takes into 
account the fact the that patient population from study LTT462X2101 and this combination 
study are not identical and that in this combination study a single-agent model is used to account 
for both the effect of rineterkib and potential interaction with ruxolitinib. 
The MAP prior for (log(α), log(β)) is a mixture of four multivariate normal distributions and it 
is summarized in Table 5-9. 
Table 5-9 
Prior distribution for the model parameters 
Prior for (log(α), log(β)) in the single agent DLT-model for the combination of siremadlin and ruxolitinib 
  
Mean 
Standard 
Deviations 
Correlation 
Weight 
MAP component 1 
(-1.737, 0.330) 
(1.135, 0.685) 
-0.089 
0.190 
MAP component 2 
(-1.518, 0.571) 
(0.648, 0.478) 
-0.289 
0.163 
MAP component 3 
(-1.491, -0.211) 
( 0.764, 0.868) 
-0.018 
0.147 
MAP component 4 
(logit(1/4), 0) 
(2, 1) 
0 
0.5 
Prior summaries for DLT rates for are summarized in Table 5-10. 
Table 5-10 
Summary of prior distribution of DLT rates for the combination of 
rineterkib and ruxolitinib 
Rineterkib 
Dose (mg) 
Prior Probabilities that P(DLT) is in 
the interval: 
Mean 
SD 
Quantiles 
(0, 0.16) 
(0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
100 
0.7673 
0.1171 
0.1155 
0.1273 
0.1905 
0.0002 
0.0492 
0.7552 


Novartis 
Confidential 
Page 62 
SAP 
 
CINC424H12201 
 
 
 
Rineterkib 
Dose (mg) 
Prior Probabilities that P(DLT) is in 
the interval: 
Mean 
SD 
Quantiles 
(0, 0.16) 
(0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
200 
0.6126 
0.1989 
0.1885 
0.1966 
0.2183 
0.0040 
0.1142 
0.8444 
300 
0.4217 
0.2923 
0.2860 
0.2705 
0.2378 
0.0114 
0.1934 
0.8999 
5.4.4 
Hypothetical on-study data scenarios 
To illustrate the performance of the Bayesian model used to guide dose escalation, hypothetical 
dose escalations scenarios following the provisional dose levels specified in Section 6.5.1 in 
protocol are displayed. In each case, the maximum dose that can be used in the next cohort of 
subjects is shown. This recommended Phase 2 dose is determined using the model-based 
assessment of the risk of DLT in future subjects and the dose escalation rules as described in 
Section 6.5.1 in protocol. In practice, a dose below the maximum might be chosen based on 
additional safety, PK or PD information (Section 6.5 in protocol). 
The first three hypothetical dose escalation scenarios in Table 5-11 are for the case that the first 
cohort contains six subjects being administered a combination treatment with a siremadlin dose 
of 20 mg. Scenarios 4, 5, 6 and 7 are for the second cohort and the case that the first cohort 
contains six subjects receiving 20 mg siremadlin and two subjects having DLTs. Scenarios 8 
and 9 demonstrate if enrolling 2 and 3 subjects in Arm 1, the first 2 subjects experience a DLT, 
then further enrollment of Arm 1 will stop and the combination treatment will not open in Part 
2.  
Table 5-11 
Hypothetical dose escalation scenarios for a cohort size of n=6 
subjects receiving a dose of 20 mg 
Scenario 
Siremadlin 
Dose [mg] 
Number of 
Possible next dose levels 
patients 
DLTs 
Dose [mg] 
Median P(DLT) 
P(excessive 
toxicity) 
1 
20 
6 
0 
40 
0.162 
0.122 
2 
20 
6 
1 
30 
0.192 
0.148 
3 
20 
6 
2 
20 
0.206 
0.219 
4 
20 
6 
2 
 
 
 
 
20 
3 
0 
30 
0.233 
0.222 
5 
20 
6 
2 
 
 
 
 
20 
4 
0 
30 
0.221 
0.183 
6 
20 
6 
2 
 
 
 
 
20 
5 
0 
30 
0.212 
0.159 
7 
20 
6 
2 
 
 
 
 
20 
3 
1 
20 
0.233 
0.247 
Scenario 
Siremadlin 
Dose [mg] 
Number of 
Provisional lower dose levels 
patients 
DLTs 
Dose [mg] 
Median P(DLT) 
P(excessive 
toxicity) 
8 
20 
2 
2 
10* 
0.554 
0.696 
9 
20 
3 
2 
10* 
0.275 
0.435 


Novartis 
Confidential 
Page 63 
SAP 
 
CINC424H12201 
 
 
 
Scenario 
Siremadlin 
Dose [mg] 
Number of 
Possible next dose levels 
patients 
DLTs 
Dose [mg] 
Median P(DLT) 
P(excessive 
toxicity) 
*The possible next dose level is not available, as the probability of excessive toxicity of the lower 
dose does not satisfy EWOC criteria. The combination treatment will not open in Part 2. 
5.5 
Statistical considerations for MAP prior in sensitivity analysis 
This appendix provides details of the statistical model, the derivation of robustified MAP 
prior (Schmidli et al 2014) distributions from historical data.  
In Section 5.5.1, the statistical methodology for MAP priors is described and in Section 5.5.2 
the robust MAP prior for the ruxolitinib arm is derived.  
5.5.1 
Meta-analytic-predictive (MAP) approach hierarchical model 
5.5.1.1 
Statistical model 
Assume that there are H historical trials for ruxolitinib with the number of responders denoted 
as Y1,...,YH.  
For historical studies: 
𝑌𝑌ℎ ~ 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 (𝜋𝜋ℎ, 𝑛𝑛ℎ), and  𝜃𝜃ℎ= 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝜋𝜋ℎ), where ℎ= 1, … , 𝐻𝐻. 
For new study: 
𝑌𝑌∗ ~ 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 (𝜋𝜋∗, 𝑛𝑛∗), and  𝜃𝜃∗= 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝜋𝜋∗). 
The parameters 𝜃𝜃1, … , 𝜃𝜃𝐻𝐻, 𝜃𝜃∗ are assumed to be exchangeable and normally distributed 
𝜃𝜃1, … , 𝜃𝜃𝐻𝐻, 𝜃𝜃∗|𝛽𝛽, 𝜏𝜏2 ~ 𝑁𝑁(𝛽𝛽 , 𝜏𝜏2),  
where the prior distributions for hyper-parameters population mean 𝜇𝜇 and between-trial standard 
deviation 𝜏𝜏 are as follows: 
𝛽𝛽~𝑁𝑁(0, 𝜎𝜎𝛽𝛽 
2) 
𝜏𝜏~𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 (0, 𝜎𝜎𝜏𝜏 2) 
5.5.1.2 
MAP prior and robustification 
The MAP prior for the parameter in the new study 𝜋𝜋∗ is the predictive distribution  
𝜋𝜋∗|𝑌𝑌ℎ, 𝑛𝑛ℎ, where ℎ= 1, … , 𝐻𝐻 
The predictive distribution is not available analytically. A very large sample from this distribution using 
Markov chain Monte Carlo (MCMC) approach is simulated. This is implemented using JAGS 
version 4.2.0. The sample from this distribution is then approximated by a mixture of beta 
distributions. The beta mixtures with increasing numbers of mixture components are fitted to 
the sample using the expectation-maximization (EM) algorithm (Dempster et al 1977). The 
optimal number of components of the mixture is then identified using the Akaike information 
criterion (AIC) (Akaike H 1974). The mixture components 𝑘𝑘 are defined by a triplet 
(𝑤𝑤𝑘𝑘, 𝑎𝑎𝑘𝑘, 𝑏𝑏𝑘𝑘), where 𝑤𝑤𝑘𝑘 is the prior weight of the 𝑘𝑘th component, 𝑎𝑎𝑘𝑘 𝑎𝑎𝑎𝑎𝑎𝑎 𝑏𝑏𝑘𝑘 are the two prior 
beta distribution parameters of the 𝑘𝑘th component. The approximated MAP prior is  


Novartis 
Confidential 
Page 64 
SAP 
 
CINC424H12201 
 
 
 
𝑝𝑝(𝜋𝜋∗) = ෍𝑤𝑤𝑘𝑘𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵(𝜋𝜋∗|𝑎𝑎𝑘𝑘, 𝑏𝑏𝑘𝑘)
𝐾𝐾
𝑘𝑘=1
 
with positive weights 𝑤𝑤𝑘𝑘 summing up to one. 
A robust version of the MAP prior, is introduced by (Schmidli et al 2014) in consideration of 
potential prior-data conflict as follows.  
𝑝𝑝𝑅𝑅(𝜋𝜋∗) = (1 −𝑤𝑤𝑅𝑅)𝑝𝑝(𝜋𝜋∗) + 𝑤𝑤𝑅𝑅𝑝𝑝𝑅𝑅(𝜋𝜋∗), 
where 𝑝𝑝(𝜋𝜋∗) is the approximated MAP prior, 𝑝𝑝𝑅𝑅(𝜋𝜋∗) is a vague conjugate prior, and 𝑤𝑤𝑅𝑅 is the 
prior probability that the new trial differs systematically from the historical trials. The prior 
information is discarded with increasing prior-data conflict due to the heavy tail of the 
robustified MAP prior. 
5.5.2 
Robustified MAP prior calculation for ruxolitinib monotherapy 
The robustified MAP prior will be used for the response rate in the ruxolitinib monotherapy 
arm in the sensitivity analysis 1 as specified in Section 2.5.4. The MAP approach as described 
in Section 5.5.1 will be used for the prior derivation based on  historical data from INCB18424-
351 (Comfort I) and CINC424A2352 (Comfort II). The vague prior for the response rate in the 
combination arm is beta(1/2, 1/2), the same as the primary analysis. 
The prior distributions for the parameters of the MAP model, outlined in Section 5.5.1.1, for 
the ruxolitinib monotherapy arm are as follows: 
𝛽𝛽~𝑁𝑁(0, 10 2) 
𝜏𝜏~𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 (0, 𝜎𝜎𝜏𝜏 2) 
where a vague prior is set for  𝛽𝛽, and the Half-normal distribution for 𝜏𝜏 assumes a substantial between 
trial heterogeneity with standard deviation 0.91. 
Historical data from Comfort I and Comfort II studies were used for deriving the MAP prior of 
the ruxolitinib monotherapy arm. The response rate was derived following the definition 
described in Section 1.2, as applicable, for Comfort I and Comfort II. The MF symptoms were 
measured using MFSAF v2.0 questionnaire with total symptom score (TSS) range from 0-60. 
Follow the same definition, a TSS in increase of 10 or more from baseline is considered as 
symptoms worsening for Comfort I. MF symptoms were not assessed for Comfort II and the 
response rate is calculated based on two criteria: anemia improvement and no spleen volume 
progression. The Comfort I RR at Week 24 is 5.81%, 9 responders out of 155 subjects in the 
ruxolitinib arm. The Comfort II RR at Week 24 is 6.16%, 9 responders out of 146 subjects in 
the ruxolitinib arm.  
To obtain the robustified MAP prior for 𝜋𝜋∗ the predictive distribution obtained from the 
Comfort I and Comfort II RR data will be mixed with a vague prior assuming a weight of 0.5. 
This mixing takes into account the differences in patient population and symptom assessments 
between the COMFORT studies and CINC424H12201.  


Novartis 
Confidential 
Page 65 
SAP 
 
CINC424H12201 
 
 
 
The MAP prior for 𝜋𝜋∗, is a mixture of three beta distributions and it is summarized in Table 5-
12. The prior has mean 0.29, standard deviation 0.30, median 0.11, 95% credible interval (0.02, 
0.95).  
Table 5-12 
Prior distribution for the model parameters 
MAP Prior Components 
a 
b 
Weight 
MAP component 1 
5.56 
86.70 
0.40 
MAP component 2 
0.69 
4.19 
0.10 
Robust 
1.000 
1.000 
0.500 
The density plot of the MAP prior distribution is displayed in Figure 5-1.  
Figure 5-2 
Density plot of the MAP prior distribution 
 


Novartis 
Confidential 
Page 66 
SAP 
 
CINC424H12201 
 
 
 
5.6 
MFSAF v4.0 PRO 
 


Novartis 
Confidential 
Page 67 
SAP 
 
CINC424H12201 
 
 
 
5.7 
EORTC QLQ-C30 PRO 
 


Novartis 
Confidential 
Page 68 
SAP 
 
CINC424H12201 
 
 
 
 


Novartis 
Confidential 
Page 69 
SAP 
 
CINC424H12201 
 
 
 
5.8 
Scoring the QLQ-C30 
  


Novartis 
Confidential 
Page 70 
SAP 
 
CINC424H12201 
 
 
 
5.9 
Simulation for hypothetical Part 2 and Part 3 study scenarios 
The simulation assumed three groups for Part 2 and Part 3 of the study. Group 1 included 
Combination 1, Combination 2 and Ruxolitinib monotherapy; Group 2 included Combination 
3, Combination 4 and Ruxolitinib monotherapy; Group 3 included Combination 5 and 
Ruxolitinib monotherapy. The three groups are assumed to be enrolled in a sequential manner 
within Part 2 and Part 3. Three scenarios are simulated with the true RR for each treatment arm 
shown in Table 5-13. The probabilities for a list of operating characteristic parameters for the 
three hypothetical scenarios are presented in Table 5-14. 
Table 5-13 
Hypothetical true RR for each treatment arm 
Scenarios 
True RR 
RUX 
COMB1 
COMB2 
COMB3 
COMB4 
COMB5 
Scenario1 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
Scenario2 
0.05 
0.3 
0.05 
0.05 
0.05 
0.05 
Scenario3 
0.05 
0.05 
0.2 
0.3 
0.05 
0.25 
Table 5-14 
Probabilities for a list of operating characteristic parameters for 
hypothetical scenarios of the study 
Scenarios  
Probabilities 
All combo arms 
are futile 
All combo arms are 
futile at IA or not 
success at PA 
Any combo arm(s) is 
not futile at IA and 
success at PA 
Any combo arm(s) 
with true RR>0.2 is 
not futile at IA and 
success at PA 
Scenario1 
0.9651 
0.9800 
0.0200 
0.0000 
Scenario2 
0.0894 
0.1145 
0.8855 
0.8841 
Scenario3 
0.0100 
0.0177 
0.9823 
0.9713 
Scenario 1 assumed all treatment arms have equal true RR and do not warrant further 
development (RR=0.05). The column ‘All combo arms are futile at IA or not success at PA’ in 
Table 5-14 shows the probability to reject all inefficacious treatments at interim or primary 
analysis. Scenario 2 assumed one combination treatment in Group 1 has a true RR of interest 
(i.e. RR>0.2). Scenario 3 assumed one combination treatment in each Group has true RR of 
interest (i.e. RR>0.2). The column ‘Any combo arm(s) with true RR>0.2 is not futile at IA and 
success at PA’ shows the probability to select any combination arm or arms that are of interest 
for the study. 
 


Novartis 
Confidential 
Page 71 
SAP 
 
CINC424H12201 
 
 
 
6 
Reference 
1. Aaronson N. et Al (1993) The European Organization for Research and Treatment of 
Cancer QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical Trials in 
Oncology journal of National Cancer Institute, Vol. 85, No. 5 Marche 3. 1993 p. 365-76. 
2. Akaike H (1974) A new look at the statistical model identification. Selected Papers of 
Hirotugu Akaike. Springer, New York, NY, p. 716-23. 
3. Dempster AP, Laird NM, Rubin DB (1977) Maximum likelihood from incomplete data 
via the EM algorithm. Journal of the Royal Statistical Society, Series B p. 39(1):1-38. 
4. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.Gwaltney C, Paty J, Kwitkowski VE, 
et al (2017) Development of a harmonized patient-reported outcome questionnaire to 
assess myelofibrosis symptoms in clinical trials. Leuk. Res. p. 26-31. 
5. Neuenschwander, B., et al. (2010). "Summarizing historical information on controls in 
clinical trials." Clinical Trials 7(1): 5-18. 
6. Neuenschwander B, Matano A, Tang Z, et al (2014) A Bayesian Industry Approach to 
Phase I Combination Trials in Oncology. Statistical Methods in Drug Combination 
Studies p. 96 - 135. 
7. Schmidli, H., et al. (2014). "Robust meta‐analytic‐predictive priors in clinical trials 
with historical control information." Biometrics 70(4): 1023-1032. 
8. Spiegelhalter DJ, Abrams KR and Myles JP (2004). Bayesian Approaches to Clinical 
Trials and Health-care Evaluation. Chichester, Wiley.