Conditions: Myelofibrosis Primary Myelofibrosis Post Essential Thrombocythemia Myelofibrosis Post Polycythemia Vera Myelofibrosis
Keywords: INCB050465 ruxolitinib parsaclisib LIMBER LIMBER-304 MF MPN Myeloproliferative Neoplasm Myelofibrosis Myoproliferative Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 177
Healthy volunteers: no

Brief summary:
The purpose of the study is to compare the efficacy and safety of parsaclisib when combined with ruxolitinb versus placebo combined with ruxolitinib in participants with myelofibrosis who have suboptimal response while receiving ruxolitinib monotherapy.

Detailed description:
Prospective participants must be on stable doses of ruxolitinib ranging from 5 mg BID to 25 mg BID and will have been on that dose for at least the last 8 weeks prior to Day 1. At least 3 months duration of prior ruxolitinib is required. Participants must meet Protocol-defined criteria for suboptimal response to ruxolitinib monotherapy. After participants have been determined to be eligible for the study and completed the baseline symptom diary assessment for 7 days, they will be randomized to 1 of 2 treatment groups, with stratification for platelet count (≥ 100 × 10\^9/L vs 50 to \< 100 × 10\^9/L inclusive) and DIPSS risk category (high vs intermediate-2 vs intermediate-1).

Once a participant has completed the week 24 assessments, the participant's treatment assignment will then be unblinded and if found to be placebo, the participant will have the opportunity to crossover to begin receiving parsaclisib, together with continued ruxolitinib, as long as hematology parameters are adequate.

Arms:
arm 1: Participants will receive parsaclisib starting from Day 1 for the duration of study, while continuing to receive the stable dose of ruxolitinib they were taking for the 8 weeks prior to Day 1. arm 2: Participants will receive placebo starting from Day 1 for the duration of study, while continuing to receive the stable dose of ruxolitinib they were taking for the 8 weeks prior to Day 1.

Interventions: intervention 1: parsaclisib intervention 2: ruxolitinib intervention 3: placebo
Intervention descriptions: intervention 1: parsaclisib will be administered QD orally intervention 2: ruxolitinib will be administered BID orally intervention 3: placebo will be administered QD orally

Protocol document:
Prot_000.pdf: 
Official Title:    A Randomized, Double-Blind, Placebo-Controlled Study of the PI3Kδ Inhibitor 
Parsaclisib Plus Ruxolitinib in Participants With Myelofibrosis Who Have 
Suboptimal Response to Ruxolitinib
NCT Number: 
 NCT04551053 
Document Date: 
Protocol Amendment 2: 20-Oct-2022


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Protocol INCB 50465-304 Am 2 
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CONFIDENTIAL 
Clinical Study Protocol 
TITLE PAGE 
INCB 50465-304 
A Randomized, Double-Blind, Placebo-Controlled Study of the 
PI3Kδ Inhibitor Parsaclisib Plus Ruxolitinib in Participants With 
Myelofibrosis Who Have Suboptimal Response to Ruxolitinib 
Product: 
Parsaclisib (INCB050465) 
IND Number: 
147,207 
EudraCT Number: 
2020-003415-98 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
17 JUL 2020 
Amendment 1: 
07 OCT 2021 
Amendment 2: 
20 OCT 2022 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and country-specific regulations in which the study is being conducted. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 


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INVESTIGATOR'S AGREEMENT 
I have read the INCB 50465-304 Protocol Amendment 2 (Version 3 dated 20 OCT 2022) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR'S AGREEMENT ................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................12 
2. 
INTRODUCTION ......................................................................................................22 
2.1. 
Overview of Myelofibrosis .........................................................................................22 
2.2. 
Role of Janus Kinase Pathway in Myelofibrosis ........................................................23 
2.3. 
Role of PI3K/Protein Kinase B Signaling Pathway in Myelofibrosis ........................24 
2.4. 
Treatment of Myelofibrosis ........................................................................................24 
2.5. 
Study Rationale ...........................................................................................................25 
2.5.1. 
Scientific Rationale for Study Design ........................................................................25 
2.5.2. 
Justification for Dose ..................................................................................................26 
2.6. 
Benefit/Risk Assessment ............................................................................................26 
2.6.1. 
Risks and Benefits of Parsaclisib ................................................................................26 
2.6.1.1. 
Potential Risks of Parsaclisib Based on Preclinical Findings .....................................26 
2.6.1.2. 
Potential Risks of Parsaclisib Based on Prior and Ongoing Clinical Studies .............26 
2.6.1.3. 
Potential Risks of PI3K Inhibition Based on Other Agents in Class ..........................27 
2.6.1.4. 
Potential Benefits of Parsaclisib .................................................................................27 
2.6.2. 
Risks of Ruxolitinib ....................................................................................................28 
2.6.2.1. 
Potential Risks of Ruxolitinib .....................................................................................28 
2.6.2.2. 
Potential Risks of Parsaclisib Plus Ruxolitinib ..........................................................28 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................29 
4. 
STUDY DESIGN .......................................................................................................31 
4.1. 
Overall Design ............................................................................................................31 
4.1.1. 
Study Schedule/Procedures ........................................................................................31 
4.1.2. 
Unblinding and Crossover ..........................................................................................32 
4.1.3. 
Early Unblinding and Crossover ................................................................................32 
4.1.4. 
Early Unblinding/Crossover Process ..........................................................................33 
4.1.5. 
Participant Unblinding/Crossover Process After Completion of the Week 24 
Assessments ................................................................................................................34 
4.2. 
Overall Study Duration ...............................................................................................34 


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4.3. 
Study Termination ......................................................................................................34 
5. 
STUDY POPULATION .............................................................................................35 
5.1. 
Inclusion Criteria ........................................................................................................35 
5.2. 
Exclusion Criteria .......................................................................................................36 
5.3. 
Lifestyle Considerations .............................................................................................38 
5.4. 
Screen Failures ............................................................................................................38 
5.5. 
Replacement of Participants .......................................................................................38 
5.6. 
Data Monitoring Committee .......................................................................................39 
6. 
STUDY TREATMENT ..............................................................................................39 
6.1. 
Study Treatments Administered .................................................................................39 
6.2. 
Preparation, Handling, and Accountability ................................................................41 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................42 
6.4. 
Dose and Requirement to Start Dosing After Crossover ............................................42 
6.5. 
Study Treatment Compliance .....................................................................................43 
6.6. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
and/or Pharmacologically Active Dose ......................................................................43 
6.7. 
Dose Modifications .....................................................................................................43 
6.7.1. 
Dose Increases for Inadequate Efficacy .....................................................................43 
6.7.2. 
Dose Decreases of Parsaclisib/Placebo for Toxicity ..................................................43 
6.7.3. 
Supportive Care for Diarrhea/Colitis ..........................................................................46 
6.7.4. 
Follow-Up for Immune Related Adverse Events .......................................................47 
6.7.5. 
COVID-19 ..................................................................................................................47 
6.7.6. 
Criteria for Permanent Discontinuation of Parsaclisib/Matching Placebo .................48 
6.7.7. 
Dose Decreases of Ruxolitinib for Safety ..................................................................48 
6.8. 
Concomitant Medications and Procedures .................................................................49 
6.8.1. 
Permitted Medications ................................................................................................49 
6.8.2. 
Pneumocystis jirovecii Pneumonia Prophylaxis .........................................................49 
6.8.3. 
Use of Growth Factors Such as Erythropoietin ..........................................................50 
6.8.4. 
Restricted Medications and Procedures ......................................................................50 
6.8.5. 
Prohibited Medications and Procedures .....................................................................50 
6.8.6. 
Treatment After Week 24 ...........................................................................................51 
7. 
DISCONTINUATION OF STUDY TREATMENTS AND PARTICIPANT 
WITHDRAWAL ........................................................................................................51 


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7.1. 
Discontinuation of Study Treatment ...........................................................................51 
7.1.1. 
Reasons for Discontinuation .......................................................................................51 
7.1.2. 
Discontinuation Procedures ........................................................................................52 
7.2. 
Participant Withdrawal From the Study .....................................................................52 
7.3. 
Lost to Follow-Up.......................................................................................................53 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................54 
8.1. 
Administrative and General Procedures .....................................................................54 
8.1.1. 
Informed Consent Process ..........................................................................................54 
8.1.2. 
Screening Procedures ..................................................................................................55 
8.1.3. 
Baseline .......................................................................................................................55 
8.1.4. 
Interactive Response Technology Procedure ..............................................................56 
8.1.5. 
Distribution of Reminder Cards ..................................................................................56 
8.1.6. 
Prior and Concomitant Medications ...........................................................................56 
8.1.7. 
Demography and Medical History ..............................................................................57 
8.1.7.1. 
Demographics and General Medical History .............................................................57 
8.1.7.2. 
Disease Characteristics and Treatment History ..........................................................57 
8.1.7.3. 
Transfusion History Status .........................................................................................57 
8.1.7.4. 
Dosing Diary ...............................................................................................................57 
8.1.7.5. 
Screening Symptom Form ..........................................................................................57 
8.1.8. 
Study Site Visit Coordination .....................................................................................57 
8.2. 
Efficacy Assessments .................................................................................................58 
 
58 
 
58 
8.2.3. 
Imaging .......................................................................................................................58 
8.2.4. 
Symptom Diary ...........................................................................................................59 
 
59 
8.2.6. 
Eastern Cooperative Oncology Group Status .............................................................59 
 
59 
 
59 
 
60 
 
60 
 
60 
 
60 


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60 
8.3. 
Safety Assessments .....................................................................................................60 
8.3.1. 
Adverse Events ...........................................................................................................60 
8.3.2. 
Physical Examinations ................................................................................................61 
8.3.3. 
Vital Signs ..................................................................................................................61 
8.3.4. 
Electrocardiograms .....................................................................................................61 
8.3.5. 
Laboratory Assessments .............................................................................................62 
8.3.5.1. 
Chemistry ....................................................................................................................62 
8.3.5.2. 
Hematology .................................................................................................................62 
8.3.5.3. 
Urinalysis ....................................................................................................................62 
8.3.5.4. 
Serology and Virology ................................................................................................63 
8.3.5.5. 
Lipid Panel ..................................................................................................................63 
8.3.5.6. 
Pregnancy Testing ......................................................................................................63 
8.3.5.7. 
Coagulation Panel .......................................................................................................63 
 
65 
 
65 
 
66 
 
66 
 
66 
 
66 
8.6. 
Unscheduled Visits .....................................................................................................67 
8.7. 
End of Treatment and/or Early Termination ..............................................................67 
8.8. 
Follow-Up ...................................................................................................................67 
8.8.1. 
Safety Follow-Up ........................................................................................................67 
8.8.2. 
Survival Follow-Up ....................................................................................................68 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................68 
9.1. 
Definition of Adverse Event .......................................................................................68 
9.2. 
Definition of Serious Adverse Event ..........................................................................69 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........70 
9.4. 
Reporting of Serious Adverse Events .........................................................................72 
9.5. 
Adverse Events of Special Interest .............................................................................73 
9.6. 
Emergency Unblinding of Treatment Assignment .....................................................74 


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9.7. 
Pregnancy ...................................................................................................................74 
9.8. 
Warnings and Precautions ..........................................................................................75 
9.9. 
Product Complaints ....................................................................................................75 
9.10. 
Treatment of Overdose ...............................................................................................76 
10. 
STATISTICS ..............................................................................................................76 
10.1. 
Sample Size Determination ........................................................................................76 
10.2. 
Populations for Analysis .............................................................................................76 
10.3. 
Level of Significance ..................................................................................................77 
10.4. 
Statistical Analyses .....................................................................................................77 
10.4.1. 
Primary and Secondary Analyses ...............................................................................77 
10.4.2. 
Safety Analyses ..........................................................................................................80 
 
81 
10.5. 
Interim Analysis ..........................................................................................................82 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................83 
11.1. 
Investigator Responsibilities .......................................................................................83 
11.1.1. 
Identification of the Coordinating Principal Investigator ...........................................84 
11.2. 
Data Management .......................................................................................................84 
11.3. 
Data Quality Assurance ..............................................................................................87 
11.4. 
Data Privacy and Confidentiality of Study Records ...................................................87 
11.5. 
Financial Disclosure ...................................................................................................88 
11.6. 
Publication Policy .......................................................................................................88 
11.7. 
Study and Site Closure................................................................................................89 
12. 
REFERENCES ...........................................................................................................90 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................93 
APPENDIX B. WORSENING SYMPTOMATIC SPLENOMEGALY FORM ........................94 
APPENDIX C. SCREENING SYMPTOM FORM ....................................................................95 
APPENDIX D. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS .......................................................................................96 
 
97 
 
 
 
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APPENDIX G. INHIBITORS AND INDUCERS OF CYTOCHROME P450........................100 
APPENDIX H. INSTRUCTION TO PARTICIPANTS FOR HANDLING STUDY 
DRUG (PARSACLISIB OR PLACEBO) AND REFERENCE 
TREATMENT (RUXOLITINIB) .............................................................................107 
 
108 
APPENDIX J. PROTOCOL AMENDMENT SUMMARY OF CHANGES ...........................109 
 
LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................12 
Table 2: 
Key Study Design Elements .......................................................................................13 
Table 3: 
Schedule of Activities for Randomized Participants in Group A, Group B, 
and After Crossover ....................................................................................................15 
Table 4: 
Schedule of Additional Study Visits for Participants Who Cross Over .....................18 
Table 5: 
Schedule of Laboratory Assessments for All Participants .........................................19 
Table 6: 
Risk Categories for Myelofibrosis ..............................................................................23 
Table 7: 
Objectives and Endpoints ...........................................................................................29 
Table 8: 
Risk Categories According to DIPSS .........................................................................35 
Table 9: 
Risk Factors and Point Assignments for DIPSS .........................................................35 
Table 10: Study Treatment Information .....................................................................................40 
Table 11: Guidelines for Interruption and Restarting of Parsaclisib/Matching Placebo ............44 
Table 12: Dose Strengths for Parsaclisib/Matching Placebo ......................................................46 
Table 13: Dose Reductions/Interruptions and Restarts for Hematologic Toxicities That 
Persist for > 14 Days After Interruption of Parsaclisib ..............................................48 
Table 14: Required Laboratory Analytes ....................................................................................64 
 
65 
Table 16: Populations for Analysis .............................................................................................77 
Table 17: Primary and Secondary Analyses Methods and Populations .....................................78 
Table 18: Criteria for Clinically Notable Electrocardiogram Abnormalities .............................80 
Table 19: Interim Analysis for Spleen Volume With HSD(2) ...................................................82 
Table 20: Interim Analysis for MFSAF TSS With HSD(1) .......................................................83 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................14 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AE 
adverse event 
AKT 
protein kinase B 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
 
 
BID 
twice daily 
CALR 
calreticulin 
CI 
clinical improvement 
 
 
CMH 
Cochran-Mantel-Haenzel 
CMV 
cytomegalovirus 
COVID-19  
coronavirus disease 2019 
CR 
complete response  
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DIPSS 
Dynamic International Prognostic Scoring System 
DMC 
Data Monitoring Committee  
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
 
 
 
EOT 
end of treatment 
ET 
essential thrombocythemia 
FDA 
Food and Drug Administration 


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Abbreviations and 
Special Terms 
Definition 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HGB 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1986 
HIV 
human immunodeficiency virus 
HSD 
Hwang-Shih-DeCani 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IL 
interleukin 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous 
 
 
IXRS 
interactive web/voice response system 
JAK 
Janus kinase 
LCM 
left costal margin 
LDL 
low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MFSAF v4.0 
Myelofibrosis Symptom Assessment Form v4.0 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MPN 
myeloproliferative neoplasms 
 
 
MRI 
magnetic resonance imaging 
MRT 
Myeloproliferative Neoplasms Research and Treatment 


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Abbreviations and 
Special Terms 
Definition 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
 
  
PET-MF 
post-essential thrombocythemia myelofibrosis 
 
 
PI3K 
phosphatidylinositol 3-kinase 
 
 
PJP 
Pneumocystis jirovecii pneumonia 
PMDA 
Pharmaceutical and Medical Devices Agency 
PMF 
primary myelofibrosis 
PP 
per protocol 
PPV-MF 
post-polycythemia vera myelofibrosis 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PV 
polycythemia vera 
Q12W 
every 12 weeks 
QD 
once daily 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SoA 
schedule of activities 
SOP 
standard operating procedure 
STAT 
signal transduction and activator of transduction 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
TSS 
total symptom score 
ULN 
upper limit of normal 
WBC 
white blood cell 
 
 
 


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1. 
PROTOCOL SUMMARY 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled Study of the PI3Kδ Inhibitor 
Parsaclisib Plus Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response 
to Ruxolitinib 
Protocol Number:  INCB 50465-304 
Objectives and Endpoints: 
Table 1 presents the primary and major/key secondary objectives and endpoints. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate and compare the efficacy of 
parsaclisib plus ruxolitinib versus placebo plus 
ruxolitinib on spleen volume at Week 24. 
Proportion of participants achieving ≥ 25% 
reduction in spleen volume from baseline to 
Week 24 as measured by MRI (or CT scan in 
applicable participants). 
Major/Key Secondary 
To evaluate and compare the effect of parsaclisib 
plus ruxolitinib versus placebo plus ruxolitinib 
on participant reports of MF symptoms. 
Proportion of participants who have a ≥ 50% 
reduction in TSS from baseline to Week 24 as 
measured by the MFSAF v4.0 diary. 
Change in TSS from baseline to Week 24 as 
measured by the MFSAF v4.0 diary. 
Time to the first ≥ 50% reduction in TSS as 
measured by the MFSAF v4.0 diary. 
To evaluate and compare the effect of parsaclisib 
plus ruxolitinib versus placebo plus ruxolitinib 
with respect to OS. 
OS determined from the date of randomization 
until death due to any cause. 
To evaluate and compare the safety and 
tolerability of parsaclisib plus ruxolitinib versus 
placebo plus ruxolitinib. 
Safety and tolerability will be assessed by 
monitoring the frequency and severity of AEs, 
performing physical examinations, and evaluating 
changes in vital signs, ECGs, and laboratory 
results. 
Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 


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Table 2: 
Key Study Design Elements 
Study Phase 
Phase 3 
Clinical Indication 
Treatment of patients with primary and secondary MF 
Population 
Participants with primary or secondary MF who have residual signs and 
symptoms while on a stable dose of ruxolitinib.   
Number of 
Participants 
Approximately 212 participants will be randomized 1:1 to 1 of 2 groups 
(106 participants per group). 
Note:  Certain countries must meet a minimum enrollment regulatory 
requirement; therefore, enrollment in these countries may continue after 
enrollment in other countries ends. 
Group A:  parsaclisib plus ruxolitinib 
Group B:  placebo plus ruxolitinib 
Study Design 
Randomized, double-blind.  Participants will be randomized on Day 1 to 
Group A or Group B with stratification for baseline platelet count 
(≥ 100 × 109/L versus 50 to < 100 × 109/L inclusive) and DIPSS risk category 
(high vs intermediate-2 vs intermediate-1).  If a participant's platelet count has 
decreased to < 50 × 109/L at baseline, the platelet count at screening will be 
used for stratification/randomization. 
Estimated Duration 
of Study 
Participation 
Screening:  Up to 28 days. 
Baseline:  7 days before first dose of parsaclisib/matching placebo plus 
ruxolitinib. 
Treatment period:  Begins with the first dose of parsaclisib or matching 
placebo and ruxolitinib (Day 1).  Participants will receive daily doses of 
parsaclisib or matching placebo of 5 mg together with ruxolitinib.  The 
primary endpoint portion of study treatment is from Day 1 to the end of 
Week 24. 
Extension period:  After 24 weeks, participants may enter the extension period 
of the study.  Treatment will continue as long as the regimen is tolerated and 
the participant does not meet discontinuation criteria. 
Participants who discontinue study treatment will be followed for subsequent 
MF treatments and survival. 
When a participant has completed the Week 24 visit with assessments 
(including imaging), this participant will be unblinded, and if found to have 
been randomized to the placebo/ruxolitinib group may crossover to treatment 
with parsaclisib plus ruxolitinib.  Early crossover is possible in exceptional 
circumstances for participants who demonstrate worsening symptomatic 
splenomegaly. 
Follow-up period:  30 to 35 days after the last dose of medication is taken. 
Survival follow-up period:  Until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
It is estimated that an individual participant will be in the study for 
approximately 24 months.   
DSMB/DMC 
Yes (external) 


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Table 2: 
Key Study Design Elements (Continued) 
Interim Analyses 
Two interim futility analyses will be performed.  The first interim analysis will 
be performed when the first 30% of participants have been randomized to the 
2 groups (approximately 32 per group) and have completed Week 12 
assessments (including imaging).  The second interim analysis will be 
performed when the first 30% of participants have completed Week 24 
assessments (including imaging).    
Coordinating 
Principal 
Investigator 
, MD, PhD 
 
 
, France 
Treatment Groups and Duration: 
This is a Phase 3, randomized, double blind study of the combination of the PI3Kδ inhibitor 
parsaclisib or matching placebo and the JAK1/2 inhibitor ruxolitinib in participants with PMF or 
secondary MF (PPV-MF or PET-MF) who have suboptimal response while receiving ruxolitinib 
monotherapy.  Prospective participants must be on stable doses of ruxolitinib ranging from 5 mg 
BID to 25 mg BID and will have been on that dose for at least the last 8 weeks.  At least 
3 months duration of prior ruxolitinib is required.  Participants must meet Protocol-defined 
criteria for suboptimal response to ruxolitinib monotherapy.  After participants have been 
determined to meet all criteria, they will be randomized to 1 of 2 treatment groups and will 
receive parsaclisib or matching placebo at a dose of 5 mg QD beginning on Day 1.  Participants 
will also continue to receive the stable dose of ruxolitinib they were taking for the 8 weeks prior 
to Day 1.  Both parsaclisib/matching placebo and ruxolitinib dosing will continue for the 
duration of participation in the study. 
Figure 1 presents the study design schema, and Table 3, Table 4, and Table 5 show the SoA for 
study site visit assessments, post-crossover assessments, and laboratory assessments, 
respectively.  Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
Figure 1: 
Study Design Schema 
 


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Table 3: 
Schedule of Activities for Randomized Participants in Group A, Group B, and After Crossover 
Visit Day (Range) 
Screening 
Day −35 
to Day −8 
Baseline 
Day –7 
to 
Day –1 
Day 1 
End of 
Week 2 
± 3 
Days 
End of 
Weeks 4, 
8, 16, 20 
± 5 Days 
End of 
Week 12 
and 24 
± 5 Days 
Extension 
Visits (Q12W 
After Week 24) 
± 7 Days 
EOT or 
ET Visit 
± 5 Days 
Safety 
Follow-Up 
EOT +  
30-35 Days 
Survival 
Follow-Up 
Every 
12 Weeks 
± 2 Weeks 
Notes 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Contact IXRS 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
General and disease 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense 
parsaclisib/matching 
placebo 
 
 
X 
 
X 
X 
X 
 
 
 
 
Administer 
parsaclisib/matching 
placebo and ruxolitinib 
at clinic visit 
 
 
X 
X 
X 
X 
 
 
 
 
 
Distribute reminder 
cards and dosing diary 
where applicable 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect study drug and 
review dosing diary 
 
 
 
 
X 
X 
X 
X 
 
 
 
Assess drug compliance 
 
 
 
 
X 
X 
X 
X 
 
 
 
Transfusion history 
status 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Record of transfusions must 
include at least 12 weeks prior 
to screening visit. 
Safety assessments 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body systems with symptoms 
should be physically 
examined. 
Physical examination 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Complete physical 
examination at screening and 
EOT visits, targeted physical 
examination at the other visits. 
Height at screening only. 


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Table 3: 
Schedule of Activities for Randomized Participants in Group A, Group B, and After Crossover (Continued) 
Visit Day (Range) 
Screening 
Day −35 
to Day −8 
Baseline 
Day –7 
to 
Day –1 
Day 1 
End of 
Week 2 
± 3 
Days 
End of 
Weeks 4, 
8, 16, 20 
± 5 Days 
End of 
Week 12 
and 24 
± 5 Days 
Extension 
Visits (Q12W 
After Week 24) 
± 7 Days 
EOT or 
ET Visit 
± 5 Days 
Safety 
Follow-Up 
EOT +  
30-35 Days 
Survival 
Follow-Up 
Every 
12 Weeks 
± 2 Weeks 
Notes 
Vital signs, weight 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
 
 
 
 
X* 
 
X 
 
 
*Week 24 only. 
PJP 
 
X 
X 
X 
X 
X 
X 
X 
 
PJP prophylaxis can be started 
anytime beginning at Baseline 
visit up to Day 1 and will 
continue through at least 
2-6 months beyond the last 
dose of study treatment. 
Efficacy assessments 
Screening Symptom 
Form 
X 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy 
and aspirate 
X* 
*Screening 
 
 
  Screening 
 
 not required if biopsy 
from prior 2 months available 
(report and samples). 
MRI/CT scan of the 
upper and lower 
abdomen and pelvis 
 
X 
 
 
 
X 
X 
 
 
 
No MRI/CT scan after 
Week 108. 
Dispense and/or bring 
MFSAF v4.0 diary to 
visit 
 
X 
X 
 
X 
X 
 
 
 
 
 
MFSAF v4.0 diary  
 
Completed every evening from baseline through 
Week 24 
 
 
 
 
 
ECOG performance 
status 
X 
 
 
 
 
X 
 
 
X 
 
 


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Table 3: 
Schedule of Activities for Randomized Participants in Group A, Group B, and After Crossover (Continued) 
Visit Day (Range) 
Screening 
Day −35 
to Day −8 
Baseline 
Day –7 
to 
Day –1 
Day 1 
End of 
Week 2 
± 3 
Days 
End of 
Weeks 4, 
8, 16, 20 
± 5 Days 
End of 
Week 12 
and 24 
± 5 Days 
Extension 
Visits (Q12W 
After Week 24) 
± 7 Days 
EOT or 
ET Visit 
± 5 Days 
Safety 
Follow-Up 
EOT +  
30-35 Days 
Survival 
Follow-Up 
Every 
12 Weeks 
± 2 Weeks 
Notes 
Laboratory 
assessments* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
* Participants will also have 
laboratory-only visits to 
collect hematology samples at 
Week 6, Week 10, Week 30 
and every 12 weeks thereafter 
(except where coincident with 
study visit); see Table 5. 
Survival follow-up data 
collection 
 
 
 
 
 
 
 
 
 
X 
 


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Table 4: 
Schedule of Additional Study Visits for Participants Who Cross Over 
Visit Day (Range) 
Crossover Visit 
4 Weeks Post-Crossover 
± 5 Days 
Notes 
Administrative 
Contact IXRS 
X 
X 
 
Review criteria for crossover 
X 
 
 
Concomitant medications 
X 
X 
 
Dispense parsaclisib 
X 
X 
 
Distribute reminder cards  
X 
X 
 
Collect study drug and review diary cards 
X* 
X† 
*Parsaclisib/matching placebo bottles to be collected. 
†Parsaclisib bottles to be collected. 
Transfusion history/status 
X 
X 
 
Safety assessments 
Record AEs 
X 
X 
Body systems with symptoms should be physically examined. 
PJP 
X 
X 
Prophylaxis continues from crossover visit through at least 2-6 months beyond the 
last dose of study treatment. 
Efficacy assessments 
Dispense and/or bring MFSAF v4.0 diary 
to visit 
X 
X 
Diary continues only for early crossover before Week 24 and ends at Week 24. 
MFSAF v4.0 diary  
X 
X 
Diary continues only for early crossover before Week 24 and ends at Week 24. 
ECOG performance status 
 
X 
 
Laboratory assessments 
Serum chemistry 
X 
X 
Then follow Table 5. 
Hematology 
X 
X 
Then follow Table 5. 


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Table 5: 
Schedule of Laboratory Assessments for All Participants 
Window 
Screening Baseline Day 1 
End of 
Weeks 2, 6, 10, 
and 30 and 
Then Q12W 
End of 
Weeks 4, 8, 12, 
16, 20, and 24, 
and Then 
Q12W 
EOT or 
Early 
Termination 
Visit  
Safety 
Follow-Up 
30-35 Days 
After Last Dose 
of Parsaclisib 
Notes 
 
 
 
The window for laboratory-only visits is ± 3 days through 
Week 10 inclusive, and ± 7 days for laboratory-only visits 
beginning at Week 30 and Q12W 
 
Local laboratory assessments 
Serum chemistry 
X 
X* 
 
X 
X 
X 
*Should be taken as close as possible to Day 1 
but may be drawn up to 3 days before first dose.  
Only 1 sample for baseline/Day 1 is required. 
Hematology 
X 
X* 
X 
X 
X 
X 
*Should be taken as close as possible to Day 1 
but may be drawn up to 3 days before first dose.  
Only 1 sample for baseline/Day 1 is required. 
Note that if platelet count is < 50 × 109/L at 
baseline, the platelet count at screening will be 
used for stratification/randomization. See 
Section 8.1.3. 
Coagulation panel 
X 
 
 
 
X* 
X 
X 
*Required at Weeks 12 and 24 and Q12W 
thereafter. 
Urine pregnancy test 
 
X 
 
 
X* 
X* 
 
All female participants of childbearing potential. 
*Pregnancy tests should be repeated if required 
by local regulations. 
Bone marrow biopsy 
and aspirate analysis 
X* 
Local pathologist to document findings. 
*Predose biopsy/aspirate is not required if biopsy 
has occurred within previous 2 months of 
screening as long as biopsy/aspirate and data are 
available for review by investigator and/or 
sponsor. 
 
 
 
 
 
 
. 


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Table 5: 
Schedule of Laboratory Assessments for All Participants (Continued) 
Window 
Screening Baseline Day 1 
End of 
Weeks 2, 6, 10, 
and 30 and 
Then Q12W 
End of 
Weeks 4, 8, 12, 
16, 20, and 24, 
and Then 
Q12W 
EOT or 
Early 
Termination 
Visit  
Safety 
Follow-Up 
30-35 Days 
After Last Dose 
of Parsaclisib 
Notes 
 
 
 
The window for laboratory-only visits is ± 3 days through 
Week 10 inclusive, and ± 7 days for laboratory-only visits 
beginning at Week 30 and Q12W 
 
Central laboratory samples* 
*The central laboratory is the sponsor or 
sponsor's designee. 
Lipid panel (requires 
overnight fast) 
X 
 
 
 
X* 
X 
 
*Required at Weeks 12 and 24 and Q12W 
thereafter. 
Virology and serology 
(hepatitis and HIV) 
X 
 
 
 
 
 
 
HBV, HCV, HIV. 
Virology - CMV 
X 
 
 
 
X* 
 
 
*CMV measured at Weeks 4, 8, and 12 and 
Q12W thereafter. 
Urinalysis 
X 
 
 
 
X* 
 
X 
*Required at Weeks 12 and 24 and Q12W 
thereafter. 
Serum pregnancy test 
X 
 
 
 
 
 
X 
All female participants of childbearing potential. 
FSH level 
X 
 
 
 
 
 
 
To document hormonal menopause in relevant 
participants. 


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Table 5: 
Schedule of Laboratory Assessments for All Participants (Continued) 
Window 
Screening Baseline Day 1 
End of 
Weeks 2, 6, 10, 
and 30 and 
Then Q12W 
End of 
Weeks 4, 8, 12, 
16, 20, and 24, 
and Then 
Q12W 
EOT or 
Early 
Termination 
Visit  
Safety 
Follow-Up 
30-35 Days 
After Last Dose 
of Parsaclisib 
Notes 
 
 
 
The window for laboratory-only visits is ± 3 days through 
Week 10 inclusive, and ± 7 days for laboratory-only visits 
beginning at Week 30 and Q12W 
 
 


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2. 
INTRODUCTION 
Parsaclisib (INCB050465) represents a novel, potent, and selective inhibitor of the Class IA 
PI3K enzymes, with selectivity for the δ isoform, which is proposed for development for 
treatment of hematologic malignancies.  For a thorough discussion of the pharmacology of 
INCB054065, refer to the parsaclisib IB.  Ruxolitinib, a potent and selective inhibitor of the JAK 
family of protein tyrosine kinases, JAK1 and JAK2, is approved in multiple jurisdictions for the 
treatment of MF, with variations on the specific indication language, and is currently in 
development for the treatment of MPNs, hematologic malignancies, and solid tumors.  For a 
thorough discussion of the pharmacology of ruxolitinib (INCB018424), refer to the ruxolitinib 
IB and the Jakafi® package insert (Jakafi 2021). 
2.1. 
Overview of Myelofibrosis 
The classic MPNs include chronic myelogenous leukemia, PV, ET, and PMF.  Myelofibrosis can 
present as a de novo disorder (PMF) or evolve secondarily from previous PV or ET (PPV-MF or 
PET-MF).  Regardless of whether MF is a primary or secondary disorder, it is characterized by a 
clonal stem cell proliferation associated with production of elevated serum levels of multiple 
inflammatory and proangiogenic cytokines, a characteristic bone marrow stromal pattern that 
includes varying degrees of collagen fibrosis, osteosclerosis and angiogenesis, and a peripheral 
blood smear showing a leukoerythroblastic pattern with varying degrees of circulating progenitor 
cells.  Clinically, MF is characterized by progressive anemia, leukopenia or leukocytosis, 
thrombocytopenia or thrombocythemia, and multiorgan extramedullary hematopoiesis most 
prominently involving the liver and spleen.  Patients may experience debilitating symptoms 
(Mesa et al 2013a, Mesa et al 2013b), sequelae of massive splenomegaly (pain, limitations of 
movement, early satiety and shortness of breath, hepatic obstruction, and splenic infarction), a 
hypermetabolic state with cachexia, progressive hematopoietic failure, progression to leukemia, 
and premature death. 
The median age at diagnosis of MF is approximately 60 to 67 years, and the incidence of PMF 
has been estimated at 4 to 6 cases per 100,000 people in the United States (Stein et al 2015).  
Survival in MF varies with the presence or absence of specific risk factors.  Analysis of risk 
factors over the past 20 years has resulted in a number of prognostic scoring systems (for a 
review, refer to Bose and Verstovsek 2016).  A prognostic scoring system based on a 
time-dependent risk evaluation has been developed:  the DIPSS for PMF (Passamonti et al 
2010).  Age older than 65 years, presence of constitutional symptoms, anemia (hemoglobin 
< 100 g/L), leukocytosis (WBC count > 25 × 109/L), and a circulating blast percentage of ≥ 1% 
were assessed for their impact on survival when analyzed as time-dependent covariates in a 
multivariate Cox proportional hazards model.  The approach showed that acquisition of anemia 
over time affects survival with a hazard ratio roughly double that of other parameters, and 
therefore anemia was assigned a score of 2, while the other 4 factors were assigned scores of 1.  
Four risk categories with nonoverlapping survival curves are described in Table 6. 


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Table 6: 
Risk Categories for Myelofibrosis 
Total Risk Score 
Risk Category 
Median Survival (years) 
0 
Low 
Not reached 
1 or 2 
Intermediate-1 
14.2 
3 or 4 
Intermediate-2 
4 
5 or 6 
High 
1.5 
Recent literature has indicated that although the prognostic factors for OS for patients with 
PET-MF and PPV-MF overlap with those for patients with PMF, the relative importance of these 
factors and their associated outcomes show differences.  Additional improvements in scoring 
systems that include disease subtypes is warranted (Masarova et al 2017).  Although not included 
in the DIPSS, somatic mutations in PMF, JAK2 V617F point mutations, mutations in exon 9 of 
the gene encoding CALR, and mutations in the gene encoding the thrombopoietin receptor 
(MPL) have been examined for impact on DIPSS score, thrombotic risk, and OS and together are 
grouped as "driver" mutations.  These mutations often coexist with several somatic mutations:  
genes for the epigenetic regulators EZH2 (enhancer of zeste 2 polycomb repressive complex 2 
subunit), ASXL1 (additional sex combs-like 1 transcriptional regulator), the splicing gene 
SRSF2 (serine/arginine-rich splicing factor), and the genes encoding the Krebs cycle enzymes 
isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2).  These factors have been combined into 
genetic-based scoring systems, although they are currently restricted to PMF (Tefferi et al 2018). 
2.2. 
Role of Janus Kinase Pathway in Myelofibrosis 
In recent years, it was discovered that approximately 95% of patients with PV and approximately 
50% of patients with PMF and ET have a somatic gain-of-function mutation in the JAK2 gene 
resulting in substitution of phenylalanine for valine at position 617 (JAK2 V617F) within the 
pseudokinase domain of the encoded protein.  Janus kinase 2 is 1 of 4 members of the JAK 
family, along with JAK1, JAK3, and TYK2.  The JAKs are responsible for transduction of cell 
signaling from Type I and II cytokine receptor families, because these receptors do not possess 
intrinsic kinase activity to activate downstream signal transduction.  Under physiologic 
conditions, the JAKs associate with the intracellular domain of the cytokine receptors in response 
to cytokine binding.  They then undergo autophosphorylation, resulting in conformational 
changes that enable them to transduce intracellular signaling by phosphorylating and activating 
transcription factors called STAT proteins.  The activated STATs translocate to the nucleus 
where they regulate transcription of a number of genes involved in cellular activation, 
proliferation, and survival.  JAKs associate with the intracellular domain of the Type I and II 
cytokine receptors in pairs, which may be homodimers (eg, 2 JAK2s) or heterodimers (eg, a 
JAK1 and a JAK2).  A large number of inflammatory mediators, such as IL-6, interferon-γ, and 
IL-17, are known to signal primarily through receptors that utilize JAK heterodimers. 
It is also apparent that MF, as well as ET and even PV, occur in the absence of the JAK2 V617F 
mutation.  In a minority of patients, other mutations in the JAK-STAT pathway have been 
identified, but in many patients, the mutations have not been identified yet or may not exist.  
Regardless, it appears that the majority of patients with MF have overactivation of the 
JAK-STAT pathway.  In MF, excessive cytokine signaling through both JAK1 and JAK2 has 
been observed both in patients harboring the JAK2V617F mutation and in patients without 


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known mutations.  Therefore, JAK inhibitors have the potential to treat some or all of the 
manifestations of MF, despite the potential for mechanism-based myelosuppression. 
2.3. 
Role of PI3K/Protein Kinase B Signaling Pathway in Myelofibrosis 
Recent evidence suggests that other regulatory pathways in addition to the JAK-STAT pathway 
are dysregulated in MPNs.  Targeting multiple signaling pathways might provide synergistic 
effects on the overall pathogenic process of MF.  The PI3K/AKT pathway is a signal 
transduction pathway that promotes survival and growth of cells in response to extracellular 
signals.  There are several isoforms of PI3K.  When activated, PI3Ks generate the lipid second 
messenger PIP3, leading to activation of several kinases, including AKT.  Activated AKT 
initiates numerous downstream effects, including on cell survival, proliferation, growth, 
migration, and metabolism (Thorpe et al 2015, Tzenaki et al 2013).  Meadows et al (2013) 
reported that the primary isoform of PI3K expressed in CD34+ cells obtained from 
ruxolitinib-treated or -naive patients with MF was PI3Kδ.  Bartalucci et al (2013) and Khan et al 
(2013) demonstrated that inhibition of the PI3K/mTOR pathway in combination with JAK2 
inhibition was synergistic in mouse models of MPN as well as in clonogenic assays of 
hematopoietic progenitors of patients with PMF.  Hermouet et al (2015) recently reviewed the 
multiple pathways activated by inflammatory cytokines and grown factors and affected by 
MPN-associated mutations.  Activators such as granulocyte colony-stimulating factor, 
erythropoietin, and thrombopoietin stimulate both JAK and PI3K-AKT pathways with 
considerable overlap and potential for synergistic effects. 
2.4. 
Treatment of Myelofibrosis 
The early drug therapies used in MF, including hydroxyurea, busulfan, 6-mercaptopurine, 
anagrelide, thalidomide, lenalidomide, interferon, corticosteroids, and erythropoiesis-stimulating 
agents or growth factors, have not been shown to improve survival.  Some can increase the risk 
of leukemic transformation and can be poorly tolerated, and all have limited effectiveness in 
improving splenomegaly and constitutional symptoms. 
Ruxolitinib, a potent and selective inhibitor of JAKs 1 and 2, is approved for use in patients with 
intermediate- or high-risk MF, including PMF, PPV-MF, and PET-MF.  Registration studies 
showed improvement in spleen size, symptom burden, and OS with ruxolitinib use in this patient 
population (Cervantes et al 2013, Harrison et al 2012, Mesa et al 2013a, Mesa et al 2013b, 
Vannucchi et al 2015, Verstovsek et al 2012, Verstovsek et al 2015).  Another JAK inhibitor, 
fedratinib, was approved more recently (August 2019) for intermediate-2 or high-risk MF.  Both 
a significant decrease in spleen volume and reduction in MF-related symptoms were observed in 
double-blind, placebo-controlled studies (Pardanani et al 2015). 
For the subset of patients who are younger (generally younger than 65 years), are otherwise 
healthy, and have a histocompatible donor, allogeneic stem cell transplantation may provide a 
curative option, although with a substantial risk of mortality (10%-20%; Deeg et al 2003, Robin 
et al 2019).  Splenectomy, performed in approximately 10% of the patient cohort reported by 
Cervantes et al (2009), is associated with significant morbidity and mortality.  Splenic irradiation 
is also used to reduce symptoms secondary to splenomegaly, but symptomatic improvement is 
variable and short-lived; moreover, transient and life-threatening pancytopenia and an 
approximate 20% treatment-related mortality have been noted. 


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Currently, there are no approved agents designed specifically for use when response to JAK 
therapy becomes suboptimal or declining.  A number of agents are under investigation in this 
setting.  Results of a limited study examining the effects of the JAK2 inhibitor fedratinib have 
shown effects on spleen size and symptoms in MF patients previously treated with ruxolitinib 
(Harrison et al 2017).  Preliminary data using buparlisib, a pan-PI3K inhibitor, together with 
ruxolitinib demonstrated effects on both spleen size and symptoms in patients with MF with or 
without prior JAK therapy, but these results did not demonstrate synergy, and the anticipated 
risk/benefit profile was modest (Durrant et al 2019).  However, the current studies in ruxolitinib 
refractory patients is confounded by the way in which refractoriness or ruxolitinib failure has 
been defined, precluding clear demonstrations of efficacy from newly added agents. 
2.5. 
Study Rationale 
Not all MF patients treated with the JAK inhibitor ruxolitinib experience optimal and/or stable 
response.  Targeting additional signaling pathways might have clinically relevant effects on the 
overall disease burden of MF.  The present study compares the impact of added PI3K delta 
inhibitor, parsaclisib, on signs and symptoms of MF in participants on stable ruxolitinib doses 
who have suboptimal or declining response to ruxolitinib monotherapy. 
2.5.1. 
Scientific Rationale for Study Design 
Despite statistically significant improvements in signs and symptoms of MF and OS rates 
compared with either placebo or best available therapy demonstrated in the registration studies, 
ruxolitinib therapy fails to provide optimal response for some patients.  For some of these 
patients, individual genetic or systemic factors may impact the effects of JAK inhibition on 
overall disease.  For other patients, declining hemoglobin levels or platelet counts may preclude 
optimal ruxolitinib dosages.  Regardless of etiology, there is a patient population for whom 
ruxolitinib monotherapy is insufficient for optimal response (Pardanani and Tefferi 2014). 
The persistent activation of the PI3K/AKT pathway in patients with MF suggests that this 
pathway may also be a driver of MPN diseases.  For example, Bartalucci et al (2013) and Khan 
et al (2013) demonstrated that inhibition of the PI3K/mTOR pathway in combination with JAK2 
inhibition was synergistic in mouse models of MPN as well as in clonogenic assays of 
hematopoietic progenitors of patients with PMF. 
An ongoing Phase 2 study in participants with MF, INCB 50465-201, showed that additional 
alleviation of both symptoms and splenomegaly occurred when the PI3Kδ inhibitor parsaclisib 
(INCB050465) was added to the regimen of participants with suboptimal response to ruxolitinib 
monotherapy.  Preliminary data showed > 20% reduction in spleen volume after 24 weeks of 
daily parsaclisib therapy together with continued ruxolitinib along with reductions in symptoms 
(Yacoub et al 2021). 
The present Phase 3 study (INCB 50465-304) will explore the addition of parsaclisib in 
participants with MF with residual disease-related signs and symptoms while on stable 
ruxolitinib therapy.  The study population is rigorously defined so that activity of the newly 
added agent (parsaclisib) can be demonstrated.  The study design is placebo-controlled, 
double-blind as a combination of parsaclisib or placebo with ongoing ruxolitinib therapy.  The 
objective measurement of spleen volume at 24 weeks is the primary endpoint.  The study is 
blinded; symptom data will be collected objectively using daily electronic diary entries.  


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Participants randomized to placebo will have the opportunity to crossover to receive parsaclisib 
once Week 24 has been reached and all data have been entered and verified for the participant; 
early crossover will be available to participants who have symptomatic spleen growth meeting 
Protocol-defined criteria. 
2.5.2. 
Justification for Dose 
In the ongoing Phase 2 study in MF (INCB 50465-201), dose-limiting toxicities were not 
observed with daily doses of parsaclisib of up to 20 mg for 8 weeks followed by weekly dosing 
at 10 or 20 mg, or with continuous daily dosing of 5 mg, or 20 mg for 8 weeks followed by daily 
dosing of 5 mg.  In the INCB 50465-201 study, AEs frequently reported with first-generation 
PI3K inhibitors (Coutré et al 2015, Flinn et al 2018), including hepatotoxicity (fatal or serious 
elevations of liver enzymes), severe and/or fatal diarrhea and colitis, intestinal perforation, and 
infections such as CMV retinitis, have not been observed (colitis, CMV retinitis, intestinal 
perforation) or rarely observed (diarrhea, elevated liver enzymes) with either daily or weekly 
parsaclisib dosing in the MF population.  One SAE of diarrhea has been reported (Grade 3), 
unrelated to study drug, and resolved with drug interruption.  This same participant also had 
Grade 4 elevation of bilirubin; multiple AEs involving the renal, gastrointestinal, and pulmonary 
system (assessed as unrelated to study medication); and increased peripheral blasts and 
subsequently died, with a cause of death of disease progression.  The present Phase 3 study will 
use an all daily dose regimen as add-on therapy to a stable ruxolitinib regimen, with 5 mg of 
parsaclisib or matching placebo being administered QD from Day 1 until a given participant 
discontinues treatment. 
2.6. 
Benefit/Risk Assessment 
The following sections describe risks and benefits of the study drug (parsaclisib) and risks for 
reference (background) treatment (ruxolitinib). 
2.6.1. 
Risks and Benefits of Parsaclisib 
2.6.1.1. 
Potential Risks of Parsaclisib Based on Preclinical Findings 
Based on the nonclinical toxicology studies, the primary potential risk associated with clinical 
administration of parsaclisib is immunosuppression and associated inflammatory complications 
and/or infections.  Participants receiving parsaclisib should be frequently monitored and 
appropriate treatment, including but not limited to drug withdrawal, should be considered.  
Immunosuppressive findings showed evidence of recovery following 4 to 6 weeks of drug 
withdrawal, confirming the reversibility of immunosuppressive complications. 
2.6.1.2. 
Potential Risks of Parsaclisib Based on Prior and Ongoing Clinical Studies 
As of the data cutoff of 30 MAR 2022, 1159 unique individuals have been exposed to parsaclisib 
monotherapy, including healthy participants and participants with renal or hepatic impairment 
(N = 69), as monotherapy in oncology indications (N = 592), as monotherapy in inflammation 
and autoimmunity indications (N = 35), or in combination with other agents in oncology 
indications (N = 463).  


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The most common AEs with parsaclisib monotherapy in advanced malignancies (N = 592) have 
been diarrhea, nausea, cough, fever, and fatigue. 
Parsaclisib has effects on the immune system and serious infection events have occurred in 
patients treated with parsaclisib, including PJP, CMV, and COVID-19.  Therefore, participants 
must be monitored closely for evidence of infections or new cancers, and administration should 
be discontinued if there is evidence of clinically significant infection or new cancer.  All irAEs 
must be completely resolved to baseline for 2 weeks before starting parsaclisib. 
Four cases of PJP have been reported with the use of parsaclisib as monotherapy and another in 
combination with pembrolizumab.  None of these events occurred in the MF population.  None 
of the participants were on PJP prophylaxis at the time of the event.  Participants in the present 
study will receive PJP prophylaxis beginning with the baseline visit. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of parsaclisib may be found in the parsaclisib IB. 
2.6.1.3. 
Potential Risks of PI3K Inhibition Based on Other Agents in Class 
Idelalisib was approved by the FDA in July 2014 for treatment of relapsed/refractory follicular 
lymphoma and relapsed small lymphocytic lymphoma and for treatment of chronic lymphocytic 
leukemia in combination with rituximab.  Severe toxicities seen with the use of this agent include 
hepatotoxicity (fatal and/or serious occurring in 16%-18%), fatal and/or serious diarrhea or 
colitis (14%-20%), intestinal perforation, pneumonitis, and infections (fatal and/or serious 
occurring in 21%-48%). PJP infection and CMV infection have also been reported (Zydelig® 
2018). 
Copanlisib was approved in 2017 for the treatment of relapsed follicular lymphoma.  Clinically 
important toxicities observed with this agent include SAEs, including fatal infections (19%), 
usually pneumonia, Grade 3 or 4 hyperglycemia (41%), and Grade 3 hypertension (26%).  
Serious PJP occurred in 0.6% of patients treated with copanlisib (Aliqopa® 2019). 
Duvelisib was approved in 2019 for the treatment of relapsed or refractory chronic lymphocytic 
leukemia, small lymphocytic lymphoma, or follicular lymphoma.  Clinically important toxicities 
observed with this agent include fatal and/or serious infections (31%), fatal and/or serious 
diarrhea or colitis (18%), fatal and/or serious cutaneous reactions (5%), or fatal and/or serious 
pneumonitis (5%).  Serious, including fatal, PJP occurred in 1% of patients taking duvelisib, and 
CMV reactivation also occurred in 1% of patients taking duvelisib (Copiktra® 2019). 
Participants in the present study will be monitored closely for the development of bacterial, 
fungal, or viral infections and will have treatment interrupted and dose reduced as appropriate.  
Participants will receive prophylaxis for PJP and will be monitored for CMV viremia during the 
study. 
2.6.1.4. 
Potential Benefits of Parsaclisib 
The ongoing Phase 2 study showed that additional alleviation of both symptoms and 
splenomegaly occurred when the PI3Kδ inhibitor parsaclisib (INCB050465) was added to 
participants on a stable ruxolitinib regimen.  Specifically, at the time of efficacy data cutoff of 
27 AUG 2020, 35 participants had been enrolled to receive all daily dosing regimens (18 dosed 
with 5 mg QD from Day 1 forward and 17 dosed with 20 mg QD for the first 8 weeks followed 


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by 5 mg QD going forward).  The median reduction in spleen volume at 12 and 24 weeks was 
13.0% and 21.8%, respectively.  Seven of 23 participants (30%) had at least 25% reduction in 
spleen volume at Week 24.  Thirty percent of participants had 50% reduction in TSS at Week 12 
and 19% at Week 24 (Yacoub et al 2021).  These preliminary findings suggest the combination 
of parsaclisib and ruxolitinib may be efficacious in the difficult-to-treat population with 
suboptimal response to ruxolitinib. 
2.6.2. 
Risks of Ruxolitinib 
2.6.2.1. 
Potential Risks of Ruxolitinib 
The primary clinical risks with ruxolitinib treatment are the potential sequelae of decreased 
hematopoietic proliferation attributable to the inhibition of growth factor pathways associated 
with JAK inhibition.  Dose-dependent, reversible thrombocytopenia has been observed in studies 
of participants with MF.  Anemia and, less frequently, neutropenia have also been observed in 
studies in participants with MF.  Increased rates of infection and anemia are potential risks of 
myelosuppression, and there are multiple sequelae of anemia, including the burden and risks of 
transfusion.  In healthy volunteers, participants with rheumatoid arthritis, and participants with 
hormone-refractory prostate cancer with greater bone marrow reserve, the effects on 
hematopoietic proliferation appear to be less pronounced (ruxolitinib IB, Jakafi 2021, Jakavi® 
2022). 
2.6.2.2. 
Potential Risks of Parsaclisib Plus Ruxolitinib 
As of the data cutoff date of 30 MAR 2022, 74 participants with MF had received parsaclisib 
together with continued ruxolitinib in Study INCB 50465-201.  The most common AEs observed 
were thrombocytopenia, diarrhea, nausea, abdominal pain, anemia, fall, and platelet count 
decreased. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 7 presents the objectives and endpoints. 
Table 7: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate and compare the efficacy of parsaclisib plus 
ruxolitinib versus placebo plus ruxolitinib on spleen 
volume at Week 24. 
Proportion of participants achieving ≥ 25% reduction in 
spleen volume from baseline to Week 24 as measured 
by MRI (or CT scan in applicable participants). 
Secondary 
To evaluate and compare the effect of parsaclisib plus 
ruxolitinib versus placebo plus ruxolitinib on participant 
reports of MF symptoms. 
Proportion of participants who have a ≥ 50% reduction 
in TSS from baseline to Week 24 as measured by the 
MFSAF v4.0 diary. 
Change in TSS from baseline to Week 24 as measured 
by the MFSAF v4.0 diary. 
Time to the first ≥ 50% reduction in TSS as measured 
by the MFSAF v4.0 diary. 
To evaluate and compare the effect of parsaclisib plus 
ruxolitinib versus placebo plus ruxolitinib with respect 
to OS. 
OS determined from the date of randomization until 
death due to any cause. 
To evaluate and compare the safety and tolerability of 
parsaclisib plus ruxolitinib versus placebo plus 
ruxolitinib. 
Safety and tolerability will be assessed by monitoring 
the frequency and severity of AEs, performing physical 
examinations, and evaluating changes in vital signs, 
ECGs, and laboratory results. 
To evaluate and compare the time to onset and duration 
of response in spleen volume of participants receiving 
parsaclisib plus ruxolitinib versus placebo plus 
ruxolitinib. 
Time to the first ≥ 25% reduction in spleen volume and 
duration of maintenance of a ≥ 25% reduction in spleen 
volume. 


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Table 7: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 3, randomized, double blind study of the combination of the PI3Kδ inhibitor 
parsaclisib or matching placebo and the JAK1/2 inhibitor ruxolitinib in participants with PMF or 
secondary MF (PPV-MF or PET-MF) who have suboptimal response while receiving ruxolitinib 
monotherapy.  Prospective participants must be on stable doses of ruxolitinib ranging from 5 mg 
BID to 25 mg BID and will have been on that dose for at least the last 8 weeks prior to Day 1.  
At least 3 months duration of prior ruxolitinib is required.  Participants must meet 
Protocol-defined criteria for suboptimal response to ruxolitinib monotherapy.  After participants 
have been determined to be eligible for the study and completed the baseline symptom diary 
assessment for 7 days, they will be randomized to 1 of 2 treatment groups, with stratification for 
baseline platelet count (≥ 100 × 109/L vs 50 to < 100 × 109/L inclusive) and DIPSS risk category 
(high vs intermediate-2 vs intermediate-1).  Note that if a participant's platelet count is 
< 50 × 109/L at baseline,  the platelet count at screening will be used for 
stratification/randomization.  Participants will receive study drug or matching placebo at a dose 
of 5 mg QD beginning on Day 1 and will continue to receive the stable dose of ruxolitinib they 
were taking for the 8 weeks prior to Day 1.  Both parsaclisib/matching placebo and ruxolitinib 
dosing will continue for the duration of the participation in the study. 
Figure 1 (see Section 1) presents the study design schema, and Table 3, Table 4, and Table 5 
present the SoA for study site visit assessments, post-crossover assessments, and laboratory 
assessments, respectively. 
4.1.1. 
Study Schedule/Procedures 
There will be study site visits and laboratory-only visits in the study. 
Participants will have a regularly scheduled study site visit at screening, baseline, Day 1, and at 
the end of 2, 4, 8, 12, 16, 20, and 24 weeks of treatment (ie, visits designated Week 2, Week 4, 
and so on) and then every 12 weeks thereafter if continuing on treatment in the extension period.  
During these visits, assessments, including blood samples and spleen measurements, will be 
performed.  All serology, lipid profile, and urinalysis laboratory assessments will be analyzed by 
a central laboratory.  Serum chemistry, hematology, and coagulation parameters will be assessed 
using local laboratories.  
 
 
Participants will have laboratory-only visits to collect hematology laboratory samples at Week 6, 
Week 10, and, if continuing beyond Week 24, every 12 weeks beginning with Week 30 (except 
where coincident with study visit).  Participants may visit a local laboratory or a location 
convenient to the participant for these interim hematology assessments provided that the 
laboratory data and corresponding normal ranges can be scanned and e-mailed to the 
investigative site; interim laboratory visits at the study site laboratory are preferred.  Additional 
and unscheduled laboratory assessments may be performed at investigator discretion, including 
following changes in dose, or if laboratory parameters are at Grade 3 or Grade 4 levels based on 
CTCAE v5.0. 


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Participants who crossover (defined in the following text) will have 2 additional study site visits:  
the day of crossover and 4 weeks after crossover.  Participants who have crossed over will 
otherwise remain on the same study schedule they were on prior to crossover.  Of note, these 
crossover participants may not need to have the laboratory visit at Week 30 as this may coincide 
with the Week 4 post-crossover visit. 
Participants will have an MRI of the upper and lower abdomen and pelvis to determine the 
spleen volume at baseline, Week 12, Week 24, and every 12 weeks thereafter through Week 108. 
A CT scan will be substituted for participants who are not candidates for MRI or when MRI is 
not readily available.  
 
 
 
Participants will complete an electronic symptom diary (MFSAF v4.0) daily from baseline 
through the Week 24 visit (total of 25 weeks). 
All participants must receive prophylaxis against PJP beginning as early as the baseline visit and 
no later than Day 1 through at least 2 to 6 months after the last dose of study drug. 
After 24 weeks, participants may enter the extension period of the study.  Treatment will 
continue as long as the regimen is tolerated and the participant does not meet discontinuation 
criteria. 
4.1.2. 
Unblinding and Crossover 
When a participant has completed the Week 24 assessments, and the data entered has been 
verified and cleaned through the Week 24 visit (including imaging), the database for that 
participant will be frozen through the Week 24 visit. The participant's treatment assignment will 
then be unblinded and if found to be placebo, the participant will have the opportunity to 
crossover to begin receiving parsaclisib, together with continued ruxolitinib, as long as 
hematology parameters are adequate (see Section 6.4 for hematology requirements).  If a 
participant who has completed the Week 24 assessments is found to have been randomized to 
parsaclisib, treatment with parsaclisib, together with continued ruxolitinib, will be continued as 
long as the regimen is tolerated and the participant does not meet discontinuation criteria. 
4.1.3. 
Early Unblinding and Crossover 
Participants with Protocol-defined spleen growth may be eligible for unblinding and, if found to 
have been randomized to the placebo group, may be eligible for crossover to parsaclisib, together 
with continued ruxolitinib, before reaching Week 24. 
Participants who show symptomatic spleen growth may be eligible for unblinding and cross over 
if they meet both of the following criteria: 


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• Score of 5 or higher on at least 2 of 3 symptoms related to spleen size (abdominal 
discomfort, pain under the left ribs, early satiety), as assessed by the Worsening 
Symptomatic Splenomegaly Form (see Appendix B). 
• Participants must demonstrate worsening spleen growth measured as an increase of 
≥ 25% in spleen volume by MRI (or CT scan in applicable participants) compared 
with baseline.  In addition to the regularly scheduled MRIs (or CT scans in applicable 
participants) at Week 12 and Week 24, 1 additional MRI (or CT scan in applicable 
participants) may be conducted between Week 2 and Week 10 and/or between 
Week 14 and Week 22 provided the participant meets the definition of worsening 
symptoms above.  Only MRI or CT scans performed by the Protocol-qualified 
facilities and submitted to the central imaging laboratory may be used.  No other MRI 
or CT scans for the purpose of documenting spleen growth are permitted. 
 
 
 
Participants who meet both criteria and are unblinded and found to have been randomized 
to placebo must either cross over or be discontinued from the study treatments (placebo 
and ruxolitinib) and have an EOT visit scheduled. 
Participants with worsening symptomatic spleen growth as described above for early 
crossover and who are found to have been randomized to parsaclisib must discontinue 
from the study treatments (parsaclisib and ruxolitinib) and have an EOT visit scheduled. 
At any time, once unblinded, a placebo-randomized participant must either cross over or 
be discontinued from study treatments (placebo and ruxolitinib) and have an EOT visit 
scheduled.  All participants who cross over will continue to take ruxolitinib in addition to 
parsaclisib. 
4.1.4. 
Early Unblinding/Crossover Process 
The site, CRO, central imaging laboratory, and IXRS system will work together to ensure 
efficient data capture and verification of criteria for unblinding and crossover.  The process steps 
will include the following: 
• The investigator will begin to complete the Worsening Symptomatic Splenomegaly 
Form in the eCRF, with appropriate entries for symptom scores.   
• The investigator will send the MRI (or CT scans for applicable participants) to the 
central imaging laboratory. 
• The site will start entering all available data in the eCRF up to the current visit. 
• The eCRF system will verify that the data fulfill the symptom criteria, and a 
notification will be sent to the site and to the central imaging laboratory that the 
participant has fulfilled the symptom-based criteria for early crossover. 


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• The central imaging laboratory will process the scan and compare it with the baseline 
scan.  If the on-study scan shows a ≥ 25% increase from baseline, the CRO and IXRS 
will be notified.  The CRO will confirm in the IXRS that the spleen growth-based 
criteria for early crossover have been met. 
• The eCRF system will verify that all data up to the current visit are indeed in the 
eCRF and are verified and cleaned. The database for that participant will then be 
frozen through the current visit. 
• IXRS will be notified that final conditions have been met.  
• An e-mail will be sent to the site, CRO, and sponsor that the participant may be 
unblinded. 
4.1.5. 
Participant Unblinding/Crossover Process After Completion of the Week 24 
Assessments 
The site, CRO, central imaging laboratory, and IXRS system will work together to ensure 
efficient data capture and verification of participant unblinding/crossover timing.  The process 
steps will include the following: 
• The site will be advised to continuously enter data into the eCRF and address queries. 
• The imaging vendor will communicate to the sponsor and CRO that the Week 24 
spleen volume image has been read and verified. 
• The eCRF system will verify that all data up to the Week 24 visit are in the eCRF and 
are verified and cleaned. The database for that participant will then be frozen through 
the Week 24 visit. 
• IXRS will be notified that final conditions have been met.  
• An e-mail will be sent to the site, CRO, and sponsor that the participant may be 
unblinded.   
4.2. 
Overall Study Duration 
The study begins when the first participant signs the ICF.  Treatment will continue for an 
individual participant as long as the regimen is tolerated and the participant does not meet 
discontinuation criteria.  The end of the study is defined as the date of the last visit/last contact of 
the last participant in the study. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator/head of study site (Japan) is to notify the 
IRB/IEC of the study's completion or early termination in writing, send a copy of the notification 
to the sponsor or sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively if, for example, required by regulatory decision 
or upon advice of the DMC.  If the study is terminated prematurely, the sponsor will notify the 
investigators/head of study site (Japan), the IRBs and IECs, and the regulatory bodies of the 


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decision and reason for termination of the study.  The DMC may recommend termination of the 
study if warranted, as described in Sections 5.6 and 10.5.  For Japan, the head of the study site 
will notify the investigators and IRBs of the decision and reason for termination of the study. 
5. 
STUDY POPULATION 
Male or female participants aged 18 years or older (19 years or older in South Korea) who have 
been diagnosed with PMF or secondary MF (PPV-MF or PET-MF) and who have a suboptimal 
response while receiving ruxolitinib monotherapy for a period of at least 3 months with a stable 
ruxolitinib dose regimen for at least 8 weeks before the first administration of 
parsaclisib/matching placebo. 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Men and women aged 18 years or older. 
Note:  For South Korea, men and women aged 19 years or older. 
2. Diagnosis of PMF, PPV-MF, or PET-MF. 
3. DIPSS risk category of intermediate-1, intermediate-2, or high (see Table 8 and Table 9). 
Table 8: 
Risk Categories According to DIPSS 
Number of Risk Factor Points Present 
Risk Category 
0 
Low 
1-2 
Intermediate-1 
3-4 
Intermediate-2 
5-6 
High 
Table 9: 
Risk Factors and Point Assignments for DIPSS 
Risk Factor 
Points Assigned 
Age older than 65 years 
1 
Presence of constitutional symptoms 
1 
Hemoglobin < 10 g/dL 
2 
WBC count > 25 × 109/L 
1 
Presence of peripheral blood blasts (laboratory value ≥ 1%) 
1 


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4. Treated with ruxolitinib for ≥ 3 months with a stable dose for at least the last 8 weeks 
prior to Day 1 (acceptable doses are 5 mg BID to 25 mg BID, split doses are allowed 
[total daily dose at least 10 mg], QD dosing not allowed). 
5. Evidence of suboptimal response to ruxolitinib (both 5a and 5b must be satisfied): 
a. Palpable spleen of ≥ 5 cm below the left subcostal margin on physical examination at 
the screening visit, AND 
b. Active symptoms of MF at the screening visit as demonstrated by the presence of a 
TSS of ≥ 10 using the Screening Symptom Form (see Appendix C). 
6. Participants with an ECOG performance status score of 0, 1, or 2 (see Appendix D). 
7. Screening bone marrow biopsy specimen and pathology report(s) available that was 
obtained within the prior 2 months or willingness to undergo a bone marrow biopsy at 
screening/baseline; willingness to undergo bone marrow biopsy at Week 24 and every 
24 weeks thereafter.  Screening/baseline biopsy specimen must show diagnosis of MF. 
8. Life expectancy of at least 24 weeks. 
9. Willingness to avoid pregnancy or fathering children based on the criteria below.  
a. Female participants without childbearing potential (ie, surgically sterile with a 
hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at 
least 50 years of age) are eligible. 
b. Female participants with childbearing potential must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test before the first dose 
on Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at 
least 99% certainty) from screening through safety follow-up.  Permitted methods that 
are at least 99% effective in preventing pregnancy (see Appendix A) should be 
communicated to the participant and their understanding confirmed. 
c. Male participants with childbearing potential must agree to take appropriate 
precautions to avoid fathering children (with at least 99% certainty) from screening 
through 93 days after the last dose of study drug and must refrain from donating 
sperm during this period.  Permitted methods that are at least 99% effective in 
preventing pregnancy (see Appendix A) should be communicated to the participant 
and their understanding confirmed. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Prior therapy with any drug that inhibits PI3K (examples of drugs targeting this pathway 
include but are not limited to INCB040093, idelalisib, duvelisib, buparlisib, copanlisib 
and umbralisib). 
2. Use of experimental drug therapy for MF or any other standard drug used for MF 
(whether for treatment of MF or another indication), with the exception of ruxolitinib, 
within 3 months of starting study drug, and/or lack of recovery from all toxicities from 
previous therapy (except ruxolitinib) to Grade 1 or better. 


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3. Inability to swallow food or any condition of the upper gastrointestinal tract that 
precludes administration of oral medications. 
4. Recent history of inadequate bone marrow reserve; examples include but are not limited 
to the following: 
a. Platelet count < 50 × 109/L in the 4 weeks before screening or at the screening 
laboratory assessment; or platelet transfusion(s) within 8 weeks before screening. 
b. Absolute neutrophil count < 0.5 × 109/L in the 4 weeks before screening or at the 
screening laboratory assessment. 
c. Peripheral blood blast count of ≥ 10% at the screening hematology assessment. 
5. Inadequate liver function at screening visit, as demonstrated by the following: 
a. Total bilirubin > 2.0 × ULN.  Note:  if total bilirubin is > 2.0 × ULN, the participant 
may enroll if the direct bilirubin is < 2.0 × ULN.  
b. ALT or AST > 2.5 × ULN. 
6. Inadequate renal function at screening, as demonstrated by creatinine clearance 
≤ 50 mL/min estimated based on Cockcroft-Gault formula.  The cutoffs for mild, 
moderate, and severe renal insufficiency based on the Cockcroft-Gault formula are 60 to 
90 mL/min, 30 to 59 mL/min, and 0 to 29 mL/min, respectively.  If the investigator 
prefers, he/she may use measured creatinine clearance instead of estimated. 
7. Active bacterial, fungal, parasitic, or viral infection that requires therapy.  Participants 
with acute infections requiring treatment should delay screening/enrollment until the 
course of therapy has been completed and the event is considered resolved.  Prophylactic 
antibiotics or antivirals will be permitted. 
8. Active HBV or HCV infection that requires treatment or at risk for HBV reactivation.  
Hepatitis B virus DNA and HCV RNA must be undetectable upon testing.  At risk for 
HBV reactivation is defined as hepatitis B surface antigen positive or anti–hepatitis B 
core antibody positive.  Cytomegalovirus must be undetectable by polymerase chain 
reaction. 
9. Known HIV infection. 
10. Uncontrolled, severe, or unstable cardiac disease that in the investigator's opinion may 
jeopardize the safety of the participant or compliance with the Protocol. 
11. Active invasive malignancy over the previous 2 years except treated basal or squamous 
carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix, and 
completely resected papillary thyroid and follicular thyroid cancers.  Participants with 
malignancies with indolent behavior such as prostate cancer treated with radiation or 
surgery may be enrolled as long as they have a reasonable expectation to have been cured 
with the treatment modality received. 
12. Splenic irradiation within 6 months before receiving the first dose of study drug. 
13. Concurrent use of any prohibited medications (see Section 6.8.5 for specific prohibited 
medications and the associated timeframe over which they are prohibited). 


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14. Active alcohol or drug addiction that would interfere with the ability to comply with the 
study requirements. 
15. Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives 
(whichever is longer) before the first dose of study drug or anticipated during the study. 
16. Inadequate recovery from toxicity and/or complications from a major surgery before 
starting therapy. 
17. Currently breastfeeding or pregnant. 
18. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study drug and attending required study visits; 
pose a significant risk to the participant; or interfere with interpretation of study data. 
19. Inability to comprehend or unwilling to sign the ICF. 
20. History of Grade 3 or 4 irAEs from prior immunotherapy. 
a. Any irAEs of Grade 1 or 2 must be resolved before receiving the first dose of study 
drug. 
21. Receipt of any live vaccine within 30 days of the first dose of study drug. 
22. Unwillingness to receive RBC transfusions to treat low hemoglobin levels. 
23. Known hypersensitivity or severe reaction to parsaclisib or ruxolitinib or excipients of 
parsaclisib/matching placebo or ruxolitinib formulations. 
5.3. 
Lifestyle Considerations 
No restrictions are required. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study treatment/entered in the study. 
Results from the screening visit evaluations will be reviewed to confirm participant eligibility 
before enrollment/randomization or the administration of study drug.  Tests with results that fail 
eligibility requirements may be repeated once during screening if the investigator believes the 
results to be in error.  For screening assessments that are repeated, the most recent available 
result before randomization/treatment assignment will be used to determine participant 
eligibility. 
Additionally, a participant who fails screening may repeat the screening process 1 time if the 
investigator believes that there has been a change in eligibility status (eg, after recovery from an 
infection).  Participants who rescreen must reconsent and be assigned a new participant number. 
5.5. 
Replacement of Participants 
No participants will be replaced at any time during this study. 


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5.6. 
Data Monitoring Committee 
Preplanned analyses of safety and efficacy will be provided to an independent DMC as specified 
in the DMC charter.  The process by which the DMC will review data and make 
recommendations and decisions will be documented in the DMC charter.  The external DMC 
will also conduct the interim analyses (see Section 10.5). 
6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered 
Table 10 presents the study treatment information. 


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Table 10: 
Study Treatment Information 
 
Study Treatment 1 
Study Treatment 2 
Reference (Background) 
Treatment 
Study treatment name: 
Parsaclisib 
Placebo 
Ruxolitinib 
Dosage formulation: 
Tablets 
Tablets 
Tablets 
Starting dose: 
5 mg QD without regard to food 
5 mg QD without regard to food 
5 mg BID to 25 mg BID without 
regard to food 
Doses of different AM and PM 
strengths allowed provided total dose 
is at least 10 mg and no greater than 
50 mg.   
Start day for dosing 
Day 1 
Day 1 
Continuing from prestudy dosing.  
Date of Day 1 dose for study will be 
recorded 
Time of dosing 
Morning 
Morning 
Morning/evening, approximately 
12 hours apart 
Unit dose strength(s)/dosage 
level(s): 
5 mg tablets, 2.5 mg tablets, 1.0 mg 
tablets 
5 mg tablets, 2.5 mg tablets, 1.0 mg 
tablets 
5 mg to 25 mg tablets (all tablet 
strengths may not be available in all 
countries)  
Route, frequency of 
administration:  
Oral, QD 
Oral, QD 
Oral, BID 
Packaging and labeling: 
Parsaclisib will be provided in 
bottles. 
Each bottle will be labeled as 
required per country requirement. 
Placebo will be provided in bottles. 
Each bottle will be labeled as 
required per country requirement. 
Commercially available supplies of 
ruxolitinib will be used. 
Storage conditions 
Refer to the Pharmacy Manual. 
Refer to the Pharmacy Manual. 
Per labeling instructions. 
Status of treatment in 
participating countries: 
Experimental 
Not applicable 
Approved 
Note:  There is no order for the morning doses of parsaclisib/matching placebo and ruxolitinib.  They may be taken together or in any order in the morning. 


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6.2. 
Preparation, Handling, and Accountability 
The investigator, investigational drug storage manager (for Japan), or designee must confirm 
appropriate temperature conditions have been maintained during transit for all study treatments 
received and any discrepancies are reported and resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment.  All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator, investigational drug storage 
manager (for Japan), and authorized site staff. 
The investigator, investigational drug storage manager (for Japan), or designee is responsible for 
study treatment accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, 
and final disposition records).  Inventory and accountability records must be maintained and 
readily available for inspection by the study monitor and are open to inspection at any time by 
any applicable regulatory authorities.  The investigator, investigational drug storage manager (for 
Japan), or designee must maintain records that document: 
• Delivery of study drug to the study site. 
• Inventory of study drug at the site. 
• Participant use of the study drug, including pill counts from each supply dispensed. 
• Return of study drug to the investigator, investigational drug storage manager (for 
Japan), or designee by participants. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
(or investigational drug storage manager for Japan) will also maintain records adequately 
documenting that the participants were provided the specified study drug.  These records should 
include dates, quantities, and any available batch or serial numbers or unique code numbers 
assigned to the investigational product and study participants. 
Completed accountability records will be archived by the site.  The investigator, investigational 
drug storage manager (for Japan), or designee will be expected to collect and retain all used, 
unused, and partially used containers of study drug until verified by the study monitor (unless 
otherwise agreed to by the sponsor).  At the conclusion of the study, the investigator, 
investigational drug storage manager (for Japan), or designee will oversee shipment of any 
remaining study drug back to the sponsor or its designee for destruction according to institutional 
SOPs.  If local procedures mandate on-site destruction of the investigational supply, the site 
should (where local procedures allow) maintain the investigational supply until the study monitor 
inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study drug are provided in 
the Pharmacy Manual. 
Administration instructions for the participant are provided in Appendix H. 


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6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
This is a double-blind, placebo-controlled study.  Participants will receive ruxolitinib plus 
blinded study drug (parsaclisib or placebo).  Participants, investigators, and the sponsor will 
remain blinded to each participant's treatment assignment (Group A or Group B) throughout the 
study.  Emergency unblinding will occur if an AE requires the investigator to be made aware of 
the participant's treatment assignment (see emergency unblinding procedures in Section 9.6 and 
the Study Reference Manual). 
A sponsor-designated statistician (in-house or contract) who is not part of the study team will be 
unblinded and will provide summary aggregated data by treatment group to the DMC for 
scheduled interim analyses or other DMC meetings, but individual participant data will remain 
blinded. 
Block randomization with stratification for baseline platelet count (≥ 100 × 109/L vs 50 to 
< 100 × 109/L inclusive) and DIPSS risk category (high vs intermediate-2 vs intermediate-1) will 
be used.  If a participant's platelet count is < 50 × 109/L at baseline, the platelet count at 
screening will be used for stratification/randomization.  Participants will be randomly assigned to 
either Group A or Group B.  All participants will be centrally assigned to study treatment using 
an IXRS.  Randomization schedule will be generated by a sponsor-independent statistician and 
sent directly to the IXRS without provision to the sponsor.  Before the study is initiated, the 
telephone number and call-in directions for the IVRS and/or the login information and directions 
for the IWRS will be provided to each site.  Full details will be provided in the IXRS Manual. 
The primary endpoint, spleen volume as measured by MRI (or CT scan in applicable 
participants), will be assessed by a blinded central reader and reviewer. 
Study treatment will be dispensed at the study visits summarized in the SoA (see Table 3). 
Returned study treatment should not be redispensed to the participants. 
6.4. 
Dose and Requirement to Start Dosing After Crossover 
After criteria for crossover have been met (early or at Week 24) and sites have received 
notification that unblinding and crossover may occur, the crossover visit will be scheduled and 
dosing with parsaclisib will begin as long as the following hematology criteria are met based on 
a laboratory visit within 2 weeks of the planned parsaclisib start date: 
• Platelet count ≥ 50 × 109/L. 
• ANC ≥ 0.5 × 109/L. 
No more than 3 repeat assessments for platelet count and ANC are allowed.  Participants who 
have received 1 or more platelet transfusions must have a platelet count ≥ 50 × 109/L at least 
7 days after the most recent platelet transfusion to qualify for crossover.  Participants in whom 
the platelet count and/or ANC remain below these thresholds at the time of the later of 
(a) 4 weeks or (b) the next regularly scheduled study visit, following the date at which it was 
determined that crossover could occur, will be discontinued from the study, and that visit will 
constitute the EOT.   
The dose of parsaclisib will be 5 mg QD, taken in the morning, without regard to food.   


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6.5. 
Study Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the participant by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study. 
Participants will complete a daily dosing diary (electronic or paper) and will bring it with them to 
each study visit.  Compliance with parsaclisib/matching placebo will be calculated by the 
sponsor based on the drug accountability documented by the site staff and monitored by the 
sponsor/designee (tablet counts).  Participants will be instructed to bring all unused study drug 
with them to the study visits in order for site personnel to conduct tablet counts to assess study 
drug accountability.  The drug accountability documentation will be used by the sponsor to 
calculate treatment compliance. 
Although commercial supplies of ruxolitinib will be used, compliance with ruxolitinib will also 
be documented in the medical record and monitored by the sponsor or its designee.  Participants 
will record the doses of ruxolitinib taken on a paper diary issued by the site and collected at each 
visit. 
6.6. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose and/or Pharmacologically Active Dose 
Previously, the Phase 2 study INCB 50465-201 examined daily doses up to 20 mg for 8 weeks 
followed by doses up to 20 mg weekly or 5 mg daily.  Pharmacological activity was observed at 
all dose combinations with 8 weeks of daily dosing followed by continued daily dosing or 
weekly dosing, although activity appeared to diminish with time with weekly dosing.  
Dose-limiting toxicities were not observed in any dosing part of the study, and the maximum 
tolerated dose was not reached. 
6.7. 
Dose Modifications 
6.7.1. 
Dose Increases for Inadequate Efficacy 
Dose increases for parsaclisib:  The dose of parsaclisib (or matching placebo) will be 5 mg QD.  
Dose increases are not allowed at any time during the study.  If a dose has been reduced due to 
AEs, the dose may be increased back to the original starting dose of 5 mg QD once safety has 
adequately resolved (see Section 6.7.2). 
Dose increases for ruxolitinib:  Dose increases of ruxolitinib are not allowed.  Participants will 
remain on the stable dose they were taking for the 8 weeks prior to Day 1 throughout the study, 
unless dose decreases for toxicity are required (see Section 6.7.7). 
6.7.2. 
Dose Decreases of Parsaclisib/Placebo for Toxicity 
Parsaclisib or matching placebo should be interrupted/decreased first, with no change to the 
ruxolitinib dosage.  Adjustments to ruxolitinib may be used if interruption/dose adjustment of 
parsaclisib or matching placebo does not lead to resolution or at least improvement of the AE 
within a 14-day period (see Section 6.7.7). 
Treatment with parsaclisib or matching placebo may be delayed up to 2 weeks (14 days) to allow 
for resolution of toxicity.  Participants may resume treatment if no medical condition or other 


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circumstance exists that, in the opinion of the investigator, would make the participant unsuitable 
for further participation in the study.  The treating investigator should contact the sponsor to 
discuss the case of any participant whose treatment has been delayed for more than 14 days 
before restarting treatment with parsaclisib or matching placebo and/or ruxolitinib.  Adverse 
events that have a clear alternative explanation or transient (≤ 72 hours) abnormal laboratory 
values without associated clinically significant signs or symptoms may be exempt from 
dose-reduction rules. 
Table 11 shows dose-reduction and interruption guidelines for parsaclisib and matching placebo.  
Because participants may enter the study with extensive pretreatment and/or severe bone marrow 
infiltration by the primary disease, these dose-reduction rules are provided as guidelines (see 
Table 11).  Individual decisions regarding dose reduction/interruption should be made 
using investigator clinical judgment and in consultation with the sponsor's medical monitor 
in those cases where the guidelines will not be followed, taking into account relatedness of 
the AE to parsaclisib and the participant's underlying condition.  Available dose strengths 
for parsaclisib/matching placebo are shown in Table 12. 
Table 11: 
Guidelines for Interruption and Restarting of Parsaclisib/Matching Placebo 
Adverse Event 
Action Taken 
Chemistry 
AST and/or ALT > 5.0 × ULN (Grade 3). 
Step 1:  Interrupt parsaclisib or matching placebo for up to 2 weeks 
(14 days) until the toxicity has resolved to ≤ Grade 1 except by approval 
of the medical monitor. 
Step 2:  Restart parsaclisib or matching placebo at the same dose.  If 
assessed as related to parsaclisib or matching placebo, restart parsaclisib 
or matching placebo at the next lower dose; monitor as clinically 
indicated. 
Hematology 
• ANC < 1.0 × 109/L (Grade 3) unless because of 
underlying disease.  Applies only if this 
represents a worsening grade from baseline. 
• Platelet count ≥ 25 × 109/L and < 40 × 109/L.  
Applies only if this represents a worsening 
grade from baseline. 
Step 1:  Interrupt parsaclisib or matching placebo for up to 2 weeks 
(14 days) until the toxicity has resolved to ≤ Grade 1 or pretherapy 
baseline. 
Step 2:  Restart parsaclisib or matching placebo at the same dose and 
monitor as clinically indicated. 
• Grade 4 ANC (< 0.5 × 109/L) regardless of 
baseline grade. 
• ≥ Grade 3 ANC with temperature of at least 
38.5°C OR with ≥ Grade 3 infection regardless 
of baseline grade. 
• Platelet count is < 25 × 109/L (Grade 4), 
regardless of baseline grade. 
Step 1:  Interrupt parsaclisib or matching placebo for up to 2 weeks 
(14 days) until the toxicity has resolved to ≤ Grade 1 or pretherapy 
baseline. 
Step 2:  Restart parsaclisib or matching placebo at the next lower dose; 
monitor as clinically indicated.  Escalate to original dose with recovery 
to preinterruption levels of analyte.   
Nonhematologic toxicities 
• Diarrhea/colitis (Grade 1) 
Step 1:  Treat with antimotility agents (eg, loperamide) and initiate 
supportive care (see Section 6.7.3).  If not improved after 48 hours, treat 
per guidance for ≥ Grade 2. 


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Table 11: 
Guidelines for Interruption and Restarting of Parsaclisib/Matching Placebo 
(Continued) 
Adverse Event 
Action Taken 
• Diarrhea/colitis (Grade 2) 
Step 1:  Interrupt parsaclisib or matching placebo.  Perform workup for 
infection (including CMV, Clostridium difficile, etc) immediately.  
Initiate or continue supportive care (see Section 6.7.3).  Monitor 
approximately every 48 hours until resolution. 
Step 2:  If improved within 48 hours and/or infection* is confirmed, 
restart parsaclisib/matching placebo at the same schedule and dose 
after resolved to ≤ Grade 1 and continue to monitor. 
*For infectious diarrhea/colitis, follow institutional standard of care 
guidelines and restart parsaclisib/matching placebo according to clinical 
judgment after resolved to ≤ Grade 1.  Consult with medical monitor if 
needed. 
Step 3:  If not improved within 48 hours and infection is ruled out, start 
oral steroids or consider IV steroids if participant is being given IV 
fluids.  If no improvement with oral steroids, switch to IV steroids. 
Step 4:  When diarrhea resolves to ≤ Grade 1, continue supportive care 
and taper steroids according to institutional standard of care.  When 
taper is complete (eg, no steroid or ≤ 10 mg/day prednisone or 
equivalent) and diarrhea is ≤ Grade 1, restart parsaclisib/matching 
placebo at the next lower dose with approval of the medical monitor. 
Step 5:  If Grade 2 diarrhea reoccurs, treat per guidance for diarrhea 
(≥ Grade 3)/noninfectious colitis. 
Step 6:  If ≥ Grade 2 diarrhea reoccurs a third time, permanently 
discontinue parsaclisib/matching placebo. 
• Diarrhea (≥ Grade 3) 
• Noninfectious colitis (any grade;  confirmed or 
suspected) 
Step 1:  Interrupt parsaclisib.  Perform workup for infection (including 
CMV, C. difficile, etc) immediately.  Initiate or continue supportive care 
(see Section 6.7.3).  Consider colonoscopy with biopsy for diarrhea 
≥ Grade 3 and/or if symptoms suggestive of colitis (diarrhea 
accompanied by abdominal pain and/or mucus or blood in stool).  
Monitor every 48 hours until resolution. 
Step 2:  If infection* is ruled out, start oral steroids or consider IV 
steroids if participant is being given IV fluids.  If no improvement with 
oral steroids within 48 hours, switch to IV steroids. 
*For infectious diarrhea/colitis, follow institutional standard of care 
guidelines and restart parsaclisib according to clinical judgment after 
resolved to ≤ Grade 1.  Consult with medical monitor if needed. 
Step 3:  When diarrhea/colitis resolves to ≤ Grade 1, continue 
supportive care and taper steroids according to institutional standard of 
care.  When taper is complete (eg, no steroid or ≤ 10 mg/day prednisone 
or equivalent) and diarrhea/colitis is ≤ Grade 1, restart parsaclisib with 
approval of the medical monitor.  Continue to monitor.  
Step 4:  If ≥ Grade 3 diarrhea or noninfectious colitis (any grade) 
reoccurs, permanently discontinue parsaclisib/placebo. 
• Pneumonitis (Grade 1) 
Step 1:  Interrupt parsaclisib or matching placebo until the toxicity has 
resolved. 
Step 2:  Restart parsaclisib or matching placebo at the next lower dose.  
Monitor as clinically indicated. 
• Pneumonitis (≥ Grade 2) 
Permanently discontinue parsaclisib or matching placebo. 
• Skin toxicity (eg, rash, pruritus, etc, unless 
otherwise specified) (Grade 2-3) 
Step 1:  Interrupt parsaclisib or matching placebo until the toxicity has 
resolved to ≤ Grade 1. 
Step 2:  Restart parsaclisib or matching placebo at the same dose.  If 
assessed as related to parsaclisib or matching placebo, restart at the next 
lower dose. 


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Table 11: 
Guidelines for Interruption and Restarting of Parsaclisib/Matching Placebo 
(Continued) 
Adverse Event 
Action Taken 
• Exfoliative dermatitis (Grade 1) 
Step 1:  Interrupt parsaclisib or matching placebo until the toxicity has 
resolved. 
Step 2:  Restart parsaclisib or matching placebo at the next lower dose.  
Monitor as clinically indicated. 
• Exfoliative dermatitis (≥ Grade 2) 
Permanently discontinue parsaclisib or matching placebo. 
• Intestinal perforation (any grade) 
Permanently discontinue parsaclisib or matching placebo. 
• PJP 
Interrupt parsaclisib or matching placebo.  Permanently discontinue 
parsaclisib or matching placebo if PJP is confirmed. 
• CMV infection 
Participants with CMV viremia without associated clinical signs of 
CMV infection should be carefully monitored.  Consider interrupting 
parsaclisib or matching placebo for participants with CMV viremia and 
clinical signs of infection until the infection has resolved.  Restart 
parsaclisib or matching placebo reduced by 1 dose level if approved by 
the medical monitor. 
• Varicella zoster infection 
Interrupt parsaclisib or matching placebo.  Restart parsaclisib or 
matching placebo only by approval of the medical monitor. 
• Any Grade 1 or Grade 2 toxicity unless 
otherwise specified. 
Continue parsaclisib or matching placebo treatment and treat the 
toxicity; monitor as clinically indicated. 
• Any Grade 3 toxicity, if clinically significant 
and not manageable by supportive care unless 
otherwise specified. 
Step 1:  Interrupt parsaclisib or matching placebo for up to 2 weeks 
(14 days) until toxicity resolves to ≤ Grade 1. 
Step 2:  Restart parsaclisib or matching placebo at the same dose.  If 
assessed as related to parsaclisib or matching placebo, restart at the next 
lower dose.  If interrupted for > 14 days, contact the medical monitor 
for approval to restart parsaclisib or matching placebo.  Monitor as 
clinically indicated. 
• Any recurrent Grade 3 toxicity after 2 dose 
reductions. 
Discontinue parsaclisib or matching placebo administration and 
follow-up per Protocol.  Exceptions require approval of sponsor. 
• Any other Grade 4 toxicity. 
Discontinue parsaclisib or matching placebo administration and 
follow-up per Protocol.  Exceptions require approval of sponsor. 
Table 12: 
Dose Strengths for Parsaclisib/Matching Placebo 
Current Dose Level 
Dose After 1 Reduction 
Dose After 2 Reductions 
5 mg QD 
2.5 mg QD 
1 mg QD 
2.5 mg QD 
1 mg QD 
Contact medical monitor 
1 mg QD 
Contact medical monitor 
Contact medical monitor 
6.7.3. 
Supportive Care for Diarrhea/Colitis 
Participants should be informed to immediately report to the investigator any event of diarrhea.  
Participants should receive appropriate supportive care measures as deemed necessary by the 
investigator.  For any ≥ Grade 1 diarrhea, participants should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.  Participants should try to eat 5 to 6 small meals per day; 
low-fat, high-protein foods; and cooked instead of raw vegetables.  Participants may supplement 
their diet with bananas, rice, applesauce, and toast to reduce the number of bowel movements 
and may also try crackers, gelatin, noodles, or oatmeal.  Participants should avoid fried, fatty, 


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greasy, or spicy foods; milk, milk products, and acidic drinks; high-fiber foods and foods that 
cause gas; and alcohol, caffeine, and herbal supplements (Coutré et al 2015). 
For each occurrence, attempts should be made to rule out other causes, such as metastatic disease 
or bacterial or viral infection (including CMV), which might require additional supportive care. 
It may be necessary to perform conditional procedures such as colonoscopy with biopsy as part 
of evaluation of the event.  Note that several courses of steroid tapering may be necessary 
because symptoms may worsen when the steroid dose is decreased. 
Participants should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain or cramping, and blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 
6.7.4. 
Follow-Up for Immune Related Adverse Events 
An AE with a potential immunologic etiology, or an irAE, may be defined as an AE consistent 
with an immune phenomenon associated with study drug exposure after all other etiologies have 
been eliminated.  Immune-related AEs may be expected based on previous experience with 
parsaclisib and other drugs (eg, idelalisib) that inhibit PI3Kδ.  Special attention should be paid to 
AEs that may be suggestive of potential irAEs.  Based on emerging data from the ongoing 
parsaclisib clinical program (parsaclisib IB), most irAEs occur after the first 9 weeks of study 
drug administration.  However, an irAE could occur at any time.  Suspected irAEs should be 
discussed with the medical monitor when possible. 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of drug-related 
AEs with potential immunologic etiology are outlined in Table 11.  For each AE, attempts 
should be made to rule out other causes, including but not limited to metastatic disease or 
bacterial or viral infection, which might require specific supportive care. 
6.7.5. 
COVID-19  
Infection with SARS-CoV-2, the coronavirus that causes COVID-19, is more frequent and 
severe in patients with hematologic dysfunction (Jee et al 2022). The presence of hematologic 
malignancy, baseline neutropenia and lymphopenia, B-cell depletion, and other factors have been 
identified as risk factors for loss of humoral immunity to COVID-19, poor vaccine response, 
viral persistence, and severe disease (Lee et al 2022, Lyudovyk et al 2022, Shree et al 2022). 
Targeting B-cell function, proliferation, and survival with various therapies are current strategies 
for improving the outcome of several hematologic malignancies. PI3Kδ inhibition with 
parsaclisib alone or in combination with other therapies, which may also suppress humoral 
immunity, has the potential to negatively impact SARS-CoV-2 infection risk, vaccine 
effectiveness, recovery from COVID-19, and disease severity (Cheson 2022). Investigators and 
participants in trials of parsaclisib, alone or in combination, need to be aware of these potential 
risks and consider the local standards of care and available therapies for disease prevention, 
vaccination, and infection management of COVID-19. 
 


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6.7.6. 
Criteria for Permanent Discontinuation of Parsaclisib/Matching Placebo 
The occurrence of unacceptable toxicity not caused by the underlying disease will be presumed 
to be related to study drug treatment and will require that the study drug be permanently 
discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
participant's ability to continue study-specific procedures or is considered to not be in 
the participant's best interest. 
• An AE requiring more than 2 dose reductions. 
• Persistent AE requiring a delay of therapy for more than 2 weeks (14 days) unless a 
greater delay has been approved by the sponsor. 
See Section 7.1.2 for discontinuation procedures. 
6.7.7. 
Dose Decreases of Ruxolitinib for Safety 
Dose modifications/interruptions of ruxolitinib because of toxicity are not required unless 
parsaclisib modifications/interruptions have been first implemented for 14 days with no 
improvement in toxicity grade.  Doses of ruxolitinib may be modified/interrupted earlier if the 
study investigator deems this necessary.  Dose interruptions and modifications for ruxolitinib 
because of hematologic toxicity that continues after interruption of INCB050465 are shown in 
Table 13. 
Table 13: 
Dose Reductions/Interruptions and Restarts for Hematologic Toxicities That 
Persist for > 14 Days After Interruption of Parsaclisib 
ANC 
(× 109/L) 
 
Platelet Count 
(× 109/L) 
Dose of Ruxolitinib 
Value 
CTCAE 
Grade 
Value 
CTCAE 
Grade 
0.5 to < 1.0 
3 
or 25 to < 40 
Below 
UL of 
Grade 3 
If Grade 3 cytopenia persists for > 14 days after interrupting 
parsaclisib/matching placebo or if the primary investigator 
deems that earlier interruption of ruxolitinib is necessary, then 
ruxolitinib will be interrupted until the toxicity is resolved to 
≤ Grade 1 or pretherapy baseline and then restarted at the 
current dose.  If a Grade 3 event recurs and persists for 
> 14 days after interrupting parsaclisib/matching placebo or if 
the primary investigator deems that earlier interruption of 
ruxolitinib is necessary, then ruxolitinib will be interrupted and 
the restart dose (after recovery to ≤ Grade 1 or pretherapy 
baseline) of ruxolitinib will be 1 dose level (5 mg BID less) 
lower than the dose that resulted in the cytopenia.  A 
participant who was taking 5 mg BID will restart at 5 mg QD. 


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Table 13: 
Dose Reductions/Interruptions and Restarts for Hematologic Toxicities That 
Persist for > 14 Days After Interruption of Parsaclisib (Continued) 
ANC 
(× 109/L) 
 
Platelet Count 
(× 109/L) 
Dose of Ruxolitinib 
Value 
CTCAE 
Grade 
Value 
CTCAE 
Grade 
< 0.5 
4 
or 
< 25 
4 
If Grade 4 thrombocytopenia or neutropenia occurs and 
persists for > 14 days after interrupting parsaclisib/matching 
placebo or if the primary investigator deems that earlier 
interruption of ruxolitinib is necessary, then ruxolitinib will be 
interrupted until toxicity is resolved to ≤ Grade 1 or pretherapy 
baseline and the restart dose will be 1 dose level (5 mg BID 
less) lower than the dose that resulted in the cytopenia.  A 
participant who was taking 5 mg BID ruxolitinib will restart at 
5 mg QD. 
Neutropenic fever 
If neutropenia (ANC < 1.0) persists for > 14 days after 
interrupting parsaclisib/matching placebo or if the primary 
investigator deems that earlier interruption of ruxolitinib is 
necessary, then ruxolitinib will be interrupted until recovery of 
ANC to ≥ 1.0 × 109/L, and the restart dose will be 1 dose level 
(5 mg BID less) lower than the dose that resulted in the 
cytopenia. 
6.8. 
Concomitant Medications and Procedures 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF.  Any 
prior medication received up to 30 days before the first dose of study treatment and 30 to 35 days 
after the last dose of study treatment, or until the participant begins a new MF therapy, 
whichever occurs first, will be recorded in the eCRF.  Any addition, deletion, or change in the 
dose of these medications will also be recorded.  Concomitant medications administered after the 
last dose of study treatment should be recorded for SAEs as defined in Section 9.3.  Prior 
medication history for MF should be entered in its entirety, as well as complete ruxolitinib 
dosing history. 
6.8.1. 
Permitted Medications 
Concomitant treatments/procedures that are required to manage a participant's medical condition 
during the study will also be recorded in the eCRF.  The medical monitor should be contacted if 
there are any questions regarding concomitant or prior therapy for conditions other than MF. 
6.8.2. 
Pneumocystis jirovecii Pneumonia Prophylaxis 
All participants receiving combination study treatment with parsaclisib/matching placebo and 
ruxolitinib are required to receive a standard PJP prophylaxis regimen determined by the 
investigator.  Examples of standard PJP prophylaxis therapies for this population include 
trimethoprim-sulfamethoxazole, atovaquone, diaminodiphenylsulfone (Dapsone) with or without 
pyrimethamine, and pentamidine (National Comprehensive Cancer Network 2017).  Note:  In 
Japan, diaminodiphenylsulfone and pentamidine are not approved for PJP prophylaxis, thus these 
will not be used.  Participants with sulfonamide allergy should be treated with either inhaled 


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pentamidine or atovaquone for PJP prophylaxis; diaminodiphenylsulfone should not be used in 
such participants.  Prophylaxis should be given while participants are receiving parsaclisib and 
continue for 2 to 6 months after the last dose of study treatment.  Prophylaxis may be started as 
soon as the baseline visit but no later than Day 1 of the study. 
6.8.3. 
Use of Growth Factors Such as Erythropoietin 
Hematopoietic growth factor receptor agonists (eg, erythropoietin, granulocyte-colony 
stimulating factor, romiplostim, eltrombopag) are strongly discouraged.  Ruxolitinib may 
interfere with efficacy of growth factors, and they may cause an increase in spleen size. 
6.8.4. 
Restricted Medications and Procedures 
• Aspirin in doses exceeding 125 mg/day is not permitted.  Low-dose aspirin 
(≤ 125 mg/day) is permitted. 
• Caution should be used when administering ibuprofen or other nonsteroidal 
anti-inflammatory drugs.  Systemic corticosteroid doses less than or equal to the 
equivalent of 10 mg prednisolone per day are permitted, and higher dosages are not 
allowed.  Participants should be monitored closely for toxicity, especially for 
myelosuppression and renal and gastrointestinal toxicity. 
• Inducers of CYP3A4 may be used with caution, and investigators should seek other 
options if available (see Appendix G). 
• Moderate CYP3A4 inhibitors may be used with caution.  Differences in individual 
sensitivity and variation in potency of inhibition of various CYP enzymes may result 
in the need for a reduced dose of ruxolitinib during a period of concomitant 
medication use.  If required for safety, the dose of ruxolitinib may be reduced from 
BID to QD in these circumstances; this should be clearly documented in the treating 
physician's notes.  The sponsor's medical monitor may be consulted for advice when 
using these agents. 
If concomitant administration of an anticoagulant/antiplatelet medication is indicated, then 
caution and enhanced monitoring is required.  History of thrombocytopenia and any concurrent 
ruxolitinib-related thrombocytopenia should be a factor in the choice of anticoagulant and dose. 
6.8.5. 
Prohibited Medications and Procedures 
The following medications are prohibited during the treatment and maintenance portions of the 
study (see also Jakafi 2021 and Jakavi 2022):  
• Any concurrent MF therapy other than that specified in the Protocol. 
• Use of experimental drug therapy for MF or any other standard drug used for MF 
(whether for treatment of MF or another indication), with the exception of ruxolitinib, 
within 3 months of starting study drug (ie, Day 1). 
• Any investigational medication (for a non-MF indication) within 28 days or 5 half-lives, 
whichever is longer, before the first dose of study drug and at any time before complete 
withdrawal from the study. 


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• Use of potent inhibitors of CYP3A4 (eg, ketoconazole, clarithromycin, itraconazole, 
nefazodone or telithromycin, voriconazole or posaconazole); ketoconazole may be used 
with caution if other options are not available.  Based on the low overall bioavailability of 
topical ketoconazole, there are no restrictions on topical ketoconazole in the study. 
• Any live vaccine beginning 30 days before the first dose of study drug through the safety 
follow-up visit. 
6.8.6. 
Treatment After Week 24 
After 24 weeks, participants will enter the extension period of the study.  Treatment will 
continue as long as the regimen is tolerated and the participant does not meet discontinuation 
criteria.  Participants randomized to placebo will have the opportunity to crossover to receive 
parsaclisib (together with continued ruxolitinib) once they have reached Week 24 and all 
relevant data are entered and cleaned.  These crossover participants may also continue as long as 
the regimen is tolerated and they do not meet discontinuation criteria.  It is anticipated that 
individual participants will continue in the study for approximately 2 years.  Extension studies 
may be implemented for continued access to study treatment. 
7. 
DISCONTINUATION OF STUDY TREATMENTS AND 
PARTICIPANT WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatments (parsaclisib/matching placebo and 
ruxolitinib) for the following reasons: 
• The participant becomes pregnant. 
• Consent is withdrawn.   
Note:  Consent withdrawn means that the participant has explicitly indicated that 
he/she does not want to be followed any longer; in this case, no further data, except 
data in the public domain, may be solicited from or collected on the participant.  
Participants may choose to discontinue study treatment and remain in the study to be 
followed for progression and survival. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity such as noted in Section 6.7.2. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 


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A participant may be discontinued from study drug and reference treatment as follows: 
• If a participant is noncompliant with study procedures or study drug/treatment 
administration in the investigator's opinion, the sponsor should be consulted for 
instruction on handling the participant. 
7.1.2. 
Discontinuation Procedures 
The decision to discontinue study treatment and reference treatment will not constitute study 
withdrawal or study completion.  In the event that the decision is made to discontinue study 
treatment and reference treatment, the treatment portion will be considered complete and the 
follow-up part of the study will begin. 
If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for discontinuation must be documented in the participant's medical 
record and the primary reason for discontinuation must be included in the eCRF. 
• The EOT visit should be performed and date recorded. 
• The last date of the last dose of study drug/reference treatment will be recorded in the 
eCRF. 
• The status of the participant should be updated to EOT in the IXRS. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study drug/reference treatment–related toxicities resolve, return to baseline, or are 
deemed irreversible, whichever is longest. 
• Participants will be followed for subsequent MF treatment regimens and survival via 
periodic telephone contact.  Results of these contacts will be recorded in the eCRF. 
If the participant discontinues study treatment/reference treatment and actively withdraws 
consent for collection of follow-up data (safety follow-up or disease assessment), then no 
additional data collection should occur; however, participants will have the option of 
withdrawing consent for study treatment/reference treatment and further assessments but 
allowing survival follow-up. 
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
See Table 3 and Table 5 for data to be collected at the time of study withdrawal and follow-up 
and for any further evaluations that need to be completed. 


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7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing address 
or local equivalent methods).  These contact attempts should be documented in the 
participant's medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
All assessments mandated throughout the study must be performed on a calendar schedule; 
delays in treatment administration will not delay performance of study visits, laboratory-only 
visits, or assessments 
 
 
 see Section 8.4.1). 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the participant.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to participant records. 
− The ICF must contain all required elements and describe the nature, scope, and 
possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the applicable requirements and regulations for the country(ies) in 
which the study is being conducted as well as the IRB/IEC or study center. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws.  The level of disclosure 
must also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must provide consent to the most current version of the ICF during their 
participation in the study. 


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• A copy of the ICF(s) must be provided to the participant or the participant's legally 
authorized representative. 
• Participants who are rescreened are required to sign a new ICF. 
8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the beginning of the 7-day baseline period 
(ie, Day –35 to Day –7).  Screening may not exceed 28 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process.  Assessments to be performed are indicated in Table 3. 
Participants should arrive for the screening visit after an overnight fast (no food or liquid except 
water) of at least 8 hours or since midnight.  A participant who has not fasted should be 
scheduled for the screening blood draws on a morning when he/she can arrive after an overnight 
fast of at least 8 hours.  For participants who are randomized into the study,  information 
associated with eligibility requirements must be entered into the appropriate eCRF pages. 
Procedures conducted as part of the participant's routine clinical management and obtained 
before signing of the ICF may be used for screening provided that the procedure meets the 
Protocol-defined criteria and has been performed in the timeframe of the study (ie, up to 35 days 
before Day 1). 
Bone marrow biopsy and aspirate collection for confirmation of MF diagnosis and degree of 
fibrosis must be performed at the screening or baseline visit intervals.  Note:  Participants may 
use a historical biopsy obtained within 2 months before screening as long as a written report 
showing the diagnosis is available along with biopsy/aspirate samples.  Participants without a 
prior biopsy report and biopsy/aspirate as indicated in the preceding text must have a biopsy at 
screening/baseline in order to participate in the study.  The prior data or the newly obtained data 
must be entered into the eCRF. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
enrollment/randomization or the administration of study drug and reference treatment.  Tests 
with results that fail eligibility requirements may be repeated once during screening if the 
investigator believes the results to be in error.  For screening assessments that are repeated, the 
most recent available result before randomization/treatment assignment will be used to determine 
eligibility.  Treatment should start as soon as possible but within 3 days after the date of 
enrollment/randomization. 
See Sections 5.4 and 5.5 for information regarding screen failures and replacement of 
participants, respectively. 
8.1.3. 
Baseline 
Participants who have signed the ICF and meet all of the inclusion criteria (see Section 5.1) and 
none of the exclusion criteria (see Section 5.2) may be enrolled in the study and will be contacted 
by clinical site staff to schedule the baseline visit.  The baseline interval corresponds to the 
7 days before initiating treatment with parsaclisib/matching placebo plus ruxolitinib and during 
which the baseline MRI (or CT scan in applicable participants) and symptom diary will be 
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• The MFSAF v4.0 diary should be distributed.  Participants will be issued a handheld 
device and will complete the diary questions each night beginning on  Day –7 up to 
the Week 24 visit. 
• The MRI (or CT scan in applicable participants) should be conducted on the first or 
second day of the baseline interval to allow ample time for the laboratory to verify 
scan quality. 
• To ensure per-Protocol imaging completions, all MRI (or CT) scans for the study 
should be scheduled if possible to avoid missing scans at later timepoints in the study.  
• Baseline laboratory samples for serum chemistry and hematology should be obtained 
as close as possible to Day 1 but may be drawn up to 3 days before first dose.  Only 
1 sample for baseline/Day 1 is required.  Baseline platelet count values will be used 
for stratification/randomization.  Note that platelet count at baseline for a participant 
with a screening value of ≥ 50 × 109/L may have decreased below 50 × 109/L.  For 
such participants, the screening value for platelet count will be used for 
stratification/randomization.  
8.1.4. 
Interactive Response Technology Procedure 
The IXRS will be accessed to obtain a participant ID number when a participant enters the 
screening portion of the study.  After determining that the participant is eligible for study entry, 
and the participant has entered the baseline interval and is completing the daily diary for 
symptoms, using the platelet value determined at baseline, the IXRS will be contacted to obtain 
treatment group assignment and study drug assignment.  The IXRS will be contacted at each 
regular study visit, except for the end of Week 2 visit, to update the study drug supply and at 
EOT (see Table 3 and Table 4).  Full details will be provided in the IXRS Manual. 
8.1.5. 
Distribution of Reminder Cards 
Participants will be provided with a reminder card at each visit.  The reminder card will indicate 
the date/time of the next visit and will also remind the participant that they should not take their 
morning dose of study drug or reference treatment (ruxolitinib) on the day of the study visit.  The 
reminder card will also indicate to arrive after an overnight fast (no food or liquid except water) 
of at least 8 hours for the visits at screening, Week 12, Week 24, the extension visits every 
12 weeks thereafter, and the EOT visit, since blood samples for lipid profile will be drawn at 
these visits.  Laboratory-only visits do not require overnight fasting or holding of morning doses 
of parsaclisib/matching placebo or ruxolitinib.  Space will be provided on the reminder card for 
the Week 2 and Week 4 visits to record the time of the prior evening dose of ruxolitinib. 
8.1.6. 
Prior and Concomitant Medications 
Prior and concomitant medications and procedures will be reviewed to determine participant 
eligibility.  All concomitant medications and measures must be recorded in the CRF, and any 
medication received or procedure performed within 30 days before the first dose of 
parsaclisib/matching placebo plus ruxolitinib and up to the end of study will be recorded in the 
eCRF.  The medication record will be maintained after signing the ICF to document concomitant 
medications, including any changes to the dose or regimen.  Concomitant medications include 


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any prescription, over-the-counter, or natural/herbal preparations taken or administered during 
the study period.  Concomitant treatments and/or procedures that are required to manage a 
participant's medical condition during the study will also be recorded in the eCRF. 
8.1.7. 
Demography and Medical History 
8.1.7.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, medical and surgical 
history, and current illnesses.  Medical history will include relevant medical or surgical treatment 
within the past 10 years that are considered to be clinically significant by the investigator. 
8.1.7.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and treatment history will be collected at screening.  Details 
regarding the participant's history of MF and other MPNs, including date of diagnosis, as well as 
relevant disease characteristics and prior treatments, including systemic treatments, radiation, 
and surgical procedures, will be recorded. 
8.1.7.3. 
Transfusion History Status 
All transfusions of RBC products or platelets from at least 12 weeks before the screening visit up 
to the first dose of study drug will be recorded on the transfusion history page.  After the first 
dose of study drug, all transfusions of RBC products or platelets will be recorded on the 
transfusion page located within the logs area of the eCRF.  Information collected in the eCRF 
includes product delivered, data of transfusion, and units delivered. 
8.1.7.4. 
Dosing Diary 
A diary will be provided to the participant to record doses of parsaclisib and ruxolitinib taken 
each day.  Participant will bring the diary with them to each study visit. 
8.1.7.5. 
Screening Symptom Form 
In order to satisfy Inclusion Criteria 5, active symptoms of MF at the screening visit as 
demonstrated by the presence of a TSS of ≥ 10 using the Screening Symptom Form (see 
Appendix C) will be recorded in the eCRF. 
8.1.8. 
Study Site Visit Coordination 
Participants will follow the study visit schedule shown in Table 3.  Unblinding and potential 
crossover for participants will occur once they have completed Week 24 and the data entered 
have been verified and cleaned through the Week 24 visit (including imaging).  If the planned 
crossover visit does not coincide with a regularly scheduled study visit, an additional study visit 
may be scheduled in order to perform visit assessments; the 4-week post-crossover visit will also 
need to be scheduled (see Table 4 for crossover visit and 4-week post-crossover visit 
assessments). 
For early unblinding/crossover, a regularly scheduled visit may be used once the process defined 
in Section 4.1.4 has been completed.  If the planned crossover visit does not coincide with a 


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regularly scheduled study visit, an additional study visit may be scheduled in order to perform 
visit assessments; the 4-week post-crossover visit will also need to be scheduled (see Table 4 for 
crossover visit and 4-week post-crossover visit assessments).   
8.2. 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.3. 
Imaging 
The primary measure of spleen volume will be by MRI (or CT scan in applicable participants).  
An MRI of the upper and lower abdomen and pelvis will be performed at baseline, Week 12, 
Week 24, and every 12 weeks thereafter through Week 108.  An MRI will be performed with a 
body coil because the objective is to measure organ volume rather than to find very small 
lesions.  MRIs will be read initially by local radiologists who will be instructed to not provide a 
quantitative measure of spleen volume but may provide a qualitative assessment such as 
enlarged, smaller, larger, and so on.  However, should a quantitative result be provided to the 
investigator, this will not be considered a protocol violation, and the participant will still be 
evaluable.  The local radiologist should assess the scan for quality and send all scans (MRI or 
CT) to the central imaging laboratory the same day, if at all possible.  The scans from an 
individual participant will be read by a central reader.  The central imaging laboratory 
radiologist(s) will be blinded to initial treatment assignment.  Spleen and liver volume will be 
obtained by outlining the circumference of the organ and determining the volume using the 
validated technique of least squares.  The MRI will not determine spleen length below the costal 
margin because there are no validated approaches for determining this measurement.  


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Procedure-specific training for scanning and image capture will be provided by the vendor and in 
the Imaging Manual. 
An MRI is the preferred method for obtaining spleen volume data.  However, CT scans may be 
performed at the visits where MRI is designated if the participant is not a candidate for MRI (eg, 
because of the presence of metal clips in the body, because of claustrophobia) or if MRI is not 
readily available.  CT scans will be similarly processed by the same central laboratory as used 
for MRIs.  Procedure-specific training for scanning and image capture will be provided by the 
vendor.  Note:  The same method (MRI vs CT) must be used for all visits for a given participant 
unless a new contraindication to the use of MRI occurs (eg, pacemaker insertion). 
8.2.4. 
Symptom Diary 
Symptoms of MF will be assessed using a symptom diary (MFSAF v4.0 diary).  Participants will 
be issued a handheld device on which to record answers to queries regarding MF symptoms.  
Symptoms assessed will include filling up quickly/early satiety, abdominal discomfort, 
abdominal pain, fatigue, night sweats, itching, and bone/muscle pain.  The MFSAF v4.0 diary 
will be completed by participants each night beginning at Day –7 (first day of baseline) and 
continuing to the Week 24 visit (25 weeks total).  Participants will bring the device to the study 
site at study visits on Day 1 and Weeks 4, 8, 12, 16, and 20, so that the device charging can be 
verified and the accumulated data can be downloaded.  Note:  Participants who will have 
overnight stays associated with their study visit must also bring their docking station so that their 
device can be fully charged at all times and so that they can complete the evening diary entries.  
The device will then be returned to the participant at these same visits for continued use each 
night.  The participant will return the device and the docking station for the final time at the 
Week 24 visit so that the data can be archived.  Detailed directions for the administration of the 
MFSAF v4.0 diary will be provided in a reference manual.  Translations of the MFSAF v4.0 
diary will be available. 
 
 
 
 
8.2.6. 
Eastern Cooperative Oncology Group Status 
The ECOG performance status score (see Appendix D) will be required at screening to evaluate 
eligibility and will be assessed at visits noted in the SoA (see Table 3 and Table 4). 
 
 
 
 
 
 
 
 
 


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8.3. 
Safety Assessments 
8.3.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until at least 30 to 
35 days after the last dose of study drug (parsaclisib/placebo).  Adverse events that begin or 
worsen after informed consent should be recorded on the Adverse Events Form in the eCRF 
regardless of the assumption of a causal relationship with the study treatment.  Conditions that 
were already present at the time of informed consent should be recorded on the Medical History 
Form in the eCRF.  Adverse events (including laboratory abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible rather than by individual underlying 
signs and symptoms.  See Section 9 for full reporting requirements for AEs. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that meet 
the definition of an AE or SAE and remain responsible for following-up on AEs that are serious, 
considered related to the study treatment/procedures, or that caused the participant to discontinue 
the study treatment.  Care will be taken not to introduce bias when detecting AEs and/or SAEs.  
Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 


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All SAEs will be reported to the sponsor or designee within 24 hours.  The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs, and nonserious AEs of special interest (as defined in 
Section 9.5), will be followed until resolution, stabilization, the event is otherwise explained, or 
the participant is lost to follow-up (as defined in Section 7.3). 
8.3.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual, such as a licensed 
physician, physician assistant, or an advanced registered nurse practitioner, as local law permits.  
Abnormalities identified after the first dose of study treatment constitute an AE if they are 
considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require changes in study treatment.  Investigators should pay special attention to 
clinical signs related to previous serious illnesses. 
At the screening and EOT visits, a complete physical examination should be conducted.  The 
complete physical examination will include height (screening only) and body weight, and 
assessment(s) of the following organ or body systems:  skin; head, eyes, ears, nose, and throat; 
thyroid; lungs; cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as 
well as a brief neurological examination.  The complete examination should also include an 
assessment of body fluid abnormalities, including ascites and edema. 
Targeted physical examinations will be a symptom-directed evaluation and will include 
assessment of the body systems or organs as indicated by participant symptoms, AEs or other 
findings as determined by the investigator or designee.  The targeted examination will include 
measurement of body weight and assessment of fluid abnormalities, including ascites and edema. 
8.3.3. 
Vital Signs 
Vital sign measurements (to be taken before blood collection for laboratory tests) include blood 
pressure, pulse, respiratory rate, body weight, and body temperature and will be measured at 
study visits as shown in the SoA.  If vital signs cannot be taken before blood collection for 
laboratory tests, there must be a minimum of 30 minutes from the completion of the blood 
collection procedures to the beginning of the vital signs collection.  Blood pressure and pulse 
will be taken with the participant in the recumbent, semirecumbent, or sitting position after 
5 minutes of rest.  Abnormal vital sign results identified after the first dose of study treatment 
constitute an AE if they are considered clinically meaningful, induce clinical signs or symptoms, 
require concomitant therapy, or require changes in study treatment. 
8.3.4. 
Electrocardiograms 
Twelve-lead ECGs will be obtained as outlined in the SoA (see Table 3) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  All 
12-lead ECGs will be performed with the participant in a recumbent or semirecumbent position 
after 5 minutes of rest. 
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
participant management.  Additional 12-lead ECGs may be performed as clinically indicated to 


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manage participant safety.  The decision to include or exclude a participant or withdraw a 
participant from study treatment based on an ECG flagged as "Abnormal, Clinically Significant" 
is the responsibility of the investigator, in consultation with the sponsor's medical monitor as 
appropriate.  Clinically notable abnormalities that are considered clinically significant in the 
judgment of the investigator are to be reported as AEs. 
8.3.5. 
Laboratory Assessments 
See Table 5 for the schedule of laboratory assessments and Table 14 for the laboratory tests that 
will be performed.  All Protocol-required laboratory assessments must be conducted in 
accordance with the Laboratory Manual and the SoA.  Information regarding collection, 
processing, and shipping of laboratory assessments for the central laboratory is provided in the 
Laboratory Manual. 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
See Section 9.1 for information regarding laboratory abnormalities that should be recorded as an 
AE in the eCRF.  Additionally, if laboratory values from laboratory assessments performed at the 
institution's local laboratory require a change in participant management (eg, require treatment) 
or are considered clinically significant by the investigator then the result(s) of the specific 
laboratory assessment(s) must be recorded in the eCRF. 
Blood samples for hematology and serum chemistry analysis for baseline should be taken as 
close as possible to Day 1 but may be drawn up to 3 days before the first dose of parsaclisib.  
This blood sample will serve as the pre-parsaclisib baseline sample; a Day 1 sample is not 
required as long as the baseline sample is obtained within 3 days of the first dose of parsaclisib. 
8.3.5.1. 
Chemistry 
Serum chemistry assessments will be performed by a local laboratory using institutional best 
practices.  Results and normal ranges will be entered in the eCRF. 
8.3.5.2. 
Hematology 
Hematology assessments, including complete blood count with differential, and blast percentage 
will be performed at a local laboratory using institutional best practices.  Results and normal 
reference ranges will be entered in the eCRF. 
8.3.5.3. 
Urinalysis 
Urinalysis will be performed by a central laboratory. 


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8.3.5.4. 
Serology and Virology 
Serology and virology assessments will be performed by the central laboratory.  Assessments 
will include HBV DNA, HIV RNA, CMV DNA, and HCV RNA measurement; hepatitis B 
surface antigen; anti-hepatitis B surface antigen antibody; and anti–hepatitis B core antibody. 
8.3.5.5. 
Lipid Panel 
Lipid panel assessment will be performed by the central laboratory.  Overnight fast (no food or 
liquid except water) is required for these samples.  If the participant arrives for the study visit 
without an overnight fast of at least 8 hours or since midnight, the lipid blood draw must be 
rescheduled for a date when the participant can arrive in the fasted state. 
8.3.5.6. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
and at the safety follow-up visit.  This assessment will be performed by the central laboratory.  
Urine pregnancy tests will be conducted as outlined in Table 5, as medically indicated, or per 
country-specific requirement.  Urine pregnancy tests will be performed locally.  If a urine 
pregnancy test is positive, then the results should be confirmed with a serum pregnancy test to be 
performed at the local laboratory. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume study treatment and continue participation in the study. 
Follicle-stimulating hormone levels will be determined only at screening to verify hormonal 
menopause in relevant participants. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.7 for reporting 
requirements. 
8.3.5.7. 
Coagulation Panel 
Coagulation parameters (PT, aPTT or PTT, and INR) will be determined at a local laboratory 
using institutional best practices.  Results and normal reference ranges will be entered in the 
eCRF. 


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Table 14: 
Required Laboratory Analytes 
Serum Chemistries 
Hematology 
Urinalysis With Microscopic 
Examination 
Serology 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Amylase 
Bicarbonate (not applicable in 
Japan) 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total protein 
Uric acid 
Complete blood count, 
including: 
Hemoglobin 
Hematocrit 
Platelet count 
RBC count 
WBC count 
Blasts 
 
Differential count, including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Blasts 
Absolute values must be 
provided for: 
WBC differential results 
Platelet count 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
 
Hepatitis B surface antigen 
Hepatitis B surface antigen 
antibody 
Hepatitis B core antibody 
HBV-DNA 
HCV-RNA 
CMV DNA 
HIV RNA 
PT 
PTT or aPTT 
INR 
Lipid Panel 
MF Specifica 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
LDL 
HDL 
Bone marrow aspirate and 
biopsy 
JAK2 mutation status 
 
 
Female participants of 
childbearing potential only 
require a serum test at 
screening and follow-up 
and a urine pregnancy test 
before the first dose on 
Day 1. 
Pregnancy tests (serum or 
urine) should be repeated if 
required by local 
regulations. 
FSH only required if 
hormonal menopause must 
be verified. 
a Certain samples will only be collected in designated countries. 
Note:  Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data or to rule out a diagnosis.  
Note:  Alternative tests are also allowed as per regional standard of care. 


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8.6. 
Unscheduled Visits 
Unscheduled visits or laboratory assessments may be conducted at the investigator's discretion.  
All assessments and laboratory findings will need to be entered in the eCRF using an 
unscheduled visit page. 
8.7. 
End of Treatment and/or Early Termination 
There is no predefined EOT.  When the participant permanently discontinues parsaclisib/placebo 
and ruxolitinib, the EOT visit should be conducted.  If the EOT visit coincides with a regular 
study visit, then the EOT evaluations will supersede those of that scheduled visit, and the data 
should be entered in the EOT visit in the CRF.  The participant should be encouraged to return 
for the follow-up visit. 
8.8. 
Follow-Up 
8.8.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 to 35 days after the EOT visit (or after the last dose of study 
treatment [parsaclisib/matching placebo and ruxolitinib] if the EOT visit was not performed).  
Adverse events and SAEs must be reported up until at least 30 days after the last dose of study 
treatment, the date of the follow-up visit, or until toxicities resolve, return to baseline, or are 
deemed irreversible, whichever is longer.  Reasonable efforts should be made to have the 
participant return for the follow-up visit and report any AEs that may occur during this period.  If 
the participant cannot return to the site for the safety follow-up visit (eg, lives far away), then the 
participant should be contacted by telephone for assessment of AEs and SAEs.  Sites must 
document this contact in the source. 
Participants are required to remain on PJP prophylaxis for at least 2 to 6 months after the last 
dose of study drug (see Section 6.8.2) and should be reminded of this at the safety follow-up 
visit.  Sites should follow up with participants to confirm that they have been compliant with the 
prophylactic treatment for the duration of this period. 


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8.8.2. 
Survival Follow-Up 
Once a participant has received the last dose of study treatment, has confirmed disease 
progression, or starts a new MF therapy, the participant moves into the survival follow-up period 
and should be contacted by telephone, e-mail, or visit at least every 12 weeks (± 2 weeks) to 
assess for subsequent MF treatments and survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first. 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not it is considered drug-related. 
• An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease) are to be reported as an AE. 
• Abnormal laboratory test results are to be reported as an AE if they are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes in 
study treatment.  Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded 
in the eCRF rather than the abnormal laboratory test result (eg, low hemoglobin, platelet count 
decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition/disease, including either an increase 
in the frequency and/or intensity of the condition, is to be reported as an AE. 
• New conditions detected or diagnosed after the start of study treatment administration are to be 
reported as an AE. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction are to be reported as an 
AE. 
• Signs and/or symptoms from dosing errors of a study treatment (eg, overdose) or a concomitant 
medication are to be reported as an AE. 
• "Lack of efficacy," "disease progression," or "failure of expected pharmacological action" will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy assessments.   
• A condition that leads to a medical or surgical procedure (eg, endoscopy, appendectomy) will be 
reported as an AE if it occurs after obtaining informed consent.  If the condition is present before 
entering the study, then it should be captured as medical history.  
• Pre-existing diseases or conditions with expected fluctuations in signs or symptoms should be 
reported as an AE only if the investigator judges the fluctuation to have worsened more than expected 
for the participant's condition during study participation. 


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9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term "life-threatening" in the definition of "serious" refers to an adverse drug experience that 
places the participant, in the opinion of the initial reporter, at immediate risk of death from the adverse 
experience as it occurs.  This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment or planned surgery (eg, stent replacement, hip surgery) is not 
considered an SAE. 
Hospitalization for medical interventions in which no unfavorable medical occurrence occurred 
(ie, elective procedures or routine medical visits) are not considered SAEs.  
d. Results in persistent or significant disability/incapacity 
• The term "disability" means a substantial disruption of a person's ability to conduct normal life 
functions.   
• This definition is not intended to include experiences of relatively minor medical significance, such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle), that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is an important medical event 
An important medical event is an event that may not result in death, be immediately life-threatening, or 
require hospitalization but may be considered serious when, based on appropriate medical judgment, 
the event may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in the above definition.  Examples of such events include new invasive or 
malignant cancers, intensive treatment in an emergency department or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.  Secondary malignancies should always be considered SAEs. 
An event that may lead to disability is also considered an important medical event.  It includes a case 
that is exposed to a risk of dysfunction to an extent that interferes with daily life when the adverse drug 
reaction occurs.  It does not include an adverse drug reaction that, had the reaction been more severe, 
may have caused disability. 


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9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the 
Adverse Event Form in the eCRF.  Conditions that were present at the time informed consent was 
given should be recorded on the Medical History Form in the eCRF.   
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostic reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records 
in lieu of completing the Adverse Event Form in the eCRF. 
• There may be rare instances when copies of medical records for certain cases are requested.  In this 
case, all participant identifiers, with the exception of the participant number, will be redacted by the 
site staff on the copies of the medical records before submission.  These records can be submitted to 
Incyte Pharmacovigilance by email/fax per the contact information listed in the Study Binder. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine the following: 
• The severity grade (CTCAE v5.0 Grade 1 to 5).  See below for further instructions on the assessment 
of intensity. 
• Whether there is at least a reasonable possibility that the AE is related to the study treatment:  
suspected (yes) or not suspected (no).  See below for further instructions on the assessment of 
causality. 
• The start and end dates, unless unresolved at the final safety follow-up visit. 
• The action taken with regard to parsaclisib/matching placebo and ruxolitinib as a result of the 
AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event.  Note:  If an AE is treated with a concomitant medication 
or nondrug therapy, this action should be recorded on the Adverse Event Form and the treatment 
should be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and 
Non-Drug Therapy). 


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Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to estimate the 
grade of severity. 
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories: 
• Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment 
not indicated. 
• Grade 2:  Moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate 
activities of daily living. 
• Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
• Grade 4:  Life-threatening consequences; urgent treatment indicated. 
• Grade 5:  Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study /treatment and each occurrence 
of each AE/SAE.  If reference therapy is used in combination with an Incyte study drug or if multiple 
Incyte study drugs are used, then the relationship to each study drug/reference therapy must be 
assessed (ie for parsaclisib/placebo and for ruxolitinib)  If appropriate, the relationship to the 
combination may be assessed as well. 
• A "reasonable possibility" of a relationship conveys that there are medical facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the possibility of a relationship. 
• The investigator will also consult the RSI in the IB (for parsaclisib or ruxolitinib) or Product 
Information for ruxolitinib, in making his/her assessment. 
• Alternative causes, such as underlying or concurrent disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration, will be 
considered and investigated. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report.  However, the causality assessment is one of the criteria 
used when determining regulatory reporting requirements.  Therefore, it is very important that 
the investigator always make an assessment of causality based on the available information 
for every event before the initial transmission of the SAE. 
− The investigator may change his/her opinion of causality in light of follow-up information and 
submit the updated causality assessment. 


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Follow-Up of Adverse Events and Serious Adverse Events 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature 
and/or causality of the AE or SAE as fully as possible.  This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals. 
• Once an AE is detected, it should be followed in the AE eCRF until it has resolved or until it is 
judged to be permanent; assessment should be made at each visit (or more frequently if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions required 
to treat the event, and the outcome. 
• Updated SAE information will be recorded in the originally completed eCRF and reported to Incyte 
Pharmacovigilance or its designee as directed in the Study Binder until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up. 
• Any updated SAE data (including SAEs being downgraded to nonserious) will be submitted to the 
sponsor (or designee) within 24 hours of receipt of the information.  
9.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study drug, reference therapy or study 
procedure[s]), all SAEs occurring after the participant has signed the ICF through 30 to 35 days 
after the last dose of study treatment or until the participant starts a new MF therapy, whichever 
occurs earlier, must be reported to the sponsor (or designee) within 24 hours of learning of its 
occurrence, unless otherwise specified by the Protocol.  The investigator will submit any updated 
SAE data to the sponsor (or designee) within 24 hours of it being available.  For Japan, this 
information must also be reported immediately to the head of the study site. 
Investigators are not obligated to actively seek SAE information after the safety follow-up visit 
or 30 to 35 days after the last dose of study treatment.  If the investigator learns of any SAE, 
including death, at any time after this period, and he/she considers the event to be reasonably 
related to the study drug/treatment or study participation, then the investigator must notify the 
sponsor (or designee) within 24 hours of becoming aware of the event.   
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs and AESIs (as defined in Section 9.5) will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor regarding an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the parsaclisib IB or ruxolitinib IB (or ruxolitinib package 
insert) and is thought to be related to the study drug/treatment, the sponsor or its designee may 
urgently require further information from the investigator for expedited reporting to health 
authorities.  The sponsor or its designee may need to issue an Investigator Notification to inform 
all investigators involved in any study with the same drug that this SAE has been reported.  
Suspected unexpected serious adverse reactions will be collected and reported to the competent 
authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per 


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national regulatory requirements in participating countries.  For Japan, the sponsor will report 
suspected expected deaths and life-threatening events to the PMDA as per local regulatory 
requirements. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate, according to local requirements. 
Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must report within 24 hours of learning of its occurrence any SAE via the EDC 
system (primary method) or by completing the Serious Adverse Event Report Form in English (only 
if the EDC system is not available.  The contact information for Incyte Pharmacovigilance by 
email/fax is listed in the Study Binder). 
• In circumstances where the EDC system is not accessible for reporting SAE information (initial 
and/or follow-up SAE information) to the sponsor within 24 hours, refer to the Incyte Reference 
Guide for Completing the Serious Adverse Report Form in the Study Binder.  Once the EDC system 
is functional, the SAE report should be retrospectively added to the EDC system and follow-up 
should be completed through the EDC.  The original copy of the Serious Adverse Event Report Form 
and the email or facsimile confirmation sheet must be kept at the study site. 
• Follow-up information is also recorded in the eCRF and transmitted to Incyte Pharmacovigilance via 
the EDC system.  The follow-up report should include information that was not provided previously, 
such as the outcome of the event, treatment provided, action taken with study treatment because of 
the SAE (eg, dose reduced, interrupted, or discontinued), or participant disposition (eg, continued or 
withdrew from study participation).  Each recurrence, complication, or progression of the original 
event should be reported as follow-up to that event, regardless of when it occurs. 
• Contacts for SAE reporting can be found in the Study Binder.   
9.5. 
Adverse Events of Special Interest 
The principal toxicity of inhibiting both PI3Kδ and JAK pathways is expected to be reversible 
effects on immune function.  Combined inhibition may adversely affect both B-cell and T-cell 
immune function, with resultant increased risk of a variety of infections or other immune-related 
events.  Specific AEs or groups of AEs will be followed as part of standard safety monitoring 
activities.  An AE of special interest does not require rapid communication by an investigator to 
Incyte unless it meets criteria for rapid communication as an SAE (see Section 9.4) and consists 
of the following based on terms coded per MedDRA v19.0: 


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• Colitis 
• Diarrhoea of Grade 2 or higher 
• Rash of Grade 2 or higher 
• Pneumonitis 
• Dermatitis exfoliative 
• Intestinal perforation 
• Cytomegalovirus infection 
• Herpes simplex infection 
• Herpes (varicella) zoster virus infection 
• Pneumocystis jirovecii infection 
• Alanine aminotransferase increased ≥ 5 × ULN 
• Aspartate aminotransferase increased ≥ 5 × ULN 
Adverse events of special interest should be captured in the eCRF. 
9.6. 
Emergency Unblinding of Treatment Assignment 
In a medical emergency, if knowledge of the treatment assignment is necessary to determine 
optimal medical management of the participant, the procedure for emergency unblinding is 
provided in the IXRS/Study Reference Manual.  The decision to break the treatment code in an 
emergency situation resides at the sole discretion of the investigator.  This option may be used 
only if the participant's well-being requires the investigator to be aware of the participant's 
treatment assignment.  If a participant's treatment assignment is unblinded, the sponsor or its 
designee must be notified immediately by telephone. 
If an investigator, site personnel performing assessments, or participant is emergency unblinded, 
the participant must be withdrawn from the study treatment, unless there are ethical reasons to 
have the participant remain on the study treatment.  In these cases, the investigator must obtain 
specific approval from the sponsor's (or its designee's) medical monitor for the participant to 
continue in the study. 
9.7. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study treatment 
may have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The parsaclisib/matching placebo and ruxolitinib must be discontinued immediately 
(female participants only). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 


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Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy 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, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form in the Study Binder. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or its designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.8. 
Warnings and Precautions 
Special warnings or precautions for the study treatment, derived from safety information 
collected by the sponsor or its designee, are presented in the parsaclisib IB and ruxolitinib IB.  
Additional safety information collected between IB updates will be communicated in the form of 
Investigator Notifications.  Any important new safety information should be discussed with the 
participant during the study, as necessary.  If new significant risks are identified, they will be 
added to the ICF. 
9.9. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via e-mail or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 


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9.10. 
Treatment of Overdose 
There has been no clinical experience with overdose of parsaclisib.  Treatment of overdose 
should consist of general supportive measures. 
Refer to the approved product label of ruxolitinib for advice on overdose. 
10. 
STATISTICS 
10.1. 
Sample Size Determination 
The primary endpoint of this study is the proportion of participants with ≥ 25% spleen volume 
reduction from baseline to Week 24 as measured by MRI (or CT scan in applicable participants).  
The primary endpoint will be analyzed by CMH test stratified by baseline (or screening, if 
applicable) platelet count (≥ 100 × 109/L vs 50 to < 100 × 109/L inclusive) and DIPSS risk 
category (high vs intermediate-2 vs intermediate-1) at randomization (note that if a participant's 
platelet count is < 50 × 109/L at baseline, the platelet count at screening will be used for 
stratification/randomization).  Assuming a 25% response rate for ruxolitinib + parsaclisib versus 
5% for ruxolitinib + placebo, to achieve a 95% power to detect a statistically significant 
difference with a 2-sided Type I error of 5%, a sample size of 212 participants is required to be 
randomized equally between treatment groups. 
For the key secondary endpoint of MFSAF TSS, assuming a response rate of 35% (25%) in 
ruxolitinib + parsaclisib for normal (low) platelet participants and a response rate of 15% (10%) 
in ruxolitinib + placebo for normal (low) platelet participants, a sample size of 212 will provide 
81.3% power using CMH test given a 2-sided Type I error of 5%. 
A test for OS will be performed when 84 deaths are observed using the log-rank test at a 2-sided 
Type I error level of 0.05.  The log-rank test will provide 80% power to detect a hazard ratio of 
0.54.  Assuming a median survival time of 3.7 years for ruxolitinib + placebo and enrollment 
duration of 1 year, the expected total study duration is 4 years. 
10.2. 
Populations for Analysis 
The populations for analysis are provided in Table 16. 


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Table 16: 
Populations for Analysis 
Population 
Description 
ITT 
All randomized participants.  The ITT population will be used for the summary of 
demographics, baseline characteristics, participant disposition, and analyses of all 
efficacy data.  Participants will be analyzed according to the treatment group to 
which they were randomized regardless of the treatment received during the study. 
Per protocol 
(PP) population 
Participants in the ITT population who are considered to be sufficiently compliant 
with the Protocol. 
Safety 
All randomized participants who received at least 1 dose of parsaclisib, placebo, or 
ruxolitinib.  Treatment groups for this population will be determined according to 
the actual treatment the participant received regardless of assigned study drug 
treatment.  All safety analyses will be conducted using the safety population 
10.3. 
Level of Significance 
This study defines a single primary endpoint with a single primary analysis.  The study will be 
claimed to have achieved the primary efficacy objective when the primary endpoint shows a 
significant result at 2-sided alpha of 0.05 at final analysis. The key secondary efficacy endpoints 
will be alpha-controlled and will be analyzed only when the study has reached the efficacy 
objective in the primary endpoint.  The key secondary efficacy variables will be tested following 
a fixed-sequence-testing procedure with each at the 2-sided alpha level of 0.05 in the order 
below: 
1. The proportion of participants who have a ≥ 50% reduction from Baseline to Week 24 in 
the MFSAF TSS 
2. OS 
Other secondary 
 endpoints will be tested using a 2-sided, 5% significance level 
but are not considered alpha-controlled hypotheses. 
10.4. 
Statistical Analyses 
10.4.1. 
Primary and Secondary Analyses 
The methods and populations for primary and secondary analyses are provided in Table 17. 


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Table 17: 
Primary and Secondary Analyses Methods and Populations 
Endpoint 
Statistical Method 
Analysis 
Population 
Primary (P) or 
Supportive (S) 
Primary endpoint 
Proportion of participants 
achieving ≥ 25% reduction 
in spleen volume from 
baseline to Week 24 as 
measured by MRI (or CT 
scan in applicable 
participants). 
CMH test stratified by baseline (or 
screening, if applicable) platelet 
count (≥ 100 × 109/L vs 50 to < 100 
× 109/L inclusive) and DIPSS (high 
vs intermediate-2 vs intermediate-1) 
at randomization 
ITT 
P 
PP 
S 
Secondary endpoints 
Proportion of participants 
who have a ≥ 50% reduction 
in total symptom score from 
baseline to Week 24 as 
measured by the MFSAF 
v4.0 diary. 
CMH test stratified by baseline (or 
screening, if applicable) platelet 
count (≥ 100 × 109/L vs 50 to < 100 
× 109/L inclusive) and DIPSS (high 
vs intermediate-2 vs intermediate-1) 
at randomization  
ITT 
P 
PP 
S 
OS determined from the date 
of randomization until death 
due to any cause.   
Inference:  Log rank test stratified 
by baseline (or screening, if 
applicable) platelet count 
(≥ 100 × 109/L versus 50 to < 100 
× 109/L inclusive) and DIPSS (high 
vs intermediate-2 vs intermediate-1) 
at randomization 
Estimation:  Kaplan-Meier 
ITT 
P 
PP 
S 
Inference:  Cox regression model 
including treatment group, baseline 
(or screening, if applicable) platelet 
count (≥ 100 × 109/L vs 50 to < 100 
× 109/L inclusive) at randomization, 
and DIPSS (high vs intermediate-2 
vs intermediate-1) at randomization 
ITT 
S 
OS adjusted for crossover 
using rank preserving 
structural failure time 
(RPSFT) 
Inference:  Cox regression model 
including treatment group, baseline 
(or screening, if applicable) platelet 
count (≥ 100 × 109/L vs 50 to < 100 
× 109/L inclusive) and DIPSS (high 
vs intermediate-2 vs intermediate-1) 
at randomization 
ITT 
S 


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Table 17: 
Primary and Secondary Analyses Methods and Populations (Continued) 
Endpoint 
Statistical Method 
Analysis 
Population 
Primary (P) or 
Supportive (S) 
Secondary endpoints (continued) 
Time to the first ≥ 25% 
reduction in spleen volume  
Inference:  Log rank test with 
stratification of baseline (or 
screening, if applicable) platelet 
count (≥ 100 × 109/L versus 50 to 
< 100 × 109/L inclusive) and DIPSS 
(high vs intermediate-2 vs 
intermediate-1) at randomization 
Estimation:  Kaplan-Meier 
ITT 
P 
Duration of maintenance of a 
≥ 25% reduction in spleen 
volume 
Estimation:  Kaplan-Meier 
ITT with 
spleen 
response 
P 
Time to the first ≥ 50% 
reduction in TSS as 
measured by the MFSAF 
v4.0 diary 
Inference:  Log rank test with 
stratification of baseline (or 
screening, if applicable) platelet 
count (≥ 100 × 109/L versus 50 to 
< 100 × 109/L inclusive) and DIPSS 
(high vs intermediate-2 vs 
intermediate-1) at randomization 
Estimation:  Kaplan-Meier 
ITT 
P 
Other secondary endpoints, including change and percentage change in MFSAF TSS from 
baseline to Week 24 as measured by the MFSAF v4.0 diary, will be summarized descriptively by 
treatment group. 
For the stratifications of platelet and DIPSS, within a platelet category, in the event that a 
particular DIPSS stratification level has fewer than 30 participants randomized, it will be 
combined with the nearest adjacent DIPSS level (eg, high vs intermediate-1 vs intermediate-2).  
For example, if either intermediate-1 or high risk is too small, it will be merged with 
intermediate-2.  If intermediate-2 has too few participants, then it will be merged with the 
smaller of the 2 adjacent strata. 
In the event that 2 DIPSS stratification levels are combined, a sensitivity analysis for the primary 
endpoint without combining levels will be conducted. 
The primary endpoint will also be compared between the treatment groups within each of the 
following subgroups: 
• Baseline platelet count:  ≥ 100 × 109/L versus 50 to < 100 × 109/L inclusive        
(Note that if a participant's platelet count is < 50 × 109/L at baseline, the platelet count 
at screening will be used instead) 
• DIPSS risk category:  high vs intermediate-2 vs intermediate-1 
• Sex:  male and female 


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• Age group:  ≤ 65 years or > 65 years 
• MF type:  PMF or PPV-MF/PET-MF 
• Ruxolitinib average total daily dose during the 8 weeks before randomization:  
≥ 20 mg or less than 20 mg 
• Presence/absence of V617F mutation at baseline 
• Presence/absence of HMR mutations at baseline 
• Baseline spleen volume group:  ≤ median or > median 
• Baseline spleen palpation size group:  ≤ 10cm or > 10cm 
• Race:  white/Caucasian, black/African-American, Asian, American-Indian/Alaska 
Native, Native Hawaiian/Pacific Islander, or other 
• Ethnicity:  Hispanic/Latino, not Hispanic/Latino, or other 
10.4.2. 
Safety Analyses 
Safety analyses will be conducted for the safety population.  Adverse events will be coded by the 
MedDRA dictionary, and TEAEs (ie, AEs reported for the first time or worsening of a 
pre-existing event after first dose of study treatment) will be tabulated by preferred term and 
system organ class for all events, related events, and events of Grade 3 or higher.  Quantitative 
safety variables and their changes from baseline (laboratory, vital signs, etc) will be summarized 
with descriptive statistics.  Clinically notable abnormal values will be flagged and tabulated 
based on predefined criteria.  TEAEs of clinical interest (see Section 9.5) will be summarized 
descriptively by treatment group. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned.  In addition, distributions of key laboratory parameters may be plotted 
over time; these values will also be classified into CTCAE toxicity grades and tabulated.  
Descriptive statistics and mean change from baseline will be determined for vital signs at each 
assessment time.  Vital sign results will be reviewed for clinically notable abnormalities. 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria (see Table 18).  Participants exhibiting clinically 
notable ECG abnormalities will be listed. 
Table 18: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTc 
> 450 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS 
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR 
> 1330 ms 
< 600 ms 


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Measures of exposure (eg, days of exposure, duration of treatment, average daily dose, and total 
daily dose) of parsaclisib, placebo, or ruxolitinib will be summarized by means of summary 
statistics. 
 
 


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10.5. 
Interim Analysis 
There will be 2 planned, nonbinding, interim analyses conducted for futility for this study, based 
on the first 30% of participants enrolled in the study.  The first interim analysis will be conducted 
when the first 30% of the planned randomized participants (approximate 32 in each treatment 
group) reach Week 12 assessments of spleen volume and MFSAF TSS, or discontinue from 
treatment group.  Based on the results of this interim analysis, the DMC may recommend to 
terminate the study, continue the study with no changes to enrollment, or continue the study with 
no further enrollment permitted until review of the second interim analysis. 
The second interim analysis will be initiated when the first 30% of the planned randomized 
participants reach their Week 24 assessments of spleen volume and MFSAF TSS, or have 
discontinued from study.  The DMC may recommend to either terminate the study for futility or 
continue the study, based on the results of this analysis. 
At the interim analyses for Week 12 and Week 24 data, MFSAF TSS will be tested for futility 
only if spleen volume does not cross the futility boundary.  An HSD (Hwang et al 1990) with 
γ = 2 and HSD with γ = 1 will be used to determine the nonbinding futility boundary for spleen 
volume and MFSAF TSS, respectively.  The study may be terminated early for futility if either 
the spleen volume or the MFSAF TSS endpoints cross the futility boundary.  Table 19 and 
Table 20 provide the projected stopping rules if the second interim analysis is conducted at the 
projected number of participants.  The first interim analysis will use the futility boundaries 
defined in Table 19 and Table 20 for the second interim analysis for a preliminary look at the 
efficacy of the data on Week 12. 
Table 19: 
Interim Analysis for Spleen Volume With HSD(2) 
Number of Participants 
Second Interim Analysis 
Final Analysis 
64 
212 
Decision outcome 
Stop for Futility 
Continue to Test 
MFSAF TSS 
Do Not Reject 
Null Hypothesis 
Reject Null 
Hypothesis 
Z-statistic 
≤ 0.16 
> 0.16 
≤ 1.96 
> 1.96 
One-sided p-value 
≥ 0.436 
< 0.436 
≥ 0.025 
< 0.025 
Parsaclisib + ruxolitinib 
response ratea 
≤ 5.9% 
> 5.9% 
≤ 12.7% 
> 12.7% 
a Assumes spleen volume response rate is 5% in the ruxolitinib + placebo group. 


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Table 20: 
Interim Analysis for MFSAF TSS With HSD(1) 
Number of Participants 
Second Interim Analysis 
Final Analysis 
64 
212 
Decision outcome 
Stop for Futility 
Continue 
Do Not Reject 
Null Hypothesis 
Reject Null 
Hypothesis 
Z-statistic 
≤ 0.22 
> 0.22 
≤ 1.96 
> 1.96 
One-sided p-value 
≥ 0.413 
< 0.413 
≥ 0.025 
< 0.025 
Parsaclisib + ruxolitinib 
odds ratio (RR for 50× to 
< 100 × 109/L,  ≥ 100 × 
109/L PLT)a 
≤ 1.08 (11%, 
16%) 
> 1.08 (11%, 16%) 
≤ 2.37 (21%, 29%) 
> 2.37 (21%, 29%) 
a Assumes TSS response rate for 50 × to < 100 × 109/L inclusive and ≥ 100 × 109/L platelet is 10% and 15% in the ruxolitinib + 
placebo group. 
Preplanned analyses of safety and efficacy will be provided to an independent DMC as specified 
in the DMC charter.  The process by which the DMC will review data and make 
recommendations and decisions will be documented in the DMC charter. 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Investigator Responsibilities 
• The Protocol, Protocol Amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC and health authorities before the study is initiated. 
• The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements, the 
policies and procedures established by the IRB/IEC, and institutional requirements. 
• Any amendments to the Protocol will require approval from both health authorities 
and the IRB/IEC before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 


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• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling participants who have met 
the specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study during the 
retention period without receiving approval from the sponsor.  The investigator 
must notify the sponsor or its designee in the event of accidental loss or 
destruction of any study records.  If the investigator leaves the institution where 
the study was conducted, the sponsor or its designee must be contacted to arrange 
alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
• For Japan:  The record retainer (delegated by the head of the study site) will retain the 
J-GCP–defined essential documentation at the site until the regulatory approval of the 
study drug/treatment or at least 3 years after the discontinuation or completion of the 
study conduct, whichever is later.  If the sponsor requires retention of these 
documents for a longer period of time, the duration and method of retention will be 
decided upon through discussion between the sponsor and the study site.  It is the 
responsibility of the sponsor to inform the head of the study site as to when the 
documents no longer need to be retained. 
11.1.1. 
Identification of the Coordinating Principal Investigator 
A coordinating principal investigator will be appointed by the sponsor before the end of the 
study.  As part of their responsibilities, the coordinating principal investigator will review the 
final CSR.  Agreement with the final CSR will be documented by the dated signature of the 
coordinating principal investigator. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in the 
eCRF.  The study monitor will reference the Monitoring Plan in order to ensure that each issue 
identified is appropriately documented, reported, and resolved in a timely manner in accordance 
with the plan's requirements.  Other data outside the EDC system required in the study conduct 


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of the Protocol, such as documents or results transmitted to the sponsor via a central laboratory 
or specialized technical vendors and as designated by the sponsor, will have their own data flow 
management plans, study charters, 
, as applicable. 
The sponsor (or designee) will be responsible for the following: 
• Managing the integrity of the data and the quality of the conduct of the study, such as 
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved Protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Managing and reconciling the data generated and/or collected, including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for the following: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF. 
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (eg, laboratory data, imaging data, 
, photographs, diary data) 
or as otherwise specified in the Protocol. 
• Maintaining adequate and accurate source documents and trial records that include all 
pertinent observations on each of the site's trial participants.  Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete.  Changes to 
source data should be traceable, should not obscure the original entry, and should be 
explained if necessary (eg, via an audit trail).  Source data are, in general, all 
information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in source 
documents (original records or certified copies). 
• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 


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− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed and 
available at the investigator's site.  Examples of source documents are original 
documents, data, and records (eg, hospital records; electronic hospital records; 
clinical and office charts; laboratory notes; memoranda; participants' diaries or 
evaluation checklists; pharmacy dispensing records; recorded data from 
automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives; microfilm or 
magnetic media; x-rays; participants' files; and e-records/records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial). 
− Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, 
depending on the study.  Current applicable medical records must be available. 
• Sending participants' data, either as unique samples, or copies, or photographs, to be 
evaluated centrally or analyzed centrally, or both, by a qualified vendor designated by 
the sponsor. 
− As required by privacy and data protection regulations and Incyte's privacy 
policies, if any photographs of participants are to be taken, the photographs must 
be limited to the area of the face or the body that is strictly necessary and the 
photographs should be masked (ie, identifying features such as eyes, mouth, scars, 
tattoos, or unique markings or features should be either obscured with a black bar 
or digitally pixelated so as to not permit the reidentification of the participants and 
preserve their confidentiality) by a specially designated photography vendor prior 
to sending the photographs to Incyte or any other third-party vendors for analysis 
or further processing. 
− In accordance with French regulations, sites in France must perform the masking 
before the photographs are transferred, including to any specially designated 
photography vendor, Incyte, or any other third-party vendors for analysis or 
further processing. In addition, the participant's specific consent for photographs 
shall be collected. 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 


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− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Quality Assurance 
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations).  The sponsor or designee is responsible for the data management of this 
study, including quality checking of the data.  Further, monitoring details describing strategy, 
including definition of study-critical data items and processes (eg, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and analytical 
risk-based monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues, Protocol deviations, and monitoring techniques (eg, central, remote, or 
on-site monitoring) are provided in the Clinical Monitoring plan, Integrated Quality Risk 
Management Plan and other study plan as applicable. 
Quality tolerance limits will be predefined in the Integrated Quality Risk Management Plan to 
identify systematic issues that can impact participants' safety, efficacy results and analysis, 
and/or reliability of study results.  These predefined parameters will be monitored during the 
study and can be adjusted during the study upon data review.  Important deviations from the 
quality tolerance limits and remedial actions taken, including reporting to IRBs/IECs and health 
authorities if applicable, will be summarized in the CSR. 
11.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations.  The investigator and the sponsor or its designee are responsible for ensuring 
that personal information is handled in accordance with local data protection laws (including but 
not limited to HIPAA and GDPR) as applicable, and the sponsor operates comprehensive data 
privacy and data security programs that are applicable to this study.  Appropriate notice, or 
notice and consent (as may be required by each applicable jurisdiction), for collection, use, 
disclosure, and/or transfer (if applicable) of personal information must be obtained in accordance 
with local data protection laws. Appropriate data protection terms that comply with applicable 
laws will be included in relevant study agreements. 
To ensure confidentiality of records and protect personal data, participant names will not be 
supplied to the sponsor or its designee.  Only the participant number will be recorded in the 
eCRF; if the participant's name appears on any other document (eg, laboratory report), it must be 
obliterated on the copy of the document to be supplied to the sponsor or its designee.  Study 


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findings stored on a computer will be stored in accordance with appropriate technical and 
organizational measures as required by local data protection laws. 
In the event of a data breach involving participant data, the sponsor or its designee will follow 
the sponsor's incident response procedures.  The precise definition of a data breach varies in 
accordance with applicable law but may generally be understood as a breach of security leading 
to the accidental or unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, 
personal data.  In accordance with its incident response procedures, the sponsor will assess the 
breach to consider its notification and remediation obligations under applicable law. 
11.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure Form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research participants, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Clinical Investigator Financial Disclosure Form.  During a covered clinical 
study, any changes to the financial information previously reported by a clinical investigator 
must be reported to the sponsor or its designee.  At the conclusion of the covered clinical study, 
the clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.6. 
Publication Policy 
By signing the study Protocol, the investigator and their institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation, for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 


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Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.7. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.   
For Japan:  When the trial is completed, the investigator should inform the head of the study site 
of the completion in writing and submit a written summary of the trial's outcome, and then the 
head of the study site should promptly inform the IRB and sponsor or designee of the completion 
in writing. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the Protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 


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12. 
REFERENCES 
Aliqopa (copanlisib) [prescribing information]. Bayer HealthCare Pharmaceuticals Inc; 
December 2019. 
Bartalucci N, Tozzi L, Bogani C, et al. Co-targeting the PI3K/mTOR and JAK2 signalling 
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Bose P, Verstovsek S. The evolution and clinical relevance of prognostic classification systems 
in myelofibrosis. Cancer 2016;122:681-692. 
Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary 
myelofibrosis based on a study of the International Working Group for Myelofibrosis Research 
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Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival 
findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy 
for myelofibrosis [published correction appears in Blood 2016;128:3013]. Blood 
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Cheson BD. Death and clinical trials in the plague years. Accessed July 21, 2022. 
https://ascopost.com/issues/july-10-2022/death-and-clinical-trials-in-the-plague-years 
Clinical Trials Facilitation and Coordination Group. Recommendations related to contraception 
and pregnancy testing in clinical trials. 2014. 
Copiktra (duvesilib) [prescribing information]. Verastem, Inc; July 2019. 
Coutré S, Barrientos JC, Brown JR, et al. Management of adverse events associated with 
idelalisib treatment: expert panel opinion. Leuk Lymphoma 2015;56:2779-2786. 
Deeg HJ, Gooley TA, Flowers ME, et al. Allogeneic hematopoietic stem cell transplantation for 
myelofibrosis. Blood 2003;102:3912-3918. 
Durrant ST, Nagler A, Guglielmelli P, et al. Results from HARMONY: an open-label, 
multicenter, 2-arm, phase 1b, dose-finding study assessing the safety and efficacy of the oral 
combination of ruxolitinib and buparlisib in patients with myelofibrosis. Haematologica 
2019;104:e551-e554. 
 
 
 
Flinn IW, O'Brien S, Kahl B, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically 
active in advanced hematologic malignancies. Blood 2018;131:877-887. 
Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available 
therapy for myelofibrosis. N Engl J Med 2012;366:787-798. 
Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with 
myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, 
non-randomised, phase 2, multicentre study. Lancet Haematol 2017;4:e317-e324. 


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Hermouet S, Bigot-Corbel E, Gardie B. Pathogenesis of myeloproliferative neoplasma: role and 
mechanisms of chronic inflammation. Mediators Inflamm 2015;2015:145293. 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of Type I error 
probability spending functions. Stat Med 1990;9:1439-1445. 
Jakafi (ruxolitinib) [package insert]. Incyte Corporation; September 2021. 
Jakavi (ruxolitinib) [summary of product characteristics]. Novartis Europharm Limited; May 
2022. 
Jee J, Foote MB, Lumish M, et al. Chemotherapy and COVID-19 outcomes in patients with 
cancer. J Clin Oncol 2022;38:3538-3546. 
Khan I, Huang Z, Wen Q, et al. AKT is a therapeutic target in myeloproliferative neoplasms. 
Leukemia 2013;27:1882-1890. 
Lee CY, Shah MK, Hoyos D, et al. Prolonged SARS-CoV-2 infection in patients with lymphoid 
malignancies. Cancer Discov 2022;12:62-73. 
Lyudovyk O, Kim JY, Qualls D, et al. Impaired humoral immunity is associated with prolonged 
COVID-19 despite robust CD8 T cell responses. Cancer Cell 2022;40:738-753. 
Masarova L, Bose P, Daver N, et al. Patients with post-essential thrombocythemia and 
post-polycythemia vera differ from patients with primary myelofibrosis. Leuk Res 
2017;59:110-116. 
Meadows SA, Nguyen HM, Queva C, et al. PI3Kδ inhibitor idelalisib inhibits AKT signaling in 
myelofibrosis patients on chronic JAK inhibitor therapy. Blood 2013;122:4065. 
Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on myelofibrosis-related 
symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, 
placebo-controlled trial. J Clin Oncol 2013a;31:1285-1292. 
Mesa RA, Shields A, Hare T, et al. Progressive burden of myelofibrosis in untreated patients: 
assessment of patient-reported outcomes in patients randomized to placebo in the COMFORT-I 
study. Leuk Res 2013b;37:911-916. 
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Prevention 
and Treatment of Cancer-Related Infections Version 2. 2017. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with 
primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol 2015;1:643-651. 
Pardanani A, Tefferi A. Definition and management of ruxolitinib treatment failure in 
myelofibrosis. Blood Cancer J 2014;4:e268. 
Parsaclisib Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
 
 
 


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Robin M, de Wreede LC, Wolschke C, et al. Long-term outcome after allogeneic hematopoietic 
cell transplantation for myelofibrosis. Haematologica 2019;104:1782-1788. 
Ruxolitinib Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
Shree T, Shankar V, Lohmeyer JJK, et al. CD20-targeted therapy ablates de novo antibody 
response to vaccination but spares preestablished immunity. Blood Cancer Discov 
2022;3:95-102. 
Stein BL, Gotlib J, Arcasoy M, et al. Historical views, conventional approaches, and evolving 
management strategies for myeloproliferative neoplasms. J Natl Compr Canc Netw 
2015;13:424-434. 
 
 
 
 
 
 
Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: genetically inspired prognostic scoring 
system for primary myelofibrosis. Leukemia 2018;32:1631-1642. 
Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on 
grading bone marrow fibrosis and assessment of cellularity. Haematologica 2005;90:1128-1132. 
Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of 
activation and therapeutic targeting. Nat Rev Cancer 2015;15:7-24. 
Tzenaki N, Papakonstanti EA. p110δ PI3 kinase pathway: emerging roles in cancer. Front Oncol 
2013;3:40. 
van Elteren PH. On the combination of independent 2 sample tests of Wilcoxon. Bull Int Stat 
Inst 1960;37:351-361. 
Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in 
COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of 
myelofibrosis. Haematologica 2015;100:1139-1145. 
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for 
myelofibrosis. N Engl J Med 2012;366:799-807. 
Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety, and survival with ruxolitinib in patients 
with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica 
2015;100:479-488. 
Yacoub A, Borate U, Rampal R, et al. Add-on parsaclisib (a PI3K-delta inhibitor) in patients 
with myelofibrosis and suboptimal response to ruxolitinib: interim analysis from a phase 2 study. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For male participants in the study: 
Male participants should use a condom from screening through 93 days after the end of systemic 
exposure.  If the male participant has a partner that is of child-bearing potential, the partner should also 
use contraception through 93 days after the end of relevant systemic exposure.  In addition, male 
participants must refrain from donating sperm from screening through 93 days after the end of relevant 
systemic exposure.  Males who have had a vasectomy clinically designated as successful qualify as 
having met the requirement for a highly effective birth control method. 
For female participants in the study: 
The following methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationa 
− 
oral 
− 
intravaginalb 
− 
transdermalb 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationa 
− 
oralb 
− 
injectableb 
− 
implantableb,c  
• 
Intrauterine devicec  
• 
Intrauterine hormone-releasing systemc 
• 
Bilateral tubal occlusionc 
• 
Vasectomized partnerc,d  
• 
Sexual abstinencee (not applicable in Japan) 
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method. 
b Administration route not approved in Japan. 
c Contraception methods that in the context of this guidance are considered to have low user dependency. 
d Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
e In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. 
Source:  Clinical Trials Facilitation and Coordination Group 2014. 


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APPENDIX B. WORSENING SYMPTOMATIC SPLENOMEGALY 
FORM 
 
Date of additional MRI  _________________ 
 
Did the imaging vendor report an increase in SV of 25% or more relative to baseline?    Yes/No 
 
Ask the patient the following 3 questions and record scores here: 
 
1. During the past 7 days, how severe 
was your worst abdominal discomfort 
(feeling pressure or bloating)? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
2. During the past 7 days, how severe 
was the worst pain under your ribs on 
your left side? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
3. During the past 7 days, what was the 
worst feeling of fullness you had after 
beginning to eat? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 


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APPENDIX C. SCREENING SYMPTOM FORM 
Instructions to participants:  Please answer all questions to the best of your ability, based on your 
memory over the past 7 days (1 week).  There is no right or wrong answer. 
1. During the past 7 days, how severe 
was your worst fatigue (weariness, 
tiredness)? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
2. During the past 7 days, how severe 
were your worst night sweats (or 
feeling hot or flushed)? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
3. During the past 7 days, how severe 
was your worst itching? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
4. During the past 7 days, how severe 
was your worst abdominal discomfort 
(feeling pressure or bloating)? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
5. During the past 7 days, how severe 
was the worst pain under your ribs on 
your left side? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
6. During the past 7 days, what was the 
worst feeling of fullness you had after 
beginning to eat? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
7. During the past 7 days, how severe 
was your worst bone pain (not joint or 
arthritis pain)? 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
Investigators/Site Staff: 
 
Please complete the table below to confirm the criterion used to confirm the participant's 
eligibility in the trial based on an assessment of his/her active symptoms of myelofibrosis. 
ELIGIBILITY CRITERION 
CONFIRMATION 
Total Symptom Score of at least 10 (for the 7 items above) 
□ Yes □ No 
 


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APPENDIX D. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source:  Oken et al 1982. 


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APPENDIX G. INHIBITORS AND INDUCERS OF CYTOCHROME P450 
CYP 3A4 Inhibitors 
 
Inhibitor 
Therapeutic Class 
Potent CYP3A 
VIEKIRA PAK 
Antivirals 
Indinavir/RIT 
Protease inhibitors 
Tipranavir/RIT 
Protease inhibitors 
Ritonavir 
Protease inhibitors 
Cobicistat (GS-9350) 
None 
Ketoconazole 
Antifungals 
Indinavir 
Protease inhibitors 
Troleandomycin 
Antibiotics 
Telaprevir 
Antivirals 
Danoprevir/RIT 
Antivirals 
Elvitegravir/RIT 
Treatments of AIDS 
Saquinavir/RIT 
Protease inhibitors 
Lopinavir/RIT 
Protease inhibitors 
Itraconazole 
Antifungals 
Voriconazole 
Antifungals 
Mibefradil 
Calcium channel blockers 
LCL161 
Cancer treatments 
Clarithromycin 
Antibiotics 
Posaconazole 
Antifungals 
Telithromycin 
Antibiotics 
Grapefruit juice DS 
Food products 
Conivaptan 
Diuretics 
Nefazodone 
Antidepressants 
Nelfinavir 
Protease inhibitors 
Saquinavir 
Protease inhibitors 
Ribociclib 
Kinase inhibitors 
Idelalisib 
Kinase inhibitors 
Boceprevir 
Antivirals 
 


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Inhibitor 
Therapeutic Class 
Moderate CYP3A 
Erythromycin 
Antibiotics 
Fluconazole 
Antifungals 
Atazanavir/RIT 
Protease inhibitors 
Darunavir 
Protease inhibitors 
Diltiazem 
Calcium channel blockers 
Darunavir/RIT 
Protease inhibitors 
Dronedarone 
Antiarrhythmics 
Crizotinib 
Kinase inhibitors 
Atazanavir 
Protease inhibitors 
Letermovir 
Antivirals 
GSK2647544 
Alzheimer's disease & dementia treatments 
Aprepitant 
Antiemetics 
Casopitant 
Antiemetics 
Amprenavir 
Protease inhibitors 
Faldaprevir 
Antivirals 
Imatinib 
Antineoplastic agents 
Verapamil 
Calcium channel blockers 
Netupitant 
Antiemetics 
Nilotinib 
Kinase inhibitors 
Grapefruit juice 
Food products 
Tofisopam 
Benzodiazepines 
Cyclosporine 
Immunosuppressants 
ACT-178882 
Renin inhibitors 
Ciprofloxacin 
Antibiotics 
Magnolia vine (Schisandra sphenanthera) 
Herbal medications 
Isavuconazole 
Antifungals 
Cimetidine 
H-2 receptor antagonists 
FK1706 
Central nervous system agents 
 


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Inhibitor 
Therapeutic Class 
Weak CYP3A 
Tabimorelin 
Hormone replacement 
Amlodipine 
Calcium channel blockers 
Ranolazine 
Cardiovascular drugs 
Breviscapine 
Herbal medications 
Lomitapide 
Other antilipemics 
Fosaprepitant (IV) 
Antiemetics 
Seville orange (Citrus aurantium) juice 
Food products 
Amiodarone 
Antiarrhythmics 
Diosmin 
Herbal medications 
Chlorzoxazone 
Muscle relaxants 
M100240 
Antihypertensive agents 
Fluvoxamine 
Antidepressants 
Ranitidine 
H-2 receptor antagonists 
Goldenseal 
Herbal medications 
Clotrimazole 
Antifungals 
Tacrolimus 
Immunosuppressants 
Palbociclib 
Kinase inhibitors 
Cilostazol 
Antiplatelets 
Ticagrelor 
Antiplatelets 
Peppermint oil 
Food products 
Ivacaftor 
Cystic fibrosis treatments 
GSK2248761 
Transcriptase inhibitors 
Guan Mai Ning 
Herbal medications 
Osilodrostat 
Adrenal steroidogenesis inhibitors 
AZD2327 
Depression treatments 
Piperine 
Food products 
Resveratrol 
Food products 
Roxithromycin 
Antibiotics 
Suvorexant 
Hypnotics - sedatives 
Propiverine 
Anticholinergics 
Isoniazid 
Antibiotics 
Berberine 
Herbal medications 
Oral contraceptives 
Oral contraceptives 
Delavirdine 
NNRTIs 
Daclatasvir 
Antivirals 


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Inhibitor 
Therapeutic Class 
Weak CYP3A (continued) 
Simeprevir 
Protease inhibitors 
Atorvastatin 
HMG CoA reductase inhibitors (statins) 
Tolvaptan 
Vasopressin antagonists 
Almorexant 
Hypnotics - sedatives 
GSK1292263 
Other antilipemics 
Evacetrapib 
CETP inhibitors 
Linagliptin 
Dipeptidyl peptidase 4 inhibitors 
Grazoprevir (ingredient of Zepatier) 
Antivirals 
Lacidipine 
Calcium channel blockers 
Cranberry juice 
Food products 
Pazopanib 
Kinase inhibitors 
Fostamatinib 
Other 
Everolimus 
Immunosuppressants 
Blueberry juice 
Food products 
Flibanserin 
Central nervous system agents 
Lapatinib 
Kinase Inhibitors 
Brodalumab 
Immunomodulators biologics 
AMD070 
Fusion inhibitors 
Alprazolam 
Benzodiazepines 
Tong Xin Luo 
Herbal medications 
Glecaprevir and pibrentasvir 
Antivirals 
Bicalutamide 
Antiandrogens 
Sitaxentan 
Endothelin receptor antagonists 
Azithromycin 
Antibiotics 
Obeticholic acid 
Miscellaneous agents 
Ginkgo 
Herbal medications 
Teriflunomide 
Other immunomodulators 
 


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CYP 3A4 Inducers 
 
Inducers 
Therapeutic Class 
Potent CYP3A 
Rifampin 
Antibiotics 
Mitotane 
Other Antineoplastics 
Avasimibe 
Other Antilipemics 
Rifapentine 
Antibiotics 
Apalutamide 
Antiandrogens 
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
St John's Wort extract 
Herbal medications 
Lumacaftor 
Cystic fibrosis treatments 
Rifabutin 
Antibiotics 
Phenobarbital 
Anticonvulsants 
Moderate CYP3A 
Ritonavir and St John's wort 
None 
Semagacestat 
Alzheimer's treatments 
Efavirenz 
NNRTIs 
Tipranavir and ritonavir 
Protease inhibitors 
Dabrafenib 
Kinase inhibitors 
Lesinurad 
Antigout and uricosuric agents 
Bosentan 
Endothelin receptor antagonists 
Genistein 
Food products 
Thioridazine 
Antipsychotics 
Nafcillin 
Antibiotics 
Talviraline 
NNRTIs 
Lopinavir 
Protease inhibitors 
Modafinil 
Psychostimulants 
Pf-06282999 
Myeloperoxidase inactivators 
Etravirine 
NNRTIs 
Lersivirine 
NNRTIs 
Telotristat ethyl 
Antidiarrheals 


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Inducers 
Therapeutic Class 
Weak CYP3A 
Eslicarbazepine 
Anticonvulsants 
Telaprevir 
Antivirals 
Daclatasvir and asunaprevir and beclabuvir 
Antivirals 
Amenamevir 
Antivirals 
Garlic 
Food products 
Bexarotene 
Other antineoplastics 
Sarilumab 
Immunomodulators biologics 
Artesunate and mefloquine 
Antimalarials 
Amprenavir (fosamprenavir) 
Protease inhibitors 
Raltegravir 
HIV-integrase strand transfer inhibitors 
Vemurafenib 
Kinase inhibitors 
Troglitazone 
Thiazolidinediones 
Dicloxacillin 
Antibiotics 
Sorafenib 
Kinase inhibitors 
Rufinamide 
Anticonvulsants 
Sirukumab 
Immunomodulators biologics 
Pleconaril 
Antivirals 
Ginseng 
Herbal medications 
Boceprevir 
Antivirals 
Sulfinpyrazone 
Antigout and uricosuric agents 
Ginkgo 
Herbal medications 
Vinblastine 
Vinca alkaloids 
Nevirapine 
NNRTIs 
Armodafinil (R-modafinil) 
Psychostimulants 
Ticagrelor 
Anticoagulants and antiplatelets 
LCL161 
Cancer treatments 
Vicriviroc and ritonavir 
Treatments of AIDS 
Ritonavir 
Protease inhibitors 
Prednisone 
Corticosteroids 
Oxcarbazepine 
Anticonvulsants 
Danshen 
Herbal medications 
Clobazam 
Benzodiazepines 
Echinacea 
Herbal medications 
Ticlopidine 
Anticoagulants and antiplatelets 
Isavuconazole 
Antifungals 
Brivaracetam 
Anticonvulsants 


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Inducers 
Therapeutic Class 
Weak CYP3A (continued) 
Stribild 
Treatments of AIDS 
Pioglitazone 
Thiazolidinediones 
VIEKIRA PAK 
Antivirals 
Dexamethasone 
Corticosteroids 
Terbinafine 
Antifungals 
Quercetin 
Food products 
Glycyrrhizin 
Herbal medications 
Aprepitant 
Neurokinin-1 receptor antagonists 
Pretomanid (PA-824) 
Antibiotics 
Safinamide 
MAO-B inhibitors 
Oritavancin 
Antibiotics 
AZD 7325 
Anxiolytics 
Methylprednisolone 
Corticosteroids 
Topiramate 
Anticonvulsants 


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APPENDIX H. INSTRUCTION TO PARTICIPANTS FOR HANDLING 
STUDY DRUG (PARSACLISIB OR PLACEBO) AND 
REFERENCE TREATMENT (RUXOLITINIB) 
The participant must be instructed in the handling of study drug and reference treatment as 
follows: 
• Store all parsaclisib/matching placebo and ruxolitinib supplies at room temperature. 
• Only remove the number of tablets needed at the time of administration. 
• Not to remove doses in advance of the next scheduled administration. 
• Make every effort to take doses on schedule. 
• Report any missed doses or lost tablets. 
• If the participant vomits after taking parsaclisib/matching placebo or ruxolitinib, the 
participant should not take another dose. 
• To keep study drug and reference treatment in a safe place and out of reach of 
children. 
• To bring all used and unused study drug bottles/kits to the site at each visit. 
• If a dose of parsaclisib/matching placebo or ruxolitinib is missed by more than 
4 hours, that dose should be skipped and the next scheduled dose should be 
administered at the usual time. 


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APPENDIX J. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1 
07 OCT 2021 
Amendment 2 
20 OCT 2022 
Amendment 2 (20 OCT 2022) 
Overall Rationale for the Amendment:   
The primary purpose of this amendment is to update safety information for parsaclisib, including 
information regarding COVID-19, and the potential impact of parsaclisib therapy on infection 
risk, vaccine effectiveness, and severity of disease.  Additional clarifications are also provided. 
1. Section 1, Protocol Summary (Table 2:  Key Study Design Elements) 
Description of change:  Clarified that certain countries have minimum enrollment 
requirements and added the name of the coordinating principal investigator.  
Rationale for change:  To clarify language around enrollment requirements and add the 
name of the coordinating principal investigator. 
2. Section 2.6.1.2, Potential Risks of Parsaclisib Based on Prior and Ongoing Clinical 
Studies; Section 2.6.2.2, Potential Risks of Parsaclisib Plus Ruxolitinib 
Description of change:  Updated safety language to reflect the updated Investigator's 
Brochure (dated MAY 2022) and added a statement to include COVID-19 in potential 
risks. 
Rationale for change:  To provide updated safety information. 
3. Section 4.1.1, Study Schedule/Procedures 
Description of change:  Added language for location options for local laboratory visits.  
Rationale for change:  To provide options for participants for local laboratory visits.   
4. Section 4.1.2, Unblinding and Crossover; Section 4.1.4, Early Unblinding/Crossover 
Process; Section 4.1.5, Participant Unblinding/Crossover Process After Completion 
of the Week 24 Assessments 
Description of change:  Clarified processes and timing for database cleaning and 
freezing.  
Rationale for change:  To clarify what data/visits will be cleaned and frozen and how 
approval for unblinding will be communicated. 


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5. Section 5, Study Population; Section 5.1, Inclusion Criteria 
Description of change:  Removed requirement for age of 20 years or older for Japan and 
added language for age requirement of 19 years or older for South Korean participants. 
Rationale for change:  Age of 20 years or older is no longer a requirement for 
Japan.  Age of 19 years or older is a requirement for South Korea.  
6. Section 6.1, Study Treatments Administered (Table 10:  Study Treatment 
Information); Section 6.2, Preparation, Handling, and Accountability 
Description of change:  Replaced language regarding storage conditions with reference 
to the Pharmacy Manual.  
Rationale for change:  To improve consistency for storage condition information in the 
study.  
7. Section 6.7.5, COVID-19 
Description of change:  Added new section describing risks associated with COVID-19 
with regard to participants with hematologic disorders and treatment with parsaclisib.  
Rationale for change:  Informational purposes. 
8. Incorporation of administrative changes.  Other regulatory guidance and 
administrative changes have been incorporated throughout the Protocol and are noted in 
the redline version of the amendment.  


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Amendment 1 (07 OCT 2021) 
Overall Rationale for the Amendment:   
The primary purpose of this amendment is to address changes requested by different national 
regulatory agencies and ethics committees. 
1. Section 1, Protocol Summary (Table 2:  Key Study Design Elements) 
Description of change:  Included a note regarding the minimum enrollment regulatory 
requirement in Japan and need for potential continued enrollment after enrollment in 
other countries ends. 
Rationale for change:  To allow minimum enrollment regulatory requirement in Japan. 
2. Section 1, Protocol Summary (Table 2:  Key Study Design Elements; Table 5:  
Schedule of Laboratory Assessments for All Participants); Section 4.1, Overall 
Design; Section 6.3, Measures to Minimize Bias:  Randomization and Blinding; 
Section 8.1.3, Baseline; Section 10.1, Sample Size Determination; Section 10.4.1, 
Primary and Secondary Analyses (Table 17:  Primary and Secondary Analyses 
Methods and Populations); 
 
Description of change:  Inserted a statement that if a participant's platelet count is 
< 50 × 109/L at baseline, the platelet count at screening will be used for 
stratification/randomization.  
Rationale for change:  To provide guidance for cases in which the platelet count 
decreases between screening and baseline and to remove discrepancies in the Protocol 
regarding which value should be used. 
3. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Randomized 
Participants in Group A, Group B, and After Crossover); Section 8.8.2, Survival 
Follow-Up 
Description of change:  Added a 2-week window for survival follow-up. 
Rationale for change:  Administrative error. 
4. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Randomized 
Participants in Group A, Group B, and After Crossover; Table 4:  Schedule of 
Additional Study Visits for Participants Who Cross Over); Section 4.1.1, Study 
Schedule/Procedures 
Description of change:  Specified end date for PJP prophylaxis as at least 2 to 6 months 
after the last dose of study treatment, consistent with other sections of the Protocol. 
Rationale for change:  Administrative error. 


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5. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Randomized 
Participants in Group A, Group B, and After Crossover; Table 5:  Schedule of 
Laboratory Assessments for All Participants); Section 8.1.2, Screening Procedures; 
 
Description of change:  Removed requirement for 0% blasts at screening for an archived 
biopsy/aspirate to be used for study entry. 
Rationale for change:  Requirement for 0% blasts is not reflective of many high-risk 
patients with MF. 
6. Section 1, Protocol Summary (Table 4:  Schedule of Additional Study Visits for 
Participants Who Cross Over) 
Description of change:  Specified that IXRS needs to be contacted also at the 4 weeks 
post-crossover visit. 
Rationale for change:  Administrative error. 
7. Section 1, Protocol Summary (Table 4:  Schedule of Additional Study Visits for 
Participants Who Cross Over; Table 5:  Schedule of Laboratory Assessments for All 
Participants) 
Description of change:  Inserted statement that collection of plasma correlative samples 
will be performed approximately 12 and 24 weeks after crossover, coincident with a 
scheduled or unscheduled visit.   
Rationale for change:  To clarify timing of plasma correlative sample collection after 
crossover. 
8. Section 1, Protocol Summary (Table 5:  Schedule of Laboratory Assessments for All 
Participants) 
Description of change:  Added window values for different laboratory-only visits. 
Rationale for change:  Administrative error. 
 
 
 
 
 
 
   
 
 


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10. Section 1, Protocol Summary (Table 5:  Schedule of Laboratory Assessments for All 
Participants); 
 
(Table 14:  Required Laboratory Analytes); 
 
 
Description of change:  
 
.  
Rationale for change:  To meet regulatory and genetic testing requirements of specific 
countries. 
11. Section 2.6.1.2, Potential Risks of Parsaclisib Based on Prior and Ongoing Clinical 
Trials 
Description of change:  Updated safety information. 
Rationale for change:  To reflect current IB. 
12. Section 2.6.1.4, Potential Benefits of Parsaclisib; Section 2.6.2.2, Potential Risks of 
Parsaclisib Plus Ruxolitinib 
Description of change:  Updated information to reflect the most recent data analysis. 
Rationale for change:  To provide updated information.  
 
 
 
 
 
 
14. Section 4.1.2, Unblinding and Crossover 
Description of change:  Added statement to clarify that if, after the Week 24 
assessments, a participant is found to have been randomized to parsaclisib, treatment with 
both parsaclisib and ruxolitinib will be continued as long as protocol-defined criteria are 
met. 
Rationale for change:  Clarity. 
15. Section 4.1.3, Early Unblinding and Crossover 
Description of change:  Modified text to indicate that when a participant has undergone 
early unblinding and either is found to have been on parsaclisib or is on placebo but does 
not choose to cross over, the participant must discontinue treatment with study drugs 
(parsaclisib and ruxolitinib) and have an EOT visit scheduled.  
Rationale for change:  Clarity. 


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16. Section 4.1.5, Participant Unblinding and Crossover 
Description of change:  Modified text to describe the unblinding and crossover process 
for an individual participant rather than for the entire study. 
Rationale for change:  Clarity. 
17. Section 4.2, Overall Study Duration 
Description of change:  Clarified that end of study is defined as the date of either the last 
visit or the last contact of the last participant in the study. 
Rationale for change:  Clarity. 
18. Section 4.3, Study Termination; Section 11.6, Study and Site Closure 
Description of change:  Specified responsibility of the head of study site concerning 
study termination and study completion in Japan. 
Rationale for change:  Japan requirement. 
19. Section 5.1, Inclusion Criteria 
Description of change:  Specified Japan-specific requirements for participants under 
20 years old. 
Rationale for change:  Japan requirement. 
20. Section 5.2, Exclusion Criteria 
Description of change:  Clarified that the definition of inadequate bone marrow reserve 
is not limited to the parameters listed in the protocol, clarified that platelet count 
< 50 × 109/L and ANC < 0.5 × 109/L at screening are also exclusionary, modified the 
description of inadequate liver function to clarify the statement about direct bilirubin 
versus total bilirubin, clarified that prophylactic antivirals are allowed, moved the 
exclusion criterion for participants unwilling to receive RBC transfusions as a separate 
criterion, and added an exclusion criterion for sensitivity/allergy to study drugs or 
excipients.  
Rationale for change:  To provide flexibility to investigators to characterize what 
constitutes an inadequate bone marrow reserve, clarify that screening values are also 
considered in the exclusion/inclusion assessment, remove potentially contradictory 
language regarding bilirubin criteria, provide clarity regarding use of prophylactic 
antivirals, separate the transfusion exclusion criterion from the description of inadequate 
bone marrow reserve for clarity, and fulfill the request of multiple regulatory 
agencies/ethics committees to explicitly state that sensitivity/allergy to drug/excipients is 
an exclusion criterion.  
21. Section 5.2, Exclusion Criteria; Section 6.8.5, Prohibited Medications and 
Procedures 
Description of change:  To clarify that MF drugs used for a non-MF indication must 
also be washed out within 3 months of starting study drug. 
Rationale for change:   To clarify requirements for washout of MF medications before 
starting study drug. 


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22. Section 6.1, Study Treatments Administered (Table 10:  Study Treatment 
Information) 
Description of change:  Inserted details concerning storage conditions for the study 
treatments. 
Rationale for change:  To provide additional information regarding storage conditions. 
23. Section 6.2, Preparation, Handling, and Accountability 
Description of change:  Specified responsibility of the investigational drug storage 
manager concerning preparation, handling, and accountability in Japan. 
Rationale for change:  Japan requirement. 
24. Section 6.7.2, Dose Decreases of Parsaclisib/Placebo for Toxicity  
Description of change:  Specified that individual decisions are in regard to both dose 
reductions and interruptions. 
Rationale for change:  To provide additional clarity to dosing decisions.   
25. Section 6.7.2, Dose Decreases of Parsaclisib/Placebo for Toxicity (Table 11:  
Guidelines for Interruption and Restarting of Parsaclisib/Matching Placebo)  
Description of change:  Removed the requirement for temperature to be measured orally 
in the event of a Grade 3 or higher ANC and fever, added a description of symptoms of 
colitis, and added another step for treatment of Grade 3 or higher diarrhea or 
noninfectious colitis. 
Rationale for change:  To allow body temperature to be measured by any modality for 
neutropenic fever and administrative errors. 
26. Section 6.7.5, Criteria for Permanent Discontinuation of Parsaclisib/Matching 
Placebo 
Description of change:  Removed wording regarding exceptions by sponsor for study 
drug discontinuation because of AEs requiring more than 2 dose reductions. 
Rationale for change:  UK MHRA request. 
27. Section 6.7.6, Dose Decreases of Ruxolitinib for Safety 
Description of change:  Clarified that, at the investigator's discretion, ruxolitinib dose 
interruptions/changes for safety reasons may occur before the end of a 14-day period 
after the parsaclisib dose was modified or interrupted for safety reasons. 
Rationale for change:  UK MHRA request. 
28. Section 6.8.2, Pneumocystis jirovecii Pneumonia Prophylaxis 
Description of change:  Specified that diaminodiphenylsulfone and pentamidine will not 
be used for PJP prophylaxis in Japan. 
Rationale for change:  Japan requirement. 


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29. Section 6.8.3, Use of Growth Factors Such as Erythropoietin 
Description of change:  Added section advising caution on concomitant use of growth 
factors. 
Rationale for change:  To address multiple questions regarding allowance of growth 
factors from investigative sites. 
30. Section 6.8.4, Restricted Medications and Procedures 
Description of change:  Modified text regarding use of nonsteroidal anti-inflammatory 
drugs and added text restricting the dosage of corticosteroids. 
Rationale for change:  To recommend caution when administering nonsteroidal 
anti-inflammatory drugs in general and to provide guidance for steroid therapy, which 
may be used as supportive care, as use of these corticosteroids at high doses may interfere 
with readout of study endpoints. 
31. Section 8, Study Assessments and Procedures 
Description of change:  Clarified that delays in treatment administration will not delay 
mandated visits and assessments, 
 
 
 
Rationale for change:  Clarity. 
32. Section 8.1.1, Informed Consent Process 
Description of change:  Deleted wording regarding possible exploratory research with 
leftover samples. 
Rationale for change:  No studies of this nature are planned. 
33. Section 8.1.2, Screening Procedures; Section 8.3.5.5, Lipid Panel 
Description of change:  Clarified that participants may drink water during the overnight 
fasting period. 
Rationale for change:  Drinking water will not affect lipid panel assessments. 
34. Section 8.1.5, Distribution of Reminder Cards 
Description of change:  Clarified the visits where overnight fasting is required for lipid 
profile sample collection. 
Rationale for change:  Clarity. 
35. Section 8.1.7.3, Transfusion History Status 
Description of change:  Clarified the time periods during which RBC and platelet 
transfusion history will be collected. 
Rationale for change:  Clarity. 


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36. 
 
 
 
 
37. Section 8.3, Safety Assessments (Table 14:  Required Laboratory Analytes) 
Description of change:  Specified that bicarbonate is not analyzed in Japan and that 
direct bilirubin is a required analyte, irrespective of total bilirubin levels, and removed 
HCV antibodies from the analyte list as this will not be analyzed. 
Rationale for change:  Japan requirement, to avoid additional blood draws to determine 
direct bilirubin, and administrative error concerning HCV antibodies. 
38. Section 8.3.5.6, Pregnancy Testing 
Description of change:  Clarified that, in the case of a positive urine pregnancy test, the 
confirmatory serum pregnancy test is to be performed at the local laboratory. 
Rationale for change:  Clarity. 
 
 
 
 
 
 
 
 
40. 
 
 
 
 
 
41. Section 8.7, End of Treatment and/or Early Termination 
Description of change:  Added "or placebo" to the sentence describing when to conduct 
the EOT visit. 
Rationale for change:  Administrative error.  
42. Section 8.8.2, Survival Follow-Up 
Description of change:  Added subsequent MF treatments to the information collected 
during follow-up. 
Rationale for change:  Administrative error.  


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43. Section 9.2, Definition of Serious Adverse Event 
Description of change:  Added definition to important medical events (risk of 
dysfunction) and clarified that an event that may lead to disability is considered an 
important medical event. 
Rationale for change:  Japan requirement and alignment with protocol template. 
44. Section 9.4, Reporting of Serious Adverse Events 
Description of change:  Specified that SAEs must be reported to the head of the study 
site in Japan and that the sponsor must report suspected expected deaths and 
life-threatening events to PMDA in Japan. 
Rationale for change:  Japan requirement. 
45. Section 9.5, Adverse Events of Special Interest 
Description of change:  Clarified that only AEs of special interest that are also SAEs 
need to follow SAE reporting timelines and modified the terms for certain infections to 
include herpes and infection in each term. 
Rationale for change:  Clarity. 
46. Section 9.6, Emergency Unblinding of Treatment Assignment 
Description of change:  Clarified that the decision to break the treatment code in an 
emergency resides at the sole discretion of the investigator. 
Rationale for change:  UK MHRA request. 
47. Section 11.1, Investigator Responsibilities 
Description of change:  Added language concerning retention of documents in Japan. 
Rationale for change:  Japan requirement. 
48. Appendix A, Information Regarding Effectiveness of Contraceptive Methods 
Description of change:  Specified that certain female contraceptive methods are not 
approved or not applicable in Japan and removed list of birth control methods that have a 
failure rate of more than 1%. 
Rationale for change:  Japan requirement and to remove contraceptive methods that are 
not at least 99% effective in preventing pregnancy. 
49. Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
 


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SAP_001.pdf: 
Official Title:    A Randomized, Double-Blind, Placebo-Controlled Study of the PI3Kδ Inhibitor 
Parsaclisib Plus Ruxolitinib in Participants With Myelofibrosis Who Have 
Suboptimal Response to Ruxolitinib
NCT Number: 
 NCT04551053 
Document Date: 
Statistical Analysis Plan Amendment 1: 25-Apr-2022


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Statistical Analysis Plan 
TITLE PAGE 
INCB 50465-304 
A Randomized, Double-Blind, Placebo-Controlled Study of the 
PI3Kδ Inhibitor Parsaclisib Plus Ruxolitinib in Participants With 
Myelofibrosis Who Have Suboptimal Response to Ruxolitinib 
IND Number: 
147,207 
EudraCT Number: 
2020-003415-98 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Amendment 1 dated 07 OCT 2021 
CRF Approval Date: 
28 OCT 2020 
SAP Version: 
Amendment 1 
SAP Author: 
, Biostatistics
Date of Plan: 
25 APR 2022 
This study is being conducted in compliance with Good Clinical Practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................9 
2.1. 
Protocol and Case Report Form Version ......................................................................9 
2.2. 
Study Objectives and Endpoints ...................................................................................9 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
Randomization ............................................................................................................12 
3.2. 
Control of Type I Error ...............................................................................................12 
3.3. 
Sample Size Considerations .......................................................................................13 
3.4. 
Schedule of Assessments ............................................................................................13 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................14 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................14 
4.1.1. 
Day 1 ...........................................................................................................................14 
4.1.2. 
Day 1 of Crossover for Crossover Participants ..........................................................14 
4.1.3. 
Study Day ...................................................................................................................14 
4.1.4. 
Baseline Value ............................................................................................................14 
4.1.5. 
Handling of Missing and Incomplete Dates ...............................................................14 
4.2. 
Variable Definitions ....................................................................................................15 
4.2.1. 
Body Mass Index ........................................................................................................15 
4.2.2. 
Prior and Concomitant Medication .............................................................................15 
5. 
STATISTICAL METHODOLOGY ...........................................................................16 
5.1. 
General Methodology .................................................................................................16 
5.2. 
Treatment Groups .......................................................................................................16 
5.3. 
Analysis Endpoints .....................................................................................................16 
5.4. 
Analysis Populations ..................................................................................................18 
5.4.1. 
Intent-to-Treat Population ..........................................................................................18 
5.4.2. 
Per-Protocol Population ..............................................................................................18 
5.4.3. 
Safety Population ........................................................................................................19 
 
19 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION ......................................................20 
6.1. 
Demographics, Baseline Characteristics, and Disease History ..................................20 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................20 
6.1.2. 
Baseline Disease Characteristics ................................................................................20 
6.1.3. 
Myelofibrosis Disease History ...................................................................................20 
6.1.4. 
Prior Therapy ..............................................................................................................20 
6.1.5. 
Medical History ..........................................................................................................21 
6.1.6. 
Ruxolitinib History .....................................................................................................21 
6.2. 
Disposition of Participant ...........................................................................................21 
6.3. 
Protocol Deviations ....................................................................................................21 
6.4. 
Exposure .....................................................................................................................21 
6.5. 
Study Drug Compliance .............................................................................................22 
6.6. 
Prior and Concomitant Medication .............................................................................22 
7. 
EFFICACY .................................................................................................................22 
7.1. 
General Considerations ...............................................................................................22 
7.2. 
Efficacy Hypotheses ...................................................................................................23 
7.3. 
Analysis of the Primary Efficacy Endpoint ................................................................23 
7.3.1. 
Primary Efficacy Analysis ..........................................................................................23 
7.3.2. 
Subgroup Analyses for Primary Endpoint ..................................................................24 
7.3.3. 
Sensitivity and Supportive Analyses for Primary Endpoint .......................................24 
7.4. 
Analysis of the Secondary Efficacy Parameters .........................................................25 
7.4.1. 
Spleen Volume Reduction ..........................................................................................25 
7.4.1.1. 
Time to the First ≥ 25% Reduction in Spleen Volume ...............................................25 
7.4.1.2. 
Duration of Maintenance of a ≥ 25% Reduction in Spleen Volume ..........................25 
7.4.2. 
Myelofibrosis Symptom Assessment Form Total Symptom Score v4.0 ....................25 
7.4.2.1. 
Windowing of Myelofibrosis Symptom Assessment Form v4.0 Total 
Symptom Score ...........................................................................................................26 
7.4.2.2. 
Proportion of Participants With a ≥ 50% Reduction in Myelofibrosis 
Symptom Assessment Form v4.0 Total Symptom Score ...........................................27 
7.4.2.3. 
Mean Change and Percentage Change in Myelofibrosis Symptom 
Assessment Form v4.0 Total Symptom Score ............................................................27 
7.4.2.4. 
Time to the First ≥ 50% Reduction in Myelofibrosis Symptom Assessment 
Form v4.0 Total Symptom Score ................................................................................28 
7.4.3. 
Overall Survival ..........................................................................................................28 


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29 
 
29 
 
29 
 
30 
 
30 
 
30 
 
30 
 
31 
 
 
31 
 
31 
 
34 
 
 
34 
 
35 
 
35 
 
35 
 
 
35 
 
35 
 
35 
 
35 
9. 
SAFETY AND TOLERABILITY ..............................................................................36 
9.1. 
General Considerations ...............................................................................................36 
9.2. 
Adverse Events ...........................................................................................................36 
9.2.1. 
Adverse Event Definitions ..........................................................................................36 
9.2.2. 
Adverse Events of Special Interest .............................................................................37 
9.2.3. 
Adverse Event Summaries ..........................................................................................38 
9.3. 
Clinical Laboratory Tests ...........................................................................................40 
9.3.1. 
Laboratory Value Definitions .....................................................................................40 
9.3.2. 
Laboratory Value Summaries .....................................................................................40 
9.3.3. 
Potential Hy's Law Events ..........................................................................................41 
9.4. 
Vital Signs ..................................................................................................................41 


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9.5. 
Electrocardiograms .....................................................................................................41 
10. 
INTERIM ANALYSES ..............................................................................................43 
10.1. 
Overview of Interim Analyses ....................................................................................43 
10.2. 
Data Cutoff for Interim Analysis ................................................................................43 
10.3. 
Derivations and Calculations for Interim Analyses ....................................................43 
10.4. 
Guidelines for Decision Rules ....................................................................................44 
11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................45 
11.1. 
Changes to Protocol-Defined Analyses ......................................................................45 
11.2. 
Changes to the Statistical Analysis Plan .....................................................................45 
11.2.1. 
Amendment 1 ..............................................................................................................45 
12. 
REFERENCES ...........................................................................................................47 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................48 
 
 
 
56 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................9 
Table 2: 
Primary and Secondary Analyses Methods and Populations .....................................17 
Table 3: 
Window for Deriving Myelofibrosis Symptom Assessment Form v4.0 Total 
Symptom Score for Baseline, Week 12, and Week 24 ...............................................26 
 
33 
Table 5: 
Normal Ranges for Vital Sign Values ........................................................................41 
Table 6: 
Normal Ranges for Electrocardiogram Intervals ........................................................42 
Table 7: 
Interim Analysis for Spleen Volume With HSD(2) ...................................................44 
Table 8: 
Interim Analysis for MFSAF TSS With HSD(1) .......................................................45 
Table 9: 
Statistical Analysis Plan Versions ..............................................................................45 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................12 
Figure 2: 
Beta Spending .............................................................................................................44 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIPSS 
Dynamic International Prognostic Scoring System 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
 
 
eCRF 
electronic case report form 
 
 
 
 
 
 
 
HGB 
hemoglobin 
HR 
hazard ratio 
HSD 
Hwang-Shih-DeCani 
ITT 
intent-to-treat 
 
 
 
JAK 
Janus kinase 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities  
MF 
myelofibrosis 
MFSAF 
Myelofibrosis Symptom Assessment Form 
 
 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 


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Abbreviation 
Term 
OS 
overall survival 
PET-MF 
post–essential thrombosis myelofibrosis 
 
 
PI3K 
phosphoinositide 3-kinase 
PP 
per-protocol 
PPV-MF 
post–polycythemia vera myelofibrosis 
 
 
PT 
preferred term 
QD 
once daily 
QoL 
quality of life 
 
 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TSS 
total symptom score 
ULN 
upper limit of normal 
WHO 
World Health Organization  
 
 
 


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1. 
INTRODUCTION 
This is a Phase 3, randomized, double-blind study of the combination of the PI3Kδ inhibitor 
parsaclisib or matching placebo and the JAK1/2 inhibitor ruxolitinib in participants with PMF or 
secondary MF (PPV-MF or PET-MF) who have had suboptimal response while receiving 
ruxolitinib monotherapy.  Participants will be randomized to 1 of 2 treatment groups, with 
stratification for baseline platelet count (≥ 100 × 109/L vs 50 to < 100 × 109/L inclusive) and 
DIPSS risk category (high vs intermediate-2 vs intermediate-1). If a participant's platelet count 
has decreased to < 50 × 109/L at baseline, the platelet count at screening will be used for 
stratification/randomization.  Section 2 of the Protocol provides a detailed description of the 
investigational product, target patient population, rationale for doses to be examined, and 
potential risks and benefits of treatment with parsaclisib. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 50465-304 Protocol.  A total of 212 participants will be randomized 1:1 to parsaclisib 
plus ruxolitinib or placebo plus ruxolitinib groups using the stratification factors of platelet count 
and DIPSS risk category.  Two nonbinding futility analyses are planned at the time when the first 
30% of the participants reach Week 12 and Week 24 assessments of spleen volume and MFSAF 
TSS or discontinue from their respective treatment.  
The primary endpoint of the proportion of participants with ≥ 25% reduction in spleen volume at 
Week 24 and the key secondary endpoints of the proportion of participants with ≥ 50% reduction 
in MFSAF TSS at Week 24 and OS will be tested following a fixed-sequence-testing procedure. 
 
 
 
 


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2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 50465-304 Protocol Amendment 1 dated 07 OCT 2021 and CRFs 
approved 28 OCT 2020.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and eCRF versions. 
2.2. 
Study Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate and compare the efficacy of 
parsaclisib plus ruxolitinib versus placebo plus 
ruxolitinib on spleen volume at Week 24.a 
Proportion of participants achieving 
≥ 25% reduction in spleen volume from baseline 
to Week 24 as measured by MRI (or CT scan in 
applicable participants). 
Secondary 
To evaluate and compare the effect of parsaclisib 
plus ruxolitinib versus placebo plus ruxolitinib on 
participant reports of MF symptoms.b,c 
Proportion of participants who have a 
≥ 50% reduction in TSS from baseline to Week 24 
as measured by the MFSAF v4.0 diary. 
Change in TSS from baseline to Week 24 as 
measured by the MFSAF v4.0 diary. 
Time to the first ≥ 50% reduction in TSS as 
measured by the MFSAF v4.0 diary. 
To evaluate and compare the effect of parsaclisib 
plus ruxolitinib versus placebo plus ruxolitinib 
with respect to OS.d 
OS determined from the date of randomization 
until death due to any cause. 
To evaluate and compare the safety and 
tolerability of parsaclisib plus ruxolitinib versus 
placebo plus ruxolitinib. 
Safety and tolerability will be assessed by 
monitoring the frequency and severity of AEs, 
performing physical examinations, and evaluating 
changes in vital signs, ECGs, and laboratory 
results. 
To evaluate and compare the time to onset and 
duration of response in spleen volume of 
participants receiving parsaclisib plus ruxolitinib 
versus placebo plus ruxolitinib.e 
Time to the first ≥ 25% reduction in spleen 
volume and duration of maintenance of a 
≥ 25% reduction in spleen volume. 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
a Hypothesis 1:  Proportions of participants achieving ≥ 25% reduction in spleen volume from baseline to Week 24 
in the 2 treatment groups are different. 
b Hypothesis 2:  Proportions of participants achieving ≥ 50% reduction in TSS from baseline to Week 24 as 
measured by the MFSAF v4.0 diary in the 2 treatment groups are different. 
c Hypothesis 3:  Time to the first ≥ 50% reduction in TSS as measured by the MFSAF v4.0 diary in the 2 treatment 
groups are different. 
d Hypothesis 4:  The OS in the 2 treatment groups are different. 
e Hypothesis 5:  Time to the first ≥ 25% reduction in spleen volume and/or duration of maintenance of ≥ 25% 
reduction in spleen volume for the 2 treatment groups are different. 


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3. 
STUDY DESIGN 
This is a Phase 3, randomized, double-blind study of the combination of the PI3Kδ inhibitor 
parsaclisib or matching placebo and the JAK1/2 inhibitor ruxolitinib in participants with PMF or 
secondary MF (PPV-MF or PET-MF) who have had suboptimal response while receiving 
ruxolitinib monotherapy.  Participants must meet Protocol-defined criteria for suboptimal 
response to ruxolitinib monotherapy.  After participants have been determined to meet all 
criteria, they will be randomized to 1 of 2 treatment groups and will receive parsaclisib or 
matching placebo at a dose of 5 mg QD beginning on Day 1.  Participants will also continue to 
receive the stable dose of ruxolitinib they were taking for the 8 weeks prior to Day 1.  Both 
parsaclisib/matching placebo and ruxolitinib dosing will continue for the duration of 
participation in the study.  Figure 1 presents the study design schema. 
Figure 1: 
Study Design Schema 
 
3.1. 
Randomization 
Approximately 212 participants will be randomized 1:1 to parsaclisib plus ruxolitinib or placebo 
plus ruxolitinib with stratification for DIPSS risk category (intermediate-1 vs intermediate-2 vs 
high) and baseline platelet count (≥ 100 × 109/L vs 50 to < 100 × 109/L inclusive).  Note that if a 
participant's platelet count is < 50 × 109/L at baseline, the platelet count at screening will be used 
for stratification/randomization. 
3.2. 
Control of Type I Error 
This study defines a single primary endpoint with a single primary analysis.  The study will be 
claimed to have achieved the primary efficacy objective when the primary endpoint shows a 
significant result at 2-sided alpha of 0.05 at final analysis.  The key secondary efficacy endpoints 
will be alpha-controlled and will be analyzed only when the study has reached the efficacy 
objective in the primary endpoint.  The key secondary efficacy variables will be tested following 
a fixed-sequence-testing procedure with each at the 2-sided alpha level of 0.05 in the order 
below: 
1. The proportion of participants who have a ≥ 50% reduction from baseline to Week 24 in 
the MFSAF TSS 
2. OS 


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Other secondary 
 endpoints will be tested using a 2-sided, 5% significance level 
but are not considered alpha-controlled hypotheses. 
There will be 2 planned, nonbinding, futility analyses for this study based on the first 30% of 
participants enrolled in the study reaching Week 12 and Week 24 assessments of spleen volume 
and MFSAF TSS or discontinuing from treatment.  As no formal decision for efficacy will be 
made based on these interim analyses, no overall alpha will be spent. 
An independent DMC will be assembled to monitor safety data, efficacy data, and study conduct 
on a regular and ongoing basis during the study.  See Section 10 for details regarding the 
alpha-spending plan and interim analyses conducted in this study. 
3.3. 
Sample Size Considerations 
The primary endpoint of this study is the proportion of participants with ≥ 25% spleen volume 
reduction from baseline to Week 24 as measured by MRI (or CT scan in applicable participants).  
The primary endpoint will be analyzed by the CMH test stratified by baseline (or screening, if 
applicable) platelet count (≥ 100 × 109/L vs 50 to < 100 × 109/L inclusive) and DIPSS risk 
category (high vs intermediate-2 vs intermediate-1) at randomization.  Assuming a 25% response 
rate for ruxolitinib + parsaclisib versus 5% for ruxolitinib + placebo, to achieve a 95% power to 
detect a statistically significant difference with a 2-sided Type 1 error of 5%, a sample size of 
212 participants is required to be randomized equally between treatment groups. 
For the key secondary endpoint of MFSAF TSS, assuming a response rate of 35% (25%) with 
ruxolitinib + parsaclisib for participants with normal (low) platelet counts and a response rate of 
15% (10%) with ruxolitinib + placebo for participants with normal (low) platelet counts, a 
sample size of 212 will provide 81.3% power using the CMH test given a 2-sided Type 1 error of 
5%. 
A test for OS will be performed when 84 deaths are observed or the last participant achieved 
Week 24 assessments of spleen volume and MFSAF TSS, whichever is later, using the log-rank 
test at a 2-sided Type 1 error level of 0.05.  The log-rank test will provide 80% power to 
detect an HR of 0.54 with 84 deaths.  Assuming a median survival time of 3.7 years for 
ruxolitinib + placebo and an enrollment duration of 1 year, the expected total study duration is 
4 years. 
3.4. 
Schedule of Assessments 
Refer to Protocol INCB 50465-304 Amendment 1 dated 07 OCT 2021 for a full description of all 
study procedures and assessment schedules for this study. 


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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first dose of parsaclisib/placebo is administered to the participants. 
For randomized participants not treated with parsaclisib/placebo, Day 1 is defined as the date of 
randomization. 
4.1.2. 
Day 1 of Crossover for Crossover Participants 
For participants who cross over from placebo plus ruxolitinib to parsaclisib plus ruxolitinib, 
Day 1 of crossover is the date the first dose of open-label parsaclisib is administered to the 
participants. 
4.1.3. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date). 
A study day of –1 indicates 1 day before Day 1. 
4.1.4. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of 
parsaclisib/placebo, unless otherwise defined. 
For randomized participants not treated with any study drug, baseline is defined as the last 
nonmissing measurement before the date of randomization for all parameters. 
When scheduled assessments and unscheduled assessments occur on the same day and the time 
of the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as the baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as the baseline. 
4.1.5. 
Handling of Missing and Incomplete Dates 
In general, values for missing dates will not be handled unless methods for handling missing 
dates are specified in this section or relevant sections.  The original reported dates collected on 


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the eCRF should be used in all relevant listings.  The following rules will be used for handling 
partial dates for analyses requiring dates. 
When calculating the time since diagnosis of MF, a partial MF disease diagnosis date will be 
handled as follows in the calculation: 
• If only the day is missing, then the first day of the month will be used. 
• If both the month and day are missing, then 01 JAN of the year will be used. 
• If the diagnosis date is completely missing, then the time since diagnosis will not be 
calculated. 
When the date of the last dose is used in deriving variables such as duration of treatment or 
TEAE flag, a missing or partial date of the last dose will be handled as follows: 
• If only the day is missing, then the earlier date of the last day of the month or the date 
that the participant discontinued treatment will be used. 
• If both the month and day are missing, then the earlier date of 31 DEC of the year or 
the date that the participant discontinued treatment will be used.  
• Otherwise, the date that the participant discontinued treatment will be used as the date 
of the last dose. 
For relevant efficacy endpoints, a partial date of the death date will be handled as follows in the 
calculation: 
• If mmyyyy for the last known alive date = mmyyyy for the death date, then the death 
date will be set to the day after the last known alive date. 
• If mmyyyy for the last known alive date < mmyyyy for the death date, then the death 
date will be set to the first day of the death month. 
• Otherwise, the partial death date will not be imputed. 
4.2. 
Variable Definitions 
The following variables will only be calculated if not reported on the eCRF. 
4.2.1. 
Body Mass Index 
Body mass index will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2. 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
parsaclisib/placebo. 


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Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first administration of parsaclisib/placebo and is ongoing 
throughout the study or ends on/after the date of first study drug administration. 
• On/after the date of first administration of parsaclisib/placebo and is ongoing or ends 
during the course of study. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of parsaclisib/placebo.  In the listing, it will be indicated whether a 
medication is only prior, only concomitant, or both prior and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 
5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9 or later) will be used 
for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries for 
continuous variables will include but not be limited to the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of participants in each category. 
Interim analyses are planned for this study as defined in Section 10. 
5.2. 
Treatment Groups 
This is a randomized, double-blind, parallel treatment group design.  Participants will be 
summarized by treatment group.  A participant randomized to the control group may make a 
crossover to the active treatment prior to Week 24 if the participant meets the criteria for an early 
crossover.  Unless specified, efficacy and safety analyses for between-treatment comparisons 
(parsaclisib + ruxolitinib vs placebo + ruxolitinib) will be conducted using the data truncated at 
the time of treatment crossover for those participants who made an early treatment crossover 
prior to Week 24.  Data collected after the treatment crossover will be summarized and tabulated 
separately without treatment comparisons. 
5.3. 
Analysis Endpoints 
The methods and populations for primary and secondary analyses are provided in Table 2. 


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Table 2: 
Primary and Secondary Analyses Methods and Populations 
Endpoint 
Statistical Method 
Analysis 
Population 
Primary (P) or 
Supportive (S) 
Primary endpoint 
Proportion of participants 
achieving ≥ 25% reduction 
in spleen volume from 
baseline to Week 24 as 
measured by MRI (or CT 
scan in applicable 
participants) 
CMH test stratified by baseline (or 
screening, if applicable) platelet count 
(≥ 100 × 109/L vs 50 to < 100 × 109/L 
inclusive) and DIPSS (high vs 
intermediate-2 vs intermediate-1) at 
randomization 
ITT 
P 
PP 
S 
Secondary endpoints 
Proportion of participants 
who have a ≥ 50% reduction 
in total symptom score from 
baseline to Week 24 as 
measured by the MFSAF 
v4.0 diary 
CMH test stratified by baseline (or 
screening, if applicable) platelet count 
(≥ 100 × 109/L vs 50 to < 100 × 109/L 
inclusive) and DIPSS (high vs 
intermediate-2 vs intermediate-1) at 
randomization 
ITT 
P 
PP 
S 
OS determined from the date 
of randomization until death 
due to any cause 
Inference:  Log-rank test stratified by 
baseline (or screening, if applicable) 
platelet count (≥ 100 × 109/L vs 50 to 
< 100 × 109/L inclusive) and DIPSS 
(high vs intermediate-2 vs 
intermediate-1) at randomization 
Estimation:  Kaplan-Meier 
ITT 
P 
PP 
S 
Inference:  Cox regression model 
including treatment group, baseline (or 
screening, if applicable) platelet count 
(≥ 100 × 109/L vs 50 to < 100 × 109/L 
inclusive) at randomization, and DIPSS 
(high vs intermediate-2 vs 
intermediate-1) at randomization 
ITT 
S 


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Table 2: 
Primary and Secondary Analyses Methods and Populations (Continued) 
Endpoint 
Statistical Method 
Analysis 
Population 
Primary (P) or 
Supportive (S) 
OS adjusted for crossover 
using rank-preserving 
structural failure time 
Inference:  Cox regression model 
including treatment group, baseline (or 
screening, if applicable) platelet count 
(≥ 100 × 109/L vs 50 to < 100 × 109/L 
inclusive) and DIPSS (high vs 
intermediate-2 vs intermediate-1) at 
randomization 
ITT 
S 
Time to the first ≥ 25% 
reduction in spleen volume 
Inference:  Log-rank test with 
stratification of baseline (or screening, if 
applicable) platelet count (≥ 100 × 109/L 
vs 50 to < 100 × 109/L inclusive) and 
DIPSS (high vs intermediate-2 vs 
intermediate-1) at randomization 
Estimation:  Kaplan-Meier 
ITT 
P 
Duration of maintenance of a 
≥ 25% reduction in spleen 
volume 
Estimation:  Kaplan-Meier 
ITT with 
spleen 
response 
P 
Time to the first ≥ 50% 
reduction in TSS as 
measured by the MFSAF 
v4.0 diary 
Inference:  Log-rank test with 
stratification of baseline (or screening, if 
applicable) platelet count (≥ 100 × 109/L 
vs 50 to < 100 × 109/L inclusive) and 
DIPSS (high vs intermediate-2 vs 
intermediate-1) at randomization 
Estimation:  Kaplan-Meier 
ITT 
P 
5.4. 
Analysis Populations 
5.4.1. 
Intent-to-Treat Population 
All participants who are randomized will constitute the ITT population.  Treatment groups for 
this population will be defined according to the treatment assignment at the time of 
randomization regardless of the actual study drug the participant might take during his/her 
participation in the study. 
The ITT population will be used for the summary of demographics, baseline characteristics, 
participant disposition, and analyses of all efficacy data. 
Participants with missing baseline assessments will be excluded from the ITT population for the 
responder analyses. 
5.4.2. 
Per-Protocol Population 
Participants in the ITT population who are considered to be sufficiently compliant with the 
Protocol will compose the PP population. 


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The following procedures will be performed to identify those participants who are to be excluded 
from the PP population: 
• Clinical review of protocol deviations, including but not limited to 
− Clinical review of concomitant medications as defined in Section 6.8 of the 
Protocol 
− Clinical review of the dose administration and drug accountability listing 
− Clinical review of inclusion/exclusion criteria 
Participants with missing baseline assessments will be excluded from the PP population for the 
responder analyses. 
The determination of participants being considered for exclusion from the PP population by the 
clinical team will be prepared and signed before unblinding and database lock. 
The PP population will be used in the supportive sensitivity analyses for efficacy endpoints. 
5.4.3. 
Safety Population 
The safety population will include all participants who received at least 1 dose of 
parsaclisib/placebo or ruxolitinib.  Treatment groups for this population will be determined 
according to the actual treatment the participant received regardless of assigned study drug 
treatment. 
All safety analyses will be conducted using the safety population. 
 
 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION 
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
6.1. 
Demographics, Baseline Characteristics, and Disease History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized for the ITT 
population by treatment group:  age, sex, race, ethnicity, weight, height, and BMI. 
6.1.2. 
Baseline Disease Characteristics 
The following baseline disease characteristics will be summarized for the ITT population by 
treatment group:  ECOG performance status, neutrophils, platelets, hemoglobin, and leukocytes 
at baseline. 
6.1.3. 
Myelofibrosis Disease History 
The following MF disease history will be summarized for the ITT population by treatment 
group:  the time since diagnosis to randomization, current MF disease, prognostic factors, risk 
level as defined by the DIPSS, whether a prior splenic irradiation was performed, if splenectomy 
was performed, and whether transfusions were received in the 12 weeks before randomization. 
Time since diagnosis will be calculated as follows: 
Time since diagnosis (years) = (date of randomization – date of diagnosis + 1) / 365.25. 
The MF screening symptom individual and total scores will be summarized for the ITT 
population by treatment group. 
6.1.4. 
Prior Therapy 
The number of prior systemic regimens for MF other than ruxolitinib will be summarized for all 
participants in the ITT population by treatment group.  The component drugs of prior systemic 
therapy regimens will be coded using the WHO Drug Dictionary.  The number and percentage of 
participants who received each drug will be summarized by WHO drug class and WHO drug PT.  
The regimen name, route, dose, frequency, start and stop dates, and reason for discontinuation 
will be listed. 
The number of participants who received prior radiation for non–MF-related cancer treatment 
will be summarized for the ITT population by treatment group.  The radiotherapy type, body site, 
start and stop dates, reason for regimen, total dose, number of fractions received, and best 
response will be listed. 
The number of participants who had prior surgery or a surgical procedure for non–MF-related 
cancer treatment will be summarized for the ITT population by treatment group.  The date and 
description of the surgery/procedure will be listed. 


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6.1.5. 
Medical History 
For participants in the ITT population, medical history will be summarized by assigned treatment 
group.  This summation will include the number and percentage of participants with significant 
medical history for each body system/organ class as documented on the eCRF. 
6.1.6. 
Ruxolitinib History 
The duration and total daily dose of ruxolitinib treatment prior to Day 1, as well as the duration 
and total daily dose of stable ruxolitinib treatment prior to Day 1 will be summarized for the ITT 
population by treatment group. 
6.2. 
Disposition of Participant 
The number and percentage of participants who were randomized, who were treated, who were 
ongoing with study treatment, who discontinued study treatment with a primary reason for 
discontinuation, who were still in the study, and who withdrew from the study with a primary 
reason for withdrawal will be summarized for the ITT population by treatment group.  The 
number of participants randomized by country and/or site will also be provided by treatment 
group. 
6.3. 
Protocol Deviations 
Protocol deviations recorded in the clinical trial management system will be summarized and 
listed. 
6.4. 
Exposure 
For participants in the safety population, exposure to parsaclisib/placebo and ruxolitinib will be 
summarized descriptively as the following: 
• Duration of treatment with ruxolitinib (days):  date of last dose of ruxolitinib – 
date of first dose of ruxolitinib + 1. 
• Duration of treatment with parsaclisib/placebo (days):  date of last dose of 
parsaclisib/placebo – date of first dose of parsaclisib/placebo + 1. 
• Average daily dose of ruxolitinib (mg/day):  total actual ruxolitinib dose taken 
(mg) / duration of treatment with ruxolitinib (days). 
• Average daily dose of parsaclisib/placebo (mg/day):  total actual 
parsaclisib/placebo dose taken (mg) / duration of treatment with parsaclisib/placebo 
(days). 
Total actual dose taken will be calculated based on the information entered on the 
Drug Exposure eCRF. 
• Total dose administered for ruxolitinib (mg):  sum of ruxolitinib administered 
(mg) during treatment.  
• Total dose administered for parsaclisib/placebo (mg):  sum of parsaclisib/placebo 
administered (mg) during treatment.  


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6.5. 
Study Drug Compliance 
For participants in the safety population, overall compliance (%) for parsaclisib/placebo will be 
calculated for all participants as follows: 
compliance (%)  = 100  [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications. 
The total actual dose taken will be calculated based on information entered on the Drug 
Accountability eCRF.  If there are dispensed drugs that have not been returned yet, the actual 
dose taken starting from the dispense date of the unreturned drugs will be imputed by the dose 
taken as reported on the Dosing eCRF. 
6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary.  
The number and percentage of participants in the ITT population for each prior and concomitant 
medication will be summarized by WHO drug class and WHO drug PT for each treatment group. 
7. 
EFFICACY 
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
7.1. 
General Considerations 
Unless otherwise stated, the strata identified in the randomization process will be used in all 
efficacy analyses.  Within a platelet category, in the event that the study fails to enroll a 
sufficient number of participants in a particular DIPSS stratification level, at the time of final 
analysis for database lock, that stratification will be combined with the nearest adjacent DIPSS 
level (eg, intermediate-1 vs intermediate-2 vs high).  For example, if either intermediate-1 or 
high-risk is too small (eg, fewer than 10 participants), it will be merged with intermediate-2.  If 
intermediate-2 has too few participants (eg, fewer than 10 participants), then it will be merged 
with the smaller of the 2 adjacent strata.  At the time of interim analyses, all DIPSS stratification 
levels will be combined if too few participants (eg, fewer than 10 participants) are enrolled in 
1 DIPSS stratification level.  
The ITT population will be used for all efficacy analyses unless otherwise stated. 


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7.2. 
Efficacy Hypotheses 
The primary hypothesis is that the percentage of participants achieving ≥ 25% reduction in 
spleen volume from baseline to Week 24 in the parsaclisib plus ruxolitinib treatment group will 
not be the same as the percentage of participants achieving ≥ 25% reduction in spleen volume 
from baseline to Week 24 in the placebo plus ruxolitinib treatment group as measured by the 
odds ratio.  The hypotheses of the study are as follows: 
• H0 (null hypothesis):  θPAR = θPLB 
• HA (alternative hypothesis):  θPAR ≠ θPLB 
7.3. 
Analysis of the Primary Efficacy Endpoint 
7.3.1. 
Primary Efficacy Analysis 
The primary endpoint of this study is the proportion of participants with ≥ 25% spleen volume 
reduction from baseline to Week 24 as measured by MRI (or CT scan in applicable participants).  
The primary endpoint will be analyzed by the CMH test stratified by DIPSS risk category 
(intermediate-1 vs intermediate-2 vs high) and baseline (or screening, if applicable) platelet 
count (≥ 100 × 109/L vs 50 to < 100 × 109/L inclusive). 
The baseline spleen volume will be measured during the baseline visit (Days −7 to 1); the last 
value will be used if there are multiple values measured during the baseline visit. 
The Week 24 spleen volume will be measured during the Week 24 visit; the last value will be 
used if there are multiple values measured during the Week 24 visit.  Missing values will not be 
imputed. 
The percentage change from baseline to Week 24 will be calculated using the following formula: 
% change = 100 × [Week 24 spleen volume – baseline spleen volume] / baseline spleen 
volume. 
A participant will be considered as having achieved ≥ 25% reduction of spleen volume from 
baseline to Week 24 if the participant had both baseline and Week 24 spleen volume 
measurements, the participant did not make an early crossover to receive parsaclisib plus 
ruxolitinib prior to the Week 24 visit, and the percentage change from baseline reduction was 
≥ 25%. 
A participant who has a missing Week 24 spleen volume, discontinues treatment before 
Week 24, or makes an early crossover to receive parsaclisib plus ruxolitinib prior to the Week 24 
visit will be considered as a nonresponder for the endpoint of ≥ 25% reduction of spleen volume. 
A participant who has a missing baseline assessment will be considered as nonevaluable.  
At the time of interim analysis, a participant who is still on treatment, but has not followed up for 
the timepoint assessment and has no timepoint assessment, will also be considered as 
nonevaluable. 


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7.3.2. 
Subgroup Analyses for Primary Endpoint 
Subgroups will be formed based on the following participant characteristics and baseline 
variables for those participants whose data are available.  If the number of participants is too 
small (eg, 10 participants) in a subgroup, then the analysis will not be conducted in that 
subgroup. 
• Baseline platelet count:  ≥ 100 × 109/L versus 50 to < 100 × 109/L inclusive.  Note 
that if a participant's platelet count is < 50 × 109/L at baseline, the platelet count at 
screening will be used for stratification/randomization. 
• DIPSS risk category:  high versus intermediate-2 versus intermediate-1 
• Sex:  male versus female 
• Age group:  ≤ 65 years or > 65 years 
• MF type:  PMF, PPV-MF, or PET-MF 
• Ruxolitinib average total daily dose during the 8 weeks before randomization:  
< 20 mg, 20 to 30 mg inclusive, or > 30 mg 
• Overall duration of treatment with ruxolitinib before randomization:  ≤ median or 
> median 
• Presence/absence of V617F mutation at baseline 
• Presence/absence of HMR mutations at baseline 
• Baseline spleen volume group:  ≤ median or > median 
• Baseline spleen palpation size group:  ≤ 10 cm or > 10 cm 
• Race:  White/Caucasian, Black/African-American, Asian, American-Indian/Alaska 
Native, Native Hawaiian/Pacific Islander, or other 
• Ethnicity:  Hispanic/Latino, not Hispanic/Latino, or other 
7.3.3. 
Sensitivity and Supportive Analyses for Primary Endpoint 
The primary endpoint will be analyzed using the PP population as a supportive analysis to the 
ITT population. 
The participants who make an early crossover and later turn into responders will be considered 
as responders and analyzed in the placebo group as a supportive analysis. 
In the event that 2 DIPSS stratification levels are combined, a sensitivity analysis for the primary 
endpoint without combining levels will be conducted. 


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7.4. 
Analysis of the Secondary Efficacy Parameters 
7.4.1. 
Spleen Volume Reduction 
7.4.1.1. 
Time to the First ≥ 25% Reduction in Spleen Volume 
The time to the first ≥ 25% reduction in spleen volume is defined as the time from randomization 
to the first time participants have a ≥ 25% reduction in spleen volume.  Participants with baseline 
and postbaseline MRI or CT scan who do not have a ≥ 25% reduction in spleen volume at the 
time of analysis will be censored at the time of the last MRI or CT scan.  If the participants have 
no baseline or postbaseline MRI or CT scan, they will be censored at the date of randomization. 
The stratified log-rank test will be used to compare the time to the first ≥ 25% reduction in 
spleen volume between the 2 treatment groups in the ITT population at a 1-sided 2.5% 
significance level, stratified for baseline (or screening, if applicable) platelet count and DIPSS 
category.  The strata identified in the randomization process will be used for the analysis. 
Kaplan-Meier curves for the time to the first ≥ 25% reduction in spleen volume will be presented 
by treatment group.  The KM estimate of median time to the first ≥ 25% reduction in spleen 
volume will be presented with its 95% CI.  The 95% CI will be calculated using the 
generalization of method of Brookmeyer and Crowley (1982) with log-log transformation (Klein 
and Moeschberger 1997). 
7.4.1.2. 
Duration of Maintenance of a ≥ 25% Reduction in Spleen Volume 
The duration of a ≥ 25% reduction from baseline in spleen volume is defined as the interval 
between the first spleen volume measurement that is ≥ 25% reduction from baseline and the date 
of the first measurement that is no longer a ≥ 25% reduction from baseline.  If the end date is not 
observed before the database cutoff, the duration will be censored at the last assessment. 
The endpoint will be derived for participants who were randomized and who had at least 
1 measurement of ≥ 25% reduction from baseline. 
Kaplan-Meier estimates of median duration with 95% CIs will be provided. 
The ITT population with spleen volume response will be used. 
A supportive analysis for the duration of a ≥ 25% reduction from baseline in spleen volume 
defined as the interval between the first spleen volume measurement that is ≥ 25% reduction 
from baseline and the date of the first measurement that is no longer a ≥ 25% reduction from 
baseline that is also a > 25% increase from nadir will be provided. 
7.4.2. 
Myelofibrosis Symptom Assessment Form Total Symptom Score v4.0 
The MFSAF v4.0 is composed of 7 individual symptom scores (fatigue, night sweats, itchiness, 
abdominal discomfort, pain under left ribs, early satiety, and bone pain), each collected daily 
with a 0- to 10-point scale. 
The daily MFSAF TSS is the sum of the 7 individual symptom scores collected on the same day.  
The MFSAF TSS will be missing if there are any missing individual scores.  Observations with 
missing dates will be excluded from the analysis. 


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The baseline total score is defined as the average of daily total scores from the last 7 days before 
the first dose of parsaclisib/placebo; the baseline total score will be missing if there are 
≥ 4 missing out of the 7 daily total scores. 
The Week 12 total score will be the average of daily total scores from the first 7 consecutive 
days starting on Day 78; the Week 12 total score will be missing if there are ≥ 4 missing out of 
the 7 daily total scores. 
The Week 24 total score will be the average of daily total scores from the 7 consecutive days 
before the Week 24 visit; the Week 24 total score will be missing if there are ≥ 4 missing out of 
the 7 daily total scores. 
The percentage change from baseline to Week 12/Week 24 will be calculated using the following 
formula: 
% change = 100 × [Week 12/Week 24 MFSAF TSS – baseline MFSAF TSS] / baseline 
MFSAF TSS. 
7.4.2.1. 
Windowing of Myelofibrosis Symptom Assessment Form v4.0 Total Symptom 
Score 
7.4.2.1.1. Myelofibrosis Symptom Assessment Form v4.0 Total Symptom Score for 
Non–Time-to-Event Endpoints 
The MFSAF v4.0 TSS for baseline, Week 12, and Week 24 will be determined by averaging the 
daily MFSAF v4.0 TSS for the days between the start and end of windows as described in 
Table 3.  By-question summaries for the 7 individual symptom scores that compose the MFSAF 
TSS at baseline, Week 12, and Week 24 will use the same windowing algorithm as used for the 
daily TSS. 
The TSS and the 7 individual scores at Weeks 4, 8, 16, and 20 will be derived in a similar 
fashion using the first nonmissing daily TSS available between 
Day (7 × Week X – 6) and Day (7 × Week X) 
as the start of the window. 
Table 3: 
Window for Deriving Myelofibrosis Symptom Assessment Form v4.0 Total 
Symptom Score for Baseline, Week 12, and Week 24 
Period 
Start of Window 
End of Window 
Missing 
Baseline 
7 days before end of 
window 
Last day that a daily TSS was 
collected between Day −7 and 
Day −1 (inclusive) 
4 or more missing of the 
7 daily TSSs in the 
window 
Week 12 
First day a daily TSS was 
collected between Day 78 
and Day 84 (inclusive) 
7 days after start of window 
4 or more missing of the 
7 daily TSSs in the 
window 
Week 24 
7 days before end of 
window 
The day before the Week 24 
visit 
4 or more missing of the 
7 daily TSSs in the 
window 


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7.4.2.1.2. Myelofibrosis Symptom Assessment Form v4.0 Total Symptom Score for 
Time-To-Event Endpoints 
The MFSAF v4.0 TSS for baseline will be derived the same way as in Section 7.4.2.1.1.  The 
daily postbaseline TSS will be calculated from Day 7 to the day before the Week 24 visit.  The 
Day X TSS is the average TSS between Day X − 6 and Day X.  For example, the TSS on Day 7 
is the average of the TSS from Day 1 to Day 7.  The missing individual score and the missing 
daily TSS will follow the rule defined in Section 7.4.2. 
7.4.2.2. 
Proportion of Participants With a ≥ 50% Reduction in Myelofibrosis Symptom 
Assessment Form v4.0 Total Symptom Score 
The difference between the parsaclisib plus ruxolitinib group and the placebo plus ruxolitinib 
group in the proportion of participants who have a ≥ 50% reduction in TSS from baseline to 
Week 24 evaluated by MFSAF v4.0 will be assessed using the CMH test stratified by baseline 
(or screening, if applicable) platelet count and DIPSS category at randomization for the ITT 
population as primary analysis and the PP population as sensitivity analysis.  In the case that 
there is an insufficient number of participants enrolled in any DIPSS level within a platelet 
category, the collapsing rule specified in Section 7.1 will be applied.  Missing values will not be 
imputed. 
The percentage change from baseline to Week 24 will be calculated using the following formula: 
% change = 100 × (Week 24 total score – baseline total score) / baseline total score. 
A participant will be considered as having achieved ≥ 50% reduction of the TSS from baseline to 
Week 24 if the participant had both baseline and Week 24 TSSs, the participant did not make an 
early crossover to receive parsaclisib plus ruxolitinib prior to the Week 24 visit, and the 
percentage change from baseline was not missing and was less than or equal to −50%. 
A participant who has a missing Week 24 TSS, discontinues treatment before Week 24, is 
unblinded prior to Week 24 for early crossover to parsaclisib plus ruxolitinib, or has a baseline 
value of 0 will be considered as having not achieved the ≥ 50% reduction. 
A participant who has a missing TSS baseline assessment will be considered as nonevaluable.  
At the time of interim analysis, a participant who is still on treatment but has no timepoint 
assessment for TSS will also be considered as nonevaluable. 
7.4.2.3. 
Mean Change and Percentage Change in Myelofibrosis Symptom Assessment 
Form v4.0 Total Symptom Score 
The mean change and percentage change from baseline to Week X will be calculated using the 
following formula: 
% change = 100 × (Week X total score – baseline total score) / baseline total score. 
The mean change and percentage change in TSS, the 7 individual scores, and the total score of 
the 3 spleen-related symptoms (including abdominal discomfort, pain under left ribs, and early 
satiety) from baseline to Week X will be summarized descriptively by treatment group and every 
4 weeks using the ITT population.  Missing values will not be imputed. 
A plot of percentage change from baseline in MFSAF TSS at each visit will be provided. 


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7.4.2.4. 
Time to the First ≥ 50% Reduction in Myelofibrosis Symptom Assessment Form 
v4.0 Total Symptom Score 
The time to the first ≥ 50% reduction in TSS is defined as the time from randomization to the 
first time participants have a ≥ 50% reduction in TSS.  The daily TSS will be calculated 
according to the algorithm defined in Section 7.4.2.1.2.  Participants with valid, calculated 
baseline TSS and at least 1 postbaseline TSS who do not have ≥ 50% reduction in TSS at the 
time of analysis will be censored at the time of the last valid calculated TSS.  If the participants 
have no valid, calculated baseline or postbaseline TSS, they will be censored at the date of 
randomization. 
The stratified log-rank test will be used to compare time to the first ≥ 50% reduction in TSS 
between the 2 treatment groups in the ITT population at a 1-sided 2.5% significance level, 
stratified for baseline (or screening, if applicable) platelet count and DIPSS category.  The strata 
identified in the randomization process will be used for the analysis. 
Kaplan-Meier curves for the time to the first ≥ 50% reduction in TSS will be presented by 
treatment group.  The KM estimate of median time to the first ≥ 50% reduction in TSS will be 
presented with its 95% CI.  The 95% CI will be calculated using the generalization of method of 
Brookmeyer and Crowley (1982) with log-log transformation (Klein and Moeschberger 1997). 
7.4.3. 
Overall Survival 
Overall survival is defined as the interval between the randomization date and the date of death 
due to any cause.  Date of death will be determined using the Death Report, the Survival 
Follow-Up, and the Participant Status eCRFs.  Participants who are lost-to-follow-up or still 
alive at the time of analysis will be right-censored at the earlier of the date the participant was 
last known alive and the clinical data cutoff date for the analysis.  The last known alive date is 
defined as the later of the last study visit and the date the participant was last known alive from 
the Survival Follow-Up and Participant Status eCRFs.  Partial death dates will be handled using 
the rules described in Section 4.1.5. 
The treatment difference in survival for parsaclisib plus ruxolitinib and placebo plus ruxolitinib 
will be assessed by a log-rank test on the ITT population and PP population stratified for baseline 
(or screening, if applicable) platelet count and DIPSS category.  The strata identified in the 
randomization process will be used for the analysis.  In the event that stratification level 
combinations have limited numbers of participants, 2 or more of the strata may be combined to 
better facilitate estimation of the overall HR. 
The HR estimate and CIs will be estimated based on a stratified Cox proportional hazards model 
using the same stratification factors as for the log-rank test with Efron's method (1977) 
accounting for ties in death days. 
Kaplan-Meier time-to-event curves will be presented by treatment group.  Median survival will 
be estimated using the KM method.  Confidence intervals for median survival time will be 
calculated using the generalization of Brookmeyer and Crowley's method (1982) with log-log 
transformation (Klein and Moeschberger 1997). 
The ITT population will be used for the analysis of OS. 


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A sensitivity analysis of OS using PP population will be provided.  The sensitivity analysis of 
OS will be analyzed using the rank-preserving structural failure time method to adjust the bias in 
OS due to crossover. 


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9. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
9.1. 
General Considerations 
The safety analyses, including frequency and severity of AEs and SAEs and mean change and 
percentage change in vital signs, ECGs, and lab parameters, will be summarized by treatment 
group in the safety population. 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique PTs reported on relatively 
few participants. 
Safety analyses for treatment comparisons will exclude data collected after treatment crossover.  
Data post-treatment crossover will be analyzed separately and descriptively without any 
treatment comparisons.  Day 1 of crossover will be used for the crossover participants in the 
crossover phase. 
9.2. 
Adverse Events 
9.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first dose of study drug until 30 to 35 days after the last dose of study drug.  Analysis of AEs (as 
discussed below) will be limited to TEAEs, but data listings will include all AEs regardless of 
their timing in relation to study drug administration.  For purposes of analysis, all AEs will be 
considered TEAEs unless the AE can unequivocally be defined as not treatment-emergent. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE v5.  The CTCAE reporting guidelines and grading details are available on 
the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs.  If the investigator does not specify the relationship of the AE to study 


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drug, the AE will be considered to be treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  In addition, serious TEAEs will also be tabulated. 
To summarize TEAEs using the life-table method, the time to first occurrence of a TEAE is 
defined as the interval between the date of first dose of study drug and the date of the first 
occurrence of a TEAE.  Participants who have not experienced a TEAE at the time of analysis 
will be right-censored at the earlier of 30 to 35 days after the last dose of study drug and the date 
of last study visit through the end of safety follow-up.  The effective sample size is defined as the 
number of participants at the beginning of interval minus half the participants censored in the 
interval.  The conditional proportion is calculated as the number of first events divided by the 
effective sample size in the interval.  If participants have missing or partial last dose dates of 
study drug, the partial or missing dates will be handled using the rules explained in Section 4.1.5.  
Any missing onset date of a TEAE will be handled according the following rules: 
• If completely missing, then Day 1 will be used. 
• If only the day is missing, then the first day of the month or Day 1, whichever is later, 
will be used. 
• If both the month and day are missing, then 01 JAN of the year or Day 1, whichever is 
later, will be used. 
9.2.2. 
Adverse Events of Special Interest 
The following TEAEs, regardless of seriousness, will be tabulated by MedDRA PT for the safety 
population for each treatment group. 
• Colitis 
• Diarrhea of Grade 2 or higher 
• Rash of Grade 2 or higher 
• Pneumonitis 
• Dermatitis exfoliative 
• Intestinal perforation 
• Cytomegalovirus infection 
• Herpes simplex infection, including oral herpes and genital herpes as AE terms 
• Herpes (varicella) zoster virus infection, including herpes zoster, shingles, and VZV 
as AE terms 
• Pneumocystis jirovecii infection 
• ALT increased ≥ 5 × ULN 
• AST increased ≥ 5 × ULN 
Adverse events of special interest should be captured in the eCRF. 


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The time to onset of the first occurrence of each AESI will be analyzed using the KM method.  
Median time to onset of the first occurrence of each AESI will be estimated by the KM method.  
Participants with no AESI at the time of analysis will be censored at the time of analysis. 
The longest duration of AESI will be analyzed using the KM method for participants in the 
safety population with at least 1 occurrence of the AESI.  The median longest duration of each 
AESI will be estimated by the KM method.  Participants whose AESI was not resolved at the 
time of analysis will be censored at the time of the analysis.  Participants with nonserious TEAEs 
not resolved by 35 days after the end-of-treatment visit will be censored at 35 days after the 
end-of-treatment visit. 
Two consecutive AESIs with different toxicity grades but with the start date of the later AESI 
overlapped with the end date of the previous AESI are considered as 1 AESI in calculating the 
duration of AESI. 
9.2.3. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include the following: 
• Number (%) of participants who had any TEAEs 
• Number (%) of participants who had any serious TEAEs 
• Number (%) of participants who had any Grade 3 or higher TEAEs 
• Number (%) of participants who had any TEAEs related to parsaclisib 
• Number (%) of participants who had any TEAEs related to ruxolitinib 
• Number (%) of participants who had any TEAEs related to parsaclisib or ruxolitinib 
• Number (%) of participants who temporarily interrupted parsaclisib because of 
TEAEs 
• Number (%) of participants who temporarily interrupted ruxolitinib because of 
TEAEs 
• Number (%) of participants who permanently discontinued parsaclisib because of 
TEAEs 
• Number (%) of participants who permanently discontinued ruxolitinib because of 
TEAEs 
• Number (%) of participants who had parsaclisib dose reductions because of TEAEs 
• Number (%) of participants who had ruxolitinib dose reductions because of TEAEs 
• Number (%) of participants who had any fatal TEAEs 


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The following summaries will be produced by MedDRA term (if 10 or fewer participants appear 
in a table, a listing may be appropriate): 
• Summary of TEAEs by MedDRA SOC and PT 
• Summary of TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of TEAEs by MedDRA SOC, PT, and CTCAE grade category 
• Summary of Grade 3 or higher TEAEs by MedDRA SOC and PT 
• Summary of Grade 3 or higher TEAEs by MedDRA PT in decreasing order of 
frequency 
• Summary of serious TEAEs by MedDRA SOC and PT 
• Summary of serious TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of parsaclisib treatment-related TEAEs by MedDRA SOC and PT 
• Summary of ruxolitinib treatment-related TEAEs by MedDRA SOC and PT 
• Summary of parsaclisib/ruxolitinib treatment-related TEAEs by MedDRA SOC and 
PT 
• Summary of parsaclisib treatment-related TEAEs by MedDRA PT in decreasing 
order of frequency 
• Summary of ruxolitinib treatment-related TEAEs by MedDRA PT in decreasing order 
of frequency 
• Summary of parsaclisib treatment-related TEAEs by MedDRA SOC, PT, and 
CTCAE grade category 
• Summary of ruxolitinib treatment-related TEAEs by MedDRA SOC, PT, and CTCAE 
grade category 
• Summary of Grade 3 or higher parsaclisib treatment-related TEAEs by MedDRA 
SOC and PT 
• Summary of Grade 3 or higher ruxolitinib treatment-related TEAEs by MedDRA 
SOC and PT 
• Summary of parsaclisib treatment-related serious TEAEs by MedDRA SOC and PT 
• Summary of ruxolitinib treatment-related serious TEAEs by MedDRA SOC and PT 
• Summary of TEAEs with a fatal outcome by MedDRA SOC and PT 
• Summary of TEAEs leading to parsaclisib dose reduction by MedDRA SOC and PT 
• Summary of TEAEs leading to ruxolitinib dose reduction by MedDRA SOC and PT 
• Summary of TEAEs leading to parsaclisib dose interruption by MedDRA SOC and 
PT 
• Summary of TEAEs leading to ruxolitinib dose interruption by MedDRA SOC and 
PT 


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• Summary of TEAEs leading to discontinuation of parsaclisib by MedDRA SOC and 
PT 
• Summary of TEAEs leading to discontinuation of ruxolitinib by MedDRA SOC and 
PT 
• Summary of TEAEs by MedDRA PT:  life-table method 
• Summary of TEAEs by MedDRA SOC and PT:  life-table method 
• Summary of treatment-emergent AESIs by MedDRA PT 
• Median time to the first onset of treatment-emergent AESIs by MedDRA PT 
• Median longest duration of treatment-emergent AESIs by MedDRA PT 
9.3. 
Clinical Laboratory Tests 
9.3.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
Baseline will be determined according to Section 4.1.4.  If there are multiple values that meet the 
criteria for baseline, the value from the central laboratory has priority over the value from the 
local laboratory.  Thereafter, additional rules may be provided after consultation with the 
medical monitor to delineate which value will be defined as baseline. 
Laboratory test values will be assessed for severity based on the numerical component of 
CTCAE v5. 
9.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  Any laboratory test results and associated normal ranges from local laboratories will be 
converted to SI units. 
When there are multiple nonmissing laboratory values for a participant's particular test at a 
scheduled visit, central laboratory values have higher priority over local laboratory values.  If a 
tie still exists, the laboratory value with the smallest laboratory sequence number will be used in 
by-visit summaries. 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary.  In addition, box-and-whisker plots will be provided for 
HGB, platelet counts, leukocytes, and neutrophils. 
A table for the number of participants with abnormal ALT, AST, bilirubin, and creatinine will be 
tabulated by treatment group. 
For test results that will be summarized with available normal ranges, the number and percentage 
of participants with laboratory values being low (but never high), normal, high (but never low), 
and both low and high will be calculated for each test.  This shift summary will be produced for 
each test for the safety population.  The denominator for the percentage calculation will use the 
number of participants in the baseline category (ie, low, high, normal, missing) as the 
denominator for the percentage in each of the categories during the study. 


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Severity grades will be assigned to laboratory test values based on the numerical component of 
CTCAE v5.  Shift tables will be presented showing change in CTCAE grade from baseline to 
worst grade postbaseline.  Separate summaries for abnormally high and abnormally low 
laboratory values will be provided when the laboratory parameter has both high and low grading 
criteria.  The denominator for the percentage calculation will be the number of participants in the 
baseline category.  The number of participants who experienced worsening of laboratory 
abnormalities will be summarized by maximum severity. 
In cases where differentials of hematology parameters are obtained without corresponding 
absolute count data, efforts will be made to investigate if the conversion to an absolute value will 
lead to additional abnormalities.  This will be discussed with the clinical team regarding 
appropriate documentation and action. 
9.3.3. 
Potential Hy's Law Events 
Participants with elevated ALT or AST > 3 × ULN range and alkaline phosphatase < 2 × ULN 
range accompanied by total bilirubin > 2 × ULN range at the same visit will be listed by 
treatment group. 
9.4. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, temperature, respiratory rate, 
and weight will be summarized descriptively. 
Normal ranges for vital signs are defined in Table 5.  For participants exhibiting vital sign 
abnormalities, the abnormal values will be listed along with their assigned treatment group.  
Alert vital signs are defined as an absolute value outside the defined normal range and 
percentage change greater than 25%.  Note that the definition of alert vital signs does not apply 
for body temperature and weight.  The abnormal values for participants exhibiting alert vital sign 
abnormalities will be listed. 
Table 5: 
Normal Ranges for Vital Sign Values 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
≤ 155 mmHg 
≥ 85 mmHg 
Diastolic blood pressure 
≤ 100 mmHg 
≥ 40 mmHg 
Pulse 
≤ 100 bpm 
≥ 45 bpm 
Temperature 
≤ 38°C 
≥ 35.5°C 
Respiratory rate 
≤ 24 breaths/min 
≥ 8 breaths/min 
9.5. 
Electrocardiograms 
Twelve-lead ECGs including PR, QT, QRS, RR, and QTc intervals will be obtained for each 
participant during the study.  Values at each scheduled visit, change, and percentage change from 
baseline will be summarized for each ECG parameter.  Baseline will be determined as the 
average of all nonmissing values before the first administration of parsaclisib, placebo, or 
ruxolitinib. 


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Normal ranges for ECG values are defined in Table 6.  Electrocardiogram values will also be 
considered abnormal if the absolute percentage change from baseline is more than 25% (30% for 
QRS interval).  Participants exhibiting ECG abnormalities will be listed with study visit and 
assigned treatment group.  Abnormal values for participants with alert ECG values, defined as 
both the absolute value and the percentage change from baseline being outside normal ranges, 
will be identified and listed.  Outliers of QT and QTc values, defined as absolute values 
> 500 milliseconds, ≥ 480 milliseconds, and > 450 milliseconds for each parameter or change 
from baseline > 30 milliseconds and > 60 milliseconds for each parameter, will be summarized. 
Table 6: 
Normal Ranges for Electrocardiogram Intervals 
Parameter 
High Threshold 
Low Threshold 
PR 
≤ 220 ms 
≥ 75 ms 
QT 
≤ 500 ms 
≥ 300 ms 
QRS 
≤ 120 ms 
≥ 50 ms 
QTc 
≤ 450 ms 
≥ 295 ms 
RR 
≤ 1330 ms 
≥ 600 ms 


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10. 
INTERIM ANALYSES 
10.1. 
Overview of Interim Analyses 
There will be 2 planned, nonbinding, interim analyses conducted for futility for this study, based 
on the first 30% of participants enrolled in the study.  The first interim analysis will be conducted 
when the first 30% of the planned randomized participants (approximate 32 in each treatment 
group) reach Week 12 assessments of spleen volume and MFSAF TSS or discontinue from 
treatment.  Based on the results of this interim analysis, the DMC may recommend to terminate 
the study, continue the study with no changes to enrollment, or continue the study with no further 
enrollment permitted until review of the second interim analysis. 
The second interim analysis will be initiated when the first 30% of the planned randomized 
participants reach their Week 24 assessments of spleen volume and MFSAF TSS or have 
discontinued from treatment.  The DMC may recommend to either terminate the study for futility 
or continue the study, based on the results of this analysis. 
At the interim analyses for Week 12 and Week 24 data, MFSAF TSS will be tested for futility 
only if spleen volume does not cross the futility boundary.   
10.2. 
Data Cutoff for Interim Analysis 
For analyses of spleen volume reduction and MFSAF TSS, a cutoff for clinical data used in the 
first interim analysis will be based on the date when the first 30% of the planned randomized 
participants (approximate 32 in each treatment group) reach Week 12 assessments of spleen 
volume and MFSAF TSS or discontinue from treatment.  At the second interim analysis, the 
clinical cutoff date will be the date when the first 30% of the planned randomized participants 
reach Week 24 assessments of spleen volume and MFSAF TSS or discontinue from treatment.  
10.3. 
Derivations and Calculations for Interim Analyses 
For the second analysis of futility, an HSD spending function (Hwang et al 1990) with γ = 2 and 
an HSD spending function with γ = 1 will be used to allocate beta spending for spleen volume 
and MFSAF TSS, respectively.  Figure 2 shows that the beta spending functions allocate 
minimal beta for the second interim analysis.   
The first analysis of futility will use the same futility boundary as the second futility analysis, but 
no beta will be spent. 


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Figure 2: 
Beta Spending 
 
10.4. 
Guidelines for Decision Rules 
Table 7 and Table 8 provide the projected stopping rules if the interim analyses are conducted at 
the projected number of participants. 
Table 7: 
Interim Analysis for Spleen Volume With HSD(2) 
Number of Participants 
Second Interim Analysis 
Final Analysis 
64 
212 
Decision Outcome 
Stop for Futility 
Continue to Test 
MFSAF TSS 
Do Not Reject 
Null Hypothesis 
Reject Null 
Hypothesis 
Z-statistic 
≤ 0.16 
> 0.16 
≤ 1.96 
> 1.96 
One-sided p-value 
≥ 0.436 
< 0.436 
≥ 0.025 
< 0.025 
Parsaclisib + ruxolitinib 
response ratea 
≤ 5.9% 
> 5.9% 
≤ 12.7% 
> 12.7% 
a Assumes spleen volume response rate is 5% in ruxolitinib + placebo. 


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Table 8: 
Interim Analysis for MFSAF TSS With HSD(1) 
Number of Participants 
Second Interim Analysis 
Final Analysis 
64 
212 
Decision Outcome 
Stop for Futility 
Continue 
Do Not Reject 
Null Hypothesis 
Reject Null 
Hypothesis 
Z-statistic
≤ 0.22 
> 0.22
≤ 1.96 
> 1.96
One-sided p-value 
≥ 0.413 
< 0.413 
≥ 0.025 
< 0.025 
Parsaclisib + ruxolitinib 
odds ratio (RR for 50 × to 
< 100 × 109/L, ≥ 100 × 
109/L PLT)a 
≤ 1.08 (11%, 16%) 
> 1.08 (11%, 16%)
≤ 2.37 (21%, 29%) 
> 2.37 (21%, 29%)
a Assumes TSS response rate for 50 × to < 100 × 109/L inclusive and ≥ 100 × 109/L platelet is 10% and 15% in 
ruxolitinib + placebo group. 
Preplanned analyses of safety and efficacy will be provided to an independent DMC as specified 
in the DMC charter.  The process by which the DMC will review data and make 
recommendations and decisions will be documented in the DMC charter. 
11.
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN
All versions of the SAP are listed in Table 9. 
Table 9: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
08 JAN 2021 
Amendment 1 
25 APR 2022 
11.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
11.2. 
Changes to the Statistical Analysis Plan 
11.2.1. 
Amendment 1 
•
Section 5.4.1 was updated to clarify that participants with missing baseline
assessments will be excluded from the ITT population for the responder analyses.
•
In Section 7.1, the combination of DIPSS stratification levels at the time of interim
analyses were added.
•
In Section 7.3.1 and Section 7.4.2.2, the nonevaluable definitions for the primary
endpoint analysis of spleen volume and secondary endpoint analysis of MFSAF TSS,
respectively, were added.
•
In Section 7.4.2, the window for deriving MFSAF TSS at Week 24 was modified to
capture the assessments from the last week before participants return the device.


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•
Incorporation of administrative changes.  Other minor, administrative changes and
changes according to the Protocol Amendment 1 were incorporated throughout the
SAP.


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12. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Efron B. The efficiency of Cox's likelihood function for censored data. J Am Stat Assoc 
1977;72:557-565. 
 
 
. 
 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of Type I error 
probability spending functions. Stat Med 1990;9:1439-1445. 
Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated data. New 
York: Springer-Verlag. 1997. 
 
 
 
 
 
 
 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the CSR.  Shells are 
provided in a separate document for tables that are not in the Standard Safety Tables v1.9. 
The lists of tables, figures, and listings are to be used as guidelines.  Modifications of the lists 
that do not otherwise affect the nature of the analysis will not warrant an amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Standard 
Baseline and Demographic Characteristics 
1.1  Disposition 
1.1.1 
Analysis Populations 
ITT 
X 
1.1.2 
Summary of Participant Disposition 
ITT 
X 
1.1.3 
Summary of Number of Participants Enrolled by Country and Site 
ITT 
X 
1.1.4 
Summary of Protocol Deviations 
ITT 
X 
1.2  Demography and Baseline Characteristics 
1.2.1 
Summary of Demographics and Baseline Characteristics 
ITT 
X 
1.3  Baseline Disease Characteristics 
1.3.1 
Summary of Baseline Disease Characteristics 
ITT 
 
1.3.2 
Summary of Myelofibrosis History 
ITT 
 
1.3.3 
Summary of Myelofibrosis Screening Symptom Score 
ITT 
 
1.3.4 
Summary of Prior Systemic Cancer Therapy by WHO Drug Class and 
Preferred Term 
ITT 
X 
1.4  Prior Medication and Concomitant Medication 
1.4.1 
Summary of Prior Medications 
ITT 
X 
1.4.2 
Summary of Concomitant Medications 
ITT 
X 
1.4.3 
Summary of Prior Ruxolitinib History 
ITT 
 
1.5+  Others 
1.5.1 
Summary of General Medical History 
ITT 
X 
Efficacy 
2.1  Primary Efficacy 
2.1.1.1 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 
ITT 
 
2.1.1.2 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 
PP 
 
2.1.2.1 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by Sex 
ITT 
 
2.1.2.2 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Age Group 
ITT 
 
2.1.2.3 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by MF 
Type 
ITT 
 
2.1.2.4 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Presence/Absence of V617F Mutation at Baseline 
ITT 
 


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Table No. 
Title 
Population 
Standard 
2.1.2.5 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Presence/Absence of HMR Mutations at Baseline 
ITT 
 
2.1.2.6 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Baseline Spleen Volume Group 
ITT 
 
2.1.2.7 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Baseline Spleen Palpation Size Group 
ITT 
 
2.1.2.8 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Race 
ITT 
 
2.1.2.9 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Ethnicity 
ITT 
 
2.1.2.10 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Platelet Count 
ITT 
 
2.1.2.11 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
DIPSS 
ITT 
 
2.1.2.12 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Ruxolitinib Average Total Daily Dose 
ITT 
 
2.1.2.13 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 25% Reduction in Spleen Volume at Week 12 and Week 24 – by 
Overall Duration of Treatment With Ruxolitinib Before 
Randomization   
ITT 
 
2.2  Secondary Efficacy 
2.2.1.1 
Time to the First ≥ 25% Reduction in Spleen Volume 
ITT 
 
2.2.1.2 
Duration of Maintenance of a ≥ 25% Reduction in Spleen Volume 
ITT With 
Spleen 
Volume 
Response 
 
2.2.1.3 
Time From the First ≥ 25% Reduction in Spleen Volume to Loss of 
≥ 25% Reduction in Spleen Volume With a > 25% Spleen Volume 
Increase From Nadir  
ITT With 
Spleen 
Volume 
Response 
 
2.2.1.4 
Summary of Spleen Volume by Visit 
ITT 
 
2.2.2.1 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 50% Reduction in MFSAF v4.0 Total Symptom Score at Week 12 
and Week 24 
ITT  
 
2.2.2.2 
Cochran-Mantel-Haenszel Test of Proportion of Participants With 
≥ 50% Reduction in MFSAF v4.0 Total Symptom Score at Week 12 
and Week 24 
PP 
 
2.2.2.3 
Time to the First ≥ 50% Reduction in MFSAF v4.0 Total Symptom 
Score 
ITT 
 
2.2.2.4 
Summary of MFSAF v4.0 Total Symptom Score Using 7-Day Window 
by Visit 
ITT 
 


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Table No. 
Title 
Population 
Standard 
2.2.2.5.1 
Summary of MFSAF v4.0 Individual Symptom Scores by Visit – 
Fatigue 
ITT 
 
2.2.2.5.2 
Summary of MFSAF v4.0 Individual Symptom Scores by Visit – 
Night Sweats 
ITT 
 
2.2.2.5.3 
Summary of MFSAF v4.0 Individual Symptom Scores by Visit – 
Itchiness 
ITT 
 
2.2.2.5.4 
Summary of MFSAF v4.0 Individual Symptom Scores by Visit – 
Abdominal Discomfort 
ITT 
 
2.2.2.5.5 
Summary of MFSAF v4.0 Individual Symptom Scores by Visit – Pain 
Under Left Ribs 
ITT 
 
2.2.2.5.6 
Summary of MFSAF v4.0 Individual Symptom Scores by Visit – Early 
Satiety 
ITT 
 
2.2.2.5.7 
Summary of MFSAF v4.0 Individual Symptom Scores by Visit – Bone 
Pain 
ITT 
 
2.2.2.6 
Summary of MFSAF v4.0 Spleen-Related Symptom Scores by Visit 
ITT 
 
2.2.2.7.1 
Overall Survival  
ITT 
 
2.2.2.7.2 
Overall Survival  
PP 
 
2.2.2.7.3 
Overall Survival Adjusted by Rank-Preserving Structural Failure Time 
ITT 
 


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Table No. 
Title 
Population 
Standard 
Safety 
3.1  Dose Exposure 
3.1.1 
Summary of Exposure and Duration of Exposure to 
Parsaclisib/Placebo 
Safety 
X 
3.1.2 
Summary of Exposure and Duration of Exposure to Ruxolitinib 
Safety 
X 
3.1.3 
Summary of Parsaclisib Compliance 
Safety 
X 
3.2  Adverse Events 
3.2.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
X 
3.2.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety 
X 
3.2.3 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.4 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term, and CTCAE Grade Category 
Safety 
X 
3.2.5 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.6 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
by MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.7 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.8 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.9.1 
Summary of Parsaclisib Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.9.2 
Summary of Ruxolitinib Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.9.3 
Summary of Parsaclisib/Ruxolitinib Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.10.1 
Summary of Parsaclisib Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety 
X 
3.2.10.2 
Summary of Ruxolitinib Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety 
X 


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Table No. 
Title 
Population 
Standard 
3.2.11.1 
Summary of Parsaclisib Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class, Preferred Term, 
and CTCAE Grade Category 
Safety 
X 
3.2.11.2 
Summary of Ruxolitinib Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class, Preferred Term, 
and CTCAE Grade Category 
Safety 
X 
3.2.12.1 
Summary of Grade 3 or Higher Parsaclisib Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.12.2 
Summary of Grade 3 or Higher Ruxolitinib Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.13.1 
Summary of Parsaclisib Treatment-Related Serious 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.13.2 
Summary of Ruxolitinib Treatment-Related Serious 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.14 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.15.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Parsaclisib Dose Reduction by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.15.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib Dose Reduction by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.16.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Parsaclisib Dose Interruption by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.16.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib Dose Interruption by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.17.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Parsaclisib by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.17.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Ruxolitinib by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.18 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term:  Life-Table Method 
Safety 
X 
3.2.19 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term:  Life-Table Method 
Safety 
X 
3.2.20.1 
Summary of Treatment-Emergent Adverse Events of Special Interest 
by MedDRA Preferred Term 
Safety 
X 
3.2.20.2 
Kaplan-Meier Estimates of Time to the First Onset of 
Treatment-Emergent Adverse Events of Special Interest by MedDRA 
Preferred Term 
Safety 
X 
3.2.20.3 
Kaplan-Meier Estimates of Longest Duration of Treatment-Emergent 
Adverse Events of Special Interest by MedDRA Preferred Term 
Safety 
X 


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Table No. 
Title 
Population 
Standard 
3.3  Laboratory 
3.3.1.1 
Summary of Laboratory Values - Hematology 
Safety 
X 
3.3.1.2 
Summary of Laboratory Values - Chemistry 
Safety 
X 
3.3.1.3 
Summary of Laboratory Values - Coagulation 
Safety 
X 
3.3.1.4 
Summary of Laboratory Values - Urinalysis 
Safety 
X 
3.3.2.1 
Shift Summary of Hematology Values - to the Worst Abnormal Value 
Safety 
X 
3.3.2.2 
Shift Summary of Chemistry Values - to the Worst Abnormal Value 
Safety 
X 
3.3.2.3 
Shift Summary of Coagulation Values - to the Worst Abnormal Value 
Safety 
X 
3.3.3.1 
Shift Summary of Hematology Laboratory Values in CTC Grade - to 
the Worst Abnormal Value  
Safety 
X 
3.3.3.2 
Shift Summary of Chemistry Laboratory Values in CTC Grade - to the 
Worst Abnormal Value 
Safety 
X 
3.3.3.3 
Shift Summary of Coagulation Laboratory Values in CTC Grade - to 
the Worst Abnormal Value 
Safety 
X 
3.3.3.4 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Hematology 
Safety 
X 
3.3.3.5 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Chemistry 
Safety 
X 
3.3.3.6 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Coagulation 
Safety 
X 
3.3.4.1 
Summary of Participants With Elevations in Liver Chemistry Tests 
Safety 
X 
3.4  Vital Signs 
3.4.1 
Summary of Systolic Blood Pressure 
Safety 
X 
3.4.2 
Summary of Diastolic Blood Pressure 
Safety 
X 
3.4.3 
Summary of Pulse 
Safety 
X 
3.4.4 
Summary of Respiratory Rate 
Safety 
X 
3.4.5 
Summary of Body Temperature 
Safety 
X 
3.4.6 
Summary of Weight 
Safety 
X 
3.5  ECG 
3.5.1 
Summary of PR Interval (ms) From 12-Lead ECG 
Safety 
X 
3.5.2 
Summary of QRS Interval (ms) From 12-Lead ECG 
Safety 
X 
3.5.3 
Summary of QT Interval (ms) From 12-Lead ECG 
Safety 
X 
3.5.4 
Summary of QTc Interval (ms) From 12-Lead ECG 
Safety 
X 
3.5.5 
Summary of RR Interval (ms) From 12-Lead ECG 
Safety 
X 
3.5.6 
Summary of Outliers of QT and QTc Interval Values (ms) From 
12-Lead ECG 
Safety 
X 
3.5.7 
Summary of Clinically Significant ECG Abnormalities 
Safety 
X 


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Figures 
Figure No. 
Title 
4.2  Secondary Efficacy 
4.2.1.1 
Kaplan-Meier Estimates of Time to the First ≥ 25% Reduction in Spleen Volume 
4.2.1.2 
Kaplan-Meier Estimates of Duration of Maintenance of a ≥ 25% Reduction in Spleen Volume 
4.2.2 
Kaplan-Meier Estimates of Time to the First ≥ 50% Reduction in MFSAF v4.0 Total Symptom 
Score 
4.2.3 
Kaplan-Meier Estimates of Overall Survival 
4.2.4 
Plot of Proportion of Participants With ≥ 25% Reduction in Spleen Volume at Each Visit 
4.2.5 
Plot of Percentage Change From Baseline in MFSAF v4.0 Total Symptom Score at Each Visit 
 
 
 
 
 
 
4.6  Laboratory Data  
4.6.1 
Box-and-Whisker Plot of Selected Laboratory Values by Study Visit 
Listings 
Listing No. 
Title 
2.1  Discontinued Participants (Participant Disposition) 
2.1.1 
Participant Enrollment and Disposition Status 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.2  Protocol Deviations 
2.2.1 
Protocol Deviations 
2.3  Data Excluded From 
 Efficacy, and/or Safety Analyses 
2.3.1 
Analysis Population 
2.3.2 
Crossover Participants 
2.4  Demographic and Baseline Characteristics (Including Prior and Concomitant Medications) 
2.4.1 
Demographic and Baseline Characteristics 
2.4.2 
Disease History 
2.4.3 
Prior Radiation Treatment 
2.4.4 
Prior Systemic Therapy for MF Other Than Ruxolitinib 
2.4.5 
Prior Surgery or Surgical Procedure 
2.4.6 
Medical History 
2.4.7 
Prior and Concomitant Medication 
2.5  Drug Compliance 
2.5.1 
Study Drug Compliance of Parsaclisib 
2.5.2 
Study Drug Administration of Parsaclisib 
2.5.3 
Study Drug Administration of Placebo 
2.5.4 
Study Drug Administration of Ruxolitinib 
2.6  Efficacy 
2.6.1 
Spleen Volume 
2.6.2 
MFSAF v4.0 Total Symptom Score  
2.6.3 
Death 
 
 
 
 


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Listing No. 
Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.7  Adverse Events 
2.7.1 
Adverse Events  
2.7.3 
Serious Adverse Events 
2.7.4 
Grade 3 or Higher Adverse Events 
2.7.5 
Fatal Adverse Events 
2.7.6 
Treatment-Related Adverse Events 
2.7.7 
Adverse Events Leading to Interruption, Reduction, or Discontinuation of Parsaclisib or 
Ruxolitinib 
2.8  Laboratory Data 
2.8.1 
Clinical Laboratory Values – Hematology 
2.8.2 
Clinical Laboratory Values – Chemistry 
2.8.3 
Clinical Laboratory Values – Coagulation 
2.8.4 
Abnormal Clinical Laboratory Values 
2.8.5 
Potential Hy's Law Events 
2.8.6 
Central Laboratory Collection Times  
2.9  Vital Signs 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Sign Values 
2.9.3 
Alert Vital Sign Values 
2.10  ECG 
2.10.1 
12-Lead ECG Values 
2.10.2 
Abnormal 12-Lead ECG Values 
2.10.3 
Alert 12-Lead ECG Values 
2.11  Physical Examination 
2.11.1 
Physical Examinations 


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