Clinical trial NCT02718300
Conditions: MPN (Myeloproliferative Neoplasms)
Keywords: Primary myelofibrosis (PMF) post-polycythemia vera myelofibrosis (PPV-MF) post-essential thrombocythemia myelofibrosis (PET-MF) myeloproliferative neoplasms (MPNs) phosphoinositide 3-kinase (PI3K) inhibitor Janus kinase (JAK) inhibitor
Sponsor: Incyte Corporation
Start date: 2017-02-08; Completion date: 2022-04-29
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, and efficacy of the combination of parsaclisib and ruxolitinib in subjects with myelofibrosis.

Detailed description:

Arms: arm 1: Initial cohort dose of parsaclisib added to existing stable regimen of ruxolitinib, with subsequent cohort escalations based on protocol-specific criteria. arm 2: Part 2 will compare 2 doses of parsaclisib . arm 3: Part 3 will compare 2 different long term dosing strategies. arm 4: Part 4 will compare 2 different daily dosing strategies.
Interventions: intervention 1: Parsaclisib intervention 2: Parsaclisib intervention 3: Ruxolitinib intervention 4: Parsaclisib intervention 5: Parsaclisib
Intervention descriptions: intervention 1: Up to 3 oral once a day (QD) doses of parsaclisib. Doses will be taken once daily for 8 weeks, followed by once weekly dosing at the same dose level. intervention 2: Two recommended oral QD doses of parsaclisib. Once daily doses of parsaclisib will be taken for 8 weeks, followed by once weekly dosing at the same dose level. intervention 3: The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of parsaclisib. intervention 4: 20 mg oral QD dose of parsaclisib for 8 weeks. After 8 weeks patients will take either 20 mg once weekly or 5 mg once daily. intervention 5: 2 dose strategies will be compared:

1. 5 mg parsaclisib beginning on Day 1 until end of treatment.
2. 20 mg oral QD dose of parsaclisib for 8 weeks; after 8 weeks patients will take 5 mg once daily.

Protocol documents:
Prot_000.pdf: 
Official Title:     A Phase 2 Study of the Safety, Tolerability, and Efficacy of INCB050465 
in Combination With Ruxolitinib in Subjects With Myelofibrosis 
NCT Number: 
NCT02718300 
Document Date: Clinical Study Protocol Version 6: 11-October-2018


Incyte Corporation 
Page 1 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
Clinical Study Protocol 
INCB 50465-201 
A Phase 2 Study of the Safety, Tolerability, and Efficacy of 
INCB050465 in Combination With Ruxolitinib in Subjects 
With Myelofibrosis 
Product: 
INCB050465 
IND Number: 
 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
16 FEB 2016 
Amendment (Version) 1: 
13 APR 2016 
Amendment (Version) 2: 
18 MAY 2016 
Amendment (Version) 3: 
22 NOV 2016 
Amendment (Version) 4: 
06 JUN 2017 
Amendment (Version) 5: 
23 MAR 2018 
Amendment (Version) 6: 
11 OCT 2018 
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, Good Clinical Practices as defined in Title 21 of the 
US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
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 the prior 
written consent of Incyte Corporation. 
CONFIDENTIAL 


Incyte Corporation 
Page 2 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
INVESTIGATOR'S AGREEMENT 
I have read the INCB 50465-201 Protocol Amendment 6 (Version 6 dated 11 OCT 2018) 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) 
CONFIDENTIAL 


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Incyte Corporation 
Page 5 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
Randomization: 
During Part 2, subjects were randomized 1:1 to the 2 treatment groups using block randomization, 
stratified by Eastern Cooperative Oncology Group (ECOG) performance status at screening (ECOG 0-1 
vs ECOG 2).  
During Part 3, subjects were randomized on a 3:2 ratio between TG5 and TG20.  Stratification was by 
ECOG status as in Part 2. 
During Part 4, subjects will be randomized on a 3:2 ratio between TG5D and TG5I/M until 25 total 
subjects have been randomized, with subsequent randomization on a 1:1 ratio until approximately 
30 subjects have been enrolled in each group.  Stratification will be by ECOG status as in Part 3. 
Part 1:  Safety Run-In Portion 
The safety run-in portion was designed to test up to 3 doses of INCB050465 in combination with 
ruxolitinib for a 28-day assessment (4 weeks).  Initially, 3 subjects were to be enrolled in Cohort 1 to 
receive INCB050465 10 mg together with ruxolitinib, at the dose ongoing at the time of enrollment.  
After 28 days, subjects who took at least 22 of 28 daily doses of INCB050465 AND ruxolitinib OR had a 
dose-limiting toxicity (DLT) during the first 28 days were to be included in the evaluation cohort.  
Additional subjects would have been enrolled into Cohort 1 if discontinuations resulted in fewer than 
3 evaluable subjects.  After evaluation, the following actions were planned to occur: 
Cohort 
No. of 
Subjects 
Regimen 
DLTs 
Observed 
Action Taken 
1 
3 
INCB050465 10 mg 
QD for 8 weeks 
followed by 10 mg 
once weekly plus 
ruxolitinib 5 mg BID to 
25 mg BID* 
 
0 
Proceed to Cohort 2. 
1 
Enroll 3 additional subjects, and evaluate 
the total of 6 subjects after 28 days.  If 
< 2 subjects have a DLT, then proceed to 
Cohort 2.  If ≥ 2 subjects have a DLT, then 
proceed to Cohort 3. 
> 1 
Proceed to Cohort 3. 
2 
3 + 3 
INCB050465 20 mg 
QD for 8 weeks 
followed by 20 mg 
once weekly plus 
ruxolitinib at 5 mg BID 
to 25 mg BID* 
0 or 1 
Enroll 3 additional subjects, and evaluate 
the total of 6 subjects after 28 days.  If 
< 2 subjects have a DLT, then proceed to 
Part 2 using doses of 10 mg and 20 mg 
INCB050465. 
≥ 2 
Proceed to Cohort 3. 
3 
6 
INCB050465 5 mg QD 
for 8 weeks followed by 
5 mg once weekly plus 
ruxolitinib at 5 mg BID 
to 25 mg BID* 
 
0 or 1 
If < 2 subjects have a DLT and if Cohort 1 
exceeded the DLT allowance, then proceed 
to Part 2 as a single-group study of 5 mg 
INCB050465.  If Cohort 1 did not exceed 
the DLT allowance, proceed to Part 2 with 
doses of 5 mg and 10 mg INCB050465.   
≥ 2 
Terminate study.  Alternatively, sponsor 
may elect to assess doses lower than 5 mg.  
If Cohort 1 did not exceed the DLT 
allowance, but Cohort 3 showed DLTs, 
additional Cohort expansion might be 
conducted to assess these and other doses of 
INCB050465, pending sponsor review and 
discussion of available data. 
QD = once daily. 
*The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of INCB050465.  
The maximum dose of ruxolitinib allowed for subjects with baseline platelet count ≥ 100 × 109/L is 25 mg BID, and the 
maximum dose of ruxolitinib for subjects with baseline platelet count of ≥ 50 × 109/L to < 100 × 109/L is 10 mg BID. 
CONFIDENTIAL 


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Page 6 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
Subjects receiving dose reductions (but not meeting DLT criteria) during the first 28 days who had not 
received at least 22 days of the prescribed dose of INCB050465 and ruxolitinib for that cohort were not 
considered evaluable for the purposes of determining the maximum tolerated dose (MTD) and were 
replaced. 
The MTD of INCB050465 was planned to be the highest dose level tested that was considered tolerated 
on the basis of fewer than 2 DLTs in a cohort of 6 subjects.  Individual subject dose reductions were made 
based on events observed at any time during treatment with INCB050465; however, for the purposes of 
dose cohort escalation/de-escalation, expanding a dose cohort, and determining the MTD of 
INCB050465, decisions were made based on events that were observed from the first day of study drug 
administration through and including Day 28.  A lower MTD may have subsequently been determined 
based on relevant toxicities that became evident after Day 28.   
After the 28-day safety evaluation period, safety run-in subjects received additional combination therapy 
of INCB050465 as a daily dose for a total of 8 weeks after first dose, followed by once-weekly dosing 
plus ruxolitinib as long as adequately tolerated with study visits each month and additional laboratory 
assessments biweekly.  Measurements and procedures followed those described for the randomized 
portion.  Dose modifications after the 28-day safety evaluation period in the safety run-in cohort  
followed the dose modification rules described in the body of the Protocol. 
A DLT was defined as the occurrence of any of the toxicities shown below occurring up to and including 
Day 28, except those with a clear alternative explanation (eg, disease progression, other medications) or 
transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or 
symptoms based on investigator determination.  All DLTs were assessed by the investigator using 
CTCAE v4.03 criteria.  Subjects who received at least 22 of 28 doses of INCB050465 and ruxolitinib at 
the level assigned or had a DLT were considered evaluable for determining tolerability of the dose. 
Dose-Limiting Toxicities 
Nonhematologic 
Nonhematologic DLT is defined as any clinically significant nonhematologic AE or abnormal laboratory value 
assessed as unrelated to disease progression, intercurrent illness, or concomitant medication that occurs during 
the first 28 days of therapy, is assessed as being at least possibly related to study drugs, and meets any of the 
following criteria: 
• CTCAE Grade 3 AST or alanine aminotransferase (ALT) for > 7 days. 
• CTCAE Grade 4 AST or ALT of any duration. 
• Grade 3 nausea/vomiting, dehydration, or diarrhea lasting more than 3 days in the setting of optimal supportive 
medications. 
• Grade 3 fatigue lasting more than 5 days in the setting of optimal supportive medications 
• Grade 3 biochemical abnormalities (eg, lipase elevation or bilirubin elevation) will only be considered a DLT if 
accompanied by clinical consequences.  Grade 3 electrolyte abnormalities will only be considered DLTs if 
related to study drugs and not corrected by optimal replacement therapy or if persisting after 7 days of optimal 
replacement therapy. 
• All Grade 4 nonhematologic toxicities of any duration. 
• All other clinically significant nonhematologic AEs that are Grade 3 according to CTCAE 4.03. 
Hematologic 
Myelosuppression and cytopenias are expected outcomes of MF disease processes and MF treatments and per se 
will not constitute DLTs except as follows: 
• Grade 4 thrombocytopenia with bleeding. 
• Grade 4 neutropenia with fever that does not clinically resolve within 7 days in the setting of optimal 
interventions. 
Anemia will not be considered in the definition of DLT. 
CONFIDENTIAL 


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Page 7 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
Part 1 was conducted at selected clinical study sites.  Enrollment was controlled by distribution of 
enrollment slots to the clinical sites by the sponsor or its designee.  The sponsor conducted approximately 
weekly safety teleconferences with the investigators participating in Part 1 to review subject status and 
safety findings to ensure safe, appropriate administration. 
Part 1 has been completed.  No DLTs were observed.  The treatment groups for Part 2 were determined to 
be TG10 and TG20. 
Part 2:  Randomized Portion 
Part 2 was to be enrolled and conducted provided a tolerable dose could be established for INCB050465 
in combination with ruxolitinib in Part 1 of the study.  Part 2 was planned to enroll approximately 
60 subjects randomized 1:1 by block randomization into 2 treatment groups: 
 
Enrollment into Part 2 at a given study site is terminated effective with site-specific IRB approval of 
Protocol Amendment 5. 
Part 3:  Randomized Portion 
In Part 3, all subjects will initially receive INCB050465 at 20 mg QD for 8 weeks in combination with 
ruxolitinib.  After Week 8, subjects will be assigned to 1 of 2 dose groups based on block randomization 
at the time of entry into the study (using a randomization of 3:2 for TG5 versus TG20 for the first 
40 subjects, followed by 1:1 randomization for additional subjects, up to a total of approximately 
52 subjects): 
 
Subjects who were randomized into Part 2 before Amendment 5 and are currently receiving 10 mg QD 
will be allowed to cross over to the 20 mg QD dose if they are within the first 8 weeks of treatment, or to 
the 5 mg QD dose if they are beyond Week 8 of treatment, provided they demonstrate inadequate 
response to the current dose regimen; an adequate bone marrow reserve; and no evidence of uncontrolled 
renal, hapatic, cardiovascular, or gastrointestinal disease.  A list of requirements for crossover is provided 
in the body of the Protocol. 
CONFIDENTIAL 


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Page 8 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
As of site-specific approval of Amendment 6, there will be no further enrollment into Part 3 at the given 
site.  Subjects already enrolled into TG5 in Part 3 will continue to receive INCB050465 according to the 
original randomization for Part 3 and may continue in the study indefinitely unless criteria for 
discontinuation are met.  Subjects already enrolled into TG20 in Part 3 will have the opportunity to cross 
over to receive 5 mg QD of INCB050465 once they reach Week 8 provided they demonstrate inadequate 
response to the current dose regimen; an adequate bone marrow reserve; and no evidence of uncontrolled 
renal, hepatic, cardiovascular, or gastrointestinal disease.  A list of requirements for crossover is provided 
in the body of the Protocol. 
The TG20 group will be deemed full with enrollment of the 15th subject to that group considering all 
sites; all further enrollment to Part 3 will be to TG5 at a given site until Amendment 6 has been approved. 
Part 4:  Randomized Portion 
Part 4 of the study is designed to compare different daily dosing regimens and to address the impact of an 
initial higher dose of INCB050465 on overall response.  Subjects will be randomized to one of 2 groups:  
TG5D will receive INCB050465 5 mg QD from Day 1 until EOT.  TG5I/M will receive INCB050465 
20 mg QD for 8 weeks (induction phase) followed by 5 mg QD (maintenance phase) until EOT.  
Study drug administration will continue per the randomized group assignment indefinitely or until 
discontinuation criteria are met.  Note that TG5I/M is identical to TG5 from Part 3; subjects from these 
2 groups will be combined in the final analysis.  
 
Study Population: 
Male or female subjects aged 18 years or older 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 6 months, with a stable ruxolitinib dose for at least the last 8 weeks before the first 
dose of INCB050465.  
Inclusion Criteria: 
• Men and women aged 18 years or older. 
• Diagnosis of PMF, PPV-MF, or PET-MF.  
• Treated with ruxolitinib for ≥ 6 months with stable dose for ≥ 8 weeks  (acceptable doses are 5 mg BID 
to 25 mg BID)  
• Evidence of inadequate response to ruxolitinib: 
- Palpable spleen of > 10 cm below the left subcostal margin on physical examination at the screening 
visit OR 
- Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam AND active 
symptoms of MF at the screening visit as demonstrated by presence of 1 symptom score ≥ 5 or 
2 symptom scores ≥ 3 using the Screening Symptom Form. 
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Page 9 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
• Subjects with an ECOG performance status of 0, 1, or 2. 
• Screening bone marrow biopsy specimen available or willingness to undergo a bone marrow biopsy at 
screening/baseline; willingness to undergo bone marrow biopsy at Week 24. 
• Life expectancy of at least 24 weeks. 
• Willingness to avoid pregnancy or fathering children based on the criteria below: 
- Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral 
oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age). 
- Woman of childbearing potential who has a negative serum pregnancy test at screening and before the 
first dose on Day 1 and who agrees 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 should be communicated to the subject and their understanding 
confirmed. 
- Man who agrees to take appropriate precautions to avoid fathering children (with at least 99% 
certainty) from screening through 93 days after treatment with INCB050465.  Permitted methods that 
are at least 99% effective in preventing pregnancy should be communicated to the subject and their 
understanding confirmed. 
Exclusion Criteria: 
• Use of experimental drug therapy for MF, or any other standard drug (eg, danazol, hydroxyurea, etc) 
with the exception of ruxolitinib within 6 months of starting study (combination) therapy and/or lack of 
recovery from all toxicities from previous therapy (except ruxolitinib) to Grade 1 or better. 
• Inability to swallow food or any condition of the upper gastrointestinal tract that precludes 
administration of oral medications. 
• Unwillingness to be transfused with blood components.  
• Recent history of inadequate bone marrow reserve as demonstrated by the following: 
- Platelet count < 50 × 109/L in the 4 weeks before screening or platelet transfusion(s) within 8 weeks 
before screening. 
- Absolute neutrophil count levels < 0.5 × 109/L in the 4 weeks before screening. 
- Subjects with peripheral blood blast count of > 10% at the screening or baseline hematology 
assessments. 
- Subjects who are not willing to receive RBC transfusions to treat low hemoglobin levels.   
• Inadequate liver function at screening visit as demonstrated by the following: 
- Direct bilirubin ≥ 2.0 × the upper limit of laboratory normal (ULN).  (NOTE: direct bilirubin will 
only be determined if total bilirubin is ≥ 2.0 × ULN). 
- ALT or AST > 2.5 × ULN. 
• Inadequate renal function at screening visit as demonstrated by creatinine clearance < 50 mL/min 
measured or calculated by Cockroft-Gault equation, or glomerular filtration rate < 50 mL/min/1.73 m2 
as calculated using the Modification of Diet in Renal Disease formula. 
• Active bacterial, fungal, parasitic, or viral infection that requires therapy.  Subjects 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 will be permitted. 
• Active hepatitis B virus (HBV) or hepatitis C virus (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. 
• Known human immunodeficiency virus infection. 
• Uncontrolled, severe, or unstable cardiac disease that in the investigator's opinion may jeopardize the 
safety of the subject or the compliance with the Protocol. 
CONFIDENTIAL 


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Incyte Corporation 
Page 12 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
A difference between TG5D and TG5I/M + TG5 in total symptom score evaluated by the MFSAF v3.0 
symptom diary and the MPN-SAF will be assessed separately using a van Elteren test to account for 
stratification by ECOG performance status.  If TG5D or TG5I/M + TG5 in the randomized portion of the 
study fail to enroll a sufficient number of subjects in a particular stratum, then the difference in the 
2 treatment groups for these endpoints will be assessed separately using a 2-sample Wilcoxon rank sum 
test with a normal approximation applied to the test statistic. 
All other efficacy endpoints are exploratory in nature and will be tabulated by summary statistics. 
There will be 1 planned interim analysis conducted for futility for this study.  The interim analysis will be 
conducted during the randomized portion of the study once TG5D and TG5I/M + TG5 enroll 15 subjects 
and have been evaluated for spleen volume at Week 12.  Further enrollment in a treatment group will be 
terminated if fewer than 4 subjects in the treatment group have spleen stability or a reduction from 
baseline in spleen volume (ie, percentage  change from baseline ≤ 0%)  as measured by MRI (or CT scan 
in applicable subjects) at Week 12.  Subjects remaining in any terminated group may have their dose 
adjusted to reflect the ongoing group with sponsor approval. 
If either TG5D or TG5I/M is terminated, then Part 4 will continue as a single-group study, and the 
primary endpoint will be analyzed.  If both TG5D and TG5I/M are terminated, then the study will be 
terminated.  The probabilities of stopping a treatment group for futility for various probabilities of a 
subject achieving ≥ 0% decrease from baseline in spleen volume at Week 12 are provided in the full body 
of the Protocol. 
CONFIDENTIAL 


Incyte Corporation 
Page 13 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................21 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Overview of Myelofibrosis .........................................................................................24 
1.2. 
Role of Janus Kinase Pathway in Myelofibrosis ........................................................25 
1.3. 
Role of PI3K/Protein Kinase B–Signaling Pathway in Myelofibrosis .......................26 
1.4. 
Study Rationale ...........................................................................................................26 
1.5. 
Overview of INCB050465 ..........................................................................................27 
1.5.1. 
Pharmacology Summary .............................................................................................27 
1.5.2. 
Nonclinical Toxicology Summary ..............................................................................28 
1.5.3. 
Nonclinical Drug Metabolism and Pharmacokinetics ................................................29 
1.5.4. 
Clinical Summary .......................................................................................................29 
1.5.4.1. 
Study INCB 50465-101 ..............................................................................................30 
1.5.4.2. 
Study INCB 39110-106 ..............................................................................................31 
1.5.4.3. 
Study INCB 39110-107 ..............................................................................................32 
1.5.4.4. 
Study INCB 50465-202 ..............................................................................................32 
1.5.4.5. 
Current Study:  INCB 50465-201 ...............................................................................33 
1.6. 
Overview of Ruxolitinib .............................................................................................33 
1.6.1. 
Clinical Safety Summary ............................................................................................33 
1.6.1.1. 
Healthy Subject Studies ..............................................................................................33 
1.6.1.2. 
Phase 3 Studies in Subjects With Myelofibrosis ........................................................34 
1.6.1.3. 
Other Ongoing Studies ...............................................................................................34 
1.7. 
Justification of Study Treatment Regimen .................................................................34 
1.8. 
Potential Risks and Benefits of the Treatment Regimen ............................................35 
1.8.1. 
Potential Risks of INCB050465 Based on Preclinical Safety ....................................35 
1.8.2. 
Potential Risks of INCB050465 Based on Prior Clinical Studies ..............................35 
1.8.3. 
Potential Benefits of INCB050465 Based on Prior and Ongoing Clinical 
Studies.........................................................................................................................36 
1.8.4. 
Potential Risks of PI3Kδ Inhibition Based on Other Agents in Class ........................36 
1.8.5. 
Potential Risks of Ruxolitinib .....................................................................................37 
1.8.6. 
Potential Risks of the Combination of INCB050465 and Ruxolitinib .......................37 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................38 
CONFIDENTIAL 


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Incyte Corporation 
Page 15 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
5.3. 
Study Drugs ................................................................................................................51 
5.3.1. 
INCB050465 ...............................................................................................................51 
5.3.1.1. 
Description and Administration ..................................................................................51 
5.3.1.2. 
Supply, Packaging, and Labeling ...............................................................................51 
5.3.1.3. 
Storage ........................................................................................................................52 
5.3.2. 
Ruxolitinib ..................................................................................................................52 
5.3.2.1. 
Description and Administration ..................................................................................52 
5.3.2.2. 
Supply, Packaging, and Labeling ...............................................................................52 
5.3.2.3. 
Storage ........................................................................................................................52 
5.3.3. 
Instruction to Subjects for Handling INCB050465 and Ruxolitinib ..........................52 
5.4. 
Treatment Compliance ................................................................................................53 
5.5. 
Treatment Interruptions and Adjustments ..................................................................53 
5.5.1. 
Dose Modifications .....................................................................................................53 
5.5.2. 
Dose Limiting Toxicities ............................................................................................53 
5.5.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................53 
5.5.4. 
Follow-Up of Dose-Limiting Toxicities .....................................................................53 
5.5.5. 
Procedures for Cohort Review and Dose Escalation ..................................................53 
5.5.6. 
Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB050465 ...............................................................................................................54 
5.5.6.1. 
Supportive Care Guidelines for Diarrhea/Colitis .......................................................56 
5.5.6.2. 
Definition for Immune-Related Adverse Events ........................................................57 
5.5.7. 
Criteria for Permanent Discontinuation of INCB050465 ...........................................57 
5.5.8. 
Criteria and Procedures for Dose Interruptions or Adjustments for 
Ruxolitinib ..................................................................................................................57 
5.6. 
Withdrawal of Subjects From Study Treatment .........................................................59 
5.6.1. 
Withdrawal Criteria ....................................................................................................59 
5.6.2. 
Withdrawal Procedures ...............................................................................................59 
5.7. 
Concomitant Medications ...........................................................................................60 
5.7.1. 
Pneumocystis Pneumonia Prophylaxis .......................................................................60 
5.7.2. 
Permitted Medications ................................................................................................60 
5.7.3. 
Restricted Medications ...............................................................................................60 
5.7.4. 
Prohibited Medications ...............................................................................................61 
6. 
STUDY ASSESSMENTS ..........................................................................................61 
CONFIDENTIAL 


Incyte Corporation 
Page 16 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
6.1. 
Screening ....................................................................................................................67 
6.2. 
Baseline .......................................................................................................................68 
6.3. 
Treatment ....................................................................................................................68 
6.4. 
End of Treatment ........................................................................................................69 
6.5. 
Follow-Up ...................................................................................................................70 
6.5.1. 
Safety Follow-Up ........................................................................................................70 
6.5.2. 
Survival Follow-Up ....................................................................................................70 
6.6. 
End of Study ...............................................................................................................70 
6.7. 
Unscheduled Visits .....................................................................................................70 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................71 
7.1. 
Administration of Informed Consent Form ................................................................71 
7.2. 
Interactive Web Response System Procedure ............................................................71 
7.3. 
Demography and Medical History ..............................................................................71 
7.3.1. 
Demographics and General Medical History .............................................................71 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................71 
7.3.3. 
Transfusion History Status .........................................................................................71 
7.3.4. 
Screening Symptom Form ..........................................................................................71 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................72 
7.5. 
Safety Assessments .....................................................................................................72 
7.5.1. 
Adverse Events ...........................................................................................................72 
7.5.2. 
Physical Examinations ................................................................................................72 
7.5.2.1. 
Comprehensive Physical Examination .......................................................................72 
7.5.2.2. 
Targeted Physical Examination ..................................................................................73 
7.5.3. 
Vital Signs ..................................................................................................................73 
7.5.4. 
Electrocardiograms .....................................................................................................73 
7.6. 
Efficacy Assessments .................................................................................................73 
7.6.1. 
Bone Marrow Biopsy ..................................................................................................73 
7.6.2. 
Spleen Palpation .........................................................................................................74 
7.6.3. 
Imaging .......................................................................................................................74 
7.6.4. 
Symptom Diary ...........................................................................................................74 
7.6.5. 
Myeloproliferative Neoplasms Symptom Assessment Form .....................................75 
7.6.6. 
Eastern Cooperative Oncology Group Status .............................................................75 
7.6.7. 
Patient Global Impression of Change .........................................................................75 
CONFIDENTIAL 


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PPD


Incyte Corporation 
Page 19 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
APPENDIX E. MODIFIED MYELOFIBROSIS SYMPTOM ASSESSMENT FORM 
VERSION 3.0 ...........................................................................................................106 
APPENDIX F. MYELOPROLIFERATIVE NEOPLASMS SYMPTOM 
ASSESSMENT FORM ............................................................................................108 
APPENDIX G. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS (ECOG) ......................................................................109 
APPENDIX H. PATIENT GLOBAL IMPRESSION OF CHANGE .......................................110 
APPENDIX I. INTERNATIONAL WORKING GROUP–MYELOPROLIFERATIVE 
NEOPLASMS RESEARCH AND TREATMENT CRITERIA ..............................111 
APPENDIX J. PROTOCOL AMENDMENT SUMMARY OF CHANGES ...........................113 
 
CONFIDENTIAL 


Incyte Corporation 
Page 20 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
LIST OF TABLES 
Table 1: 
Risk Categories for Myelofibrosis ..............................................................................25 
Table 2: 
Safety Run-In Cohorts ................................................................................................44 
Table 3: 
Dose-Limiting Toxicities for Part 1 ............................................................................45 
Table 4: 
Part 1 Treatment Groups .............................................................................................49 
Table 5: 
Guidelines for Interruption and Restarting of INCB050465 ......................................54 
Table 6: 
Dose Levels for INCB050465 ....................................................................................56 
Table 7: 
Dose Reductions/Interruptions and Restarts for Hematologic Toxicities That 
Persist for > 14 Days After Interruption of INCB050465 ..........................................58 
Table 8: 
Schedule of Assessments – Part 1, Part 2, Part 3, and Part 4 .....................................62 
Table 9: 
Schedule of Laboratory Assessments – Part 1, Part 2, Part 3, and Part 4 ...................64 
Table 10: Laboratory Tests:  Required Analytes ........................................................................66 
Table 11: Schedule of Pharmacokinetic Sampling for Part 1, Part 2, Part 3, and Part 4 ............67 
Table 12: Criteria for Clinically Notable Vital Sign Abnormalities ...........................................86 
Table 13: Criteria for Clinically Notable Electrocardiogram Abnormalities .............................86 
Table 14: Matrix of Part 2 Dose Selection Based on Part 1 Safety Outcomes by Dose 
Cohort .........................................................................................................................88 
Table 15: Probability of Declaring a Dose to be Tolerable ........................................................88 
Table 16: Probability of Stopping a Treatment Group for Futility .............................................89 
 
LIST OF FIGURES 
Figure 1: 
Part 2 Study Design ....................................................................................................46 
Figure 2: 
Part 3 Study Design ....................................................................................................46 
Figure 3: 
Study Design for Part 4 ...............................................................................................47 
 
CONFIDENTIAL 


Incyte Corporation 
Page 21 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
AE 
adverse event 
AKT 
protein kinase B 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BTK 
Bruton's tyrosine kinase 
CALR 
calreticulin  
CFR 
Code of Federal Regulations 
CI 
clinical improvement 
CMR 
complete metabolic response 
CMV 
cytomegalovirus 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DIPSS 
Dynamic International Prognostic Scoring System 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMH 
extramedullary hematopoiesis 
EOS 
end of study 
EOT 
end of treatment 
ET 
essential thrombocythemia 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
CONFIDENTIAL 


Incyte Corporation 
Page 22 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IL 
interleukin 
IN 
Investigator Notification 
INR 
international normalized ratio 
irAE 
 immune-related adverse event 
IRB 
institutional review board 
ITT 
intent-to-treat 
IXRS 
interactive voice/web response system (use appropriate option and change to IVRS or 
IWRS throughout document) 
IWG 
International Working Group 
JAK 
Janus kinase 
LDL 
low-density lipoprotein 
LCM 
left costal margin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MFSAF 
Myelofibrosis Symptom Assessment Form 
MPN-SAF 
Myeloproliferative Neoplasms Symptom Assessment Form 
MPN-SAF TSS 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score 
MRI 
magnetic resonance imaging 
MRT 
Myeloproliferative Neoplasms Research and Treatment 
MTD 
maximum tolerated dose 
NHL 
non-Hodgkin lymphoma 
PD 
pharmacodynamic 
PET-MF 
post–essential thrombocythemia myelofibrosis 
PGIC 
Patient Global Impression of Change 
P-gp 
P-glycoprotein 
PI3K 
phosphatidylinositol 3-kinase 
PJP 
Pneumocystis jirovecii pneumonia 
PK 
pharmacokinetic 
PMF 
primary myelofibrosis 
PPV-MF 
post–polycythemia vera myelofibrosis 
PR 
partial response 
PRBC 
packed red blood cell 
CONFIDENTIAL 


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PPD


Incyte Corporation 
Page 24 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
1. 
INTRODUCTION 
INCB050465 represents a novel, potent, and selective inhibitor of the Class IA 
phosphatidylinositol 3-kinase (PI3K) enzymes, with selectivity for the δ isoform, which is 
proposed for development for treatment of hematological malignancies.  For a thorough 
discussion of the pharmacology of INCB054065, refer to the INCB054065 Investigator's 
Brochure (IB).  Ruxolitinib, a potent and selective inhibitor of the Janus kinase (JAK) family of 
protein tyrosine kinases, JAK1 and JAK2, is approved in multiple jurisdictions for myelofibrosis 
(MF), with variations on the specific indication language, and is currently in development for the 
treatment of myeloproliferative neoplasms, hematologic malignancies, and solid tumors.  For a 
thorough discussion of the pharmacology of ruxolitinib (INCB018424), refer to the 
ruxolitinib IB.  
1.1. 
Overview of Myelofibrosis 
The classic myeloproliferative neoplasms (MPNs) include chronic myelogenous leukemia, 
polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).  
Myelofibrosis can present as a de novo disorder (PMF) or evolve secondarily from previous PV 
or ET (post–polycythemia vera myelofibrosis [PPV-MF] or post–essential thrombocythemia 
myelofibrosis [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 65 years, and the incidence of PMF 
has been estimated at 4 to 6 cases per 100,000 people in the US (Stein et al 2015).  Survival in 
MF varies with the presence or absence of specific risk factors.  Analysis of risk factors over the 
last 20 years has resulted in a number of prognostic scoring systems (for a review, refer to 
Bose and Verstovsek 2015).  A prognostic scoring system based on a time-dependent risk 
evaluation has been developed:  the Dynamic International Prognostic Scoring System (DIPSS) 
for PMF (Passamonti et al 2010).  Age of greater than 65 years, presence of constitutional 
symptoms, anemia (hemoglobin less than 100 g/L), leukocytosis (white blood cell [WBC] count 
> 25 × 109/L), and a circulating blast percentage of 1% or higher were assessed for their impact 
on survival when analyzed as time-dependent covariates in a multivariate Cox proportional 
hazard 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 have been described in Table 1. 
CONFIDENTIAL 


Incyte Corporation 
Page 25 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
Table 1: 
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 
1.4 
Although not included in the DIPSS, cytogenetic abnormalities in PMF, JAK V617F allele 
burden, mutations in exon 9 of the gene encoding calreticulin (CALR) and mutations in the gene 
encoding the thrombopoietin receptor (MPL) have been examined for impact on DIPSS score, 
thrombotic risk, and overall survival 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 are combined into the newest prognostic scoring system, the GPSS, 
currently being validated. 
For the subset of patients who are younger (generally < 65 years), are otherwise healthy, and 
have a histocompatible donor, allogeneic stem cell transplantation may provide a curative option, 
although with substantial risks of mortality (10%-20%; Deeg et al 2003).  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.  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 employed to reduce symptoms secondary to splenomegaly, but 
symptomatic improvement is variable and short-lived; moreover, transient and life-threatening 
pancytopenia and an approximate 20% treatment-related mortality have been noted. 
1.2. 
Role of Janus Kinase Pathway in Myelofibrosis 
Within the 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 receptors 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 signal transduction and activator of transduction 
(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, 
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which may be homodimers (eg, 2 JAK2s) or heterodimers (eg, a JAK1 and a JAK2).  
Erythropoietin, which is responsible for stimulating erythropoiesis and thrombopoietin, which is 
responsible for stimulating thrombopoiesis, have been shown to signal only through receptors 
that utilize JAK2 homodimers.  A large number of inflammatory mediators, such as interleukin 
(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 have 
been observed both in patients harboring the JAK2V617F mutation and in patients without 
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. 
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 overall survival with ruxolitinib use 
in this patient population (Harrison et al 2012, Cervantes et al 2013, Mesa et al 2013a, Mesa et al 
2013b, Verstovsek et al 2012, Verstovsek et al 2015, Vannucchi et al 2015). 
1.3. 
Role of PI3K/Protein Kinase B–Signaling Pathway in Myelofibrosis 
Recent evidence suggests other regulatory pathways in addition to the JAK-STAT pathway are 
dysregulated in myeloproliferative neoplasms.  The PI3K/protein kinase B (AKT) pathway is a 
signal transduction pathway that promotes survival and growth of cells in response to 
extracellular signals.  There are multiple isoforms of PI3K; activated AKT, which results from 
interaction with activated PI3K, phosphorylates as many as 100 different substrates, leading to a 
wide range of growth and survival effects on the cell.  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.  Khan et al (2013) described studies using cell lines and patient 
samples to show that inhibition of the PI3K/AKT pathway signaling with a selective AKT 
inhibitor induced proliferative arrest and apoptosis.  Interestingly, both myeloid and erythroid 
colony formation by cells derived from PMF patient samples were more sensitive to inhibition 
by AKT inhibitor than their normal counterparts.  A combination of AKT inhibitor plus 
ruxolitinib when added to SET2 cells, which harbor the JAK V617F mutation, suppressed cell 
growth;  the combination was synergistic at all doses tested, suggesting that combining the 
2 agents may provide efficacy at lower doses of ruxolitinib.  The authors concluded that 
inhibition of the PI3K/AKT pathway represents an additional therapeutic target for treatment of 
MPNs. 
1.4. 
Study Rationale 
Despite statistically significant improvements in signs and symptoms of MF and overall survival 
rates, compared with either placebo or best available therapy demonstrated in the registration 
studies, ruxolitinib therapy fails to provide adequate and/or sustained response for some patients.  
A subgroup analysis of the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I 
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study did not identify subgroups (age, MF subtype, International Prognostic Scoring System risk 
group, baseline Eastern Cooperative Oncology Group (ECOG) score, baseline platelet or 
hemoglobin level, baseline spleen volume quartile, baseline symptom burden quartile, or 
presence/absence of V617F mutation) that did not benefit from ruxolitinib therapy 
(Verstovsek et al 2013); however, additional systemic and genetic factors may influence the 
response magnitude and duration in an individual patient.  It is possible that for some patients, 
declining hemoglobin or platelet counts associated with ruxolitinib use preclude maintenance at 
optimal ruxolitinib dosages.  Alternatively, some patients may have increases in inflammatory 
pathway signaling that is not JAK-mediated as a primary driver for their disease. 
The persistent activation of the PI3K/AKT pathway in patients chronically treated with 
ruxolitinib suggests that the PI3K/AKT pathway may be a major driver of disease in patients 
who have a less than ideal response to JAK inhibitor therapy.  These data suggest that concurrent 
PI3Kδ inhibition may envisage an efficacious and well-tolerated approach in patients with MF 
who have evidence of residual MF symptoms on chronic ruxolitinib therapy.  INCB054065 is a 
novel, potent small molecule inhibitor of PI3K-delta with approximately 20,000-fold selectivity 
for the other PI3K family members.  The present study will explore the combination of 
INCB050465 with ruxolitinib in subjects with MF with residual disease-related signs and 
symptoms while on chronic ruxolitinib therapy. 
1.5. 
Overview of INCB050465 
1.5.1. 
Pharmacology Summary 
INCB050465 potently inhibits the human PI3Kδ kinase enzyme (IC50 = 1.1 ± 0.5 nM), with 
approximately 20,000-fold selectivity for the other PI3K family member enzymes and > 300-fold 
selectivity against a broad panel of 192 other kinases.  Moreover, INCB050465 is potent (IC50 
values of ≤ 10 nM) in cell-based assays relevant to the pathogenesis of B-cell malignancies, such 
as PI3Kδ-mediated signaling and growth of malignant human B-cell lines.  This effect is not due 
to general cytotoxicity, because 10 μM INCB050465 had no significant effect on the growth of 
nonlymphoid cell lines.  Compared with inhibition of B-cell proliferation, INCB050465 is 
similarly potent in blocking T-helper cell differentiation but is > 100 times less potent in assays 
that measure effects on human T-cell and natural killer-cell proliferation or monocyte function.  
These data suggest that the impact of INCB050465 on the human immune system will largely be 
restricted to B cells and T-cell differentiation.  
In vivo, the effects of oral INCB050465 were evaluated in mice in the Pfeiffer human tumor 
xenograft model of B-cell malignancy.  In the Pfeiffer model of non-Hodgkin lymphoma (NHL), 
INCB050465 inhibited PI3Kδ signaling and tumor growth as a single agent in a dose-dependent 
manner.  
In summary, pharmacological data obtained in both in vitro and in vivo model systems support 
the potential utility of orally administered INCB050465 in the treatment of hematological 
malignancies and solid tumors.  For a complete summary of the pharmacology of INCB050465, 
refer to the INCB050465 IB. 
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1.5.2. 
Nonclinical Toxicology Summary 
Oral administration studies were conducted in rats and dogs to assess the potential systemic 
toxicity of INCB050465.  Doses evaluated in repeat-dose studies were selected based on 
tolerability in earlier studies and projected margins over human exposure.   
The most prominent findings following repeat-dose exposure to INCB050465 in both rats and 
dogs were lymphoid depletion (most notably B-cell regions) of multiple lymphoid organs, 
including lymph nodes, spleen, thymus, and gut-associated lymphoid tissue, at all doses and at 
high doses constituting the dose-limiting toxicity (DLT).  The frequency and severity of these 
findings were dose-related.  Effects secondary to immunosuppression led to euthanasia of 
1 female rat administered a dose of 100 mg/kg per day (primary cause of deteriorating condition 
was necrotizing pancreatitis) and 1 female dog administered a dose of 3 mg/kg per day (primary 
cause of deteriorating condition was severe gastrointestinal inflammation) and to the death of 
1 male dog administered 15 mg/kg per day (primary cause of death was severe pulmonary 
inflammation).  Depletion of the bone marrow was observed in 2 female rats administered a dose 
of 100 mg/kg per day (including the female that was euthanized in extremis); in addition, 1 of 
these 2 animals showed bone marrow fibrosis.  No changes in bone marrow were observed at 
lower doses or at the end of the recovery period.  There were no bone marrow lesions in dogs at 
any dose.  Plasma exposures (unbound AUC) in female rats administered 100 mg/kg were 
> 190-fold higher than projected clinical exposure at 10 mg once daily (QD).  Pharmacokinetics 
(PK) and safety data will be evaluated in all subjects at each dose level before proceeding to the 
next dose.  Effects on the lymphoid system are an expected result of immunomodulatory effects 
of PI3Kδ inhibition (Pillai and Cariappa 2009, Marone et al 2008).  Reversibility of the effects 
on the lymphoid system was clearly demonstrated and would be expected to occur in a clinical 
setting.  
There was no evidence of toxicity unrelated to the pharmacological activity (ie, "off-target" 
effects) of INCB050465 in dogs.  In male rats, minimal to mild hypospermatogenesis was 
observed in the 28-day study at doses ≥ 30 mg/kg per day.  Exposures (unbound AUC) 
associated with these findings are approximately 4-fold higher than projected human exposures 
at a dose of 30 mg QD.  In 8- and 9-day exploratory non-GLP studies in rats, evidence of 
hepatotoxicity was observed at ≥ 100 mg/kg per day, although these findings were not 
reproduced in the 28-day GLP study at 100 mg/kg per day.  Plasma exposures (unbound AUC) 
in rats administered ≥ 100 mg/kg were > 13-fold higher than projected clinical exposure at 30 mg 
QD.   
Three-month studies with INCB050465 in rats and dogs demonstrated similar pharmacological 
effects and did not reveal any "off-target" toxicities. 
INCB050465 was not mutagenic in a bacterial mutagenicity assay.  INCB050465 was not 
clastogenic in the absence of S9 metabolic activation in an in vitro chromosome aberration assay 
in human lymphocytes, although results in the presence of metabolic activation were considered 
inconclusive.  No increase in micronuclei were observed in the bone marrow of rats administered 
INCB050465 at up to the maximally tolerated dose in an in vivo micronucleus assay in rats.  
Therefore, based on the collective evidence, INCB050465 is not expected to present a genotoxic 
risk to humans. 
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The potential risk associated with INCB050465 clinical administration is expected to be low 
based on animal studies with adequate exposure margins, the demonstrated lack of findings in 
recovery animals following drug withdrawal, and comprehensive evaluation of safety and PK 
before each dose escalation in Study INCB 50465-101.  For a complete summary of the 
nonclinical toxicology of INCB050465, refer to the INCB050465 IB.  
For a complete summary of the pharmacology of INCB050465, refer to the INCB050465 IB. 
1.5.3. 
Nonclinical Drug Metabolism and Pharmacokinetics 
The absorption, distribution, metabolism, and excretion of INCB050465 have been studied in 
rats, dogs, and monkeys.  Following intravenous (IV) administration, INCB050465 displayed 
low systemic clearance, representing 26%, 2%, and 5% of the hepatic blood flow in rats, dogs, 
and monkeys, respectively.  The steady-state volume of distribution was moderate in rats 
(1.5 L/kg) and monkeys (0.7 L/kg) but low in dogs (0.3 L/kg), indicating species differences in 
distribution.  The terminal elimination half-life values were favorable, ranging from 4.0 hours 
(rat) to 7.3 hours (monkey).  The renal excretion of intact INCB050465 was minimal (< 2% 
across species).  INCB050465 has limited penetration across the rat blood-brain barrier.  
Following oral administration, INCB050465 was rapidly absorbed, with Tmax values of 0.3 hours 
(rat) to 2.5 hours (monkey).  The bioavailability of INCB050465 was complete in dogs (100%), 
and high in monkeys (79%) and rats (74%).  Based on preclinical data, the terminal elimination 
half-life of INCB050465 in human is projected to be approximately 12 hours, and the oral 
bioavailability is projected to be 70%.   
INCB050465 is a P-glycoprotein (P-gp) substrate, and the efflux transport is saturated at 
concentrations above 100 µM.  Though INCB050465 is an inhibitor of P-gp (IC50 at 18.1 µM), a 
clinical drug interaction potential with a P-gp substrate is low based on FDA Guidance for 
Industry – Drug Interaction Studies (FDA 2012).  INCB050465 is primarily metabolized by 
cytochrome P450 (CYP) 3A4 and is not an inhibitor of the major CYPs evaluated nor is it an 
inducer of CYP3A4.  Thus, the drug-drug interaction potential via P450 is low.  The metabolism 
profile of INCB050465 in rat, dog, and human in vitro preparations was quantitatively similar, 
and no human-specific in vitro metabolite was identified.  The primary phase I metabolites 
identified from in vitro preparations were oxidative.  From the drug safety perspective, no 
glutathione adducts were detected upon incubation of INCB050465 in the presence of 
glutathione, suggesting that INCB050465 should not present a risk for immune-mediated toxicity 
due to reactive metabolites formation.  Metabolites in plasma and urine samples from the rat and 
dog 28-day toxicokinetic studies were similar to that observed in vitro.  Only 1 oxidation 
metabolite was detected in rat and dog plasma at abundance greater than 10% of parent or drug 
related material.  
For additional details, refer to the INCB050465 IB. 
1.5.4. 
Clinical Summary 
As of 30 MAR 2018, INCB050465 is being evaluated in 8 ongoing clinical studies for oncology 
indications: Studies INCB 50465-101, INCB 50465-202, INCB 50465-204, and INCB 50465-
205 as monotherapy; Study INCB 50465-102 in combination with bendamustine and 
obinutuzumab; Study INCB 50465-201 in combination with ruxolitinib (JAK 1/2 inhibitor); 
Studies INCB 50465-101 and INCB 39110-106 in combination with itacitinib (JAK 1 inhibitor); 
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and Study INCB 39110-107 in combination with pembrolizumab (an anti–PD-1 monoclonal 
antibody). The combination of INCB050465 and R-ICE is also being assessed in Study INCB 
50465-101. 
As of the data cutoff, 351 unique participants have been exposed to INCB050465 as 
monotherapy (139 participants) or in combination with R-ICE (5 participants), bendamustine and 
obinutuzumab (6 participants), itacitinib (11 participants with B-cell malignancies and 73 
participants with advanced solid tumors), ruxolitinib (28 participants), or pembrolizumab (89 
participants). 
For the 342 participants included in the safety analysis (Studies INCB 50465-101,INCB 50465-
102, INCB 50465-201, INCB 50465-202, INCB 39110-106, and INCB 39110-107), 312 
participants (91.2%) had at least 1 TEAE. The most frequently reported TEAEs overall were 
fatigue (31.0%), nausea (29.5%), diarrhea (25.1%), and pyrexia (20.8%). 
The most frequently reported TEAEs for participants who received INCB050465 monotherapy 
and combination therapy are as follows: 
• INCB050465 monotherapy (n = 130):  nausea (26.9%), diarrhea (24.6%), and fatigue 
(21.5%). 
• INCB050465 and pembrolizumab combination therapy (n = 89):  fatigue (43.8%), 
nausea (37.1%), diarrhea (31.5%), and pyrexia (29.2%). 
• INCB050465 and itacitinib combination therapy (n = 84):  fatigue (39.3%), nausea 
(31.0%), decreased appetite (28.6%), vomiting (25.0%), and diarrhea and pyrexia 
(21.4% each). 
• INCB050465 and ruxolitinib combination therapy (n = 28):  cough, epistaxis, nausea, 
and thrombocytopenia (17.9% each) 
• INCB050465 and bendamustine + obinutuzumab combination therapy (n = 6):  
diarrhea (66.7%). 
• INCB050465 and R-ICE combination therapy (n = 5):  anemia (100.0%) 
Refer to the INCB050465 IB for further details. 
1.5.4.1. 
Study INCB 50465-101 
Study INCB 50465-101 is an open-label dose-escalation study in participants previously 
diagnosed with and treated for B-cell malignancies.  As of the data cutoff date of 30 MAR 2018, 
INCB050465 was administered in doses from 5 mg QD to 45 mg QD.  A regimen of 20 mg QD 
for 9 weeks followed by 20 mg QW was also administered.  Of the 72 participants who were 
administered INCB050465 monotherapy, the median duration of treatment was 124.5 days 
(range, 7-914 days).  Treatment-emergent AEs occurred in 68 participants (94.4%), with the 
most frequent TEAE being nausea and diarrhea in 26 participants (36.1%) each. 
Two participants in the monotherapy group (2.8%) had a TEAE leading to death (sepsis and 
respiratory failure).  Serious AEs were observed in all dose cohorts.  Thirty-one participants 
(43.1%) who received monotherapy had a SAE.  The most frequent SAE reported was diarrhea 
(8.3%).  Fourteen participants (19.4%) discontinued INCB050465 treatment because of a TEAE.  
None of the events that led to study drug discontinuation occurred during the QW dosing period.  
CONFIDENTIAL 


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Protocol INCB 50465-201 Am 6 
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Treatment-emergent AEs occurred in 49 participants (84.5%) with the most frequent TEAEs 
being nausea and pyrexia in 9 participants (15.5%) each.  Four participants (6.9%) had TEAEs 
leading to death (abdominal pain and pyrexia, general physical health deterioration, multiple 
organ dysfunction syndrome, and acute respiratory failure), all of which were considered related 
to disease progression.  Serious AEs were observed in both treatment groups.  Thirty-five 
participants (60.3%) had an SAE.  The most frequent SAE reported was pyrexia (8.6%).  Eleven 
participants (19.0%) discontinued INCB050465 treatment because of a TEAE.  The most 
frequent TEAE that led to discontinuation of INCB050465 was hypercalcemia (3 participants 
[5.2%]).  Refer to the INCB050465 IB for further details. 
1.5.4.5. 
Current Study:  INCB 50465-201 
Study INCB 50465-201 is the current, ongoing study to assess the safety, tolerability, and 
efficacy of the combination of INCB050465 and the JAK 1/2 inhibitor ruxolitinib in subjects 
with primary MF or secondary MF who had a suboptimal response while receiving ruxolitinib 
monotherapy.  Subjects are required to have been on ruxolitinib for at least 6 months, and at a 
stable dose for at least the 8 weeks before study entry.  Suboptimal response is defined based on 
spleen size and presence of symptoms. 
Before Amendment 6, the study had 3 parts.  Part 1 was a safety run-in part to establish tolerable 
doses.  The dosing regimen for the 2 dose groups in Part 2 was INCB050465 10 and 20 mg QD, 
respectively, for 8 weeks followed by weekly dosing at the same dose.  Part 3 explored different 
long-term dosing strategies by comparing INCB050465 5 mg QD versus 20 mg QW in subjects 
who first received 20 mg QD for 8 weeks.  As of the cutoff date (30 MAR 2018), 28 participants 
received combination therapy with INCB050465 (10 and 20 mg QD) and ruxolitinib in Parts 1 
and 2.  The median duration of treatment was 122.0 days.  Twenty-one subjects (75.0%) had a 
TEAE.  The most frequently reported TEAEs were cough, epistaxis, nausea, and 
thrombocytopenia (17.9% each) and fatigue, headache, stomatitis, and vomiting (14.3% each).  
Serious TEAEs were reported for 3 participants:  hematoma, influenza, nausea, and pyrexia in 
1 participant, fall in 1 participant, and blood bilirubin increased in 1 participant.  Subsequent to 
the elevation in bilirubin in the latter participant, a diagnosis of acute myeloid leukemia was 
made; this event was fatal.  No TEAEs led to INCB050465 discontinuation.  Refer to the 
INCB050465 IB for further details.  No data are available for subjects in Part 3. 
1.6. 
Overview of Ruxolitinib 
1.6.1. 
Clinical Safety Summary 
1.6.1.1. 
Healthy Subject Studies 
Ruxolitinib has been administered in Novartis or Incyte sponsored clinical studies to 
approximately 385 healthy volunteers as single, repeat single, or multiple doses for up to 
10 days' duration, 32 subjects with various degrees of renal impairment, and 24 subjects with 
various degrees of hepatic impairment.  In healthy volunteer studies, a transient, reversible 
decrease in neutrophil count has been seen after doses of 25 to 50 mg, which reverses 12 to 
24 hours after stopping drug.  These neutropenia events were generally of Grade 1 or Grade 2 
severity, with a single instance of severe Grade 4 neutropenia that led to study drug 
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Protocol INCB 50465-201 Am 6 
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discontinuation in 1 subject receiving 50 mg ruxolitinib twice daily (BID; highest dose).  The 
MTD in healthy volunteers was determined to be 25 mg BID or 100 mg QD. 
In a thorough cardiac QT study, it was shown that increasing plasma concentrations of 
ruxolitinib are not associated with increases in the QT interval. 
For a review of ruxolitinib clinical safety, refer to the ruxolitinib IB. 
1.6.1.2. 
Phase 3 Studies in Subjects With Myelofibrosis 
Up to 22 FEB 2018, ruxolitinib has been administered to more than 8738 subjects in Novartis- 
and Incyte-sponsored interventional clinical trials.  Two pivotal Phase 3 studies (COMFORT-I 
and COMFORT-II) enrolled subjects with MF, and together they support the efficacy and safety 
of ruxolitinib for the treatment of patients with PMF, PPV-MF, or PET- MF.  COMFORT-I, 
conducted in the United States, Canada, and Australia, was a double-blind, placebo-controlled 
study that enrolled 309 subjects, and COMFORT-II was an open-label study conducted in 
Europe that compared ruxolitinib with best available therapy in 219 patients. 
In the randomized period of the 2 pivotal studies in MF, COMFORT-I and COMFORT-II 
(cutoff:  01 MAR 2011, median duration of exposure = 10.8 months) discontinuation due to AEs, 
regardless of causality, was observed in 11.3% of subjects.  The most frequently reported 
adverse drug reactions were thrombocytopenia and anemia.  Hematologic adverse reactions (any 
CTCAE grade) included anemia (82.4%), thrombocytopenia (69.8%) and neutropenia (16.6%).  
Anemia, thrombocytopenia, and neutropenia are dose-related effects.  The 3 most frequent 
nonhematologic adverse reactions were bruising (21.6%), dizziness (15.3%), and headache 
(14.0%).  The 3 most frequent nonhematologic laboratory abnormalities were raised ALT 
(27.2%), raised AST (18.6%), and hypercholesterolemia (16.9%). 
Long-term treatment and follow-up in subjects with MF (including 615 subjects treated with 
ruxolitinib during the controlled and extension phases of studies INCB 18424-251: cutoff, 
01 OCT 2012; COMFORT-I:  15 OCT 2015; COMFORT-II: 20 APR 2015) has shown that as 
expected, the numbers and proportions of AEs and SAEs has increased.  However, no new safety 
signals have emerged (median duration of exposure for this population is 28.78 months, with 
1578.45 patient-years of exposure). 
1.6.1.3. 
Other Ongoing Studies 
For a thorough discussion of the clinical safety of ruxolitinib, refer to the ruxolitinib IB. 
1.7. 
Justification of Study Treatment Regimen  
In clinical studies to date, DLTs have not been observed at doses of INCB050465 up to 20 mg, 
and target inhibition as assessed by phosphorylated protein kinase B levels in peripheral blood 
showed > 80% inhibition at trough in subjects receiving 5 mg, 10 mg, 15 mg, or 20 mg of 
INCB050465.  Exploration of doses of 5, 10, 20, or 30 mg in the present study is therefore 
clinically reasonable.  Indeed, doses of 10 or 20 mg given daily for 8 weeks followed by weekly 
have been well tolerated, and no DLTs were observed. 
Previously, Part 3 was implemented to explore daily doses beyond Week 8.  The 8-week higher 
dose was retained, and subjects in Part 3 either switched to weekly dosing or remained on daily 
doses but at a lower dose.  Part 4 will use all daily dose regimens and will directly examine the 
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role a higher initial dose might play in overall response and duration of response.  From the 
subject's perspective, taking the same dose every day from start to finish would be the simplest 
regimen to follow.  However, the initial use of a higher dose might be critical to achieve 
significant decreases in spleen size and/or symptom scores more quickly in this refractory 
population.  Part 4 of the study will compare a group of subjects who begin receiving 
INCB050465 at 20 mg QD, then decrease to 5 mg QD after 8 weeks (dose group TG5I/M) with a 
group who begin at and remain on doses of 5 mg QD (dose group TG5D). 
All parts of the study require that subjects be on a stable dose of ruxolitinib for at least 8 weeks 
before the screening visit; doses of ruxolitinib may not exceed 25 mg BID for subjects with 
platelet counts ≥ 100 × 109/L and may not exceed 10 mg BID for subjects with platelet count 
≥ 50 × 109/L but < 100 × 109/L, which mirrors the recommendations for treatment doses in the 
ruxolitinib complete prescribing information.  The requirement for a stable dose before study 
entry further implies adequate tolerability for the dose of ruxolitinib in a given subject.  
1.8. 
Potential Risks and Benefits of the Treatment Regimen 
1.8.1. 
Potential Risks of INCB050465 Based on Preclinical Safety 
Potential risks with administration of INCB050465 based on preclinical findings include 
lymphoid depletion (refer to the INCB050465 IB).  This may result in infections, fever, or 
cytokine release resulting in fever, chills, hypotension, wheezing, and/or rash. 
In both rats and dogs, immunosuppression (evident as minimal to marked depletion of lymphoid 
tissues, including thymus, lymph nodes, spleen, and gut-associated lymphoid tissue) was 
observed at all doses and considered to be consistent with the pharmacologic activity of 
INCB050465.  The incidence and severity of these findings increased with dose. 
1.8.2. 
Potential Risks of INCB050465 Based on Prior Clinical Studies 
INCB050465 has effects on the immune system.  Therefore, subjects 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. 
For studies combining INCB050465 with a JAK inhibitor (eg, INCB039110, INCB052793, or 
ruxolitinib), all immune-related AEs must be completely resolved to baseline for 2 weeks before 
starting study medications, and subjects with history of Grade 3 or 4 immune-related AEs from 
prior immunotherapy will be excluded.  Subjects with a history of immune-related ocular AEs 
will also be excluded. 
One case of PJP has been reported with the use of INCB050465 in combination with 
pembrolizumab.  The subject had not received PJP prophylaxis before the event.  All subjects 
who receive INCB050465 (as monotherapy or combination therapy) will also receive PJP 
prophylaxis.  Subjects allergic to or at risk for standard PJP prophylaxis with sulfonamide 
antibiotics will receive either inhaled pentamidine or atovaquone (Mepron®) for prophylaxis; 
dapsone should not be used in such subjects.  Prophylaxis should be given while subjects are 
receiving study treatment and continued for 2 to 6 months after the last dose of study drug. 
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1.8.3. 
Potential Benefits of INCB050465 Based on Prior and Ongoing Clinical Studies 
Based on emerging efficacy and safety data from the ongoing Study INCB 50465-101 (see 
Section 1.5.4.1), the treatment regimen for Study INCB 50465-201 Part 1 was selected to be 
10 mg QD (Cohort 1) or 20 mg QD (Cohort 2) given for 8 weeks, followed by 10 mg (Cohort 1) 
or 20 mg (Cohort 2) given once weekly.  Doses of 10 mg or 20 mg QD provide trough 
concentrations exceeding the IC90 (based on an in vitro whole-blood assay).  Furthermore, 20 mg 
QD has demonstrated efficacy in DLBCL and in other types of NHLs.  However, 24% of all 
subjects in study INCB 50465-101 discontinued study treatment due to an AE.  Consequently, 
after administration of daily INCB050465 for 8 weeks in the present study, the dosing regimen 
was reduced to once-weekly dosing for Part 1 and Part 2. 
Pharmacodynamic data from INCB 50465-101 showed that a single dose of 20 mg exhibited 
maximal inhibition of AKT in an ex vivo pharmacodynamic assay, and PK modeling suggests 
that 20 mg once weekly will 1) achieve maximal inhibition equivalent to approximately 10 × 
IC90, 2) exceed the IC90 for approximately 36 hours, and 3) have minimal to no inhibition for 
approximately half the dosing interval.  This once-weekly regimen is similar to that of another 
PI3K inhibitor (copanlisib), which is administered IV on Days 1, 8, and 15 of a 28-day cycle, 
and which achieved 7 objective responses in 9 subjects with NHL (Patnaik et al 2016).  Among 
the 51 subjects who received study drug, 4 discontinued treatment due to an AE.  There were 
2 events of Grade 3 noninfectious pneumonitis, 1 event of Grade 3 diarrhea, and no events of 
colitis. 
This once-weekly regimen was proposed to maintain response while providing time off from 
pathway inhibition, which may reduce the frequency of AEs.  This was the dosing frequency 
used for both Part 1 (now completed) and Part 2.  As of MAR 2018, with approximately 28 total 
subjects treated with this dosing frequency in Parts 1 and 2, no DLTs had been observed, and no 
trends for late-onset toxicity had been noted using available nonverified data.  There did not 
appear to be a meaningful difference between the 10 mg and 20 mg dose groups for safety or 
efficacy.  Part 3 was initiated to compare long-term weekly dosing with long-term, low-dose 
daily dosing:  INCB050465 20 mg QD for 8 weeks followed by 20 mg once weekly (TG20) 
versus INCB050465 20 mg QD for 8 weeks followed by 5 mg QD (TG5). 
As of SEP 2018, the safety profile continues to be similar between dose groups.  Part 4 of the 
study will explore and compare 2 all daily dose regimens:  subjects in group TG5D will receive 
5 mg QD from study start until EOT; subjects in group TG5I/M will receive 20 mg QD for the 
first 8 weeks and then transition to 5 mg QD.  Part 4 thus directly assesses the impact of an initial 
higher dose on overall response in this refractory population.  
1.8.4. 
Potential Risks of PI3Kδ 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 or serious occurring in 14%), fatal and/or serious diarrhea or colitis (14%), 
intestinal perforation, and infections including pneumonitis and cytomegalovirus (CMV) 
reactivation.  Subjects will be monitored closely for the development of these conditions and will 
have treatment interrupted and dose reduced as appropriate.  Subjects will receive prophylaxis 
for PJP and will be monitored for CMV viremia during the study. 
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Based on experience with idelalisib, hepatotoxicity is a risk with this class of agents.  
Preclinically, hepatotoxicity with INCB050465 was only seen at plasma exposures > 65-fold 
higher than the projected clinical exposure at 10 mg QD.  The pharmacophore of INCB050465 is 
different from idelalisib.  Other PI3Kδ inhibitors with a different pharmacophore have not shown 
hepatotoxicity in early studies (Savona et al 2013). 
1.8.5. 
Potential Risks of Ruxolitinib 
No specific findings in nonclinical repeat-dose toxicity studies identify clinical risk other than 
noting that consequences of immunosuppression may occur.  Hypotension and increases in heart 
rate were noted at a high dose in a cardiovascular preclinical study.  However, these findings 
have not been recapitulated in a clinical setting at doses up to 25 mg BID. 
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 subjects with MF.  Anemia and, less frequently, neutropenia have also been observed in 
studies in subjects 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, rheumatoid arthritis subjects, and hormone-refractory prostate 
cancer subjects with greater bone marrow reserve, the effects on hematopoietic proliferation 
appear to be less pronounced (ruxolitinib IB). 
1.8.6. 
Potential Risks of the Combination of INCB050465 and Ruxolitinib 
The principle 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.  Subjects should be 
closely monitored for bacterial infections and opportunistic infections, and treatment will be 
interrupted for infections that can be easily managed with antibiotic therapy and discontinued for 
infections that are serious or require prolonged antibiotic therapy.  Subjects should be monitored 
for varicella-zoster virus and herpes simplex virus infections and treatment started promptly.  
Subjects will be assessed for CMV viremia periodically during the study, and treatment started 
promptly if there is evidence of CMV reactivation. 
Ongoing Study INCB 40093-102 combines another PI3Kδ inhibitor INCB040093 with the 
experimental JAK1 inhibitor INCB039110 in subjects with previously treated B-cell 
malignancies.  As of December 2015, 67 subjects have been enrolled.  Five cases of PJP have 
been reported by subjects receiving this combination therapy (7.5% incidence); PJP is a rare but 
serious complication observed in lymphoma patients undergoing treatment.  Because of the 
increased risk of PJP in subjects receiving INCB03911 in combination with INCB040093, a 
standard prophylaxis regimen is now required for all subjects; no additional cases of PJP have 
been observed.  In the present study, a standard PJP prophylaxis regimen will be required for all 
subjects receiving combination treatment with INCB050465.  Subjects who are allergic to 
sulfonamide antibiotics should be treated with either inhaled pentamidine or atovaquone for PJP 
prophylaxis.  Dapsone should not be used in such subjects. 
Effects on WBC, red blood cell (RBC), and platelet counts could result from JAK inhibition and 
result in infections, anemia, or thrombocytopenia requiring transfusions.  Subjects will be 
CONFIDENTIAL 


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3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Study Population 
Male or female individuals subjects aged 18 years or older 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 6 months, with a stable ruxolitinib dose regimen 
for at least 8 weeks before the first administration of INCB050465.   
3.2. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Men and women aged 18 years or older. 
2. Diagnosis of PMF, PPV-MF, or PET-MF. 
3. Treated with ruxolitinib for ≥ 6 months with a stable dose for ≥ 8 weeks (acceptable 
doses are 5 mg BID to 25 mg BID). 
4. Evidence of inadequate response to ruxolitinib: 
a. Palpable spleen of > 10 cm below the left subcostal margin on physical examination  
at the screening visit OR 
b. Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam 
AND active symptoms of MF at the screening visit as demonstrated by presence of 
1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening Symptom Form 
(Appendix D). 
5. Subjects with an ECOG performance status of 0, 1, or 2 (see Appendix G). 
6. Screening bone marrow biopsy specimen available or willingness to undergo a bone 
marrow biopsy at screening/baseline; willingness to undergo bone marrow biopsy at 
Week 24. 
7. Life expectancy of at least 24 weeks. 
8. Willingness to avoid pregnancy or fathering children based on the criteria below: 
a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and before the first dose on Day 1 and who agrees 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 subject and their 
understanding confirmed. 
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c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through 93 days after treatment with 
INCB050465.  Permitted methods that are at least 99% effective in preventing 
pregnancy (see Appendix A) should be communicated to the subject and their 
understanding confirmed. 
3.3. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Use of experimental drug therapy for MF or any other standard drug (eg, danazol, 
hydroxyurea, etc.), with the exception of ruxolitinib within 6 months of starting study 
(combination) therapy and/or lack of recovery from all toxicities from previous therapy 
(except ruxolitinib) to Grade 1 or better. 
2. Inability to swallow food or any condition of the upper gastrointestinal tract that 
precludes administration of oral medications. 
3. Unwillingness to be transfused with blood components.  
4. Recent history of inadequate bone marrow reserve as demonstrated by the following: 
a. Platelet count < 50 × 109/L in the 4 weeks before screening or platelet transfusion(s) 
within 8 weeks before screening. 
b. Absolute neutrophil count (ANC) levels < 0.5 × 109/L in the 4 weeks before 
screening. 
c. Subjects with peripheral blood blast count of > 10% at the screening or baseline 
hematology assessments. 
d. Subjects who are not willing to receive RBC transfusions to treat low hemoglobin 
levels. 
5. Inadequate liver function at screening visit as demonstrated by the following:  
a. Direct bilirubin ≥ 2.0 × the upper limit of laboratory normal (ULN).  (NOTE: direct 
bilirubin will only be determined if total bilirubin is ≥ 2.0 × ULN). 
b. ALT or AST > 2.5 × ULN. 
6. Inadequate renal function at screening visit as demonstrated by creatinine clearance 
< 50 mL/min measured or calculated by Cockroft-Gault equation, or glomerular filtration 
rate < 50 mL/min/1.73 m2 as calculated using the Modification of Diet in Renal Disease 
formula. 
7. Active bacterial, fungal, parasitic, or viral infection that requires therapy.  Subjects 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 will be permitted. 
8. Active hepatitis B virus (HBV) or hepatitis C virus (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. 
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9. Known human immunodeficiency virus (HIV) infection. 
10. Uncontrolled, severe, or unstable cardiac disease that in the investigator's opinion may 
jeopardize the safety of the subject or the 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.  Subjects 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 INCB050465. 
13. Concurrent use of any prohibited medications (see Section 5.7.4 for specific prohibited 
medications and the associated timeframe over which they are prohibited). 
14. Active alcohol or drug addiction that would interfere with their ability to comply with the 
study requirements. 
15. Prior therapy with any drug that inhibits PI3K (examples of drugs targeting this pathway 
include but are not limited to INCB040093, idelalisib, duvelisib, and TGR-1202). 
16. Use of any potent CYP3A4 inhibitors or inducers (Appendix B) within 14 days or 
5 half-lives (whichever is longer) before the first dose of INCB050465 or anticipated 
during the study. 
17. Inadequate recovery from toxicity and/or complications from a major surgery before 
starting therapy. 
18. Currently breastfeeding or pregnant. 
19. 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 subject; or interfere with interpretation of study data. 
20. Inability to comprehend or unwilling to sign the informed consent form (ICF). 
21. History of Grade 3 or 4 immune-related AEs from prior immunotherapy.   
a. Any immune-related AEs of Grade 1 or 2 must be resolved before receiving the first 
dose of INCB050465. 
22. History of immune-related ocular AEs of any toxicity grade. 
23. Receipt of any live vaccine within 30 days of first dose of INCB050465. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 2 study of the combination of the PI3Kδ inhibitor INCB050465 and the JAK 1/2 
inhibitor ruxolitinib in subjects with PMF or secondary MF (PPV-MF or PET-MF) who have 
suboptimal response while receiving ruxolitinib monotherapy.  Suboptimal response is based on 
assessment of suboptimal reductions in spleen size or symptoms and is defined in the inclusion 
criteria (Section 3.2).  At least 6 months of prior ruxolitinib therapy is required, including 
ruxolitinib administration at a stable dose for at least 8 weeks before randomization.  The study 
is composed of 4 parts: 
Part 1 was an open-label safety run-in portion designed to assess the safety and tolerability of 
the combination of INCB050465 with ruxolitinib and to select appropriate doses of INCB050465 
for Part 2 in this patient population.  Part 1 has been completed. 
Part 2 was planned to be a block-randomized open-label study with 2 treatment groups:  TG10 
and TG20.  Both treatment groups use daily doses for the first 8 weeks, then weekly doses at the 
same strength through EOT.  Enrollment in Part 2 was suspended with implementation of 
Amendment 5.   
Part 3 was planned to be an open-label study to compare daily versus weekly long-term doses.   
All subjects would begin with INCB050465 20 mg QD.  After 8 weeks, subjects in TG5 would 
continue receiving INCB050465 at 5 mg QD, and subjects in TG20 would continue receiving 
INCB050465 at 20 mg once weekly.  Enrollment in Part 3 will be suspended with 
implementation of Amendment 6. 
With Amendment 6, Part 4 is added to directly compare different daily dosing regimens and 
the impact of an initial higher dose of INCB050465 on long-term response.  Subjects in Part 4 
will be randomized to 1 of 2 groups:  TG5D will begin on Day 1 with a daily dose of 5 mg, and 
subjects will continue receiving 5 mg QD indefinitely or until discontinuation criteria are met; 
TG5I/M will begin on Day 1 with a daily dose of 20 mg (the induction dose), and after 8 weeks 
subjects will switch to 5 mg QD (the maintenance dose).  Treatment for subjects randomized to 
TG5I/M will continue indefinitely or until discontinuation criteria are met. 
Randomization: 
During Part 2, subjects were randomized 1:1 to the 2 treatment groups using block 
randomization, stratified by Eastern Cooperative Oncology Group (ECOG) performance status at 
screening (ECOG 0-1 vs ECOG 2).  
During Part 3, subjects were randomized on a 3:2 ratio between TG5 and TG20.  Stratification 
was by ECOG status as in Part 2. 
During Part 4, subjects will be randomized on a 3:2 ratio between TG5D and TG5I/M until 
25 total subjects have been randomized, with subsequent randomization on a 1:1 ratio until 
approximately 30 subjects have been enrolled in each group.  Stratification will be by ECOG 
status as in Part 3. 
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4.1.1. 
Part 1:  Safety Run-In Portion 
The safety run-in portion was to test up to 3 doses of INCB050465 in combination with 
ruxolitinib for a 28-day assessment (4 weeks).  Initially, 3 subjects were enrolled in Cohort 1 to 
receive INCB050465 10 mg together with ruxolitinib, at the dose ongoing at the time of 
enrollment.  After 28 days, subjects who took at least 22 of 28 daily doses of INCB050465 AND 
ruxolitinib OR had a DLT during the first 28 days (see Table 3) were included in the evaluation 
cohort.  Additional subjects were to be enrolled into Cohort 1 if discontinuations resulted in 
fewer than 3 evaluable subjects.  After evaluation, the actions listed in Table 2 were to occur. 
Table 2: 
Safety Run-In Cohorts 
Cohort 
No. of 
Subjects 
Regimen 
DLTs 
Observed 
Action Taken 
1 
3 
INCB050465 10 mg QD 
for 8 weeks followed by 
10 mg once weekly plus 
ruxolitinib 5 mg BID to 
25 mg BID
a 
0 
Proceed to Cohort 2. 
1 
Enroll 3 additional subjects, and evaluate the total 
of 6 subjects after 28 days.  If < 2 subjects have a 
DLT, then proceed to Cohort 2.  If ≥ 2 subjects have 
a DLT, then proceed to Cohort 3. 
> 1 
Proceed to Cohort 3. 
2 
3 + 3 
INCB050465 20 mg QD 
for 8 weeks followed by 
20 mg once weekly plus 
ruxolitinib 5 mg BID to 
25 mg BIDa 
0 or 1 
Enroll 3 additional subjects, and evaluate the total 
of 6 subjects after 28 days.  If < 2 subjects have a 
DLT, then proceed to Part 2 using doses of 10 mg 
and 20 mg INCB050465. 
≥ 2 
Proceed to Cohort 3. 
3 
6 
INCB050465 5 mg QD  
for 8 weeks followed by 
5 mg once weekly plus 
ruxolitinib 5 mg BID to 
25 mg BIDa 
0 or 1 
If < 2 subjects have a DLT and if Cohort 1 exceeded 
the DLT allowance, then proceed to Part 2 as a 
single-group study of 5 mg INCB050465.  If 
Cohort 1 did not exceed DLT allowance, proceed to 
Part 2 with doses of 5 mg and 10 mg INCB050465. 
≥ 2 
Terminate study.  Alternatively, sponsor may elect 
to assess doses lower than 5 mg.  If Cohort 1 did not 
exceed the DLT allowance, but Cohort 3 showed 
DLTs, additional cohort expansion might be 
conducted to assess these and other doses of 
INCB050465, pending sponsor review and 
discussion of available data. 
a The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of INCB050465.  
The maximum dose of ruxolitinib allowed for subjects with baseline platelet count ≥ 100 × 109/L is 25 mg BID, and the 
maximum dose of ruxolitinib for subjects with baseline platelet count of ≥ 50 × 109/L to < 100 × 109/L is 10 mg BID. 
Subjects receiving dose reductions (but not meeting DLT criteria) during the first 28 days who 
had not received at least 22 days of the prescribed dose of INCB050465 and ruxolitinib for that 
cohort were not considered evaluable for the purposes of determining the MTD and were 
replaced. 
The MTD of INCB050465 was planned to be the highest dose level tested that was considered 
tolerated on the basis of fewer than 2 DLTs in a cohort of 6 subjects.  Individual subject dose 
reductions were made based on events observed at any time during treatment with INCB050465; 
however, for the purposes of dose cohort escalation/de-escalation, expanding a dose cohort, and 
determining the MTD of INCB050465, decisions were made based on events that were observed 
from the first day of study drug administration through and including Day 28.  A lower MTD 
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may have subsequently been determined based on relevant toxicities that became evident after 
Day 28. 
After the 28-day safety evaluation period, safety run-in subjects received additional combination 
therapy of INCB050465 plus ruxolitinib as long as adequately tolerated with study visits each 
month and additional laboratory assessments biweekly.  INCB050465 administration was QD for 
total of 8 weeks after the first dose, followed by once-weekly administration at the cohort-
specified dose.  Measurements and procedures followed those described for the randomized 
portion.  Dose modifications after the 28-day safety evaluation period in the safety run-in cohort 
followed the dose modification rules in Section 5.5.1. 
A DLT was defined as the occurrence of any of the toxicities shown in Table 3 occurring up to 
and including Day 28, except those with a clear alternative explanation (eg, disease progression, 
other medications) or transient (≤ 72 hours) abnormal laboratory values without associated 
clinically significant signs or symptoms based on investigator determination.  All DLTs were 
assessed by the investigator using CTCAE v4.03 criteria.  Subjects who received at least 22 of 
28 doses of INCB050465 and ruxolitinib at the level assigned or had a DLT were considered 
evaluable for determining tolerability of the dose. 
Table 3: 
Dose-Limiting Toxicities for Part 1 
Dose-Limiting Toxicities 
Nonhematologic 
Nonhematologic DLT is defined as any clinically significant nonhematologic AE or abnormal laboratory 
value assessed as unrelated to disease progression, intercurrent illness, or concomitant medication that 
occurs during the first 28 days of therapy, is assessed as being at least possibly related to study drugs, and 
meets any of the following criteria: 
• CTCAE Grade 3 AST or ALT for > 7 days. 
• CTCAE Grade 4 AST or ALT of any duration. 
• Grade 3 nausea/vomiting, dehydration, or diarrhea lasting more than 3 days in the setting of optimal 
supportive medications. 
• Grade 3 fatigue lasting more than 5 days in the setting of optimal supportive medications. 
• Grade 3 biochemical abnormalities (eg, lipase elevation or bilirubin elevation) will only be considered a 
DLT if accompanied by clinical consequences.  Grade 3 electrolyte abnormalities will only be 
considered DLTs if related to study drugs and not corrected by optimal replacement therapy or if 
persisting after 7 days of optimal replacement therapy. 
• All Grade 4 nonhematologic toxicities of any duration. 
• All other clinically significant nonhematologic AEs that are Grade 3 according to CTCAE v4.03. 
Hematologic 
Myelosuppression and cytopenias are expected outcomes of MF disease processes and MF treatments and 
per se will not constitute DLTs except as follows: 
• Grade 4 thrombocytopenia with bleeding. 
• Grade 4 neutropenia with fever that does not clinically resolve within 7 days in the setting of optimal 
interventions. 
Anemia will not be considered in the definition of DLT. 
Part 1 was conducted at selected clinical study sites (in the United States only).  Enrollment was 
controlled by distribution of enrollment slots to the clinical sites by the sponsor or its designee.  
The sponsor conducted approximately weekly safety teleconferences with the investigators 
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participating in Part 1 to review subject status and safety findings to ensure safe, appropriate 
administration.  Part 1 has been completed.  No DLTs were observed.  The treatment groups for 
Part 2 were determined to be TG10 and TG20. 
4.1.2. 
Part 2:  Randomized Portion 
Part 2 was to be enrolled and conducted provided that a tolerable dose could be established for 
INCB050465 in combination with ruxolitinib in Part 1 of the study.  Part 2 was planned to enroll 
approximately 60 subjects randomized 1:1 by block randomization into 2 treatment groups, 
TG10 and TG20. 
Figure 1 shows the study design for Part 2. 
Figure 1: 
Part 2 Study Design 
 
Enrollment into Part 2 at a given study site is terminated effective with site-specific IRB 
approval of Protocol Amendment 5. 
4.1.3. 
Part 3 Randomized Portion 
In Part 3, all subjects will initially receive INCB050465 at 20 mg QD for 8 weeks in combination 
with ruxolitinib.  After Week 8, subjects will be assigned to 1 of 2 dose groups based on block 
randomization at the time of entry into the study (using a randomization of 3:2 for TG5 vs TG20 
for the first 40 subjects, followed by 1:1 randomization for additional subjects, up to a total of 
approximately 52 subjects) as shown in Figure 2. 
Figure 2: 
Part 3 Study Design 
 
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As of site-specific approval of Amendment 6, there will be no further enrollment into Part 3 at 
the given site.  Subjects already enrolled into TG5 in Part 3 will continue to receive 
INCB050465 according to the original randomization for Part 3 and may continue in the study 
indefinitely unless criteria for discontinuation are met.  Subjects already enrolled into TG20 in 
Part 3 will have the opportunity to cross over to receive 5 mg QD of INCB050465 once they 
reach Week 8 provided they demonstrate inadequate response to the current dose regimen; an 
adequate bone marrow reserve; and no evidence of uncontrolled renal, hepatic, cardiovascular, or 
gastrointestinal disease.  A list of requirements for crossover is provided in Section 5.2.3.  The 
TG20 group will be deemed full with enrollment of the 15th subject to that group considering all 
sites; all further enrollment to Part 3 will be to TG5 at a given site until Amendment 6 has been 
approved. 
4.1.4. 
Part 4 Randomized Portion 
Part 4 of the study is designed to compare different daily dosing regimens and to address the 
impact of an initial higher dose of INCB050465 on overall response.  Subjects will be 
randomized to one of 2 groups:  TG5D will receive 5 mg daily doses of INCB050465 from 
Day 1 until EOT visit.  TG5I/M will receive doses of 20 mg daily for 8 weeks (induction phase), 
followed by 5 mg daily dosing (maintenance phase).  Dosing will continue per the randomized 
group assignment indefinitely or until discontinuation criteria are met.  Note that TG5I/M is 
identical to TG5 from Part 3; subjects from these 2 groups will be combined in the final analysis.  
Figure 3 shows the study design for Part 4.  
Figure 3: 
Study Design for Part 4 
 
4.2. 
Measures Taken to Avoid Bias 
This is an open-label comparison of 2 dose regimens of INCB050465.  Subjects will be 
randomized by block randomization.  Measurements of safety and efficacy are objective 
measurements. 
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4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
Part 1 was expected to enroll 9 to 18 subjects (10 were enrolled), Part 2 was planned to enroll a 
total of 60 subjects before termination;  because Part 3 was added, only 20 subjects were 
enrolled.  Part 3 was expected to enroll approximately 52 subjects;  approximately 5 subjects 
may be enrolled.  Part 4 will enroll approximately 55 subjects.  Twenty or more clinical sites will 
participate. 
4.3.2. 
Replacement of Subjects 
As noted in Section 4.1, a minimum of 3 subjects must be deemed evaluable for each cohort of 
Part 1 that is enrolled.  If a subject becomes nonevaluable either because of dose compliance 
< 80% (correct administration of INCB050465 for 22 of 28 days in the safety evaluation period) 
or withdraws because of an AE that does not meet the criteria for a DLT, then an additional 
subject will be enrolled to ensure the minimum evaluable cohort is achieved. 
4.4. 
Duration of Treatment and Subject Participation 
Screening:  Up to 28 days. 
Baseline:  7 days before first dose of INCB050465 
Treatment:  Begins with the first dose of INCB050465 (Day 1).  Treatment will continue as 
long as the regimen is tolerated and the subject does not meet discontinuation criteria.  Subjects 
will receive daily doses of INCB050465 throughout the study, or daily doses for 8 weeks, 
followed by once-weekly administration or QD administration (determined by the study part to 
which subjects were enrolled).  Subjects who discontinue study treatment will be followed for 
subsequent MF treatments and survival. 
Follow-up:  30 to 35 days after the last dose of medication is taken. 
Survival follow-up:  Until subject dies. 
It is estimated that an individual subject will participate for approximately 24 months. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  The end of the study will occur when all 
subjects have completed the follow-up visit or discontinued study. 
4.6. 
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 is to notify the institutional review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or sponsor's designee, and retain 
1 copy for the site study regulatory file. 
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The sponsor may terminate the study electively, or if required by regulatory decision.  If the 
study is terminated prematurely, the sponsor will notify the investigators, the IRBs and IECs, and 
regulatory bodies of the decision and reason for termination of the study. 
5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Each subject will be identified in the study by a unique subject ID number, which is a 
combination of the site ID and subject number.  Site staff will work through the interactive web 
response system (IRT/IWRS) to obtain subject number. 
Enrollment for Part 1 will be controlled by distribution of enrollment slots to the clinical sites by 
the sponsor or its designee.  
Enrollment for Part 2, Part 3, and Part 4 will be controlled by the IRT/IWRS. 
Subjects who are screen failures and are not enrolled in the study will still have data entered into 
the case report form (CRF).  Consult the CRF instructions to determine which CRF pages must 
be completed for screen failures.   
5.1.2. 
Randomization  
For Part 2, Part 3, and Part 4, randomization will occur centrally by IRT/IWRS.  Full details will 
be provided in the INCB 50465-201 Study Manual. 
5.2. 
Cohorts and Treatment Groups  
5.2.1. 
Part 1:  Safety Run-In Portion 
Up to 3 doses of INCB050465 were to be explored in successive cohorts (see Table 4).  All 
subjects would also receive the same ruxolitinib dose regimen that individual subjects were 
taking at the time of the screening visit. 
Table 4: 
Part 1 Treatment Groups 
Cohort 
Dose Regimen 
Cohort 1 
INCB050465 10 mg QD for 8 weeks followed by 
 once-weekly dosing at 10 mg. 
Cohort 2 
INCB050465 20 mg QD for 8 weeks followed by 
 once-weekly dosing at 20 mg 
Cohort 3 
INCB050465 5 mg QD for 8 weeks followed by 
once-weekly dosing at 5 mg 
After the 28-day safety evaluation period, safety run-in subjects may receive additional 
combination therapy of INCB050465 plus ruxolitinib long as adequately tolerated and if no 
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discontinuation criteria are met.  Cohorts 1 and 2 were completed.  No DLTs were observed.  
Part 1 is complete. 
5.2.2. 
Part 2, Part 3, and Part 4 Treatment Groups:  Randomized Portion  
TG10:  Ruxolitinib at stable dose plus INCB050465 at 10 mg QD for 8 weeks followed by 
10 mg once weekly. 
TG20:  Ruxolitinib at stable dose plus INCB050465 at 20 mg QD for 8 weeks followed by 
20 mg once weekly.  Note that enrollment in Part 2 was suspended with implementation of 
Amendment 5. 
TG5:  Ruxolitinib at stable dose plus INCB050465 at 20 mg QD for 8 weeks followed by 
5 mg QD.  Note that enrollment in Part 3 will be suspended with implementation of 
Amendment 6. 
TG5I/M:  Ruxolitinib at stable dose plus INCB050465 at 20 mg QD for 8 weeks followed by 
5 mg QD.  Note this Part 4 dose group is identical to TG5 group in Part 3. 
TG5D:  Ruxolitinib at stable dose plus INCB050465 at 5 mg QD.   
5.2.3. 
Crossover of Part 2 or Part 3 Subjects  
It is anticipated that approximately 15 to 20 subjects will have been enrolled into Part 2.  With 
IRB approval of Protocol Amendment 5 at a given site, subjects randomized to TG10 at that site 
may cross over to either 20 mg QD followed by 5 mg QD after Week 8 (if subject is within the 
first 8 weeks of treatment at the time of crossover), or to 5 mg QD (if subject is beyond 8 weeks 
of treatment and receiving 10 mg once weekly at the time of crossover).  With IRB approval of 
Protocol Amendment 6 at a given site, subjects randomized to TG20 at that site may cross over 
to 5 mg QD once Week 8 has been reached.  All potential crossover subjects must meet all of the 
following criteria: 
1. Spleen size by palpation at most recent visit has decreased  by < 25% from baseline while 
on study. 
2.  Has recent history of adequate bone marrow reserve as demonstrated by the following: 
a. Platelet count ≥ 50 × 109/L in the 4 weeks before crossover. 
b. ANC levels ≥ 0.5 × 109/L in the 4 weeks before crossover. 
3. Has adequate liver function at most recent study visit as demonstrated by the following:  
a. Direct bilirubin < 2.0 × the ULN.  (NOTE: direct bilirubin will only be determined if 
total bilirubin is ≥ 2.0 × ULN). 
b. ALT or AST < 2.5 × ULN. 
4. Has adequate renal function at most recent visit as demonstrated by creatinine clearance 
> 50 mL/min measured or calculated by Cockroft-Gault equation. 
5. Subject has been at least 85% compliant with study drug administration per drug 
accountability assessments at visits to date. 
6. Subject has not developed a cardiovascular or gastrointestinal condition since Day 1 that 
would have excluded him/her from study entry.  
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Subjects who do not meet these criteria, or subjects who do meet the criteria but do not wish to 
cross over, may continue on the originally assigned regimen, and may crossover at any time 
provided the criteria for crossover are met and crossover is determined by subject and 
investigator to represent the best option. 
5.3. 
Study Drugs 
5.3.1. 
INCB050465 
5.3.1.1. 
Description and Administration 
Compound name 
INCB050465 
Dosage strengths 
1 mg, 2.5 mg, 5 mg, and 20 mg 
Form 
Tablet 
Active compound  
INCB050465  
Route of administration 
Oral 
Dose and regimen for 
Part 3 
20 mg QD for 8 weeks followed by randomization to either 5 mg QD or 
20 mg once weekly 
Dose and regimen for 
Part 4 
TG5I/M:  20 mg QD for 8 weeks followed by 5 mg QD until EOT 
TG5D:  5 mg QD from Day 1 until EOT 
Instructions 
INCB050465 will be taken orally with water in a fasted state except on 
mornings of monthly study visits (see Table 9) where they must arrive for 
their study visit in the fasted state for study drug administration at the visit.  
Subjects should refrain from food consumption for at least 1 hour after 
administration of INCB050465. 
For Part 3 subjects only:  Once 8 weeks of daily dosing have been 
completed, subject will switch to either 5 mg QD or 20 mg once weekly, 
beginning the next weekday after the last daily dose: 
Last daily dose 
First weekly dose 
Monday 
Tuesday, then every Tuesday 
Tuesday 
Wednesday, then every Wednesday 
Wednesday 
Thursday, then every Thursday 
Thursday 
Friday, then every Friday 
Friday 
Friday (the following week, then every 
subsequent Friday) 
Note that subjects must be instructed to withhold the morning dose of INCB050465 and to arrive 
in the fasted state until reaching the clinic for each study visit where administration will occur 
(first 24 weeks of therapy only).  The dose must be reduced or interrupted for declining platelet 
count or ANC as described in Section 5.5 and will be increased or restarted with recovery of 
hematologic parameters. 
5.3.1.2. 
Supply, Packaging, and Labeling 
INCB050465 tablets are packaged in high-density polyethylene bottles, no preparation is 
required. 
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All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country and will state "Caution: New Drug--Limited by Federal (or 
United States) law to investigational use." 
5.3.1.3. 
Storage 
Bottles of tablets/capsules should be stored at room temperature, 15°C to 30°C (59°F to 86°F). 
5.3.2. 
Ruxolitinib 
5.3.2.1. 
Description and Administration 
Ruxolitinib will be self-administered as a BID oral treatment using the dose designated as the 
stable dose at the time of the screening visit for each subject.  Acceptable doses are 5 mg BID to 
25 mg BID. 
Doses of ruxolitinib should be self-administered approximately 12 hours apart without regard to 
food. 
Note that subjects must be instructed to withhold the morning dose or ruxolitinib until reaching 
the clinic for each study visit where administration will occur.  The dose may need to be reduced 
or interrupted for declining platelet count or ANC as described in Section 5.5 and will be 
increased or restarted with recovery of hematologic parameters. 
5.3.2.2. 
Supply, Packaging, and Labeling  
Subjects will continue to take the commercial supplies of ruxolitinib that have been prescribed 
for them. 
5.3.2.3. 
Storage 
Bottles of tablets should be stored at room temperature, 15°C to 30°C (59°F to 86°F).  
5.3.3. 
Instruction to Subjects for Handling INCB050465 and Ruxolitinib 
The subject must be instructed in the handling of study drugs as follows: 
• To store at room temperature. 
• To only remove the number of tablets needed from the bottle of INCB050465 at the 
time of administration. 
• Not to remove doses in advance of the next scheduled administration. 
• To make every effort to take doses of INCB050465 and ruxolitinib on schedule. 
• To report any missed doses at the next study visit. 
• Not to take another dose if vomiting occurs taking study drug(s). 
• To keep all study medications out of reach of children. 
• To bring all used and unused study drug kits to the site at each visit.  
• To skip a dose of study drug if it is missed by more than 4 hours and to take the next 
scheduled dose at the usual time. 
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5.4. 
Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the subject by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with INCB050465 administration will be calculated by the sponsor based on the 
drug accountability documented by the site staff and monitored by the sponsor/designee (tablet 
counts).  Subjects will be instructed to bring all used and unused bottles of INCB050465 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 utilized, compliance with ruxolitinib will 
also be documented in the medical record and monitored by the sponsor or its designee.  Subjects 
will record the doses of ruxolitinib taken on a paper diary issued by the site and collected at each 
visit. 
5.5. 
Treatment Interruptions and Adjustments 
5.5.1. 
Dose Modifications 
Selections and modifications to the study drug regimen are planned for dose-escalation cohorts.  
Dose interruptions and modifications also may occur for individual study subjects.  The 
identification of DLTs will define the doses used in planned cohorts (see Table 3 and 
Section 4.1).  Further, the occurrence of DLTs and other toxicities (related or unrelated to study 
drug) will guide decisions for treatment interruptions and discontinuation for individual subjects. 
5.5.2. 
Dose Limiting Toxicities 
See Table 3 and Section 4.1 for definition of DLTs. 
5.5.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications, after 
discussion with the sponsor (whenever possible), necessary to optimally treat the subject. 
5.5.4. 
Follow-Up of Dose-Limiting Toxicities 
Any DLT should be followed until it resolves to baseline or appears to have stabilized for a 
minimum of 2 weeks.  During follow-up, subjects should be seen as often as medically indicated 
to assure safety. 
5.5.5. 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific data and overall safety data, agree on dose escalation, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
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5.5.6. 
Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB050465 
Treatment with INCB050465 may be delayed up to 2 weeks (14 days) to allow for resolution of 
toxicity.  Subjects may resume treatment if no medical condition or other circumstance exists 
that, in the opinion of the investigator, would make the subject unsuitable for further 
participation in the study.  The treating investigator should contact the sponsor to discuss the 
case of any subject whose treatment has been delayed for more than 14 days before restarting 
treatment with INCB050465. 
Table 5 shows dose reduction and interruptions for INCB050465.  Because subjects 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 5 and Table 6).  
Individual decisions regarding dose reduction 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 the study drug 
and the subject's underlying condition.  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 5: 
Guidelines for Interruption and Restarting of INCB050465 
ADVERSE EVENT 
ACTION TAKEN 
Chemistry 
• AST and/or ALT are > 5.0 × ULN. 
Note:  In subjects with bone metastasis-related 
elevations at baseline, contact sponsor to 
discuss clinical management and possible dose 
reductions. 
Step 1:  Interrupt study drug up to 2 weeks (14 days) until the 
toxicity has resolved to ≤ Grade 1 except by approval of the 
medical monitor. 
Step 2:  Restart study drug at same dose.  If assessed as related to 
study drug, restart study drug at next lower dose (or at 25% 
reduction, rounded down to the nearest pill strength); monitor as 
clinically indicated. 
Hematology 
• ANC ≤ 1.0 × 109/L unless because of 
underlying disease.  Applies only if this 
represents a worsening grade from baseline. 
• Platelet count ≥ 50 × 109/L and < 75 × 109/L 
unless because of underlying disease.  
Applies only if this represents a worsening 
grade from baseline. 
Step 1:  Interrupt study drug up to 2 weeks (14 days) until the 
toxicity has resolved to ≤ Grade 1 or pretherapy baseline. 
Step 2:  Restart study drug at same dose and monitor as clinically 
indicated. 
• Grade 4 ANC (< 0.5 × 109/L) regardless of 
baseline grade. 
• ≥ Grade 3 ANC with an oral temperature of 
at least 38.5°C OR with ≥ Grade 3 infection 
regardless of baseline grade. 
• Platelet count is < 50 × 109/L, regardless of 
baseline grade. 
Step 1:  Interrupt study drug up to 2 weeks (14 days) until the 
toxicity has resolved to ≤ Grade 1 or pretherapy baseline. 
Step 2:  Restart study drug at same dose.  If assessed as related to 
study drug, restart study drug at next lower dose; monitor as 
clinically indicated. 
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Table 5: 
Guidelines for Interruption and Restarting of INCB050465 (Continued) 
ADVERSE EVENT 
ACTION TAKEN 
Nonhematologic toxicities 
• Diarrhea/colitis (Grade 1) 
Step 1:  Treat with antimotility agents (eg, 4 mg loperamide 
followed by 2 mg every 4 hours or after every unformed stool) and 
initiate supportive care (see Section 5.5.6.1).  If not improved after 
48 hours, treat per guidance for Grade ≥ 2. 
• Diarrhea/colitis (≥ Grade 2) 
Step1:  Interrupt INCB050465.  Perform work-up for infection 
(including CMV, C. difficile, etc).  Initiate or continue supportive 
care (see Section 5.5.6.1).  Consider colonoscopy with biopsy for 
Grade ≥ 3. 
Step 2:  If infection is ruled out, start oral steroids, or consider IV 
steroids if subject is being given IV fluids.  If no improvement 
with oral steroids, switch to IV steroids. 
When diarrhea resolves to Grade ≤ 1, continue supportive care and 
taper steroids over 4 weeks.  When taper is complete and diarrhea 
is Grade ≤ 1, restart INCB050465 at next lower dose with 
approval of the medical monitor. 
If Grade ≥ 2 diarrhea reoccurs, permanently discontinue 
INCB050465. 
• Pneumonitis (Grade 1) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved.   
Step 2:  Restart INCB050465 at next lower dose.  Monitor as 
clinically indicated. 
• Pneumonitis (≥ Grade 2) 
Permanently discontinue INCB050465. 
• Skin toxicity (eg, rash, pruritus, etc, unless 
otherwise specified) (Grade 2-3) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved to 
≤ Grade 1. 
Step 2: Restart INCB050465 at same dose.  If assessed as related 
to INCB050465, restart at next lower dose. 
• Exfoliative dermatitis (Grade 1) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved. 
Step 2:  Restart INCB050465 at next lower dose.  Monitor as 
clinically indicated. 
• Exfoliative dermatitis (≥ Grade 2) 
Permanently discontinue INCB050465. 
• Intestinal perforation (any grade) 
Permanently discontinue INCB050465. 
• Pneumocystis jirovecii pneumonia infection 
Interrupt INCB050465.  Permanently discontinue INCB050465 if 
Pneumocystis jirovecii pneumonia infection is confirmed. 
• CMV infection 
Subjects with CMV viremia without associated clinical signs of 
CMV infection should be carefully monitored.  Consider 
interrupting INCB050465 for subjects with CMV viremia and 
clinical signs of infection until the infection has resolved.  Restart 
INCB050465 reduced by 1 dose level if approved by the medical 
monitor. 
• Varicella zoster infection 
Interrupt INCB050465.  Restart INCB050465 only by approval of 
the medical monitor. 
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Table 5: 
Guidelines for Interruption and Restarting of INCB050465 (Continued) 
ADVERSE EVENT 
ACTION TAKEN 
• Any Grade 1 or Grade 2 toxicity unless 
otherwise specified. 
Continue study drug 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 study drug up to 2 weeks (14 days) until toxicity 
resolves to ≤ Grade 1. 
Step 2:  Restart INCB050465 at same dose.  If assessed as related 
to INCB050465, restart at next lower dose.  If interrupted for 
> 14 days, contact the medical monitor for approval to restart 
INCB050465.  Monitor as clinically indicated. 
• Any recurrent Grade 3 toxicity after 2 dose 
reductions. 
Discontinue study drug administration and follow-up per Protocol.  
(Exceptions require approval of sponsor.) 
• Any other Grade 4 toxicity. 
Discontinue study drug administration and follow-up per Protocol.  
Exceptions require approval of sponsor. 
Table 6: 
Dose Levels for INCB050465 
Starting Dose Level 
First Dose Reduction 
Second Dose Reduction 
20 mg daily 
10 mg daily 
5 mg daily 
20 mg weekly 
10 mg weekly 
5 mg weekly 
5 mg daily 
2.5 mg daily 
1 mg daily 
5.5.6.1. 
Supportive Care Guidelines for Diarrhea/Colitis 
Subjects should be informed to immediately report to the investigator any event of diarrhea.  
Subjects should receive appropriate supportive care measures as deemed necessary by the 
investigator.  For any ≥ Grade 1 diarrhea, subjects 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.  Subjects should try to eat 5 to 6 small meals per day; low-fat, 
high-protein foods; and cooked instead of raw vegetables.  Subjects 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.  Subjects should avoid fried, fatty, 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 as 
symptoms may worsen when the steroid dose is decreased. 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain or cramping, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
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5.5.6.2. 
Definition for Immune-Related Adverse Events 
Adverse events of a potential immunologic etiology, or immune-related AEs (irAEs), 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 INCB050465 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 Study INCB 50465-101, 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. 
Subjects 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 5 and Section 5.5.6.1.  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. 
5.5.7. 
Criteria for Permanent Discontinuation of INCB050465 
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 
subject's ability to continue study-specific procedures or is considered to not be in the 
subject's best interest. 
• An AE requiring more than 2 dose reductions (exception requires sponsor approval). 
• Persistent AE requiring a delay of therapy for more than 2 weeks (14 days), unless a 
greater delay has been approved by the sponsor. 
5.5.8. 
Criteria and Procedures for Dose Interruptions or Adjustments for Ruxolitinib 
Dose modifications of ruxolitinib because of toxicity are not required unless INCB050465 
modifications/interruptions have been first implemented for 14 days with no improvement 
in toxicity grade.  In such a case, a brief interruption or dose decrease may be needed.  Dose 
interruptions and modifications for ruxolitinib because of hematologic toxicity that continues 
after interruption of INCB050465 are shown in Table 7. 
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Table 7: 
Dose Reductions/Interruptions and Restarts for Hematologic Toxicities That 
Persist for > 14 Days After Interruption of INCB050465 
ANC 
(× 109/L) 
 
Platelet Count 
(× 109/L) 
Dose of Study Drug (Ruxolitinib) 
Value 
CTCAE 
Grade 
Value 
CTCAE 
Grade 
0.5 to < 1.0 
3 
or 25 to < 50 
3 
In case of hematological toxicity, INCB050465 will be the first 
drug to be interrupted, as this is the newly added agent.  If the 
Grade 3 cytopenia persists > 14 days after interrupting 
INCB050465 or if the primary investigator deems that earlier 
ruxolitinib interruption 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 > 14 days after interrupting 
INCB050465 or if the primary investigator deems that earlier 
ruxolitinib interruption 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. 
< 0.5 
4 
or 
< 25 
4 
In case of hematological toxicity, INCB050465 will be the first 
drug to be interrupted as this is the newly added agent.  If 
Grade 4 neutropenia occurs and persists > 14 days after 
interrupting INCB050465 or if the primary investigator deems 
that earlier ruxolitinib interruption is necessary, then ruxolitinib 
will be interrupted until the toxicity 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. 
If Grade 4 thrombocytopenia occurs and persists > 14 days after 
interrupting INCB050465 or if the primary investigator deems 
that earlier ruxolitinib interruption is necessary, then the 
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. 
Neutropenic fever 
INCB050465 will be the first drug to be interrupted as this is the 
newly added agent.  If the neutropenia (ANC < 1.0) persists 
> 14 days after interrupting INCB050465 or if the primary 
investigator deems that earlier ruxolitinib interruption is 
necessary, then the 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. 
Dose reductions to daily doses below 5 mg BID are not recommended and will result in the 
discontinuation of the subject from the study.  All changes in dose should be recorded in the 
CRF, and the subject should be notified by phone with written follow-up in cases where 
laboratory data subsequent to a study visit indicate that a dose change is required. 
Except for the hematologic criteria specified above, interruption of ruxolitinib for safety reasons 
is at the discretion of the investigator with approval from the medical monitor.  In some 
circumstances, it may be necessary to temporarily interrupt treatment as a result of adverse 
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experiences that may have an unclear relationship to study drug or thought to be more likely 
attributable to the ruxolitinib.  Except for cases specified in Table 5, restart of study drug 
administration should occur at the original dose.  If the same AE recurs after restart of study 
drug, the investigator should consider reducing the study drug dose for any subsequent restart 
after recovery. 
5.6. 
Withdrawal of Subjects From Study Treatment 
5.6.1. 
Withdrawal Criteria 
A subject must be withdrawn from study treatment (INCB050465 and ruxolitinib) for the 
following reasons: 
• The subject has had an unacceptable toxicity or a toxicity that does not recover within 
14 days of drug interruptions.  Investigators who wish to continue treatment after a 
delay of > 14 days must consult with the sponsor's medical monitor for approval to 
continue/restart study treatment. 
• The subject becomes pregnant. 
• Consent is withdrawn.  NOTE: Consent withdrawn means that the subject will no 
longer be followed.  Subjects may choose to discontinue study treatment but remain 
on study to be followed for survival.   
• Further participation would be injurious to the health or well-being, in the 
investigator's medical judgment. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued from study treatment as follows: 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, then the sponsor should be consulted for instruction on 
handling the subject. 
5.6.2. 
Withdrawal Procedures 
The decision to discontinue study treatment (eg, INCB050465 and ruxolitinib) will not 
constitute study withdrawal or study completion.  In the event that the decision is made to 
discontinue study treatment, the treatment portion will be considered complete and the follow-up 
portion will begin.  Subjects who discontinue treatment with the study drug will be followed for 
subsequent MF treatment regimens and survival. 
Upon discontinuation of study treatment, the EOT visit should be completed as outlined in the 
schedules of assessments (Table 8 and Table 9).  The date of the last dose of study drug will be 
recorded in the CRF, and the reason for subject withdrawal will be recorded.  After 
discontinuation of study treatment, the subject will remain in the follow-up portion of the study, 
and site staff will conduct phone calls at approximately 12-week intervals to the study subject to 
collect data on subsequent MF treatment regimens and survival. 
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If a subject is withdrawn from the study: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the CRF. 
• The EOT visit should be performed. 
• The EOT data will be reported to IXRS. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
If the subject discontinues study 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, subjects will have the option of withdrawing consent for study treatment 
but continuing in the follow-up period of the study for safety/efficacy assessments. 
5.7. 
Concomitant Medications 
5.7.1. 
Pneumocystis Pneumonia Prophylaxis 
All subjects receiving combination study treatment with INCB050465 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, dapsone with or without pyrimethamine, and 
pentamidine (NCCN 2016).  Subjects with sulfonamide allergy should be treated with either 
inhaled pentamidine or atovaquone for PJP prophylaxis; dapsone should not be used in such 
subjects.  Prophylaxis should be given while subjects are receiving INCB050465 and continue 
for 2 to 6 months after the last dose of INCB050465. 
5.7.2. 
Permitted Medications 
All concomitant medications and treatments must be recorded in the CRF.   
5.7.3. 
Restricted Medications 
• 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 with long elimination half-lives; subjects should be 
monitored closely for toxicity, especially for myelosuppression and renal and 
gastrointestinal toxicity. 
• Inducers of CYP3A4 (Appendix B) may be used with caution, and investigators 
should seek other options if available. 
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• Moderate CYP3A4 inhibitors (Appendix B) 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, then the ruxolitinib dose may be 
reduced from BID to QD in these circumstances; this should be clearly documented 
in the treating physician 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. 
5.7.4. 
Prohibited Medications 
The following medications are prohibited during the treatment and maintenance portions of the 
study: 
• Any concurrent MF therapy other than that specified in the Protocol. 
• Any investigational medication 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. 
• Use of potent inhibitors of CYP3A4 (eg, ketoconazole, clarithromycin, itraconazole, 
nefazodone or telithromycin, voriconazole or posaconazole; see Appendix B).  
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 medication through 
the safety follow-up visit. 
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments (Table 8), 
and all laboratory assessments will be performed as indicated in Table 9.  Table 10 presents a 
summary of clinical laboratory analytes to be assessed.  Table 11 provides the PK analysis 
sample collection plan.  The order of assessments is suggested by the order of mention within the 
schedule.  See Section 7 for instructions on each assessment.  Further details of study procedures 
and assessments can be found in the study reference manual.
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11 OCT 2018 
 
Table 8: 
Schedule of Assessments – Part 1, Part 2, Part 3, and Part 4 
Visit Day (Range) 
Screening 
Day -35 to 
Day -8 
Baseline 
Day -7 to 
Day -1 
Day 1 
End of 
Week 2 
End of 
Weeks 
4, 8 
± 5 
Days 
End of 
Week 
12 
± 5 
Days 
End of 
Weeks 
16, 20 
± 5 
Days 
End of 
Week 
24 
± 5 
Days 
Extension 
Visits (Q12W 
After 
Week 24) 
± 7 Days 
EOT or 
Early 
Termination 
Visit 
± 5 Days 
Follow-Up 
30-35 Days 
After Last 
Dose of 
INCB050465 
Survival 
Follow-
Up 
Every 
12 Weeks 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Contact IXRS 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Prior medical & medication history  
X 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication review 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Transfusion history/status 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Screening Symptom Form 
X 
 
 
 
 
 
 
 
 
 
 
 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive physical 
examination 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Targeted physical examination 
 
 
 
 
X 
X 
X 
 
X 
X 
 
 
Spleen palpation 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Bone marrow biopsy
a 
X 
X 
 
 
 
 
 
X 
Xa 
 
 
 
MRI/CT of the upper and lower 
abdomen and pelvis 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
Dispense and/or bring MFSAF v3.0 
diary to visit 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
ECOG status 
X 
 
 
 
 
 
 
X 
 
 
X 
 
PGIC
b 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
IWG-MRT assessment
c 
 
 
 
 
 
 
 
X 
X 
 
 
 
Modified MFSAF v3.0 diary 
(Appendix E) 
 
Completed every evening from baseline through Week 24 
 
 
 
 
MPN-SAF (Appendix F) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Laboratory assessments
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense reminder card 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Administer study drug during visit 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dispense study drug 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
Drug accountability assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Survival follow-up data collection
e 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG = electrocardiogram; PGIC = Patient Global Impression of Change. 
a Bone marrow biopsy must be completed at screening or baseline visit, unless biopsy and data from previous 2 months are available.  Additional biopsies will be performed at 
Week 24, Week 48, and every 24 weeks. 
b Patient Global Impression of Change (Appendix H). 
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Protocol INCB 50465-201 Am 6 
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11 OCT 2018 
 
c International Working Group response will be assessed at Week 24 and every 24 weeks thereafter. 
d See Table 9 and Table 10. 
e After discontinuation of INCB050465, the subject will remain in the follow-up phase of the study, and site staff will conduct phone calls at approximately 12-week intervals to 
collect data on subsequent MF therapy and survival.  
CONFIDENTIAL 


Incyte Corporation 
Page 64 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
 
Table 9: 
Schedule of Laboratory Assessments – Part 1, Part 2, Part 3, and Part 4 
 
Screening Baseline Day 1 
Weeks 
1, 3 
(Day 8, 
22) 
Part 1 
ONLY 
End of 
Weeks 
2, 6, 10, 
14, 18, 
22, then 
Q4W 
End of 
Weeks 
4, 8, 12, 
16, 20, 
24, then 
Q12W 
EOT or 
Early 
Termination 
Visit  
Follow-Up 
30-37 Days 
After Last 
Dose of 
INCB050465 
Notes 
Window 
 
 
 
The window for laboratory visits is ± 3 days 
 
Local Laboratory Assessments 
 
 
 
 
 
 
 
 
 
Serum chemistries 
X 
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. 
Hematology 
X 
X* 
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. 
Coagulation panel 
X 
 
 
 
 
X* 
X 
X 
*Required Weeks 12 and 24 and Q12W. 
Urine pregnancy test 
 
X 
 
 
 
X* 
X* 
 
All female subjects of childbearing potential. 
*Pregnancy tests should be repeated if required 
by local regulations. 
Bone marrow biopsy, aspirate, 
and analysis 
X* 
 
 
 
 
X** 
 
 
*Predose biopsy/aspirate  is not required if 
biopsy has occurred in previous 2 months as 
long as biopsy/aspirate  and data are available 
for review by investigator and/or sponsor. 
**Week 24 and Q24W.  Samples of biopsy and 
unstained slides will be sent to a central vendor. 
Central Laboratory Samples* 
 
 
 
 
 
 
 
 
*The central laboratory is the sponsor or 
sponsor's designee. 
Lipid panel (requires overnight 
fast) 
X 
 
 
 
 
X* 
X 
 
*Required Weeks 12 and 24 and Q12W. 
Serology - hepatitis and HIV 
X 
 
 
 
 
 
 
 
HBV, HCV, HIV 
Serology - CMV 
X 
 
 
 
 
X* 
 
 
* CMV measured at Weeks 4, 8, 12, then Q12 
weeks. 
Urinalysis 
X 
 
 
 
 
X* 
 
X 
*Required Weeks 12 and 24 and Q12W. 
Serum pregnancy  
X 
 
 
 
 
 
 
X 
All female subjects of childbearing potential. 
FSH  
X 
 
 
 
 
 
 
 
To document hormonal menopause. 
PK samples 
 
 
X 
 
X* 
X* 
 
 
*PK sampling will occur on Day 1, Week 2, and 
Week 4 only.  See Table 8. 
CONFIDENTIAL 


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Page 66 of 124 
Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
 
Table 10: 
Laboratory Tests:  Required Analytes 
Serum Chemistries 
Hematology 
Urinalysis With Microscopic 
Examination 
Serology 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST  
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride  
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total 
bilirubin is elevated above 
ULN) 
Total protein 
Uric acid 
Complete blood count, 
including: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
Blasts 
 
Differential count, including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Blasts 
Absolute values must be 
provided for:  
Lymphocytes 
Neutrophils 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Hepatitis B surface antigen 
Hepatitis B surface antigen 
antibody 
Hepatitis B core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
CMV DNA 
HIV testing 
PT 
PTT 
INR 
Lipid Panel 
Other 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
LDL 
HDL 
FSH (only at screening to 
verify hormonal 
menopause) 
Female subjects of 
childbearing potential only 
require a serum test at 
screening 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. 
HDL = high-density lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein; PTT = partial thromboplastin time; PT = prothrombin time. 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
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Protocol INCB 50465-201 Am 6 
Version 6 
11 OCT 2018 
Table 11: 
Schedule of Pharmacokinetic Sampling for Part 1, Part 2, Part 3, and Part 4 
Study Day 1 
Week 2 
Week 4 
Subject arrives having withheld both 
INCB050465 and ruxolitinib
a 
Predose sample = Time 0 sample 
Administer ruxolitinib 
Timed samples
b: 
1 hour postdose 
2 hour postdose
c 
4 hour postdose 
Administer INCB050465 
Subject arrives having withheld both 
INCB050465 and ruxolitiniba 
Predose sample = Time 0 sample 
Administer INCB050465 
Timed samplesb: 
1 hour postdose 
2 hour postdosec 
4 hour postdose 
Administer ruxolitinib 
Subject arrives having withheld both 
INCB050465 and ruxolitiniba 
Predose sample = Time 0 sample 
Administer INCB050465 plus 
ruxolitinib 
Timed samplesb: 
1 hour postdose 
2 hour postdosec 
4 hour postdose 
a Subjects are also to arrive at the study visits in the fasted state. 
b Window for 1-, 2-, and 4-hour collections is ± 15 minutes. 
c Subjects may eat after the 2-hour timepoint sample has been drawn.  
6.1. 
Screening 
Screening is the interval between signing the ICF and the beginning of the 7-day baseline period 
(ie, Day -35 to Day -8).  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. 
Subjects should arrive for the screening visit after an overnight fast of at least 8 hours or since 
midnight.  A subject who has not fasted should be scheduled for the screening assessment blood 
draws on a morning when he/she can arrive after an overnight fast of at least 8 hours or since 
midnight. 
Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
serum chemistry) and obtained before signing of informed consent 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 28 days before Day 1).  All information associated with 
eligibility requirements must be entered into the appropriate CRF pages.  Eastern Cooperative 
Oncology Group assessment will be used to stratify subjects for Parts 2, 3, and 4 and must be 
reported via IXRS at the time. 
Bone marrow biopsy (and additional aspirate collection) for confirmation of MF diagnosis and 
degree of fibrosis must be performed at the screening or baseline visit intervals.  NOTE:  
Subjects without circulating blasts at the screening hematology assessment may use a historical 
biopsy obtained within 2 months before screening, and all data and reports are available for 
investigator's review.  Subjects without a prior biopsy report as indicated above must have a 
biopsy at screening or baseline or will not be able to enroll in the study.  The prior data will need 
to be entered into the CRF for this study, with explanation as to the origin of the data (date of 
biopsy/aspirate). 
Results from the screening visit evaluations will be reviewed to confirm subject 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 
CONFIDENTIAL 


Incyte Corporation 
Page 68 of 124 
Protocol INCB 50465-201 Am 6 
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11 OCT 2018 
result before randomization/treatment assignment will be used to determine subject eligibility.  
Treatment should start as soon as possible, but within 3 days after the date of 
enrollment/randomization.  Additionally, a subject 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).  In this case, a new subject number must be assigned via IXRS.   
6.2. 
Baseline 
Subjects who have signed the ICF and meet all the entry criteria (see Section 3) 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 INCB050465 and 
during which the baseline MRI (or CT scan in applicable subjects) and symptom diary will be 
initiated. 
• The modified MFSAF v3.0 diary (Appendix E) should be distributed.  Subjects will 
be issued a hand-held device and will complete the diary questions each night 
beginning on Day -7 up to the Week 24 visit.  Subjects will be instructed to place the 
device on the docking station (also provided) for automatic data transmittal each night 
after completing the questions.  Subjects will be instructed to leave the device in the 
docking station when not answering the questions so that the unit remains fully 
charged.  Subjects will receive training on the device by study site staff before 
leaving the site.  Subjects will bring the device with them to study visits on Day 1, 
Week 4, Week 8, Week 12, Week 16, and Week 20 so that the device charging can be 
verified and to download accumulated data.  The device will then be returned to the 
subject at these same visits for continued use each night.  Subjects will return the 
device and the docking station for the final time at the Week 24 Visit, so that all data 
can be archived. 
• The MRI (or CT scan in applicable subjects) should be conducted on the first or 
second day of the baseline interval to allow ample time for the laboratory to verify 
scan quality.   
• Blood samples for hematology and serum chemistry analyses should be taken as close 
as possible to Day 1 but may be drawn up to 3 days before first dose of INCB050465.  
This blood sample will serve as the pre-INCB050465 baseline sample; a Day 1 
sample is not required provided the baseline sample is within 3 days of the first dose 
of INCB050465. 
6.3. 
Treatment 
The treatment period begins with the first dose of INCB050465 (Day 1) through the point at 
which the investigator determines the subject will be permanently discontinued from study drug. 
There will be study visits and laboratory-only visits in the study.  Table 8, Table 9, and Table 10 
provide the scheduled assessments for each study visit and laboratory-only visit. 
Subjects will have a regularly scheduled study visit at screening, baseline, Day 1, and after 4, 8, 
12, 16, 20, and 24 weeks of treatment (ie, visits designated Week 4, Week 8, Week 12, Week 16, 
Week 20, and Week 24) and then every 12 weeks thereafter if continuing on treatment, where 
blood samples, spleen measurements, and other assessments will be obtained.  There is also a 
CONFIDENTIAL 


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Protocol INCB 50465-201 Am 6 
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11 OCT 2018 
6.5. 
Follow-Up 
6.5.1. 
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 drug 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 drug, 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 subject return for the follow-up visit and report any AEs that may 
occur during this period.  If the subject cannot return to the site for the safety follow-up visit (eg, 
lives far away), then the subject should be contacted by telephone for assessment of AEs and 
SAEs.  Sites must document this contact in the source. 
Subjects are required to remain on PJP prophylaxis for at least 2 to 6 months after the last dose 
of study drug (see Section 5.7.1) and should be reminded of this at the safety follow-up visit.  
Sites should follow up with subjects to confirm that they have been compliant with the 
prophylactic treatment for the duration of this period. 
6.5.2. 
Survival Follow-Up 
Once a subject has received the last dose of study drug, the subject moves into the survival 
follow-up period and should be contacted by telephone, email, or visit at least every 12 weeks to 
assess for subsequent MF treatments and survival status until death, withdrawal of consent, or 
end of study (EOS), whichever occurs first. 
6.6. 
End of Study 
The EOS will occur when the last enrolled/randomized subject has completed the follow-up visit.  
6.7. 
Unscheduled Visits 
Unscheduled visits may be held at any time at the investigator's discretion, and appropriate 
clinical and laboratory measurements may be performed based on AEs or other findings. 
CONFIDENTIAL 


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Protocol INCB 50465-201 Am 6 
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11 OCT 2018 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2. 
Interactive Web Response System Procedure 
The IWRS will be accessed to obtain a subject ID number when a subject enters the screening 
portion.  Upon determining that the subject is eligible for study entry, and using the screening 
ECOG score, the IWRS will be contacted to obtain treatment group and study drug assignment.  
Additionally, the IWRS will be contacted at each regular study visit to update the study drug 
supply.  Full details will be provided in the IWRS manual. 
7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History    
Demographic data will be collected at screening, including age, sex, race, and ethnicity.  A 
complete medical history will be obtained. 
7.3.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history will be collected at screening.  Date of MF 
diagnosis and prior bone marrow biopsy data as to fibrosis stage will be recorded.  All treatments 
for MF, including a complete history of ruxolitinib usage, will be recorded. 
7.3.3. 
Transfusion History Status 
All transfusions of RBC products or platelets from at least 16 weeks before the screening visit 
will be recorded.  The product(s) delivered, date of transfusion, and units delivered will be 
recorded on the CRF. 
7.3.4. 
Screening Symptom Form 
In order to satisfy inclusion Criterion 4,  active symptoms of MF at the screening visit as 
demonstrated by presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening 
Symptom Form (Appendix D) will be recorded on the CRF.  
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7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
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 INCB050465 
and up to the end of study will be recorded in the CRF.  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 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 subject's medical condition during the 
study will also be recorded in the CRF. 
7.5. 
Safety Assessments 
7.5.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and CRFs regardless of the assumption of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
7.5.2. 
Physical Examinations 
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
7.5.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination will include height (at screening) 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 comprehensive physical examination should also 
include an assessment of body fluid abnormalities including ascites and edema. 
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7.5.2.2. 
Targeted Physical Examination 
A targeted physical examination will be a symptom-directed evaluation and will include 
assessment(s) of the body systems or organs, as indicated by subject symptoms, AEs, or other 
findings as determined by the investigator or designee.  A targeted physical examination must 
include a measurement of the subject's body weight (within 1 lb. or 0.5 kg), including an 
assessment of body fluid abnormalities of edema and ascites, and an evaluation of any AEs or 
symptoms that the subject has had previously. 
7.5.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the subject in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Clinically notable abnormalities that are considered 
clinically significant in the judgment of the investigator are to be reported as AEs. 
7.5.4. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semi recumbent position 
after 5 minutes of rest.  Electrocardiograms will be performed at the screening visit, Week 24 
and the EOT visits, or as clinically indicated at investigator discretion.  
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
subject management.  The decision to include or exclude a subject or withdraw a subject from 
the study 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 relative to the screening ECG that are considered clinically significant in 
the judgment of the investigator are to be reported as AEs. 
7.6. 
Efficacy Assessments 
7.6.1. 
Bone Marrow Biopsy 
Bone marrow biopsy (and additional aspirate collection) will be collected at screening, at 
Week 24, and every 24 weeks thereafter.  Subjects without circulating blasts at the screening 
hematology assessment may use a historical biopsy obtained within the 2 months before 
screening, and all data and reports are available for investigator's review.  The previous data will 
need to be entered into the CRF for this study, with explanation as to the origin of the data (date 
of biopsy/aspirate).  Subjects without a previous biopsy report as indicated above must have a 
biopsy at screening or baseline or they will not be able to enroll in the study.  Collection, 
processing, and staining of bone marrow samples will be performed in accordance with standard 
procedures at the investigative sites.  The bone marrow biopsy and optional aspirate should be 
assessed by an experienced hematopathologist using his/her standard examination.  Samples of 
bone marrow biopsy and aspirate will be sent to Incyte or its designee for additional immune and 
molecular profiling. 
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7.6.2. 
Spleen Palpation 
Spleen length will be assessed by manual palpation at every study visit (laboratory-only visits 
not included) and will be used for routine subject management.  Investigators will be provided 
with a soft centimeter ruler so that palpable spleen length is measured in centimeters and not in 
finger breadths.  The edge of the spleen shall be determined by palpation and measured in 
centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion.  
Spleen length must be recorded on the CRF. 
7.6.3. 
Imaging  
The primary measure of spleen size will be by MRI (or CT scan in applicable subjects).  An MRI 
of the upper and lower abdomen and pelvis will be performed at baseline, Week 12 and 
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, not to find very small lesions.  The 
MRIs will be read initially by local radiologists who will 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 subject will be read by a central reader.  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, as there are no validated approaches for determining this measurement.  
Procedure-specific training for scanning and image capture will be provided by the vendor. 
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 subject 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 subject 
unless a new contraindication to the use of MRI occurs (eg, pacemaker insertion). 
7.6.4. 
Symptom Diary 
Symptoms of MF will be assessed using a symptom diary (modified MFSAF v3.0 diary; 
Appendix E).  Subjects will be issued a hand-held device on which to record answers to queries 
regarding MF symptoms.  Symptoms assessed will include filling up quickly/early satiety, 
abdominal discomfort, abdominal pain, inactivity, night sweats, itching, and bone/muscle pain.  
The modified MFSAF v3.0 diary will be completed by subjects each night beginning at Day -7 
(first day of baseline) and continuing to the Week 24 visit (25 weeks total).  Subjects 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:  Subjects 
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 subject at these same visits for 
continued use each night.  The subject 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 modified MFSAF v3.0 diary will be provided in a reference manual.  
French and Spanish translations of the modified MFSAF v3.0 diary will be available. 
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7.6.5. 
Myeloproliferative Neoplasms Symptom Assessment Form 
The MPN-SAF (Emanuel et al 2012; Appendix F) will be completed by subjects at the study 
visits noted in Table 8.  
7.6.6. 
Eastern Cooperative Oncology Group Status 
Eastern Cooperative Oncology Group performance scores (see Appendix G) will be required at 
screening to evaluate eligibility and stratification category and will be assessed at other study 
visits noted in Table 8. 
7.6.7. 
Patient Global Impression of Change 
The PGIC will be administered at each visit beginning with Week 4 and consists of a single 
question to which the subject answers on a scale of 1 to 7.  See Appendix H. 
7.6.8. 
IWG-MRT Assessment 
Overall response assessment will be graded according to the IWG consensus criteria for 
treatment response in PMF, PPV-MF, and PET-MF (Tefferi et al 2013).  International Working 
Group–MRT assessment will be performed at Week 24 and every 24 weeks thereafter as per 
Table 8.  Recently published response criteria developed by the IWG on MF will be utilized in 
this study (Tefferi et al 2013) and are defined as described in Appendix I.   
7.7. 
Laboratory Assessments 
Refer to Table 9 and Table 10 for the schedule of laboratory assessments and the laboratory tests 
that will be performed.  All blood draws for laboratory assessments will be performed before 
administration of INCB050465 or morning ruxolitinib dose.  
7.7.1. 
Chemistry   
Serum chemistries will be performed by the local laboratory using institutional best practices.  
Results and normal reference ranges will be entered onto the CRF.     
7.7.2. 
Hematology 
Hematology assessments including complete blood count with differential will be performed at 
the local laboratory using institutional best practices.  Results and normal reference ranges will 
be entered onto the CRF. 
7.7.3. 
Urinalysis 
Urinalysis will be performed by a central laboratory. 
7.7.4. 
Coagulation 
Coagulation parameters will be determined at the local laboratory using institutional best 
practices.  Results and normal reference ranges will be entered onto the CRF. 
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7.10. 
Other Study Procedures 
7.10.1. 
Distribution of Subject Reminder Cards  
Subjects will be provided with a reminder card at each visit.  The subject reminder card will 
indicate the date and time of the next visit, remind subjects to hold their morning dose of both 
INCB050465 and ruxolitinib on the day of the visit (all study visits including Week 2, not 
laboratory-only visits), and remind subjects that overnight fast of at least 12 hours is required for 
all study visits (including Week 2, not laboratory-only visits).  Space will be provided on 
reminder cards for the Week 2 and Week 4 visit to record the time of the evening dose of 
ruxolitinib for the day before these visits.   
7.10.2. 
Data Collection for Survival Follow-Up 
For subjects having entered the survival follow-up period of the study, the site will use 
continuing subject records to supply data on subsequent treatment regimens, tumor assessments 
(if discontinued treatment for a reason other than progression), and overall survival in the CRF.  
For subjects who do not intend to return to the study investigator for their ongoing care, 
follow-up should be maintained by phone contact, subject records, and public records/databases 
at intervals of no longer than 12 weeks. 
8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an AE is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related, that occurs 
after a subject provides informed consent.  Abnormal laboratory values or test results occurring 
after informed consent constitute AEs only if they induce clinical signs or symptoms, are 
considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the CRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the CRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 30 days after the last dose of study.  Adverse events 
(including laboratory abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible rather than by individual underlying signs and symptoms.  When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
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When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE (eg, 
resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the CRF. 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 4.  The CTCAE 
v4.03 severity of Grade 5 will not be used; AEs resulting in death will be graded accordingly 
using Grades 1 through 4 and have the outcome noted as fatal.  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: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention 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 intervention indicated. 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per SAE definition provided in Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the CRF. 
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Once an AE is detected, it should be followed 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 drug, the interventions required to 
treat the event, and the outcome. 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an 
AE, which lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
reported as an AE with a start date equal to the day the event met the Grade 1 AE definition and 
a stop date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The 
Grade 3 event will also be reported as an AE, with the start date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the CRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 (severe) AE does not automatically indicate an SAE unless it meets the definition 
of serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may 
be required (see Section 5.5) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition.   
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
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− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant 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 subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study drug(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 30 days after the last dose of study drug, whichever is later) must be reported to 
the sponsor (or designee) within 24 hours of learning of its occurrence, unless otherwise 
specified by the Protocol.  Any SAEs occurring more than 30 days after the last dose of study 
drug should be reported to the sponsor or its designee only if the investigator suspects a causal 
relationship to the study drug.   
Information about all SAEs is collected and recorded on the Adverse Event form of the CRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatments (INCB050465 and ruxolitinib).   
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Causality must be assessed for INCB050465, for ruxolitinib and for 
the combination.  Refer to the Incyte Reference Guide for Completing the Serious Adverse Event 
Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study participation).  Each 
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recurrence, complication, or progression of the original event should be reported as follow-up to 
that event, regardless of when it occurs. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification (IN) to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.5.8 for the maximum permitted duration of study drug interruption). 
• 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. 
Data on fetal outcome and breastfeeding 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. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
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8.6. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the Investigator's Brochure (IB).  Additional safety 
information collected between IB updates will be communicated in the form of Investigator 
Notifications (INs).  Any important new safety information should be discussed with the 
subject during the study, as necessary.  If new significant risks are identified, they will be added 
to the ICF. 
8.7. 
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 email 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 reported as described in Section 8.1.2 of this Protocol. 
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. 
9. 
STATISTICS 
9.1. 
Study Populations 
The intent-to-treat (ITT) population includes all randomized subjects.  
The per protocol population includes all randomized subjects who were sufficiently compliant 
with the Protocol.  Specific criteria for this population will be defined in the Statistical Analysis 
Plan (SAP). 
The safety population includes all randomized subjects who received at least 1 dose of study 
drug.   
The safety run-in population includes all subjects enrolled in the safety run-in portion of the 
study (Part 1) taking at least 1 dose of study drug. 
The PK
evaluable population includes all subjects who received at least 1 dose of study drug 
and provided at least 1 sample for PK
  
9.2. 
Selection of Sample Size 
The sample size and power calculations for the randomized portion of the study are based on a 
2-sample Wilcoxon rank sum test with a normal approximation applied to the test statistic.  For a 
2-sided Type I error of 0.10 and Type II error of 0.10 with 30 subjects per treatment group, the 
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test is powered to detect an 11.4 percentage point location shift between the 2 groups in regards 
to percentage change in spleen volume.  The 2 populations are assumed to be normally 
distributed with a common standard deviation of 14.5. 
9.3. 
Level of Significance 
The level of significance for detecting a difference between TG5D and TG5I/M + TG5 for the 
primary endpoint is 10% (2-sided).  In other words, there is a 10% risk of declaring a difference 
in the percentage change in spleen volume between the 2 groups when it is not so. 
9.4. 
Statistical Analyses 
A full description of all analyses will be included in the SAP document. 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary Efficacy Analyses 
The primary endpoint is change in percentage spleen volume from baseline at 12 weeks as 
measured by MRI (or CT scan in applicable subjects).  Statistical comparisons between treatment 
groups for the primary endpoint will only be performed between subjects randomized to TG5D 
and TG5I/M + TG5 in Parts 3 and 4 of the study. 
A location shift in percentage change in spleen volume between TG5D and TG5I/M accounting 
for stratification by ECOG performance status at screening (ECOG 0-1 vs 2) will be assessed 
using a van Elteren test (van Elteren 1960).   
Within each stratum, subjects who discontinue from the study or who have missing values for the 
Week 12 spleen volume will be imputed as having the largest possible increase in percentage 
spleen volume and given the lowest rank in the stratum.  The subject with the largest percentage 
reduction in spleen volume in a stratum will be given the highest rank within the stratum.  In the 
case of ties, average ranks will be assigned.  
If the randomized portion of the study fails to enroll a sufficient number of subjects in a 
particular stratum, then the primary endpoint will be assessed using a 2-sample Wilcoxon rank 
sum test with a normal approximation applied to the test statistic, for purposes of calculation 
stability.  Ranking will be carried out using the same approach but without stratification. 
Results for subjects enrolled to TG10 and TG20 will be summarized descriptively with no formal 
statistical comparisons performed. 
9.4.1.2. 
Secondary Efficacy Analyses 
Secondary efficacy analyses will be conducted for the ITT population.  Change and percentage 
change from baseline in quantitative variables will be summarized using descriptive statistics.  
Results for subjects enrolled to TG10 and TG20 will be compared descriptively to those of the 
other treatment groups, but no direct statistical comparisons are planned.  A location shift in 
percentage change in total symptom score evaluated by the MFSAF v3.0 symptom diary and the 
MPN-SAF between TG5D and TG5I/M + TG5 in Parts 3 and 4 of the study accounting for 
stratification by ECOG performance status will be assessed separately using a van Elteren test 
with the same approach applied for the primary endpoint.  If the randomized portion of the study 
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fails to enroll a sufficient number of subjects in a particular stratum, then the location shift in 
percentage change in total symptom score evaluated by the MFSAF v3.0 symptom diary, and the 
MPN-SAF between the 2 treatment groups will be assessed separately using a 2-sample 
Wilcoxon rank sum test with a normal approximation applied to the test statistic.  The number of 
subjects with responses according to the 2013 IWG consensus criteria will be tabulated.  Patient 
Global Impression of Change scores will be tabulated at scheduled assessments. 
9.4.1.3. 
Other Efficacy Analyses 
All other analyses will be conducted for the ITT population, with summary statistics provided for 
both treatment groups. 
9.4.1.4. 
Statistical Methods for a Single-Group Study 
In the event that only 1 dose is selected during the Part 1 safety-run in portion of the study or if 
either TG5D or TG5I/M is terminated, the median spleen volume reduction will be estimated and 
a confidence interval constructed based on the exact binomial confidence interval. 
9.4.2. 
Safety Analyses 
9.4.2.1.1. Adverse Events 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include 
all AEs regardless of their timing to study drug administration.  Adverse events will be tabulated 
by the MedDRA preferred term and system organ class.  Severity of AEs will be based on the 
National Cancer Institute CTCAE v4.03 using Grades 1 through 4. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, then the AE will be considered treatment-related.  The incidence of AEs 
and treatment-related AEs will be tabulated. 
9.4.2.2. 
Clinical Laboratory Tests 
Laboratory test values outside of the normal range will be assessed for severity based on the 
normal ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values 
and shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into Grades 1 through 4 using CTCAE v4.03.  The following 
summaries will be produced for the laboratory data: 
• Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
of baseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
• Shift tables from baseline to the worst postbaseline value using CTCAE grade. 
• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
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9.4.2.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 12), and subjects 
exhibiting clinically notable vital sign abnormalities will be listed.  A value will be considered an 
"alert" value if it is outside the established range and shows a > 25% change from baseline. 
Table 12: 
Criteria for Clinically Notable Vital Sign Abnormalities 
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 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
9.4.2.4. 
Electrocardiograms 
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 (Table 13).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed. 
Table 13: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1330 msec 
< 600 msec 
QTcF = Fridericia correction. 
9.4.2.5. 
Adverse Events of Special Interest 
The principle 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.  These events (regardless of seriousness) will be reported per the SAE reporting 
timelines (see Section 8.3.2). 
• ALT ≥ 5 × ULN 
• AST ≥ 5 × ULN 
• Colitis 
• Diarrhea ≥ Grade 2  
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9.5. 
Interim Analysis 
9.5.1. 
Interim Safety Analysis 
The Part 1 safety run-in portion of the study will test up to 3 doses of INCB50465 in 
combination with ruxolitinib for a 28-day assessment.  During the safety-run in portion of the 
study, dose escalation between Cohorts 1 and 2 will follow a 3 + 3 design algorithm.  Doses will 
be selected for Part 2 based on the safety outcomes in the Part 1 safety run-in portion of the study 
according to the rules outlined in Table 14.  In the table, a cohort is considered toxic if 2 or more 
of the first 6 subjects experience a DLT.  A cohort is considered safe if fewer than 2 of the first 
6 subjects experience a DLT (see Table 2 and Section 4.1.1), with the exception that Cohort 1 
will also be considered for escalating to Cohort 2 if 0 of the first 3 subjects experience a DLT.  
There will be alternative allowance to assess additional doses if Cohort 3 is determined to be 
above the MTD.   
Table 14: 
Matrix of Part 2 Dose Selection Based on Part 1 Safety Outcomes by Dose 
Cohort 
Cohort 1 
10 mg QD 
Cohort 2 
20 mg QD 
Cohort 3 
5 mg QD 
Decision for Part 2 
Toxic 
Toxic 
Safe 
Single group or explore dose < 5 mg QD 
Safe 
Toxic 
Safe 
Randomized between 5 mg QD and 10 mg QD 
Safe 
Safe 
 
Randomized between 10 mg and 20 mg QD 
Toxic 
Toxic 
Toxic 
Terminate or explore doses < 5 mg 
The probabilities of declaring a dose to be tolerable for the 3 cohorts at various DLT rates are 
provided in Table 15.  
Table 15: 
Probability of Declaring a Dose to be Tolerable 
True DLT Rate 
Probability of Declaring the Dose to be Tolerable 
In Cohort 1 
In Cohorts 2 and 3 
20% 
70.8% 
65.7% 
30% 
49.4% 
42.0% 
40% 
30.9% 
23.3% 
50% 
17.2% 
10.9% 
60% 
8.02% 
4.01% 
For example, if the true DLT rate is 50% for a cohort, then there is a 17.2% chance that the dose 
in Cohort 1 will be considered tolerable and selected for treatment in Part 2 and a 10.9% chance 
that the dose in Cohorts 2 and 3 would be declared tolerable for treatment in Part 2.  Further, if 
the true DLT rate is 20%, then there is a 70.8% chance that the dose in Cohort 1 would be 
declared to be tolerable for treatment in Part 2 and a 65.7 % chance that the dose in Cohorts 2 
and 3 would be declared tolerable for treatment in Part 2. 
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9.5.2. 
Interim Efficacy Analysis 
There will be 1 planned interim analysis conducted for futility for this study.  The interim 
analysis will be conducted during the randomized portion of the study once TG5D and TG5I/M 
+ TG5 enroll 15 subjects and have been evaluated for spleen volume at Week 12.  Further 
enrollment in a treatment group will be terminated if fewer than 4 subjects in the treatment group 
have spleen stability or a reduction from baseline in spleen volume (ie, percentage change from 
baseline ≤ 0%)  as measured by MRI (or CT scan in applicable subjects) at Week 12.   Subjects 
remaining in any terminated group may have their dose adjusted to reflect the ongoing group 
with sponsor approval. 
If either TG5D or TG5I/M is terminated, then Part 4 will continue as a single-group study, and 
the primary endpoint will be analyzed as described in Section 9.4.1.4.  If both of the treatment 
groups are terminated, then the study will be terminated.  The probabilities of stopping a 
treatment group for futility for various probabilities of a subject achieving ≥ 0% decrease in 
spleen volume at Week 12 are provided in Table 16. 
Table 16: 
Probability of Stopping a Treatment Group for Futility 
Probability of Subject Having ≥ 0% Decrease in 
Spleen Volume at Week 12 in a Treatment Group 
Probability of Stopping a Treatment Group 
for Futility 
5% 
99.5% 
10% 
94.4% 
20% 
64.8% 
25% 
46.1% 
30% 
29.7% 
40% 
9.1% 
50% 
1.8% 
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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• 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 
subject records at each monitoring visit. 
− 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 subjects. 
− 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 CRFs 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. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− 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 subject.  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 subject records. 
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• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• 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 subjects 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 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 CRF 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 CRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
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 or designee must maintain records that document: 
• Delivery of study drug to the study site. 
• Inventory of study drug at the site. 
• Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
• Return of study drug to the investigator or designee by subjects. 
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The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects 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 subjects. 
Completed accountability records will be archived by the site.  The investigator 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 or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of 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. 
10.3. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that a CRF can be completed 
for each subject.  Entries made in the CRF must be verifiable against source documents; if 
updates to the database are not possible, any discrepancies should be explained and documented.  
The investigator will be responsible for reviewing all data and CRF entries, and will sign and 
date the designated forms in each subject's CRF, verifying that the information is true and 
correct.  The investigator is responsible for the review and approval of all query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the CRF.  
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. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee is responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the CRF, where permitted; if the subject'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 findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 
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the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.5. 
Financial Disclosure 
Not applicable. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), 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. 
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11. 
REFERENCES 
Bose P, Verstovsek S. The evolution and clinical relevance of prognostic classification systems 
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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. Blood 2013;122:4047-4053. 
Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. 2014. http://www.hma.eu/ctfg.html. Accessed February 9, 
2016. 
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. 
Emanuel RM, Dueck AC, Gever HL, et al. Myeloproliferative neoplasm (MPN) symptom 
assessment form total symptom score: prospective international assessment of an abbreviated 
symptom burden scoring system among patients with MPNs. J Clin Oncol 2012;30:4098-4103. 
Harrison C, Kiladjia JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available 
therapy for myelofibrosis. N Engl J Med 2012;366:787-798. 
INCB018424 Investigator's Brochure (IB). Wilmington, DE: Incyte Corporation. 
INCB050465 Investigator's Brochure (IB). Wilmington, DE: Incyte Corporation. 
Khan I, Huang Z, Wen Q, et al. AKT is a therapeutic target in myeloproliferative neoplasms. 
Leukemia 2013;27:1882-1890. 
Marone R, Cmiljanovic V, Giese B, Wymann MP. Targeting phosphoinositide 3-kinase: moving 
towards therapy. Biochim Biophys Acta 2008;1784:159-185. 
Meadows SA, Nguyen HM, Queva C, et al. PI3Kδ inhibitor idelalisib inhibits AKT signaling in 
myelofibrosis patients on chronic JAK inhibitor therapy. Blood 2013;122:4065-4067. 
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-1 
study. Leuk Res 2013b;37:911-916. 
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11 OCT 2018 
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. 
Prevention and Treatment of Cancer-Related Infections Version 2. 2017. 
https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed May 31, 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. 
Passamonti F, Cervantes F, Vannucchi AM, et al. Adynamic prognostic model to predict survival 
in primary myelofibrosis: a study by the IWG-MRT (International Working Group for 
Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115:1703-1708. 
Patnaik A, Appleman LJ, Tolcher AW, et al. First-in-human phase I study of copanlisib 
(BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients 
with advanced solid tumors and non-Hodgkin's lymphomas. Ann Oncol 2016;27:1928-1940. 
Pillai S, Cariappa A. The follicular versus marginal zone B lymphocyte cell fate decision. Nat 
Rev Immunol 2009;9:767-777. 
Savona M, Gutierrez M, Lanasa M, et al. A phase I dose escalation study of TGR-1202, a novel 
PI3K-δ Inhibitor, for patients with relapsed or refractory hematologic malignancies. Blood 
2013;122:Abstract 4373. 
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, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International 
Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and 
European LeukemiaNet (ELN) consensus report. Blood 2013;122:1395-1398. 
Thiele J, Kvasnicka HM, Facchetti F, et al. European consensus on grading bone marrow fibrosis 
and assessment of cellularity. Haematologica 2005;90:1128-1132. 
US Food and Drug Administration (FDA). Guidance for Industry: Drug Interaction Studies – 
Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. 2012. 
Available at https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf. Accessed 
May 31, 2017. 
van Elteren PH. On the combination of independent 2 sample tests of Wilcoxon. Bulletin of the 
International Statistical Institute 1960;37:351-361. 
Vannucchi AM, Kantarjian HM, Kiladjia JJ, et al. A pooled analysis of overall survival in 
COMFORT-1 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. The clinical benefit of ruxolitinib across patient 
subgroups: analysis of a placebo-controlled, phase III study in patients with myelofibrosis. Br J 
Haematol 2013;161:508-516. 
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. Haematologica 2015;100:479-488. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating 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.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success.  
4  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 trial and the preferred 
and usual lifestyle of the subject. 
Source:  CTFG 2014. 
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APPENDIX B. CYTOCHROME P450 INHIBITORS AND INDUCERS 
CYP 3A4 Inhibitors 
Inhibitor 
Therapeutic Class 
Potent CYP3A Inhibitors  
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 Inhibitors  
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 Inhibitors 
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 Inhibitors 
Simeprevir 
Protease inhibitors 
Atorvastatin 
HMG CoA reductase inhibitors (statins) 
Tolvaptan 
Vasopressin antagonists 
Almorexant 
Hypnotics - sedatives 
GSK1292263 
Other antilipemics 
Evacetrapid 
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 Inducers  
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 Inducers  
Ritonavir and St. Johns 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 Inducers 
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 
Stribild 
Treatments of AIDS 
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Inducers 
Therapeutic class 
Weak CYP3A Inducers 
Pioglitazone 
Thiazolidinediones 
VIEKIRA PAK 
Antivirals  
Dexamethasone 
Corticosteroids  
Terbinafine 
Antifungals  
Quercetin 
Food products 
Glycyrrhizin 
Herbal medications  
Aprepitant 
Neurokinin-1 receptor antagonists 
Pretomanib (PA-824) 
Antibiotics  
Safinamide 
MAO-B inhibitors 
Oritavancin 
Antibiotics  
AZD 7325 
Anxiolytics 
Methylprednisolone 
Corticosteroids  
Topiramate 
Anticonvulsants  
 
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APPENDIX C. PHARMACOKINETIC ANALYTICAL PARAMETERS 
Cave 
Average steady-state plasma concentration (AUC0-12h/12h or 
AUC0-24h/24h) 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration during the dosing interval 
Tmax 
Time to maximum plasma concentration 
AUC0-t 
Area under the single-dose plasma concentration-time curve from Hour 0 
to the last quantifiable measurable plasma concentration, calculated by the 
linear trapezoidal rule for increasing concentrations and the log 
trapezoidal rule for decreasing concentrations 
AUC0-τ (ie, 
AUC0-12h or 
AUC0-24h) 
Area under the steady-state plasma concentration-time curve over 
1 dosing interval (ie, from Hour 0 to 12 for BID administration or from 
Hour 0 to 24 for QD administration), calculated by the linear trapezoidal 
rule for increasing concentrations and the log trapezoidal rule for 
decreasing concentrations 
λz 
Apparent terminal phase disposition rate constant, where λz is the 
magnitude of the slope of the linear regression of the log concentration 
versus time profile during the terminal phase 
t½ 
Apparent plasma terminal phase disposition half-life (whenever possible), 
where t½ = (ln2) / λz 
Cl/F 
Oral dose clearance 
Vz/F 
Apparent oral dose volume of distribution 
Fluctuation 
Steady-state fluctuation ([Cmax – Cmin]/Cave) 
 
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APPENDIX D. SCREENING SYMPTOM FORM 
Instructions to Subjects:  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 
were your worst night sweats (or 
feeling hot or flushed) due to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
2. During the past 7 days, how severe 
was your worst itchiness due to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
3. During the past 7 days, how severe 
was your worst abdominal discomfort 
(feel uncomfortable, pressure or 
bloating) due to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
4. During the past 7 days, how severe 
was your worst pain under the ribs on 
the left side due to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
5. During the past 7 days, what was the 
worst feeling of fullness (early satiety) 
you had after beginning to eat, due to 
MF? 
 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
6. During the past 7 days, how severe 
was your worst bone or muscle pain 
due to MF (diffuse, not joint or 
arthritis pain)? 
 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
7. During the past 7 days, what was the 
worst degree of inactivity (including 
work and social activities) you had due 
to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
Investigators/Site Staff: 
 
Please complete the table below to confirm the criterion used to confirm the subject's eligibility 
in the trial based on an assessment of his/her active symptoms of myelofibrosis. 
 
ELIGIBILITY CRITERION 
CONFIRMATION 
A symptom score of at least 5 on at least1 of the symptoms 
□ Yes □ No 
A symptom score of 3 or greater on at least 2 of the symptoms 
□ Yes □ No 
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APPENDIX E. MODIFIED MYELOFIBROSIS SYMPTOM ASSESSMENT FORM VERSION 3.0 
Please complete this diary at night before bedtime.  The diary asks about your MF symptoms during the past 24 hours.  There is no 
right or wrong answer.  Please give the answer that best reflects your opinion. 
1. 
During the past 24 hours, how severe were your worst night 
sweats (or feeling hot or flushed) due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
2. 
During the past 24 hours, how severe was your worst fatigue due 
to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
3. 
During the past 24 hours, how severe was your worst itchiness 
due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
4. 
During the past 24 hours, how severe was your worst feeling of 
low energy due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
5. 
During the past 24 hours, how severe was your worst abdominal 
discomfort (feel uncomfortable, pressure of bloating) due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
6. 
During the past 24 hours, how severe was your worst exhaustion 
due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
7. 
During the past 24 hours, how severe was your worst pain under 
the ribs on the left side due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
8. 
During the past 24 hours, how severe was your worst feeling of 
physical weakness due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
9. 
During the past 24 hours, what was your worst feeling of fullness 
(early satiety) you had after beginning to eat, due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
10. During the past 24 hours, how severe was your worst feeling 
bone or muscle pain due to MF (diffuse not joint or arthritis 
pain)? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
11. During the past 24 hours, how severe was your worst feeling of 
heavy limbs due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
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12. During the past 24 hours, what was the worst tiredness due 
to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
13. During the past 24 hours, what was your worst feeling of 
confusion due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
14. During the past 24 hours, what was your worst feeling of 
forgetfulness due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
15. In the past 24 hours, how much did MF interfere with your 
physical activity? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
16. In the past 24 hours, how much did MF interfere with your daily 
activities? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
17. In the past 24 hours, what was your worst level of frustration due 
to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
18. During the past 24 hours, what was your worst degree of 
inactivity (including work and social activities) you had due 
to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
 
When answering the following question, please think about the time since you woke up today 
19. Since waking up today, how severe was your worst feeling of 
sleepiness due to MF? 
 
0 (Absent) 1    2   3    4   5    6    7   8    9   10 (Worst Imaginable) 
 
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APPENDIX F. MYELOPROLIFERATIVE NEOPLASMS SYMPTOM 
ASSESSMENT FORM 
Subject 
Number 
 
 
 
 
 
Symptom 
1 to 10 (0 if absent) ranking - 1 is most 
 favorable and 10 least favorable 
Please rate your fatigue (weariness, tiredness) by 
circling the one number that best describes your 
WORST level of fatigue during the past 24 hours. 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Circle the one number that describes, during the past week, how much difficulty you had 
with each of the following symptoms 
Night sweats 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Itching (pruritus) 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Bone pain (diffuse, not joint pain or arthritis) 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Fever (> 100°F) 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Unintentional weight loss in the last 6 months 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Filling up quickly when you eat (early satiety) 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Abdominal discomfort 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Inactivity 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Problems with concentration - 
 compared to prior to my MPD 
0 (Absent)     1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
 
 
 
TSS:    ____________________ 
 
MD Signature/Date 
Per IWG-MRT 2013 Criteria: TSS to include fatigue, 
concentration, early satiety, inactivity, night sweats, itching, 
bone pain, abdominal discomfort, weight loss, and fevers. 
 
Staff Signature/Date 
 
 
 
 
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APPENDIX G. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS (ECOG) 
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 H. PATIENT GLOBAL IMPRESSION OF CHANGE 
Instructions:  circle the answer that is most appropriate. 
Since the start of the treatment you've received in this study, your myelofibrosis symptoms are: 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
 
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APPENDIX I. INTERNATIONAL WORKING GROUP–
MYELOPROLIFERATIVE NEOPLASMS RESEARCH 
AND TREATMENT CRITERIA 
Response 
Categories 
Required Criteria (for All Response Categories, Benefit Must Last for ≥ 12 Weeks to 
Qualify as a Response) 
CR 
Bone marrow
a:  Age-adjusted normocellularity; < 5% blasts; ≤ Grade 1 MF
b and 
Peripheral blood:  Hemoglobin ≥ 100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and 
< UNL; 
Platelet count ≥ 100 × 109/L and < UNL; < 2% immature myeloid cells
c and 
Clinical:  Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH 
PR 
Peripheral blood:  Hemoglobin ≥ 100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and 
< UNL; platelet count ≥ 100 × 109/L and < UNL; < 2% immature myeloid cellsc and 
Clinical:  Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH or 
Bone marrow:a  Age-adjusted normocellularity; < 5% blasts; ≤ Grade 1 MFb; and peripheral 
blood:  hemoglobin ≥ 85 g/L but < 100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and 
< UNL; platelet count ≥ 50 × 109/L but < 100 × 109/L and < UNL; < 2% immature myeloid 
cellsc and 
Clinical:  Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH 
CI 
The achievement of anemia, spleen or symptoms response without progressive disease or 
increase in severity of anemia, thrombocytopenia, or neutropenia
d 
Anemia response 
Transfusion-independent patients:  a ≥ 20 g/L increase in hemoglobin level
e 
Transfusion-dependent patients:  becoming transfusion-independent
f 
Spleen response
g 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable
h 
or 
A baseline splenomegaly that is palpable at > 10 cm, below the LCM, decreases by ≥ 50%h 
A baseline splenomegaly that is palpable at < 5 cm, below the LCM, is not eligible for spleen 
response 
A spleen response requires confirmation by MRI or CT showing ≥ 35% spleen volume 
reduction 
Symptoms 
response 
A ≥ 50% reduction in the MPN-SAF TSS
i 
Progressive disease
j 
Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or 
A ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 cm 
or 
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm or 
Leukemic transformation confirmed by a bone marrow blast count of ≥ 20% or 
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Response 
Categories 
Required Criteria (for All Response Categories, Benefit Must Last for ≥ 12 Weeks to 
Qualify as a Response) 
A peripheral blood blast content of ≥ 20% associated with an absolute blast count of 
≥ 1 × 109/L that lasts for at least 2 weeks 
Stable disease 
Belonging to none of the above-listed response categories 
Relapse 
No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 
Loss of anemia response persisting for at least 1 month or 
Loss of spleen response persisting for at least 1 month 
CI = clinical improvement; CR = complete response; CT = computed tomography; EMH = extramedullary hematopoiesis; LCM = 
left costal margin; MF = myelofibrosis; MPN-SAF TSS = Myeloproliferative Neoplasm Symptom Assessment Form Total 
Symptom Score; MRI = magnetic resonance imaging; PR = partial response; PRBC = packed red blood cell; UNL = upper 
normal limit. 
a Baseline and post-treatment bone marrow slides are to be interpreted at 1 sitting by a central review process.  Cytogenetic and 
molecular responses are not required for CR assignment. 
b Grading of MF is according to the European classification (Thiele et al 2005).  It is underscored that the consensus definition of a 
CR bone marrow is to be used only in those patients in which all other criteria are met, including resolution of 
leukoerythroblastosis.  It should also be noted that it was a particularly difficult task for the working group to reach a consensus 
regarding what represents a complete histologic remission. 
c Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood cells.  In 
splenectomized patients, < 5% immature myeloid cells is allowed. 
d See above for definitions of anemia response, spleen response, and progressive disease.  Increase in severity of anemia 
constitutes the occurrence of new transfusion dependency or a ≥ 20 g/L decrease in hemoglobin level from pretreatment baseline 
that lasts for at least 12 weeks.  Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade decline, from 
pretreatment baseline, in platelet count or absolute neutrophil count, according to the CTCAE version 4.0.  In addition, 
assignment to CI requires a minimum platelet count of ≥ 25,000 × 109/L and absolute neutrophil count of ≥ 0.5 × 109/L. 
e Applicable only to patients with baseline hemoglobin of < 100 g/L.  In patients not meeting the strict criteria for transfusion 
dependency at the time of study enrollment (see as follows), but have received transfusions within the previous month, the 
pretransfusion hemoglobin level should be used as the baseline. 
f Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of PRBCs, in the 12 weeks prior to 
study enrollment, for a hemoglobin level of < 85 g/L, in the absence of bleeding or treatment-induced anemia.  In addition, the 
most recent transfusion episode must have occurred in the 28 days prior to study enrollment.  Response in transfusion-dependent 
patients requires absence of any PRBC transfusions during any consecutive "rolling" 12-week interval during the treatment 
phase, capped by a hemoglobin level of ≥ 85 g/L. 
g In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy. 
h Spleen or liver responses must be confirmed by imaging studies where a ≥ 35% reduction in spleen volume, as assessed by MRI 
or CT, is required.  Furthermore, a ≥ 35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response 
regardless of what is reported with physical examination. 
i Symptoms are evaluated by the MPN-SAF TSS.  The MPN-SAF TSS is assessed by the patients themselves and this includes 
fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers.  
Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is 
the summation of all the individual scores (0-100 scale).  Symptoms response requires ≥ 50% reduction in the MPN-SAF TSS. 
j Progressive disease assignment for splenomegaly requires confirmation by MRI or CT showing a ≥ 25% increase in spleen 
volume from baseline.  Baseline values for both physical examination and imaging studies refer to pretreatment baseline and not 
to posttreatment measurements. 
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APPENDIX J. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
13 APR 2016 
Amendment (Version) 2: 
18 MAY 2016 
Amendment (Version) 3: 
22 NOV 2016 
Amendment (Version) 4: 
06 JUN 2017 
Amendment (Version) 5: 
23 MAR 2018 
Amendment (Version) 6: 
11 OCT 2018 
Amendment 6 (11 OCT 2018) 
Overall Rationale for the Amendment: 
The purpose of this amendment is to add Part 4 to the study.  Part 4 will examine the role an 
initial higher dose may play in overall efficacy and safety.  There are 2 groups in Part 4: 
• TG5I/M:  20 mg QD for 8 weeks followed by 5 mg QD until EOT 
• TG5D:  5 mg QD from Day 1 until EOT 
1. Synopsis; Section 1.7, Justification of Study Treatment Regimen; 1.8.3, Potential 
Benefits of INCB050465 Based on Prior and Ongoing Clinical Studies; Section 2, 
Study Objectives and Endpoints; Section 4.1, Overall Study Design; Section 4.3.1, 
Planned Number of Subjects; Section 5, Treatment 
Description of change:  Added Part 4, which will compare a group of subjects who 
receive an initial higher dose of INCB050465 20 mg QD for 8 weeks followed by 5 mg 
QD with a group who will receive 5 mg QD from Day 1.  Further enrollment into Part 3 
is suspended effective with site-specific IRB approval of Amendment 6. 
Rationale for change:  To examine the role an initial higher INCB050465 dose may play 
in overall efficacy and safety. 
2. Synopsis; Section 4.1, Overall Study Design; Section 5.2.2, Part 2, Part 3, and Part 4 
Treatment Groups:  Randomized Portion  
Description of change:  Simplified the description of the 4 parts of the study and 
indicated that Parts 2 and 3 are no longer enrolling subjects.  
Rationale for change:  To simplify and remove redundant language and to clarify that 
Parts 2 and 3 are no longer enrolling. 
3. Synopsis; Section 5.2.3, Crossover of Part 2 and Part 3 Subjects 
Description of change:  Described how subjects randomized to TG20 in Part 3 may 
cross over to receive INCB050465 5 mg QD once they have reached Week 8. 
Rationale for change:  To provide criteria for Part 3 subjects to cross over. 
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4. Synopsis; Section 9.4.1, Efficacy Analysis 
Description of change:  Changed treatment group comparisons from all ITT subjects in 
TG5 and TG20 groups in Parts 2 and 3 to TG5D and TG5I/M + TG5 groups in Parts 3 
and 4.  
Rationale for change:  Updated analysis for new treatment groups. 
5. Synopsis; Section 9.5.2, Interim Efficacy Analysis 
Description of change:  Updated to include subjects in TG5I/M and TG5D in Part 4.  
Note that TG5 subjects from Part 3 will also be included in the TG5I/M group. 
Rationale for change:  Updated analysis for new treatment groups. 
6. Section 1.5.4, Clinical Summary 
Description of change:  Updated clinical information for INCB050465. 
Rationale for change:  To provide updated information and alignment with the current 
Investigator's Brochure. 
7. Section 1.6, Overview of Ruxolitinib 
Description of change:  Updated information on ruxolitinib safety data in healthy 
volunteers and MF patients. 
Rationale for change:  To simplify and provide updated information consistent with the 
current Investigator's Brochure. 
8. Section 1.8.2, Potential Risks of INCB050465 Based on Prior Clinical Studies 
Description of change:  Deleted information regarding potential phototoxicity. 
Rationale for change:  Phototoxicity studies have been conducted and did not show any 
phototoxocitity. 
9. Appendix B, Cytochrome P450 Inhibitors and Inducers 
Description of change:  Replaced old table of inducers and inhibitors with a new one. 
Rationale for change:  To provide updated information for investigators. 
10. 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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Amendment 5 (23 MAR 2018) 
Overall Rationale for the Amendment: 
The purpose of this amendment is to add Part 3 to the study in order to compare INCB050465 
20 mg QD for 8 weeks followed by 20 mg once weekly versus INCB050465 20 mg QD for 
8 weeks followed by 5 mg QD.  As of March 2018, with approximately 25 total subjects treated 
with the once-weekly dosing frequency in Parts 1 and 2, no DLTs have been observed, and no 
trends for late onset toxicity have been noted using available nonverified data.  There does not 
appear to be a meaningful difference between the 10 mg and 20 mg dose groups for safety or 
efficacy.  Therefore, it is reasonable to simplify the dosing regimen so that all patients begin 
receiving INCB050465 at 20 mg QD with comparison between different long-term dose 
strategies. 
1. Synopsis; Section 1.7.2, Potential Risks of INCB050465 Based on Prior Clinical 
Studies; Section 2, Study Objectives and Endpoints; Section 4.1, Overall Study 
Design; Section 5, Treatment 
Description of change:  Added Part 3, which compares dose regimens for long-term 
administration of INCB050465.  Further enrollment into Part 2 is suspended effective 
with site-specific IRB approval of Amendment 5.  
Rationale for change:  Part 3 will explore 2 dose options beyond 8 weeks.  
2. Synopsis; Section 1.7.2, Potential Risks of INCB050465 Based on Prior Clinical 
Studies; Section 4, Investigational Plan; Section 5, Treatment; Section 9, Statistics 
Description of change:  Added designations for dose groups:  TG10 (10 mg QD × 
8 weeks followed by 10 mg once weekly), TG20 (20 mg QD × 8 weeks followed by 
20 mg once weekly), and TG5 (20 mg QD × 8 weeks followed by 5 mg QD). 
Rationale for change:  To simplify the Protocol sections discussing dose groups. 
3. Synopsis; Section 4.1, Overall Study Design; Section 5.2.1, Part 1: Safety Run-In 
Portion 
Description of change:  Add wording to indicate Part 1 has been completed.  Change 
tense for enhanced readability.  
Rationale for change:  Part 1 was completed. 
4. Synopsis; Section 5.2.3, Crossover of Part 2 Subjects to Part 3 
Description of change:  Described how subjects randomized to 10 mg in Part 2 may 
cross over to Part 3 doses. 
Rationale for change:  To provides criteria for Part 2 subjects to cross over to Part 3.  
5. Synopsis; Section 4.4, Duration of Treatment and Subject Participation; Section 6, 
Study Assessments (Table 8, Schedule of Assessments); Section 6.1, Screening 
Description of change:  Change screening windows from Day -28 to Day -8 to Day -35 
to Day -8 (increases period from 21 days to 28 days) 
Rationale for change:  A 28-day screening period is consistent with other protocols. 
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6. Section 6, Study Assessments (Table 11, Schedule of Pharmacokinetic Sampling for 
Part 1, Part 2, and Part 3) 
Description of change:  Added footnotes.  
Rationale for change:  To provide windows for sample collection and fasting details. 
7. Synopsis; Section 9.4.1, Efficacy Analysis 
Description of change:  Changed treatment group comparisons from all ITT subjects in 
Part 2 to TG5 and TG20 subjects in both Parts 2 and 3.  
Rationale for change:  Updated analysis for new treatment groups. 
8. Synopsis; Section 9.5.2, Interim Efficacy Analysis 
Description of change:  Updated to include subjects in TG5 and TG20 in Parts 2 and 3. 
Rationale for change:  Updated analysis for new treatment groups. 
9. 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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Amendment 4 (06 JUN 2017) 
The primary purpose of this amendment is to update the clinical safety and efficacy information 
for the study drug INCB050465, to clarify visit scheduling and cohort enrollment, and to add 
1 additional exclusion criteria. 
This amendment includes the changes to the Protocol INCB 50465-201 Amendment 3 (dated 
22 NOV 2016) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
1. Synopsis; Section 4.1.1, Part 1:  Safety Run-In Portion (Table 2, Safety Run-In 
Cohorts; Table 3, Dose-Limiting Toxicities for Part 1); Section 4.3.1, Planned 
Number of Subjects 
Description of change:  The language describing how many subjects are enrolled in each 
cohort and what the action taken will be has been clarified.  The description of 
ruxolitinib-related neutrophil margination has been removed.  
Rationale for change:  The wording caused some confusion regarding the total number 
of subjects enrolled in Cohort 2 and the outcome if 10 mg QD doses are not tolerated.  
Because new onset neutropenia will be handled by discontinuing INCB050465, the 
ruxolitinib wording is not needed. 
2. Synopsis; Section 3.2, Subject Inclusion Criteria  
Description of change:  The inclusion criteria regarding willingness to avoid fathering a 
child has been modified to provide for continued precautions from screening through 
93 days after treatment with INCB050465. 
Rationale for change:  For consistency with other protocols using INCB050465. 
3. Synopsis; Section 3.3, Subject Exclusion Criteria; Section 5.7.4, Prohibited 
Medications 
Description of change:  Exclusion criteria regarding liver and renal function tests 
modified to specify that the screening test, rather than both screening and baseline tests, 
will be used for inclusion/exclusion.  Exclusion criterion added to prohibit receipt of live 
vaccines within 30 days before the first dose of INCB050465, and live vaccines added to 
prohibited medications list. 
Rationale for change:  Consistency with other INCB050465 protocols and clarification. 
4. Section 5.3.1.1, Description and Administration 
Description of change:  Added descriptive wording to indicate how to schedule weekly    
doses following the 8 weeks of daily dose administration of INCB050465. 
Rationale for change:  Provide clarification for study site personnel.  
5. Section 5.5.6, Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB050465 (Table 6, Dose Levels for INCB050465) 
Description of change:  Added descriptive wording to indicate that medical monitor 
should be consulted for dose modifications below 5 mg QD or once weekly. 
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Rationale for change:  Provide clarification for study site personnel. 
6. Synopsis; Section 6, Study Assessments (Table 8, Schedule of Assessments; Table 9, 
Schedule of Laboratory Assessments); Section 6.3, Treatment 
Description of change:  Clarification of visit scheduling to indicate that study visits 
occur at the end of indicated weeks (eg, Week 4 is after 4 weeks of treatment). 
Rationale for change:  To clarify visit scheduling. 
7. Synopsis; Section 1.7.2, Potential Risks of INCB050465 Based on Prior Clinical 
Studies; Section 5.7.1, Pneumocystis Pneumonia Prophylaxis; Section 6.5.1, Safety 
Follow-Up 
Description of change:  Extended Pneumocystis jirovecii prophylaxis to 2 to 6 months 
after the last dose of INCB050465. 
Rationale for change:  To provide updated information consistent with new 
Investigator's Brochure (IB). 
8. Section 6, Study Assessments (Table 8, Schedule of Assessments); Section 7.6.8, 
IWG-MRT Assessment 
Description of change:  Removal of IWG-MRT assessment at baseline. 
Rationale for change:  Typographical error in original protocol. 
9. Section 1.5, Overview of INCB050465 
Description of change:  Language for Section 1.5.1 (Pharmacology Summary), 
Section 1.5.2 (Nonclinical Toxicology Summary), Section 1.5.3 (Nonclinical Drug 
Metabolism and Pharmacokinetics), and Section 1.5.4 (Clinical Summary) updated to 
reflect new IB. 
Rationale for change:  To provide updated information consistent with new IB. 
10. Section 1.7, Potential Risks and Benefits of the Treatment Regimen 
Description of change:  Language for Section 1.7.1 (Potential Risks of INCB050465 
Based on Preclinical Safety) and Section 1.7.2 (Potential Risks of INCB050465 Based on 
Prior Clinical Studies) updated to reflect new IB. 
Rationale for change:  To provide updated information consistent with new IB. 
11. 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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Amendment 3 (22 NOV 2016) 
The primary purpose of this amendment is to update the clinical safety and efficacy information 
for the study drug INCB050465, and to modify the dosing regimen for both Part 1 and Part 2. 
1. Synopsis; Section 4.1.1, Part 1:  Safety Run-In Portion; Section 4.4, Duration of 
Treatment and Subject Participation; Section 5.2, Cohorts and Treatment Groups; 
Section 5.3.1.1, Description and Administration 
Description of change:  The doses and administration schedule for Part 1 have been 
changed.  Cohorts 1, 2, and 3 will test doses of 10 mg, 20 mg, and 5 mg, respectively.  
Doses will be given once daily for 8 weeks, followed by once weekly at the same dose. 
Rationale for change:  As of 02 SEP 2016, among all subjects (n = 46) in study 
INCB 50465-101, 11 (24%) have discontinued study drug due to an adverse event (AE).  
Among the subjects with an objective response (n = 20), 7 (35%) discontinued study 
treatment due to an AE.  The dose has been change to potentially reduce the frequency of 
AEs that lead to study drug discontinuation. 
2. Synopsis; Section 4.1.1, Safety Run-In Cohorts (Table 2); Section 9.5.1, Interim 
Safety Analysis 
Description of change:  Information regarding subject enrollment and dose-limiting 
toxicity evaluation in the safety run-in cohorts has been updated.  Interim safety analysis 
information was updated accordingly. 
Rationale for change:  To provide updated cohort descriptions and decisions based on 
safety observations. 
3. Section 1.5.3, Clinical Summary 
Description of change:  Safety and efficacy data for study INCB 50465-101 have been 
updated based on a data cut of 02 SEP 2016. 
Rationale for change:  To provide investigators with up-to-date information and support 
the rationale for the new dose schedule. 
4. Section 1.7.1, Potential Risks of INCB050465 Based on Preclinical Safety 
Description of change:  Reworded for clarity. 
Rationale for change:  To clarify risks based on preclinical safety studies. 
5. Section 1.7.2, Potential Risks of INCB050465 Based on Clinical Studies 
Description of change:  The potential risks and benefits of the treatment regimen were 
updated based on the 02 SEP 2016 data cut of study INCB 50465-101. 
Rationale for change:  To provide current interpretation of risks based on the most 
recent data. 
6. Section 5.5.6, Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB050465 
Description of change:  Table 5 (Guidelines for Interruption and Restarting of 
INCB050465) was updated, Table 6 (Dose Level for INCB050465) was added, and 
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supportive care guidelines for diarrhea/colitis and definition of the term "immune-related 
adverse event" were added. 
Rationale for change:  New guidance was provided for AEs that have caused treatment 
discontinuation in Study INCB 5-465-101 to assist physicians managing these AEs. 
7. Section 9.4.2.5 Adverse Events of Special Interest  
Description of change:  The list of adverse events of special interest was expanded to 
match other sponsored studies with INCB050465. 
Rationale for change:  The list of AEs reflects risks of inhibition of immune function in 
general, and includes AEs that have led to treatment discontinuation in study 
INCB 50465-101. 
8. Appendix F, Myeloproliferative Neoplasms Symptom Assessment Form for Use in 
IWG-MRT Response Criteria 
Description of change:  The MPN-SAF questionnaire was modified to 10 items.  The 
full MPN-SAF contains 18 questions or items; only 10 of the items will be analyzed in 
the study as part of the IWG-MRT response. 
Rationale for change:  To simplify the administration of the questionnaire for both 
subject and site staff, the MPN-SAF for the present study will present only the 
10 questions of interest. 
9. 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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Amendment 2 (18 MAY 2016) 
The primary purpose of this amendment is to update the clinical safety and efficacy information 
for the study drug INCB050465, and to include additional exclusion criteria related to subject 
history of immune-related adverse events. 
1. Synopsis; Section 3.3, Subject Exclusion Criteria 
Description of change:  Two new exclusion criteria were added (#21 and 22): 
21.  History of Grade 3 or 4 immune-related AEs from prior immunotherapy.   
− Any immune-related AEs of Grade 1 or 2 must be resolved before 
receiving the first dose of INCB050465. 
22. History of immune-related ocular AEs of any toxicity grade.   
Rationale for change:  A serious immune-related adverse event occurred when 
INCB050465 was combined with a JAK 1 inhibitor (not ruxolitinib).  Although the role 
INCB050465 may have played in the event is unclear, subjects with a history of such 
events will be excluded from the study. 
2. Section 1.5.3, Clinical Summary 
Description of change:  Updated data as of 30 MAR 2016 have been added for studies 
INCB 50465-101, INCB 39110-106, and INCB 39110-107. 
Rationale for change:  To provide investigators with up-to-date information. 
3. Section 1.7.2, Potential Risks of INCB050465 Based on Prior Clinical Studies 
Description of change:  Background information added on the potential risk of the 
infection or new cancer and immune-related adverse events, based on prior clinical 
studies with INCB050465. 
Rationale for change:  To provide investigators with up-to-date information. 
4. Section 1.7.5, Potential Risks of the Combination of INCB050465 and Ruxolitinib; 
Section 5.7.1, Pneumocystis Pneumonia Prophylaxis 
Description of change:  Revised to indicate that subjects who are allergic to sulfonamide 
antibiotics should be treated with either inhaled pentamidine or atovaquonone for 
Pneumocystis jirovecii pneumonia (PCP) prophylaxis, and dapsone should not be used in 
such subjects. 
Rationale for change:  To provide instructions for PCP prophylaxis for subjects with 
sulfa allergies. 
5. Section 6, Study Assessments  
Description of change:  Table 7 (Schedule of Assessments – Part 1 and Part 2 Subjects) 
was updated to include the survival follow-up phase. After discontinuation of 
INCB050465, the subject will remain in the follow-up phase of the study, and site staff 
will conduct phone calls at approximately 12-week intervals to collect data on subsequent 
MF therapy and survival. 
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Rationale for change:  To provide consistency with study processes described in 
subsequent Protocol sections. 
6. Section 6.2, Baseline 
Description of change:  Sentence indicating that blood samples for hematology and 
serum chemistry should be taken as close as possible to Day 1, but may be drawn up to 
3 days before the anticipated date of the first dose of INCB050465, has been deleted. 
Rationale for change:  Sentence was a duplicate of subsequent sentence. 
7. 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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Amendment 1 (13 APR 2016) 
The primary purpose of this amendment is to: 
• Add language regarding mandatory prophylaxis for pneumocystis pneumonia.  Delete 
Serum (1,3)-β-D-glucan testing as it is unnecessary with prophylaxis. 
• Add language indicating that subjects must be monitored for CMV reactivation. 
• Clarify the need for overnight fasting before each study visit. 
• Clarify that a Day 1 blood sample for serum chemistry/hematology is not required 
provided the baseline blood samples were drawn within 3 days before first dose of 
study drug. 
• Provide language regarding dose adjustments in the case of a group being terminated 
as the result of interim analysis. 
Additional revisions were also made to provide internal consistency within the Protocol. 
1. Synopsis; Section 1.7, Potential Risks and Benefits of the Treatment Regimen; 
Section 3.3, Subject Exclusion Criteria; Section 5.7.1, Pneumocystis Pneumonia 
Prophylaxis; Section 6, Study Assessments (Table 8: Schedule of Laboratory 
Assessments; Table 9: Laboratory Tests:  Required Analytes); Section 6.5.1, Safety 
Follow-Up; Section 7.7.8, Serum (1,3)-β-D glucan; Section 9.4.2.5, Adverse Events of 
Special Interest 
Description of change:  Added mandatory prophylaxis for pneumocystis pneumonia and 
deleted serum (1,3)-β-D-glucan testing. 
Rationale for change:  To provide additional patient safety for the combination of 
PI3Kδ inhibitor plus JAK inhibitor.  B-D-glucan testing was deleted as it is unnecessary 
with prophylaxis. 
2. Synopsis; Section 1.7, Potential Risks and Benefits of the Treatment Regimen; 
Section 3.3, Subject Exclusion Criteria; Section 7.7.7, Serology; Section 6, Study 
Assessments (Table 8: Schedule of Laboratory Assessments; Table 9: Laboratory 
Tests: Required Analytes); Section 9.4.2.5, Adverse Events of Special Interest 
Description of change:  Added serology test for cytomegalovirus (CMV) viremia at 
screening.  Require periodic determination of CMV viremia during study, as well as 
varicella-zoster virus and herpes simplex virus infections. 
Rationale for change:  To provide additional patient safety for the combination of 
PI3Kδ inhibitor plus JAK inhibitor. 
3. Section 6, Study Assessments (Table 7: Schedule of Assessments); Section 6.3, 
Treatment; Section 7.10.1, Distribution of Subject Reminder Cards 
Description of change:  Provided clarification that subjects will arrive for all study 
visits, including Week 2, in the fasted state and having held morning drug doses. 
Rationale for change:  Previous wording was unclear. 
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Version 6 
11 OCT 2018 
4. Section 6, Study Assessments (Table 8: Schedule of Laboratory Assessments); 
Section 6.2 Baseline 
Description of change:  Clarified that a Day1 blood sample for serum chemistry and 
hematology need not be drawn if the baseline blood draw was within the 3 days before 
the first dose of study drug. 
Rationale for change:  Simplify procedures for sites. 
5. Synopsis; Section 9.5.2, Interim Efficacy Analysis 
Description of change:  Added language regarding possible dose adjustments in the case 
that a Part 2 group is terminated because of the interim analysis.   
Rationale for change:  To clarify that there is possibility for dose adjustments for 
subjects continuing in the study in a terminated group. 
6. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment, to provide consistency within the Protocol. 
CONFIDENTIAL 

SAP_001.pdf: 
Official Title:    A Phase 2 Study of the Safety, Tolerability, and Efficacy of INCB050465 
in Combination With Ruxolitinib in Subjects With Myelofibrosis 
NCT Number: 
NCT02718300 
Document Date: 
Statistical Analysis Plan Version 3: 21-May-2021


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Incyte Corporation 
Page 3 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
4.2. 
Variable Definitions ....................................................................................................18 
4.2.1. 
Age ..............................................................................................................................18 
4.2.2. 
Prior and Concomitant Medication .............................................................................18 
4.2.3. 
Prior Ruxolitinib .........................................................................................................19 
5. 
STATISTICAL METHODOLOGY ...........................................................................19 
5.1. 
General Methodology .................................................................................................19 
5.2. 
Treatment Groups .......................................................................................................19 
5.3. 
Analysis Populations ..................................................................................................20 
5.3.1. 
Safety Population ........................................................................................................20 
5.3.2. 
Spleen Volume Evaluable Population at Week XX ...................................................20 
5.3.3. 
Crossover Population ..................................................................................................20 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................21 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............21 
6.1.1. 
Demographics .............................................................................................................21 
6.1.2. 
Baseline Disease Characteristics ................................................................................21 
6.1.3. 
Disease History ...........................................................................................................21 
6.1.4. 
Prior Therapy ..............................................................................................................21 
6.2. 
Disposition of Participants ..........................................................................................22 
6.3. 
Protocol Deviations ....................................................................................................22 
6.4. 
Exposure .....................................................................................................................22 
6.5. 
Study Drug Compliance .............................................................................................23 
6.6. 
Prior and Concomitant Medication .............................................................................24 
7. 
EFFICACY .................................................................................................................24 
7.1. 
General Considerations ...............................................................................................24 
7.2. 
Efficacy Hypotheses ...................................................................................................24 
7.2.1. 
Primary Endpoint ........................................................................................................24 
7.3. 
Analysis of the Primary Efficacy Parameter ..............................................................24 
7.3.1. 
Primary Efficacy Analysis ..........................................................................................24 
7.3.2. 
Subgroup Analyses for Primary Endpoint ..................................................................25 
7.4. 
Analysis of the Secondary Efficacy Parameter ..........................................................25 
7.4.1. 
Change and Percent Change in Spleen Volume at Week 24 ......................................25 
7.4.2. 
Total Symptom Score and Total Symptom Score – Fatigue ......................................26 


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Incyte Corporation 
Page 5 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
LIST OF TABLES 
Table 1: 
Safety Run-In Cohorts ................................................................................................13 
Table 2: 
Matrix of Part 2 Dose Selection Based on Part 1 Safety Outcomes by Dose 
Cohort .........................................................................................................................15 
Table 3: 
Probability of Declaring a Dose to be Tolerable ........................................................15 
Table 4: 
Window for Deriving MFSAF v3.0 Total Symptom Score for Baseline, 
Week 12, and Week 24 ...............................................................................................28 
Table 5: 
Adverse Events of Special Interest .............................................................................31 
Table 6: 
Identification of Records for Postbaseline By-Visit Summaries ................................33 
Table 7: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................35 
Table 8: 
Probability of Stopping a Treatment Group for Futility .............................................36 
Table 9: 
Statistical Analysis Plan Versions ..............................................................................37 
 
LIST OF FIGURES 
Figure 1: 
Part 2 Study Design ....................................................................................................11 
Figure 2: 
Part 3 Study Design ....................................................................................................12 
Figure 3: 
Part 4 Study Design ....................................................................................................12 
Figure 4: 
Plot of Power at Various Differences Between Treatment Groups ............................16 
 


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Incyte Corporation 
Page 11 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
3. 
STUDY DESIGN 
This is an open-label, Phase 2 study in participants who have been diagnosed with primary or 
secondary MF (PPV-MF or PET-MF) and who have had suboptimal response while receiving 
ruxolitinib monotherapy for a period of at least 6 months.  The study consists of an open-label, 
safety run-in portion (Part 1) evaluating the combination of the PI3Kδ inhibitor INCB050465 
and the JAK 1/2 inhibitor ruxolitinib and an open-label, randomized portion (Part 2) evaluating 
the 2 dose levels determined in Part 1.  With Amendment 5, another open-label, randomized 
portion (Part 3) was added to the study to evaluate a new dose level in comparison with the one 
dose level chosen from Part 1.  With Amendment 6, there will be no further enrollment into 
Part 3 at the given site.  Another randomized portion (Part 4) is designed to compare different 
daily dosing regimens and to address the impact of an initial higher dose of INCB050465 on 
overall response. 
The safety run-in portion of the study was to examine up to 3 cohorts to confirm the safety and 
tolerability of INCB050465 in combination with ruxolitinib and to select 2 dose levels of 
INCB050465 to be evaluated in the randomized portion (Part 2) of the study.  The cohorts were 
to be tested sequentially beginning with Cohort 1 (ruxolitinib + INCB050465 10 mg QD) and 
then Cohort 2 (ruxolitinib + INCB050465 20 mg QD).  If Cohort 2 failed, Cohort 3 
(ruxolitinib + INCB050465 5 mg QD) would be examined.  If ≥ 2 participants in any cohort 
experienced a DLT, this dose level would be considered as not tolerated.  More details of the 
safety run-in portion are provided in Section 3.1. 
Part 2 was planned to be a randomized open-label study with 2 treatment groups:  TG10 and 
TG20.  Randomization occurred centrally, using an interactive response technology.  Block 
randomization was used with the strata for each participant determined by the participant's 
ECOG performance status (0 or 1 vs 2) at time of screening.  Participants with ECOG 
performance status of 3 or greater were not eligible for participation in this study.  The study 
design for Part 2 is shown in Figure 1. 
Figure 1: 
Part 2 Study Design 
 
With Amendment 5, Part 3 was added to be an open-label block-randomized study where all 
participants will begin with INCB050465 20 mg QD.  After 8 weeks, participants in TG5 will 
continue receiving INCB050465 at 5 mg QD, and participants in TG20 will continue receiving 
INCB050465 at 20 mg once weekly.  Part 3 will use the same stratification as that in Part 2.  The 
study design for Part 3 is shown in Figure 2.  Note that enrollment in Part 3 was suspended with 


Incyte Corporation 
Page 12 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104
CONFIDENTIAL 
implementation of Protocol Amendment 6.  Participants randomized to TG20 at that site may 
cross over to 5 mg QD once Week 8 has been reached.   
Figure 2: 
Part 3 Study Design 
With Amendment 6, Part 4 is added to be an open-label, block-randomized study.  Participants 
will be randomized to one of 2 groups:  TG5D will receive 5 mg daily doses of INCB050465 
from Day 1 until EOT visit.  TG5I/M will receive doses of 20 mg daily for 8 weeks, followed by 
5 mg daily dosing.  Dosing will continue per the randomized group assignment indefinitely or 
until discontinuation criteria are met.  Figure 3 shows the study design for Part 4.   
Figure 3: 
Part 4 Study Design 
Ruxolitinib will be self-administered as a BID oral treatment using the dose designated as the 
stable dose at the time of the screening visit for each participant.  Acceptable doses of ruxolitinib 
are 5 mg BID to 25 mg BID.  INCB050465 will be self-administered QD.  Participants who 
discontinue treatment with the study drug will be followed for subsequent treatment regimens 
and survival.  
3.1. 
Part 1 Safety Run-In Portion 
The safety run-in portion was designed to test up to 3 doses of INCB050465 in combination with 
ruxolitinib for a 28-day assessment (4 weeks).  Initially, 3 participants were to be enrolled in 
Cohort 1 to receive INCB050465 10 mg together with ruxolitinib, at the dose ongoing at the time 
of enrollment.  After 28 days, participants who took at least 22 of 28 daily doses of INCB050465 
AND ruxolitinib OR had a DLT during the first 28 days (refer to Table 3 of the Protocol) were to 


Incyte Corporation 
Page 13 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
be included in the evaluation cohort.  Additional participants were to be enrolled into Cohort 1 if 
discontinuations result in fewer than 3 evaluable participants.  After evaluation, the actions listed 
in Table 1 would occur. 
Table 1: 
Safety Run-In Cohorts 
Cohort 
No. of 
Participants 
Regimen 
DLTs 
Observed 
Action Taken 
1 
3 
INCB050465 10 mg QD 
for 8 weeks, followed by 
10 mg once weekly plus 
ruxolitinib at 5 mg BID 
to 25 mg BIDa 
0 
Proceed to Cohort 2. 
1 
Enroll 3 additional participants, and evaluate 
the total of 6 participants after 28 days.  If 
< 2 participants have a DLT, then proceed to 
Cohort 2.  If ≥ 2 participants have a DLT, 
proceed to Cohort 3. 
> 1 
Proceed to Cohort 3. 
2 
3 
INCB050465 20 mg QD 
for 8 weeks, followed by 
20 mg once weekly plus 
ruxolitinib 5 mg BID to 
25 mg BIDa 
0 or 1 
Enroll 3 additional participants, and evaluate 
the total of 6 participants after 28 days.  If 
< 2 participants have a DLT, then proceed to 
Part 2 using doses of 10 mg and 20 mg of 
INCB050465. 
≥ 2 
Proceed to Cohort 3. 
3 
6 
INCB050465 5 mg QD 
for 8 weeks, followed by 
5 mg once weekly plus 
ruxolitinib 5 mg BID to 
25 mg BIDa 
0 or 1 
If < 2 participants have a DLT and if 
Cohorts 1 and 2 exceeded DLT allowance, 
then proceed to Part 2 as a single arm study of 
5 mg of INCB050465.  If Cohort 1 did not 
exceed DLT allowance, proceed to Part 2 with 
doses of 5 mg and 10 mg INCB050465. 
≥ 2 
Terminate study.  Alternatively, sponsor may 
elect to assess doses lower than 5 mg. 
a The dose of ruxolitinib will be that which the participants had been taking for at least 8 weeks before the first 
dose of INCB050465.  The maximum dose of ruxolitinib allowed for participants with baseline platelet 
count ≥ 100 × 109/L is 25 mg BID, and the maximum dose of ruxolitinib for participants with baseline platelet 
count of ≥ 50 × 109/L to < 100 × 109/L is 10 mg BID. 
3.2. 
Part 2 Randomized Portion 
The open-label randomized portion of the study was planned to enroll approximately 
60 participants randomized 1:1 by block randomization into 2 treatment groups, TG10 and 
TG20.  
Enrollment into Part 2 at a given study site was terminated effective with site-specific IRB 
approval of Protocol Amendment 5.  
3.3. 
Part 3 Randomized Portion 
In Part 3, all participants were planned to initially receive INCB050465 at 20 mg QD for 8 weeks 
in combination with ruxolitinib.  After Week 8, participants were to be assigned to 1 of 2 dose 
groups based on block randomization at the time of entry into the study (using a randomization 
of 3:2 for TG5 vs TG20 for the first 40 participants, followed by 1:1 randomization for 
additional participants, up to a total of approximately 52 participants).   


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Enrollment in Part 3 was suspended with implementation of Amendment 6.  Participants already 
enrolled into TG5 in Part 3 would continue to receive INCB050465 according to the original 
randomization for Part 3 and may continue in the study indefinitely unless criteria for 
discontinuation are met.  Participants already enrolled into TG20 in Part 3 would have the 
opportunity to cross over to receive INCB050465 5 mg QD once they reach Week 8 provided 
they demonstrate inadequate response to the current dose regimen. 
3.4. 
Part 4 Randomized Portion 
During Part 4, participants will be randomized on a 3:2 ratio between TG5D and TG5I/M until 
25 total participants have been randomized, with subsequent randomization on a 1:1 ratio until 
approximately 30 participants have been enrolled in each group.  Stratification will be by ECOG 
status as in Part 3. 
3.5. 
Crossover Portion 
With IRB approval of Protocol Amendment 5 at a given site, participants randomized to TG10 in 
Part 2 at that site may cross over to either 20 mg QD followed by 5 mg QD after Week 8 (if 
participant is within the first 8 weeks of treatment at the time of crossover), or to 5 mg QD (if 
participant is beyond 8 weeks of treatment and receiving 10 mg once weekly at the time of 
crossover).  With IRB approval of Protocol Amendment 6 at a given site, participants 
randomized to TG20 at that site may cross over to 5 mg QD once Week 8 has been reached.  All 
potential crossover participants must meet the criteria listed in Protocol Amendment 6, 
Section 5.2.3. 
Participants who do not meet these criteria, or participants who do meet the criteria but do not 
wish to cross over, may continue on the originally assigned regimen, and may crossover at any 
time provided the criteria for crossover are met and crossover is determined by participant and 
investigator to represent the best option. 
The crossover portion starts when the participants are assigned to and receive their first dose of a 
different treatment.  The original portion of the study for crossover participants ends the day 
before crossover.   
3.6. 
Control of Type I Error 
For the primary endpoint in Parts 2, 3, and 4, the overall 2-sided Type I error is 0.10 for 
detecting a difference between TG5D and TG5 (TG5I/M).  This means that there is a 10% risk of 
observing a significant location shift in percentage change of spleen volume from baseline 
between TG5D and TG5 (TG5I/M) even when there is none. 
3.7. 
Sample Size Considerations 
3.7.1. 
Cohort Size in Safety Run-In Portion 
For the safety run-in portion, the decision to de-escalate the dose was driven by the number of 
observed toxicities and could be calculated based on the binomial distribution.  During the safety 
run-in portion of the study, dose escalation between Cohorts 1 and 2 was to follow a 3 + 3 design 
algorithm.  Doses were to be selected for Part 2 based on the safety outcomes in the Part 1 safety 


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run-in portion of the study, according to the rules outlined in Table 2.  In the table, a cohort is 
considered toxic if 2 or more of the first 6 participants experienced a DLT.  A cohort is 
considered safe if fewer than 2 of the first 6 participants experienced a DLT with the exception 
that Cohort 1 will also be considered safe for escalating to Cohort 2 if 0 of the first 3 participants 
experience a DLT.  There was alternative allowance to assess additional doses if Cohort 3 was 
determined to be above the MTD. 
Table 2: 
Matrix of Part 2 Dose Selection Based on Part 1 Safety Outcomes by Dose 
Cohort 
Cohort 1 
10 mg QD 
Cohort 2 
20 mg QD 
Cohort 3 
5 mg QD 
Decision for Part 2 
Toxic 
Toxic 
Safe 
Single arm or explore 
dose < 5 mg QD 
Safe 
Toxic 
Safe 
Randomized between 
5 mg QD and 10 mg QD 
Safe 
Safe 
 
Randomized between 
10 mg and 20 mg QD 
Toxic 
Toxic 
Toxic 
Terminate or explore 
doses < 5 mg 
During Part 1, the probabilities of declaring a dose to be tolerable for the 3 cohorts at various 
DLT rates are provided in Table 3.  
Table 3: 
Probability of Declaring a Dose to be Tolerable 
True DLT Rate 
Probability of Declaring the Dose to be Tolerable 
In Cohort 1 
In Cohorts 2 and 3 
20% 
70.8% 
65.7% 
30% 
49.4% 
42.0% 
40% 
30.9% 
23.3% 
50% 
17.2% 
10.9% 
60% 
8.02% 
4.01% 


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3.7.2. 
Sample Size in Randomized Portion 
The sample size and power calculations for the randomized portion of the study are based on a 
2-sample Wilcoxon rank sum test with a normal approximation applied to the test statistic.  The 
data from Study INCB 18424-351 (COMFORT-1) suggested a mean reduction of 8.44 in 
percentage change from baseline of spleen volume with a standard deviation of 14.5 from 
baseline to Week 12 for the active group in that study.  For a 2-sided Type I error of 0.10 and 
Type II error of 0.10 with 30 participants per treatment group, the test is powered to detect an 
11.4 percentage point location shift between the 2 groups in regards to percentage change in 
spleen volume.  The 2 populations are assumed to be normally distributed with a common 
standard deviation of 14.5.  
In the event that only 1 dose was selected during the Part 1 safety-run in portion of the study or 
the event that 1 of the treatment groups was terminated for futility at the interim analysis during 
the randomized portion, the median spleen volume reduction would be estimated and a CI 
constructed based on the exact binomial CI.  Figure 4 plots the power of the design with 
30 participants per treatment group at various percentage point location shifts between the 
2 groups in spleen volume reduction. 
Figure 4: 
Plot of Power at Various Differences Between Treatment Groups 
 
3.8. 
Schedule of Assessments 
Refer to Protocol Amendment 6 dated 11 OCT 2018 for a full description of all study procedures 
and assessment schedules for this study. 
0
5
10
15
20
0.2
0.4
0.6
0.8
1.0
Differnce in Percentage Spleen Volume Reduction
Power


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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 study drug INCB050465 is administered to the 
participants.  For randomized participants not treated with any study drug, Day 1 is defined as 
the day of randomization. 
4.1.2. 
Day 1 of Crossover for Crossover Participants 
For participants who cross over from TG10/TG20 to TG5D, Day 1 of crossover is the date that 
the participants are assigned to TG5D based on the assigned dose in the exposure CRF. 
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 within the baseline window before the 
first administration of INCB050465, unless otherwise defined.   
For randomized participants not treated with any study drug, baseline is defined as the last 
nonmissing assessment before randomization for all parameters.  
When scheduled assessments and unscheduled assessments occur on the same day and 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 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 baseline. 
4.1.5. 
Last Available Value 
The last available value is the last nonmissing measurement obtained after starting INCB050465 
and within 30 days after the last dose of INCB050465. 


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4.1.6. 
Handling of Missing and Incomplete Data 
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections.  
Partial MF diagnosis date will be handled as follows:  
• If only the day is missing, then the imputed day will be the first of the month.  
• If both the month and day are missing, then the imputed day and month will be 
01 JAN.  
• No imputation will be done if the date is completely missing.  
Missing or partial date of last dose will be handled as follows:  
• If only the day is missing, then the imputed date of the last dose will be the earlier 
date of the first day of the month or the date that the participant discontinued 
treatment.  
• Otherwise, the date that the participant discontinued treatment will be used as the date 
of the last dose.  
4.2. 
Variable Definitions 
The following variables will only be calculated if not reported on the CRF.  
4.2.1. 
Age 
Participant age will be calculated as the integer part of the number of years from date of birth to 
the date of signing the informed consent form (ICF), using the following formula: 
Age = integer part of (date of informed consent – date of birth + 1) / 365.25 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
INCB050465. 
Concomitant medication is defined as any nonstudy medication that is started accordingly:  
• Before the date of first administration of INCB050465 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 INCB050465 and is ongoing or ends 
during the course of study drug. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of INCB050465.  In the listing, it will be indicated whether a 
medication is prior-only, concomitant-only, or both prior and concomitant medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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All participants receiving combination study treatment with INCB050465 and ruxolitinib are 
required to receive a standard PCP prophylaxis regimen determined by the investigator.  
A summary will be provided for PCP prophylaxis regimen. 
4.2.3. 
Prior Ruxolitinib 
A complete history of ruxolitinib usage before screening will be recorded on the CRF and 
produced as a listing by participant. 
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. 
5.2. 
Treatment Groups 
As the study was terminated early, participants from all parts will be combined.  Data will be 
summarized overall and by treatment group based on the dose regimen initially assigned in the 
initial portion: 
• TG10:  Ruxolitinib at stable dose plus INCB050465 10 mg QD for 8 weeks followed 
by 10 mg once weekly.  
• TG20:  Ruxolitinib at stable dose plus INCB050465 20 mg QD for 8 weeks followed 
by 20 mg once weekly. 
• TG5, TG5I/M:  Ruxolitinib at stable dose plus INCB050465 20 mg QD for 8 weeks 
followed by 5 mg QD. 
• TG5D:  Ruxolitinib at stable dose plus INCB050465 5 mg QD from Day 1 until EOT 
visit. 
Note that TG5I/M in Part 4 is identical to TG5 from Part 3; participants from these 2 groups will 
be combined in the final analysis. 
The crossover participants will be summarized in the initial portion from the date of 
randomization to the date before crossover. 
In the crossover portion, the crossover participants will be summarized in TG5D from the date of 
crossover to the end of study.  Only the crossover participants will be summarized in the 
crossover portion.  Participants in TG5 (TG5I/M) and TG5D and the participants in TG10 or 
TG20 who do not meet the crossover criteria will remain in the treatment group initially assigned 
in the initial portion. 


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5.3. 
Analysis Populations 
5.3.1. 
Safety Population 
The safety population includes all participants in Parts 1, 2, 3, and 4 who received at least 1 dose 
of study drug.  Treatment groups for this population will be determined according to the actual 
treatment the participant received regardless of assigned study drug treatment.  The safety 
population will be used for all analyses. 
The participants in TG5D and TG5 (TG5I/M) will be summarized under TG5D and TG5 
(TG5I/M), respectively, in the initial portion.  The participants crossed over from TG10/TG20 to 
TG5D will be summarized under TG10/TG20 in the initial portion before crossover and under a 
separate crossover group after crossover. 
5.3.2. 
Spleen Volume Evaluable Population at Week XX 
The spleen volume evaluable population includes all participants enrolled in the study who 
received at least 1 dose of study drug (INCB050465 or ruxolitinib), completed a spleen volume 
baseline assessment, and met at least 1 of the following criteria: 
• The participant has Week XX spleen volume assessment. 
• The participant has been on study for a minimum of (7 × XX + 7) days of follow-up. 
• The participant has discontinued from treatment on or before Week XX. 
5.3.3. 
Crossover Population 
The crossover population includes all participants enrolled in TG10/TG20 who receive at least 
1 dose of study drug and later crossover to TG5D. 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
The lists of tables, figures, and listings are provided in Appendix A.  Sample data displays are 
provided in a separate document.  The lists and the shells are to be used as a guideline.  
Modifications of the lists or shells that do not otherwise affect the nature of the analysis will not 
warrant an amendment to the SAP. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
Data will be summarized overall and by treatment group based on the dose regimen initially 
assigned for the safety population. 
6.1.1. 
Demographics 
The following demographics will be summarized for the safety population by treatment group:  
age, sex, race, ethnicity, weight (kg), and height. 
6.1.2. 
Baseline Disease Characteristics 
The following baseline disease characteristics will be summarized for the safety population by 
treatment group:  disease subtype (PMF, PPV-MF, or PET-MF), baseline TSS, and ECOG 
performance status reported to IWRS. 
6.1.3. 
Disease History 
Date of MF diagnosis and prior bone marrow biopsy data as to fibrosis grade, cellularity, and 
transfusion history in the prior 12 weeks to enrollment; prior splenic irradiation; and MF 
prognostic factors including:  age > 65 years, presence of constitutional symptoms (weight 
loss > 10% of the baseline value in the year preceding MF diagnosis, unexplained fever, or 
excessive night sweats persisting for more than 1 month), marked anemia (Hgb < 10g/dL) at 
screening, WBC > 25 × 109/L at screening, circulating blasts ≥ 1% at screening, and risk level as 
defined by IWG (Passamonti et al 2010) will be recorded and summarized for the safety 
population by treatment group. 
Time since diagnosis will be calculated as:  
Time since diagnosis (years) = (date of Day 1 – date of diagnosis + 1) / 365.25 
6.1.4. 
Prior Therapy 
Number of prior systemic cancer therapy regimens will be summarized for all participants in the 
safety population by treatment group.  Regimen name, component drugs, start and stop date, 
purpose of the regimen, best response, reason for discontinuation, and date of 
relapse/progression will be listed. 
Number of participants who received prior radiation will be summarized for safety population by 
treatment group.  Radiotherapy type, body site, start and stop date, total dose, and best response 
will be listed. 


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Number of participants who had prior surgery or surgical procedure for the malignancies under 
study will be summarized for the safety population by treatment group.  Date and description of 
the surgery/procedure will be listed. 
All treatments for MF, including a complete history of ruxolitinib usage, will be summarized for 
all participants in the safety population by treatment group. 
6.2. 
Disposition of Participants 
The number and percentage of participants who were enrolled, randomized, treated, completed 
the study, discontinued study treatment with a primary reason for discontinuation, and 
discontinued from the study with a primary reason for withdrawal will be summarized for all 
participants in the safety population by treatment group.  The number of participants 
randomized/enrolled by site will also be provided for the safety population by treatment group. 
6.3. 
Protocol Deviations 
Protocol deviations recorded on the CRF will be presented in the participant data listings. 
6.4. 
Exposure 
For participants in the safety population, exposure to INCB050465 and ruxolitinib will be 
summarized descriptively by treatment group for initial portion and crossover portion separately 
as the following: 
• Duration of treatment with study drug (INCB050465):  Date of last dose of 
INCB050465– date of first dose of INCB050465 + 1 
• Duration of treatment with study drug (ruxolitinib):  Date of last dose of 
ruxolitinib – date of first dose of ruxolitinib + 1 
• Dose intensity for INCB050465:  Let S be the earliest study day after permanent 
discontinuation from study, last study visit, or participant death; let 𝐷1, 𝐷2, … , 𝐷𝐾, be 
the K daily doses (mg) of INCB050465 prescribed to the participant accounting for 
dose increases on study days 𝑆1, 𝑆2, … , 𝑆𝐾,.  Dose intensity for INCB050465 is 
defined as 
dose intensity (%) = 100 × [total dose (mg)] / [assigned dose (mg)], 
where a participant's assigned dose of INCB050465 is defined as the sum of the doses 
prescribed had the participant not experienced dose delays or reductions on each of 
the S study days.  Formally expressed, 
assigned dose = ∑
𝐷𝑖(𝑡𝑖+1 −𝑡𝑖)
𝐾
𝑖=1
 where 𝑡1 = 1 and 𝑡𝐾+1 = 𝑆 
For example, suppose a participant is assigned INCB050465 10 mg QD, dose 
escalates per investigator decision to 20 mg QD on Day 19, and discontinues on 
Day 31.  The assigned dose of INCB050465 for the participant in question is 
assigned dose = (19 −1) × 10 + (31 −19) × 20 = 420 mg.  


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• Dose intensity for ruxolitinib:  Let S be the earliest study day after permanent 
discontinuation from study, last study visit, or participant death; let 𝐷1, 𝐷2, … , 𝐷𝐾, be 
the K daily doses (mg) of ruxolitinib prescribed to the participant accounting for dose 
increases on study days 𝑆1, 𝑆2, … , 𝑆𝐾,.  Dose intensity for ruxolitinib is defined as 
dose intensity (%) = 100 × [total dose(mg)]/[assigned dose (mg)], 
where a participant's assigned dose of ruxolitinib is defined as the sum of the doses 
prescribed had the participant not experienced dose delays or reductions on each of 
the S study days.  Formally expressed, 
assigned dose = ∑
𝐷𝑖(𝑡𝑖+1 −𝑡𝑖)
𝐾
𝑖=1
 where 𝑡1 = 1 and 𝑡𝐾+1 = 𝑆 
For example, suppose a participant is assigned ruxolitinib 10 mg BID, dose 
de-escalates per investigator decision to 5 mg BID on Day 19, and discontinues on 
Day 31.  The assigned dose of ruxolitinib for the participant in question is 
assigned dose = (19 −1) × 20 + (31 −19) × 10 = 480 mg.  
• Average daily dose of INCB050465 (mg/day):  total actual INCB050465 dose 
taken (mg) / duration of treatment with INCB050465 (days).  
• Average daily dose of ruxolitinib (mg/day):  total actual ruxolitinib dose 
taken (mg) / duration of treatment with ruxolitinib (days). 
Total actual dose taken will be calculated based on the information entered on the 
drug accountability CRF. 
• INCB050465 dose modifications:  Number of participants who had INCB050465 
dose reduction, escalation, and interruption will be summarized.  
• Ruxolitinib dose modifications:  Number of participants who had ruxolitinib dose 
reduction, escalation, and interruption will be summarized.  
• Starting dose of ruxolitinib:  The starting dose of ruxolitinib at the time of the first 
dose of INCB050465 will be summarized. 
6.5. 
Study Drug Compliance 
The participants in the safety population by treatment group for the initial portion and crossover 
portion separately, overall compliance (%) for INCB050465 will be calculated as  
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 CRF.  If there is dispensed drug that have not been returned yet, the actual dose 
taken starting from the dispense date of the unreturned drug will be imputed by the dose taken as 
reported on the dosing CRF. 
Ruxolitinib will be commercially supplied, and the compliance of ruxolitinib will not be 
calculated. 


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6.6. 
Prior and Concomitant Medication 
For participants in the safety population by treatment group, prior medications and concomitant 
medications will be coded using the WHO Drug Dictionary and summarized by WHO drug class 
and WHO drug term.  Results will be summarized as number and percentage of participants with 
prior and concomitant medications by PT and WHO drug class for the safety population by 
treatment group. 
Prior medication information will also be used to identify medications for MF received by 
participants before enrollment into the study.  Prior MF medication data will be summarized and 
presented for participants in the safety population by treatment group, as well as provided in a 
listing. 
7. 
EFFICACY 
The lists of tables, figures, and listings are provided in Appendix A.  Sample data displays are 
provided in a separate document.  The lists and the shells are to be used as a guideline.  
Modifications of the lists or shells that do not otherwise affect the nature of the analysis will not 
warrant an amendment to the SAP. 
7.1. 
General Considerations 
Unless otherwise stated, the strata identified in the randomization process will be used in all 
efficacy analyses. 
7.2. 
Efficacy Hypotheses 
7.2.1. 
Primary Endpoint 
The primary hypothesis is that there will be a location shift in the percentage change from 
baseline at 12 weeks in spleen volume between TG5D and TG5I/M. 
7.3. 
Analysis of the Primary Efficacy Parameter 
7.3.1. 
Primary Efficacy Analysis 
The primary endpoint is change and percentage change in spleen volume from baseline at 
12 weeks as measured by MRI (or CT scan in applicable participants).  A location shift in 
percentage change in spleen volume between TG5D and TG5I/M for stratification by ECOG 
performance status at screening (0 or 1 vs 2) will be assessed using a van Elteren test 
(van Elteren 1960). 
The baseline spleen volume will be measured by MRI (or by CT for applicable participants) 
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 12 spleen volume will be measured by MRI (or by CT for applicable participants) 
during the Week 12 visit (Day 84 ± 7 days); the last value will be used if there are multiple 
values measured during the Week 12 visit. 


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Within each stratum, participants who discontinue from the study or who have missing values for 
the Week 12 spleen volume will be imputed as having the largest possible percentage increase in 
spleen volume and given the lowest rank in the stratum.  The participant with the largest 
percentage reduction in spleen volume in a stratum will be given the highest rank within the 
stratum.  In the case of ties, average ranks will be assigned. 
If the study fails to enroll a sufficient number of participants in a particular stratum, a sensitivity 
analysis using a 2-sample Wilcoxon rank sum test with a normal approximation applied to the 
test statistic, for purposes of calculation stability, will be conducted.  Ranking will be carried out 
using the same approach but without stratification. 
Results for participants enrolled to TG10 or TG20 will be summarized descriptively with no 
formal statistical comparisons performed. 
Statistical comparison will be conducted for TG5D versus TG5 (TG5I/M).  To explore the 
difference in daily dosing and daily/weekly dosing, the statistical comparison will also be 
performed for daily dosing (TG5D + TG5I/M) versus daily/weekly dosing (TG10 + TG20).  
In the event of a single-arm trial, a 95% CI for median percentage change in spleen volume from 
baseline at Week 12 will be calculated from the exact binomial distribution. 
The percentage change from baseline at Week 12 will be calculated using the formula: 
% change = 100 × [Week 12 spleen volume – baseline spleen volume] / baseline spleen 
volume 
The number of participants with spleen volume reductions from baseline to every 12 weeks will 
be summarized categorically.  The number of participants with < 0% reduction (increase), 0% to 
< 10% reduction, ≥ 10% to < 35% reduction, and ≥ 35% reductions will be summarized by 
treatment group.  For the analysis of spleen volume reduction response rate, the 
Cochran-Mantel-Haenszel test will be applied to these categories and stratified by ECOG 
performance status (0 or 1 vs 2) at screening, and a 95% CI will be reported using the row mean 
scores differ option under SAS PROC FREQ.  This option accounts for the ordinal nature of the 
response categories. 
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:  disease subtype and baseline spleen 
volume by tertile. 
7.4. 
Analysis of the Secondary Efficacy Parameter 
7.4.1. 
Change and Percent Change in Spleen Volume at Week 24 
Baseline spleen volume is defined in Section 7.3.1 and percent change in spleen volume from 
baseline at 24 weeks takes the same definition given in Section 7.3.1 for percentage change in 
spleen volume from baseline at 12 weeks.  Change and percentage change in spleen volume from 
baseline at 24 weeks as measured by MRI (or CT scan in applicable participants) will be 
analyzed as described in Section 7.3.1.  Results for participants enrolled to TG10 or TG20 will 


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be compared descriptively with those of the other treatment groups, but no direct statistical 
comparisons are planned. 
Statistical comparison will be conducted for TG5D versus TG5 (TG5I/M) and for daily dosing 
(TG5D + TG5I/M) versus daily/weekly dosing (TG10 + TG20).  
7.4.2. 
Total Symptom Score and Total Symptom Score – Fatigue 
The difference between TG5D and TG5 (TG5I/M) in change and percentage change in TSS from 
baseline to Week 12 and baseline to Week 24 evaluated by the MFSAF v3.0 symptom diary and 
the MPN-SAF will be assessed separately using a van Elteren test to account for stratification by 
ECOG performance status.  If the study fails to enroll a sufficient number of participants in a 
particular stratum, the difference in the 2 treatment groups for these endpoints will be assessed 
separately using a 2-sample Wilcoxon rank sum test with a normal approximation applied to the 
test statistic as a sensitivity analysis.  The difference between TG5D and TG5 (TG5I/M) in 
change and percentage change in TSS – Fatigue from baseline to Week 12 and baseline to 
Week 24 evaluated by the MFSAF v3.0 will use the same rule as regular TSS. 
The difference in TSS between daily dosing (TG5D + TG5I/M) and daily/weekly dosing 
(TG10 + TG20) will be assessed in the same way. 
7.4.2.1. 
MFSAF v3.0 
The MFSAF v3.0 is comprised of 19 individual symptom scores (night sweats, fatigue, itchiness, 
low energy, abdominal discomfort, exhaustion, pain under left ribs, physical weakness, early 
satiety, bone/muscle pain, heavy limbs, tiredness, confusion, forgetfulness, interference with 
physical activity, interference with daily activities, frustration, inactivity, sleepiness), each 
collected daily with a 0 to 10 point scale.   
The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, 
abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same 
day.  The TSS – Fatigue is composed of 13 individual symptom scores that are related to fatigue 
(fatigue, low energy, exhaustion, physical weakness, heavy limbs, tiredness, confusion, 
forgetfulness, interference with physical activity, interference with daily activities, frustration, 
inactivity, sleepiness). 
Regular TSS and TSS – Fatigue will be missing if there are any missing individual scores.  
Observations with missing dates will be excluded from the analysis. 
The baseline total score is defined as the average of daily total scores from the last 7 days before 
the first dose of INCB050465; 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 last 7 consecutive days 
before the Week 12 visit; the Week 12 total score will be missing if there are ≥ 4 missing out of 
the 7 daily total scores, or the 28 days are completed outside the window for Week 12 visit 
(Day 84 ± 7). 
The Week 24 total score will be the average of daily total scores from the last 7 consecutive days 
before the Week 24 visit; the Week 24 total score will be missing if there are ≥ 4 missing out of 


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the 7 daily total scores or if the 7 days are completed outside the window for the Week 24 visit 
(Day 168 ± 7). 
The percentage change from baseline to Week 12 and baseline to Week 24 will be calculated 
using the formulas:  
% change = 100 × (Week 12 total score – Baseline total score) / Baseline total score 
% change = 100 × (Week 24 total score – Baseline total score) / Baseline total score 
7.4.2.1.1. Windowing of MFSAF v3.0 Total Symptom Score 
The MFSAF v3.0 TSS for baseline, Week 12, and Week 24 will be determined by averaging the 
daily MFSAF v3.0 TSS for the days between the start and end of windows as described in 
Table 4.  By-question summaries for the 6 individual symptom scores that compose the TSS at 
baseline, Week 12, and Week 24 will use the same windowing algorithm as used for the daily 
TSS.  By-question summaries will also be provided for all 19 individual symptom scores 
included in the MFSAF v3.0 at baseline, Week 12, and Week 24 using the same windowing 
algorithm used for the daily TSS.  
The TSS and the 19 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) 
and 
Day (7 × week) + 7 
as the end of the window. 
Change and percentage change from baseline for the 19 individual scores and change and 
percentage change from baseline for the TSS will be summarized by week.  
The number of participants with reductions in MFSAF v3.0 TSS from baseline at Weeks 12 and 
24 will also be summarized categorically.  The number of participants with < 0% reduction 
(increase), 0% to 25% reduction, 25 to < 50% reduction, and ≥ 50% reductions will be 
summarized by treatment group.  For the analysis of MFSAF v3.0 TSS reduction rate, the 
Cochran-Mantel-Haenszel test will be applied to these categories and stratified by ECOG 
performance status (0 or 1 vs 2) at screening, and a 95% CI will be reported using the row mean 
scores differ option under SAS PROC FREQ.  This option accounts for the ordinal nature of the 
response categories. 


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Table 4: 
Window for Deriving MFSAF v3.0 Total Symptom Score for Baseline, 
Week 12, and Week 24 
Period 
Start of Window 
End of Window 
Missing 
Baseline 
7 days on or 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, or no 
measurement between 
Day -7 and Day -1 
Week 12 
First day a daily TSS was 
collected between 
Day 78 and Day 84 
(inclusive) 
7 days on or after start of 
window 
4 or more missing of the 
7 daily TSSs in the 
window, or no 
measurement between 
Day 84 and Day 90 
Week 24 
First day a daily TSS was 
collected between 
Day 162 and Day 168 
(inclusive) 
7 days on or after start of 
window 
4 or more missing of the 
7 daily TSSs in the 
window, or no 
measurement between 
Day 168 and Day 174 
7.4.2.2. 
MPN-SAF 
The MPN-SAF weekly total score is defined as the sum of 10 individual symptom scores 
(fatigue, nights sweats, itchiness, bone pain, fever, unintentional weight loss last 6 months, early 
satiety, abdominal discomfort, inactivity, problems with concentration, each with a 0 to 10 point 
scale) collected at the same visit; the score will be missing if there are any missing individual 
scores. 
The number of participants with reductions in MPN-SAF TSS from baseline to every 4 weeks 
will be summarized categorically, and a Cochran-Mantel-Haenszel test will be applied as 
described in Section 7.4.2.1.1. 
7.4.3. 
Analysis of IWG-MRT Consensus Criteria 
IWG-MRT criteria provides criteria for response to treatment in MF.  Recently published 
response criteria developed by the IWG on MF will be used in this study (Tefferi et al 2013).  
Overall response assessment will be graded according to the IWG-MRT consensus criteria for 
treatment response in PMF, PPV-MF, and PET-MF.  The criteria for response assessment 
according to IWG-MRT is provided in Appendix B. 
The IWG-MRT assessment will be performed at baseline, Week 24, and every 24 weeks 
thereafter.  The number of participants with responses according to investigator-reported 
IWG-MRT consensus criteria will be summarized by treatment group.  Best overall response 
under the IWG-MRT consensus criteria will also be summarized.  Best overall response is 
defined as the highest overall response achieved postbaseline prior to and including the first 
confirmed progressive disease in the order of complete response, partial response, clinical 
improvement, stable disease, partial disease, and relapse.  A listing of the clinical data used by 
Incyte to derive the IWG-MRT responses will be provided.  


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8. 
SAFETY AND TOLERABILITY 
The lists of tables, figures, and appendices are provided in Appendix A.  Sample data displays 
are provided in a separate document.  The lists and the shells are to be used as a guideline.  
Modifications of the list or shells that do not otherwise affect the nature of the analysis will not 
warrant an amendment to the SAP. 
8.1. 
General Considerations 
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.   
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first 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. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE.  The CTCAE version 4.03 is used for this study.  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 
drug, the AE will be considered to be treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  In addition, SAEs will be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity.  
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment emergent.   
8.2.2. 
Dose-Limiting Toxicities 
A DLT or dose limiting toxicity will be defined as the occurrence of a toxicity, with the 
exception of events clearly associated with the underlying disease, disease progression, a 
concomitant medication, or comorbidity; the list of toxicities that will be designated as DLTs are 
provided in Table 3 of the Protocol. 
The number of participants with DLTs and the type of DLT will be listed by treatment group. 


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8.2.3. 
Maximum Tolerated Dose 
The MTD of INCB050465 is the highest treatment group tested that is considered tolerated on 
the basis of fewer than 2 DLTs in a cohort of 6 participants.   
8.2.4. 
Adverse Events of Special Interest 
The principle 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.  Infections and inflammation reactions will be monitored and comprise AEs of special 
interest as indicated in Table 5. 
Liver chemistry tests as assessed by ALT, AST, total bilirubin, alkaline phosphatase tests are 
also considered as events of special interest and will be summarized for the safety population by 
dose group for initial portion and crossover portion separately.  Participants with elevations in 
liver chemistry tests will be summarized, and a listing for participants with ALT ≥ 5 × ULN or 
AST ≥ 5 × ULN will be provided. 
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities.  
The number and proportion of participants experiencing the events listed in Table 5 (regardless 
of seriousness) will be summarized by treatment group.  The AESIs will be summarized for the 
safety population by dose group for the initial portion and crossover portion separately. 
Table 5: 
Adverse Events of Special Interest 
Category of AEs 
Specific AEs in Category 
Liver Chemistry Tests 
ALT/AST elevations equal to or above 5 × ULN 
Inflammation/reactions 
Colitis, diarrhea ≥ Grade 2, rash ≥ Grade 2, pneumonitis, 
exfoliative dermatitis, intestinal perforation 
Infections 
CMV infection, herpes simplex virus infection, varicella zoster 
virus infection, Pneumocystis jirovecii infection 
8.2.5. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include: 
• Number (%) of participants reporting any TEAEs 
• Number (%) of participants reporting any DLTs 
• Number (%) of participants reporting any SAEs 
• Number (%) of participants reporting any Grade 3 or 4 TEAEs 
• Number (%) of participants reporting any TEAEs related to INCB050465 
• Number (%) of participants reporting any TEAEs related to ruxolitinib  
• Number (%) of participants who temporarily interrupted INCB050465 because of 
TEAEs 


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• Number (%) of participants who temporarily interrupted ruxolitinib because of 
TEAEs 
• Number (%) of participants who permanently discontinued INCB050465 because of 
TEAEs 
• Number (%) of participants who permanently discontinued ruxolitinib because of 
TEAEs 
• Number (%) of participants with INCB050465 dose reductions because of TEAEs  
• Number (%) of participants with ruxolitinib dose reductions because of TEAEs  
• Number (%) of participants who had a fatal TEAE 
• Number (%) of participants who withdrew from study because of an TEAE 
• Number (%) of participants reporting any treatment-emergent AESIs 
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 SOC and PT 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of TEAEs by SOC, PT, and maximum severity 
• Summary of Grade 3 or 4 TEAEs by SOC and PT 
• Summary of  INCB050465 treatment-related AEs by SOC and PT 
• Summary of Grade 3 or 4 INCB050465 treatment-related AEs by SOC and PT 
• Summary of  INCB050465 treatment-related AEs by SOC, PT, and maximum 
severity 
• Summary of ruxolitinib treatment-related AEs by SOC and PT 
• Summary of Grade 3 or 4 ruxolitinib treatment-related AEs by SOC and PT 
• Summary of ruxolitinib treatment-related AEs by SOC, PT, and maximum severity 
• Summary of TEAEs leading to death by SOC and PT 
• Summary of treatment-emergent SAEs by SOC and PT 
• Summary of treatment-emergent SAEs by PT in descending order of frequency 
• Summary of INCB050465 treatment-related SAEs by SOC and PT 
• Summary of ruxolitinib treatment-related SAEs by SOC and PT 
• Summary of TEAEs leading to INCB050465 dose reduction by SOC and PT 
• Summary of TEAEs leading to ruxolitinib dose reduction by SOC and PT 
• Summary of TEAEs leading to INCB050465 dose interruption by SOC and PT 
• Summary of TEAEs leading to ruxolitinib dose interruption by SOC and PT 


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• Summary of TEAEs leading to discontinuation of INCB050465 by SOC and PT 
• Summary of TEAEs leading to discontinuation of ruxolitinib by SOC and PT 
• Summary of TEAEs by SOC and PT:  life-table method 
• Summary of treatment-emergent AESIs 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
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, additional rules may be provided after consultation with the medical monitor 
to delineate which value will be defined as baseline. 
Laboratory test values outside the normal range will be assessed for severity based on CTCAE 
grade where clinical intervention is required for CTCAE grading.  The incidence of abnormal 
laboratory values and shift tables relative to baseline will be tabulated. 
8.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  All tests with numeric values will have a unique unit per test.  Any laboratory test results 
and associated normal ranges from local laboratories will be converted to SI units.  For the 
limited number of cases where the associated normal ranges from a local laboratory cannot be 
obtained despite due diligence, if query is unsuccessful at resolving the issues and analysis is 
mandatory, then the clinical scientist and medical monitor can provide a suitable normal range to 
be used in determining CTC grading and flags for above and below normal. 
When there are multiple laboratory nonmissing values for a participant's particular test within a 
visit window, the convention described in Table 6 will be used to determine the record used for 
by-visit tabulations and summaries. 
Table 6: 
Identification of Records for Postbaseline By-Visit Summaries 
Priority 
Laboratory Visit 
Central or Local 
Laboratory 
Proximity to Visit 
Window 
Tiebreaker 
1 
Scheduled 
Central 
In-window 
Use smallest 
laboratory 
sequence number 
2 
Scheduled 
Local 
In-window 
3 
Unscheduled 
Central 
In-window 
4 
Unscheduled 
Local 
In-window 
5 
Scheduled 
Central 
Out-of-window 
6 
Scheduled 
Local 
Out-of-window 
Shift tables based on worst postbaseline value recorded will use all postbaseline values occurring 
within 30 days of stopping study treatment. 


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Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary.  In addition, line graphs and box-and-whisker plots will 
be provided for Hgb, platelet counts, WBC, and neutrophils. 
For test results that will be summarized with available normal ranges, the number and percentage 
of participants with the 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 treatment period. 
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.   
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. 
Participants with the following elevations in liver chemistry tests will be summarized by 
treatment group for the safety population: 
• ALT > 5 × ULN 
• AST > 5 × ULN 
• ALT or AST > 5 × ULN 
• TBL > 2 × ULN 
• ALT or AST > 5 × ULN and TBL > 2 × ULN and ALP < 2 × ULN 
8.4. 
Vital Signs 
Values at each scheduled visit, change, and percent change from baseline for vital signs, 
including weight, height, SBP, DBP, pulse, respiration rate, and body temperature will be 
summarized descriptively.   
Criteria for clinically notable vital sign abnormalities are defined in Table 7.  The abnormal 
values for participants exhibiting clinically notable vital sign abnormalities will be listed along 
with their assigned treatment group.  Alert vital signs are defined as an absolute value outside the 
defined range and percentage change greater than 25%.  The abnormal values for participants 
exhibiting alert vital sign abnormalities will be listed. 


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Table 7: 
Criteria for Clinically Notable Vital Sign Abnormalities 
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 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
8.5. 
Electrocardiograms 
Twelve-lead ECGs will be obtained for each participant during the study.  Electrocardiogram 
abnormalities, both at baseline and postbaseline visits, will be tabulated by treatment group for 
the initial portion and crossover portion separately.  Incidences of abnormalities will be listed 
with study visit, assigned treatment group, and a description of the abnormality. 


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9. 
INTERIM ANALYSES 
There will be no planned, formal interim analyses for the Part 1 dose escalation portion of the 
study.  The review of accrued clinical data will be conducted by Incyte and provided to study 
investigators via teleconferences at the end of Part 1 of the study.  Based on review of the most 
current safety data, the sponsor (in consultation with the study investigators and using the 
dose-escalation/de-escalation rules) will determine if and at what dose additional participants 
should be treated in the study. 
For TG5D and TG5 (TG5I/M) in the safety population, a formal interim analysis for futility is 
planned after 15 participants are enrolled into each treatment group and have discontinued or had 
their Week 12 visit.  If 4 or fewer participants in a given dose group have spleen stability or a 
reduction from baseline in spleen volume (ie, percentage change from baseline ≤ 0%) as 
measured by MRI (or CT scan in applicable participants), then the dose in question will be 
terminated. 
If either TG5D or TG5 (TG5I/M) is terminated, then Part 4 will continue as a single-arm study, 
and the primary endpoint will be analyzed as described in Section 3.6.  If both of the treatment 
groups are terminated, the study will be terminated.  The probabilities of stopping a treatment 
group for futility for various probabilities of a participant achieving ≥ 0% decrease in spleen 
volume at Week 12 are provided in Table 8.  Additional operational details of the interim 
analyses, including TFLs provided to the DMC, will be provided in the DMC Charter. 
Table 8: 
Probability of Stopping a Treatment Group for Futility 
Probability of Participant Having ≥ 0% 
Decrease in Spleen Volume at Week 12 in a 
Treatment Group 
Probability of Stopping a Treatment Group 
for Futility 
5% 
99.5% 
10% 
94.4% 
20% 
64.8% 
25% 
46.1% 
30% 
29.7% 
40% 
9.1% 
50% 
1.8% 


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10. 
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 
27 JAN 2017 
Amendment 1 
17 MAY 2017 
Amendment 2 
30 APR 2019 
Amendment 3 
21 MAY 2021 
10.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
10.2. 
Changes to the Statistical Analysis Plan 
10.2.1. 
Original to Amendment 1 
Additional summaries for the primary and secondary endpoints were incorporated into the SAP.  
The number of participants with spleen volume reductions from baseline, changes in 
MFSAF v3.0 TSS from baseline, and changes in MPN-SAF TSS from baseline will be 
summarized categorically.  Two-sided Cochran-Mantel-Haenszel tests will be performed for 
spleen volume reduction rate, MFSAF v3.0 TSS reduction rate, and MPN-SAF TSS reduction 
rate stratified by ECOG performance status (0 or 1 vs 2) at screening.  The Cochran-Mantel-
Haenszel tests will incorporate the ordinality of the response categories.  Best overall response 
for investigator-reported IWG-MRT response assessments will also be summarized.  These 
changes led to updates in Sections 7.3 and 7.4, including descriptions of the response categories 
for spleen volume reductions, MFSAF v3.0 TSS reductions, and MPN-SAF TSS reductions, as 
well as a description of how best overall response is determined under the IWG-MRT consensus 
criteria. 
Other minor updates include the following: 
Appendix A was modified with additional summaries added to reflect the additional 
analyses.  Additional minor edits and renumbering of tables were included in this section for 
internal consistency. 


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10.2.2. 
Amendment 1 to Amendment 2 
• The analyses of Part 4 were added to the study in order to compare INCB050465 
5 mg QD from Day 1 to EOT versus INCB050465 20 mg QD for 8 weeks followed 
by 5 mg QD.  How participants enrolled in Part 2 TG10 and Part 3 TG20 may cross 
over to TG5 was described, and the handling of analyses population for crossover 
participants regarding the efficacy and safety analyses was defined.  
• The window of MFSAF TSS was revised from the last 28 consecutive days to last 
7 consecutive days before the assessment visit.  The total score will be missing if 
there are ≥ 4 missing out of the 7 daily total scores.  
• The analyses of MFSAF TSS – Fatigue were added. 
• Analyses for the AESIs including a summary of treatment-emergent AESIs and 
summary of participants with elevations in liver chemistry tests were added.  A 
summary of TEAE life table by SOC and PT was added to summarize the frequencies 
of TEAEs separately for ≤ 8 weeks, > 8 weeks and ≤ 16 weeks, > 16 weeks and 
≤ 24 weeks, and > 24 weeks. 
• Table shells were moved to a separate document from the SAP. 
• Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the SAP. 
10.2.3. 
Amendment 2 to Amendment 3 
The primary purpose of this amendment is to update the statistical analyses as enrollment has 
been terminated early. 
• Intent-to-treat population, per-protocol population, and safety run-in population were 
removed.  All analyses will be conducted using the safety population. 
• In addition to the comparison between TG5D and TG5I/M, the comparison between 
daily dosing (TG5D + TG5I/M) and daily/weekly dosing (TG10 + TG20) in the 
endpoints of interest were added. 
• The algorithm of the window for deriving MFSAF v3.0 total symptom score for 
baseline, Week 12, and Week 24 in Table 4 was updated to fix the issue when the 
participants have missing values in the end of window. 
• Elevations in liver chemistry tests were added. 
• Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the SAP. 


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11. 
REFERENCES 
Passamonti F, Cervantes F, Vannucchi AM, et al. Adynamic prognostic model to predict survival 
in primary myelofibrosis: a study by the IWG-MRT (International Working Group for 
Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115:1703-1708. 
Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International 
Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and 
European LeukemiaNet (ELN) consensus report. Blood 2013;122:1395-1398. 
Thiele J, Kvasnicka HM, Facchetti F, et al. European consensus on grading bone marrow fibrosis 
and assessment of cellularity. Haematologica 2005;90:1128-1132. 
van Elteren PH. On the combination of independent two sample tests of Wilcoxon. Bulletin de 
l'Institut International de Statistique 1960;37:351-361. 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned TFLs for the CSR.  Standard tables will follow the 
conventions in the Standard Safety Tables initial version.  Shells are provided for nonstandard 
tables.  In-text tables are identical in structure and content as appendix tables but follow a Rich 
Text Format. 
The list of TFLs and the shells are to be used as guideline.  Modifications of the list or shells 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 
All Participants 
X 
1.1.2.1 
Summary of Participant Disposition 
Safety  
X 
1.1.2.2 
Summary of Participant Disposition – Daily vs Daily/Weekly 
Safety 
X 
1.1.3.1 
Summary of Number of Participants Enrolled by Site 
Safety 
X 
1.2  Demography 
1.2.1.1 
Summary of Demographics 
Safety 
X 
1.2.1.2 
Summary of Demographics – Daily vs Daily/Weekly 
Safety  
X 
1.3  Baseline Characteristics 
1.3.1.1 
Summary of Baseline Disease Characteristics 
Safety 
 
1.3.1.2 
Summary of Baseline Disease Characteristics – Daily vs 
Daily/Weekly 
Safety  
 
1.3.2.1 
Summary of Disease History  
Safety 
 
1.3.2.2 
Summary of Disease History – Daily vs Daily/Weekly 
Safety 
 
1.3.3.1 
Summary of Prior Cancer Therapy 
Safety 
 
1.4  Prior Medication and Concomitant Medication 
1.4.1.1 
Summary of Prior Medications 
Safety  
X 
1.4.2.1 
Summary of Concomitant Medications 
Safety 
X 
1.4.3.1 
Summary of Prior Ruxolitinib History 
Safety 
 
1.4.3.2 
Summary of Prior Ruxolitinib History – Daily vs 
Daily/Weekly 
Safety 
 
1.5+  Others 
1.5.1.1 
Summary of General Medical History 
Safety 
X 
Efficacy 
2.1  Primary Efficacy 
2.1.1.1 
Summary of Percent Change in Spleen Volume by Visit 
Safety Initial Portion 
 
2.1.1.2 
Summary of Percent Change in Spleen Volume by Visit 
Safety Crossover Portion 
 
2.1.1.3 
Summary of Percent Change in Spleen Volume by Visit – 
Daily vs Daily/Weekly 
Safety Initial Portion 
 
2.1.2.1 
Van Elteren Test of Percent Change in Spleen Volume for 
TG5 (TG5I/M) and TG5D 
Safety Initial Portion 
 
2.1.2.2 
Van Elteren Test of Percent Change in Spleen Volume for 
Daily and Daily/Weekly Dosing 
Safety  Initial Portion 
 


Incyte Corporation 
Page 41 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
2.1.3.1 
Summary of Response Categories for Spleen Volume 
Reduction for TG5 (TG5I/M) and TG5D 
Safety Initial Portion 
 
2.1.3.2 
Summary of Response Categories for Spleen Volume 
Reduction for Daily and Daily/Weekly Dosing 
Safety  Initial Portion 
 
2.2  Secondary Efficacy 
2.2.1.1 
Summary of  MFSAF v3.0 Total Symptom Score Using 
7-Day Window by Visit 
Safety Initial Portion 
 
2.2.1.2 
Summary of  MFSAF v3.0 Total Symptom Score Using 
7-Day Window by Visit 
Safety Crossover Portion 
 
2.2.1.3 
Summary of  MFSAF v3.0 Total Symptom Score Using 
7-Day Window by Visit – Daily vs Daily/Weekly 
Safety Initial Portion 
 
2.2.1.4 
Summary of  MFSAF v3.0 Total Symptom Score - Fatigue 
Using 7-Day Window by Visit 
Safety Initial Portion 
 
2.2.1.5 
Summary of  MFSAF v3.0 Total Symptom Score - Fatigue 
Using 7-Day Window by Visit 
Safety Crossover Portion 
 
2.2.2.1 
Summary of Percent Change in MFSAF v3.0 Total Symptom 
Score Using 7-Day Window at Weeks 12 and 24  
Safety Initial Portion 
 
2.2.2.2 
Summary of Percent Change in MFSAF v3.0 Total Symptom 
Score Using 7-Day Window at Weeks 12 and 24 
Safety Crossover Portion 
 
2.2.2.3 
Summary of Percent Change in MFSAF v3.0 Total Symptom 
Score Using 7-Day Window at Weeks 12 and 24 – Daily vs 
Daily/Weekly 
Safety Initial Portion 
 
2.2.2.4 
Summary of Percent Change in MFSAF v3.0 Total Symptom 
Score - Fatigue Using 7-Day Window at Weeks 12 and 24  
Safety Initial Portion 
 
2.2.2.5 
Summary of Percent Change in MFSAF v3.0 Total Symptom 
Score - Fatigue Using 7-Day Window at Weeks 12 and 24 
Safety Crossover Portion 
 
2.2.3.1 
Van Elteren Test of MFSAF v3.0 Total Symptom Score for 
TG5 (TG5I/M) and TG5D 
Safety Initial Portion 
 
2.2.3.2 
Van Elteren Test of MFSAF v3.0 Total Symptom Score for 
Daily vs Daily/Weekly Dosing 
Safety Initial Portion 
 
2.2.3.3 
Van Elteren Test of MFSAF v3.0 Total Symptom Score - 
Fatigue for TG5 (TG5I/M) and TG5D 
Safety Initial Portion 
 
2.2.3.4 
Van Elteren Test of MFSAF v3.0 Total Symptom Score - 
Fatigue for  Daily vs Daily/Weekly Dosing 
Safety Initial Portion 
 
2.2.4.1 
Summary of Response Categories for MFSAF v3.0 Total 
Symptom Score by Visit for TG5 (TG5I/M) and TG5D 
Safety Initial Portion 
 
2.2.4.2 
Summary of Response Categories for MFSAF v3.0 Total 
Symptom Score by Visit for Daily vs Daily/Weekly 
Safety Initial Portion 
 
2.2.4.3 
Summary of Response Categories for MFSAF v3.0 Total 
Symptom Score - Fatigue by Visit for TG5 (TG5I/M) and 
TG5D 
Safety Initial Portion 
 
2.2.4.4 
Summary of Response Categories for MFSAF v3.0 Total 
Symptom Score - Fatigue by Visit for Daily vs Daily/Weekly 
Safety Initial Portion 
 
2.2.5.1 
Summary of MPN-SAF Total Symptom Score by Visit 
Safety Initial Portion 
 
2.2.5.2 
Summary of MPN-SAF Total Symptom Score by Visit 
Safety Crossover Portion 
 
2.2.5.3 
Summary of MPN-SAF Total Symptom Score by Visit - 
Daily vs Daily/Weekly 
Safety Initial Portion 
 
2.2.6.1 
Summary of Percent Change in MPN-SAF Total Symptom 
Score at Weeks 12 and 24 
Safety Initial Portion 
 


Incyte Corporation 
Page 42 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
2.2.6.2 
Summary of Percent Change in MPN-SAF Total Symptom 
Score at Weeks 12 and 24 - Daily vs Daily/Weekly 
Safety Initial Portion 
 
2.2.7.1 
Van Elteren Test of MPN-SAF Total Symptom Score for 
TG5 (TG5I/M) and TG5D  
Safety Initial Portion 
 
2.2.7.2 
Van Elteren Test of MPN-SAF Total Symptom Score for 
Daily vs Daily/Weekly Dosing 
Safety Initial Portion 
 
2.2.8.1 
Summary of Response Categories for MPN-SAF Total 
Symptom Score for TG5 (TG5I/M) and TG5D 
Safety Initial Portion 
 
2.2.8.2 
Summary of Response Categories for MPN-SAF Total 
Symptom Score for Daily vs Daily/Weekly Dosing 
Safety Initial Portion 
 
2.2.9.1 
Summary of Patient Global Impression of Change (PGIC) 
Score 
Safety Initial Portion 
 
2.2.9.2 
Summary of Patient Global Impression of Change (PGIC) 
Score 
Safety Crossover Portion 
 
2.2.9.3 
Summary of Patient Global Impression of Change (PGIC) 
Score - Daily vs Daily/Weekly 
Safety Initial Portion 
 
2.2.10.1 
Summary of Investigator-Reported IWG-MRT Response 
Assessment for TG5 (TG5I/M) and TG5D 
Safety Initial Portion 
 
2.2.11.1 
Summary of Best Overall Response for 
Investigator-Reported IWG-MRT Response Assessment for 
TG5 (TG5I/M) and TG5D 
Safety Initial Portion 
 
2.2.12.1.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Night Sweats 
Safety Initial Portion 
 
2.2.12.1.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Night Sweats 
Safety Crossover Portion 
 
2.2.12.2.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Itchiness 
Safety Initial Portion 
 
2.2.12.2.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Itchiness 
Safety Crossover Portion 
 
2.2.12.3.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Abdominal Discomfort 
Safety Initial Portion 
 
2.2.12.3.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Abdominal Discomfort 
Safety Crossover Portion 
 
2.2.12.4.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Pain Under Left Ribs 
Safety Initial Portion 
 
2.2.12.4.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Pain Under Left Ribs 
Safety Crossover Portion 
 
2.2.12.5.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Early Satiety 
Safety Initial Portion 
 
2.2.12.5.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Early Satiety 
Safety Crossover Portion 
 
2.2.12.6.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Bone/Muscle Pain 
Safety Initial Portion 
 
2.2.12.6.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Bone/Muscle Pain 
Safety Crossover Portion 
 
2.2.12.7.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Fatigue 
Safety Initial Portion 
 


Incyte Corporation 
Page 43 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
2.2.12.7.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Fatigue 
Safety Crossover Portion 
 
2.2.12.8.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Low Energy 
Safety Initial Portion 
 
2.2.12.8.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Low Energy 
Safety Crossover Portion 
 
2.2.12.9.1 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Exhaustion 
Safety Initial Portion 
 
2.2.12.9.2 
Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Exhaustion 
Safety Crossover Portion 
 
2.2.12.10.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Physical Weakness 
Safety Initial Portion 
 
2.2.12.10.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Physical Weakness 
Safety Crossover Portion 
 
2.2.12.11.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Heavy Limbs 
Safety Initial Portion 
 
2.2.12.11.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Heavy Limbs 
Safety Crossover Portion 
 
2.2.12.12.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Tiredness 
Safety Initial Portion 
 
2.2.12.12.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Tiredness 
Safety Crossover Portion 
 
2.2.12.13.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Confusion 
Safety Initial Portion 
 
2.2.12.13.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Confusion 
Safety Crossover Portion 
 
2.2.12.14.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Forgetfulness 
Safety Initial Portion 
 
2.2.12.14.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Forgetfulness 
Safety Crossover Portion 
 
2.2.12.15.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Interference With Physical Activity 
Safety Initial Portion 
 
2.2.12.15.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Interference With Physical Activity 
Safety Crossover Portion 
 
2.2.12.16.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Interference With Daily Activities 
Safety Initial Portion 
 
2.2.12.16.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Interference With Daily Activities 
Safety Crossover Portion 
 
2.2.12.17.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Frustration 
Safety Initial Portion 
 
2.2.12.17.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Frustration 
Safety Crossover Portion 
 
2.2.12.18.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Inactivity 
Safety Initial Portion 
 
2.2.12.18.2 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Inactivity 
Safety Crossover Portion 
 
2.2.12.19.1 Summary of MFSAF v3.0 Individual Symptom Scores by 
Visit, Sleepiness 
Safety Initial Portion 
 


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Incyte Corporation 
Page 45 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
3.2.7.1 
Summary of Grade 3 or 4 INCB050465 Treatment-Related 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety Initial Portion 
X 
3.2.7.2 
Summary of Grade 3 or 4 INCB050465 Treatment-Related 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety Crossover Portion 
X 
3.2.8.1 
Summary of Grade 3 or 4 INCB050465 Treatment-Related 
Adverse Events by MedDRA Preferred Term in Order of 
Decreasing Frequency 
Safety Initial Portion 
X 
3.2.8.2 
Summary of Grade 3 or 4 INCB050465 Treatment-Related 
Adverse Events by MedDRA Preferred Term in Order of 
Decreasing Frequency 
Safety Crossover Portion 
X 
3.2.9.1 
Summary of Ruxolitinib Treatment-Related Adverse Events 
by MedDRA System Organ Class and Preferred Term 
Safety Initial Portion 
X 
3.2.9.2 
Summary of Ruxolitinib Treatment-Related Adverse Events 
by MedDRA System Organ Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.10.1 
Summary of Grade 3 or 4 Ruxolitinib Treatment-Related 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety Initial Portion 
X 
3.2.10.2 
Summary of Grade 3 or 4 Ruxolitinib Treatment-Related 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety Crossover Portion 
X 
3.2.11.1 
Summary of Ruxolitinib Treatment-Related Adverse Events 
by MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
Safety Initial Portion 
X 
3.2.11.2 
Summary of Ruxolitinib Treatment-Related Adverse Events 
by MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
Safety Crossover Portion 
X 
3.2.12.1 
Summary of Serious Treatment-Emergent Adverse Events 
With a Fatal Outcome by MedDRA System Organ Class and 
Preferred Term 
Safety Initial Portion 
X 
3.2.12.2 
Summary of Serious Treatment-Emergent Adverse Events 
With a Fatal Outcome by MedDRA System Organ Class and 
Preferred Term 
Safety Crossover Portion 
X 
3.2.13.1 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety Initial Portion 
X 
3.2.13.2 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.14.1 
Summary of Serious Treatment-Emergent Adverse Events by 
Preferred Term in Decreasing Order of Frequency 
Safety Initial Portion 
X 
3.2.14.2 
Summary of Serious Treatment-Emergent Adverse Events by 
Preferred Term in Decreasing Order of Frequency 
Safety Crossover Portion 
X 
3.2.15.1 
Summary of Non-Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety Initial Portion 
X 
3.2.15.2 
Summary of Non-Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.16.1 
Summary of INCB050465Treatment-Related Serious 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety Initial Portion 
X 


Incyte Corporation 
Page 46 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
3.2.16.2 
Summary of INCB050465Treatment-Related Serious 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety Crossover Portion 
X 
3.2.17.1 
Summary of Ruxolitinib Treatment-Related Serious Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety Initial Portion 
X 
3.2.17.2 
Summary of Ruxolitinib Treatment-Related Serious Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.18.1 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB050465 Dose Reduction by MedDRA System Organ 
Class and Preferred Term 
Safety Initial Portion 
X 
3.2.18.2 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB050465 Dose Reduction by MedDRA System Organ 
Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.19.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib Dose Reduction by MedDRA System Organ 
Class and Preferred Term 
Safety Initial Portion 
X 
3.2.19.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib Dose Reduction by MedDRA System Organ 
Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.20.1 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB050465 Dose Interruption by MedDRA System Organ 
Class and Preferred Term 
Safety Initial Portion 
X 
3.2.20.2 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB050465 Dose Interruption by MedDRA System Organ 
Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.21.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib Dose Interruption by MedDRA System Organ 
Class and Preferred Term 
Safety Initial Portion 
X 
3.2.21.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib Dose Interruption by MedDRA System Organ 
Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.22.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of INCB050465 by MedDRA System Organ 
Class and Preferred Term 
Safety Initial Portion 
X 
3.2.22.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of INCB050465 by MedDRA System Organ 
Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.23.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Ruxolitinib by MedDRA System Organ 
Class and Preferred Term 
Safety Initial Portion 
X 
3.2.23.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Ruxolitinib by MedDRA System Organ 
Class and Preferred Term 
Safety Crossover Portion 
X 
3.2.24.1 
Summary of Treatment-Emergent Adverse Events of Special 
Interest 
Safety Initial Portion 
X 
3.2.24.2 
Summary of Treatment-Emergent Adverse Events of Special 
Interest 
Safety Crossover Portion 
X 
3.2.25.1 
Summary of Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term:  Life Table Method 
Safety Initial Phase 
X 


Incyte Corporation 
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INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
3.2.25.2 
Summary of Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term:  Life Table Method 
Safety Crossover Portion 
X 
3.3  Laboratory 
3.3.1.1 
Summary of Laboratory Values – Hematology 
Safety Initial Portion 
X 
3.3.1.2 
Summary of Laboratory Values – Hematology 
Safety Crossover Portion 
X 
3.3.2.1 
Shift Summary of Hematology Laboratory Values in CTC 
Grade – To the Worst Abnormal Value  
Safety Initial Portion 
X 
3.3.2.2 
Shift Summary of Hematology Laboratory Values in CTC 
Grade – To the Worst Abnormal Value  
Safety Crossover Portion 
X 
3.3.3.1 
Summary of Laboratory Values – Chemistry 
Safety Initial Portion 
X 
3.3.3.2 
Summary of Laboratory Values – Chemistry 
Safety Crossover Portion 
X 
3.3.4.1 
Shift Summary of Chemistry Laboratory Values in CTC 
Grade – To the Worst Abnormal Value 
Safety Initial Portion 
X 
3.3.4.2 
Shift Summary of Chemistry Laboratory Values in CTC 
Grade – To the Worst Abnormal Value 
Safety Crossover Portion 
X 
3.3.5.1 
Summary of Laboratory Values – Coagulation 
Safety Initial Portion 
X 
3.3.5.2 
Summary of Laboratory Values – Coagulation 
Safety Crossover Portion 
X 
3.3.6.1 
Shift Summary of Coagulation Values in CTC Grade – To 
the Worst Abnormal Value 
Safety Initial Portion 
X 
3.3.6.2 
Shift Summary of Coagulation Values in CTC Grade – To 
the Worst Abnormal Value 
Safety Crossover Portion 
X 
3.3.7.1 
Summary of Participants With Elevations in Liver Chemistry 
Tests 
Safety Initial Portion 
X 
3.3.7.2 
Summary of Participants With Elevations in Liver Chemistry 
Tests 
Safety Crossover Portion 
X 
3.4  Vital Signs 
3.4.1.1 
Summary of Systolic Blood Pressure (mmHg) 
Safety Initial Portion 
X 
3.4.1.2 
Summary of Systolic Blood Pressure (mmHg) 
Safety Crossover Portion 
X 
3.4.2.1 
Summary of Diastolic Blood Pressure (mmHg)  
Safety Initial Portion 
X 
3.4.2.2 
Summary of Diastolic Blood Pressure (mmHg)  
Safety Crossover Portion 
X 
3.4.3.1 
Summary of Heart Rate (bpm) 
Safety Initial Portion 
X 
3.4.3.2 
Summary of Heart Rate (bpm) 
Safety Crossover Portion 
X 
3.4.4.1 
Summary of Respiration Rate (bpm) 
Safety Initial Portion 
X 
3.4.4.2 
Summary of Respiration Rate (bpm) 
Safety Crossover Portion 
X 
3.4.5.1 
Summary of Body Temperature (°C) 
Safety Initial Portion 
X 
3.4.5.2 
Summary of Body Temperature (°C) 
Safety Crossover Portion 
X 
3.4.6.1 
Summary of Weight (kg) 
Safety Initial Portion 
X 
3.4.6.2 
Summary of Weight (kg) 
Safety Crossover Portion 
X 
3.5  ECG 
3.5.1.1 
Summary of Treatment Emergent, Clinically Significant 
ECG Abnormality From Baseline 
Safety Initial Portion 
 
3.5.1.2 
Summary of Treatment Emergent, Clinically Significant 
ECG Abnormality From Baseline 
Safety Crossover Portion 
 


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Incyte Corporation 
Page 49 of 51 
INCB 50465-201 SAP Amendment 3 
21 MAY 2021 
VV-CLIN-000104 
CONFIDENTIAL 
Listing No. 
Title 
2.7.7 
Treatment-Related Adverse Events 
2.7.8 
Adverse Events Leading to Interruption, Reduction, or Discontinuation of INCB050465 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 
Clinical Laboratory Values – Serology 
2.8.5 
Abnormal Clinical Laboratory Values 
2.8.6 
Participants With AST ≥ 5 × ULN or ALT ≥ 5 × ULN 
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 
2.11.2 
Body Weight 


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Page 50 of 51 
INCB 50465-201 SAP Amendment 3 
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VV-CLIN-000104 
CONFIDENTIAL 
APPENDIX B. IWG-MRT CRITERIA FOR TREATMENT RESPONSE 
IWG-MRT Criteria for Treatment Response 
Response 
Categories 
Required Criteria (for All Response Categories, Benefit Must Last for ≥ 12 Weeks to 
Qualify as a Response) 
CR 
Bone marrowa:  Age-adjusted normocellularity; < 5% blasts; ≤ Grade 1 MFb and 
Peripheral blood:  Hemoglobin ≥ 100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and 
< UNL; 
Platelet count ≥ 100 × 109/L and < UNL; < 2% immature myeloid cellsc and 
Clinical:  Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH 
PR 
Peripheral blood:  Hemoglobin ≥ 100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and 
< UNL; platelet count ≥ 100 × 109/L and < UNL; < 2% immature myeloid cellsc and 
Clinical:  Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH or 
Bone marrow:a  Age-adjusted normocellularity; < 5% blasts; ≤ Grade 1 MFb; and 
peripheral blood:  hemoglobin ≥ 85 g/L but < 100 g/L and < UNL; neutrophil count ≥ 1 × 
109/L and < UNL; platelet count ≥ 50 × 109/L but < 100 × 109/L and < UNL; < 2% 
immature myeloid cellsc and 
Clinical:  Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH 
CI 
The achievement of anemia, spleen or symptoms response without progressive disease or 
increase in severity of anemia, thrombocytopenia, or neutropeniad 
Anemia response 
Transfusion-independent patients:  a ≥ 20 g/L increase in hemoglobin levele 
Transfusion-dependent patients:  becoming transfusion-independentf 
Spleen responseg 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not 
palpableh or 
A baseline splenomegaly that is palpable at > 10 cm, below the LCM, decreases by ≥ 50%h 
A baseline splenomegaly that is palpable at < 5 cm, below the LCM, is not eligible for 
spleen response 
A spleen response requires confirmation by MRI or CT showing ≥ 35% spleen volume 
reduction 
Symptoms 
response 
A ≥ 50% reduction in the MPN-SAF TSSi 


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INCB 50465-201 SAP Amendment 3 
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IWG-MRT Criteria for Treatment Response (Continued) 
Response 
Categories 
Required Criteria (for All Response Categories, Benefit Must Last for ≥ 12 Weeks to 
Qualify as a Response) 
Progressive diseasej 
Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or 
A ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 cm 
or 
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm or 
Leukemic transformation confirmed by a bone marrow blast count of ≥ 20% or 
A peripheral blood blast content of ≥ 20% associated with an absolute blast count of 
≥ 1 × 109/L that lasts for at least 2 weeks 
Stable disease 
Belonging to none of the above-listed response categories 
Relapse 
No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 
Loss of anemia response persisting for at least 1 month or 
Loss of spleen response persisting for at least 1 month 
CI = clinical improvement; CR = complete response; CT = computed tomography; EMH = extramedullary hematopoiesis; 
LCM = left costal margin; MF = myelofibrosis; MPN-SAF TSS = Myeloproliferative Neoplasm Symptom Assessment Form 
Total Symptom Score; MRI = magnetic resonance imaging; PR = partial response; PRBC = packed red blood cell; 
UNL = upper normal limit. 
a Baseline and post-treatment bone marrow slides are to be interpreted at 1 sitting by a central review process.  Cytogenetic and 
molecular responses are not required for CR assignment. 
b Grading of MF is according to the European classification (Thiele et al 2005).  It is underscored that the consensus definition of 
a CR bone marrow is to be used only in those patients in which all other criteria are met, including resolution of 
leukoerythroblastosis.  It should also be noted that it was a particularly difficult task for the working group to reach a consensus 
regarding what represents a complete histologic remission. 
c Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood cells.  In 
splenectomized patients, < 5% immature myeloid cells is allowed. 
d See above for definitions of anemia response, spleen response, and progressive disease.  Increase in severity of anemia 
constitutes the occurrence of new transfusion dependency or a ≥ 20 g/L decrease in hemoglobin level from pretreatment 
baseline that lasts for at least 12 weeks.  Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade 
decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according to the CTCAE version 4.0.  In 
addition, assignment to CI requires a minimum platelet count of ≥ 25,000 × 109/L and absolute neutrophil count of 
≥ 0.5 × 109/L. 
e Applicable only to patients with baseline hemoglobin of < 100 g/L.  In patients not meeting the strict criteria for transfusion 
dependency at the time of study enrollment (see as follows), but have received transfusions within the previous month, the 
pretransfusion hemoglobin level should be used as the baseline. 
f Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of PRBCs, in the 12 weeks prior 
to study enrollment, for a hemoglobin level of < 85 g/L, in the absence of bleeding or treatment-induced anemia.  In addition, 
the most recent transfusion episode must have occurred in the 28 days prior to study enrollment.  Response in 
transfusion-dependent patients requires absence of any PRBC transfusions during any consecutive "rolling" 12-week interval 
during the treatment phase, capped by a hemoglobin level of ≥ 85 g/L. 
g In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy. 
h Spleen or liver responses must be confirmed by imaging studies where a ≥ 35% reduction in spleen volume, as assessed by 
MRI or CT, is required.  Furthermore, a ≥ 35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response 
regardless of what is reported with physical examination. 
i Symptoms are evaluated by the MPN-SAF TSS.  The MPN-SAF TSS is assessed by the patients themselves and this includes 
fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers.  
Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item.  The MPN-SAF TSS 
is the summation of all the individual scores (0-100 scale).  Symptoms response requires ≥ 50% reduction in the MPN-SAF 
TSS. 
j Progressive disease assignment for splenomegaly requires confirmation by MRI or CT showing a ≥ 25% increase in spleen 
volume from baseline.  Baseline values for both physical examination and imaging studies refer to pretreatment baseline and 
not to posttreatment measurements.