A Phase 3, Randomized, Double-blind, Active-Control Study of Pelabresib (CPI-0610) and Ruxolitinib vs. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients
Phase: PHASE3
Conditions: Myelofibrosis, Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis
Sponsor: Novartis Pharmaceuticals

CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
Constellation Pharmaceuticals, 
A MorphoSys Company 
Confidential 
1 
 
CLINICAL TRIAL PROTOCOL 
 
A Phase 3, Randomized, Double-Blind, Active-Control Study of Pelabresib 
(CPI-0610) and Ruxolitinib vs. Placebo and Ruxolitinib in JAKi Treatment Naive 
MF Patients 
Clinical Trial Protocol No: 
CPI 0610-04 
Clinical Trial Protocol Name: 
MANIFEST-2 
Version: 
CTP v. 6.0, 04-Oct-2023 
Clinical Trial Phase: 
3 
Product Name: 
Pelabresib (CPI-0610) 
Sponsor: 
Constellation Pharmaceuticals, Inc. (Constellation 
Pharmaceuticals, Inc. is a fully owned subsidiary of 
MorphoSys U.S. Inc.) 
Sponsor’s Address: 
470 Atlantic Avenue, Suite 1401  
Boston, MA 02210 
United States 
EU Trial Number: 
2020-001989-10 
IND No: 
147351 
The concepts and information contained in this document are considered proprietary and are provided for the 
exclusive use of investigators and other persons involved in the study who have a need to know. Subject to the 
foregoing, the content of this document may not be disclosed unless law or regulations require such disclosure, or 
Constellation Pharmaceuticals, Inc. has granted prior written approval. 
 

CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
Constellation Pharmaceuticals, 
A MorphoSys Company 
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Sponsor Signatory: 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
Medical Monitor Name and Contact Information: Refer to the Investigator Site File  
 

CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
Constellation Pharmaceuticals, 
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3 
PRINCIPAL INVESTIGATOR’S SIGNATURE 
 
 
I agree to conduct the clinical trial in accordance with this clinical trial protocol, the 
International Council for Harmonisation (ICH) E6 Guideline for Good Clinical Practice 
(GCP), the principles which have their origin in the Declaration of Helsinki, and applicable 
local regulations, including the following: 
• Personally, conduct or supervise the investigation 
• Ensure that an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), that complies with the requirements of GCP and local regulations, will be 
responsible for the initial and continuing review and approval of the clinical trial.  
• Promptly report to the IRB/IEC (directly or through the sponsor) changes in the 
research activity, and new information that may adversely affect the safety of the 
patients or the conduct of the trial.  
• Not implement any deviation from, or changes to the protocol without agreement by 
the sponsor and prior review and documented approval/favorable opinion from the 
IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to patients 
• Inform patients, that the investigational medicinal product is being used for 
investigational purposes and ensure that the requirements relating to obtaining 
informed consent, including IRB/IEC review and approval thereof, are met. 
• Report adverse events to the sponsor. 
• Read and understand the information in the investigator’s brochure. 
• Ensure that sub-investigator(s) and other staff assisting in the conduct of the 
clinical trial are informed about their obligations in meeting this commitment.  
• Maintain adequate and accurate records, provide direct access to those records 
for monitoring, audits, and inspection, and allow any regulatory agency to 
inspect the trial site. 
Signature: 
 
  Date: 
 
 
 
 
(DD Mmm YYYY) 
Name: 
 
 
 
 
 
 
 

CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
Constellation Pharmaceuticals, 
A MorphoSys Company 
Confidential 
4 
PROTOCOL HISTORY 
 
Version 
Date 
Reason for Change 
Amendment 5 (Version 6.0) 
04 Oct 2023 
Updated contraception 
language; study design 
modifications 
Amendment 4 (Version 5.2) 
11 Apr 2023 
Canada Only 
Amendment 4 (Version 5.1) 
30 Mar 2023 
Germany Only 
Amendment 4 (Version 5.0) 
10 Mar 2023 
Study design change 
Amendment 3 (Version 4.4) 
14 Oct 2022 
Romania only 
Amendment 3 (Version 4.3) 
19 Jul 2022 
Germany only 
Amendment 3 (Version 4.2) 
13 Apr 2022 
Czech Republic only 
Amendment 3 (Version 4.1) 
15 Dec 2021 
Germany only 
Amendment 3 (Version 4.0) 
15 Nov 2021 
Study design change 
Amendment 2 (Version 3.1) 
24 Sep 2021 
Czech Republic only 
Amendment 2 (Version 3):  
26 Feb 2021 
Study design change 
Amendment 1 (Version 2.2):  
02 Dec 2020 
France only 
Amendment 1 (Version 2.1):  
20 Nov 2020 
United Kingdom only 
Amendment 1 (Version 2):  
14 Sep 2020 
Study design change 
Original Protocol (Version 1): 17 April 2020 
Not applicable 
 
 
 
 

CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
Constellation Pharmaceuticals, 
A MorphoSys Company 
Confidential 
5 
TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY .............................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema ............................................................................................................................16 
1.3. 
Schedule of Activities (SoA) ..........................................................................................17 
2. 
INTRODUCTION ........................................................................................................22 
2.1. 
Background .....................................................................................................................22 
2.2. 
Study Rationale ...............................................................................................................23 
2.3. 
Benefit/Risk Assessment ................................................................................................24 
2.3.1. 
Risk Assessment .............................................................................................................24 
2.3.2. 
Benefit Assessment .........................................................................................................25 
2.3.3. 
Overall Benefit-Risk Conclusion ....................................................................................26 
3. 
OBJECTIVES AND ENDPOINTS .............................................................................26 
4. 
STUDY DESIGN...........................................................................................................30 
4.1. 
Overall Design ................................................................................................................30 
4.2. 
Scientific Rationale for Study Design ............................................................................30 
4.3. 
Justification for Dose ......................................................................................................31 
4.4. 
DSMB .............................................................................................................................32 
4.5. 
Study Participation ..........................................................................................................32 
4.5.1. 
Screen Failures ................................................................................................................32 
4.5.2. 
Duration of Treatment and Study Participation ..............................................................32 
4.5.3. 
Patient Follow-Up ...........................................................................................................32 
4.5.4. 
End of Study ...................................................................................................................33 
5. 
STUDY POPULATION ...............................................................................................33 
5.1. 
Inclusion Criteria ............................................................................................................33 
5.2. 
Exclusion Criteria ...........................................................................................................34 
6. 
STUDY DRUG ..............................................................................................................36 
6.1. 
Study Drugs Administered..............................................................................................37 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................38 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................39 
6.4. 
Study Drug Compliance..................................................................................................40 
6.5. 
Ruxolitinib and Pelabresib/Placebo Starting Doses and Dose 
Modification Guidelines .................................................................................................40 
6.5.1. 
Starting Doses of Pelabresib/Placebo and Ruxolitinib ...................................................40 
6.5.2. 
Criteria and Process to Increase Doses of Ruxolitinib and 
Pelabresib/Placebo ..........................................................................................................41 
6.5.3. 
Ruxolitinib and Pelabresib/Placebo Dose Modification and 
Restarting Rules for Platelet Count Decrease and Other 
Toxicities.........................................................................................................................42 
6.5.4. 
Re-escalation Criteria and Process..................................................................................48 
6.6. 
Crossover Period .............................................................................................................49 
6.6.1. 
Crossover Design ............................................................................................................49 
6.6.2. 
Operational Considerations for Crossover ......................................................................50 

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pelabresib 
Study CPI 0610-04 Protocol  
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6.6.3. 
Clinical Considerations for Crossover ............................................................................51 
6.6.4. 
Statistical Considerations for Crossover .........................................................................52 
6.7. 
Supportive Care ..............................................................................................................53 
6.7.1. 
Nausea and/or Vomiting .................................................................................................53 
6.7.2. 
Management of Diarrhea ................................................................................................53 
6.7.3. 
Management of Rash ......................................................................................................54 
6.7.4. 
Management of Ruxolitinib Discontinuation Syndrome (RDS) .....................................54 
6.8. 
Concomitant Therapy .....................................................................................................55 
6.9. 
Contraception ..................................................................................................................56 
6.9.1. 
Female Patients ...............................................................................................................56 
6.9.2. 
Male Patients ...................................................................................................................57 
6.9.3. 
Female Partners (WOCBP, Non-pregnant) of Male Patients .........................................57 
6.9.4. 
Oocyte and Sperm Donation ...........................................................................................58 
7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
WITHDRAWAL FROM THE STUDY ......................................................................58 
7.1. 
Discontinuation of Study Drug .......................................................................................58 
7.2. 
Patient Withdrawal from the Study Treatment/Study.....................................................59 
7.3. 
Lost to Follow-up............................................................................................................59 
8. 
STUDY ASSESSMENTS AND PROCEDURES .......................................................60 
8.1. 
Demographics and Medical History Assessments ..........................................................60 
8.2. 
Efficacy Assessments .....................................................................................................61 
8.2.1. 
Disease Status Assessments ............................................................................................61 
8.2.2. 
Patient-Reported Outcomes ............................................................................................62 
8.3. 
Safety Assessments .........................................................................................................62 
8.3.1. 
Concomitant Medications ...............................................................................................62 
8.3.2. 
Physical Examinations, Including Spleen Examination, and Vital 
Signs ................................................................................................................................62 
8.3.3. 
ECOG Performance Status .............................................................................................63 
8.3.4. 
Electrocardiograms .........................................................................................................63 
8.3.5. 
Clinical Safety Laboratory Assessments ........................................................................64 
8.4. 
AEs and SAEs .................................................................................................................64 
8.4.1. 
AE and SAE Definitions .................................................................................................64 
8.4.2. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................65 
8.4.3. 
Method of Detecting AEs and SAEs ..............................................................................66 
8.4.4. 
Follow-up of AEs and SAEs ...........................................................................................67 
8.4.5. 
Regulatory Reporting Requirements for SAEs ...............................................................67 
8.4.6. 
Pregnancy ........................................................................................................................67 
8.4.7. 
Disease-Related Events and/or Disease-Related Outcomes ...........................................68 
8.4.8. 
Adverse Events of Special Interest (AESIs) ...................................................................69 
8.5. 
Treatment of Overdose ...................................................................................................69 
8.6. 
Pharmacokinetics ............................................................................................................69 
8.7. 
Pharmacodynamics .........................................................................................................70 
9. 
STATISTICAL CONSIDERATIONS ........................................................................71 
9.1. 
Study Endpoints ..............................................................................................................71 

CPI-0610 
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Study CPI 0610-04 Protocol  
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9.1.1. 
Primary Endpoint ............................................................................................................71 
9.1.2. 
Key Secondary Endpoints ...............................................................................................71 
9.1.3. 
Secondary Endpoints ......................................................................................................71 
9.1.4. 
Exploratory Endpoints ....................................................................................................72 
9.2. 
Analysis Populations.......................................................................................................73 
9.3. 
Statistical Analyses .........................................................................................................74 
9.3.1. 
General Considerations ...................................................................................................74 
9.3.2. 
Demographic and Baseline Characteristics ....................................................................74 
9.3.3. 
Efficacy Analyses ...........................................................................................................74 
9.3.4. 
Safety Analyses ...............................................................................................................77 
9.3.5. 
PK/PD Analyses..............................................................................................................77 
9.4. 
Sample Size Determination ............................................................................................78 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ....................................................................................................78 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................78 
10.1.1. Regulatory and Ethical Considerations ...........................................................................78 
10.1.2. Financial Disclosure........................................................................................................78 
10.1.3. Informed Consent Process ..............................................................................................79 
10.1.4. Data Protection................................................................................................................79 
10.1.5. Use of Information ..........................................................................................................79 
10.1.6. Dissemination of Clinical Study Data.............................................................................80 
10.1.7. Data Quality Assurance ..................................................................................................80 
10.1.8. Source Documents ..........................................................................................................80 
10.1.9. Study Monitoring ............................................................................................................80 
10.1.10. Investigator and Site Responsibility for Drug Accountability ........................................81 
10.1.11. Study and Site Start and Closure ....................................................................................81 
10.1.12. Publication Policy ...........................................................................................................82 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................82 
10.3. 
Appendix 3: Procedures for Recording, Evaluating, and Follow-
up of AEs ........................................................................................................................84 
10.4. 
Appendix 4: WHO Diagnostic Criteria for MF ..............................................................86 
10.5. 
Appendix 5: DIPSS .........................................................................................................87 
10.6. 
Appendix 6: MFSAF, Version 4 .....................................................................................88 
10.7. 
Appendix 7: IWG-MRT Response Criteria ....................................................................89 
10.8. 
Appendix 8: Strong CYP3A4 Inducers or Inhibitors......................................................90 
10.9. 
Appendix 9: Study Conduct in Unforeseen Circumstances............................................92 
10.10. 
Appendix 10: Abbreviations ...........................................................................................97 
11. 
REFERENCES............................................................................................................100 

CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
Constellation Pharmaceuticals, 
A MorphoSys Company 
Confidential 
8 
LIST OF TABLES 
Table 1: 
Study Drugs to be Administered................................................................................ 37 
Table 2: 
Starting Doses of Pelabresib/Placebo and Ruxolitinib and Dose Increase at 
Cycle 2 Day 1 ............................................................................................................ 41 
Table 3: 
Ruxolitinib and Pelabresib/Placebo Dose Modification Guidance for Platelet 
Count Decrease after Initial Dosing on Cycle 1 Day 1 ............................................. 43 
Table 4: 
Ruxolitinib and Pelabresib/Placebo Dose Modifications for Other Toxicities ......... 46 
Table 5: 
Pharmacokinetic Collection Time Points .................................................................. 69 
Table 6: 
Biomarker Assessment Collection Time Points ........................................................ 70 
Table 7: 
Analysis Populations ................................................................................................. 74 
 
LIST OF FIGURES 
Figure 1: 
Guidance for Dose Modification After Prior Dose Reduction/Hold for 
Thrombocytopenia ..................................................................................................... 45 
Figure 2: Sequential Testing of Pre-Specified Endpoints ............................................................. 76 
 
 

CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
Constellation Pharmaceuticals, 
A MorphoSys Company 
Confidential 
9 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company: Constellation Pharmaceuticals 
Name of Investigational Product: Pelabresib (CPI-0610) 
Protocol Number:  CPI 0610-04 
Title of Study:  A Phase 3, Randomized, Double-blind, Active-Control Study of Pelabresib (CPI-0610) 
and Ruxolitinib vs. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients 
Primary Study Period (years):  
Actual date first patient enrolled: 23 April 2021 
Estimated date last patient will complete Week 24: Q3 2023 
Phase of Development:  
Phase 3 
Objectives and Endpoints:  
Primary 
 
• To determine the efficacy of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib 
• Splenic response at Week 24 
Key Secondary 
 
• To determine the effect of pelabresib + 
ruxolitinib on the absolute change in TSS at 
Week 24 vs Baseline compared with placebo 
+ ruxolitinib 
• Absolute change in TSS at Week 24 
compared to baseline 
• To determine the efficacy of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib 
• TSS50 response at Week 24 
Secondary 
 
• To determine the effect of pelabresib + 
ruxolitinib on the percent change in TSS at 
Week 24 vs Baseline compared with placebo 
+ ruxolitinib 
• Percent change in TSS at Week 24 compared 
to baseline 
• To characterize the effects of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib in the bone marrow 
• Improvement in bone marrow fibrosis by at 
least 1 grade at Week 24 compared to 
baseline  
• To determine the effect of pelabresib + 
ruxolitinib on the durability of splenic 
• Splenic response at Week 48 

CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
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A MorphoSys Company 
Confidential 
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response compared with placebo + 
ruxolitinib 
• To determine the effect of pelabresib + 
ruxolitinib on the durability of TSS response 
compared with placebo + ruxolitinib 
• TSS50 response at Week 48 
• To determine the effect of pelabresib + 
ruxolitinib on the durability of absolute 
change in TSS at Week 48 vs Baseline 
compared with placebo + ruxolitinib 
• Absolute change in TSS at Week 48 
compared to baseline 
• To determine the effect of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on the rate of RBC transfusion 
over the first 24 weeks of treatment 
• Rate of RBC transfusion over the first 24 
weeks of treatment 
• To determine the effect of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on the conversion from RBC 
transfusion dependence to independence  
• Conversion from RBC transfusion 
dependence at baseline to independence 
• To evaluate the PGIC at Week 24 
• Categorical change of PGIC at Week 24 
compared to Baseline 
• To evaluate PFS in patients treated with 
pelabresib + ruxolitinib compared with 
placebo + ruxolitinib 
• PFS 
• To evaluate OS in patients treated with 
pelabresib + ruxolitinib compared with 
placebo + ruxolitinib 
• OS 
• To evaluate AML conversion in patients 
treated with pelabresib + ruxolitinib 
compared with placebo + ruxolitinib 
• Proportion of patients with transformation to 
blast phase (AML) 
• To determine the safety and tolerability of 
pelabresib + ruxolitinib compared with 
placebo + ruxolitinib 
• AEs of all grades and SAEs  
• To characterize the PK of pelabresib 
• Population PK assessment including 
determination of exposure metrics and 
secondary parameters (i.e., AUC0-t, Tmax, 
Cmax, T1/2, Vd/F, CL/F) 

CPI-0610 
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Study CPI 0610-04 Protocol  
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• To characterize the effects, if any, of 
pelabresib on the PK of ruxolitinib 
• Descriptive assessment of ruxolitinib plasma 
concentrations in the presence or absence of 
pelabresib 
• To determine the effect of pelabresib + 
ruxolitinib on the duration of splenic 
response compared with placebo + 
ruxolitinib 
• Duration of the splenic response 
• To determine the effect of pelabresib + 
ruxolitinib on the modified TSS compared 
with placebo + ruxolitinib 
• Modified TSS response at Week 24 (TSS 
score without the fatigue sub-domain) 
• To determine the effect of pelabresib + 
ruxolitinib on the duration of TSS response 
compared with placebo + ruxolitinib 
• Duration of the TSS50 response 
• Exploratory 
 
• To determine the efficacy of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on the percent change in splenic 
volume at Week 24 
• Percent change in splenic volume at 
Week 24 
• To determine the effect of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on RBC transfusion dependence 
rate 
• RBC transfusion dependence at Week 24 
• To determine the effect of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on hemoglobin response 
• Hemoglobin response 

CPI-0610 
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Study CPI 0610-04 Protocol  
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• To characterize the PD effects of pelabresib 
+ ruxolitinib compared with placebo + 
ruxolitinib in the blood 
• Post-treatment changes from baseline in 
circulating concentrations of cytokines 
• Post-treatment changes from baseline in the 
ratio of mutant to wild type JAK2, 
 
 
• To determine the effect of pelabresib + 
ruxolitinib on the time to splenic response 
compared with placebo + ruxolitinib 
• Time to first SVR35 response 
AE = adverse event; AML = acute myeloid leukemia; AUC = area under the plasma concentration-time curve; 
BET = bromodomain and extra terminal; Cmax= maximal concentration; ECG = electrocardiogram; HRQOL = 
health related quality of life; 
 = International Working Group
 Neoplasms Research 
 Treatment; MF = myelofibrosis; OS = overall survival; PD = pharmacodynamic; PFS = progression-free 
survival; PGIC = Patient Global Impression of Change; PK = pharmacokinetics; RBC = red blood cell; SAE = 
serious adverse event; T1/2 = half-life; Tmax = time to maximal concentration; TSS = total symptom score. 
Study Design: This is a Phase 3, global, multicenter, randomized, double-blind, active-controlled study 
of pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment naïve patients with 
primary MF (PMF), post-polycythemia vera (PV) MF (PPV-MF) or post-essential thrombocythemia 
(ET) MF (PET-MF). 

CPI-0610 
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Following screening eligible patients will be randomized in a 1:1 ratio to one of two treatment groups: 
1) pelabresib + ruxolitinib (experimental group) or 2) placebo + ruxolitinib (control group).  Patients 
will be assessed for the primary and key secondary endpoints, splenic and total symptom score (TSS) 
response, respectively, at Week 24.  After 24 weeks, patients in the control group who have progressive 
disease by radiological parameters (increase in splenomegaly) may be treated with pelabresib + 
ruxolitinib provided that they remain eligible for the study. 
Patient randomization will be stratified by the following factors:  
• 
Dynamic International Prognostic Scoring System (DIPSS) risk category:  Intermediate-1 vs. 
Intermediate-2 vs. High 
• 
Platelet count:  > 200 × 109/L vs. 100 – 200 × 109/L 
• 
Spleen volume:  ≥ 1800 cm3 vs. < 1800 cm3 
Number of patients (planned): Approximately 400 patients (200 in the pelabresib + ruxolitinib group 
and 200 in the placebo + ruxolitinib group) will be enrolled in the study.  
Diagnosis and study population (key eligibility criteria): Eligible patients are adults who have a 
confirmed diagnosis of MF (PMF or PPV-MF or PET-MF) in accordance with the 2016 World Health 
Organization (WHO) criteria, have never received a JAKi for treatment of a myeloproliferative 
neoplasm, and are DIPSS risk category Intermediate-1 or higher. 
Investigational product, dosage, and mode of administration:  
Double-blind treatment (pelabresib or matching placebo) will be administered once daily (QD) for 
14 consecutive days followed by a 7-day break, which is considered 1 cycle of treatment (1 cycle = 21 
days).  Ruxolitinib will be administered twice daily (BID) for all 21 days within each cycle.   
The MANDATORY starting dose for the treatment regimen at Cycle 1 Day 1 will be pelabresib/placebo 
at 125 mg QD for all patients and ruxolitinib at 10 mg BID (for patients with baseline platelet count 100 
– 200 × 109/L) or 15 mg BID (for patients with baseline platelet count > 200 × 109/L) (5 mg BID lower 
than the recommended dose in the applicable approved package insert). 
It is MANDATORY to increase the ruxolitinib dose by 5 mg BID at Cycle 2 Day 1 if platelet count is 
>125 × 109/L and ANC is > 0.75 × 109/L at Cycle 2 Day 1 and the patient did not have ≥ Grade 3 non-
hematological toxicity in Cycle 1 that required dose interruption or reduction (regardless of percent 
change in spleen size by palpation from pre-treatment baseline). 
In the case of lack of spleen response, the ruxolitinib dose may be increased according to the applicable 
approved package insert and local clinical practice starting at Cycle 3 Day 1 provided patients meet 
criteria for doing so.  If these criteria are met, the ruxolitinib dose should be increased in 5 mg BID 
increments, not more frequently than once every cycle, to up to 25 mg BID.  Pelabresib/placebo dose 
increase is only allowed from Cycle 5 Day 1 or thereafter provided that patients meet criteria for doing 
so.  If these criteria are met, the pelabresib/placebo dose can be increased in 25 mg QD increments, not 
more frequently than once every 2 cycles, to a maximum dose of 175 mg QD.  Both ruxolitinib and 
pelabresib/placebo doses cannot be increased in the same cycle. 
If a patient experiences a treatment-emergent adverse event (TEAE), the doses of ruxolitinib and/or 
pelabresib/placebo may be down-titrated.  The doses may be re-escalated after resolution of toxicities 
provided patients meet criteria for doing so. 
Duration of treatment: Patients may receive blinded treatment in the study until disease progression or 
discontinuation or withdrawal from treatment, whichever occurs first, and will subsequently be followed 
for progression-free survival or overall survival.  Patients who have enrolled in the control group (i.e., 
treated with placebo + ruxolitinib) and have progressive disease after 24 weeks of treatment by 
radiological parameters may be crossed over to receive the experimental treatment of pelabresib + 
ruxolitinib. 

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Statistical Considerations: 
Analysis populations: 
• 
Modified Intent-to-Treat (mITT) Population: All randomized patients who were administered at 
least one dose of study drug. This is the population for some sensitivity analysis on efficacy 
endpoints.  All analyses using this population will be based on the treatment assigned by the 
Interactive Response Technology (IRT) system. 
• 
Intent-to-Treat (ITT) Population: All randomized patients. This is the primary population for all 
efficacy endpoints.  All analyses using this population will be based on the treatment assigned by the 
Interactive Response Technology (IRT) system. 
• 
Safety Population:  A subset of the ITT population that includes all randomized patients who were 
administered at least one dose of study drug. This population will be used for the safety analyses.  
All analyses using this population will be based on the treatment actually received. 
• 
Per Protocol (PP) Population:  A subset of the ITT population that includes patients who have 
received adequate exposure to on-study therapy and do not have any protocol deviations that could 
confound the interpretation of the primary analyses conducted on the ITT population.  All protocol 
deviations or conditions leading to exclusion from the PP population will be specified in the 
statistical analysis plan (SAP).  All analyses using this population will be based on the treatment 
received. 
• 
PK/pharmacodynamic (PD) Population: All randomized and treated patients who have at least 1 
evaluable sample for PK/PD analysis. 
Efficacy analysis: 
To ensure family-wise error rate is controlled at 5% (two-sided) the following endpoints will be tested 
hierarchically in the following order: 
1. Primary Endpoint: SVR35 at week 24 using CMH test  
2. Key Secondary Endpoint: Absolute change in TSS at Week 24 compared to baseline 
using ANCOVA model  
3. Key Secondary Endpoint: TSS50 at Week 24 using CMH test 
The probability of a splenic response at Week 24 will be estimated by calculating the splenic response 
rate, or the percentage of patients with a splenic response, at Week 24 for each of the two treatment 
groups.  The response rate between the two treatment groups will be compared using a Cochran-Mantel-
Haenszel (CMH) test controlling for baseline DIPSS (Intermediate-1 vs. Intermediate-2 vs. High), 
platelet count (100-200 × 109/L vs. > 200 × 109/L), and spleen volume (≥ 1800 cm3 vs. < 1800 cm3). 
An ANCOVA (Analysis of Covariance) model will be used to analyze the absolute change from 
baseline in TSS at Week 24. The dependent variable is change from baseline in TSS at Week 24, with 
treatment group as independent variable, baseline DIPSS (Intermediate-1 vs. Intermediate-2 vs. High), 
baseline platelet count (100-200 × 109/L vs. > 200 × 109/L) and baseline spleen volume (< 1800 cm3 vs. 
≥ 1800 cm3) and the baseline TSS as covariates. 
Similar to SVR35, the difference in proportion of TSS50 responders between Experimental Group and 
Control Group will be obtained using the CMH test controlling for the same strata used in SVR35 
analysis. 
Safety analysis: 

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Safety will be evaluated by incidence of TEAEs and by changes from baseline in physical examinations, 
vital signs, electrocardiograms (ECGs), and clinical laboratory values using the population evaluable for 
safety.  Exposure to study drug and reasons for discontinuation will also be summarized. 
Sample size determination: 
Assuming a splenic response rate of 62% in the experimental group and 29% in the control group, and 
assuming a TSS response rate of 57% in the experimental group, and 42.2% in the control group, a 
sample size of approximately 200 patients in each treatment group (approximately 400 patients in total) 
will provide > 99% power for testing the primary endpoint and 81% power for testing the key secondary 
endpoint TSS50 at the final analysis, using the 2-group continuity corrected χ² test with a 5% 2-sided 
significance level and accounting for 2% non-evaluable patients.  
Data and Safety Monitoring Board (DSMB): 
An independent DSMB will be used to review data to monitor patient safety in the study.  Membership, 
roles, and responsibilities of the DSMB will be described in the DSMB charter. 
 
 
 

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1.2. 
Schema  
 
 

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1.3. 
Schedule of Activities (SoA) 
Procedure 
Section 
Screening 
Period 
Treatment Period (including crossover) 
Follow-Up Periodb 
Screening 
(within 28 
days of C1D1) 
C1 or initiation of 
crossover 
treatmenta 
C2-8 
C9 and 
all odd 
cycles 
afterf 
C10 and 
all even 
cycles 
after 
EOT 
(within 7 
days after 
last dose of 
pelabresib/
placebo) 
Safety F/U 
(30 days 
[±3d] after 
last dose of 
pelabresib/
placebo) 
PD F/U 
(every 3 
months 
[±14d] after 
last MRI/ 
CT scan) 
Survival 
F/U 
(every 3 
months 
[±14d] 
after 
PD) 
D1 
D14 
(±1d) 
D1 
(±3d) 
D1 
 (±3d) 
D1  
(±3d) 
Informed 
consent 
10.1.3 
X 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
5.1, 5.2 
X 
 
 
 
 
 
 
 
 
 
Demographics 
8.1 
X 
 
 
 
 
 
 
 
 
 
Medical history 
8.1 
X 
 
 
 
 
 
 
 
 
 
Full PE and VS 
8.3.2 
X 
X 
 
 
 
 
 
 
 
 
Targeted PE and 
VS 
8.3.2 
 
 
X 
X 
X 
 
X 
 
 
 
Height 
8.3.2 
X 
 
 
 
 
 
 
 
 
 
Weight 
8.3.2 
X 
X 
X 
X 
X 
 
X 
 
 
 
MF risk category 
10.5 
X 
 
 
 
 
 
 
 
 
 
Transfusion 
history 
8.1 
X 
X 
 
X 
X 
X 
X 
 
X 
 
ECOG status 
8.3.3 
X 
X 
 
X 
 
 
X 
 
 
 
IWG-MRT 
response 
evaluation 
10.7 
X 
X 
 
 
Cycle 9 
only 
 
 
 
 
 

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Procedure 
Section 
Screening 
Period 
Treatment Period (including crossover) 
Follow-Up Periodb 
Screening 
(within 28 
days of C1D1) 
C1 or initiation of 
crossover 
treatmenta 
C2-8 
C9 and 
all odd 
cycles 
afterf 
C10 and 
all even 
cycles 
after 
EOT 
(within 7 
days after 
last dose of 
pelabresib/
placebo) 
Safety F/U 
(30 days 
[±3d] after 
last dose of 
pelabresib/
placebo) 
PD F/U 
(every 3 
months 
[±14d] after 
last MRI/ 
CT scan) 
Survival 
F/U 
(every 3 
months 
[±14d] 
after 
PD) 
D1 
D14 
(±1d) 
D1 
(±3d) 
D1 
 (±3d) 
D1  
(±3d) 
12-lead ECGc 
8.3.4 
X 
X 
 
X (C2, 
C3, C5, 
C7 
only) 
X 
 
X 
 
 
 
Serum or urine 
pregnancy test 
(WOCBP only)d 
8.3.5 
X 
X 
 
X 
X 
X 
X and 
monthly 
thereafter 
until 184 
days after 
the last 
dose of 
study drug 
 
 
 
Hematology 
8.3.5 
X 
X 
(within 
72 hrs 
of 
C1D1)e 
X 
X 
X 
 
X 
 
X 
 
Clinical 
chemistry 
8.3.5 
X  
X 
(within 
72 hrs 
of 
C1D1)e 
X 
X 
X 
 
X 
 
 
 
Coagulation 
parameters 
8.3.5 
X 
C3 D1, and every odd cycle thereafter 
 
X 
 
 
 
Iron studies 
8.3.5 
X 
C5 D1, C9 D1, and every 4 cycles thereafter 
 
 
 
 

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Procedure 
Section 
Screening 
Period 
Treatment Period (including crossover) 
Follow-Up Periodb 
Screening 
(within 28 
days of C1D1) 
C1 or initiation of 
crossover 
treatmenta 
C2-8 
C9 and 
all odd 
cycles 
afterf 
C10 and 
all even 
cycles 
after 
EOT 
(within 7 
days after 
last dose of 
pelabresib/
placebo) 
Safety F/U 
(30 days 
[±3d] after 
last dose of 
pelabresib/
placebo) 
PD F/U 
(every 3 
months 
[±14d] after 
last MRI/ 
CT scan) 
Survival 
F/U 
(every 3 
months 
[±14d] 
after 
PD) 
D1 
D14 
(±1d) 
D1 
(±3d) 
D1 
 (±3d) 
D1  
(±3d) 
HbA1c and 
serum lipid panel 
8.3.5 
X 
Every 6 months after screening (follow the local 
approved ruxolitinib labeling for the frequency of lipid 
monitoring if different) 
X 
 
 
 
TB testing 
8.3.5 
X (per local 
regulations) 
 
 
 
 
 
 
 
 
 
Assess hepatitis 
B/C, HIV, and 
COVID-19 risk 
and test if 
indicated 
5.2 
X 
 
 
 
 
 
 
 
 
 
MRI (or CT) 
scan 
8.2.1 
X 
Every 12 weeks from C1 D1 (window ±14 days) irrespective of any delay in cycle due to drug hold 
until PD or initiation of another anti-cancer therapy  
MRI is preferred method. Method of assessment used at screening should remain consistent 
throughout study.  Repeated at EOT only if PD has not been previously documented (or in the 
absence of PD, if imaging has not been performed within the previous 6 weeks). 
 
Bone marrow 
biopsy 
8.2.1, 
Table 6 
X (only if not 
done within 12 
weeks of 
C1 D1) 
Every 24 weeks (window ±14 days) from C1 D1 to Week 72, then every 48 weeks thereafter 
(window ±28 days), irrespective of any delay in cycle due to drug hold, and at EOT (EOT sample 
does not need to be collected if performed within previous 12 weeks), until PD or initiation of 
another anti-cancer therapy 
 
MFSAF v4.0 
8.2.2 
X (daily for at 
least 5 of 7 
days before 
randomization) 
Once daily (completed around the same time each day) until 12 weeks after EOT 
 
PGIC 
8.2.2 
 
Once weekly (completed on the same day each week) until 12 weeks after EOT 
 

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Procedure 
Section 
Screening 
Period 
Treatment Period (including crossover) 
Follow-Up Periodb 
Screening 
(within 28 
days of C1D1) 
C1 or initiation of 
crossover 
treatmenta 
C2-8 
C9 and 
all odd 
cycles 
afterf 
C10 and 
all even 
cycles 
after 
EOT 
(within 7 
days after 
last dose of 
pelabresib/
placebo) 
Safety F/U 
(30 days 
[±3d] after 
last dose of 
pelabresib/
placebo) 
PD F/U 
(every 3 
months 
[±14d] after 
last MRI/ 
CT scan) 
Survival 
F/U 
(every 3 
months 
[±14d] 
after 
PD) 
D1 
D14 
(±1d) 
D1 
(±3d) 
D1 
 (±3d) 
D1  
(±3d) 
EQ-5D 
8.2.2 
X (once 
weekly) 
Once weekly (completed on the same day each week) until 12 weeks after EOT 
 
PK 
8.6, 
Table 5 
 
X 
X 
C3D1 
and 
C7D1  
X 
(C9 only) 
 
 
 
 
 
Biomarker 
sampling 
8.7, 
Table 6 
 
X 
X 
 
X  
(C9, C17 
only) 
 
 
 
 
 
Randomization 
6.3 
X 
 
 
 
 
 
 
 
 
 
Pelabresib or 
placebo 
administration 
6.1 
 
QD for first 14 days of each cycle 
If dose increases on even cycle, odd cycle activities 
should be followed. 
 
 
 
 
Ruxolitinib 
administration 
6.1 
 
BID for all 21 days of each cycle  
If dose increases on even cycle, odd cycle activities 
should be followed. 
 
 
 
 
AE review 
8.4 
 
Throughout 
 
 
Concomitant 
medication 
review 
8.1 
 
Throughout 
 
 
Subsequent anti-
MF therapy 
review 
7.1 
 
 
 
 
 
 
 
Throughout 
AE = adverse event; BID = twice daily; C = cycle; CT = computerized tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; F/U = 
follow-up; MFSAF = Myelofibrosis Symptom Assessment Form; MRI = magnetic resonance imaging; PD = progressive disease; PE = physical exam; PGIC = Patient Global Impression of Change; 
PK = pharmacokinetic; QD = once daily; QTcF =  Fridericia-corrected QT interval; TB = tuberculosis; VS = vital signs; WOCBP = women of childbearing potential. 

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Note:  Laboratory assessments and other safety assessments must be performed predose when a window is specified. 
Note:  Assessments performed at unscheduled visits due to safety reasons are at the discretion of the Investigator. 
a  Patients who cross over should be re-consented at the initiation of crossover treatment.  Details on the crossover part of the study are provided in Section 6.6. 
b  Follow-up visits may be conducted via telephone when clinic visits are not required. Patients who discontinue treatment for reasons other than documented disease progression as defined in 
Section 7.1 should have follow-up visits every 12 weeks to document response by imaging, and transfusion requirements until initiation of another anti-cancer therapy, disease progression, death, or 
the end of the study, whichever comes first (PD F/U period). Continuing ruxolitinib monotherapy as standard of care treatment after the discontinuation of treatment on study is not considered the 
initiation of another anti-cancer medication/therapy. Patients who discontinue study treatment for documented disease progression or start another anti-cancer medication/therapy should have a follow-
up visit/phone call every 12 weeks to document overall survival (Survival F/U). Information on subsequent anti-MF medication will be collected in both PD F/U and Survival F/U periods. 
c  QTcF (Fridericia) is to be used at screening to evaluate eligibility per Section 5.1 and throughout the study to maintain consistency. 
d  For WOCBP, pregnancy testing (serum preferred) at Screening and at C1D1 before study drug administration; thereafter pregnancy testing can be either highly sensitive urine or serum testing at D1 
of every Cycle before study drug administration, at EOT and thereafter at monthly intervals during 184 days after last dose of study drug; urine pregnancy testing may be conducted at home when 
clinic visits are not required.  The Investigator must be informed immediately about the results of home pregnancy tests, and the results are to be recorded by the Investigator.  
e  Laboratory assessments for C1D1 do not need to be repeated, and screening values may be used, if performed within 72 hours of C1D1 assessments. 
f  After C9D1 patients may come in every odd cycle if they meet criteria listed in Section 8.  
 
  
 
 

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2. 
INTRODUCTION 
2.1. 
Background 
MF is a clonal myeloproliferative disease. It shares many of the characteristics of the other 
myeloproliferative diseases (essential thrombocythemia and polycythemia vera) but is 
characterized by more exaggerated abnormalities in megakaryocytes and by a more aggressive 
disease course with complications from cytopenias and transformation to acute leukemia (Ciurea 
et al., 2007). The megakaryocytes of patients with MF are hyperplastic, and this hyperplasia 
accounts for the thrombocytosis that may be seen early in the natural history of the disease. The 
hyperplastic megakaryocytes are also functionally abnormal. In the bone marrow, they release 
abnormal amounts of TGF-β, which stimulates the proliferation of fibroblasts (Kuter et al., 
2007). The fibroblasts deposit collagen in the bone marrow, leading to the fibrosis that is a 
hallmark of this disease and that impairs normal hematopoiesis. The hyperplastic 
megakaryocytes also release a diverse array of cytokines that account for many of the 
constitutional symptoms of the disease. Many cytokines signal through the JAK-STAT pathway, 
which explains why JAKi have activity in this disease. In addition, approximately 50% of 
patients with MF have activating mutations in JAK2 (Pikman et al., 2006; Tefferi et al., 2011). 
Regardless of the JAK2 mutational status of patients, it is thought that patients with MF have 
deregulated JAK-STAT signaling, which is why they respond to JAKi therapy regardless of their 
mutational status. Irrespective of the presence of mutations, the JAK/STAT pathway has been 
implicated in the inflammatory state of MF and other myeloproliferative diseases. More recently, 
the elevated pro-inflammatory cytokines present in MF have also been linked to the NF-ĸB 
pathway (Kleppe et al., 2018).  The resultant inflammation in MF has several downstream 
ramifications, including bone marrow fibrosis, constitutional symptoms and EMH. The bone 
marrow fibrosis and EMH are some of the key factors leading to anemia, one of the signature 
features of MF (Naymagon & Mascarenhas, 2017). In fact, at the time of diagnosis, 
approximately 40% of patients have anemia (defined as hemoglobin <10g/dL), and about 25% of 
patients require RBC transfusions (Tefferi et al., 2012).  As MF progresses, virtually all patients 
end up developing anemia. 
The only potentially curative treatment for MF is allogeneic HSCT, but HSCT is associated with 
high mortality rates and cannot be used in patients who are elderly and/or have multiple 
comorbidities (Gerds, 2016; Tefferi & Barbui, 2019; Vannucchi, 2011). The current approved 
treatment options for MF are JAKi (e.g., ruxolitinib and fedratinib); however, these agents have 
limited effects on underlying disease modification and bone marrow fibrosis. Both of these 
agents were associated with treatment-emergent new or worsening ≥ Grade 3 anemia, worsening 
transfusion dependence, and Grade ≥3 thrombocytopenia (FDA JAKAFI™ [ruxolitinib] label; 
FDA INREBIC™ [fedratinib] label). The need for frequent transfusions significantly reduces 
patient’s quality of life and imposes additional risks for complications (Newberry et al., 2017). In 
addition, fedratinib is associated with more frequent gastrointestinal toxicities (e.g., diarrhea, 
nausea, and vomiting) and has a box warning for serious and fatal encephalopathy including 
Wernicke’s (FDA INREBIC™ label). Thus, there remains a major unmet medical need to 
improve treatment options for patients with advanced MF. 

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Therapeutic agents developed in recent years that target epigenetic mechanisms of disease have 
shown promise in hematological malignancies (Kleppe et al., 2018).  Pelabresib is a potent, oral, 
and selective small molecule that is currently being developed in patients with MF.  Pelabresib 
belongs to the class of BETi. BET proteins are transcriptional regulators that control key 
oncogenic pathways, including NF-κB and TGF-β signaling, important drivers of inflammation 
and fibrosis, respectively, in MF.  Pelabresib can potentially improve constitutional symptoms 
and spleen volumes and may elicit an effect on the underlying disease through its inhibitory 
effects on: (I) megakaryocyte differentiation and proliferation; (II) inflammatory cytokine 
expression and release via the NF-κB signaling pathway; (III) targeting genes of TGF-ß 
signaling, especially secretion of collagen by fibroblasts, and (IV) bone marrow fibrosis through 
inhibition of pro-fibrotic pathways (Kleppe et al., 2018; Nicodeme et al., 2010). 
Pelabresib has been evaluated in three Phase 1 clinical studies in patients with various 
hematologic malignancies (lymphoma [Study 0610-01]; AML, MDS, or MDS/MPN 
[Study 0610-02]; or multiple myeloma [Study 0610-03]).  Pelabresib monotherapy showed 
antitumor activity in patients with lymphoma, including patients with follicular lymphoma, T cell 
histiocyte rich B cell lymphoma, and NF-κB-dependent activated B cell diffuse large B cell 
lymphoma. In addition, BET target engagement, demonstrated by downregulation of IL8 mRNA, 
was also achieved at well-tolerated doses in these patients.  Refer to the Investigator’s Brochure 
(IB) for more detailed information.  
Thrombocytopenia reported in the Phase 1 studies was dose-dependent in both incidence and 
severity, reversible, and non-cumulative. The consistency and predictability of this finding, along 
with the observation that thrombocytopenia was a common finding with other BET inhibitors, 
led to the investigation of the effects of pelabresib on megakaryocytes and subsequently the 
inclusion of patients with MF in the ongoing global, multicenter, open label Phase 2 expansion 
portion of Study 0610-02 (MANIFEST; NCT02158858).  
A detailed description of the chemistry, pharmacology, safety, and efficacy of pelabresib is 
provided in the IB (see Sections 3.1-3.4 for chemistry, Section 5.2 for pharmacology, and 
Section 5.3 for safety and efficacy). 
2.2. 
Study Rationale 
Preclinical studies suggest that a combination of a BETi and JAKi can result in synergistic 
reduction of splenomegaly, bone marrow fibrosis, and mutant cell burden (Kleppe et al., 2018).  
These findings support the potential complementary activity of pelabresib and a JAKi for MF 
treatment (Mascarenhas et al., 2021).  
Pelabresib is currently being investigated in the Phase 2 MANIFEST study as a monotherapy in 
patients with MF who are refractory/intolerant to ruxolitinib, as an add-on to ruxolitinib in 
patients who have suboptimal or lost response to ruxolitinib, or in combination with ruxolitinib 
in JAKi treatment naïve patients with MF. Due in part to the effects on SVR and TSS observed 
in the Phase 2 MANIFEST study, along with the potential for disease-modifying effects, the 
Sponsor is evaluating pelabresib in this Phase 3 study in patients with MF who have never been 
treated with a JAKi or BETi. 

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2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of pelabresib may be found in the pelabresib Investigator’s Brochure. 
2.3.1. 
Risk Assessment 
The following events are potential anticipated AEs with pelabresib: 
• Thrombocytopenia:  Thrombocytopenia has been the most consistent and 
predictable toxicity of pelabresib in patients enrolled in the Phase 1 and Phase 2 
studies of pelabresib.  In the three Phase I dose escalation clinical studies, this 
thrombocytopenia was dose-dependent in both incidence and severity, reversible 
(sometimes requiring 14 days off treatment), and non-cumulative.  This protocol 
includes directions for dose interruption for hematologic toxicities. 
• Anemia, neutropenia, and lymphopenia:  Although AEs of anemia, neutropenia, 
and decreased lymphocyte count have occurred in patients treated with pelabresib in 
the Phase 1 and Phase 2 studies; these cases have been infrequent and without 
apparent relationship to pelabresib dose.  The frequency of opportunistic infections 
has been consistent with that expected in the patient populations treated.  This 
protocol includes directions for dose interruption for hematopoietic cytopenias and 
infections.  Support with antibiotics and transfusions should follow standard medical 
practice and institutional guidelines. 
• Gastrointestinal toxicity:  The clinical experience with pelabresib in the Phase 1 and 
Phase 2 studies to date demonstrates a GI toxicity profile.  Nausea, vomiting, and 
diarrhea have been among the most frequently observed events.  Patients with 
impaired GI function or GI diseases (including active IBD) that may alter the 
absorption of study drug are ineligible to participate in clinical studies of pelabresib.  
This protocol includes recommendations for managing GI toxicities during pelabresib 
treatment. 
• Hyperglycemia:  Mild to moderate increases in serum glucose were observed in the 
preclinical toxicology studies of pelabresib.  In clinical experience, hyperglycemia 
related to pelabresib has been observed in approximately < 5% of patients treated 
with pelabresib in Phase 1 and Phase 2 studies, the majority of which at low grade 
only.  Serum glucose will be monitored throughout this study. 
• Testicular toxicity:  Degeneration of the germinal epithelium with oligo/aspermia 
was observed in the preclinical toxicology studies of pelabresib.  Interference with 
germ cell formation is expected with BET bromodomain inhibition, given the role of 
MYC in proliferating tissues and the expression of BRDT (as well as the other BET 
family members) in the testis. 
• Embryofetal toxicity: Preclinical animal studies have demonstrated that pelabresib 
has teratogenic potential.  Both male and female patients must agree to use highly 
effective contraception methods during treatment with study drug, as outlined in 
Section 6.9. 

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• Genotoxicity:  In a rat bone marrow micronucleus study, pelabresib induced 
statistically significant increases in micronucleus formation in all test article treatment 
groups when compared with the vehicle control article group and was thus 
determined to be likely genotoxic.  The clinical implication of the rat micronucleus 
study is uncertain, and these findings may not translate into an increased risk of 
second primary malignancies in human studies.  Additional information about the risk 
of genotoxicity with pelabresib may be found in the pelabresib Investigator’s 
Brochure. 
• Treatment withdrawal syndrome:  Respiratory distress was observed after 
treatment discontinuation in 2 patients treated in Arm 3 (combination treatment with 
pelabresib and ruxolitinib) of the MANIFEST study.  Patients remained on study for 
22 and 26 cycles, respectively, before a decision was made to discontinue treatment 
due to Grade 3 thrombocytopenia and in the setting of progressive disease.  The event 
of acute respiratory distress syndrome (ARDS) was reported for both patients 5 days 
after last ruxolitinib dose and 12 days after last pelabresib dose.  These 2 reported 
cases of ARDS have been considered by the treating Investigator to be part of a 
“ruxolitinib discontinuation syndrome” (RDS).  Instances of severe adverse events 
occurring subsequent to ruxolitinib withdrawal have been reported in the literature.  
RDS includes clinical manifestations ranging from acute relapse of disease-related 
symptoms, rapid spleen volume enlargement, and worsening of cytopenias to more 
severe complications, such as acute respiratory distress, disseminated intravascular 
coagulation (DIC), splenic infarction, and tumor lysis-like syndrome (Palandri et al., 
2021). Additional information about these cases, the risk of RDS, and guidance for 
the Investigator may be found in the pelabresib IB. 
The effects of pelabresib on response to viral infections, including COVID-19, is not yet known. 
Physicians should use their clinical judgment and weigh the benefit/risk of study participation 
during the COVID-19 pandemic for each patient. 
More detailed information about the known and expected risks of pelabresib may be found in the 
pelabresib IB. 
The risks of ruxolitinib are outlined in the applicable approved package insert. 
2.3.2. 
Benefit Assessment 
There are several mechanisms by which pelabresib has the potential to improve constitutional 
symptoms and spleen enlargement, and may elicit an effect on the underlying disease through its 
inhibitory effects on: i) megakaryocyte differentiation and proliferation; ii) inflammatory 
cytokine expression and release via the NF-κB signaling pathway; iii) targeting genes of TGF-β 
signaling, especially secretion of collagen by fibroblasts; and iv) bone marrow fibrosis through 
inhibition of pro-fibrotic pathways.  Support for these hypotheses is provided in the reduction of 
pro-inflammatory cytokines, platelet counts, spleen volume, mutant allele burden in peripheral 
blood, and fibrosis in mouse models of MF following BET inhibition (Kleppe et al., 2018).  
Importantly, some of these effects were of greater magnitude when BET inhibition was 
combined with ruxolitinib, supporting the potential for complementary activity of pelabresib and 
JAKi in the treatment of MF.  The clinical data in patients with newly diagnosed or advanced 

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MF treated with pelabresib alone and in combination with ruxolitinib give credence to these 
nonclinical findings.  Encouraging clinical activity has been observed with the combination of 
pelabresib and ruxolitinib in JAKi treatment naïve patients with MF in spleen volume reduction 
and symptom improvement (Harrison et al., 2019).  Furthermore, patients with 
relapsed/refractory MF or sub-optimal response to ruxolitinib treated with pelabresib 
monotherapy or as add-on to ruxolitinib, respectively, have shown improvements in hemoglobin 
levels, conversions from transfusion dependence to independence, and improvement in bone 
marrow fibrosis, as well as improvement in symptoms and SVR (Mascarenhas et al., 2019). 
More detailed information about the clinical activity observed with pelabresib is available in the 
pelabresib IB. 
2.3.3. 
Overall Benefit-Risk Conclusion 
The improvements in spleen volume, constitutional symptoms, hemoglobin levels, and bone 
marrow fibrosis in patients with MF, when combined with the generally acceptable and 
manageable safety profile of pelabresib and risk minimization measures, support its continued 
evaluation in patients with MF. 
3. 
OBJECTIVES AND ENDPOINTS 
The following are the objectives and endpoints to be evaluated in this study.   
Further description of endpoints, including definitions used and applicable assessments, may be 
found in Section 9.3. 
Objectives 
Endpoints 
Primary 
 
• To determine the efficacy of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib 
• Splenic response at Week 24 
Key Secondary 
 
• To determine the effect of pelabresib + 
ruxolitinib on the absolute change in TSS at 
Week 24 vs Baseline compared with placebo 
+ ruxolitinib 
• Absolute change in TSS at Week 24 compared 
to baseline 
• To determine the efficacy of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib 
• TSS50 response at Week 24 
Secondary 
 

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• To determine the effect of pelabresib + 
ruxolitinib on the percent change in TSS at 
Week 24 vs Baseline compared with placebo 
+ ruxolitinib 
• Percent change in TSS at Week 24 compared to 
baseline 
• To characterize the effects of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib in the bone marrow 
• Improvement in bone marrow fibrosis by at 
least 1 grade at Week 24 compared to baseline  
• To determine the effect of pelabresib + 
ruxolitinib on the durability of splenic 
response compared with placebo + ruxolitinib 
• Splenic response at Week 48 
• To determine the effect of pelabresib + 
ruxolitinib on the durability of TSS response 
compared with placebo + ruxolitinib 
• TSS50 response at Week 48 
• To determine the effect of pelabresib + 
ruxolitinib on the durability of absolute 
change in TSS at Week 48 vs Baseline 
compared with placebo + ruxolitinib 
• Absolute change in TSS at Week 48 compared 
to baseline 
• To determine the effect of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on the rate of RBC transfusion 
over the first 24 weeks of treatment 
• Rate of RBC transfusion over the first 24 weeks 
of treatment 
• To determine the effect of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on the conversion from RBC 
transfusion dependence to independence  
• Conversion from RBC transfusion dependence 
at baseline to independence 
• To evaluate the PGIC at Week 24 
• Categorical change of PGIC at Week 24 
compared to Baseline 
• To evaluate PFS in patients treated with 
pelabresib + ruxolitinib compared with 
placebo + ruxolitinib 
• PFS 
• To evaluate OS in patients treated with 
pelabresib + ruxolitinib compared with 
placebo + ruxolitinib 
• OS 

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• To evaluate AML conversion in patients 
treated with pelabresib + ruxolitinib compared 
with placebo + ruxolitinib 
• Proportion of patients with transformation to 
blast phase (AML) 
• To determine the safety and tolerability of 
pelabresib + ruxolitinib compared with 
placebo + ruxolitinib 
• AEs of all grades and SAEs 
• To characterize the PK of pelabresib 
• Population PK assessment incl. determination of 
exposure metrics and secondary parameter (i.e., 
AUC0-t, tmax, Cmax, T1/2, Vd/F, CL/F) 
• To characterize the effects, if any, of 
pelabresib on the PK of ruxolitinib 
• Descriptive assessment of ruxolitinib plasma 
concentrations in the presence or absence of 
pelabresib 
• To determine the effect of pelabresib + 
ruxolitinib on the duration of splenic response 
compared with placebo + ruxolitinib 
• Duration of the splenic response 
• To determine the effect of pelabresib + 
ruxolitinib on the modified TSS compared 
with placebo + ruxolitinib 
• Modified TSS response at Week 24 (TSS score 
without the fatigue sub-domain) 
• To determine the effect of pelabresib + 
ruxolitinib on the duration of TSS response 
compared with placebo + ruxolitinib 
• Duration of the TSS50 response 
• Exploratory 
 
• To determine the efficacy of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on the percent change in splenic 
volume at Week 24 
• Percent change in splenic volume at Week 24 
• To determine the effect of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on RBC transfusion dependence 
rate 
• RBC transfusion dependence at Week 24 
• To determine the effect of pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib on hemoglobin response 
• Hemoglobin response 

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• To characterize the PD effects pelabresib + 
ruxolitinib compared with placebo + 
ruxolitinib in the blood 
• Post-treatment changes from baseline in 
circulating concentrations of cytokines 
• Post-treatment changes from baseline in the 
ratio of mutant to wild type JAK2, 
 
• To determine the effect of pelabresib + 
ruxolitinib on the time to splenic response 
compared with placebo + ruxolitinib 
• Time to first SVR35 response 

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AE = adverse event; AML = acute myeloid leukemia; AUC = area under the plasma concentration-time curve; BET = bromodomain and extra 
terminal; Cmax= maximal concentration; ECG = electrocardiogram; HRQOL = health related quality of life; 
 
 MF = myelofibrosis; OS = overall survival; PD = pharmacodynamic; 
PFS = progression-free survival; PGIC = Patient Global Impression of Change; PK = pharmacokinetics; RBC = red blood cell; SAE = serious 
adverse event; T1/2 = half-life; Tmax = time to maximal concentration; TSS = total symptom score. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 3, global, multicenter, randomized, double-blind, active-controlled study of 
pelabresib + ruxolitinib vs placebo + ruxolitinib in JAKi-treatment naïve patients with PMF, 
PPV-MF, or PET-MF. 
The study design schematic is shown in Section 1.2. 
The 28-day screening period begins on the day the patient signs the Informed Consent Form 
(ICF).  Patients deemed eligible for enrollment will be randomized in a 1:1 ratio to 1 of 2 
treatment groups: 1) pelabresib + ruxolitinib (experimental group), or 2) placebo + ruxolitinib 
(control group).  Dosing should begin as soon as possible following randomization and both 
randomization and dosing (C1D1) must occur within 28 days from the beginning of screening.  
Patients who have not been randomized during the screening period can be rescreened if they 
fulfill the criteria outlined in Section 4.5.1 (Screen failures).  Patients who have been 
randomized, but not dosed within 28 days since the start of Screening cannot be rescreened and 
will be terminated from the study. 
Patients will be assessed for the primary and key secondary endpoints, splenic and TSS response, 
respectively, at Week 24.  After 24 weeks, patients in the control group who have progressive 
disease by radiological parameters as defined in Section 7.1 (increase in splenomegaly) may be 
crossed over and treated with pelabresib + ruxolitinib provided that they remain eligible for the 
study (Section 6.6).   
Double-blind treatment (pelabresib or matching placebo) will be administered QD for 14 
consecutive days followed by a 7-day break, which is considered 1 cycle of treatment 
(1 cycle = 21 days).  Ruxolitinib will be administered BID for all 21 days within each cycle. 
Patient randomization will be stratified by DIPSS, platelet count, and spleen volume 
(Section 6.3). 
Approximately 400 patients (approximately 200 per treatment arm) will be enrolled in the study 
(Section 9.4). 
4.2. 
Scientific Rationale for Study Design 
Since its global approvals, ruxolitinib is currently the standard of care for patients with MF 
(NCCN, 2019).  Ruxolitinib has been proven to primarily reduce spleen volume and to provide 
symptomatic relief in patients (≥35% reduction from baseline spleen size [SVR35 response] 
= 29–42% and ≥50% reduction in total symptom score [TSS response] = 42–46% at Week 24 
(Verstovsek et al., 2012).  Patients receiving ruxolitinib may achieve suboptimal responses or 
can develop treatment-emergent anemia and worsening transfusion dependence (Harrison et al., 
2017a; Mesa et al., 2017).  Synergistic therapeutic agents are needed, including agents with a 

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novel mechanism of action with potential for disease-modifying effects leading to overall 
improvement in the prognosis of MF. BET proteins are transcriptional regulators that control key 
oncogenic pathways, including NFκB, and TGF-β signaling, important drivers of inflammation 
and fibrosis, respectively, in MF.  Preclinical studies suggest that inhibition of both BET and 
JAK pathways can result in synergistic reduction of splenomegaly, bone marrow fibrosis and 
mutant cell burden (Kleppe et al., 2018).  Pelabresib is a selective and potent oral small molecule 
BETi with effects on megakaryocyte differentiation and cytokine expression in preclinical 
studies (see pelabresib IB), as well as clinical studies (Mertz et al., 2018), and has shown 
antitumor activity and a wide therapeutic window in a Phase 1 lymphoma study (Blum et al., 
2018). 
This combination of pelabresib and ruxolitinib has the potential to improve upon the clinical 
activity of ruxolitinib alone, as evidenced by the preliminary clinical data from the ongoing 
Phase 2 MANIFEST study of this combination in JAKi naïve patients with MF (Harrison et al., 
2019).  This Phase 3 study is intended to confirm the splenic and TSS responses observed in 
Phase 2 while also evaluating disease-modifying effects of pelabresib, such as improvement in 
bone marrow fibrosis and other clinically relevant endpoints. 
4.3. 
Justification for Dose 
After a review of the safety data on pelabresib across three Phase 1 studies in hematologic 
malignancies, 225 mg QD was considered to be the recommended Phase 2 dose of pelabresib as 
monotherapy.  However, a lower starting dose of pelabresib (125 mg QD) was chosen for the 
Phase 2 MANIFEST study based on the Phase 1 experience in which target engagement was 
near maximal at 125 mg QD with acceptable reversible and low-grade thrombocytopenia, which 
was the most consistent and predictable toxicity of pelabresib.  In the Phase 2 MANIFEST study, 
patients with MF have been treated with pelabresib up to 225 mg QD doses both as monotherapy 
(Arm 1) and in combination with ruxolitinib (Arms 2 and 3).  Because of the known risk of 
thrombocytopenia with ruxolitinib and pelabresib, in the Phase 2 MANIFEST study, the SRC 
reviewed data from the first six patients enrolled in Arm 3 of the ongoing Phase 2 MANIFEST 
study in June 2019.  The SRC recommended a starting ruxolitinib dose of 5 mg BID lower than 
the recommended starting dose in the label, with dose increases to be made as needed in 
combination with pelabresib 125 mg QD. 
Approximately 70% of patients in the Phase 3 COMFORT-1 study of ruxolitinib had dose 
reductions of ruxolitinib and the onset of thrombocytopenia was found to be typically within 4 
weeks of initiation of treatment (FDA Medical Review of Ruxolitinib, 2011).  Thus, the potential 
lower starting dose is consistent with that recommended in the approved product labeling 
(Jakafi®, US Prescribing Information, 2017; Jakavi®, Summary of Product Characteristics, 
2019).   
This dose modification paradigm was used in the Phase 2 MANIFEST study in which benefit for 
patients treated with pelabresib has been demonstrated with a manageable AE profile. 
Based on the mechanism of action of ruxolitinib and the expected synergistic effects of 
pelabresib and ruxolitinib, there is a possibility that this combination may cause increased 
thrombocytopenia.  Therefore, a conservative approach to initial ruxolitinib dosing (the same 
used in the Phase 2 MANIFEST study) will be used.  This study also utilizes a lower starting 

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dose of ruxolitinib in Cycle 1 (5 mg BID below the recommended dose in the local approved 
product labeling) in order to enhance safety and tolerability for the first cycle.  The ruxolitinib 
dose will be increased at Cycle 2 Day 1 (i.e., after 3 weeks) to the target dose levels per approved 
product labeling as long as prespecified criteria are met.  This approach is aligned with clinical 
practice (Talpaz et al., 2018). 
4.4. 
DSMB 
An independent DSMB will be used to review data to monitor patient safety in the study.  The 
DSMB will review safety data at regular intervals.  The DSMB will also be provided with 
enrollment updates. 
The DSMB may provide recommendations based on their review of the data, including whether 
to halt the study due to safety issues. 
The DSMB will consist of at least 2 independent hematologists/oncologists and at least 1 
biostatistician. 
Further details about the membership, meeting frequency, and operational aspects of the DSMB 
can be found in its charter. 
4.5. 
Study Participation 
4.5.1. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently enrolled in the study or randomly assigned to study drug. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure patients to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Patients who are considered screen failures only based on Inclusion Criterion #7 
(Section 5.1) may be rescreened only after a 6-week period.  Rescreened patients should not be 
assigned the same patient number as for the initial screening.  If a patient is a screen failure and 
later becomes eligible for the study, the screening MRI or CT scan may not need to be repeated 
if obtained within 4 weeks of Cycle 1 Day 1 and the screening bone marrow biopsy may not 
need to be repeated if obtained within 12 weeks of Cycle 1 Day 1. 
4.5.2. 
Duration of Treatment and Study Participation 
Patients may receive treatment in the study until disease progression or discontinuation or 
withdrawal from treatment (Section 7.1), whichever occurs first, and will subsequently be 
followed for disease progression and overall survival.   
4.5.3. 
Patient Follow-Up 
Patients who discontinue treatment in the absence of disease progression will enter the 
progression-free survival (PFS) follow-up period until disease progression (central radiology 
assessment confirmation is required for splenic progression) or until initiation of another 

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systemic anti-cancer therapy. All patients with documented disease progression or initiation of 
another systemic anti-cancer therapy will continue to be followed for overall survival (Section 
1.3). A patient is considered to have completed the study (EOS) if all parts of the study were 
completed, including the EOT visit, safety follow-up, and the visits in the PFS/survival follow-
up period to assess disease progression and overall survival.   
4.5.4. 
End of Study 
The sponsor may end the study when the availability of an early access program or roll-over 
protocol exists into which patients remaining on study may enter and continue to receive access 
to drug if they are deriving clinical benefit and/or being monitored for long-term follow-up. Such 
a protocol would be written for pelabresib if pelabresib is not yet commercially available. A 
patient who is still on study without disease progression and deriving clinical benefit may be 
consented to an extension/roll-over protocol or compassionate use protocol or transition to 
commercial supply if available at the time.  The date of the end of the study (study completion) 
is defined as the date of the last visit of the last patient in the study before transitioning to a roll-
over or compassionate use program or commercial supply (if available).    
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to eligibility criteria, also known as protocol waivers 
or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. ≥ 18 years of age at the time of signing the informed consent 
Type of Patient and Disease Characteristics 
2. Have a confirmed diagnosis of MF (PMF or PPV-MF or PET-MF) in accordance with the 
2016 WHO criteria (Section 10.4) 
3. Require therapy for MF in the opinion of the Investigator and are eligible for treatment 
with ruxolitinib 
4. Have DIPSS risk category Intermediate-1 or higher (Section 10.5) 
5. Have spleen volume of ≥ 450 cm3 by MRI or CT scan (either local or central read) 
6. Have completed the MFSAF v4.0 (Section 10.6) at least 5 of 7 days prior to 
randomization 
7. Have at least 2 symptoms with an average score ≥ 3 over the 7-day period prior to 
randomization or an average total score of ≥ 10 over the 7-day period prior to 
randomization using the MFSAF v4.0 (Section 10.6) 
8. Have acceptable laboratory assessments obtained within 28 days prior to the first dose of 
study medication: 
• ANC ≥ 1 × 109/L in the absence of growth factors or transfusions for the previous 
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• Platelet count ≥ 100 × 109/L in the absence of growth factors or transfusions for 
the previous 4 weeks 
• Peripheral blood blast count < 5% 
• Isolated elevation of AST and/or ALT ≤ 2.5 × ULN of the local reference interval 
(≤ 5 × if the elevation can be ascribed to liver involvement, e.g., presence of 
hepatomegaly) 
• Isolated elevation of serum direct bilirubin < 2.0 × ULN of the local reference 
interval 
• Calculated or measured CrCl of ≥ 45 mL/min* 
9. ECOG performance status of ≤ 2 
10. Life expectancy > 24 weeks per Investigator assessment 
11. Have fully recovered from major surgery, intervention, and from the residual Grade 1 
toxicity from prior MF-specific therapy (grade 1 peripheral neuropathy and alopecia are 
allowed). 
12. Both male and female patients and partners of patients, with reproductive potential, must 
agree to use at least one highly effective contraceptive method (preferably low user 
dependency contraception methods, as in Section 6.9, in particular when contraception is 
introduced as a result of participation in a clinical study) while on study therapy and for 
94 days after the last dose of study drug for male patients and male partners of female 
patients, and for 184 days after the last dose of study drug for female patients and female 
partners of male patients.  Patients of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year.  NOTE: Patients may 
consider seeking information from the study investigator regarding donation and 
cryopreservation of germ cells prior to treatment.  Male patients should be informed of 
the risk of testicular toxicity and provided with adequate advice regarding sperm 
preservation. 
*Equation used for calculating the estimated creatinine clearance will be captured in the eCRF.  
Informed Consent 
13. Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Had splenic irradiation within 6 months of starting study drug. 
2. Had prior splenectomy. 
3. Are a candidate for, and willing to undergo allogeneic HSCT, and, in the opinion of the 
Investigator, the benefit of proceeding to an allogeneic HSCT prior to treatment with a 
JAK2 inhibitor outweighs its risks. 

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4. Have current known active or chronic infection with HIV, hepatitis B, or hepatitis C. 
Screening of patients with serologic testing for these viruses is not required. However, 
patients who have a past history of viral hepatitis or in whom there is a current suspicion 
of viral hepatitis should have serologic testing for hepatitis B and hepatitis C performed 
to determine whether there is any current evidence for ongoing infection with these 
viruses. Patients considered to be at risk for HIV infection should have HIV testing 
performed. 
5. Have an active infection. Patients will not be eligible for enrollment until recovery to ≤ 
Grade 1 for at least 2 weeks prior to the first dose of study drug.  Testing for COVID-19 
is not mandatory during the screening for this study.  However, based on the local 
epidemiologic situation and each patient’s individual COVID-19 exposure risk and/or 
vaccination status, investigators should consider testing and in the case of COVID-19 
positivity consider delaying the start of the study treatment until the infection is resolved. 
6. Have impaired gastrointestinal function or gastrointestinal disease, including active IBD, 
that could significantly alter the absorption of study drug, including any unresolved 
nausea, vomiting, or diarrhea > Grade 1. 
7. Have known hypersensitivity to the investigational agent or ruxolitinib, or its metabolites 
or formulation excipients. 
8. Have a history of progressive multifocal leukoencephalopathy. 
9. Have impaired cardiac function or clinically significant cardiac diseases, including any of 
the following: 
• Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to 
starting study drug 
• QTcF > 500 msec on the screening ECG (QTcF interval is not relevant in patients 
with pacemaker-controlled arrythmia) 
• New York Heart Association Class III or IV congestive heart failure 
• Uncontrolled clinically significant cardiac arrhythmia (patients with rate-
controlled arrhythmias are not excluded) 
Note that patients with a history of coronary artery disease and revascularization are not 
excluded. 
10. Have ongoing uncontrolled hypertension (resting systolic blood pressure >160 mmHg 
and resting diastolic blood pressure >100 mmHg) despite maximal treatment with at least 
2 anti-hypertensive agents. 
11. Have ongoing uncontrolled blood glucose increase/uncontrolled diabetes (HbA1c ≥9%) 
despite maximal treatment with oral and/or injectable anti-hyperglycemic agents. 
12. Have a history of a concurrent or second malignancy except for adequately treated local 
basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, asymptomatic prostate cancer without known metastatic disease and with 
no requirement for therapy or requiring only hormonal therapy and with normal prostate-
specific antigen for ≥ 1 year prior to randomization, adequately treated Stage 1 or 2 
cancer currently in complete remission, or any other cancer that has been in complete 
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13. Have any other concurrent severe and/or uncontrolled concomitant medical condition that 
in the opinion of the Investigator could compromise participation in the study or analysis 
of study data. This includes but is not limited to clinically significant pulmonary disease 
or neurological disorders. 
Prior/Concomitant Therapy 
14. Had prior treatment with any JAKi or BET inhibitor for treatment of a myeloproliferative 
neoplasm. 
15. Had systemic anti-cancer treatment, with the exception of hormonal therapy, less than 2 
weeks (or 5 half-lives, whichever is longer) before the first dose of study drug. NOTE: 
Hydroxyurea and anagrelide are permitted up to 24 hours prior to start of study drug.  
Consult the Medical Monitor with questions if needed.  
16. Had any investigational agent (whether as cancer treatment or not) less than 2 weeks (or 
5 half-lives, whichever is longer) before the first dose of study drug.  
17. Had hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating 
agent, thrombopoietin mimetic) or androgenic steroids less than 4 weeks before the first 
dose of study drug. 
18. Had a strong CYP3A4 inhibitor or inducer within 2 weeks prior to the first dose of study 
drug (Section 10.8), including St. John’s wort. Initiation of treatment or concomitant use 
of a strong CYP3A4 inhibitor or inducer during study treatment is prohibited. 
19. Require systemic corticosteroids of >10 mg QD prednisolone or equivalent 4 weeks 
before the first dose of study drug.  Patients who received topical, nasal, intra-articular, 
inhaled, and other forms of corticosteroids without systemic activity are eligible. 
20. Had a live vaccination within 30 days prior to the first dose of study drug (Czech 
Republic only). 
 
Other Exclusions 
21. Females who are breastfeeding or pregnant (as documented by a highly sensitive urine or 
serum β-hCG pregnancy test consistent with pregnancy, obtained within 72 hours prior to 
the first dose of study drug) or expecting to conceive or males expecting to father 
children within the projected duration of the trial, starting with the screening visit through 
184 days after the last dose of study drug.  Female patients of non-child bearing potential 
(post-menopausal for more than 1 year; underwent a hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy) do not require a serum pregnancy test. 
22. Are unwilling or unable to comply with this study protocol or study requirements. 
6. 
STUDY DRUG 
Study drug is defined as any investigational intervention, marketed product, or placebo intended 
to be administered to a study patient for evaluation of safety and efficacy according to the study 
protocol.  

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Study treatment is defined as the combination of pelabresib + ruxolitinib or placebo + 
ruxolitinib. 
Pelabresib (CPI-0610) tablets, 25 mg and 100 mg contain the active pharmaceutical ingredient 
(pelabresib monohydrate) and the following inactive excipients: microcrystalline cellulose, 
lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium, sodium lauryl sulfate, 
colloidal silicon dioxide, magnesium stearate, poly vinyl alcohol, titanium dioxide, polyethylene 
glycol and talc.  Both tablet strengths (25 mg and 100 mg) are supplied in HDPE bottles with 
heat induction sealed caps.  Each bottle contains 15 count, film-coated, plain-faced white tablets.  
Matching placebo contains all above excipients (no active pharmaceutical ingredient) and is 
visibly identical to experimental drug in size, shape, and packaging. 
6.1. 
Study Drugs Administered 
The study drugs outlined in Table 1 will be administered. 
Table 1: 
Study Drugs to be Administered 
Arm Name 
Experimental Group 
(pelabresib + ruxolitinib) 
Control Group 
(placebo + ruxolitinib) 
Treatment 
Pelabresib monohydrate tablets + 
ruxolitinib phosphate tablets 
Matching placebo tablets + 
ruxolitinib phosphate tablets 
Starting Dosage Levels and 
Administration 
Pelabresib 125 mg PO QD + 
ruxolitinib 10 or 15 mg PO BID 
for 14 consecutive days followed 
by ruxolitinib 10 or 15 mg PO 
BID for 7 days in a 21-day cycle 
Matching placebo PO QD + 
ruxolitinib 10 or 15 mg PO BID 
for 14 consecutive days followed 
by ruxolitinib 10 or 15 mg PO 
BID for 7 days in a 21-day cycle 
Use 
Experimental 
Placebo/active comparator 
Definition 
Pelabresib: IMP 
Ruxolitinib: NIMP (SOC) 
Placebo: IMP 
Ruxolitinib: NIMP (SOC) 
Sourcing 
Pelabresib provided centrally by 
the Sponsor; ruxolitinib sourcing 
varies by country and site. 
Blinded placebo provided 
centrally by the Sponsor; 
ruxolitinib sourcing varies by 
country and site. 
Packaging and Labeling 
Pelabresib will be provided in 
HDPE bottles with heat induction 
sealed caps. Each bottle will be 
labeled as required per country 
requirement. 
Matching placebo will be 
provided in HDPE bottles with 
heat induction sealed caps. Each 
bottle will be labeled as required 
per country requirement 
BID = twice daily; HDPE = high density polyethylene; IMP = investigational medicinal product; NIMP = non-
investigational medicinal product; PO = by mouth; QD = once daily, SOC = standard of care. 
 

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Patients should be instructed to take their daily dose of pelabresib or placebo at approximately 
the same time each day.  Pelabresib or placebo should be taken in the morning unless otherwise 
instructed (see supportive care guidelines for nausea and vomiting in Section 6.7.1).  Each daily 
dose of pelabresib or placebo should be taken with a glass of water and consumed over as short a 
time as possible (e.g., all tablets within 5 minutes).  Patients should be instructed to swallow 
tablets whole and to not chew them. 
Ruxolitinib is a standard of care and should be taken according to the local approved package 
insert unless otherwise defined in this protocol, including if discontinuation of ruxolitinib is 
required. 
No food should be consumed for 2 hours prior to and 1 hour after their daily dose of study drugs 
unless otherwise instructed (see supportive care guidelines for nausea and vomiting in Section 
6.7.1).  The tablets should be swallowed whole, with water, at home first thing in the morning 
except for days that study drug will be administered in the study center under the observation of 
the study personnel. 
On days when PK and/or pharmacodynamic samples need to be collected prior to taking study 
drug, the patient should take that day’s pelabresib/placebo and/or ruxolitinib dose in the clinic.  
If vomiting occurs during the course of the treatment, then no re-dosing of the patient is allowed 
before the next scheduled dose. 
If the patient forgets to take his/her daily dose of pelabresib, then he/she should take their daily 
dose within 10 hours after the missed dose.  If more than 10 hours have passed, then that day’s 
dose should be omitted, and the patient should resume treatment with the next scheduled dose. 
If the daily morning dose of ruxolitinib is missed, then the patient should take their daily dose 
within 10 hours after the missed dose.  If more than 10 hours have passed, then that morning’s 
dose should be omitted, and the patient should resume treatment with the next scheduled dose in 
the evening.  If the daily evening dose of ruxolitinib is missed, then the dose should be omitted 
and the patient should resume treatment with the next scheduled dose the following morning. 
6.2. 
Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported and 
resolved before use of the study drug. 
Only patients enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug.  All study drug must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff.   
Pelabresib/placebo tablets should remain in the bottle provided, even after being dispensed to 
patients.  The bottles should be stored at the investigational site at controlled room temperature 
(15-30°C).  Containers should be kept closed during storage. 
The Investigator is responsible for study drug accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 

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All non-dispensed, and dispensed but unused, study drug will be retained at the site until it is 
inventoried by the monitor.  All non-dispensed, dispensed but unused, or expired study drug 
should be destroyed by sites per their own internal destruction procedures.  If a site’s procedures 
do not allow for destruction, unused/expired/damaged study drug should be returned to the 
supplying depot for subsequent destruction.  All material containing study drug will be treated 
and disposed of as hazardous waste in accordance with governing regulations. 
Further guidance and information for the final disposition of unused study drug are provided in 
supplemental study materials. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This study has a double-blind design in which patients and investigators are blinded to study 
drug; study drugs will be packaged identically (Section 6.1). 
All patients will be randomly assigned to either treatment group in a 1:1 ratio using a centralized 
IVRS/IWRS.  Before the study is initiated, operational logistics for the IVRS will be provided to 
each site in an IRT manual. Note: dosing should begin as soon as possible following 
randomization, and no later than 28 days from start of the screening period (Section 4.1). 
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an emergency, 
the Investigator has the responsibility for determining if unblinding of a patient’s intervention 
assignment is warranted. Patient safety must always be the first consideration in making such a 
determination.  If the Investigator decides that unblinding is warranted, the Investigator should 
make every effort to contact the Sponsor or the CRO medical monitor prior to unblinding a 
patient’s intervention assignment unless this could delay emergency treatment of the patient.  If a 
patient’s intervention assignment is unblinded, the Sponsor must be notified within 24 hours that 
emergency unblinding was performed. It is important that the Sponsor remains blinded and the 
patient’s intervention assignment is not to be shared with the study team until primary analysis 
takes place.  The date that the blind was broken must be recorded in the source documentation 
and IVRS/IWRS, as applicable.  
Each patient in the study is identified by a unique patient number.  The procedures for patient 
numbering and coordination between the study sites will be provided in a separate document 
prior to study start.  The unique patient number is a combination of his/her study center number 
and a second number reflecting the sequence of patient enrollment.  The study center number is 
assigned by the Sponsor to each investigative site.  Upon signing the ICF, the patient is assigned 
a patient number.  Once assigned to a patient, a patient number will not be reused. 
To ensure balance between treatment arms, patient randomization will be stratified by the 
following factors: 
• DIPSS risk category:  Intermediate-1 vs. Intermediate-2 vs. High 
• Platelet count:  > 200 × 109/L vs. 100 – 200 × 109/L 
• Spleen volume:  ≥ 1800 cm3 vs. < 1800 cm3 

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6.4. 
Study Drug Compliance 
When patients are dosed at the site, they will receive study drug directly from the Investigator or 
designee, under medical supervision.  The date and time of each dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF. The dose of study drug and 
study patient identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study drug. 
Study drug administration should be recorded on the patient dosing diary, and compliance will 
be assessed at each visit.  Compliance will also be assessed by counting tablets during the site 
visits and documented in the source documents and eCRF/IRT. Deviation(s) from the prescribed 
dosage regimen should be recorded in the eCRF. 
A record of the number of study drug tablets dispensed to and taken by each patient must be 
maintained and reconciled with study drug and compliance records.  Intervention start and stop 
dates, including dates for drug delays and/or dose reductions will also be recorded in the eCRF.  
6.5. 
Ruxolitinib and Pelabresib/Placebo Starting Doses and Dose Modification 
Guidelines 
Topic 
Ruxolitinib 
Pelabresib /Placebo 
Starting dose 
Section 6.5.1 
Section 6.5.1 
Dose increase for lack of spleen response 
Section 6.5.2.1 
Section 6.5.2.2 
Dose modification and restarting rules for toxicities 
Section 6.5.3,  
Table 3 and Table 4 
Section 6.5.3,  
Table 3 and Table 4 
Dose re-escalation following reduction for toxicity 
Section 6.5.4.1 
Section 6.5.4.2 
6.5.1. 
Starting Doses of Pelabresib/Placebo and Ruxolitinib 
The starting doses for ruxolitinib and pelabresib/placebo at Cycle 1 Day 1 and the subsequent 
ruxolitinib dose increase at Cycle 2 Day 1 are detailed in Table 2. 
o The MANDATORY starting dose for the treatment regimen at Cycle 1 Day 1 will 
be pelabresib/placebo at 125 mg QD for all patients.  
o Ruxolitinib is started at 10 mg BID (for patients with baseline platelet count 100 – 
200 × 109/L) or 15 mg BID (for patients with baseline platelet count > 200 × 
109/L) (i.e., 5 mg BID lower than the recommended dose in the applicable 
approved package insert). 
It is MANDATORY to increase the ruxolitinib dose by 5 mg BID at Cycle 2 Day 1 if:  
o Platelet count is >125 × 109/L and  
o ANC is > 0.75 × 109/L at Cycle 2 Day 1 and  
o The patient did not have ≥ Grade 3 non-hematological toxicity in Cycle 1 that 
required dose interruption or reduction (regardless of percent change in spleen 
size by palpation from pre-treatment baseline).  

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Table 2: 
Starting Doses of Pelabresib/Placebo and Ruxolitinib and Dose Increase at 
Cycle 2 Day 1 
Treatment 
Cycle/Day 
Ruxolitinib  
(mg BID) 
Pelabresib/placebo 
(mg QD) 
Treatment Cycle 
C1D1  
(starting dose) 
10 (if PLT  
100-200 × 
109/L) 
OR 
15 (if PLT  
>200 × 109/L) 
125 
MANDATORY to start ruxolitinib at 10 or 
15 mg BID (5 mg BID below the 
recommended dose per PLT count at baseline 
as described in the ruxolitinib local approved 
product labeling) 
(regardless of hemoglobin or transfusion status 
at C1D1) 
C2D1 
10 to 15  
OR 
15 to 20 
125 
MANDATORY to increase ruxolitinib dose by 
5 mg BID if: 
• PLT ≥125 × 109/L and ANC >0.75× 109/L 
• No ≥ G3 non-hematological toxicity in C1 
requiring dose interruption or reduction 
(regardless of % change in spleen size by 
palpation from pretreatment baseline) 
BID = twice daily; C = cycle; D = day; G= grade; PLT = platelet; QD = once daily. 
6.5.2. 
Criteria and Process to Increase Doses of Ruxolitinib and Pelabresib/Placebo 
6.5.2.1. 
Ruxolitinib Dose Increases for Lack of Spleen Response 
Following the mandatory dose increase on Cycle 2 Day 1 described above in Section 6.5.1 and 
Table 2,  the ruxolitinib dose may be increased by 5 mg BID increments from Cycle 3 Day 1 or 
thereafter if all the criteria outlined below are met. If these criteria are met, the ruxolitinib dose 
may be increased in 5 mg BID increments, not more frequently than once every cycle, to a 
maximum of 25 mg BID. 
The following criteria must be met for ruxolitinib dose increase from Cycle 3 Day 1 and 
thereafter: 
• Failure to achieve a reduction from pretreatment baseline in either palpable spleen 
length by 50% or by MRI or CT scan by 35% 
• Platelet count ≥125 × 109/L over the course of the prior one cycle  
• ANC >0.75 × 109/L 
• No AE requiring any dose interruption and/or reduction in the previous cycle 
NOTE: both ruxolitinib and pelabresib/placebo doses cannot be increased in the same cycle. 
6.5.2.2. 
Pelabresib/Placebo Dose Uptitration Rules for Lack of Spleen Response 
Pelabresib/placebo dose increase is only allowed from Cycle 5 Day 1 or thereafter based on the 
criteria outlined below. Patients who have not had a dose reduction or hold because of an AE in 
previous cycles may increase the pelabresib/placebo dose from Cycle 5 Day 1 or thereafter only 
if all the following criteria are met.  If these criteria are met, the pelabresib/placebo dose can be 

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increased in 25 mg QD increments, not more frequently than once every 2 cycles, to a maximum 
dose of 175 mg QD. 
The following criteria must be met for a pelabresib/placebo dose increase from Cycle 5 Day 1 
and thereafter: 
• The ruxolitinib dose is at least 20 mg BID for the previous 1 cycle. 
• Failure to achieve a spleen response by MRI/CT scan at Week 12 (i.e., has not 
achieved ≥35% reduction in spleen volume).  Note: spleen response by palpation will 
not be considered for response evaluation. 
• Platelet count ≥125 × 109/L over the course of the prior one cycle  
• ANC >0.75 × 109/L 
• No AE requiring any dose interruption and/or reduction in the previous cycles 
Note:  both ruxolitinib and pelabresib/placebo doses cannot be increased in the same cycle. 
6.5.3. 
Ruxolitinib and Pelabresib/Placebo Dose Modification and Restarting Rules for 
Platelet Count Decrease and Other Toxicities 
Guidance for dose modification of ruxolitinib is outlined below.   
If a patient experiences a TEAE (e.g., platelet count decrease or other toxicities as specified in 
Table 3 and Table 4, respectively), follow the actions required as outlined in the tables below.  In 
general, for a ruxolitinib dose reduction, the dose will be decreased by at least 5 mg BID per day 
(minimum dose level 5 mg QD).  For a pelabresib/placebo dose reduction, the dose will be 
titrated downwards at least by 25 mg QD per day (minimum dose level 50 mg QD). 
During the course of treatment, if ruxolitinib must be held for >28 days and/or if a ruxolitinib 
dose lower than 5 mg QD is required due to toxicity, ruxolitinib must be discontinued.  If 
pelabresib/placebo must be held for >35 days due to toxicity, pelabresib/placebo must be 
permanently discontinued and the patient must come off study treatment, unless the investigator 
has provided the sponsor medical team with a benefit-risk assessment that supports the patient’s 
continuation on study treatment. Assessment of clinical benefit vs. risk to justify continuation on 
study treatment may include, but is not limited to, reviewing changes in spleen volume, safety 
labs, adverse events, and other factors that could be impacting study drug hold.  
Cycles are defined throughout the study as every 3 weeks or 21 days. In the event that treatment 
with pelabresib/placebo (and/or ruxolitinib) is interrupted, the duration of cycle/treatment will 
not be extended and missed doses will not be made up.  This means, for example, if a patient 
misses Days 8-14 of a cycle, the patient will remain off pelabresib for Days 15-21 (the 
prescribed 7-day off period per regimen schedule).  Patients should have a minimum of 7 days 
off pelabresib/placebo in between cycles. 
Guidance for dose modifications, including reduction and/or hold of ruxolitinib and/or 
pelabresib/placebo, due to platelet count decrease are provided in Table 3 and Figure 1, and due 
to other toxicities are provided in Table 4.  Dose reductions should be considered if the platelet 
counts decrease as outlined in Table 3 with the goal of avoiding dose interruptions for 
thrombocytopenia.  Note:  these dose modifications do not apply to starting dose in Cycle 1. 

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Directions for possible re-escalation after dose reduction for toxicity are provided in Section 
6.5.4.1 for ruxolitinib and in Section 6.5.4.2 for pelabresib/placebo. 
In case a patient becomes infected with COVID-19 during the study, the Investigator should use 
their clinical judgment about study drug interruption, depending on the patient’s symptoms, 
disease status, comorbidities, and concomitant medications.  Per Table 4, pelabresib/placebo 
should be held for ≥ Grade 3 infection.  In cases of Grade 1-2 COVID-19 infection and/or 
COVID-19-related medical conditions, study drug may also be held per investigator clinical 
judgment and according to local and institutional standards of care. 
Table 3: 
Ruxolitinib and Pelabresib/Placebo Dose Modification Guidance for Platelet 
Count Decrease after Initial Dosing on Cycle 1 Day 1  
PLT Count 
after C1D1  
Dose at the Time of PLT Decline 
 
Ruxolitinib Dosea 
Pelabresib/Placebo 
Dosea 
25 mg BID 
20 mg 
BID 
15 mg 
BID 
10 mg 
BID 
5 mg 
BID 
75 – 125 mg QD 
100 - <125 × 
109/L 
20 mg BID 
15 mg 
BID 
No 
Change 
No 
Change 
No 
Change 
No Change 
75 - <100 × 
109/L 
10 mg BID 
10 mg 
BID 
10 mg 
BID 
No 
Change 
No 
Change 
75 mg QD 
50 - <75 × 
109/L (G2) 
• Ruxolitinib 5 mg BID and pelabresib/placebo 75 mg QD 
• If PLT ≥ 50 × 109/L for at least 3 weeks or >100 × 109/L for at least one week, may 
increase ruxolitinib to 10 mg BID and maintain dose of pelabresib/placebo at 75 mg 
QD 
• Maintain the above dose regimen until PLT recovers to ≥ 125 × 109/L and follow 
Figure 1 for further dose escalation 
<50 × 109/L 
(G3 – 4) 
• HOLD both ruxolitinib and pelabresib/placebo until PLT recovery to ≥ 50 × 109/L.  
NOTE: if a patient is considered to be at high risk for ruxolitinib discontinuation 
syndrome (RDS, see Section 6.7.4), HOLD pelabresib and consider tapering 
ruxolitinib instead of an abrupt stop.  The risk of thrombocytopenia vs risk of 
developing RDS has to be considered by the treating physician, and if a taper is 
implemented, platelets need to be followed closely per treating physician judgment. 
1. If PLT recovers to ≥ 50 × 109/L for at least 3 weeks or >100 × 109/L for at least 
one week, restart ruxolitinib 5 mg BID and pelabresib/placebo at 50 mg QD  
2. If PLT ≥ 50 × 109/L for another 3 weeks or >100 × 109/L for at least one week, 
increase ruxolitinib to 10 mg BID and maintain pelabresib/placebo at 50 mg QD  
3. If PLT ≥ 50 × 109/L for another 3 weeks or >100 × 109/L for at least one week, 
maintain ruxolitinib 10 mg BID and increase pelabresib/placebo to 75 mg QD  
• Maintain the above dose regimen until PLT recovers to ≥ 125 × 109/L and follow 
Figure 1 for further dose escalation 
• If G3 PLT recurs after restarting the start of treatment, HOLD both ruxolitinib and 
pelabresib/placebo until PLT recovers to ≥ 50 × 109/L and follow Steps 1 – 3 above. 
• If ruxolitinib is held for >28 days, DISCONTINUE treatment. 

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• If pelabresib/placebo is held for >35 days, DISCONTINUE treatment unless the 
benefit-risk assessment supports the continuation on study treatment (e.g., safety and 
signs of efficacy) after discussion with the Sponsor’s medical team. 
BID = twice daily; C = cycle; D = day; G = grade; PLT = platelet; QD = once daily. 
a.  Both ruxolitinib and pelabresib/placebo cannot be increased in the same cycle. 
NOTE: These dose modifications do not apply to starting dose in Cycle 1.  
 

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Figure 1: 
Guidance for Dose Modification After Prior Dose Reduction/Hold for Thrombocytopenia 
 
 
BID = twice daily; pel = pelabresib (CPI-0610); PLT = platelet; QD = once daily; rux = ruxolitinib; TCP = thrombocytopenia; wks = weeks. 
Note:  PLT (platelets) units × 109/L or 103/mm3 
Note:  both ruxolitinib and pelabresib/placebo doses cannot be increased in the same cycle. 
a.  If pelabresib dosing is held for >35 days AND/OR ruxolitinib dosing is held for >28 days, DISCONTINUE study treatment. 
b.  If G4 recurs after starting ruxolitinib 5 mg BID and pelabresib 50mg QD, DISCONTINUE study treatment. 
c.  If pelabresib/placebo is already at 75 mg QD, wait until PLT ≥125 × 109/L for further dose escalation. 
 
Estimated maximum dose re-escalation PLT ≥50 × 109/L: ruxolitinib 10 mg BID and pelabresib/placebo 75 mg QD 
Estimated maximum dose re-escalation for PLT ≥125 × 109/L: ruxolitinib ≥20 mg BID and pelabresib/placebo 125 mg QD 
Pel/PBO: HOLDa 
Rux: HOLDa 
Until PLT ≥50 for at least 3 wks or >100 for at least 1 wk 
PLT ≥50  
for 3 wks  
or >100 for 1 wk 
PLT ≥50  
for 3 wks  
or >100 for 1 wk 

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Table 4: 
Ruxolitinib and Pelabresib/Placebo Dose Modifications for Other Toxicities 
Toxicity 
Actions Required 
Hematology 
G4 neutropenia  
(ANC < 0.5 × 109/L)  
• 
HOLD ruxolitinib for up to 28 days and pelabresib/placebo for up to 35 
days.  NOTE: if a patient is considered to be at high risk for ruxolitinib 
discontinuation syndrome (RDS, see Section 6.7.4), HOLD pelabresib and 
consider tapering ruxolitinib instead of an abrupt stop.  The risk of 
neutropenia vs risk of developing RDS has to be considered by the treating 
physician, and if a taper is implemented, neutrophils need to be followed 
closely per treating physician judgment. 
• 
Repeat CBC at least weekly until resolution to > 0.75 × 109/L 
• 
Once resolved to > 0.75 × 109/L, restart: 
o 
Ruxolitinib reduced by 5 mg per dose 
o 
Pelabresib/placebo reduced by 25 mg/day 
• 
In the case of febrile neutropenia, administer GCSF according to 
institutional guidelines. 
Anemia 
• 
Blood transfusion should be considered for severe (Hgb <8.0 g/dL) and/or 
symptomatic anemia 
• 
No pelabresib/placebo dose reduction or interruption is needed for anemia, 
dose increase is allowed if other criteria in Section 6.5.4.2 are met 
Reduction in platelet 
count 
• 
Repeat CBC as clinically indicated and at least once weekly until resolution 
to ≤ G1 
• 
Refer to Table 3 and Section 6.5.4.1 for ruxolitinib dose modification and 
re-escalation rules 
• 
Refer to Table 3 and Section 6.5.4.2 for pelabresib/placebo dose 
modification and re-escalation rules  
Hepatic 
≥ Direct bilirubin  
>3 × ULN 
• 
HOLD pelabresib/placebo for up to 35 days 
• 
Repeat direct bilirubin at least weekly until resolution to ≤ G1 or baseline 
• 
Once resolves to ≤ G1, restart pelabresib/placebo reduced by 25 mg/day 
• 
If ≥ G3 recurs despite pelabresib/placebo reduction, continue 
pelabresib/placebo at the reduced dose and HOLD ruxolitinib for up to 28 
days 
• 
Repeat direct bilirubin at least weekly until resolution to ≤ G1 or baseline 
• 
Once resolves to ≤ G1, restart ruxolitinib reduced by 5 mg per dose 
≥ G3 ALT (>5 × ULN) 
in patients who enroll 
with ≤ G1 ALT 
 
OR 
 
Tripling of ALT in 
patients who enroll with 
G2 ALT 
• 
HOLD pelabresib/placebo for up to 35 days 
• 
Repeat serum transaminases at least weekly until resolved to ≤ G1/baseline 
• 
Once resolves to ≤ G1, restart pelabresib/placebo reduced by 25 mg/day 
• 
If ≥ Gr 3 recurs despite pelabresib/placebo reduction, continue 
pelabresib/placebo at the reduced dose and HOLD ruxolitinib for up to 
28 days. 
• 
Repeat serum transaminases at least weekly until resolved to ≤ G1/baseline 
• 
Once resolves to ≤ G1, restart ruxolitinib reduced by 5 mg per dose 

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Toxicity 
Actions Required 
≥ Direct bilirubin >1.5 × 
ULN AND ≥ G2 ALT 
(>3 × ULN) in patients 
who enroll with ≤ G1 
ALT 
 
OR 
 
≥ Direct bilirubin >1.5 × 
ULN AND tripling of 
ALT in patients who 
enroll with G2 ALT  
• 
HOLD ruxolitinib for up to 28 days and pelabresib/placebo for up to 35 days 
• 
Once resolved to ≤ G1/baseline, if another cause is identified, restart 
pelabresib/placebo and ruxolitinib at same dose 
• 
Permanently discontinue pelabresib/placebo in the absence of biliary 
obstruction or other potential causes deemed responsible for the concurrent 
elevation of direct bilirubin and ALT 
• 
Investigator may restart ruxolitinib off protocol at his/her discretion. 
Gastrointestinal 
G3 nausea, or 
≥ G3 vomiting, or 
≥ G3 diarrhea  
• 
Treat with optimal supportive care as per guidelines provided in 
Section 6.7.1.2 until resolution to ≤ G1 
• 
HOLD pelabresib/placebo up to 35 days 
• 
Patient should be contacted by the Investigator or study nurse daily until 
resolution to ≤ G1 or increase support (e.g., hospitalization) 
• 
Resume pelabresib/placebo in the presence of symptomatic prophylaxis at 
same dose if duration is ≤ 72 hours, or resume with dose reduced by 
25 mg/day if the duration is >72 hours or if hospitalization is required 
despite optimal supportive care 
• 
If ≥ G3 persists >72 hours despite holding pelabresib/placebo dose, then also 
HOLD ruxolitinib for up to 28 days.  NOTE: if a patient is considered to be 
at high risk for RDS (see Section 6.7.4), consider tapering ruxolitinib instead 
of an abrupt stop.   
• 
Resume ruxolitinib at same dose once recovers to ≤ G1 and resume 
pelabresib/placebo in the presence of symptomatic prophylaxis at same dose 
if duration is ≤ 72 hours, or resume with dose reduced by 25 mg/day if the 
duration is >72 hours or if hospitalization is required despite optimal 
supportive care 
 
NOTE:  If toxicity recurs, and a hold of ruxolitinib was previously required 
because the duration was >72 hours, HOLD pelabresib/placebo for up to 35 days 
and ruxolitinib for up to 28 days. 
NOTE:  In some instances, separation of pelabresib and ruxolitinib intake by a 
few hours or pelabresib intake in the evening prior to bedtime has mitigated 
gastrointestinal AEs. 
Rash 
≤ G2 
• 
Provide supportive care (Section 6.7.3) 
G3 
• 
Provide supportive care (Section 6.7.3) 
• 
If resolution to ≤ G1 takes >72 hours, continue ruxolitinib and HOLD 
pelabresib/placebo until resolution to ≤ G1 or for a maximum of 35 days, 
whichever occurs first 
• 
Resume pelabresib/placebo with dose reduced by 25 mg/day 
G4 
• 
Provide supportive care (Section 6.7.3) 
• 
Permanently discontinue pelabresib treatment 
Infection* 
≤ G2 
• 
Provide active treatment and supportive care, as needed 
• 
Continue ruxolitinib and pelabresib/placebo at the same dose 

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Toxicity 
Actions Required 
≥ G3 
• 
Provide active treatment and supportive care, as needed 
• 
HOLD pelabresib/placebo until resolution to ≤ G1 or for up to 35 days, 
whichever occurs first, continue ruxolitinib 
• 
HOLD pelabresib/placebo and ruxolitinib for G4 until resolution to ≤ G1, or 
for up to 28 days for ruxolitinib and up to 35 days for pelabresib/placebo 
• 
Resume pelabresib/placebo with dose reduced by 25 mg/day following hold 
• 
Resume ruxolitinib with dose reduced by 5 mg per dose following hold 
Other non-specified, including Renal and Electrolytes* 
≥ G2 that, in the opinion 
of the Investigator, 
requires dose reduction  
• 
For G2, consider dose reduction of pelabresib/placebo by 25 mg daily: for 
G3, HOLD offending agent(s) up to 28 days for ruxolitinib and up to 35 
days for pelabresib/placebo 
• 
Evaluate at least once weekly until toxicity resolves to ≤ G1 or stabilizes 
• 
Resume with dose of offending agent(s) reduced by 1 level (i.e., reduce 
25 mg/day for pelabresib/placebo or 5 mg per dose for ruxolitinib). 
Any toxicity that 
requires >35 days hold 
of pelabresib/placebo 
• 
Discontinue pelabresib/placebo unless there is clear evidence of clinical 
benefit and after a discussion with the Sponsor’s medical team 
Any toxicity that 
requires >28 day hold of 
ruxolitinib 
• 
Discontinue ruxolitinib 
Note:  Pseudo hyperkalemia is a common finding in myeloproliferative disorders that may lead to inappropriate management of patients. These 
elevations of plasma potassium in the majority of MF patients may be due to in vitro hemolysis.  ≥ Grade 2 plasma potassium increase requires 
specific laboratory assessments (Section 10.2) and ≥ Grade 3 plasma potassium increase require an ECG (Section 8.3.4). If dose modification is 
required, follow the relevant instructions in the “Other non-specified” area of the table above. 
Note: Any AE that causes a drug hold of >28 days for ruxolitinib or >35 days for pelabresib/placebo, regardless of relationship, will cause the 
patient to discontinue treatment and enter the follow-up phase, as per protocol Section 6.5.3. 
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; CBC = complete blood count; D = day; G = grade; 
GCSF = granulocyte colony stimulating factors; Hgb = hemoglobin; PLT = platelet; QD = once daily; ULN = upper limit of normal. 
*Please refer to ruxolitinib package insert for guidance on dose adjustment/hold for disseminated herpes simplex virus 
6.5.4. 
Re-escalation Criteria and Process 
6.5.4.1. 
Re-escalation of Ruxolitinib after Dose Reduction for Toxicity 
If a dose of ruxolitinib has been reduced for a given patient, the dose may be increased on Day 1 
of the next cycle.  Doses may be increased in 5 mg BID increments and should not be increased 
more frequently than once every cycle (3 weeks). 
When considering re-escalation of ruxolitinib, the goal should be to keep increasing the dose 
regardless of spleen response until it reaches the dose level at the time of reduction.  Further 
escalation may be considered for failure to achieve a reduction from pretreatment baseline in 
either palpable spleen length of ≥50% or a ≥35% reduction in spleen volume as measured by 
MRI or CT scan at Week 12. 
The following criteria must be met for the dose of ruxolitinib to be considered for re-escalation: 
• If the dose has been reduced due to thrombocytopenia, a dose increase can be 
instituted based on platelet count, as indicated in Table 3 and Figure 1. 
• If the dose has been reduced due to neutropenia, a dose increase cannot be instituted 
until the ANC is > 0.75 × 109/L for at least 1 cycle. 
• There are no safety concerns requiring pelabresib/placebo dose interruption or 
reduction on the day the ruxolitinib dose increase is under consideration. 

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• If the dose has been reduced for a non-hematologic toxicity, a dose increase cannot be 
instituted until the toxicity has resolved to ≤ Grade 1 for at least 1 cycle. If the same 
toxicity recurs after dose re-escalation, further dose increases are prohibited. 
• If the dose has been reduced due to Grade 4 non-hematologic toxicity, a subsequent 
dose increase is prohibited. 
If the above criteria are met, a ruxolitinib dose increase can be considered.  After the dose level 
prior to dose reduction is reached, subsequent dose increase of ruxolitinib is allowed provided 
that the criteria described in Section 6.5.2.1 are met. 
NOTE: both ruxolitinib and pelabresib/placebo dose cannot be increased in the same cycle. 
6.5.4.2. 
Re-escalation of Pelabresib/Placebo after Dose Reduction for Toxicity 
Patients who have had a dose reduction or dose hold of ruxolitinib or pelabresib/placebo because 
of an AE may increase the dose of pelabresib/placebo only if all of the following criteria are met: 
• The ruxolitinib dose has reached at least 10 mg BID for the previous 1 cycle (see 
exceptions in Table 3 and Figure 1). 
• If dose has been reduced due to thrombocytopenia, a dose increase can be instituted 
based on platelet count, as indicated in Table 3 and Figure 1. 
• If dose reduced due to neutropenia, a dose increase cannot be instituted until the ANC 
is > 0.75 × 109/L for at least 1 cycle. 
• There are no safety concerns requiring ruxolitinib dose interruption or reduction on 
the day the pelabresib/placebo dose increase is under consideration. 
• If dose has been reduced for a non-hematologic toxicity, a dose increase cannot be 
instituted until the toxicity has resolved to ≤ Grade 1 for at least 1 cycle. If the same 
toxicity recurs after dose re-escalation, further dose increases are prohibited. 
• If the dose is reduced due to Grade 4 non-hematologic toxicity, a subsequent dose 
increase is prohibited. 
If these criteria are met, the pelabresib/placebo dose can be increased in 25 mg QD increments, 
not more frequently than once every 2 cycles, to a maximum dose of 125 mg QD.   
NOTE:  both ruxolitinib and pelabresib/placebo dose cannot be increased in the same cycle. 
6.6. 
Crossover Period 
Patients who have enrolled in the control group (i.e., treated with placebo + ruxolitinib) and have 
progressive disease after 24 weeks of treatment by radiological parameters may be crossed over 
to receive the experimental treatment of pelabresib + ruxolitinib.  The following sections detail 
the design, operational, and statistical aspects of the crossover part of the study. 
6.6.1. 
Crossover Design 
All patients who have progressive disease at any time will be required to discontinue the double-
blind- study treatment.  Patients in the control group who have progressive disease due to 

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splenomegaly (i.e., defined as enlargement of spleen volume by MRI or CT scan of ≥25% 
compared to the baseline value, as confirmed by the central review; not due to leukemic 
transformation or an increase in peripheral blood blast percentage of ≥20% associated with an 
absolute blast count of ≥1 × 109/L that persists for at least 2 weeks; see Section 7.1) at or after 
Week 24 may have the option to cross over to receive the experimental treatment of 
ruxolitinib + pelabresib in an open label fashion.  Patients in the control group who have to 
discontinue study treatment due progressive disease due to splenomegaly prior to Week 24 will 
not have the option to cross over. In addition, patients in the experimental group who have 
progressive disease due to splenomegaly at any time will not have the option to cross over.  Data 
collected as part of the crossover period will be analyzed descriptively. 
6.6.2. 
Operational Considerations for Crossover 
At the time of crossover consideration, patients will be fully informed of the crossover treatment 
option within the study, as well as all available treatment options, including approved and 
investigational, outside of the study as part of re-consenting (Section 10.1.3).  Patients who opt 
in for the crossover treatment must also be re-evaluated against applicable entry criteria 
(Section 6.6.3) to determine if they are still eligible for study participation.  While awaiting 
determination of eligibility for crossover, patients will continue receiving treatment with 
ruxolitinib without dose increases.  Patients who discontinue the double-blind study treatment 
without crossing over and those who cross over and subsequently discontinue the open label 
study treatment will remain on study for survival follow-up (Section 4.5.3).  Unblinding will 
only occur after it is confirmed by the unblinded medical monitor that the patient met eligibility 
criteria for crossover. 
Since patients will have to be unblinded before a crossover decision can be made, selected data 
collected up to the point when a patient is being considered for a possible crossover will be 
cleaned and locked prior to the revelation of treatment assignment.  In the event that any of the 
locked data change after unblinding, such a change will be treated as an unlocking of a locked 
patient variable and documented in full detail.   
The goal prior to unblinding is to minimize any potential for bias in measures that could have 
impact due to their subjectivity.  The following are variables that would be locked prior to 
unblinding at a patient level for a potential crossover: 
• Spleen volume (Section 8.2.1)  
• MFSAF (Section 8.2.2)  
• Bone marrow fibrosis scoring (Section 8.2.1)  
• Transfusion data (Section 8.1) 
• Hematology values (Section 8.3.5) 
• PGIC (Section 8.2.2)  
• EQ-5D (Section 8.2.2)  
• AE components, including relatedness, seriousness, and intensity (Section 8.4) 
 

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6.6.3. 
Clinical Considerations for Crossover 
Eligibility 
Patients must meet the following inclusion criteria at the time of crossover being considered: 
• Splenic progression (>25% increase from baseline) assessed by central review within 
28 days of initiating crossover  
• Have acceptable laboratory assessments obtained within the 28-day crossover 
screening interval: 
− ANC ≥ 1 × 109/L in the absence of growth factors for the previous 4 weeks 
− Platelet count ≥ 75 × 109/L in the absence of growth factors or platelet 
transfusions for the previous 4 weeks 
− Peripheral blood blast count < 5% 
− AST and/or ALT ≤ 2.5 × ULN of the local reference interval (≤ 5 × if the 
elevation can be ascribed to hepatic MF involvement, e.g., presence of 
hepatomegaly) 
− Serum direct bilirubin < 2.0 × ULN of the local reference interval 
− Calculated or measured CrCl of ≥ 45 mL/min 
• ECOG performance status of ≤ 2 
• Life expectancy > 24 weeks per Investigator assessment 
• Have fully recovered from major surgery and interventions 
• Both male and female patients and partners of patients, with reproductive potential, 
must agree to use at least one highly effective contraceptive method per Inclusion 
Criteria 12 (Section 5.1) 
• Capable of giving signed informed consent as described in Section 10.1.3, which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol 
• Receiving ruxolitinib for ≥24 weeks and on a stable dose of ruxolitinib for ≥8 weeks 
• Has not received another systemic anti-cancer treatment, except for hormonal therapy 
and ruxolitinib, during the crossover screening interval.  
 
Patients who have progressive disease based on leukemic transformation or who are unable to 
continue on ruxolitinib due to AEs will not be eligible for crossover. 
 
Starting Doses and Uptitration Criteria 
The ruxolitinib dose should remain the same as at the time of crossover and for at least 2 
crossover cycles unless a dose modification is required for toxicity. 

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The starting dose of pelabresib in the crossover will be 125 mg QD, the same as used in the 
experimental group at Cycle 1 Day 1.  Dose increase up to 175 mg QD is allowed if the criteria 
defined below are met: 
• Platelet count ≥125 × 109/L over the course of the previous cycle 
• ANC >0.75 × 109/L 
• No AE requiring any dose interruption and/or reduction in the previous crossover 
cycles 
NOTE: if the above criteria are met, the pelabresib dose can be increased in 25 mg QD 
increments and not more frequently than once every 2 cycles, to a maximum dose of 175 mg 
QD. 
 
Dose Modifications 
Follow the guidelines specified in Section 6.5.3. 
 
Assessments and Procedures 
Patients who cross over will follow the same SoA as in the double-blind treatment period 
(Section 1.3).  However, patients will restart the crossover treatment at Cycle 1 Day 1 
assessments (i.e., Cycle 1 Day 1 of the crossover treatment is the day on which the patient 
receives the first dose of the open-label experimental treatment). 
Patients who discontinue crossover study treatment will still continue on study for survival 
follow-up according to the time points in the SoA. 
6.6.4. 
Statistical Considerations for Crossover 
The crossover design will have no impact on the analysis of the primary (splenic response at 
Week 24) and key secondary (TSS response at Week 24) endpoints, as the crossover will only 
occur after the Week 24 assessments.  Since spleen volume will be independently assessed in a 
blinded fashion, and since the MFSAF questionnaire cannot be altered for any reason, these 
endpoints will not be affected by unblinding. 
The efficacy data collected during the crossover treatment period will be summarized in a 
descriptive manner.  For safety analysis, an AE that occurs after the administration of the first 
dose of open-label experimental treatment will be considered treatment-emergent for the 
crossover treatment period.  However, a TEAE for the crossover treatment period that occurs 
within 30 days after the last dose of double-blind treatment will be considered treatment-
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6.7. 
Supportive Care 
6.7.1. 
Nausea and/or Vomiting 
6.7.1.1. 
Prophylaxis for Nausea and/or Vomiting 
It is strongly recommended that patients receive oral nausea/vomiting prophylaxis for the first 
2 cycles prior to doses of pelabresib/placebo.  To this end, patients are recommended to receive 
ondansetron 4 to 8 mg QD PO (or a comparable antiemetic) 30 minutes before each 
pelabresib/placebo dose from Cycle 1 Day 1 through the first 6 weeks of treatment or other anti-
emetic therapy as per the Investigator’s clinical judgment with regards to potential drug-drug 
interaction. 
6.7.1.2. 
Management of Nausea and/or Vomiting 
If a patient still experiences ≥ Grade 3 nausea/vomiting despite prophylaxis, consider following 
the NCCN guidelines or local applicable guidelines for the treatment of nausea/vomiting. 
From the Phase 2 experience, separation of pelabresib/placebo and ruxolitinib intake by a few 
hours or pelabresib/placebo intake in the evening prior to bedtime may mitigate gastrointestinal 
AEs (i.e., nausea and vomiting).  Evening administration of pelabresib/placebo should be 
avoided on days prior to PK assessments (time points noted in the SoA [Section 1.3]). 
In addition to using prophylactic/supportive medications for these gastrointestinal AEs, it is 
important to guide patients to drink plenty of non-caffeinated fluids to replace the body fluid lost 
and follow a proper diet. The Sponsor also recommends close monitoring of renal function for 
early identification of any potential abnormality secondary to dehydration and/or other 
comorbidities. 
Refer to Table 4 for ruxolitinib and pelabresib/placebo dose hold and restarting criteria and dose 
for nausea and vomiting. 
6.7.2. 
Management of Diarrhea 
Patients who develop diarrhea should be treated with anti-diarrhea medication, such as 
loperamide, as per standards of care and/or institutional guidelines.  Fluid intake should be 
maintained to avoid dehydration. 
Patients who develop significant new or worsening diarrhea during study treatment must be 
contacted by the Investigator or study nurse daily until it is clear that the problem has resolved or 
requires additional support (e.g., hospitalization). Subsequently, the prophylactic use of anti-
diarrheal medication is allowed for those patients as needed. 
From the Phase 2 experience, separation of pelabresib/placebo and ruxolitinib intake by a few 
hours or pelabresib/placebo intake in the evening prior to bedtime may mitigate gastrointestinal 
AEs, including diarrhea. 
Refer to Table 4 for ruxolitinib and pelabresib/placebo dose hold and restarting criteria and dose 
for diarrhea. 

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6.7.3. 
Management of Rash 
Patients who develop rash should be treated with supportive care as follows: for Grade 1, provide 
an oral antihistamine (e.g., hydroxyzine) as needed and a topical corticosteroid cream as needed.  
For ≥ Grade 2, begin a course of oral prednisone 10 mg once daily for 1 week, followed by 5 mg 
once daily until rash resolves to ≤ Grade 1.  For subsequent doses, premedication may be 
administered at the discretion of the Investigator.  In cases of Grade 4 rash, pelabresib/placebo 
must be discontinued. 
Refer to Table 4 for ruxolitinib and pelabresib/placebo dose hold and restarting criteria and dose 
for rash. 
6.7.4. 
Management of Ruxolitinib Discontinuation Syndrome (RDS) 
Instances of severe adverse events occurring subsequent to ruxolitinib withdrawal have been 
reported in the literature.  RDS includes clinical manifestations ranging from acute relapse of 
disease-related symptoms, rapid spleen volume enlargement, and worsening of cytopenias to 
more severe complications, such as acute respiratory distress, DIC, splenic infarction, and tumor 
lysis-like syndrome. 
The incidence of RDS has been reported in approximately 15% of patients after discontinuation 
of ruxolitinib, with severe cases (defined as requiring IV medication, hospitalization, 
splenectomy, or HSCT delay) occurring in 1-11% of cases (Palandri et al., 2021; Shanavas et al., 
2016; Tefferi et al., 2011).  The risk of RDS was significantly higher in patients with a greater 
burden of the disease with massive splenomegaly; patients with low platelet count were also at 
an increased risk (Palandri et al., 2021).  RDS is mainly a diagnosis of exclusion.  There are no 
specific clinical features, laboratory or histopathology findings that are diagnostic, and the 
syndrome can be suspected based on the temporal relationship between drug withdrawal and 
onset of clinical manifestations that can appear from less than 24 hours up to 3 weeks after 
discontinuation, with median time of onset of 7 days after the last ruxolitinib dose, with severe 
cases typically occurring earlier (Palandri et al., 2021). 
Based on the literature, the following steps are reasonable measures to mitigate this risk once a 
decision about treatment discontinuation or interruption is made: 
• A ruxolitinib taper instead of abrupt discontinuation is recommended where 
appropriate: 
− Example of commonly used tapering strategy: decrease ruxolitinib dose by 5 mg 
BID every 2 weeks, consider additional lowest dose of 5 mg daily dose before 
stopping 
• For high-risk patients (high disease burden, low platelets), consideration may be 
given to a planned bridge to alternative MF therapy to start immediately after 
ruxolitinib discontinuation 
• For patients developing symptoms of RDS, consider urgent resumption of treatment 
with ruxolitinib, steroids, and supportive care (Palandri et al., 2021; Tefferi et al., 
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• Provide patient education about the symptoms of RDS and the importance of prompt 
reporting and the need to be evaluated in person for signs and symptoms of RDS if 
needed during the window when RDS may be expected (up to 3 weeks after 
ruxolitinib discontinuation) 
6.8. 
Concomitant Therapy 
The following concomitant medications are prohibited during study treatment (and some require 
a washout period, as noted below): 
• Systemic anti-neoplastic medications, including hydroxyurea and anagrelide.  Patients 
should discontinue hydroxyurea or anagrelide 24 hours prior to the first dose of study 
drug.  If alternative anti-MF therapy is required for treatment of the patient’s disease, 
the patient should be discontinued from study drug and the reason for removal 
recorded in the eCRF. 
• Myeloid, erythroid or thrombopoietin growth factor or androgenic steroids.  Patients 
should discontinue use of any of these growth factors or androgenic steroids 4 weeks 
prior to the first dose of study drug. 
• Strong CYP3A4 inhibitors or inducers, including St. John’s wort (Section 10.8) 
• Immunosuppressive agents with systemic activity (topical agents without systemic 
activity like eye drops with calcineurin inhibitors such as cyclosporine A or 
tacrolimus are allowed) 
• Live vaccinations.  Live vaccination within 30 days prior to the first dose of study 
drug, during study treatment, and for 90 days after the last dose of study drug, is 
prohibited except for COVID-19 vaccination (see below). 
− The potential effects of pelabresib on COVID-19 vaccine efficacy or safety is not 
known at this time. Vaccination with synthetic or inactivated anti-COVID-19 
vaccines is not prohibited during the study; however, whenever feasible, it is 
recommended to complete vaccination against COVID-19 before the start of 
study treatment. Potential of vaccination with live anti-COVID vaccines or with 
any anti-COVID vaccines which use live viral vector as a platform of delivery 
should be discussed with the Sponsor’s Medical Monitor and applied on a case-
by-case basis with regards to existing clinical safety and efficacy data, risk/benefit 
analysis, and patient status as per investigator’s clinical judgment, local and 
institutional regulations, and standards of care. 
• Pelabresib inhibits CYP2C19 in vitro.  Therefore, concomitant medications with a 
narrow therapeutic window metabolized through CYP2C19 should be monitored for 
adverse reactions.  Alternative treatment to clopidogrel should be considered if 
indicated.  If warfarin is indicated, it is recommended to monitor international 
normalized ratio (INR) more closely when treatment with pelabresib is initiated. 
• Pelabresib showed potential to inhibit CYP2C8 and to induce CYP2C8 and CYP3A 
in vitro.  Narrow therapeutic index substrates of CYP2C8 and CYP3A should be used 
with caution and monitored for drug-related adverse events and loss of efficacy. In 

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addition, concomitant use of pelabresib with hormonal contraceptives should be 
avoided. If concomitant use cannot be avoided, an alternative contraceptive that is not 
affected by enzyme inducers (e.g., intrauterine system) or additional non-hormonal 
contraception (e.g., condoms) should be recommended since pelabresib has the 
potential to reduce the exposure, and possibly the efficacy of the hormonal 
contraceptives. 
Pelabresib has demonstrated no potential to prolong the QT interval during its preclinical 
evaluation, including a study in telemeterized dogs.  To date, there has been no clinically 
relevant prolongation of QTc noted on ECGs in any of the three Phase 1 studies of pelabresib.  
Despite this, it is recommended that treatment with medications that are known to prolong the 
QT interval be used with caution. 
Acceptable concomitant medications include: 
• Topical, nasal intra-articular, and inhaled corticosteroids, and daily doses of ≤ 10 mg 
QD oral prednisone or equivalent (pelabresib/placebo dose hold not required).  Daily 
doses up to 20 mg oral prednisone or equivalent may be allowed for ≤7 days if 
indicated, after consultation with the Sponsor or its designee.  A pelabresib/placebo 
dose hold is required and can be resumed at least 1 week after completion of the 
higher dose (≥10 mg) steroid treatment. 
• Supportive care measures, as detailed in Section 6.7 
6.9. 
Contraception 
Instructions on the use of effective contraceptive measures during and after study treatment 
follow the current recommendations of the HMA/CTFG and EMA. 
6.9.1. 
Female Patients 
Female patients of childbearing potential (WOCBP) are required to use at least one highly 
effective method of contraception (preferably low user dependency contraception methods, in 
particular when contraception is introduced as a result of participation in a clinical study) while 
receiving study drug and for 184 days after the last dose of study drug. 
Women will be considered of childbearing potential after the onset of their first menstrual 
period.  Women who are documented as being of nonchildbearing potential (postmenopausal or 
having undergone surgical sterilization) are exempt from this requirement.  Women will be 
considered postmenopausal if they have had 12 months of consecutive spontaneous amenorrhea 
or less than 12 months of consecutive spontaneous amenorrhea and a serum FSH level > 40 
mIU/mL at Screening.  Women will be considered surgically sterile if they are post-
hysterectomy, 6 months post-surgical bilateral oophorectomy, or 6 months post-surgical 
salpingectomy. 
In accordance to CTFG guidelines,  highly effective contraceptive methods for WOCBP are: 
• Combined (estrogen and progestogen containing) hormonal birth control associated 
with inhibition of ovulation# 
o Oral* 

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o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation# 
o Oral* 
o Injectable 
o Implantable** 
• Intrauterine device (IUD)** 
• Intrauterine hormone-releasing system (IUS)**,# 
• Bilateral tubal occlusion** 
• Vasectomised partner**, + 
• Sexual abstinence if the preferred and usual lifestyle of the male and female subjects, 
and partners of subjects 
# Concomitant use of pelabresib with hormonal contraceptives should be avoided.  If 
concomitant use cannot be avoided an alternative contraceptive that is not affected by 
enzyme inducers (e.g., intrauterine system) or additional non-hormonal contraception (e.g., 
condoms) should be used, since pelabresib has the potential to reduce the exposure, and 
possibly the efficacy, of hormonal contraceptives. 
* If patients have been experiencing vomiting or diarrhea, the investigator should consider 
avoiding oral hormonal contraceptives as highly effective contraceptive methods and should 
consider other contraceptive methods listed above.** Contraception methods that are 
considered to have low user dependency. 
+ Azoospermia must be documented in repeated examinations of the ejaculate before the first 
dose of study drug (Day 1) and/or demonstration of the absence of the vas deferens on 
ultrasound before the first dose of study drug (Day 1). 
It is highly recommended for male partners of female patients of childbearing potential to use 
additional highly effective contraception methods in combination.  
6.9.2. 
Male Patients 
Due to the potential risk of genotoxicity based on pre-clinical data, male patients regardless of 
fertility must use a condom during sexual intercourse while receiving study drug and for 94 days 
after the last dose of study drug.   
6.9.3. 
Female Partners (WOCBP, Non-pregnant) of Male Patients  
It is highly recommended for female (WOCBP, non-pregnant) partners of male patients to use 
additional highly effective contraception methods (listed above) in combination with male 
condom.  

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6.9.4. 
Oocyte and Sperm Donation 
Donation of oocytes by the female patients during the study and for 184 days after the last dose 
of study drug is not allowed.  Donation of sperm by the male patients during the study and for 94 
days after the last dose of study drug is not allowed. 
7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT WITHDRAWAL 
FROM THE STUDY 
7.1. 
Discontinuation of Study Drug 
Study treatment is to be permanently discontinued for patients meeting any of the following 
criteria: 
• Patients who were randomized, but not able to start treatment within 28 days of the 
start of screening. Study treatment is defined as the combination of pelabresib + 
ruxolitinib or placebo + ruxolitinib.  
• Unacceptable toxicity 
• Disease progression (as defined below), with the exception of patients in the control 
group who cross over to receive the experimental treatment (Section 6.6) 
• Patients undergoing splenectomy 
• Patients proceeding to stem cell transplantation (permitted for eligible patients who 
have completed at least 24 weeks of study treatment) 
• Need for intervention or therapy (determined by the Investigator to be medically 
necessary) that is precluded by study participation according to the protocol. 
• Patient noncompliance with study treatment/procedures or voluntary withdrawal of 
consent 
• Female patient who becomes pregnant or suspects pregnancy   
Progressive disease is defined by meeting 1 of the following criteria:  
• Progressive splenomegaly, defined as enlargement of spleen volume by MRI or CT 
scan of ≥25% compared to the baseline value, as confirmed by the central radiology 
review 
• Leukemic transformation, confirmed by a bone marrow blast count of ≥20%  
• A peripheral blood blast percentage of ≥20% associated with an absolute blast count 
of ≥1 × 109/L that persists for at least 2 weeks 
For patients progressing via imaging (MRI or CT scan), confirmation of progression by central 
radiology review is required.  Study drug should only be discontinued while waiting for 
confirmation of progression if the patient is experiencing toxicities.  Central review of imaging 
and confirmation of disease progression is not required for the other two clinical criteria for 
progression, i.e., leukemic transformation of bone marrow and increase in peripheral blood blast 
percentage.  Patients who are determined by the central read of the scans not to have progressive 

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disease will continue on study treatment unless there is progression by clinical criteria. Patients 
who have progressed may either be discontinued from treatment (if in the experimental group) or 
crossed over to the treatment group (if in the control group; Section 6.6). 
EOT and follow-up visits for progression and survival are required for all patients according to 
the timing detailed in the SoA (Section 1.3).  The safety follow-up visit may be conducted by 
telephone.  All patients will be followed for AEs and SAEs for 30 days following the last dose of 
pelabresib/placebo or the start of alternative (off-study) treatment for MF, whichever occurs first, 
at the time points noted in the SoA.  Patients who discontinue study treatment and refuse to 
return for the EOT visit will be contacted for safety evaluations during the 30 days following the 
last dose of pelabresib/placebo.  Patients who discontinue treatment for reasons other than 
documented disease progression should have follow-up visits every 12 weeks to document 
response by imaging, and transfusion requirements until initiation of another anti-cancer therapy, 
progression, death, or the end of the study, whichever comes first. Continuing ruxolitinib 
monotherapy as standard-of-care treatment after the discontinuation of treatment on study is not 
considered the initiation of another anti-cancer medication/therapy. Imaging collected during the 
progression-free survival follow-up will be sent to central review for analysis.  Patients who 
discontinue study treatment for documented disease progression or start another anti-cancer 
medication/therapy should have a follow-up visit/phone call every 12 weeks to document overall 
survival. Information on subsequent anti-MF therapy will be collected in both follow-up periods. 
7.2. 
Patient Withdrawal from the Study Treatment/Study 
A patient may withdraw from the study treatment/study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
Patients have the option to withdraw from study treatment and stay in the follow-up or to 
withdraw from the study entirely. At the time of withdrawing from study treatment, if possible, 
an EOT visit should be conducted, as shown in the SoA (Section 1.3).  The patient will be 
permanently discontinued from study treatment and enter the appropriate follow-up period. 
Patient’s may withdraw from the follow-up phase at the same time as study treatment or later.  
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
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the study.  These contact attempts should be documented in the patient’s medical 
record. 
• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls).  
These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study (Section 7.2).  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.11. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed.  Adherence to the study design requirements, 
including those specified in the SoA, is essential and required for study conduct. 
All screening evaluations must be completed to confirm that potential patients meet all eligibility 
criteria. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) and 
obtained before signing of the ICF may be utilized for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA. If an AE or SAE occurs that causes a drug hold, directions in Section 6.5 
should be followed regarding study visits and dose holds. If a visit is delayed for reasons other 
than an AE/SAE, e.g., a winter storm delays the visit by 3 days, Day 1 of the cycle and dosing 
should be delayed until the patient is able to come to the clinic. If a visit occurs early due to any 
reason, no dosing should occur until the patient has completed the mandatory 7-day break 
between cycles.  
As detailed in the SoA, patients should be seen in the clinic by the Investigator or designee 
during screening, and on Days 1 and 14 of Cycle 1.  Subsequently, patients should be seen in the 
clinic by the Investigator or designee on Day 1 of all cycles through Cycle 9 Day 1 to assess 
wellbeing and compliance with the study.  After the Cycle 9 Day 1 visit, the frequency of study 
visits may be reduced such that patients are only seen in the clinic by the Investigator or designee 
every odd cycle (Cycle 11, Cycle 13, etc.) provided that the patient is tolerating the study 
treatment and the doses of pelabresib/placebo and ruxolitinib have remained stable for at least 6 
weeks. 
8.1. 
Demographics and Medical History Assessments 
Patient demographics will be documented during screening and will include patient’s year of 
birth, gender, ethnicity, and race. 
The patient will have a complete medical history taken to include all past and ongoing medical 
conditions. The medical history will also include details on the MF diagnosis with a description 
of all related prior therapies, including treatment dates, dosage, response on therapy including 
symptom, spleen and transfusion responses, and reasons for treatment discontinuation.  

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Additionally, concomitant medications will be listed and will include all medications being taken 
at the time points included in the SoA (Section 1.3). 
8.2. 
Efficacy Assessments 
8.2.1. 
Disease Status Assessments 
The patient’s disease status will be evaluated by measurement of peripheral blood counts, 
history/documentation of transfusion requirements, MF-associated symptoms, spleen size by 
palpation and by MRI/CT, and grading of bone marrow fibrosis as assessed by bone marrow 
biopsy. Disease status assessment should be performed at the end of double-blind treatment and 
at the end of progressive disease follow-up. 
A complete transfusion history for the 16 weeks prior to Cycle 1 Day 1 and throughout the study 
will be taken at the time points noted in the SoA (Section 1.3) to include the date, type (e.g., 
whole blood, platelets, packed cells), number of units of the transfusion, as well as the 
hemoglobin and platelet values prior to the transfusion. 
MRI is preferred method of imaging for spleen volume measurement.  An MRI (or CT scan) will 
be done at the time points noted in the SoA (Section 1.3).  The imaging method should remain 
consistent throughout the study (i.e., if MRI was used at screening, MRI should also be used for 
all subsequent visits).  An MRI or CT scan should be repeated at the EOT visit only if 
progressive disease has not been previously documented or, in the absence of documented 
progressive disease, imaging has not been performed within the previous 6 weeks.  Local 
practices for spleen volume assessment should be used.  Imaging data for spleen volume 
measurement (imaging studies, derived assessments, and reports) must be available for central 
radiology review for all imaging time points noted in the SoA, including screening.  Details on 
the central radiology review will be provided in a charter, provided as a document separate from 
the protocol. 
Bone marrow biopsy samples will be collected as specified in the SoA (Section 1.3) and assessed 
by a local hematopathologist for grading of bone marrow fibrosis following the European 
classification (Thiele et al., 2005) for a timepoint IWG-MRT response evaluation (Tefferi et al., 
2013) (Section 10.7).  Three stained slides [one slide of each: H&E, reticulin, and trichrome] that 
were used for local review and 6-10 unstained slides should be sent to the central lab for storage 
prior to analysis for central pathology review and exploratory assessment. If stained slides are 
unable to be sent for central review per institution policy or due to any other reason, 10 unstained 
slides should be sent to the central lab for central pathology review and exploratory assessment.  
Refer to the laboratory manual and flow chart for details on the collection, handling, storage, 
and/or shipping of bone marrow samples. 
The bone marrow biopsy sample at screening does not need to be repeated if obtained within 
12 weeks of Cycle 1 Day 1.  The EOT bone marrow biopsy does not need to be collected if a 
biopsy has been performed within the previous 12 weeks. 
Bone marrow biopsy samples may also be used for exploratory assessment of changes in 
hematopoietic cell populations and transcriptomic analyses. 

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8.2.2. 
Patient-Reported Outcomes 
The MFSAF assessment (version 4.0) should be completed electronically every day irrespective 
of any cycle delays starting from at least 7 days prior to randomization until 12 weeks after the 
end of treatment. The MFSAF asks patients to rate the severity of each of seven symptoms 
(fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early 
satiety, and bone pain) at its worst during the past 24 hours using a 0 (absent) to 10 (worst 
imaginable) numeric rating scale.  See Section 10.6 for more information about the MFSAF. 
Patients are requested to complete the PGIC assessment electronically on a weekly basis after the 
start of study treatment irrespective of any delay in cycle due to drug hold.  Patients should 
complete the PGIC on the same day each week until 12 weeks after the end of treatment.  The 
PGIC is a single question to assess the patient’s impression of change in their MF symptoms 
since the start of study treatment.  The PGIC has been widely used to evaluate a patient’s overall 
sense of whether a treatment has been beneficial.  The patient will answer the following 
question: “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.” 
Patients are requested to complete the EQ-5D assessment electronically on a weekly basis during 
both the screening and treatment periods irrespective of any delay in cycle due to drug hold.  
Patients should complete the EQ-5D on the same day each week until 12 weeks after the end of 
treatment.  The EQ-5D measures a patient’s health-related quality of life across 5 different 
domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
8.3. 
Safety Assessments 
Any patient who receives treatment on this protocol will be evaluable for toxicity.  Each patient 
will be assessed periodically for the development of any toxicity according to the SoA 
(Section 1.3).  Toxicity will be assessed according to the NCI CTCAE, v5.0.  The Investigator 
should carefully assess all treatment-associated toxicities and, whenever possible, determine if 
they can be attributed to ruxolitinib alone, pelabresib/placebo alone, or to the combination of 
ruxolitinib + pelabresib/placebo. 
8.3.1. 
Concomitant Medications 
Any other permitted medication or vaccine (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the patient is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
8.3.2. 
Physical Examinations, Including Spleen Examination, and Vital Signs 
A complete physical examination will be performed at the time points noted in the SoA 
(Section 1.3) and will include general appearance, HEENT, neck, cardiovascular, thorax/lungs, 
breasts, abdomen, genitourinary, musculoskeletal, lymph nodes, skin, neurological and mental 

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status examination.  Abdominal examination will include splenomegaly and hepatomegaly.  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.  Targeted physical exams 
may be focused on areas of known disease and potential areas of MF involvement.  A targeted 
physical examination must include weight and examination of the abdomen to assess the spleen 
length by palpation.   
Height and weight will be assessed at the time points noted in the SoA (Section 1.3).  BMI will 
be calculated using these assessments. 
The physical examination performed during screening does not need to be repeated on Cycle 1 
Day 1 if it is conducted within 72 hours of the first dose of study drug. 
Vital signs (temperature, pulse rate, respiratory rate, and blood pressure) will be assessed at the 
time points noted in the SoA.  Vital signs should be conducted ≤ 72 hours before the start of each 
scheduled cycle.  Blood pressure and pulse measurements should be assessed in the same 
position at each time point and should be preceded by at least 5 minutes of rest for the patient in 
a quiet setting without distractions. 
The Investigator will evaluate the clinical significance of any abnormal findings on physical 
examinations or vital sign assessments.  Pre-existing conditions diagnosed through assessments 
and examinations at the screening visit or during the screening period are not AEs, but are 
recorded as medical history.  If any clinically significant abnormal findings are reported after 
informed consent or if any pre-existing conditions worsen during the study, these must be 
recorded as AEs. 
8.3.3. 
ECOG Performance Status 
ECOG performance status will be assessed at the time points noted in the SoA (Section 1.3).  
ECOG assessment should be conducted ≤ 72 hours before the start of each scheduled cycle. 
8.3.4. 
Electrocardiograms 
A single 12-lead ECG will be obtained at the time points noted in the SoA (Section 1.3) at least 1 
hour after dosing of study drug.  Additional unscheduled ECGs should be performed per 
investigator judgment (e.g., in the event of ≥ Grade 3 plasma potassium increase [see Section 
10.2] or hyperkalemia). 
The Investigator will evaluate the clinical significance of the ECGs. Clinically significant 
abnormal findings will be reported as AEs. 
Approximately 200 patients will have ECGs from screening to Week 24 assessed both locally for 
safety and centrally for QT/QTcF effects of patients taking ruxolitinib and pelabresib in 
comparison to patients taking ruxolitinib and placebo. ECGs will be collected and sent to the 
vendor to be centrally read in real time or may be centrally read retrospectively. Patient selection 
for ECG analysis will be based on time of enrollment into study. Approximately the last half of 
patients enrolled will be sent to central review for analysis. 

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8.3.5. 
Clinical Safety Laboratory Assessments 
The laboratory assessments to be collected during the study at the time points noted in the SoA 
(Section 1.3) are detailed in Section 10.2.  These assessments include hematology, clinical 
chemistry, coagulation parameters, serum lipids, HbA1c, and pregnancy testing (only in female 
patients of childbearing potential). 
Laboratory assessments should be completed at a local lab whenever possible. 
Laboratory assessments performed during screening do not need to be repeated on Cycle 1 Day 1 
if they are conducted within 72 hours of the first dose of study drug. 
The Investigator will review the laboratory results and evaluate and record whether the results 
are normal or abnormal and whether abnormal results are non-clinically significant or clinically 
significant.  Pre-existing clinically significant conditions diagnosed as a result of the screening 
procedures must be recorded as medical history.  If any clinically significant abnormal findings 
are discovered after signing the ICF or any pre-existing conditions worsen during the trial, these 
must be recorded as AEs.  The laboratory report will be signed and dated by the Investigator. 
8.4. 
AEs and SAEs 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE throughout the study and remain 
responsible for following up AEs that are considered at least possibly related to the study drug or 
study procedures, or that caused the patient to discontinue study drug or withdraw from the study 
(Section 7), and all SAEs until event resolution, stabilization, the event is otherwise explained, or 
the patient is lost to follow up (Section 7.3). 
8.4.1. 
AE and SAE Definitions 
An AE is any untoward medical occurrence in a patient administered a study drug that does not 
necessarily have a causal relationship with the study drug.  An AE can therefore be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a study drug, whether or not it is considered to be related to 
the study drug.  This includes any newly occurring event or previous condition that has increased 
in severity or frequency since the administration of study drug. 
A clinical laboratory AE is any laboratory value that is considered clinically significant by the 
Investigator and has caused a medical intervention, dose hold, dose reduction or schedule 
change. Laboratory abnormalities that have not required medical intervention should not be 
recorded as AEs and will be captured and reported in the clinical study report. 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening.  Life-threatening means that the patient was at immediate risk of 
death from the event as it occurred (i.e., it does not include an event that 
hypothetically might have caused death had it occurred in a more severe form). 
• Requires in-patient hospitalization or prolongation of existing hospitalization (see 
clarification below on planned hospitalizations).  Hospitalization means that the 

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patient was admitted to the hospital as an in-patient for a period of at least 24 hours.  
Over-night stays for observation, stays at an emergency department, or treatment on 
an out-patient basis do not constitute hospitalizations.  However, medical judgment 
must always be exercised and when in doubt the case should be considered serious 
(i.e., if case fulfills the criterion for a medically important event).  Hospitalizations 
for administrative or social purposes do not constitute an SAE. 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect 
• Is an important medical event. An important medical event is an event that may not 
immediately result in death, be life-threatening, or require hospitalization but may be 
considered an SAE when, based upon appropriate medical judgment, it may 
jeopardize the patient or may require medical or surgical intervention to prevent 1 of 
the outcomes listed in the definition above for SAEs.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in patient 
hospitalization, or the development of drug dependency or drug abuse. 
Intensity and seriousness should be independently assessed when recording AEs and SAEs on 
the eCRF. 
8.4.2. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs, both non-serious and serious, and deaths will be collected and recorded on the eCRF 
from the signing of the ICF through 30 (±3) days after administration of the last dose of 
pelabresib/placebo or the start of alternative (off-study) treatment for MF, whichever occurs first, 
at the time points noted in the SoA. 
All SAEs, including deaths that occur during the course of the study and designated safety 
follow-up period, must be recorded, and reported by the Investigator to the safety contract 
research organization following instructions provided in supplemental study materials within 24 
hours from the point in time when the Investigator becomes aware of the SAE. 
Any SAE, including deaths, that occurs at any time after 30 days after the last dose of 
pelabresib/placebo and that the Investigator considers to be related to pelabresib/placebo must be 
recorded and reported to the Safety CRO within 24 hours of the site’s knowledge of the event. 
See Section 10.3 for more information about reporting SAEs. 
In addition to the above, AEs meeting either of the below criteria, although not serious per ICH 
definition, are reportable to the Sponsor or its designee in the same timeframe as SAEs to meet 
certain local requirements: 
• Is a secondary malignancy that is not a condition of this study 
• Is associated with an overdose (Section 8.4.8) 
Each case of COVID-19 infection, including asymptomatic infections and/or COVID-19-related 
medical conditions, should be recorded as an AE in the clinical database and appropriately 

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assessed for intensity/severity and for seriousness. If available, Investigators should provide 
additional information on the confirmatory test, COVID-19 vaccination status, treatment 
received for COVID-19 infection, and actions taken with study drugs due to COVID-19 infection 
events. 
8.4.3. 
Method of Detecting AEs and SAEs 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded in the appropriate section of the eCRF.  When possible, signs and symptoms 
indicating a common underlying pathology should be noted as 1 comprehensive event. 
If a patient suffers from the same AE more than once and the patient recovers in between the 
events, the AEs should be recorded separately. If an AE changes in intensity, a worst-case 
approach should be used when recording the event, i.e., the highest intensity and the longest 
duration of the event. 
Any laboratory abnormality, vital sign finding, or finding from physical examination that is 
assessed as clinically significant by the Investigator will be considered as an AE (pre-existing 
conditions diagnosed through assessments and examinations at the screening visit or during the 
screening period are not AEs, but are recorded as medical history). 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the study or before study drug was given are not to be considered AEs 
unless the condition deteriorated in an unexpected manner during the trial (e.g., surgery was 
performed earlier or later than planned). 
NOTE: A procedure is not an AE; the reason for conducting the procedure is. Hospitalization is 
not an AE; the reason for hospitalization is. Death is not an AE; the cause of death is (an 
exception is sudden death of unknown cause, which is an AE). 
The Investigator must report all SAEs, whether or not considered to be causally related to the 
study drug, that occurred from the signing of the ICF through 30 days (± 3 days) after 
administration of the last dose of pelabresib/placebo or the start of alternative (off-study) 
treatment for study indication, whichever occurs first, and all SAEs considered related to 
pelabresib/placebo that occurs after 30 days of the last dose of pelabresib/placebo, to the Safety 
CRO as noted in Section 8.4.2.  The information collected will include a minimum of the 
following: patient identification number, a narrative description of the event, and an assessment 
by the Investigator as to the intensity of the event and relatedness to study intervention.  A 
sample of the SAE Form may be found in the supplemental study materials. Follow-up 
information on the SAE may be requested by the Sponsor or the Safety CRO. 
When recording a death on an eCRF or SAE paper report form, the event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept. 
Further details on recording and follow-up of AEs and SAEs can be found in Section 10.3. 
Intensity for each AE and SAE, including any laboratory abnormality, will be determined by 
using the NCI CTCAE, Version 5.0 (Section 10.3). 

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For both non-serious AEs and SAEs, relationship to study intervention administration will be 
determined by the Investigator according to best medical judgment by selecting one of the 
options of definitely related, probably related, possibly related, unlikely related and not related.  
Further details are provided in Section 10.3. 
8.4.4. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All AEs considered at least possibly related to study drug and all 
SAEs that occur during the reporting period (during the course of the study and designated safety 
follow-up period) will be followed until resolution, stabilization, the event is otherwise 
explained, or the patient is lost to follow-up (as defined in Section 7.3). Further information on 
follow-up procedures is provided in Section 10.3. 
8.4.5. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the Sponsor or its designee (Safety CRO) of a SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of patients and 
the safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
Sponsor or Safety CRO will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, IRB/IEC, and Investigators. SAEs will be considered 
reportable regardless of whether or not the study intervention was used in accordance with the 
provisions in the protocol and the Investigator’s Brochure. In addition, all AEs resulting from 
study drug overdose (Section 8.5) and all secondary malignancies, even if not meeting any 
seriousness criterion, should be reported as if they were SAEs (Section 8.4.2). 
Investigator safety reports must be prepared by the Sponsor and/or Safety CRO for SUSAR 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor and/or Safety CRO will 
review and then file it along with the current version of the Investigator’s Brochure and will 
notify the IRB/IEC, if appropriate according to local requirements. 
8.4.6. 
Pregnancy 
A positive urine pregnancy test requires immediate interruption of study drug until serum HCG 
is performed and found to be negative. If a female patient or a female partner of a male patient 
becomes pregnant or suspects pregnancy while participating in this study and during the follow-
up contraception period (184 days after the last dose of study drug), the Investigator must be 
informed immediately. If a female patient becomes pregnant or suspects pregnancy, they must 
permanently discontinue study drug (if applicable).  The pregnancy must be reported to the 
Safety CRO within 24 hours of the site’s knowledge of the pregnancy in accordance with the 
instructions provided in the supplemental study materials.  The pregnancy must be followed 
through the final pregnancy outcome and one month after the expected due date.  Abnormal 

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pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs. Any outcome which the Investigator and/or the 
Sponsor considers to be related to the study intervention will be treated as an expedited report. 
8.4.7. 
Disease-Related Events and/or Disease-Related Outcomes 
The FDA guidance on safety reporting directs Sponsors to specify AEs that may be common in 
the study population and as such may not meet the guidance criteria for expedited reporting. Per 
the guidance, a limited number of occurrences of an AE in a study population in which 
occurrences of the event are anticipated independent of drug exposure, do not constitute an 
adequate basis to conclude that the event is a “suspected adverse reaction.” An individual 
occurrence of one of these SAEs is uninformative as a single case, and therefore it will not be 
considered as a “suspected adverse reaction.” 
Patients with advanced hematological malignancies, the patient population to be enrolled in this 
study, are at risk for many AEs as a result of their disease and the consequences of prior therapy. 
Expected events due to MF or to the treatment of MF are listed below and will not be subject to 
expedited reporting to the Health Authorities as an ICSR unless they are thought to be related to 
study drug; however, if any of the below meet the definition of serious during the study reporting 
period, they should be reported to the Safety CRO as noted in Section 8.4.2: 
• AEs related to myelosuppression and bone marrow activity 
o Anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia, leukocytosis 
• Electrolyte abnormalities (sodium, potassium, bicarbonate, magnesium) 
• Chemistry abnormalities (LDH, phosphate, calcium, protein, albumin, uric acid, 
glucose) 
• Liver function test abnormalities (ALT, AST, direct and total bilirubin, alkaline 
phosphatase) 
• Renal function test abnormalities (creatinine, BUN/urea) 
• Coagulation abnormalities 
• Bone, joint, or muscle pain 
• Renal failure related to tumor lysis syndrome  
When reporting an event of progression of the disease under investigation, specific 
manifestations, or signs/symptoms of the progression (e.g., “malignant pleural effusion,” 
“lymphadenopathy from underlying cancer”) should be reported, rather than the general term 
“disease progression.”  If a death is attributed to progression of disease, where the specific 
manifestations of the progression cannot be identified, record “disease progression” as the SAE 
term on the SAE paper report form. 
The occurrence of these AEs will be monitored by the Sponsor and an expedited report will be 
submitted if an aggregate analysis indicates that the events are occurring more frequently or at 
greater intensity or for longer duration than in historical control groups. 

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8.4.8. 
Adverse Events of Special Interest (AESIs) 
Selected non-serious and serious adverse events are also known as AESIs and must be reported 
within 24 hours to the Safety CRO.  For the time period beginning when the ICF is signed 
through 30 days after administration of the last dose of pelabresib/placebo or the start of 
alternative (off-study) treatment for MF, whichever is earlier, any AESI, or follow up to an 
AESI, whether related to study drug or not, must be reported within 24 hours to the Safety CRO.  
AESIs for this trial include: 
1. Treatment discontinuation syndrome:  exacerbation of MF symptoms following 
interruption or discontinuation of study treatment, fever, respiratory distress, 
hypotension, DIC, or multi-organ failure 
2. Acute respiratory distress syndrome (ARDS) 
8.5. 
Treatment of Overdose 
For this study, any dose of study drug greater than the recommended Phase 2 dose of pelabresib 
(225 mg QD; Section 4.3) per day or greater than 50 mg (25 mg BID) of ruxolitinib per day will 
be considered an overdose.  The Sponsor does not recommend specific treatment for an 
overdose.  In the event of an overdose, the Investigator should contact the Sponsor’s Medical 
Monitor or its designee immediately and the patient should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated.  Overdoses 
should be reported according to Section 8.4.2. 
8.6. 
Pharmacokinetics 
Blood samples (approximately 4 mL per sample) will be collected for the determination of 
pelabresib and its metabolites M542/M544 as well as ruxolitinib concentrations in plasma. The 
specific collection timepoints are listed in Table 5.  When PK sampling coincides with 12-lead 
ECGs, blood draws for PK should be taken within 5 minutes after ECG assessment. 
Actual collection date and time of each PK sample will be recorded on the eCRF.  On days when 
PK and/or pharmacodynamic samples need to be collected prior to taking study drug, the patient 
should take that day’s pelabresib/placebo and/or ruxolitinib dose in the clinic. 
Additional details regarding the collection, handling and shipping of samples are provided in the 
laboratory manual and flow chart. 
Table 5: 
Pharmacokinetic Collection Time Points 
Dosing Day 
Collection Timepoint and Windows 
C1 D1, C1 D14, C9 D1 
Predose 
30 m to 1 h postdose 
3 to 4.5 h postdose 
C3 D1, C7 D1 
Predose  
5 m post ECG assessment 
C = cycle; D = day; h = hour; m = minute. 

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8.7. 
Pharmacodynamics 
The following biomarker assessments will be completed in all patients. Table 6 outlines the 
pharmacodynamic sampling schedule. 
Additional details regarding the collection, handling and shipping of samples are provided in the 
laboratory manual. 
All blood and bone marrow samples collected as detailed in the SoA (Section 1.3) may be used 
for additional exploratory analysis of predictive biomarkers of response and to further understand 
the mechanism of action of pelabresib.  Since biomarker science is a rapidly evolving area of 
investigation, and AEs in particular are difficult to predict, it is not possible to specify 
prospectively all tests that will be done on the specimens provided. Any results from exploratory 
biomarkers analyses may be reported separately from the CSR. 
Bone marrow biopsy evaluation 
Bone marrow biopsy samples will be collected for grading of bone marrow fibrosis and for 
exploratory assessment of hematopoietic cell populations and read centrally, as described in 
Section 8.2.1.  Samples will be collected according to the time points in the SoA (Section 1.3).   
Circulating analytes evaluation 
Peripheral blood samples (approximately 10 mL of whole blood at each time point) will be 
collected for the measurement of circulating concentrations of cytokines and other analytes. 
Samples will be collected prior to the administration of study drug at the time points in the SoA 
(Section 1.3).   
Mutant allele burden evaluation 
Peripheral blood samples (approximately 10 mL of whole blood at each time point) will be 
collected for the measurement of mutant allele burden of selected genes (e.g., JAK2, CALR) 
using a focused NGS assay. Samples will be collected according to the time points in the SoA 
(Section 1.3). Correlation of mutation profile and response to pelabresib in combination with 
ruxolitinib will be used to identify predictive biomarkers. Additionally, changes in allelic burden 
of specific mutations in patients may identify increase in activity of certain mutational contexts 
to pelabresib. 
Table 6: 
Biomarker Assessment Collection Time Points 
Sample Collected 
Dosing Day 
Time Point 
Bone marrow biopsy 
See time points in SoA (Section 1.3) 
Anytime up to 2 years after study 
treatment until PD 
Mutant allele burden 
C1 D1, C17 D1 
Pre-dose 
Circulating analytes 
C1 D1, C1 D14, C9 D1, C17 D1 
Pre-dose (+matched to mutant allele 
burden sampling, when applicable) 
 
 
 

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9. 
STATISTICAL CONSIDERATIONS 
A more technical and detailed description of the statistical methods will be provided in the SAP. 
9.1. 
Study Endpoints 
9.1.1. 
Primary Endpoint 
The primary endpoint of the study is splenic response, defined as a ≥ 35% reduction from 
baseline in spleen volume as measured by MRI or CT and assessed by central radiology read, at 
Week 24. 
9.1.2. 
Key Secondary Endpoints 
The key secondary endpoints of the study are the absolute change in TSS at Week 24 compared 
to baseline and TSS response, defined as a ≥ 50% decrease from baseline in TSS as measured by 
the MFSAF v4.0, at Week 24. 
Baseline TSS is calculated as the average of non-missing daily total symptom scores over the 7-
day period prior to day of randomization.  The TSS for a treatment week is the average of non-
missing daily total symptom scores over that week.  However, the weekly TSS will be 
considered missing if there are less than 4 daily total symptom scores available for that week. A 
window of +/- 3 weeks will be applied for patients with missing TSS at Week 24.   
9.1.3. 
Secondary Endpoints 
The following secondary endpoints will be calculated and summarized for each treatment group: 
• Percent change in TSS at Week 24 compared to baseline 
• Improvement in bone marrow fibrosis by at least 1 grade at Week 24 compared to 
baseline  
• Splenic response at Week 48, defined as a ≥35% reduction from baseline in spleen 
volume as measured by MRI or CT and assessed by central radiology read, at 
Week 48 
• TSS response at Week 48, defined as a ≥50% decrease from baseline in TSS  as 
measured by the MFSAF v4.0, at Week 48 
• TSS response at Week 48, defined as the absolute change in TSS as measured by the 
MFSAF v4.0 at Week 48 
• Rate of RBC transfusions, defined as the average number of units of RBC transfusion 
per month (4 weeks), over the first 24 weeks of treatment 
• Conversion from RBC transfusion dependence (≥6 units of RBC transfusion during 
the 12-week baseline period prior to dosing) to independence (no RBC transfusions 
during any 12-week period post baseline) 
• Categorical change of PGIC at Week 24 compared to Baseline 

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• PFS, defined as the time from randomization until documented progression (see 
definition of progression in Section 7.1), or until death from any cause for patients 
without documented progression 
• OS, defined as the time from randomization until death from any cause 
• Proportion of patients with transformation to blast phase (AML) 
• AEs of all grades and SAEs  
• Population PK assessment including determination of exposure metrics and 
secondary parameter (i.e., AUC0-t, tmax, Cmax, T1/2, Vd/F, CL/F) 
• Descriptive assessment of ruxolitinib plasma concentrations in the presence or 
absence of pelabresib 
• Duration of splenic response, defined as the time from onset of splenic response until 
the time at which the patient has a <35% decrease from baseline in spleen volume and 
a >25% increase from nadir, as confirmed by the central review) or death, whichever 
comes first 
• Modified TSS50 response at Week 24 (TSS score without the fatigue sub-domain). 
• Duration of TSS response, defined as the time from onset of TSS50 response until the 
time at which the patient has a <50% reduction in TSS from baseline and an increase 
of ≥25% from nadir 
9.1.4. 
Exploratory Endpoints 
The following exploratory endpoints may be calculated and summarized for each treatment 
group: 
• Percent change in splenic volume at Week 24 
• RBC transfusion dependence, defined as ≥ 6 units of RBC transfusion during the 
prior 12 weeks, at Week 24 
• Hemoglobin response, defined as a ≥ 1.5 g/dL increase in hemoglobin from baseline 
in the absence of transfusion during the previous 12 weeks 
• 
  
 
 
 
 
• Post-treatment changes from baseline in circulating concentrations of cytokines 

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• Post-treatment changes from baseline in the ratio of mutant to wild type JAK2, 
 
 
• Time to first SVR35 response 
• 
 
 clinical improvement modified from IWG
 response criteria, where 
 
 
 
 
 
9.2. 
Analysis Populations 
The analysis populations for this study are defined in Table 7. 
 

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Table 7: 
Analysis Populations 
Population 
Description 
mITT  
All randomized patients who were administered at least one dose of study 
drug.  This is the population for some sensitivity analysis on efficacy 
endpoints.  All analyses using this population will be based on the treatment 
assigned by the Interactive Response Technology (IRT) system. 
ITT 
All randomized patients.  This is the primary population for all efficacy 
endpoints. All analyses using this population will be based on the treatment 
assigned by the Interactive Response Technology (IRT) system.  
Safety 
A subset of the ITT population that includes all randomized patients who were 
administered at least one dose of study drug.  This population will be used for 
the safety analyses.  All analyses using this population will be based on the 
treatment actually received. 
Per Protocol 
A subset of the ITT population that includes patients who have received 
adequate exposure to on-study therapy and do not have any protocol 
deviations that could confound the interpretation of the primary analyses 
conducted on the ITT population.  All protocol deviations or conditions 
leading to exclusion from the PP population will be specified in the statistical 
analysis plan (SAP).  All analyses using this population will be based on the 
treatment received. 
PK/PD 
All randomized and treated patients who have at least 1 evaluable sample for 
PK or PD analysis. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum).  Categorical variables will be summarized 
showing the number and percentage (n, %) of patients within each classification.  Two-sided 
95% confidence intervals will also be presented as appropriate. 
If Cycle 1 Day 1 (baseline) visit assessment is not available, screening visit value will be used 
for statistical analysis purposes. 
9.3.2. 
Demographic and Baseline Characteristics 
Patient demographics (e.g., age, sex, race, ethnicity) and physical characteristics (e.g., height, 
weight, BMI) will be summarized by treatment group.  Baseline disease characteristics (e.g., MF 
subtype, risk status, mutational profile, ECOG performance score, RBC transfusion status, total 
symptom score, spleen volume) will also be summarized by treatment group. 
9.3.3. 
Efficacy Analyses 
9.3.3.1. 
Analysis of Primary and Key Secondary Endpoints 
The primary analysis will take place after all randomized patients have either completed their 
Week 24 visit or been prematurely discontinued.  By this time, it is expected that at least 50% of 

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the randomized patients will have completed their Week 36 visit.  Until the primary analysis 
takes place, patients, investigators, and the Sponsor will remain blinded to patient allocation to 
study arms, except for those patients who were enrolled into the crossover portion of the study at 
or after Week 24 and therefore had to be unblinded. 
The continuous key secondary efficacy endpoint of this study is defined as absolute change in 
TSS at Week 24 compared to baseline. Descriptive summary statistics including the number of 
patients (n), mean, standard deviation, median, Q1, Q3, minimum, and maximum of TSS values 
at Baseline and Week 24, and the absolute change from baseline at Week 24 will be present.  
An ANCOVA (Analysis of Covariance) model will be used to analyze the absolute change from 
baseline in TSS at Week 24. The dependent variable is change from baseline in TSS at Week 24, 
with treatment group, baseline DIPSS (Intermediate-1 vs. Intermediate-2 vs. High), baseline 
platelet count (100-200 × 109/L vs. > 200 × 109/L) and baseline spleen volume (< 1800 cm3 vs. 
≥ 1800 cm3) as fixed effects and the baseline TSS as a covariate. 
For the binary primary endpoint, the null hypothesis that the probability of a splenic response at 
Week 24 for patients treated with pelabresib + ruxolitinib is equal to the probability for patients 
treated with placebo + ruxolitinib will be tested against the alternative hypothesis that the 
probability of a splenic response at Week 24 for patients treated with pelabresib + ruxolitinib is 
not equal to the probability for patients treated with placebo + ruxolitinib.  Likewise, for the 
binary key secondary endpoint TSS50, the null hypothesis that the probability of a TSS response 
at Week 24 for patients treated with pelabresib + ruxolitinib is equal to the probability for 
patients treated with placebo + ruxolitinib will be tested against the alternative hypothesis that 
the probability of a TSS response at Week 24 for patients treated with pelabresib + ruxolitinib is 
not equal to the probability for patients treated with placebo + ruxolitinib. 
The probability of a splenic response at Week 24 will be estimated by calculating the splenic 
response rate, or the percentage of patients with a splenic response, at Week 24 for each of the 
two treatment groups.  Likewise, the probability of a TSS response at Week 24 will be estimated 
by calculating the TSS response rate, or the percentage of patients with a TSS50 response, at 
Week 24 for each of the two treatment groups.  The response rate between the two treatment 
groups will be compared using a CMH test controlling for baseline DIPSS (Intermediate-1 vs. 
Intermediate-2 vs. High), platelet count (100-200 × 109/L vs. > 200 × 109/L), and spleen volume 
(< 1800 cm3 vs. ≥ 1800 cm3).  Pooling of stratum will be performed in the case of insufficient 
information in any stratum.  Details will be provided in SAP, which will be finalized prior to 
unbinding of data for primary analysis. 
Multiplicity and Type I Error Control 
To ensure family-wise error rate is controlled at 5% (two-sided) the following endpoints will be 
tested hierarchically in the following order: 
1. Primary Endpoint: SVR35 at week 24 using CMH test  
2. Key Secondary Endpoint: Absolute change in TSS at Week 24 compared to 
baseline using ANCOVA model   
3. Key Secondary Endpoint: TSS50 at Week 24 using CMH test 

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If for a given endpoint p-value >0.05 (two-sided) at any stage of the hierarchy, the remaining 
endpoints will not be tested for statistical significance. However, p-values might be reported for 
descriptive purposes.  
Figure 2: Sequential Testing of Pre-Specified Endpoints 
 
 
The main analysis will be performed on ITT population. 
Handling of Missing Data 
For the main analysis of the primary and key secondary endpoints, all ITT patients will be 
included in the calculation and analysis of response rates.  Patients without the Week 24 
assessment will be considered non-responders. 
In addition, the following sensitivity analyses will be conducted to assess the impact of missing 
data: 
• Multiple imputation with SAS PROC MI: missing Week 24 spleen volume/TSS will 
be imputed using a parametric regression model with the assumption of multivariate 
normality and a monotone missing data pattern. If there are patients with a non-
monotone missing data pattern, datasets with only monotone missing data patterns 
will be created first by imputing the intermediate missing values using the Markov 
Chain Monte Carlo method. 
• LOCF: missing Week 24 spleen volume/TSS will be imputed using the last non-
missing value 
Additional details of missing data imputation will be included in the SAP 
9.3.3.2. 
Analysis of Other Efficacy Endpoints 
Details of the analyses of other secondary endpoints and exploratory endpoints will be provided 
in the SAP. 

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9.3.4. 
Safety Analyses 
All safety analyses will be conducted using the Safety Population. 
Safety will be evaluated by incidence of TEAEs and by changes from baseline vital signs, ECGs, 
and clinical laboratory values.  Exposure to study drug and reasons for discontinuation will also 
be summarized. 
Treatment-emergent AEs are those that first occur or worsen in severity after the administration 
of first dose of study drug.  Treatment-emergent AEs will be tabulated according to the 
MedDRA by system organ class and preferred term and will include the following categories: 
• TEAEs 
• TEAEs related to study drug 
• TEAEs of Grade 3 or higher 
• TEAEs related to study drug that are Grade 3 or higher in severity 
• TEAEs resulting in study drug discontinuation 
• Treatment-emergent SAEs 
• Treatment-emergent SAEs related to study drug 
• Treatment-emergent SAEs resulting in study drug discontinuation 
• Treatment-emergent SAEs resulting in death 
The most commonly reported treatment-emergent AEs (i.e., those events reported by ≥10% of all 
patients) will be summarized by MedDRA System Organ Class and Preferred Term. 
Adverse event of interest including, but not limited to, treatment discontinuation syndrome and 
ARDS will be summarized separately.  
Descriptive statistics for the actual values of clinical laboratory parameters and changes from 
baseline in clinical laboratory parameters will be presented over time.  Mean laboratory values 
over time will be plotted for key laboratory parameters. Clinically significant hematologic and 
non-hematologic laboratory abnormalities will be listed and summarized according to the NCI 
CTCAE (version 5.0). 
Descriptive statistics for the actual values and the changes from baseline vital signs, and weight 
over time will be tabulated by scheduled time point. 
All concomitant medications collected from screening through the study period will be classified 
according to the WHO drug dictionary. 
Additional safety analyses may be determined to further define the safety profile of 
pelabresib + ruxolitinib. 
9.3.5. 
PK/PD Analyses 
PK data evaluation will be performed using an integrated population PK approach. PK/PD data 
evaluation will be provided in a separate document. 

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9.4. 
Sample Size Determination  
Assuming a splenic response rate of 62% in the experimental group and 29% in the control 
group, and assuming a TSS response rate of 57% in the experimental group and 42.2% in the 
control group (Mascarenhas et al., 2019; Mesa et al., 2017), if the sequential testing of the 
primary (splenic response) and key secondary (TSS response) endpoints is conducted at a 
2-sided significance level of 0.05 at the final analysis, a sample size of approximately 200 
patients in each treatment group (approximately 400 patients in total) will provide > 99% power 
for testing the primary endpoint and 81% power for testing the key secondary endpoint at the 
final analysis, using the 2-group continuity corrected χ² test with a 5% two-sided significance 
level and accounting for 2% non-evaluable patients. This sample size will also provide more than 
90% power to reject the null hypothesis of equal means when mean absolute TSS change from 
baseline difference between two arms is 4 points with a standard deviation for both groups of 12 
using the two-sample t-test with a 5% two-sided significance level. The assumption of absolute 
change difference of 4 points is based on the median percentage change difference observed 
from Mesa et al., 2017 and Mascarenhas et al., 2019.  
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with the ICH GCP and the appropriate regulatory 
requirement(s).  The clinical study can only begin once approval from all required authorities has 
been received. The Investigator will be thoroughly familiar with the appropriate use of the study 
drug as described in the protocol and Investigator’s Brochure. Essential clinical documents will 
be maintained to demonstrate the validity of the study and the integrity of the data collected.  
Master files should be established at the beginning of the study, maintained for the duration of 
the study, and retained according to the appropriate regulations. 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki.  The IRB will review all appropriate study documentation in order to safeguard the 
rights, safety and wellbeing of the patients.  The study will only be conducted at sites where IRB 
approval has been obtained.  The protocol, Investigator’s Brochure, ICF, advertisements (if 
applicable), written information given to the patients (including diary cards), safety updates, 
annual progress reports, and any revisions to these documents will be provided to the IRB by the 
Investigator or the Sponsor, as allowable by local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 

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10.1.3. 
Informed Consent Process 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH GCP and all applicable regulatory requirement(s) and will be subject to approval by 
the Sponsor or its designee. 
Patients who are rescreened or who are crossed over to receive experimental treatment with 
pelabresib (Section 6.6) are required to sign a new ICF. 
10.1.4. 
Data Protection 
In order to maintain patient privacy, all eCRFs, study drug accountability records, study reports 
and communications will identify the patient by the assigned patient number.  The Investigator 
will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the patient’s original medical records for verification of data collected on 
the eCRFs and to audit the data collection process.  The patient’s confidentiality will be 
maintained in accordance with all applicable laws and regulations. 
The Sponsor or its designees will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the eCRFs 
for the patients for which they are responsible. 
eCRFs will be completed for each study patient.  It is the Investigator’s responsibility to ensure 
the accuracy, completeness, clarity, and timeliness of the data reported in the patient’s eCRF.  
Source documentation supporting the eCRF data should indicate the patient’s participation in the 
study and should document the dates and details of study procedures, AEs, other observations, 
and patient status. 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected.  An explanation should be provided for all missing data. 
The audit trail entry will show the user’s identification information, and the date and time of the 
correction. The Investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the 
patients for which he is responsible. 
The Sponsor or its designees will retain the eCRF data and corresponding audit trails. A copy of 
the final archival eCRF in the form of a compact disc or other electronic media will be placed in 
the Investigator’s study file. 
10.1.5. 
Use of Information 
All information regarding pelabresib supplied by or on behalf of the Sponsor to the Investigator 
is privileged and confidential information. The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor. It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study. The information obtained from the clinical trial will be used towards the 
development of pelabresib and potentially other product candidates and may be disclosed to 

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regulatory authority(ies), other Investigators, existing or potential corporate or financing 
partners, or consultants. 
10.1.6. 
Dissemination of Clinical Study Data 
Upon completion of the clinical trial and evaluation of results by the Sponsor, hospital or 
institution and/or Investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement. 
Study information and tabular study results will be available on publicly accessible sites, such as 
the US National Institute of Health’s website http://www.clinicaltrials.gov. 
10.1.7. 
Data Quality Assurance 
The Sponsor or its designated representative will conduct a study site visit to verify the 
qualifications of each Investigator, inspect trial site facilities, and inform the Investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study patient. 
Study data will be entered into an eCRF by site personnel using a secure, validated web-based 
EDC application. The Sponsor will have read-only access to all data upon entry in the EDC 
application. 
All information recorded on the eCRFs for this study must be consistent with the patient’s source 
documentation. During the course of the study, the study monitor will make study site visits to 
review protocol compliance, verify eCRFs against source documentation, assess drug 
accountability (including verification of IRT entries), and ensure that the study is being 
conducted according to pertinent regulatory requirements. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. 
Study monitors will discuss instances of missing or uninterpretable data with the Investigator for 
resolution. Any changes to study data will be made to the eCRF and documented via an 
electronic audit trail associated with the affected eCRF. 
10.1.8. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
10.1.9. 
Study Monitoring 
Monitoring and auditing procedures developed or approved by the Sponsor will be followed, in 
order to comply with GCP guidelines.  On-site and remote review of the eCRFs for completeness 
and clarity, cross-checking with source documents, and clarification of administrative matters 
will be performed. 

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The study will be monitored by the Sponsor or its designee.  Monitoring will be done by personal 
visits from a representative of the Sponsor or its designee (site monitor) who will review the 
eCRFs and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent communications (letter, 
telephone, e-mail, and fax). 
All non-dispensed, dispensed but unused, or expired study drug should be destroyed by sites per 
their own internal destruction procedures.  If a site’s procedures do not allow for destruction, 
unused/expired/damaged study drug should be returned to the supplying depot for subsequent 
destruction. 
10.1.10. 
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at the study site is the responsibility of the Investigator.  The 
Investigator will ensure that the study drug is used only in accordance with this protocol. 
Where allowed, the Investigator may choose to assign some of the drug accountability 
responsibilities to a pharmacist or other appropriate individual.  Drug accountability records 
indicating the drug’s delivery date to the site, inventory at the site, use by each patient, and 
amount returned to the Sponsor (or disposal of the drug, if approved by the Sponsor) will be 
maintained by the clinical site.  These records will adequately document that the patients were 
provided the doses as specified in the protocol and should reconcile all study drug received from 
the Sponsor.  Accountability records will include dates, quantities, batch/serial numbers, 
expiration dates (if applicable), and patient numbers.  The Sponsor or its designee will review 
drug accountability at the site on an ongoing basis during monitoring visits. 
10.1.11. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
Recruitment and enrollment strategies for this study may include recruitment from the 
Investigators’ local practices or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the IRB or IEC. Any other arrangements will 
be described in the study manual. 
The Sponsor may also terminate the study at any time for any reason (eg, SAEs, an unfavorable 
change to risk-benefit ratio, recommendations of the DSMB) at the discretion of the Sponsor. 
The Sponsor or its designee also reserves the right to close study sites. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.  
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 

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• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study drug development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or follow-up. 
10.1.12. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission 
and to comply with the applicable provisions of any clinical trial agreement. This allows the 
Sponsor to protect proprietary information and to provide comments. 
The Sponsor and site will comply with the requirements for publication of study results as 
defined in the clinical trial agreement. In accordance with standard editorial and ethical practice, 
the Sponsor will generally support publication of multicenter studies only in their entirety and 
not as individual site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in the table below will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 5 of the protocol. 
• The results of each test must be entered into the eCRF.  Investigators must document 
their review of each laboratory safety report. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• If a particular laboratory test is not available locally, an equivalent test assessing the 
same parameter may be used instead 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count, RBC count, hemoglobin, hematocrit, RBC indices: MCV (optional), 
MCH, % reticulocytes (optional), WBC count with differential (percentages and/or 
absolute values):  neutrophils, lymphocytes, monocytes, eosinophils, basophils, % 
blasts 
 
Note:  Automated CBC analyzers should be used whenever possible. 

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ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; β-hCG = beta human 
chorionic gonadotropin; CBC = complete blood count; CRP = C-reactive protein; EPO = erythropoietin; HDL = high density lipoprotein; 
INR = International Normalized Ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; LDH = lactate 
dehydrogenase; LDL = low density lipoprotein; PT = prothrombin time; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; SoA = Schedule of Activities; TB = tuberculosis; WBC = white blood cell; 
 
 
Clinical 
chemistry 
Sodium, potassium*, carbon dioxide (bicarbonate), serum glucose, serum 
creatinine, total and direct bilirubin, alkaline phosphatase, AST/SGOT, ALT/SGPT, 
LDH, uric acid, calcium, phosphorus/phosphate, EPO (optional – only if feasible at 
local institution), CRP, iron**, total iron binding capacity (TIBC)**, ferritin**, 
transferrin**, transferrin saturation**, HbA1c*** 
 
*  if ≥ Grade 2 plasma potassium increase is observed, consider repeating plasma 
potassium using Li-Heparin or Na-Heparin tubes for confirmation if appropriate 
according to institutional standards of care 
**  Iron, TIBC, ferritin, transferrin, and transferrin saturation are required at 
Screening, after 12 weeks of treatment (Cycle 5 Day 1), after 24 weeks of treatment 
(Cycle 9 Day 1), every 12 weeks (4 cycles) thereafter.  Note that TIBC, serum 
transferrin, and transferrin saturation values are related to each other and can be 
calculated if necessary. If all of the above tests are not available on the testing 
menu, measuring serum iron and transferrin OR serum iron and TIBC OR serum 
iron and transferrin saturation is sufficient. 
***  HbA1C is required at Screening, every 6 months throughout the study, and at 
EOT. 
Coagulation 
parameters 
PT and/or INR, aPTT 
Serum lipids 
Serum lipid panel including total cholesterol, cholesterol LDL, cholesterol HDL, 
triglycerides 
 
Note:  Investigators are advised to follow the local approved ruxolitinib labeling for 
the frequency of lipid monitoring if different from the SoA.  Serum lipid levels can 
be measured in either fasting or non-fasting state. 
Pregnancy test 
Highly sensitive urine/serum β-hCG pregnancy test in female patients of 
childbearing potential 
TB test 
Per local regulations 

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10.3. 
Appendix 3: Procedures for Recording, Evaluating, and Follow-up of AEs 
 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
available documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information in the appropriate 
AE eCRF and/or SAE paper report form. 
• It is not acceptable for the Investigator to send photocopies of the patient’s medical 
records to the Safety CRO in lieu of completion of the appropriate AE eCRF and/or 
SAE paper report form. 
• There may be instances when copies of medical records for certain cases are requested 
by the Safety CRO or the Sponsor or another designee of the Sponsor. In this case, all 
patient identifiers, with the exception of the patient number, will be redacted on the 
copies of the medical records before submission. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study using the NCI CTCAE, Version 5.0.  In the case that an intensity grade is not able to 
be made using NCI CTCAE, the Investigator will make an assessment of severity using the 
WHO grading system (mild, moderate, severe, life threatening and death). 
Assessment of Seriousness 
The Investigator will make an assessment of seriousness for each AE reported during the study 
using the ICH E2A Guidelines on the seriousness assessment of AEs or reactions as noted in 
Section 8.4.1. 
Assessment of Causality 
• For both AEs and SAEs, the Investigator must determine the relationship of the event 
to each study drug.  The causal relationship to study drugs will be determined by the 
Investigator according to best medical judgment, as follows: 
o Definitely related:  This category applies when, after careful medical 
consideration, there is almost no consideration of other causation. 
o Probably related:  There is a clinically plausible time sequence between onset 
of the AE and administration of study drugs.  The AE is unlikely to be caused 
by a concurrent and/or underlying illness, other drugs, or procedures. If 
applicable, the AE follows a clinically consistent resolution pattern upon 
withdrawal of study drugs. 

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o Possibly related:  There is a clinically plausible time sequence between onset of 
the AE and administration of study drugs, but the AE could also have been 
caused by the concurrent/underlying illness, other drugs, or procedures.  
Information regarding withdrawal of study drugs may be lacking or unclear. 
“Possible” should be used when study drug administration is 1 of several 
biologically plausible causes of the AE. 
o Unlikely related:  The AE is most likely due to a non-study drug-related cause.  
However, association with study drugs cannot be completely ruled out. 
o Not related:  Another cause of the AE is most plausible, and a clinically 
plausible temporal sequence is inconsistent with the onset of the AE and 
administration of study drugs and/or a causal relationship is considered 
biologically implausible. 
• The Investigator will also consult the IB in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report. However, it is very important that 
the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data via the SAE paper report form. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Safety 
CRO or the Sponsor to elucidate the nature and/or causality of the AE or SAE as fully 
as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data to the Safety CRO within 24 hours 
of receipt of the information via the SAE paper report form. 
 
 

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10.4. 
Appendix 4: WHO Diagnostic Criteria for MF 
 
WHO criteria for overt PMF** 
Major Criteria 
1. Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen 
fibrosis grades 2 or 3* 
2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid 
neoplasms 
3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another 
clonal marker,† or absence of reactive MF‡ 
Minor Criteria 
Presence of at least 1 of the following, confirmed in 2 consecutive determinations: 
a. Anemia not attributed to a comorbid condition 
b. Leukocytosis ≥11 × 109/L 
c. Palpable splenomegaly 
d. LDH increased to above ULN of institutional reference range 
e. Leukoerythroblastosis 
Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criterion 
Source: (Arber et al., 2016) 
CML = chronic myeloid leukemia; LDH = lactate dehydrogenase; MF = myelofibrosis; ULN = upper limit of normal; WHO = World Health 
Organization. 
* Refer to Table 8 of (Arber et al, 2016) 
** Refer to Table 6 of (Arber et al, 2016) for WHO criteria for prePMF 
† In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (e.g., ASXL1, EXH2, TET2, 
IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease. 
‡ Bone marrow fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell leukemia or other 
lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies. 
For classification criteria for PPV-MF and PET-MF refer to (Barosi et al, 2008) 
 
 

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10.5. 
Appendix 5: DIPSS 
The DIPSS score is calculated based on the following 5 variables: 
a. 
Age >65: 1 point 
b. 
Leukocyte count >25 × 109/L: 1 point 
c. 
Hemoglobin <10 g/dL: 2 points 
d. 
Circulating blast cells ≥1%: 1 point 
e. 
Constitutional symptoms*: 1 point 
* Weight loss >10% of the baseline value in the year preceding MF diagnosis, and/or 
unexplained fever or excessive sweats persisting for more than one month. 
 
The resulting DIPSS score is interpreted as follows: 
• 0 points: low risk 
• 1-2 points: intermediate-1 risk 
• 3-4 points: intermediate-2 risk 
• 5-6 points: high risk 
 
 

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10.6. 
Appendix 6: MFSAF, Version 4 
The response scale for the questions below: 0 (Absent) to 10 (Worst Imaginable).  
• During the past 24 hours how severe was your worst fatigue (weariness, tiredness)? 
• During the past 24 hours how severe was your worst night sweats (or feeling hot or 
flushed)? 
• During the past 24 hours how severe was your worst itching? 
• During the past 24 hours how severe was your worst abdominal discomfort (feeling 
pressure or bloating)? 
• During the past 24 hours how severe was the worst pain under your ribs on the left 
side? 
• During the past 24 hours what was the worst feeling of fullness you had after 
beginning to eat? 
• During the past 24 hours how severe was your worst bone pain (not joint or arthritis 
pain)? 
 
 
 

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10.7. 
Appendix 7: IWG-MRT Response Criteria 
 
Category 
Required criteria  
(for all response categories, benefit must last for ≥12 wk to qualify as a response) 
CR 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤ Grade 1 MF† 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‡ 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 cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH or 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤ Grade 1 MF†, and peripheral blood: 
Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil count ≥1 × 109/L and <UNL; platelet 
count ≥50, but <100 × 109/L and <UNL; <2% immature myeloid cells‡ 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§ 
SD 
Belonging to none of the above listed response categories 
PD 
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 
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 
Source: (Tefferi et al., 2013). 
CI = clinical improvement; CR = complete remission; EMH = extramedullary hematopoiesis; LCM = left costal margin; MF = myelofibrosis; PD 
= progressive disease; PR = partial remission; SD = stable disease; UNL = upper normal limit. 
* Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review process. Cytogenetic and molecular 
responses are not required for CR assignment. 
† 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. 
‡ Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood cells. In splenectomized 
patients, <5% immature myeloid cells is allowed. 
§ 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 ANC of ≥0.5 × 109/L. 
 

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10.8. 
Appendix 8: Strong CYP3A4 Inducers or Inhibitors 
The following lists were compiled from these resources and is not considered an all-inclusive 
list:  
• 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers. See: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/dr
uginteractionslabeling/ucm093664.htm. 
• 
Indiana University Department of Medicine Clinical Pharmacology Drug 
Interaction Tables. See: http://medicine.iupui.edu/CLINPHARM/DDIS 
• 
Bloomer J, Derimanov G, Dumont E et al. Optimizing the in vitro and clinical 
assessment of drug interaction risk by understanding co-medications in patient 
populations. Expert Opin. Drug Metab. Toxicol. 2013;9(6):737-751. 
 
 

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Strong CYP3A4 Inhibitors 
Strong CYP3A4 Inducers 
amprenavir 
carbamazepine 
atazanavir 
efavirenz 
boceprevir 
enzalutamide 
clarithromycin 
etravirine 
cobicistat 
mitotane 
conivaptan 
phenobarbital 
diltiazem 
phenytoin 
fosamprenavir 
rifabutin 
grapefruit (fruit or juice)a 
rifampin 
idelalisib 
rifapentine 
indinavir 
St. John’s wortb 
itraconazole 
 
ketoconazole 
 
lopinavir 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavir 
 
saquinavir 
 
starfruit (fruit or juice) 
 
suboxone 
 
telaprevir 
 
telithromycin 
 
troleandomycin 
 
voriconazole 
 
a. The effect of grapefruit juices varies widely among brands and is concentration, dose, and preparation dependent. Studies have shown that it 
can be classified as a “strong CYP3A4 inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate 
CYP3A4 inhibitor” when another preparation was used (e.g., low does, single strength). 
b. The effect of St. John’s wort varies widely and is preparation-dependent. 
 

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10.9. 
Appendix 9: Study Conduct in Unforeseen Circumstances 
Summary: 
This appendix may be utilized by clinical trial sites during unforeseen circumstances that would 
result in increased risk associated with completion of the protocol conduct for study patients, 
such as during natural disasters (floods, tornadoes, earthquakes, hurricanes) or acts of people 
(e.g., acts of terrorism, riots, strikes, wars), and pandemics (e.g., COVID-19).  These measures 
may be implemented if allowed by applicable country laws and regulations. These optional 
measures are put in place to preserve the risk-benefit for study participation.  Measures should be 
documented by the site and reported by the Sponsor in the CSR. 
This appendix describes possible adaptations to: 
1. Consent Process 
2. IMP Shipment  
3. Patient Visits 
4. Trial Assessments 
5. Sample Collection 
6. Adverse Event Reporting 
7. Protocol Deviations 
Topic Requiring Adaptation 
Section 
Description 
Consent Process 
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
Original consent to enter the 
study must be performed in 
person at the clinical site.  
10.1.3 Informed Consent If original consent to enter the 
study has been obtained, 
subsequent remote consent is 
allowable for patients unwilling 
or unable to come to study site. 
Alternative consents, in line with 
local/institutional guidelines, 
such as usage of electronic 
signatures, faxing the signed 
consent forms, online 
consenting, oral consenting if 
the consent is obtained through 
audio/video communication 
through different 

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telecommunication applications. 
The specific consent process and 
the patient’s consent should be 
documented in the patient’s 
chart.  The patient should re-sign 
the consent once able to visit the 
clinic. 
Study Drug Shipment  
All safety assessments must be 
carried out at the clinical trial 
site prior to the first treatment 
cycle and study drug being 
dispensed to the patient for the 
first time 
6.1 Study Drugs 
Administered 
6.2 Preparation/ 
Handling/Storage/ 
Accountability 
If patients are unable to pick up 
drug, Sites may ship study drug 
directly to patients per local 
procedures and using the below 
guidelines. Constellation (the 
Sponsor) cannot ship drug 
directly to the patient. The chain 
of custody must be documented 
at each step below: 
• Prior to shipping, confirm 
the patient’s address. Also, 
confirm availability to 
receive drug. 
• Investigator Pharmacy can 
ship directly or may sign out 
to appropriate study team 
members. Whoever signs out 
the drug is requested to 
package and ship the drug 
• Ship the same day or 
overnight (Monday-
Thursday only), signed 
receipt is required, and 
tracking number recorded in 
the appropriate pharmacy 
records/systems, as well as 
provided to the study 
coordinator for filing in the 
patient’s chart for 
reconciliation by the Study 
Monitor. Temperature 
Controlled Device is not 
required. 
• Confirm receipt (email or 
phone) and document the 
reception in the patient 
records. 

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• Invoice the Sponsor for pass-
through costs associated with 
the study drug shipments 
(Privacy rules prevent us 
from using our account for 
shipping as we would get the 
patients’ address on the 
form). Up to 2 cycles of drug 
may be dispensed to patients 
as needed.  
Patient Visits 
Screening and Day 1 of Cycle 1 
must be conducted in person at 
the clinical trial site 
1.3 Schedule of 
Activities 
8 Study Assessments 
and Procedures 
If the investigator believes that 
travel to the study site for a 
study assessment would place 
the study patient at increased 
risk relative to the benefit of the 
in-person assessment, the 
assessment can be conducted 
remotely through telemedicine 
(phone, video call, etc.) by a 
trained clinician on the study 
team. These can be billed as a 
visit while conducting standard 
assessments and to identify 
adverse events and ensure 
continuous medical care and 
oversight for the MANIFEST-2 
trial. Visit changes will be 
considered a Protocol Deviation 
related to the unforeseen 
circumstances, such as 
COVID-19, and should be 
documented by study standard 
procedures.  

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Study Assessments (including 
imaging and laboratory 
assessments) 
 
All safety assessments must be 
carried out at the clinical trial 
site prior to the first treatment 
cycle and study drug being 
dispensed to the patient for the 
first time 
1.3 Schedule of 
Activities 
8 Study Assessments 
and Procedures 
Laboratory assessment can be 
completed locally and sent to the 
study site, taking into 
consideration study drug may 
get sent for more than 1 cycle 
worth, that safety labs must be 
reviewed by an investigator to 
verify if the patient is fit for 
treatment continuation. 
Communication pathway should 
be agreed to with local office, 
including when to expect results, 
prior to completion of the 
assessment. 
• Patient-Reported Outcome 
Assessments: Please 
remember to remind patients 
about the importance of 
ePRO assessments. 
• Imaging assessment and 
protocol-mandate bone 
marrow biopsies should be 
conducted as soon as they 
are considered safe and 
feasible; out of window 
assessments are preferable to 
a missed assessment. Visit 
changes will be considered a 
Protocol Deviation related to 
the unforeseen 
circumstances, such as 
COVID-19, and should be 
documented by study 
standard procedures. 
Performing an out of 
window imaging assessment 
is preferable to missing the 
assessment entirely. 
Sample Collection 
 
In the event that a research 
laboratory is not accepting 
samples, the site should hold the 
samples at the requested 
shipping temperature per the 
Laboratory Manual. 

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AE Reporting  
8.4.2 Time Period and 
Frequency for Collecting 
AE and SAE 
Information 
8.4.5 Regulatory 
Reporting Requirements 
for SAEs 
10.3 Procedures for 
Recording, Evaluation, 
and Follow-Up of AEs 
and SAEs 
If physical visits are reduced or 
postponed, the investigators will 
continue collecting AEs from 
the patient through alternative 
means, e.g., by phone calls or 
telemedicine visits, as 
appropriate. 
Protocol Deviations  
 
Protocol deviations (e.g., out of 
visit windows, etc.) should be 
captured per the usual 
study/institutional requirements.  

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10.10. 
Appendix 10: Abbreviations 
AE 
adverse event 
ALT 
aspartate aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
alanine aminotransferase 
AUC 
area under the plasma concentration-time curve 
BET 
bromodomain and extraterminal 
BETi 
bromodomain and extraterminal inhibitor 
BID 
twice daily 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cmax 
maximal concentration 
CMH 
Cochran-Mantel-Haenszel 
CrCl 
creatinine clearance 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIPSS 
Dynamic International Prognostic Scoring System 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EMH 
extramedullary hematopoiesis 
EOT 
end of treatment 
GCP 
Good Clinical Practice 
HDPE 
high density polyethylene 
HEENT 
head, eyes, ears, nose, and throat 
HIV 
human immunodeficiency virus 
HRQOL 
health-related quality of life 
HSCT 
hematopoietic stem cell transplant 

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IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICSR 
individual case safety report 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IVRS/IWRS 
interactive voice response system/interactive web response system 
IWG-MRT 
International Working Group-Myeloproliferative Neoplasms Research and 
Treatment 
JAK 
Janus kinase 
JAKi 
Janus kinase inhibitor 
LDH 
lactate dehydrogenase 
LOCF 
last observation carried forward 
MDS 
myelodysplastic syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MFSAF 
Myelofibrosis Symptom Assessment Form 
mITT 
modified intent-to-treat 
MPN 
myeloproliferative neoplasms 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NIMP 
Non-investigational medicinal product 
OS 
overall survival 

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PD 
pharmacodynamic 
PET-MF 
post essential thrombocythemia myelofibrosis 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PMF 
primary myelofibrosis 
PO 
per os (by mouth) 
PPV-MF 
post-polycythemia vera myelofibrosis 
QD 
once daily 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoA 
Schedule of Activities 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SVR 
spleen volume response 
T1/2 
half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximal concentration 
TSS 
total symptom score 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 
 

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11. 
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CPI-0610 
pelabresib 
Study CPI 0610-04 Protocol  
Version 6, 04 Oct 2023 
Constellation Pharmaceuticals, 
A MorphoSys Company 
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