Conditions: Myeloproliferative Neoplasm
Keywords: Anemia
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This study assesses the potential of using a TGFβ receptor inhibitor for the treatment of anemic patients with myeloproliferative neoplasms. TGFβ signaling is known to be abnormally high in patients with myeloproliferative neoplasms and it is thought that abnormal TGFβ signals cause many of the problems with blood cell formation in these diseases. The study design allows all patients to receive the study drug, vactosertib. The dose of vactosertib is individualized within a pre-set range based upon its effectiveness and tolerability. A total of up to 37 patients will be treated.

Detailed description:
This is a two-tiered multi arm Phase 2 trial of vactosertib (TEW-7197) for the treatment of anemia in Ph-neg MPNs. Both tiers use a rule-based, accelerated dose escalation scheme to efficiently assess the potential of vactosertib to safely and effectively treat anemic patients with Ph-neg MPNs. The first tier of this trial (Tier 1) is an intra-patient dose finding study in 12 patients that uses a low starting dose of vactosertib for all patients. Treatment dose is escalated according to prospectively-defined rules, and a toxicity and treatment effect algorithm during the period of 16 weeks (4 treatment cycles). If pre-established efficacy and safety endpoints are met, then Tier 1 of the study will be followed by a Tier 2 expansion study with an additional 25 patients for a period of 24 weeks (6 treatment cycles).

Vactosertib will be administered concurrently with the patient's current treatment (if any). Prior to enrollment, patients must be on a stable dose of their current therapy for 3 months prior to entering the study. Supportive care measures including packed red blood cell (PRBC) transfusions for HGB \<7g/dL, or symptomatic anemia, will be permitted. Administration of erythropoiesis stimulating agents (ESAs), however, will not be permitted on the trial (patients recruited would have serum EPO \>125 U/L above which the benefit of ESAs is not supported).

Arms:
arm 1: Vactosertib intra-patient dose finding cohort. arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: Vactosertib intervention 2: Vactosertib intervention 3: Vactosertib intervention 4: Vactosertib intervention 5: Vactosertib
Intervention descriptions: intervention 1: 50 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. intervention 2: 100 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. intervention 3: 150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. intervention 4: 200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs. intervention 5: The lowest dose level of vactosertib for which no DLT was observed in Tier 1 AND The lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 met Criteria for Clinical Benefit. Or, if a single dose level does not fulfil both Criterion 1 and Criterion 2, the starting dose level for Tier 2 will lowest dose from Tier 1 for which no DLT was identified.

Protocol document:
Prot_SAP_000.pdf: 
Title: A two-tiered, phase II, rule-based, intra-patient dose escalation study to investigate 
safety and feasibility of vactosertib (TEW-7197) as monotherapy or in combination with 
ruxolitinib for the treatment of anemic patients with Philadelphia chromosome-negative 
Myeloproliferative Neoplasms (Ph-neg MPNs) 
 
NCT # NCT04103645    
 
Document Date: 09Apr2024 


Protocol # 19-06020285 
Version Date 09Apr2024 
 
 
Page # i 
 
TITLE:  A two-tiered, phase II, rule-based, intra-patient dose escalation study to investigate 
safety and feasibility of vactosertib (TEW-7197) as monotherapy or in combination with 
ruxolitinib for the treatment of anemic patients with Philadelphia chromosome-negative 
Myeloproliferative Neoplasms (Ph-neg MPNs) 
 
 
IRB Protocol #: 19-06020285 
IND/IDE #: 145051 
Version Date: 09Apr2024 
Funding Source(s):  Medpacto, Inc. 
 
Principal Investigator: 
 
Joseph M. Scandura 
525 East 68th street, Box 113, New York, NY, 10021 
Telephone +1 646-962-2700 
Fax +1 646-962-0115 
jms2003@med.cornell.edu 
 
 
 
 
Statistician: 
 
 
Paul Christos 
 
Pac2001@med.cornell.edu 
 
 
 
 
 
 


Protocol # 19-06020285 
Version Date 09Apr2024 
 
 
Page # ii 
 
Table of Contents 
STATEMENT OF COMPLIANCE .............................................................................................. VII 
CONFIDENTIALITY STATEMENT ............................................................................................ VII 
LIST OF ABBREVIATIONS ..................................................................................................... VIII 
1. PROTOCOL SUMMARY ....................................................................................................... 1 
1.1 
Schema ...................................................................................................................... 3 
1.2.1  ............................................................................................................. Primary Objectives
 ........................................................................................................................................ 4 
1.2.2  ......................................................................................................... Secondary Objectives
 ........................................................................................................................................ 5 
1.2.3  ....................................................................................................... Exploratory Objectives
 ........................................................................................................................................ 5 
2. BACKGROUND ................................................................................................................... 5 
2.1 
Disease ...................................................................................................................... 5 
2.2 
Investigational Agent/Device ..................................................................................... 5 
2.2.1. .......................................................................................... Pharmacology and Toxicology
 ........................................................................................................................................ 5 
2.2.2. ...................................................................................................... Drug-Drug interactions
 ........................................................................................................................................ 8 
2.2.3. .............................................................................................................. Adverse reactions
 ........................................................................................................................................ 9 
2.3. 
Rationale ................................................................................................................... 9 
2.4 
 Risk/Benefit Assessment ......................................................................................... 12 
2.5 
Correlative Studies Background ................................................................................ 12 
2.5.1. Correlating clinical endpoints with SMAD 2/3 phosphorylation. ............................ 12 
2.5.2. ... Correlating clinical endpoints with the VAF of hematopoietic stem, progenitor and 
mature cell subpopulations. ........................................................................................... 12 
3. STUDY DESIGN ................................................................................................................. 13 
3.1 
Overall Design .......................................................................................................... 13 
3.2 
Scientific Rationale for Study Design ........................................................................ 13 
3.3 
Justification for Dose ............................................................................................... 14 
3.4 
End of Study Definition ............................................................................................ 15 
4. SUBJECT SELECTION ......................................................................................................... 15 
4.1 
Study Population ..................................................................................................... 15 
4.2 
Inclusion Criteria ...................................................................................................... 15 
4.3 
Exclusion Criteria ..................................................................................................... 16 
4.4 
Lifestyle Considerations ........................................................................................... 17 


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4.5 
Screen Failures ......................................................................................................... 17 
4.6 
Strategies for Recruitment and Retention ................................................................ 18 
5. REGISTRATION PROCEDURES ........................................................................................... 18 
5.1 
Subject Registration ................................................................................................. 18 
6. STUDY PROCEDURES ........................................................................................................ 18 
6.1 
Schedule of Assessments ......................................................................................... 18 
Table 1a. Tier 1 schedule of trial events 6.1.1.................................................................. 18 
6.2. Screening Visit (-21 days before start of treatment) ................................................. 20 
6.2.1. .............................................................................................................. Informed consent
 ...................................................................................................................................... 20 
6.2.2. ............... Once Informed Consent is provided, subjects will complete screening tests:
 ...................................................................................................................................... 20 
6.2.2.1. ................................................................................................. Screening Blood Studies
 ...................................................................................................................................... 20 
6.2.2.2. .................................................................................................................................. EKG
 ...................................................................................................................................... 20 
6.2.2.3. ...................................................................................... Transthoracic Echocardiogram
 ...................................................................................................................................... 20 
6.2.2.4. ........................... Abdominal Sonogram of upper left quadrant to record Spleen size
 ...................................................................................................................................... 20 
6.2.2.5. ............................................................................................. History and Physical Exam
 ...................................................................................................................................... 20 
6.2.2.6. .......................................................................................... Record palpated spleen size
 ...................................................................................................................................... 20 
6.2.2.7. ................................................................................. Record ECOG performance status
 ...................................................................................................................................... 20 
6.2.2.8. ..................................................................... Bone marrow aspirate (BMA) and biopsy
 ...................................................................................................................................... 20 
6.2.2.9. ..... Collection of Research blood and bone marrow specimens (for pSMAD and VAF 
quantification). .............................................................................................................. 20 
6.2.2.10. Recording of Transfusion History for the two months (8 weeks) prior to screening.
 ...................................................................................................................................... 20 
6.3.................................................................................................................... Treatment Phase
 ...................................................................................................................................... 21 
6.3.1. ...........................................................................  Cycle 1, Day 1 Testing and Procedures:
 ...................................................................................................................................... 21 
6.3.2. ................................................................................... Follow-up Testing and Procedures
 ...................................................................................................................................... 21 
6.3.4. ............................................................... Additional Scheduled Studies and Procedures:
 ...................................................................................................................................... 23 


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6.3.5. ................................................................................. End of Tier Testing and Procedures:
 ...................................................................................................................................... 23 
6.3.6. ........................................................................................................ Tier 2 Treatment Plan
 ...................................................................................................................................... 24 
7. STUDY INTERVENTION ..................................................................................................... 25 
7.1 
Study Intervention/Device Description ..................................................................... 25 
7.2 
Availability ............................................................................................................... 26 
7.3 
Acquisition and Accountability ................................................................................. 26 
7.4 
Formulation, Appearance, Packaging, and Labeling .................................................. 26 
7.5 
Product Storage and Stability ................................................................................... 26 
 
 
7.6 
Preparation.............................................................................................................. 27 
7.7 
Dosing and Administration ....................................................................................... 27 
7.7.1..................................................................................... Dosing Delays/Dose Modifications
 .............................................................................................. Error! Bookmark not defined. 
7.8 
General Concomitant Medication and Supportive Care Guidelines ........................... 29 
7.9 
Duration of Therapy and Criteria for Removal from Study ........................................ 29 
7.9.1. Tier 1 duration is 16 weeks (4 treatment cycles) and Tier 2 duration is 24 weeks (6 
treatment cycles). .......................................................................................................... 29 
7.9.2. In the absence of treatment delays due to adverse event(s), treatment may continue 
for 6-10 cycles or until one of the following criteria applies: ........................................... 29 
7.10 Duration of Follow Up ................................................................................................ 29 
7.11 Measures to Minimize Bias: Randomization and Blinding ............................................ 29 
7.12 Study Intervention/Follow-up Compliance .................................................................. 29 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...................................................................................... 30 
8.1 
Discontinuation of Study Intervention ...................................................................... 30 
8.1.1. Tier 1 Stopping Rule: ................................................................................................ 30 
8.1.2. 
Tier 2 Stopping Rule: ............................................................................................. 30 
8.2 
Participant Discontinuation/Withdrawal from the Study .......................................... 31 
8.3 
Lost to Follow Up ..................................................................................................... 31 
9. CORRELATIVE/SPECIAL STUDIES ....................................................................................... 32 
9.1. 
On-target Pharmacodynamic Response Reported by SMAD2/3 Phosphorylation ...... 32 
9.2........ Molecular Response Reported by JAK2V617F, CALR type 1 or type 2, MPLW515L/K 
Driver Mutation Variant Allele Frequency ....................................................................... 32 
10.  MEASUREMENT OF EFFECT ............................................................................................ 32 
10.1. Response Criteria (Criteria for Clinical Benefit) ........................................................... 32 
10.1.1. ................................................................................................... Symptomatic Response
 ...................................................................................................................................... 33 


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10.1.2. .............................................................................................................. Splenic Reponse
 ...................................................................................................................................... 33 
10.1.3. ................................................................................................. Erythropoietic Response
 ...................................................................................................................................... 33 
10.2 
Duration of Response ........................................................................................... 33 
10.3 Progression-Free Survival ........................................................................................... 33 
10.4. 
Other Response Parameters ................................................................................. 33 
10.4.1. Molecular response: measured by change in blood (and/or marrow) allelic ratio of 
MPN driver mutations (JAK2, CALR or MPL). ................................................................... 33 
10.4.2. ..... Histologic response: measured by change in bone marrow biopsy cellularity and 
fibrosis grade. ................................................................................................................ 34 
10.4.3. ...... SMAD2/3 phosphorylation: Measured in peripheral blood and/or bone marrow 
hematopoietic cells. ....................................................................................................... 34 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ...................................................... 34 
11.1 Data Collection ........................................................................................................... 34 
11.1.1 REDCap ................................................................................................................ 34 
11.2 Regulatory Considerations .......................................................................................... 34 
11.2.1 Institutional Review Board/Ethics Committee Approval ....................................... 34 
11.2.2 Ethical Conduct of the Study ................................................................................ 35 
11.2.3 Informed Consent ................................................................................................ 35 
11.2.4 Compliance with Trial Registration and Results Posting Requirements ................. 35 
11.2.5 Record Retention ................................................................................................. 36 
12.1 
Study Design/Endpoints........................................................................................ 36 
12.1.1. Optimal Two-Stage Design, and Criteria to Proceed to Tier 2: .............................. 36 
12.2.2. ......................................................................... Composite response/ Toxicity measure
 ...................................................................................................................................... 37 
12.2 Sample Size/Accrual Rate ........................................................................................... 37 
12.3 Stratification Factors .................................................................................................. 37 
12.4 Analysis of Endpoints ................................................................................................. 37 
12.4.1 ......................................................................................... Analysis of Primary Endpoints
 ...................................................................................................................................... 37 
12.4.2 ..................................................................................... Analysis of Secondary Endpoints
 ...................................................................................................................................... 37 
12.5 Interim Analysis ......................................................................................................... 39 
12.6 Reporting and Exclusions ............................................................................................ 39 
12.6.1 ....................................................................................................... Evaluation of Toxicity
 ...................................................................................................................................... 39 
12.6.2 .................................................................................................... Evaluation of Response
 ...................................................................................................................................... 39 
13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................................ 39 
13.1 Adverse Event Definition ............................................................................................ 40 


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13.1.1 .......................................................... Investigational Agent (Expected Adverse Events)
 ...................................................................................................................................... 40 
Dose Limiting Toxicity. ....................................................................................................... 45 
13.1.2 ................................................ Adverse Event Characteristics and Related Attributions
 ...................................................................................................................................... 45 
13.1.3 ........................................................................................... Recording of Adverse Events
 ...................................................................................................................................... 46 
13.1.4 ........................................................................................... Reporting of AE to WCM IRB
 ...................................................................................................................................... 46 
13.1.5 ......................................................................................... Reporting Events to WCM IRB
 ...................................................................................................................................... 46 
13.1.6 ................................................................................................. Events of Special Interest
 ...................................................................................................................................... 46 
13.1.7 .................................................................................................... Reporting of Pregnancy
 ...................................................................................................................................... 46 
13.2 Definition of SAE ........................................................................................................ 46 
13.2.1 .................................................................................................... Reporting of SAE to IRB
 ...................................................................................................................................... 47 
13.2.2 ................................................................................................... Reporting of SAE to FDA
 ...................................................................................................................................... 47 
13.2.3 ..................................................................................Reporting of SAE to MedPacto Inc.
 ...................................................................................................................................... 47 
13.3 AE/SAE Follow Up ...................................................................................................... 48 
13.4 Time Period and Frequency for Event Assessment and Follow Up ............................... 48 
14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS ....................... 48 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO) 48 
14.1.2 ................................................................................... Unanticipated Problem Reporting
 ...................................................................................................................................... 49 
15. DATA AND SAFETY MONITORING PLAN (DSMP) ............................................................. 49 
REFERENCES ........................................................................................................................ 54 
 
 
 
 
 
 
 
 
 


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Statement of Compliance 
 
The trial will be conducted in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR). The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor, 
funding agency and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the 
conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form.] 
 
 
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards. The contents of this document shall not be disclosed to others without written 
authorization from WCM. 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
AE
Adverse Event
CFR
Code of Federal Regulations
CRF
Case Report Form
CTSC
ddPCR 
Clinical Translational Science Center 
Droplet Digital Polymerase Chain Reaction 
DL
Dose Level
DLT
Dose Limiting Toxicity
DSMB
Data Safety Monitoring Board
DSMP
Data Safety Monitoring Plan
EPO
Erythropoietin
ESA
ET 
Erythropoiesis Stimulating Agent
Essential Thrombocythemia 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
HRBFA
Human Research Billing Analysis Form
HSPC
Hematopoietic Stem and Progenitor Cells
HUD
Humanitarian Use Device 
ICF
Informed Consent Form
IDE
Investigational Device Exemption 
IND
Investigational New Drug
IRB
Institutional Review Board
IWG-MRT
MF 
International Working Group-Myeloproliferative Neoplasms Research
Myelofibrosis 
MFI
Mean Fluorescence Intensity
MPNs
Myeloproliferative Neoplasms
MTD
Maximum Tolerated Dose
NOAEL
No Observed Adverse-Effect-Level
Ph-neg
Philadelphia Chromosome Negative 
PHI
PV 
Protected Health Information
Polycythemia Vera 
PI
Principal Investigator
REDCap
RCM 
Research Electronic Data Capture
Red Cell Mass 
SAE
Serious Adverse Event
SOC
Standard of care
SUSAR
Suspected Unexpected Serious Adverse Reaction 
UAP
Unanticipated Problem
VAF
Variant Allelic Frequency
WB
Whole Blood
WCM
Weill Cornell Medicine
WHO
World Health Organization


Protocol # 19-06020285 
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Page # 1 
 
1. Protocol Summary 
 
Full Title: 
A two-tiered, phase II, rule-based, intra-patient dose escalation study to 
investigate safety and feasibility of vactosertib (TEW-7197 for the treatment of 
anemic patients with Philadelphia chromosome-negative Myeloproliferative 
Neoplasms (Ph-neg MPNs) 
    
Short Title:  
 
TGFR1 inhibition in Ph-neg MPNs  
 
Clinical Phase:  
II 
 
Principal Investigator: Joseph M Scandura, M.D., Ph.D. 
 
Study Description:  
This is a two-tiered single arm Phase 2 trial of vactosertib (TEW-7197) for the 
treatment of anemia in Ph-neg MPNs. Both tiers use a rule-based, accelerated 
dose escalation scheme to efficiently assess the potential of vactosertib to 
safely and effectively treat anemic patients with Ph-neg MPNs.  The first tier of 
this trial (Tier 1) is an intra-patient dose finding study in 12 patients that uses a 
low starting dose of vactosertib for all patients. Treatment dose is escalated 
according to prospectively-defined rules, and a toxicity and treatment effect 
algorithm (Table 3 in section 7) during the period of 16 weeks (4 treatment 
cycles). If pre-established efficacy and safety endpoints are met (section 12.1), 
then Tier 1 of the study will be followed by a Tier 2 expansion study with an 
additional 25 patients for a period of 24 weeks (6 treatment cycles).  
 
 
 
Vactosertib will be administered in combination with stable dose of current 
therapy. Prior to enrollmentpatients must be on a stable dose of their current 
therapy for 3 months prior to entering the study. For patients not receiving 
cytoreductive therapies (e.g., interferon, hydroxyurea, DNA hypomethylating 
agents or other cytotoxic chemotherapy) must be off their most recent for a 
period of at least 14 days or 5 half-lives, whichever is longer. Supportive care 
measures including packed red blood cell (PRBC) transfusions for HGB <7g/dL, or 
symptomatic anemia, will be permitted. Administration of erythropoiesis 
stimulating agents (ESAs), however, will not be permitted on the trial (patients 
recruited would have serum EPO >125 U/L above which the benefit of ESAs is 
not supported)1. 
 
Sample Size: 
Total = 37 subjects (N = 12 for Tier 1, N = 25 for Tier 2) 
 
Enrollment: 
This study will enroll 37 subjects and screen up to 100 subjects.   
  
Study Population: 
Patients of age  18 with anemia due to Ph-neg MPNs 
 
Enrollment Period: 
72 months  
 


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Study Design:  
This is a two-tiered single arm Phase 2 trial of vactosertib (TEW-7197) for the treatment of anemia in Ph-
neg MPNs. Both tiers use a rule-based, accelerated dose escalation scheme to efficiently assess the 
potential of vactosertib to safely and effectively treat anemic patients with Ph-neg MPNs.  The first tier 
of this trial (Tier 1) is an intra-patient dose finding study in 12 patients that uses a low starting dose of 
vactosertib for all patients. Treatment dose is escalated according to prospectively-defined rules, and a 
toxicity and treatment effect algorithm (Table 3 in section 7) during the period of 16 weeks (4 treatment 
cycles). If pre-established efficacy and safety endpoints are met (section 12.1), then Tier 1 of the study 
will be followed by a Tier 2 expansion study with an additional 25 patients for a period of 24 weeks (6 
treatment cycles). 
Study Duration: 
 
24 months (4 months for tier 1, 6 months for tier 2, and follow-up after intervention (2 months for 
patients who come off study and 12 months for patients completing study). 
 
Participant Duration: 
Approximately 18 months 
 
Study Agent: Vactosertib  
 
Intervention Description: 
Vactosertib is given oral twice a day for 5 days followed by 2 days off. The starting DL is 50mg 
BID (see Table 2 in section 6 for DLs). A cycle is defined as 4 weeks of treatment.Primary 
Objective: 
 
 
 
 
To establish a safe and tolerable dose and schedule of vactosertib in Ph-neg MPNs as 
determined by the study dose escalation algorithm (Table 3 in section 7). 
 
To preliminarily assess efficacy of vactosertib in treating anemic patients with Ph-neg MPNs 
as reported by symptomatic, splenic and/or erythropoietic response (section 9.1). 
 
To determine the safety and tolerability of vactosertib administered alone or in combination 
with cytoreductive therapies for MPN (approved and standard of care). 
 
Secondary Objectives:  
 
 
 
To evaluate on target molecular activity of vactosertib in anemic patients with Ph-neg MPNs 
as determined by the following parameters:  
o Molecular response, measured by change in blood (and/or marrow) variant allelic 
frequency (VAF) of MPN driver mutations (JAK2, CALR or MPL). 
o Histologic response, measured by change in bone marrow biopsy cellularity and 
fibrosis grade. 
o SMAD2/3 phosphorylation measured by flow cytometry of peripheral blood and/or 
bone marrow hematopoietic cells and/or by immunohistochemical staining of bone 
marrow biopsy sections. 
 
To identify common toxicities of vactosertib in patients with Ph-neg MPNs. 


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Exploratory Objectives:  
 
 
To assess the stem cell directed effect of vactosertib by quantifying the VAF of MPN driver mutations in 
stem, progenitor and mature cell populations isolated from PB or BM samples before and after 
treatment with vactosertib. 
Endpoints: 
 
 
 
Primary Endpoints: (Safety and Efficacy) 
 
Tier 1 (Safety endpoints):  
o Define the safest, minimally effective starting DL for Tier 2 (section 5.3.5.1). 
o Identify DLTs and, possibly the MTD of vactosertib in patients with MPN 
 
Tier 2 Efficacy endpoints (section 9.1):  
o Erythropoietic response as defined by the IWG-MRT criteria  
o Clinical response in symptoms as defined by IWG criteria. 
o Splenic response as defined by IWG criteria.2,3 
 
Tier 2 Safety endpoints: Identify DLT and, possibly MTD 
 
Secondary Endpoints:  
 
Histologic response defined by any reduction in grade of bone marrow fibrosis by 
histopathologic assessment at 16 weeks.  
 
Molecular response defined by a decrease in VAF of MPN-driver mutations (eg. JAK2, CALR, 
and MPL allelic ratio) in blood and/or bone marrow cells.  
 
Pharmacodynamic Response defined as any of the following:  
o Reduced immunohistochemical staining for SMAD2/3 phosphorylation in bone marrow 
biopsy sections (See Figure 1).  
o Reduced mean fluorescence intensity (MFI) of SMAD2/3 phosphorylation staining in 
peripheral blood and/or bone marrow HSPCs or mature progeny as assessed by flow 
cytometry (See Figure 2).  
 
The incidence of hematologic toxicities, infections, disease progression, thrombosis events, and 
the probability of overall and progression free survival, will be monitored. 
 
1.1 Schema 
Section 6.1, Schedule of Assessments, e.g., Visit 1; Visit 2; etc.    
 
 
 
 
 
 
 
 


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Prior to 
Enrollment 
 
 
 
 
 
 
 
  
 
 
 
D0 (C1D1) 
 
 
 
Visit 2-16 (tier1) 
Visit 2-24 (tier2) 
 
 
 
 
 
 
 
 
Visit X (end of 
tier 1, end of tier2) 
 
 
1.2 Study Objectives 
 
 
 
1.2.1  
Primary Objectives 
 
 
 
To establish a safe and tolerable dose and schedule of vactosertib in Philadelphia 
chromosome negative (Ph-neg) Myeloproliferative Neoplasms (MPNs). 
 
To preliminarily assess efficacy of vactosertib in treating anemic patients with Ph-neg 
MPNs as reported by symptomatic, splenic and/or erythropoietic response. 
 
To determine the safety and tolerability of vactosertib administered alone or in 
combination with available cytoreductive therapies for MPN (approved and standard of 
care). 
Obtain informed consent. Screen potential participants by inclusion and exclusion 
criteria; obtain history, document. 
Perform baseline assessments, provide drug. 
Section 6.1, Schedule of Assessments 
Final Assessment of study endpoints and 
safety 
Section 6.1, Schedule of Assessments
Tier 2 
25 participants 
Tier 1 
12 participants 
Follow-up assessments, safety and efficacy evaluation and dose titration, refer to 
Section 6.1, Schedule of Assessments for assessments and follow up intervals 


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1.2.2  
Secondary Objectives  
 
 
To evaluate the on target molecular activity of vactosertib in anemic patients with Ph-neg 
MPNs. This will be determined by the following parameters:  
o Molecular response, measured by change in blood (and/or marrow) allelic ratio of 
MPN driver mutations (JAK2, CALR or MPL). 
o Histologic response, measured by change in bone marrow biopsy cellularity and 
fibrosis grade. 
o SMAD2/3 phosphorylation measured by flow cytometry of peripheral blood and/or 
bone marrow hematopoietic cells or by immunohistochemical staining of bone 
marrow biopsy sections. 
 
To identify common toxicities of vactosertib in patients with Ph-neg MPNs. 
 
1.2.3  
Exploratory Objectives 
 
 
 
To assess the stem cell directed effect of vactosertib by quantifying the VAF of MPN 
driver mutations in stem, progenitor and mature cell populations isolated from PB or 
BM samples before and after treatment with vactosertib. 
 
2. Background 
 
2.1 Disease 
 
Ph-neg MPNs are clonal hematologic malignancies categorized into the 3 major subtypes of Essential 
Thrombocythemia, Polycythemia Vera, and Primary Myelofibrosis by the WHO criteria. The Ph-neg 
MPNs are phenotypically diverse with very different disease course and overall survival4. However, a 
common issue across the different subtypes particularly during advanced stages is anemia and its 
treatment is currently limited to supportive care.  
 
2.2 Investigational Agent/Device 
 
(from MedPacto Investigation Brochure (IB) section 6: Summary of Data and Guidance for the 
Investigator)5 
 
2.2.1. Pharmacology and Toxicology 
 
Vactosertib (INN name, other names: TEW-7197, EW-7197, EW7197) is a highly selective, potent 
inhibitor of the protein serine/threonine kinase activity of transforming growth factor (TGF)-β 
receptor type 1 (TGFBR1; also known as activin receptor-like kinase 5 [ALK5]). Vactosertib inhibits 
the phosphorylation of the ALK5 substrates SMAD2 and SMAD3, as well as the intracellular 
signaling of TGFβ. 
 


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Nonclinical studies conducted to date include in vitro and in vivo pharmacology studies, and PK 
studies in mice, rats, and dogs. The safety of vactosertib was evaluated in an in vitro human hERG 
assay, in a CNS and respiratory safety study in rats, and in a cardiovascular safety study in 
conscious, telemetry-instrumented Beagle dogs. Vactosertib produced a concentration-
dependent inhibition of hERG-mediated potassium currents from 10 to 100 μM (IC50 = 31.04 μM); 
no inhibition was observed at 1 μM. No treatment-related changes in the safety pharmacology 
studies on the central nervous and respiratory systems tested in rats and dogs were observed 
after oral administration of vactosertib at doses of up to 100 mg/kg. With respect to 
cardiovascular effects of vactosertib in Beagle dogs, a NOAEL of at least 100 mg/kg was 
established for orally administered vactosertib.  
The toxicological profile of vactosertib has been evaluated in a single-dose GLP study in rats, 
repeated-dose non-GLP studies up to 14 days in rats and dogs, repeated-dose GLP studies up to 
28 days in rats and dogs, a 13-week repeated-dose GLP study in rats, and in GLP genotoxicity 
studies.  
Results from the single-dose toxicity study in rats suggested the NOAEL to be 100 mg/kg, the 
highest dose tested. Based on the results from the 4-week repeated-dose toxicity studies, the 
NOAEL was considered to be 20 to 50 mg/kg/day in rats. However, the MTD was considered to be 
less than 100 mg/kg/day when administered orally to dogs for 14 days. Genotoxicity studies did 
not show any potential genetic toxicity concerns. The pharmacokinetics of vactosertib was 
evaluated using plasma concentration data collected from patients with advanced-stage solid 
tumors who were enrolled in a Phase 1 study (NCT02160106; First-in-Human Dose-Escalation 
Study of TEW-7197 Monotherapy in Subjects with Advanced Stage Solid Tumors). The plasma 
concentration-time data for vactosertib  were obtained from patients with advanced-stage solid 
tumors who orally received vactosertib tablets once or twice daily under fasted conditions for a 
28-day treatment cycle (5 day on/ 2 day off regimen). After the first oral administration of 
vactosertib, the maximum plasma concentration (Cmax) of vactosertib was achieved at a median 
time (tmax) ranging from 0.52 to 1.77 hours across all doses studied. Following the attainment of 
the Cmax, the plasma concentrations of vactosertib declined in a multi-exponential manner with 
an average apparent terminal half-life of 1.86 to 5.47 hours across all doses studied. After 
repeated oral administrations once daily for five days, the plasma concentrations appear to reach 
a steady state, as supported by the short apparent terminal half- lives in the range from 0.4 hours 
to 18.1 hours. Following the oral administrations for 5 days, the accumulation of vactosertib was 
negligible with the median accumulation ratio of AUC (RAUC) ranging from 0.75 to 1.16. The AUC 
values of vactosertib demonstrated an increasing trend in proportion to the escalation 
vactosertib.  
The plasma pharmacokinetic parameters for vactosertib in NCT02160106, following the first 
(Cycle 1, Day 1) and multiple (Cycle 1, Day 5) oral administrations are summarized in Table X 
below. 
Table 1: Summary of the plasma pharmacokinetic parameters of vactosertib estimated in 
patients with advanced-stage solid tumors 


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Abbreviations: QD = once daily; BID = twice daily; AUC0‑last = area under the concentration‑time curve from hour 0 to 
the last measurable concentration; BID = twice daily; Cmax = maximum plasma concentration; Cmin = minimum plasma 
concentration over a dosing interval; tmax = time of maximum plasma concentration; t1/2 = apparent terminal 
elimination half‑life; CV = coefficient variation.. 
 
Vactosertib PK analysis was undertaken in a prospective, open label, multicenter, dose escalation 
and dose expansion study in patients with low or intermediate risk myelodysplastic syndrome 
(NCT03074006; Phase 1/2 Study of TEW-7197 Monotherapy in Patients with Low or Intermediate 
Risk Myelodysplastic Syndromes (MDS)). Results are shown in Table 2 below. 
 
Table 2: Summary of the plasma pharmacokinetic parameters of vactosertib estimated in 
patients with myelodysplastic syndromes. 
 
 
a geometric mean (CV%), except Tmax shown as median (minimum-maximum). 


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b Cmax and AUC0-last are expressed as arithmetic mean of 3 subjects (values of 2 subjects except 1003).  T1/2 
is expressed as arithmetic mean of 2 subjects. Tmax is shown as median of 3 subjects (median of 2 subjects 
except 1003). 
 
2.2.2. Drug-Drug interactions 
 
No formal drug interaction trials have been conducted with vactosertib. In nonclinical studies, 
vactosertib was shown to be a substrate for efflux transporters MDR1, BCRP, and MRP1, but not 
MRP2. Vactosertib does not appear to be a substrate for the uptake transporters OCT1, OCT2, 
NTCP, OAT1, OAT3, OATP1B1, OATP1B3, and OATP2B1. In vitro, vactosertib was a strong inducer 
of MDR1 at concentrations as low as 0.1 μM and induced CYP1A2, CYP2B6, CYP3A4, and UGT1A1 
at concentrations as low as 1.0 μM and UGT1A4 at 10 μM. Vactosertib inhibited CYP3A4, CYP2C8, 
and CYP2D6 with IC50 values of 8.9, 21.8, and 17.9 μM, respectively, and UGT1A1 with an IC50 
value of 13.5 μM. Vactosertib also inhibited MDR1 transport (IC50 10 μM) and the uptake 
transporters OCT1, OCT2, OAT1, and OATP1B1 with IC50 values of 4, 5, 17, and 6 μM, respectively. 
In a non-clinical study, sorafenib did not substantially inhibit vactosertib metabolism. However, 
vactosertib inhibited formation of sorafenib metabolites when tested in human liver microsomes. 
CYP3A4 is an enzyme which is inhibited substantially by vactosertib, and CYP3A4-mediated 
sorafenib N-oxidation (M2), hydroxylation (M3) and desmethylation (M4) were substantially 
inhibited by vactosertib with IC50 values of 3.1, 5.4, and 3.6 μM, respectively. The potential for in 
vivo inhibition of human CYP3A4 was evaluated by calculating R-values, which were >1.75 and 
>1.80 with doses of vactosertib 100 mg and 140 mg, respectively. 
 
For CYP450, vactosertib did not show significant inhibition of CYP1A2, 2A6, 2B6, 2C9, or 2C19 
activities in human liver microsomes (IC50 > 50 μM). CYP2C8-mediated rosiglitazone 
hydroxylation and CYP2D6-mediated dextromethorphan O-demethylation were slightly inhibited 
by vactosertib, with IC50 values of 21.8 and 17.9 μM, respectively. Midazolam 1’-hydroxlyation 
and imatinib N-demethylation were moderately inhibited in the presence of vactosertib, with IC50 
values of 13.4 and 8.9 μM, respectively. 
 
Vactosertib appears to display competitive inhibition against midazolam 1’-hydroxylation, 
imatinib N-demethylation, and 17β-estradiol-3-glucuronidation, with estimated Ki values of 2.6, 
1.4, and 8.9 μM in human liver microsomes, respectively. Considering the in vitro results, drug 
interactions may need to be considered when vactosertib is co-administered with CYP3A 
substrates with narrow therapeutic ranges. 
 
Although no formal drug interaction trials have been conducted with vactosertib, the most likely 
interacting drugs are those metabolized by CYP3A, CYP2C8 or CYP2D6. Midazolam, rosiglitazone 
and dextromethorphan should be used with caution in patients taking vactosertib.  
 
Major metabolites of vactosertib (EW-7332, EW-7434, and INT-EW-8) did not substantially inhibit 
the activities of CYPs and UGTs (IC50 > 50 μM) except for marginal inhibition of CYP1A2 by EW-
7332. All three metabolites significantly increased mRNA expressions of CYP2B6, UGT1A1, and 
UGT1A4 in human hepatocytes at higher than 1 μM (> 2-fold increase) to a similar extent. The 
metabolites did not show any inhibitory effects on efflux transporters, P- gp, BCRP, MRP1 or MRP2 
(IC50 > 100 μM). EW-7332 inhibited transport activities of OCT1 and OAT3 with IC50 values of 0.5 


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and 2.0 μM, respectively. EW-7434 only inhibited transport activity of OAT3 (IC50, 1.9 μM). On 
the contrary, the metabolite INT-EW-8 showed strong inhibition of OCT1, OCT2, OAT1 and OAT3 
with IC50 values of 0.4, 1.6, 0.7 and 1.4 μM, respectively. The activities of OATPs were slightly 
inhibited at 100 μM of the metabolites. Unlike the parent vactosertib, the metabolites did not 
affect mRNA expression levels of MDR1, BCRP, and OATP1B1 in human hepatocytes.  
 
2.2.3. Adverse reactions 
 
In the phase 1 study of vactosertib (NCT02160106, MP-001), 29 patients were treated with 
vactosertib once daily in 7 cohorts at the dose range of 30 ~340 mg and 5 patients in 200 mg twice 
daily cohort (Cohort 8) for 5 days with 2 days off. 
 
In the phase 1/2 clinical trial (NCT03074006) for patients with low or intermediate risk 
myelodysplastic syndrome, vactosertib 200 mg BID cohort completed cycle 1 (28 days) without 
dose-limiting toxicity. In the 3 patients enrolled in the third cohort of vactosertib 300 mg BID, no 
patient experienced DLT. The safety and efficacy evaluation of vactosertib 300 mg BID is currently 
underway in MP-VAC-204 (NCT03724851) and GC-01 (NCT03698825) trials. 
 
Vactosertib was safe and well tolerated, and the maximum tolerated dose was not determined. 
The most frequent TRAEs were mainly mild to moderate including fatigue, nausea, anorexia, and 
headache, while Grade 3/4 abdominal pain, ALT/AST elevation, cerebrovascular accident, and 
pulmonary edema were reported. One DLT of stroke was seen at 100 mg only daily (QD) in a 72-
yr-old penile cancer patient who was ex-smoker and history of pulmonary thromboembolism. He 
developed stroke on C1D6 following 5-day 100 mg vactosertib treatment and was hospitalized 
with diagnosis of brain infarction with irregular plaque in both carotid arteries. After standard 
treatment, he recovered on C1D8 with sequelae of difficulty in fine motor movement.Adverse 
events incurred in MP-VAC-105 (Food Effect) clinical phase 1 study and assessed to have causal 
relationship with vactosertib are as follows headache, nausea, diarrhea. Serious adverse event 
assessed to have causal relationship with vactosertib incurred in MP-VAC-105 (Food Effect) clinical 
phase 1 study is presyncope. Finally, no abnormalities in echocardiography or cardiac enzyme 
levels were reported in this study but echocardiography with Doppler and cardiac enzyme levels 
should be performed to monitor cardiac valvulopathy or potential myocardium damage at the 
screening and every 12 weeks and at the end of the treatment. Unexpected serious adverse 
events that have been determined to be related to vactosertib in the ongoing Phase 1b/2a trial 
MP-VAC-203 were one case of interstitial lung disease and one case of lung infiltration. 
Unexpected serious adverse events that have been determined to be related to vactosertib in the 
ongoing Phase 1b/2a trial MP-VAC-204 were one case of asthma and one case of tubulointerstitial 
nephritis. 
 
2.3. Rationale 
 
Anemia and bone marrow fibrosis are prominent features of higher-risk Philadelphia 
chromosome negative myeloproliferative neoplasms (Ph-neg MPNs) and both portend a worse 
prognosis. Current therapies for this population, outside of clinical trials, is supportive and 
directed towards improving symptoms and reducing thrombotic risk.  There is no single 
standard approach to treating these diseases. Supportive measures (e.g., transfusions, 


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erythroid stimulating agents), cytoreductive agents (e.g., hydroxyurea or interferon), ruxolitinib 
for symptomatic disease, and a panoply of other non-FDA approved therapies 
(lenalidomide/prednisone, DNA hypomethylating agents, etc…) are used to temporize 
symptoms or normalize blood counts. Cytoreductive therapies and ruxolitinib typically worsen 
anemia6. Even patients with myelofibrosis (MF) who have good symptom control on ruxolitinib, 
generally need to pursue other therapies within three years due to disease progression7,8 .  In 
transplant ineligible patients, there is no effective therapy for anemia nor any means to reverse 
marrow fibrosis, so management is primarily supportive and includes erythrocyte transfusions 
and erythropoiesis stimulating agents (ESAs) for symptomatic anemia1,9. But ESAs are often 
ineffective in this population and patients frequently become refractory to repeated 
transfusion. This is an area of unmet need where clinical trials are needed to identify new 
treatment approaches. 
 
A promising approach to overcome some of the morbidities associated with advanced MPNs is 
therapeutic targeting of the Transforming Growth Factor beta (TGFβ) pathway. TGFβ, and 
members of the TGFβ superfamily, have been studied as potential regulators of 
erythropoiesis10–13. Specifically, TGFβ induces hematopoietic stem cell (HSC) quiescence, 
prevents progenitor cell proliferation and accelerates terminal erythroid maturation through 
canonical SMAD-dependent signaling pathways 14,15. The Scandura lab has recently found that 
TGFβ signaling suppresses production of early erythroid committed progenitors and that 
blockade of TGFβ signaling can sensitize to erythropoietin. Therefore, inhibition of TGFβ could 
promote regeneration of normal HSCs and proliferation of erythroid progenitors to treat the 
underlying hypoproliferative anemia in advanced MPNs.  
 
Inhibitors of TGFβ pathway have yielded encouraging pre-clinical results in the management of 
anemia due to ineffective erythropoiesis resulting from myelodysplastic syndrome (MDS)16–18 
and Fanconi anemia19. In MDS, a phase II clinical trial of an inhibitor of ALK5 (TGFβ receptor I, 
TGFBR1), Galunisertib, demonstrated hematologic improvement with reduced transfusion 
dependency in 10 of 38 (26%) patients with low to intermediate risk MDS 20. Two new ligand 
traps (luspatercept and sotatercept) have shown promising initial results in anemic patients 
with MDS18 and MPNs (clinicaltrials.gov NCT03194542 & NCT01712308) and luspatercept met 
its primary endpoint of hematologic efficacy in the MEDALIST phase III clinical trial 
(clinicaltrials.gov NCT02631070). 
 
In MF, TGFβ is a potent inducer of fibrosis and several studies have explored its crucial role in 
disease pathogenesis. Indeed, MF megakaryocytes (MKs) release significantly higher levels of 
TGFβ compared to MKs of healthy controls, and genetic ablation or inhibition of TGFβ pathway 
signaling cured important features of these diseases in several murine models 21–26. Aberrant 
TGFβ expression also appears to play a pathogenic role in fibrotic progression of polycythemia 
vera (PV), essential thrombocythemia (ET)27 and other hematologic malignancies28. We have 
found the bone marrow of virtually all patients with MPNs have evidence of abnormal TGFβ 
signaling as reported by nuclear SMAD2/3 phosphorylation (Figure 1).  
 
The rationale for TGFβ inhibition in the treatment of myelofibrosis is based on our hypothesis 
and extensive pre-clinical data that blocking excess TGFβ found in MPN bone marrow will 
release suppression of normal hematopoiesis thereby contributing to improved blood counts 
and reduced MPN mutation variant allele frequency (VAF) 29. Because we have also found in 


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preclinical models that blockade of TGFβ can sensitize the erythropoietic response to ESAs, we 
also anticipate that blockade of TGFβ signaling will improve cytopenias, notably anemia, in 
patients with advanced MPNs. We believe the preferential advantage conferred upon normal 
rather than MPN hematopoietic stem and progenitor cells (HSPCs) is due to refractoriness of 
MPN HSPCs to the cytostatic activity of TGFβ signaling.  As a potent, orally-active inhibitor of 
ALK5, with favorable pharmacokinetics and promising early phase results demonstrating 
feasibility and tolerability in cancer patients, vactosertib is an appealing test agent for treatment 
of anemia and fibrosis in patients with Ph-neg MPNs. 
 
 
 
Figure 1: TGFβ Signaling Is Increased in MPN Bone Marrow: Bone marrow biopsy sections from 
normal (A) and patient with MPN (B) are shown. Immunohistochemsitry for SMAD2/3 
phosphorylation is shown as brown nuclear signal. Megakaryocytes are indicated by Mk.  
 
 
0
- 103
103
104
105
Comp- PE- A :: PSMAD
0
20
40
60
80
100
Normalized To Mode


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Figure 2: TGFβ Signaling Detected by Intracellular Flow Cytometry of Bone Marrow Cells: Histograms of 
intracellular immunofluorescence staining of bone marrow hematopoietic stem cells are shown for 
normal mice (red colors) or mice with TGFβ1 knocked out (blue histograms) or for the fluorescence 
minus one control with no secondary antibody to detect phospho-Smad2/3. These results show the 
utility of intracellular flow cytometry to report TGFβ signaling in well-defined hematopoietic 
subpopulations.   
2.4  Risk/Benefit Assessment  
 
 
Vactosertib is a potent, orally-active inhibitor of ALK5, with favorable pharmacokinetics and safety 
profile (see section 2.2).  The benefit of using vactosertib is based on the promising preclinical data of 
the effectiveness of TGFβ pathway inhibition in the treatment of anemia (see section 2.3). This is also 
evidenced by the efficacy of a different TGFβ pathway inhibitor in the treatment of anemia in 
Myelodysplastic Syndrome (MEDALIST phase III trial, www.clinicaltrials.gov NCT02631070). An 
additional benefit of using vactosertib is the potential for a disease modifying effect by targeting the 
MPN stem cell. This is evidenced by several studies demonstrating that the TGFβ pathway is essential 
in the pathogenesis of MPNs and inhibiting this pathway can treat marrow fibrosis as well (see section 
2.3). Finding agents with stem cell directed activity is critical in the management of MPNs as there are 
currently no curative therapies aside from transplant. Therefore, the many potential benefits of 
vactosertib likely outweigh the few potential risks.  
 
2.5 Correlative Studies Background 
 
2.5.1. Correlating clinical endpoints with SMAD 2/3 phosphorylation. 
TGFβ signals via a heterodimeric receptor pair TGFβR2 and TGFβR1 (ALK5). TGFβ binding to 
TGFβR2 activates TGFβR1 thereby inducing it to phosphorylate the intracellular messenger 
proteins SMAD2 & SMAD3. For these reasons, measuring SMAD2/3 phosphorylation is a 
good biochemical reporter of TGFβR1 activity. Because vactosertib is a TGFβR1 inhibitor, 
measuring SMAD2/3 phosphorylation (pSMAD2/3) is a way to monitor vactosertib activity 
in the body. Flow cytometry is a tool that allows for cell mixtures such as blood to be 
decorated using antibodies to identify different subpopulations of cells within the mixture. 
Flow cytometry can also be used to assess pSMAD2/3 phosphorylation with the signal 
intensity reporting the degree of pSMAD2/3 within each cell (Figure 2). In this way the 
pSMAD2/3 mean fluorescence intensity (MFI) can be used to report the average TGFβR1 
signaling in a subpopulation of cells.  
 
2.5.2 Correlating clinical endpoints with the VAF of hematopoietic stem, progenitor and mature 
cell subpopulations. 
Monitoring whole blood (WB) variant allele frequency (VAF) of the MPN driver mutation is 
routinely done in clinical trials to measure molecular responses. Molecular responses as 
measured by WB VAF have a general correlative trend with hematologic response. However, 
the molecular response does not correlate as well with bone marrow response30. Therefore, 
WB VAF monitoring alone is a suboptimal method for determining the clinical efficacy of the 
investigational drug on a molecular level. This is primarily because WB is predominantly 
granulocytes and other mature hematopoietic cells with a <1% contribution from the stem 


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and progenitor cell compartment. It was found that the VAF at the level of stem and 
progenitor cells varies from that of the mature cells and can differ amongst MPN 
phenotypes31.Since MPNs originate from hematopoietic stem cell, identifying the change in 
VAF in the CD34+ hematopoietic compartments is likely to be informative of a potential 
disease modifying activity of an investigational agent. We hypothesize that molecular 
responses on the level of stem and progenitor cells correlate with bone marrow responses 
and the correlative studies on research blood samples will determine this. The blood will be 
deconvoluted into immunophenotypically defined hematopoietic subpopulations using a 
combination of Ficoll separation, CD34+ immunomagnetic selection, and finally 
fluorescence-activated cell sorting (FACS). The VAF of the sorted populations will be 
determined by digital droplet polymerase chain reaction (ddPCR).  
 
3. Study Design 
 
3.1 Overall Design 
 
• 
This is a two-tiered single arm phase 2 trial of vactosertib. Both tiers use a rule-based, accelerated 
dose titration scheme to efficiently assess the potential of vactosertib to safely and effectively 
treat anemic patients with Ph-neg MPNs.  The two-tier design of this phase II study serves to limit 
exposure of subjects to vactosertib if we observe unexpected toxicity in the treatment of MPN 
patients in tier 1 before proceeding to the larger/ longer tier 2 portion of the study. The rule-
based accelerated dose titration allows quick identification of the minimally effective dose range 
and therefore approximating “real world” clinical practice because it allows individualized dose 
adjustments.   
 
3.2 Scientific Rationale for Study Design 
 
The rationale for TGFβ inhibition in the treatment of myelofibrosis is based on our hypothesis and 
extensive pre-clinical data that blocking excess TGFβ found in MPN bone marrow will release 
suppression of normal hematopoiesis thereby contributing to improved blood counts and 
reduced MPN mutation variant allele frequency (VAF) 29. Because we have also found in preclinical 
models that blockade of TGFβ can sensitize the erythropoietic response to ESAs, we also 
anticipate that blockade of TGFβ signaling will improve cytopenias, notably anemia, in patients 
with advanced MPNs, who often have elevated serum erythropoietin levels. We believe the 
preferential advantage conferred upon normal rather than MPN hematopoietic stem and 
progenitor cells (HSPCs) is due to refractoriness of MPN HSPCs to the cytostatic activity of TGFβ 
signaling.  As a potent, orally-active inhibitor of ALK5, with favorable pharmacokinetics and 
promising early phase results demonstrating feasibility and tolerability in cancer patients, 
vactosertib is an appealing test agent for treatment of anemia and fibrosis in patients with Ph-neg 
MPNs. 
 
Many approved or standard of care therapies for MPNs (e.g., hydroxyurea, JAK2-inhibitors such 
as ruxolitinib) are associated with variable degrees of treatment-induced cytopenias. These 
cytopenias often complicate therapy as caregivers balance the benefits against the cytopenias. 
The rationale for adding vactosertib to available therapy complicated by cytopenias is to improve 
blood counts while also potentially improving stem and progenitor directed activity of therapy. 
 


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3.3 Justification for Dose  
 
Dose selection is based on the toxicology results in rats and early clinical experience in humans, 
since the rat appears to be the most sensitive species in the GLP toxicology studies. The dog 
appears to be less sensitive, tolerating higher doses (once scaled to HED) than the rat. In the non-
GLP study TED-106 (14-day oral dose range in rat), the MTD was set at 80 mg/kg/day which scales 
to a HED of approximately 12.9 mg/kg or approximately 800 mg (based on a 60-kg body weight in 
humans). In the 4-week GLP dose range study in rats with 2-week recovery (TED-107), a 60 
mg/kg/day dose was not associated with any mortality (HED of 9.7 mg/kg or approximately 600 
mg). This dose was associated with macroscopic and/or microscopic changes in the heart (valvular 
fibroplasia) and in the bone (femur and sternum, consisting of growth plate dysplasia and 
metaphyseal hyperostosis). Other test substance-related changes were observed in kidneys, 
lungs, skin, stomach, liver, spleen, female genital system, and clinical chemistry and hematology. 
Most of these findings were reversible or partially reversible at the highest (120 mg/kg/day) dose 
level tested in this study. In a subsequent 4-week GLP toxicology study in rats with 4-week 
recovery (TED-177) which included doses up to 50 mg/kg/day (HED of approximately 8.1 mg/kg 
or 500 mg), there were no mortalities during the terminal or recovery phases of the study.  
 
For the first in human study, a starting dose of 30mg/day vactosertib was selected (based on the 
combined pharmacology and toxicology data and using body surface area scaling) for the Phase 1 
clinical trial MP-001. This dose falls into the pharmacologically active dose range in mouse 
xenograft models and is 1/20 of the Severely Toxic Dose in 10% of the animals (STD10) in rodents. 
The provisional dose escalation for this study includes an initial 100% dose escalation, followed 
by decreasing incremental increases of approximately 67 to 40% in subsequent doses (60, 100, 
140, and 200 mg/day).  
In the phase 1 study of vactosertib (NCT02160106, MP-001), 29 patients were treated with 
vactosertib once daily in 7 cohorts at the dose range of 30 ~340 mg and 5 patients in 200 mg twice 
daily cohort (Cohort 8) for 5 days with 2 days off.   
In the phase 1/2 clinical trial (NCT03074006) for patients with low or intermediate risk 
myelodysplastic syndrome, vactosertib 200 mg BID cohort completed cycle 1 (28 days) without 
dose-limiting toxicity. In Tthe 3 patients enrolled in the third cohort of vactosertib 300 mg BID,  is 
currently under DLT evaluation in this study no patient experienced DLT. The safety and efficacy 
evaluation of vactosertib 300 mg BID is currently underway in MP-VAC-204 (NCT03724851) and 
GC-01 (NCT03698825) trials. 
 
Preliminary data indicate that vactosertib has been well tolerated with mild toxicity observed to 
date.  
In the MP-001 study, Vactosertib was safe and well tolerated, and the maximum tolerated dose 
was not determined. The most frequent TRAEs were mainly mild to moderate including fatigue, 
nausea, anorexia, and headache, while Grade 3/4 abdominal pain, ALT/AST elevation. Serious 
adverse events assessed to have causal relationship with vactosertib incurred in MP-001 phase 1 
clinical study are one case of cerebrovascular accident and one case of respiratory failure. One 
DLT of stroke was seen at 100 mg only daily (QD) in a 72-yr-old penile cancer patient who was ex-
smoker and history of pulmonary thromboembolism. He developed stroke on C1D6 following 5-


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day 100 mg vactosertib treatment and was hospitalized with diagnosis of brain infarction with 
irregular plaque in both carotid arteries. After standard treatment, he recovered on C1D8 with 
sequelae of difficulty in fine motor movement.  
 
Finally, no abnormalities in echocardiography or cardiac enzyme levels were reported in this study 
but echocardiography with Doppler and cardiac enzyme levels should be performed to monitor 
cardiac valvulopathy or potential myocardium damage at the screening and every 12 weeks and 
at the end of the treatment. 
Vactosertib monotherapy in this phase 1 clinical study with 200 mg BID of vactosertib in patients 
with advanced solid cancer showed good tolerability and safety. Vactosertib 300 mg BID as 
monotherapy in patients with MDS is currently being evaluated (NCT03074006), and vactosertib 
100 mg and 200 mg BID in combination with immune check point inhibitors, cytotoxicity 
chemotherapeutic drugs, and target agents are also under evaluation in other sold and 
hematologic malignancies (NCT03698825, NCT03732274, NCT03724851, NCT03143985, 
NCT03666832, NCT03802084).  
For patients receiving vactosertib combinations, the dose of cytoreductive treatments (e.g., 
hydroxyurea, ruxolitinib) is determined by the treating physician according to the package insert 
and clinical judgement and is maintained at a stable dose for at least 3 months prior to 
enrollment. 
 
3.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Assessments 
(SoA), Section 6.1. The end of the study is defined as completion of the last visit or procedure shown 
in the SoA in the trial globally. 
 
4. Subject Selection 
 
4.1 Study Population 
Patients meeting WHO 2016 criteria for the diagnosis of Ph-neg MPN including PV, ET, MF, 
MDS/MPN and MPN-U 32 with anemia and meeting the inclusion criteria, but not the exclusion 
criteria, will be eligible. 
 
4.2 Inclusion Criteria 
 
 
Age ≥ 18 years  
 
Patients meet the WHO 2016 criteria for a Ph-neg MPN (including PV, ET, MF, MDS/MPN, 
MPN-U).  
 
Patients with MF must have DIPSS+ Intermediate or High-risk MF (primary of post-PV/ET)  
 
Patients should be on a stable dose of current cytoreductive therapy for at least 3 months 
prior to C1D1. 
 
Anemia as defined by HGB < 10 g/dL, or transfusion of ≥ 2 packed red blood cell (PRBC) 
unit within the past 4 weeks with HGB ≤8.5g/dL. The anemia, in the investigator’s opinion, 


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must be due to underlying MPN and not due to other causes such as the toxic effects of 
prior cytoreductive chemotherapy. 
 
Ineligible, unsuitable or refractoriness to ESA therapy defined as any of the following: 
o Serum erythropoietin (EPO) >125 U/L4. 
o Proven ESA unsuitability is defined by history of any of the following:  
o Loss of erythroid hematologic improvement while receiving stable or 
increased ESA dose; or 
o ESA-attributed toxicity that, in the treating physician’s opinion, makes ESA 
therapy unsuitable for subject.  
o ESA refractoriness defined by lack of erythroid hematologic improvement to 
ESA:27  
o Less than 1.5 g/dL increase in hemoglobin after at least 6 weeks of 
ESA therapy; or 
o Ongoing transfusion dependence that has not been reduced by > 4U 
over an 8-week period compared to ESA pre-treatment 8 weeks.  
 
ECOG Performance status ≤ 2 
 
Able to swallow tablets 
 
Able to give written informed consent 
 
Willing and able to comply with scheduled visits, treatment plans, tests and procedures. 
 
Acceptable Organ Function as defined by:  
o serum creatinine ≤ 2 mg/dL or > 50 mL/min/1.73m2 by direct measure 
o AST(SGOT)/ALT(SGPT) ≤ 3x institutional upper limit of normal 
o Total bilirubin ≤ 2x institutional upper limit of normal  
Note: Subjects with documented diagnosis of Gilbert’s Syndrome resulting in 
elevated total bilirubin levels will be eligible provided all other eligibility criteria are 
met.  
Note: Subjects with total bilirubin 2-3 mg/dL and direct (conjugated) bilirubin in the 
normal range will be eligible, provided all other eligibility criteria are met.  
 Acceptable Cardiovascular status as defined by:  
o Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤ 
450 ms for males, and ≤ 470 ms for females on screening ECG. 
o Left ventricular ejection fraction (LVEF) greater than institutional lower limit 
of normal as determined by cardiac doppler echocardiogram (Echo) or 
cardiac magnetic resonance imaging (MRI).  
o Cardiac troponin, brain natriuretic peptide (BNP), and creatinine kinase MB 
isoform (CK-MB) levels that are within institutional range of normal 
 
Female subjects of childbearing potential must have a negative serum pregnancy test 
within 7 days of the first administration of study drug. 
 
4.3 Exclusion Criteria  
 
 
 
 
Any other serious medical condition which in the Investigator's opinion would preclude 
safe participation in the study. 
 
Subjects, in the opinion of the Investigator, who are unsuitable to participate in the study. 


Protocol # 19-06020285 
Version Date 09Apr2024 
 
 
Page # 17 
 
 
Known history of difficulty swallowing, malabsorption or other conditions that may 
reduce absorption of the product. 
 
Patients with history of TIA or stroke within the past 12 months are excluded. 
 
Subjects with significant cardiac dysfunction as defined by the following:   
o Myocardial infarction within 6 months prior to study registration;  
o Unstable angina pectoris;  
o New York Heart Association (NYHA) Class III/IV congestive heart failure; 
o Uncontrolled hypertensive urgency or emergency; 
o Cardiac conduction abnormalities (e.g., symptomatic or sustained atrial or 
ventricular arrhythmias, second- or third-degree atrioventricular block, 
complete bundle branch blocks) that, in the investigator’s medical 
judgement, makes them unsuitable for clinical trial.  
o Moderate or severe valvular heart disease, documented by cardiac doppler 
echocardiogram (Echo) or cardiac MRI (CMR), that in the investigator’s 
medical judgement, makes them unsuitable for clinical trial. 
 
Pregnancy or breast-feeding for the entire duration of study participation or in the 30 
days following the last dose of study drug. Due to the potentially teratogenic effects of 
TGFβ inhibition during development, pregnant and nursing subjects may not be enrolled 
and pregnancy must be avoided.  
 
Note: Women of child-bearing potential—defined as sexually active woman who has not 
undergone hysterectomy and who has had menses any time within the preceding 24 
months—must have a negative serum or urine pregnancy test 7 days prior to registration.  
 
Female subjects who are breastfeeding, or intend to breastfeed, during the study or in 
the 30 days following the last dose of study drug are excluded. 
 
Women and men of childbearing potential must either commit to continued abstinence 
from heterosexual intercourse or commit to simultaneous use of two acceptable methods 
of birth control—one highly effective method (e.g., IUD, tubal ligation or vasectomy) of 
patient or partner, and one additional effective method (e.g., latex condom, diaphragm 
or cervical cap) from the time of screening through 90 days following the last dose of 
study drug. Use of oral contraceptives is not allowed. 
 
Current or planned use of any of the following classes of drugs during the study period: 
o Drugs which are exclusively or primarily eliminated by cytochrome P-450 
isozyme 3A4 (CYP)3A4 or by UDP glucuronyltransferase 1A1 (UGT)1A1. 
o Drugs which are substrates for the drug transporter multidrug resistance 
protein 1 (MDR1) and have a narrow therapeutic window; or which are strong 
inhibitors of drug transporter MDR1. 
o Any major surgeries within 28 days of study enrollment. 
 
4.4 Lifestyle Considerations 
 
 
Not applicable 
 
4.5 Screen Failures  
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently assigned to the study intervention or entered in the study. Individuals who do not 


Protocol # 19-06020285 
Version Date 09Apr2024 
 
 
Page # 18 
 
meet the criteria for participation in this trial (screen failure) because of a modifiable factor may 
potentially be rescreened. Rescreened participants should be assigned the same participant number 
as for the initial screening. 
 
4.6 Strategies for Recruitment and Retention 
 
 
 
The study will be listed or otherwise included on government (clinicaltrials.gov), philanthropic 
(MPN-RF, CR&T) and institutional (Richard T Silver MPN Center) websites, Facebook and Twitter 
accounts (as applicable).  
 
 
5. Registration Procedures 
 
5.1 Subject Registration 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure for this 
process. 
 
6. Study Procedures 
 
6.1 Schedule of Assessments 
 
Table 1a. Tier 1 schedule of trial events 6.1.1 
 
 
 
Tier 1 Schedule of 
Assessments 
Screening 
Treatment Tier 1 
End of Tier 1 – PaƟents meeƟng composite response and toxicity endpoint may conƟnue vactoserƟb 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Pre-study 
D-28 to -1 
Wk1a 
Wk2a 
Wk3a 
Wk4a 
Wk5a 
Wk6a 
Wk7a 
Wk8a 
Wk9a 
Wk10a 
Wk11a 
Wk12a 
Wk13a 
Wk14a 
Wk15a 
Wk16a 
Informed Consent 
Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
ExaminaƟonc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MedicaƟons 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity / AE 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Med 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood testsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Troponin, BNP, CK-
MB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
EPO level 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(EKG)e 
X 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 


Protocol # 19-06020285 
Version Date 09Apr2024 
 
 
Page # 19 
 
Echocardiography 
with Dopplerf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Bone Marrow 
Aspirate and Biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Ultrasound (leŌ 
upper quadrant) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Research blood 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Research Bone 
Marrow 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Treatment 
AdministraƟon Form 
and Compliance 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MPN-SAF form 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record HgB level 
and HgB changeg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record RBC 
transfusion history 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Composite response 
and toxicity 
endpoint 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a. Visits are weekly if there is a dose change (escalated or reduced or held for toxicity). Visits are biweekly if dose is maintained. Visits are  
extended to every 4 weeks (once per cycle) as long as dose is maintained for 4 weeks. 
b. Must record baseline comorbidities, pre-existing symptoms 
c. Spleen size should be recorded 
d. Blood tests are: CBC, CMP, UA, Phosphorous, LDH 
e. Electrocardiogram required at screening. Only required at subsequent visits in the event of a dose increase. 
f. Echocardiogram or Cardiac MRI will be done once every 2 cycles (8 weeks or 56 days) 
g. Baseline HgB is defined as median HgB within 28 days of Cycle 1, Day 1 
h. Include erythrocyte transfusion history 8 weeks prior to screening 
 
 
 
 
Tier 2 Schedule of Assessments 
Screening 
Treatment Tier 2 
End of Tier2 p paƟents meeƟng composite response and toxicity endpoints may conƟnue vactoserƟb 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Pre-study 
D-28 to -1 
Wk1a 
Wk2 a 
Wk3 a 
Wk4 a 
Wk5 a 
Wk6 a 
Wk7 a 
Wk8 a 
Wk9 a 
Wk10 a 
Wk11 a 
Wk12 a 
Wk13 a 
Wk14 a 
Wk15 a 
Wk16 a 
Wk17 a 
Wk18 a 
Wk19 a 
Wk20 a 
Wk21 a 
Wk22 a 
Wk23 a 
Wk24  
Informed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical ExaminaƟonc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MedicaƟons 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity / AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Med assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood testsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Troponin, BNP, CK-MB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
EPO level 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (EKG)e 
X 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
e 
Echocardiography with 
Dopplerf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Bone Marrow Aspirate and 
Biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Ultrasound (leŌ upper 
quadrant) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Research blood 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Research Bone Marrow 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Treatment AdministraƟon 
Form and Compliance 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MPN-SAF form 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol # 19-06020285 
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Page # 20 
 
Record HgB level and HgB 
changeg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record RBC transfusion 
history 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Composite response and 
toxicity endpoint assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Patients who have completed Tier 1 would not require repeat assessments if done within 28 days of Tier 2 enrollment 
a. Visits are weekly if there is a dose change (escalated or reduced or held for toxicity). Visits are biweekly if dose is maintained. Visits are extended to every 4 weeks 
(once per cycle) as long as dose is maintained for 4 weeks. 
b. Must record baseline comorbidities, pre-existing symptoms  
c. Spleen size should be recorded 
d. Blood tests are: CBC, CMP, UA, Phosphorous, LDH 
e. Electrocardiogram required at screening. Only required at subsequent visits in the event of a dose increase. 
f. Echocardiogram or Cardiac MRI will be done once every 2 cycles (8 weeks or 56 days) 
g. Baseline HgB is defined as median HgB within 28 days of Cycle 1, Day 1 
h. Include erythrocyte transfusion history 8 weeks prior to screening 
 
6.2. Screening Visit (-21 days before start of treatment) 
 
Potentially eligible patients will be identified by chart review and treating physicians and offered 
an opportunity to provide informed consent.  Screening laboratory, history and physical 
examination will be performed after subjects have provided written informed consent. Eligible 
subjects will be enrolled on study within 21 days of screening and subjects will begin vactosertib 
(DL1) within 28 days of screening. The following procedures will be performed within 28 days of 
starting the first dose of vactosertib (DL1): 
 
6.2.1. Informed consent 
Potentially eligible subjects will be identified by treating physician and written Informed 
Consent Obtained before any study-specific procedures are performed.  
 
6.2.2. Once Informed Consent is provided, subjects will complete screening tests: 
6.2.2.1. Screening Blood Studies 
 
CBC 
 
CMP, Uric Acid, Phosphorus and LDH  
 
Serum erythropoietin (EPO) level 
 
Cardiac troponin, BNP, and CK-MB 
 
Myeloid molecular panel by NGS 
6.2.2.2. EKG 
6.2.2.3. Transthoracic Echocardiogram 
6.2.2.4. Abdominal Sonogram of upper left quadrant to record Spleen size 
6.2.2.5. History and Physical Exam 
6.2.2.6. Record palpated spleen size  
6.2.2.7. Record ECOG performance status 
6.2.2.8. Bone marrow aspirate (BMA) and biopsy 
6.2.2.9. Collection of Research blood (20mL) and bone marrow specimens (for pSMAD and 
VAF quantification). 
6.2.2.10. 
Recording of Transfusion History for the two months (8 weeks) prior to screening. 
 
 
 
 


Protocol # 19-06020285 
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Page # 21 
 
 
 
6.3. 
Treatment Phase 
 
 
 
 
 
6.3.1.  Cycle 1, Day 1 (D0) Testing and Procedures:   
 
6.3.1.1.1. 
6.3.1.1.     Pre-dose evaluation:History and Physical Exam 
6.3.1.1.2. 
Record palpated Spleen size 
6.3.1.1.3. 
Laboratory Testing 
 
CBC 
 
CMP 
 
Uric Acid 
 
Phosphorus 
 
LDH 
6.3.1.1.4. 
Establish and Record Baseline Hemoglobin: Baseline Hemoglobin is defined 
as the median hemoglobin within 28 days of Cycle 1, Day 1 (D0).  
6.3.1.1.5. 
EKG (QTc) in the event of a dose increase 
6.3.1.1.6. 
Complete MPN-SAF-TSS Myeloproliferative symptom assessment form total 
symptom score)33 (Appendix A) 
6.3.1.1.7. 
Record baseline co-morbidities and pre-existing symptoms. 
 
6.3.1.2. Dispense study drug (vactosertib 50 mg tabs, #130) for cycle from research 
pharmacy and deliver to eligible subject during clinic visit.  
6.3.1.3. Starting dose for Tier 1  is DL1. Subject will receive the one dose of vactosertib (DL1) 
under supervision of treating physician or research study nurse.  
6.3.1.4. Research blood sample (20mL) will be collected either with SOC labs (if they are on 
a stable dose of vactosertib) or one hour after vactosertib dose (if dose of 
vactosertib is modified).  
6.3.1.5. Subject will return for Follow-up Testing and Procedures (section 6.3.2) in 7 (± 2) 
days after first dose of vactosertib. 
 
6.3.2. Follow-up Testing and Procedures  
 
The following testing and procedures will be performed at all scheduled follow-up time 
points. This includes all of the following settings:  
 
 7 days (±2) days after Cycle 1, Day 1 (D0); 
 On Day 1 of any subsequent Cycle (N>1); 
 7 days (±2) days after a decision to Escalate dose; 
 7 days (±2) days after a decision to Hold vactosertib,   
 7 days (±2) days after decision to Restart vactosertib following a Hold,  
 14 days (±4) days after an initial decision to Maintain vactosertib dose, and 
 Day 1 of the next cycle of vactosertib after at least two, consecutive ‘Maintain’ dose-
adjustment decisions at the same dose level. 
 


Protocol # 19-06020285 
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Page # 22 
 
6.3.2.1. Pre-dose evaluation: 
 
6.3.2.1.1. 
History and Physical Exam 
6.3.2.1.2. 
Record palpated spleen size 
6.3.2.1.3. 
Laboratory testing 
 
CBC, CMP, Uric Acid, Phosphorus, LDH 
6.3.2.1.4. 
EKG (QTc) in the event of a dose increase 
6.3.2.1.5. 
Complete MPN-SAF-TSS (Myeloproliferative symptom assessment form total 
symptom score)(Appendix A) 
6.3.2.1.6. 
Pill Counts to assess compliance (subjects return all vials at visit for pill 
counts). 
6.3.2.1.7. 
Toxicity assessment (CTCAE v5 criteria) 
6.3.2.1.8. 
Erythropoietic Response assessment (see Table 3 andsection 10.1) 
6.3.2.1.8.1. Record Interval PRBC Transfused Volume 
6.3.2.1.8.2. Record Current Hemoglobin 
6.3.2.1.8.3. Record Hemoglobin change = Current Hemoglobin – Baseline 
Hemoglobin (g/dL) 
6.3.2.1.8.4. If Day 1 of Cycle, serum EPO is measured. 
 
6.3.2.2. Record Dose Adjustment Decision (see Table 3 section 7), the dose adjustment 
decision options are outlined in section 6.3.3 
6.3.2.3. Dose Adjustment Testing and Procedures (section 6.3.2.2) 
6.3.2.4. If Day 1 of Cycle, 
 
Pill Counts to assess compliance (subjects return all vials at visit for pill 
counts). 
 
Dispense study drug (vactosertib 50 mg tabs) for one cycle from research 
pharmacy and deliver to subject during clinic visit. 
 
Research blood sample (20mL) will be collected one hour after vactosertib 
dose (also collected on C1D8).  
 
6.3.3. Dose Adjustment Decision (see Table 3 section 7) 
6.3.3.1. Escalate to next dose level 
 
Subject will receive one dose of vactosertib at escalated dose level under 
supervision of treating physician or research study nurse. 
 
Research blood sample (20mL) will be collected approximately 1hr after 
escalated dose taken. 
 
If dose is at maximum level (DL4), and patient has at least stable disease, then 
patient can remain on study at maximum level (DL4).  
 
If dose is at maximum level (DL4), and patient has progressive disease, then 
patient will be removed from study. 
 
Subject will return for Follow-up Testing and Procedures in 7 (± 2) days from 
start of new dose level. 
 
6.3.3.2. Maintain current dose level 
6.3.3.2.1. 
New Maintain Decision: 
 
Subject will return for Follow-up Testing and Procedures in 14 (± 3) days. 


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Page # 23 
 
6.3.3.2.2. 
Ongoing Maintain Decision:  
 
After at least two, consecutive Maintain dose-adjustment decision at the 
same dose level, subject will return for Follow-up Testing and Procedures no 
later than Day 1 of the next cycle of vactosertib.  
 
6.3.3.3. Hold vactosertib 
 
If last dose received is at minimum dose level (DL0), patient will be removed 
from study. Otherwise: 
6.3.3.3.1. 
New Hold Decision  
 
Subject will return for Follow-up Testing and Procedures in 7 (± 2) days. 
6.3.3.3.2. 
Ongoing Hold Decision 
 
If dose is held > 28 days, subject will be removed from study. 
 
If dose is held < 28 days, subject will return for Follow-up Testing and 
Procedures in 7 (±2) days 
 
6.3.3.4. Restart vactosertib 
 
Vactosertib dose will be reduced to one dose level lower than the last 
dose level received.  
 
If last dose received was at minimum dose level (DL0), patient should 
have already been removed from study. 
 
Subject will return for Follow-up Testing and Procedures in  7 (± 2) days 
from start of new dose level. 
 
Subject will receive one dose of vactosertib at restarted dose level under 
supervision of treating physician or research study nurse. 
 
Research blood sample (20mL) cycle 1 will be collected approximately 1hr 
after dose taken. 
 
6.3.4. Additional Scheduled Studies and Procedures: 
Additional studies will be performed at regular intervals for all Subjects independent of 
the current dose of vactosertib; provided the indicated studies have not already been 
performed within 7 days.  
 
6.3.4.1. Cardiac Evaluation after every three cycles is completed (every 84 ± 7 days): 
 
Transthoracic Echocardiogram 
 
Cardiac troponin, BNP, CK-MB 
6.3.4.2. Serum EPO is measured on Day 1 of each cycle (every 28 ± 3 days). 
6.3.4.3. Subjects will maintain a diary to record adverse events that occur between clinic 
visits (e.g., patient diaries). 
  
6.3.5. End of Tier Testing and Procedures: 
At the end of Cycle 4 (approximately Week 16 ± 7 days), the following procedures will be 
performed for all Subjects.  
6.3.5.1. History and Physical Exam 
 
Record palpated spleen size 
6.3.5.2. Laboratory testing 
 
CBC 


Protocol # 19-06020285 
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Page # 24 
 
 
CMP, Uric Acid, Phosphorus, LDH 
 
Serum EPO level 
 
Cardiac troponin, BNP, CK-MB 
6.3.5.3. Abdominal Sonogram of upper left quadrant to record Spleen size 
6.3.5.4. EKG (QTc) in the event of a dose increase 
6.3.5.5. Complete MPN-SAF-TSS (Myeloproliferative symptom assessment form total 
symptom score)(Appendix A) 
6.3.5.6. Bone marrow aspirate and biopsy to assess response. 
6.3.5.7. Collection of Research Blood and Bone Marrow Specimens  
6.3.5.8. Pill Counts to assess compliance (subjects return all vials at visit). 
6.3.5.9. Toxicity assessment (CTCAE v5 criteria) 
6.3.5.10. Erythropoietic Response assessment (Table 3) 
 
Record Interval PRBC Transfused Volume 
 
Record Current Hemoglobin 
 
Record Current Hemoglobin – Baseline Hemoglobin Change (g/dL) 
 
Record Epo Level 
6.3.5.11. Subjects also follow Follow-up Testing and Procedures.   
 
Patients continue to follow on study until all laboratory and pathology 
results are available for evaluation of criteria for ongoing treatment (see 
Section 6.3.7 Ongoing Treatment for Patients Demonstrating Clinical 
Benefit) 
6.3.5.12. Full Revised IWG-MRT/ELN Response Criteria for MF/PV/ET will be recorded as 
appropriate2,3  
 
Note: After the planned study treatment, subjects meeting the criteria for ongoing 
treatment (see Section 6.3.7 Ongoing Treatment for Patients Demonstrating Clinical Benefit) 
will have the option to continue receiving vactosertib until disease progression or 
unacceptable toxicity. 
 
6.3.6. Tier 2 Treatment Plan 
 
The study will proceed to Tier 2 as long as vactosertib is deemed safe and tolerable 
according to predefined criteria (see Criteria for Decision to Proceed to Tier 2 and 
Statistical Considerations and Justification of Proposed Sample Size sections). The Tier 2 
arm will enroll additional patients to reach a statistically predetermined cohort size that 
can preliminarily assess efficacy of vactosertib, or lack thereof, with sufficient power and 
statistical significance (see Statistical Considerations and Justification of Proposed Sample 
Size section).  
 
6.3.6.1. Screening, enrollment and registration for Tier 2 will be performed as described for 
Tier 1. 


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6.3.6.2. Treatment phase of Tier 2 including clinical follow-up visits and rules for dose 
adjustment and/or removal from study will proceed as for Tier 1 with the possible 
exception of starting dose level.   
6.3.6.3. Starting Dose for Tier 2:  
The starting dose on Tier 2 will be identified as follows: 
 
The lowest dose level of vactosertib for which no DLT was observed in Tier 1 AND 
The lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 
met Criteria for Clinical Benefit. 
 
Or, if a single dose level does not fulfil both Criterion 1 and Criterion 2, the 
starting dose level for Tier 2 will lowest dose from Tier 1 for which no DLT was 
identified.  
6.3.6.4. Each subject will follow Intrapatient Dose Adjustment Rules (Table 3). The same 
schema for dose escalation and monitoring for toxicity outlined in the description 
of the Tier 1 patients will be followed. 
6.3.6.5. Subjects enrolled on Tier 2 will have bone marrow exam at the end of Cycle 4 
(approximately Week 16 ± 7 days). 
6.3.6.6. End of Tier 2 testing and procedures will be performed as per Tier 1 End of cycle 4 
testing and procedures with the exception that it will be performed after 
completion of the 6th cycle of vactosertib. An End of Tier bone marrow exam is not 
required for subjects enrolled on Tier 2 since a scheduled exam is performed at the 
completion of Cycle 4.  
6.3.6.7. After the planned 6 cycles of study treatment, subjects meeting the criteria for 
ongoing treatment (see Section 6.3.7 Ongoing Treatment for Patients 
Demonstrating Clinical Benefit) will have the option to continue receiving 
vactosertib until disease progression or unacceptable toxicity. 
6.3.7. Ongoing Treatment for Patients Demonstrating Clinical Benefit: 
After completion of planned study vactosertib treatment on either Tier, subjects 
meeting one of the following criteria will be provided the option of continuing 
vactosertib for up to 2 years or until such a time that they manifest disease progression 
or unacceptable toxicity: 
 
Subject meets Criteria for Clinical Benefit after completion of planned therapy 
on their study Tier of vactosertib, or  
 
Subject has not experienced a dose limiting toxicity (DLT) from vactosertib and 
has maintained at least stable disease after completion of planned therapy on 
their study Tier as per IWG-MRT/ELN Response Criteria. 
 
7. Study Intervention 
 
7.1 Study Intervention/Device Description   
Vactosertib is an off-white solid, and a crystalline, non-hygroscopic material, with a single 
endothermic event at 143.5ºC. Vactosertib exhibits a high aqueous solubility at low pH range which 
decreases with increasing pH, a behavior consistent with a weak basic molecule (TED-133). General 
information regarding the drug substance is provided below: 
 


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7.2 Availability 
 
Vactosertib is an investigational agent supplied to investigators by MedPacto Inc. 
 
7.3 Acquisition and Accountability  
 
Vactosertib Inventory Records– The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all agents received 
from MedPacto Inc. on a Drug Accountability Record Form (DARF).  
 
7.4 Formulation, Appearance, Packaging, and Labeling  
 
For clinical studies, film-coated tablets containing 10, 20, 50, 100 and 200 mg of vactosertib are 
currently available. The vactosertib film-coated tablets are formulations for oral administration. They 
are plain, white to off-white, round, biconvex tablets containing vactosertib drug substance. 
The vactosertib film-coated tablets contain the following inactive ingredients: lactose monohydrate 
(Fastflo 316), microcrystalline cellulose(Avicel PH 102), crospovidone (Kollidon CL F), povidone 
Kollidon 30, magnesium stearate, and opadry white. The proposed clinical drug product vactosertib 
(10, 20, 50,100 and 200 film-coated tablets) is compressed from 5% w/w (10, 20mg), 10% w/w(50mg), 
40%w/w(100, 200mg) drug loaded common stock wet granulation, and the same manufacturing 
process is used for all film-coated tablets. 
 
7.5 Product Storage and Stability 
 
Vactosertib tablets (10, 20, 50 and 100 mg) are packaged in tightly closed, white, opaque, HDPE 
bottles with a 1-g silica gel desiccant canister. The bottles are heat-induction sealed with a child-
resistant cap. Based on the available laboratory stability data, vactosertib tablets (10, 20, 50, 100 
and 200mg), should be stored at 15°C to 25°C (59°F to 77°F) and protected from light. Recent data 
indicate that 10 mg, 20 mg, and 50 mg vactosertib remain stable up to 36 months, 60 months, and 
30 months, respectively, under all testing conditions with the exception of high-intensity fluorescent 
visible light with a minimum of 200-watt h/m2 UV-A irradiation. 100 mg and 200 mg Vactosertib 
remain stable up to 3 months under the same testing conditions as above. Stability test for a longer 


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time period is underway: 50 mg, 100 mg, and 200 mg vVactosertib up to 60 months, 24 months, and 
24 months, respectively.   
The product should be stored in the bottle provided and used according to the instructions on the 
label. 
7.6 Preparation 
 
N/A 
 
7.7 Dosing and Administration 
 
Vactosertib tablets will be administered orally twice a day in a 5-days on, 2 days off regimen. 
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks 
are described in Section 13.  Appropriate dose modifications for vactosertib are described in Section 
6.   
7.7.1 Dose adjustment rules for Tier 1, C1D1 (D0) and interval study visits 
 
Tier 1 - C1D1 (D0) 
Overview of study visit interval:  
All subjects begin treatment on C1D1 (D0) at DL1 of vactosertib (50mg BID). All subjects return one 
week (7 days ± 2) after C1D1 (D0) and the vactosertib dose is adjusted according to the dose 
adjustment rules defined in Section 7.7.1 Table 3. The study visit interval is weekly (7 days ± 2) any 
time the dose adjustment rule dictates dose escalation or a dose hold. If the dose adjustment rule 
dictates maintaining the current dose, then the visit interval is extended to approximately every 2 
weeks. After at least two, consecutive ‘Maintain’ dose-adjustment decisions at the same dose level, 
then the next visit is extended to no later than Day 1 of the next cycle of vactosertib (approximately 
every 4 weeks). 
Once Tier 1 has enrolled 3 patients, enrollment will be held until each patient has completed at least 
the first cycle of therapy before enrollment is re-opened.  
Study Visit Interval Based Upon Dose Adjustment Decision:  
 
All subjects begin treatment on C1D1 (D0) at DL1 of vactosertib (50mg BID for Tier 1). All subjects 
return one week (7 days ± 2) after C1D1 (D0) and the vactosertib dose is adjusted according to the 
dose adjustment rules defined in Section 7.7.1 Table 3. The study visit interval is weekly (7 days ± 2) 
any time the dose adjustment rule dictates dose escalation or a dose hold. If the dose adjustment 
rule dictates maintaining the current dose, then the visit interval is extended to approximately2 
weeks. After at least two, consecutive Maintain dose-adjustment decisions at the same dose level, 
then the next visit is extended to no later than Day 1 of the next cycle of vactosertib (approximately 
every 4 weeks).   
 


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7.7.2 Dosing Delays/Dose Modifications for vactosertib 
 
 
Clinical Parameter 
Escalate to 
Next Dose 
Level 
Maintain 
Current Dose 
Level 
Hold Dose 
Restart After 
Dose Hold 
Erythropoietic Response
 
Inadequate
 
Adequate
 
 
 
Hemoglobin (HGB) absolute value, change in 
HGB from baseline*, and Erythrocyte 
transfusion 
HGB ≤10 g/dL
AND ≤2 g/dL 
increase from 
baseline HGB 
OR any 
Erythrocyte 
transfusion 
HGB >10 g/dL
OR > 2g/dL 
increase from 
baseline HGB 
AND No 
Erythrocyte 
transfusion 
HGB >12 
g/dL 
HGB<12 
g/dL 
Current Toxicity 
(CTCAE v5) 
≤Grade 2 
 
≤Grade 2
OR 
>Grade 2 
not requiring 
change in 
treatment 
>Grade 2 
Requiring 
Change in  
Treatment 
<Grade 2 
and 
Requiring 
No New 
Change in  
Treatment 
Dose hold Toxicity during Cycle 
Dose Hold Not 
Required 
During Cycle 
Dose Hold Not 
Required 
During Cycle 
 
 
Current Dose 
< Highest 
Dose Level 
≤ Highest 
Dose Level 
 
Most Recent 
Dose >(DL0) 
Dose Levels:
(DL0) 50 mg daily; (DL1) 50 mg bid; (DL2) 100 
mg bid; (DL3) 150 mg bid; (DL4) 200 mg bid. 
Dosing schedule, 5 days on, 2 days off 
 
 
 
 
Rule
All True
All True
Any True
All True
Next Study Visit† 
7±2 days 
1st Maintain§
14±3 days 
2nd or greater 
Maintain D1 
of next cycle 
7±2 days 
7±2 days 
Table 3: Intrapatient Dose Adjustment Rules. 
The parameters shown are used to adjust the vactosertib dose on a continuing basis. The dose is escalated to 
the next level if ALL criteria for escalation are met. The decision to Hold vactosertib is made if ANY hold 
criteria is met at any point during the cycle. Otherwise the dose level is maintained. The criteria to Escalate, 
Maintain or Hold a dose are non-overlapping. Dose decrements by one level will follow any HOLD. * Baseline 
HGB is defined as the median HGB in the 4 weeks prior to D1 of protocol treatment. † Subject will maintain a 
diary of adverse events between study visits.  § Visits are weekly if there is a dose change (Escalate, Hold or 
Restart). Visits are bi-weekly if the decision is to Maintain the current dose. Visits are extended to every 4 
weeks (D1 of each new cycle) after the second or greater, consecutive Maintain decision.  


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7.8 General Concomitant Medication and Supportive Care Guidelines 
1) Transfusions:  
a) Packed red blood cell (PRBC) transfusions for HGB <7g/dL, or symptomatic anemia, are 
permitted.  
b) Platelet transfusions are permitted for bleeding or platelet counts < 10,000/μL. 
 
2) Growth Factors and Antimicrobials:  
a) Administration of ESAs is not be permitted on the trial1. 
b) Administration of GCSF and use of prophylactic antimicrobials for severe neutropenia is 
permitted at the discretion of the investigator.  
 
7.9 Duration of Therapy and Criteria for Removal from Study 
 
7.9.1. Tier 1 duration is 16 weeks (4 treatment cycles) and Tier 2 duration is 24 weeks (6 
treatment cycles).  
7.9.2. In the absence of treatment delays due to adverse event(s), treatment may continue for 
6-10 cycles or until one of the following criteria applies: 
7.9.2.1. Disease progression at the MTD, 
7.9.2.2. Intercurrent illness that prevents further administration of treatment, 
7.9.2.3. Unacceptable adverse events, specifically: 
 Adverse event(s) that necessitate a dose hold for >28 days, 
 Adverse events that occur at DL0 
7.9.2.4. Patient decides to withdraw from the study, or 
7.9.2.5. General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
7.10 Duration of Follow Up 
 
Patients will be followed for 6 months after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event. 
 
 
7.10 
Measures to Minimize Bias: Randomization and Blinding  
 
 
N/A. This study is an open label single arm (non-randomized) study 
 
 
7.12 Study Intervention/Follow-up Compliance 
 
Subject compliance with the dosing schedule will be entered on a drug diary that the subject will 
complete and return to the site for review.  A participant will be considered lost to follow-up if he or 
she fails to return for scheduled visits and is unable to be contacted by the study site staff (see 
section 8.3) 
 


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8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
See section 7.9 
 
8.1.1 
Discontinuation of Study Intervention 
 
8.1.1. Tier 1 Stopping Rule:  
 
The primary objective of Tier 1 is to assess the feasibility of protocol therapy in subjects with 
advanced MPNs as measured by the incidence of dose limiting toxicity (DLT, see Definition of 
Dose Limiting Toxicity section). Toxicities are assessed by CTCAEv5 criteria. Up to a total of 12 
patients will be accrued to Tier 1. Tier 1 will be stopped for safety considerations under the 
following conditions: 
 
Any patient has grade 5 (lethal) DLT occurring within the first 12 weeks of starting 
vactosertib; or  
 
More than two patients experience a dose-limiting toxicity (DLT) at any dose, within 
the first 12 weeks on study. 
 
Trial accrual will be suspended and a DSMB convened if either of these Tier 1 Stopping Rule 
criterion is triggered. If more than two patients have a DLT at the same dose level, then further 
accrual to that dose level and higher dose levels will be suspended. Pending review with DSMB, 
the study may be re-opened with amendment reflecting changes to the permitted dose levels. A 
planned stop to Tier 1 accrual will occur after 12 subjects have received at least one dose of 
vactosertib. At this time, the DSMB will be convened if fewer than 1 of the first 12 patients 
experience clinical benefit.  
 
Protocol therapy will be considered safe if the Tier 1 Stopping Rule is not triggered. The 
following table provides the marginal probability of declaring the intervention unsafe for 
different rates of severe toxicity (as defined by Tier 2 Stopping Rule). This Tier 1 Stopping Rule 
protects against an unexpectedly high rate of severe toxicity. 
 
Tier 1  
 
 
 
 
True Rate of Severe Toxicity 
5% 
10% 
15% 
20% 
30% 
Probability of Declaring Unsafe  
              12%        35% 
56% 
73% 
91% 
 
If the Tier 1 safety boundaries are not crossed, this treatment strategy will be considered safe 
for expansion to Tier 2. Feasibility and toxicity will continue to be monitored in the Tier 2 
portion of the study. A total of 37 patients will be accrued (Tier 1 + Tier 2) and the Tier 2 rule 
stopping rule applies to all subjects (up to 37) enrolled.  
 
8.1.2. Tier 2 Stopping Rule:  
 
 
Any patient has grade 5 (lethal) DLT occurring within the first 12 weeks of starting 
vactosertib; or  


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 
More than five patients experience a dose-limiting toxicity (DLT) at any dose, within 
the first 12 weeks on study.  
 
 
Protocol therapy will be considered safe if the Tier 2 Stopping Rule is not triggered. The 
following table provides the marginal probability of declaring the intervention unsafe for 
different rates of severe toxicity (as defined by Tier 2 Stopping Rule). The Tier 2 Stopping Rule 
protects against an unexpectedly high rate of severe toxicity. 
 
Tier 2  
 
 
 
True Rate of Severe Toxicity 
5% 
10% 
15% 
20% 
30% 
Probability of Declaring Unsafe               3.1%       31% 
67% 
89% 
99% 
 
 
8.2 Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
 
Pregnancy 
 
Significant study intervention non-compliance  
 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
 
Disease progression which requires discontinuation of the study intervention 
 
Participant lost to follow-up after several attempts to contact subject to schedule study visit. 
 
8.3 Lost to Follow Up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits and is 
unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls. These contact 
attempts should be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
 
 
 


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9. Correlative/Special Studies  
 
9.1. On-target Pharmacodynamic Response Reported by SMAD2/3 Phosphorylation 
9.1.1. Collection of Specimen(s): 
9.1.1.1. Blood specimens are collected at the following times: 
9.1.1.1.1. 
Screening and at End of Tier Testing. 
9.1.1.1.2. 
One hour after observed dose any time a new dose level is used (e.g., 
following a dose escalation, dose restart, dose reduction).  
9.1.1.2. Bone marrow Specimens 
9.1.1.2.1. 
Bone marrow aspirate specimens are collected at Screening and at end of 
Cycle 4 (16 weeks ± 7 days). In the event of a dry tap, the requirement for 
the bone marrow aspirate is waived (a biopsy is still required). 
9.1.1.2.2. 
Bone marrow biopsy sections will be obtained at Screening and at end of 
Cycle 4. Sections will be obtained from hematopathology after clinical 
evaluation is complete. Unstained, sections will be cut from the residual 
tissue block. No separate research specimen is required. 
9.1.2. Handling of Specimens(s):  
9.1.2.1. Blood specimens are collected in standard EDTA (purple top) vacutainer tubes. 
9.1.2.2. Bone marrow aspirate specimens will be collected into heparinized syringes and 
transferred to standard heparin (green top) vacutainer tubes. 
9.1.2.3. Bone marrow biopsy sections will be obtained from Weill Cornell Medicine 
hematopathology director Giorgio Inghirami, MD, PhD.  
9.1.3. Shipping of Specimen(s): Specimens will be hand-delivered to the Scandura Lab.  
 
9.2. Molecular Response Reported by JAK2V617F, CALR type 1 or type 2, MPLW515L/K Driver 
Mutation Variant Allele Frequency 
9.2.1. Collection of Specimen(s): 
9.2.1.1. Blood specimens are collected at Screening, at end of Cycle 4 (16 weeks ± 7 days) 
and at End of Tier Test.  
9.2.1.2. Bone marrow aspirate specimens are collected at Screening and at end of Cycle 4.   
9.2.1.3. Bone marrow biopsy sections will be obtained from hematopathology after clinical 
evaluation is complete. Unstained, sections will be cut from the residual tissue 
block. No separate research specimen is required.  
9.2.2. Handling of Specimens(s):  
9.2.2.1. Blood specimens are collected in standard EDTA (purple top) vacutainer tubes. 
9.2.2.2. Bone marrow aspirate specimens will be collected into heparinized syringes and 
transferred to standard heparin (green top) vacutainer tubes. 
9.2.3. Shipping of Specimen(s): Specimens will be hand-delivered to Scandura Lab. 
 
10.  Measurement of Effect 
 
 
10.1. Response Criteria (Criteria for Clinical Benefit) 
The following criteria are used to decide if subject can be offered the opportunity to receive more 
than 4 cycles of vactosertib AND for decision to proceed to the Tier 2 expansion phase after Tier 1. 
These are adapted from the IWG-MRT and ELN consensus reports on response determination in 
patients with MPNs. 


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10.1.1 Symptomatic Response  
 
Defined by a reduction in MPN-SAS total score by ≥ 50% compared to 
pretreatment score. 
10.1.2 Splenic Response 
Defined by: 
 
Non-palpable spleen when baseline spleen size was 5-10 cm below left costal 
margin; 
 
At least 50% reduction in spleen size when baseline spleen is > 10 cm below 
left costal margin 
 
At least 35% reduction in spleen size as assessed by US, CT or MRI. 
Note: A baseline spleen size < 5 cm below left costal margin is not eligible for 
spleen response; 
10.1.3 Erythropoietic Response  
Defined by any of the following: 
 
HGB increase of 1.5g/dL compared to baseline HGB; 
 
Reduction in PRBC transfusion rate to ≤ 50% of pre-treatment transfusion 
rate; or 
 
Reduction in PRBC transfusions by ≥ 4 Units over an 8-week period. 
 
10.2 
Duration of Response  
 
10.2.1. Duration of overall response:   
 
The duration of overall response is measured from the time measurement criteria are met for 
symptomatic, splenic or erythropoietic response (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started) 
 
10.2.2. Duration of stable disease: 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
 
10.3 Progression-Free Survival  
 
PFS is defined as the duration of time from start of treatment to time of progression. 
 
10.4. 
Other Response Parameters 
 
10.4.1. Molecular response: measured by change in blood (and/or marrow) allelic ratio of MPN 
driver mutations (JAK2, CALR or MPL). 


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10.4.2 Histologic response: measured by change in bone marrow biopsy cellularity and fibrosis 
grade. 
10.4.3 SMAD2/3 phosphorylation: Measured in peripheral blood and/or bone marrow 
hematopoietic cells. 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, efficacy, 
and adverse event data for all enrolled subjects.  
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system that is 
fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for the creation of 
customized, secure data management systems that include Web-based data-entry forms, 
reporting tools, and a full array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data manipulation and 
export procedures.  REDCap is maintained on CTSC-owned servers that are backed up nightly and 
support encrypted (SSL-based) connections.  Nationally, the software is developed, enhanced and 
supported through a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the patients, and any other relevant study documentation will be submitted to the 
appropriate Ethics Committee. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the IP is released to the Investigator. 
Any necessary extensions or renewals of IEC/IRB approval must be obtained for changes to the 
study, such as amendments to the protocol, the ICF, or other study documentation. The written 
approval of the IEC/IRB together with the approved ICF must be filed in the study files.  
The Investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit written 
summaries of the study status to the IEC/IRB as required. On completion of the study, the IEC/IRB 
will be notified that the study has ended.  
 
Neither the Investigator nor MedPacto will modify or alter this protocol without the agreement 
of the other. All agreed protocol amendments will be clearly recorded on a protocol amendment 
form and will be signed and dated by the original protocol approving signatories. All protocol 


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amendments will be submitted to the relevant institutional IEC/IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this case, 
the necessary action will be taken first, with the relevant protocol amendment following shortly 
thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead site, Weill 
Cornell Medicine, updated documents will be provided to participating sites. Weill Cornell 
Medicine must approve all consent form changes prior to local IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the ethical 
principles based on the Declaration of Helsinki, GCP, ICH guidelines and the applicable national 
and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable ethics 
committees and investigations will be undertaken by scientifically and medically qualified 
persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-GCP 
and local regulations, as applicable, from each potential subject or each subject’s legally 
authorized representative prior to participating in the research study. Subjects who agree to 
participate will sign the approved informed consent form and will be provided a copy of the signed 
document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided to the 
subject must approved by IRB prior to use. The ICF will adhere to IRB/IEC requirements, applicable 
laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to http://www.clinicaltrials.gov. Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a 
central contact number for further information on appropriate trial locations and trial site contact 
information. 
 


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11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced.  After completion of the study, all documents and 
data relating to the study will be kept in an orderly manner by the Investigator in a secure study 
file.  Essential documents should be retained for 2 years after the final marketing approval in an 
ICH region or for at least 2 years since the discontinuation of clinical development of the IP. In 
addition, all subjects’ medical records and other source documentation will be kept for the 
maximum time permitted by the hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
 
12.1 
Study Design/Endpoints 
 
12.1.1. Optimal Two-Stage Design, and Criteria to Proceed to Tier 2: 
 
A Simon Two-stage Optimum Design was used to minimize the number of subjects exposed 
to vactosertib if it is found to be an unsuitable agent for the treatment of anemic patients 
with Ph-neg MPNs. Further development of vactosertib would be warranted if ≥20% of 
subjects met Criteria for Clinical Benefit (section 10.1) without dose-limiting toxicity (see 
Definition of Dose Limiting Toxicity section). The study will be terminated early if fewer than 
1 subject treated in the first tier (up to 12 subjects) meet these criteria. Using these criteria, 
there is less than a 10% chance of inappropriately accepting (α, type 1 error) vactosertib if 
it is not truly useful. Conversely, there is less than a 10% chance of inappropriately rejecting 
(β, type 2 error) vactosertib if it is actually a useful drug for anemic patients with Ph-neg 
MPNs. 
 
 
The Simon Two-stage Optimum Design is expected to minimize the number of subjects 
exposed to vactosertib if it is found to be an unsuitable agent for the treatment of anemic 
patients with Ph-neg MPNs (see Criteria for Decision to Proceed to Tier 2 section). If 1 or 
more subjects meets the Composite Response & Toxicity Endpoint (Table 5) then the study 
will proceed to Tier 2 and another 25 subjects will be enrolled. After completion of Tier 2, if 
four or more subjects meet the Composite Response & Toxicity Endpoint then vactosertib 
Table 4: Optimal Two Stage Design 
Response Probability Indicating Unacceptably Low vactosertib Activity 
0.05 
Response Probability Indicating Substantial vactosertib Activity 
0.20 
Probability of Accepting Poor Drug 
0.1 
Probability of Rejecting Good Drug 
0.1 
Number of Tier 1 Subjects 
12 
Number of Tier 1 Responders to Advance to Tier 2 
≥1 
Maximal Number of Subjects 
37 
Number of Tier 2 Responders to Advance Development 
≥4 


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will have shown preliminary efficacy and feasibility to justify further evaluation as an agent 
to treat anemic patients with Ph-Neg MPNs.  
 
12.2.2 Composite response/ Toxicity measure 
Responding subjects will have met Criteria for Clinical Benefit (section 9.1) for at least 8 
weeks. This will ensure that a stable vactosertib dosing schedule can be achieved. 
Responding subjects will not experience dose limiting toxicity (see Definition of Dose 
Limiting Toxicity). Only subjects meeting all criteria will be considered responders. 
 
 
12.2 Sample Size/Accrual Rate 
 
Total sample size of the study is 37 patients, 12 for Tier 1 and 25 for Tier 2. The number of potentially 
eligible subjects seen at our institution is on average 10 per month based on an i2b2 database query. 
The projected accrual rate to the study is estimated to be 2 patients per month. 
 
12.3 Stratification Factors  
 
The study is not powered for statistical analysis of subgroups. Relevant factors that will be collected 
include MPN diagnosis, MPN duration and driver mutation, demographic variables such as subject age 
and gender. Monitoring and efficacy determination will be done for the entire population without 
stratification.  
 
 12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 
 
Please see Table 4 and Section 12.1 for the detailed analysis of the Primary Endpoints. 
 
12.4.2 Analysis of Secondary Endpoints 
 
Clinical response to vactosertib will be assessed using the Criteria for Clinical Benefit 
outlined above as a composite endpoint. Patients achieving any of these criterial will be 
considered to have achieved clinical benefit. This endpoint will be used to define a 
preliminary estimate of the potential efficacy of vactosertib in the study population. 
Complete enrollment to both tiers (37 total) will allow us to confidently identify a Clinical 
Benefit response rate of more than 30%. This estimate has a significance of ≤0.1 and a 
power of 0.8 and is based upon a reported clinical improvement rate of ≤10% (almost 
Table 5: Composite Response & Toxicity Endpoint 
Adequate Response 
Meets Criteria for Clinical Benefit 
Stable Response 
Meets Criteria for Clinical Benefit to 
vactosertib for ≥ 8 weeks 
Tolerable 
No Dose Limiting Toxicity Experienced


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entirely due to symptomatic response) in similar patient populations with best available 
therapy34,35.  Reported rates of splenic and/or erythropoietic responses to best available 
therapy are ≤ 3%. The 37 subjects enrolled on this study will allow Splenic Response and 
Erythropoietic Response rates of at least 20% to be individually tested with a power of 
80% and a significance of < 0.1%.  If after complete accrual of 37 subjects, more than 11 
patients meet criteria for Composite Response, or more than 7 patients meet criteria for 
Splenic or Erythropoietic Response, vactosertib will be considered to have sufficient 
efficacy for definitive testing in a randomized study.  
 
The secondary endpoints of erythropoietic (HGB and RBC transfusion), symptomatic, and 
splenic responses will be directly tested as described in the preceding section. While 
limited by the small sample size, additional endpoints will be assessed including molecular 
(MPN driver variant allele frequency), pharmacodynamic (SMAD2/3 phosphorylation in 
bone marrow and/or blood CD34+ hematopoietic stem and progenitor cells), and 
histologic (bone marrow cellularity and fibrosis score) responses. The incidence of 
hematologic toxicities, infections, disease progression, thrombosis events, and the 
probability of overall and progression free survival, will be monitored. Secondary endpoints 
will be reported using descriptive statistics but no formal hypothesis testing will be 
performed.  
Other secondary endpoints will be reported using descriptive statistics but no formal 
hypothesis testing will be performed. The following endpoints will be analyzed: 
 
12.4.2.1 Histologic response defined by any reduction in grade of bone marrow fibrosis by 
histopathologic assessment at 16 weeks.  
12.4.2.2 Molecular response defined by a decrease in allelic ratio of MPN-driver mutations (eg. 
JAK2, CALR, and MPL allelic ratio) in blood and/or bone marrow cells.  
12.4.2.3 Pharmacodynamic Response defined as any of the following:  
 
Reduced immunohistochemical staining for SMAD2/3 phosphorylation 
in bone marrow biopsy sections (See Figure 1).  
 
Reduced mean fluorescence intensity of SMAD2/3 phosphorylation 
staining in peripheral blood hematopoietic stem and progenitor cells 
(HSPCs) or mature progeny as assessed by flow cytometry (See Figure 2).  
 
Reduced mean fluorescence intensity of SMAD2/3 phosphorylation 
staining in bone marrow hematopoietic stem and progenitor cells 
(HSPCs) or mature progeny as assessed by flow cytometry. 
12.4.2.4 ToxicityThe incidence of hematologic toxicities, infections, disease progression, 
thrombosis events, and the probability of overall and progression free survival, will be 
monitored.  


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12.5 Interim Analysis 
 
Reports of toxicity and efficacy will be submitted for DSMB review at the following time points: 
 
completion of Tier1;  
 
completion of Tier2;  
 
any time one of the stopping rules is met. 
Unscheduled Interim Analysis will be performed if more than three patients have a DLT at the same 
dose level or if more than five patients in both tiers, at any dose level, have a DLT. In the former 
situation, further accrual to that dose level and higher dose levels will be suspended. In the latter 
situation, further accrual to the study with be halted. Reports of toxicity and efficacy will be submitted 
for DSMB review in that instance for review and guidance as to whether the dose level can be re-
opened or accrual to the study can proceed and if the study should be amended to permanently close 
the problematic dose levels or closed altogether. 
 
 12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with vactosertib. 
Consultation with the Biostatistics Office will allow for completion of this section. 
 
12.6.2 Evaluation of Response 
 
All patients included in the study will be assessed for response to treatment if they have received 
at least 4 cycles of treatment.  Consultation with the Biostatistics Office will allow for completion 
of this section. 
 
12.6.3 Definition of Safe Minimum Dose 
 
 
The lowest dose level of vactosertib for which no DLT was observed in Tier 1 AND  
 
The lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 
met Criteria for Clinical Benefit. 
Or, if a single dose level does not fulfil both Criterion 1 and Criterion 2, the Safe Minimum Dose 
will be the lowest dose from Tier 1 for which no DLT was identified. 
 
13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The investigator will 
be required to provide appropriate information concerning any findings that suggest significant hazards, 
contraindications, side effects, or precautions pertinent to the safe use of the drug or device under 
investigation.  Safety will be monitored by evaluation of adverse events reported by subjects or observed 


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by investigators or research staff, as well as by other investigations such as clinical laboratory tests, x-rays, 
electrocardiographs, etc. 
 
13.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, and does not imply any judgment about causality. An adverse event can arise with any use of the 
drug (e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose.  
 
 
13.1.1 Investigational Agent (Expected Adverse Events) 
 
Advanced MPNs are associated with significant and potentially life-threatening toxicities. In the 
patient population eligible for study treatment, we expect rare grade 3 or grade 4 drug-related 
toxicities. However, a subset of patients are likely to have pre-existing grade 3 or grade 4 
hematologic and non-hematologic toxicities. Pre-existing toxicities will be carefully recorded 
prior to start of vactosertib. There are no data regarding the vactosertib in patients with 
advanced MPNs.  
 
   Table 6: Treatment emergent AEs (≥5%) from vactosertib monotherapy trials 
 
 
AE terms 
MP-001 
(n=35), n (%) 
MP-VAC-105 
(n=16), n (%) 
MP-MDS-01 
(n=9), n (%) 
Total 
(n=60), n % 
All 
35 (100) 
6 (38) 
7 (78) 
48 (80) 
Headache 
9 (26) 
5 (32) 
1 (12) 
15 (25) 
Nausea 
13 (38) 
1 (7) 
0 (0) 
14 (24) 
Fatigue 
12 (35) 
0 (0) 
1 (12) 
13 (22) 
Decreased appetite 
11 (32) 
0 (0) 
1 (12) 
12 (20) 
Diarrhea 
8 (23) 
1 (7) 
2 (23) 
11 (19) 
Abdominal pain 
7 (20) 
0 (0) 
1 (12) 
8 (14) 
Constipation 
7 (20) 
0 (0) 
1 (12) 
8 (14) 
Anaemia 
5 (15) 
0 (0) 
2 (23) 
7 (12) 
Dyspnoea 
7 (20) 
0 (0) 
0 (0) 
7 (12) 
Vomiting 
6 (18) 
0 (0) 
1 (12) 
7 (12) 
Back pain 
6 (18) 
0 (0) 
0 (0) 
6 (10) 
Muscular weakness 
6 (18) 
0 (0) 
0 (0) 
6 (10) 
Pruritus 
4 (12) 
0 (0) 
1 (12) 
5 (9) 
Pyrexia 
5 (15) 
0 (0) 
0 (0) 
5 (9) 
Arthralgia 
4 (12) 
0 (0) 
0 (0) 
4 (7) 
Aspartate aminotransferase increased 
4 (12) 
0 (0) 
0 (0) 
4 (7) 


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Cough 
3 (9) 
0 (0) 
1 (12) 
4 (7) 
Hyponatraemia 
3 (9) 
0 (0) 
1 (12) 
4 (7) 
Hypophosphataemia 
3 (9) 
0 (0) 
1 (12) 
4 (7) 
Pain 
4 (12) 
0 (0) 
0 (0) 
4 (7) 
Pleural effusion 
4 (12) 
0 (0) 
0 (0) 
4 (7) 
Asthenia 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Blood alkaline phosphatase increased 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Dehydration 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Dermatitis acneiform 
2 (6) 
0 (0) 
1 (12) 
3 (5) 
Dizziness 
2 (6) 
0 (0) 
1 (12) 
3 (5) 
Dyspepsia 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Hypokalaemia 
2 (6) 
0 (0) 
1 (12) 
3 (5) 
Muscle spasms 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Non-cardiac chest pain 
2 (6) 
0 (0) 
1 (12) 
3 (5) 
Oedema peripheral 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Rash maculo-papular 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Respiratory failure 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Rhinitis allergic 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Urinary tract infection 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Weight decreased 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
 
Table 7: Grade 3 or 4 treatment emergent AEs from vactosertib monotherapy trials 
 
AE Terms 
MP-001 (n=35), 
n (%) 
MP-MDS-01 
(n=9), n (%) 
Total 
(n=60), n % 
All 
16 (46) 
6 (67) 
22 (37) 
Respiratory failure 
3 (9) 
0 (0) 
3 (5) 
Abdominal pain 
2 (6) 
0 (0) 
2 (4) 
Anaemia 
0 (0) 
2 (23) 
2 (4) 
Back pain 
2 (6) 
0 (0) 
2 (4) 
Hyponatraemia 
2 (6) 
0 (0) 
2 (4) 
Acidosis 
1 (3) 
0 (0) 
1 (2) 
Alanine aminotransferase increased 
1 (3) 
0 (0) 
1 (2) 
Arthritis 
0 (0) 
1 (12) 
1 (2) 
Aspartate aminotransferase increased 
1 (3) 
0 (0) 
1 (2) 
Asthma 
0 (0) 
1 (12) 
1 (2) 


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Blood bilirubin increased 
1 (3) 
0 (0) 
1 (2) 
Cerebrovascular accident 
1 (3) 
0 (0) 
1 (2) 
Convulsion 
1 (3) 
0 (0) 
1 (2) 
Dehydration 
1 (3) 
0 (0) 
1 (2) 
Dyspnoea 
1 (3) 
0 (0) 
1 (2) 
Gastrointestinal haemorrhage 
1 (3) 
0 (0) 
1 (2) 
Headache 
1 (3) 
0 (0) 
1 (2) 
Hemiparesis 
1 (3) 
0 (0) 
1 (2) 
Hypokalaemia 
1 (3) 
0 (0) 
1 (2) 
Hypophosphataemia 
0 (0) 
1 (12) 
1 (2) 
Nausea 
1 (3) 
0 (0) 
1 (2) 
Pleural effusion 
1 (3) 
0 (0) 
1 (2) 
Pulmonary oedema 
1 (3) 
0 (0) 
1 (2) 
Pyelonephritis 
1 (3) 
0 (0) 
1 (2) 
Sepsis 
1 (3) 
0 (0) 
1 (2) 
Sinus tachycardia 
1 (3) 
0 (0) 
1 (2) 
Small intestinal obstruction 
1 (3) 
0 (0) 
1 (2) 
Stridor 
1 (3) 
0 (0) 
1 (2) 
Tumour pain 
1 (3) 
0 (0) 
1 (2) 
Upper gastrointestinal haemorrhage 
0 (0) 
1 (12) 
1 (2) 
Vomiting 
1 (3) 
0 (0) 
1 (2) 
Weight decreased 
1 (3) 
0 (0) 
1 (2) 
No subjects experienced Grade 3 or 4 AEs in MP-VAC-105 study. And three grade 5 events were reported 
from vactosertib monotherapy trials; disease progression (MP-001), gastric ulcer perforation (MP-001), and 
metastatic ovarian cancer (MP-001), none of which were causally related with vactosertib. 
 
Listed below are the adverse events that were deemed related to, or from which one could not exclude 
the possibility of its relationship with vactosertib, as determined by MedPacto. For the purpose of 
determining regulatory authority reportability, when assessing expectedness, listed below are the 
adverse events that are considered to be expected (Table X).  
Table 8 
List of adverse events of Vactosertib that can be considered expected 
System Organ Class (MedDRA SOC)
Adverse Event (MedDRA PT)
Gastrointestinal disorders 
Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting


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Immune system disorders 1) 
Asthma
Interstitial lung disease
Renal and urinary disorder
Tubulointerstitial nephritis
Respiratory, thoracic and mediastinal disorders 
Lung infiltration 2) – not related, as a 
descriptive term rather than diagnostic. 
However, it can be considered as related 
when there is underlying immune 
mechanism involved. 
General disorders and administration site conditions
Fatigue
Investigations 
Alanine aminotransferase increased
Aspartate aminotransferase increased
Nervous system disorders
Headache
Skin and subcutaneous tissue disorders 
Rash 3)
Pruritus
1) 
Considered related, in line of worsening of immune-related AE when combined with immune checkpoint inhibitor 
2) 
Considered not related, as a descriptive term rather than diagnostic. However, it can be considered as related when there is underly
ing immune mechanism involved. 
3) 
Even though the preferred term of reported AE is not exactly ‘rash’, if the event is not significantly different from ‘rash’ in clinical 
perspective, it could be assessed as ‘expected’ 
But among the adverse events listed in this table, those with the severity of 4 or 5 are 
considered unexpected. 
 
   Table 9: Serious AEs from vactosertib monotherapy trials 
 
 
AE Terms 
MP-001 
(n=35), n (%) 
MP-VAC-105 
(n=16), n (%) 
MP-MDS-01 
(n=9), n (%) 
Total 
(n=60), n % 
All 
16 (46) 
1 (7) 
2 (23) 
19 (32) 
Respiratory failure 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Abdominal pain 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Asthma 
0 (0) 
0 (0) 
1 (12) 
1 (2) 
Back pain 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Cerebrovascular accident 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Convulsion 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Dehydration 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Disease progression 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Dyspnoea 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Gastric ulcer perforation 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Gastrointestinal haemorrhage 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Hemiparesis 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Nausea 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Ovarian cancer metastatic 
1 (3) 
0 (0) 
0 (0) 
1 (2) 


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Pericarditis 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Pleural effusion 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Pneumonia 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Presyncope 
0 (0) 
1 (7) 
0 (0) 
1 (2) 
Pyelonephritis 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Sepsis 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Small intestinal obstruction 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Stridor 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Tumour pain 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Upper gastrointestinal haemorrhage 
0 (0) 
0 (0) 
1 (12) 
1 (2) 
Vomiting 
1 (3) 
0 (0) 
0 (0) 
1 (2) 
Three SAEs from vactosertib monotherapy were reported as vactosertib related AEs: cerebrovascular accident 
(MP-001), respiratory failure (MP-001), presyncope (MP-VAC-105). 
 
Table 10: 
Treatment   emergent   AEs   leading   to   vactosertib   discontinuation   from vactosertib 
monotherapy trials 
 
AE terms 
MP-001 
(n=35), n (%)
Total 
(n=60), n %
All 
8 (23) 
8 (14) 
Cerebrovascular accident 
1 (3) 
1 (2) 
Convulsion 
1 (3) 
1 (2) 
Dyspnoea 
1 (3) 
1 (2) 
Gastric ulcer perforation 
1 (3) 
1 (2) 
Ovarian cancer metastatic 
1 (3) 
1 (2) 
Respiratory failure 
1 (3) 
1 (2) 
Small intestinal obstruction 
1 (3) 
1 (2) 
Stridor 
1 (3) 
1 (2) 
   No patients from MDS-01 and MP-VAC-105 studies experience AE leading to treatment discontinuation. 
 
   Table 11: Adverse drug reaction (≥3%) from vactosertib monotherapy 
 
AE Term s 
MP-001 
(n=35), n (%) 
MP-VAC-105 
(n=16), n (%) 
MP-MDS-01 
(n=9), n (%) 
Total 
(n=60), n (%) 
Headache 
5 (15) 
5 (32) 
1 (12) 
11 (19) 
Fatigue 
10 (29) 
0 (0) 
1 (12) 
11 (19) 
Nausea 
9 (26) 
1 (7) 
0 (0) 
10 (17) 
Diarrhoea 
5 (15) 
1 (7) 
1 (12) 
7 (12) 
Decreased appetite 
6 (18) 
0 (0) 
0 (0) 
6 (10) 


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Vomiting 
5 (15) 
0 (0) 
0 (0) 
5 (9) 
Hypophosphataemia 
3 (9) 
0 (0) 
1 (12) 
4 (7) 
Constipation 
4 (12) 
0 (0) 
0 (0) 
4 (7) 
Dermatitis acneiform 
2 (6) 
0 (0) 
1 (12) 
3 (5) 
Aspartate aminotransferase increased 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Pruritus 
3 (9) 
0 (0) 
0 (0) 
3 (5) 
Abdominal pain 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Alanine aminotransferase increased 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Amylase increased 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Anaemia 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Blood alkaline phosphatase increased 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Dysgeusia 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Dyspepsia 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Lipase increased 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Muscular weakness 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Pyrexia 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
Rash maculo-papular 
2 (6) 
0 (0) 
0 (0) 
2 (4) 
 
 
Vactosertib may increase immunologic toxicities of when administered in 
combination with anti-cancer PD1/PD-L1 pathway inhibitors. 
Dose Limiting Toxicity. 
 
 
Dose limiting toxicity is defined as any of the following: Any occurrence of death as 
result of adverse event regardless of attribution;  
 
Any non-hematologic grade ≥3 toxicity (CTCAEv5 criteria), except for nausea, vomiting 
or diarrhea lasting 3 days or less; 
 
Any grade 4 neutropenia (CTCAEv5 criteria) of any duration; 
 
Any grade ≥ 3 neutropenia that has not recovered to grade ≤ 2 within 7 days of onset;  
 
Any grade ≥ 3 febrile neutropenia (temperature ≥ 38.5ºC);  
 
Any grade ≥ 3 thrombocytopenia associated with clinically significant bleeding; or 
requiring platelet transfusion.  
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 


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reporting.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
 
Attribution of the AE: 
- All adverse events will be considered possibly related to the study drug unless there 
is clear evidence that the event is not related to the study drug. 
 
 
 
13.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be maintained by 
the research staff and kept in the subject’s research chart.    
 
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:   
https://research.weill.cornell.edu/compliance-integrity/wcm-institutional-review-
board/immediate-reporting-policy 
 
13.1.5 Reporting Events to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli
cy.pdf.  
 
13.1.6 Events of Special Interest 
 
Not applicable. 
 
13.1.7 Reporting of Pregnancy 
 
If a female subject becomes pregnant during study, they will be withdrawn from study and all 
study procedures.  Permission will be requested from subject to follow pregnant woman to 
pregnancy outcome. Pregnancy will be reported as an SAE as outlined in sections 13.2. 
 
13.2 Definition of SAE 
 
In accordance with US Food and Drug Administration (FDA) regulations, an AE will be classified as a 
Serious Adverse Event (SAE), whether or not it is considered to be associated with the study drug, 
when it meets any of the following criteria:  
 
 
Results in death; 
 
Is life-threatening (that is, places patient at immediate risk of death);  


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 
Requires inpatient hospitalization or prolongation of existing hospitalization (note: 
planned hospitalization or outpatient surgery due to a pre-existing condition will not be 
regarded as an SAE in this study);  
 
Results in persistent or significant disability/incapacity; or 
 
Other important medical events that, based upon appropriate medical judgment, are 
thought to jeopardize the patient and/or require medical or surgical intervention to 
prevent one of the other outcomes defining an SAE.  
 
13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli
cy.pdf.  
 
13.2.2 Reporting of SAE to FDA  
 
IND application sponsor must report any suspected adverse reaction or adverse reaction to study 
treatment that is serious. Fatal or life-threatening suspected adverse reactions represent 
especially important safety information and must be reported to FDA as soon as possible but no 
later than 7 calendar days following the sponsor’s initial receipt of the information. 
 
i. death, 
ii. a life-threatening adverse event,   
iii. in-patient hospitalization or prolongation of existing hospitalization, 
iv. a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or   
v. a congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or research subject and may require medical or surgical intervention 
to prevent one of the outcomes listed as serious 
CDER INDs:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Central Document Room 
5901-B Ammendale Road  
Beltsville, Maryland  20705-1266  
 
13.2.3 Reporting of SAE to MedPacto Inc. 
 
Institution will send MedPacto copies of any and all serious adverse event reports filed with the 
FDA or other applicable regulatory authorities, as well as copies of any correspondence with the 
FDA or other applicable regulatory authorities, regarding any and all serious adverse events, 
irrespective of association with the Study Drug(s) in the course of the Clinical Trial, within five (5) 


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business days of such report or correspondence being sent to the FDA or other applicable 
regulatory authorities.  Copies should be faxed directly to MedPacto Safety Department at 82-31-
888-9949.   
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This 
requirement indicates that follow-up may be required for some events after the patient 
discontinues participation from the study.  
 
13.4 Time Period and Frequency for Event Assessment and Follow Up 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs occurring while on study must be documented appropriately regardless of relationship. All AEs 
will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates at 
any time during the study, it will be recorded as an AE.  
 
Reportable events will be monitored with start dates occurring any time after informed consent is 
obtained until 30 days after the last day of study participation.  At each study visit, the investigator 
will inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed for outcome 
information until resolution or stabilization. 
 
14. Unanticipated Problems Involving Risks to Subjects or Others 
 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO) 
 
Note: Per FDA IND guidance, no attribution of relatedness or expectedness to study agent is to be 
considered separately from other adverse events.  
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks 
to participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the Institutional Review Board 
(IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 


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• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
14.1.2 Unanticipated Problem Reporting 
 
The investigator will report unanticipated problems (UPIRTSOs) to the reviewing Institutional 
Review Board (IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). 
The UPIRTSO report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UPIRTSO;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UPIRTSO. 
 
To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the following 
timeline:   
 
• 
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB and to the 
DCC/study sponsor within  24 hours of the investigator becoming aware of the event.  
• 
Any other UPIRTSO will be reported to the IRB and to the DCC/study sponsor within 24 
hours of the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
Food and Drug Administration (FDA), and the Office for Human Research Protections 
(OHRP) within the IRB’s receipt of the report of the problem from the investigator. 
 
15. Data and Safety Monitoring Plan (DSMP) 
 
Subjects will be closely monitored by the treating physician and investigators. Laboratory and clinical 
evaluations will be performed regularly to assess efficacy and potential toxicities. All subjects will 
undergo a thorough physical examination at least once per cycle and at more frequent intervals when 
study agent doses are being adjusted per prospective rules Decision (see Table 3). Subjects will be 
provided with contact information and instructions to contact research staff to report any new or 
worrisome symptoms. Safety data will be evaluated by the investigator on an ongoing basis. Adverse 
event reporting is described Section 13 Adverse Event Reporting Requirements. 
 
The principal investigator will be primarily responsible for monitoring the safety of the study, adverse 
events, both serious and non-serous and deaths that occur during study participation by subjects. All 
adverse events will be monitored until they resolve or are clearly determined to be due to a subject’s 
disease or intercurrent illness(es).  
 
At the completion of Tier 1, all data necessary to evaluate Criteria for Decision to Proceed to Tier 2 
section) will be reported to WCM Statistician, WCM DSMB and Medpacto. The Simon Two-stage 


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Optimum Design is expected to minimize the number of subjects exposed to vactosertib if it is found 
to be an unsuitable agent for the treatment of anemic patients with Ph-neg MPNs. If 1 or more 
subjects meets theendpoint then the study will proceed to Tier 2 and another 25 subjects will be 
enrolled). This decision will be submitted to WCM IRB at the time of continuing review.  
 
After completion of Tier 2, all data necessary to evaluate will be reported to WCM Statistician, WCM 
DSMB and Medpacto. If four or more subjects meet the Composite Response & Toxicity Endpoint then 
vactosertib will have shown preliminary efficacy and feasibility to justify further evaluation as an 
agent to treat anemic patients with Ph-Neg MPNs. This interpretation will be submitted to WCM IRB 
at the time of continuing review. 
 
Should the Stopping Rules for Tier 1 or for Tier 2 be met, accrual of new subjects will be immediately 
suspended and the WCM IRB and Medpacto will be notified. The study DSMB will meet to review 
study data. The DSMB may either recommend permanent closure of the study or may allow protocol 
revision/amendment and submission to WCM IRB for review. DSMB recommendations will be 
submitted to Medpacto and WCM IRB.    
 
All protocol amendments and consent form modifications will be made by the Principal Investigator. 
Medpacto will have the opportunity to review and approve the changes prior to submission of these 
changes to the local IRB.  
 
Section 7.9, Criteria for Removal from Study, details treatment stopping rules for individual patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A 
 
 
 


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Appendix B 
 
The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS): 
Prospective International Assessment of an Abbreviated Symptom Burden Scoring System among 1408 
MPN Patients  
SCHERBER et. al. 
 
 Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) 
 
Symptom 
1 to 10 (0 if absent) ranking 
1 is most favorable and 10 least favorable 
Please rate your fatigue (weariness, 
tiredness) by circling the one 
number that best describes your 
WORST level of fatigue during 
past 24 hours* 
 
 
 
(No Fatigue) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Circle the one number that describes how, during the past week how much difficulty 
you have had with each of the following symptoms 
Filling up quickly when you eat 
(Early satiety) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal discomfort 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Inactivity 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Problems with concentration - 
Compared to prior to my MPD 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Numbness/ Tingling (in my hands 
and feet) 
 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Night sweats 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
 
Itching (pruritus) 
 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Bone pain (diffuse not joint pain or 
arthritis) 
 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
 
Fever (>100 F) 
 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Daily) 
Unintentional weight loss last 6 
months 
 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
 
* Question used with permission from the MD Anderson Cancer Center Brief Fatigue 
Inventory © 
 


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