Conditions: Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis
Keywords: Keywords provided by NS Pharma, Inc.: JAK2 kinase inhibitor NS-018 Myeloproliferative Neoplasms Primary Myelofibrosis post-Polycythemia Vera Myelofibrosis post-Essential Thrombocythemia Myelofibrosis Additional relevant MeSH terms: Bone Marrow Diseases Hematologic Diseases Polycythemia Vera Thrombocythemia, Essential PMF post-PV MF post-ET MF
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 77
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety and tolerability of orally administered NS-018 in patients with Primary Myelofibrosis (PMF), Post-polycythemia Vera Myelofibrosis (post-PV MF), or Post-essential Thrombocythemia Myelofibrosis (post-ET MF)

Detailed description:
This is a Phase 1/2 study that is currently enrolling Janus kinase 2 (JAK2) failures into the Phase 2 portion of the study.

Arms:
arm 1: In Phase 1 part, subjects were treated with oral NS-018 at a dose of 75 - 400 mg once daily or 100 - 400 mg twice daily. In Phase 2 part, subjects were treated with oral NS-018 at a dose of 300 mg once daily.

Interventions: intervention 1: NS-018
Intervention descriptions: intervention 1: Treatment will be administered continuously as oral daily therapy in cycles of 4 weeks in duration (28 day treatment cycles).

Protocol document:
Prot_SAP_000.pdf: 
NS-018-101: A Phase 1/2, Open-label, Dose-escalation, Multi-center Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered 
NS-018 in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or 
Post-Essential Thrombocythemia Myelofibrosis 
ClinicalTrials.gov Identifier: NCT01423851 
Amendment 10: Date 21Apr2015 


CLINICAL STUDY PROTOCOL 
 
A Phase 1/2, Open-label, Dose-escalation, Multi-center Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally 
Administered NS-018 in Patients with Primary Myelofibrosis, 
Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia 
Myelofibrosis 
Investigational Product: NS-018 
Protocol Number: NS-018-101 
 
Sponsor: 
NS Pharma, Inc. 
140 E Ridgewood Ave, 2nd Floor 
Paramus, New Jersey 07652 
Telephone: 201-986-3860 
Facsimile: 201-986-3865 
 
Version Number: 10.0 
Original Protocol: 29 November 2010 
Amendment 1: 16 December 2010 
Amendment 2: 12 January 2011 
Amendment 3: 06 April 2011 
Amendment 4: 12 July 2011 
Amendment 5: 03 July 2012 
Amendment 6: 14 December 2012 
Amendment 7: Date 20May 2014 
Amendment 8:  Date 16 Jul 2014 
Amendment 9:  Date 11Aug2014 
Amendment 10:  Date 21Apr2015 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the 
written consent of NS Pharma, Inc. (NS Pharma) except to the extent that disclosure 
would be required by law and for the purpose of evaluating and/or conducting a clinical 
study for NS Pharma. You are allowed to disclose the contents of this document only to your 
Institutional Review Board (IRB) and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the 
information is confidential and proprietary to NS Pharma and that it may not be further 
disclosed to third parties. 




 
 
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SYNOPSIS 
TITLE:  A Phase 1/2, Open-label, Dose-escalation, Multi-center Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered NS-018 in 
Patients with Primary 
Myelofibrosis, Post-polycythemia Vera 
Myelofibrosis, or 
Post-essential Thrombocythemia Myelofibrosis 
 
PROTOCOL NUMBER:  NS-018-101 
 
INVESTIGATIONAL PRODUCT:  NS-018 
 
PHASE:  1/2 
 
INDICATION(S):Primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis 
(post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF) 
 
OBJECTIVES: 
 
Phase 1: The primary objective of the Phase 1 portion of the study is to evaluate the safety, 
tolerability, maximum tolerated dose (MTD), and clinically active dose of NS-018 when 
orally administered in patients with PMF, post-PV MF, or post-ET MF. 
 
The secondary objectives of the Phase 1 portion of the study are to determine plasma 
pharmacokinetics (PK), evaluate pharmacodynamic (PD) correlates, and evaluate 
preliminary efficacy of NS-018 in patients with PMF, post-PV MF, or post-ET MF. 
 
Phase 2: The primary objective of the Phase 2 portion of the study is to further evaluate the 
safety and efficacy of the selected dose(s) of NS-018 in patients with PMF, post-PV MF, or 
post-ET MF. 
 
The secondary objectives of the Phase 2 portion of the study are to further determine 
plasma PK and evaluate PD correlates of NS-018 in patients with PMF, post-PV MF, or 
post-ET MF. 
 
POPULATION: 
 
The population for this study includes male and female patients ≥18 years of age with PMF, 
post-PV MF, or post-ET MF that requires therapy, including patients with intermediate-1, 
intermediate-2, or high-risk MF according to the International Prognostic Scoring System 
(IPSS). Patients must have symptomatic palpable splenomegaly. Patients must have Eastern 
Cooperative Oncology Group (ECOG) Performance Status of ≤ 3 at study entry (screening). 
 


 
 
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STUDY DESIGN AND DURATION: 
 
This is a Phase 1/2, open-label study of NS-018 in patients with PMF, post-PV MF, or 
post-ET MF. Approximately 24 evaluable patients will be enrolled during the Phase 1 
portion.  Sequential cohorts of 3 to 6 patients each will be treated with escalating doses of 
NS-018 until MTD is established.  Patients in the first cohort will self-administer NS-018 
orally at a starting dose of 75 mg daily; additional planned daily doses are 125 mg, 200 mg, 
and 300 mg. A twice daily (BID) dosing schedule may be initiated by the Safety Review 
Committee based on results from PK analysis. Patients will remain on NS-018, administered 
continuously as daily therapy in cycles of 28 days duration, in the absence of progressive 
disease and demonstration of acceptable product tolerance. Once the MTD or clinically 
active dose (CAD) is determined, a Phase 2 portion that will include up to an additional 20 
patients will be initiated (treated at the MTD).  Consideration by the Safety Review 
Committee will also be given to suspending Phase 2 enrollment at the MTD, and instead 
adding the same total number of patients at a second dose level, the CAD.  The expansion 
cohorts for the MTD and CAD, should they both be pursued, will not be concurrently open 
for enrollment. The two dose levels would instead be expanded sequentially. Consideration 
will also be given to enroll patients only at the CAD but not MTD level, based on the 
risk/benefit of therapy as judged by the investigator/medical monitor and sponsor.   
 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
 
NS-018 will be self-administered orally as daily therapy in cycles of 28 days in duration. 
NS-018 will be self-administered 2 hours or more after the last meal and at least 1 hour 
before the next meal. The starting dose cohort (first cohort) will receive 75 mg daily. 
Appropriate numbers of 25 mg and/or 100 mg tablets will be supplied to the patients to 
enable self-administration at their assigned dose level. Additional planned daily doses are 
125 mg, 200 mg, and 300 mg. If twice daily dosing requires evaluation, dosing would start at 
one total daily dose level below the last once per day dose level that was declared safe.  For 
example, if 300 mg QD was declared safe, the starting dose for BID dosing would be 100 mg 
twice daily, 12 hours apart [representing a total daily dose 200 mg]). 
 
SAFETY: 
 
Adverse events (AEs) occurring after any administration of NS-018 will be followed until 
the event resolves, until the event is judged stable and not expected to resolve completely, or 
until the patient begins alternative treatment. Investigators will record and grade AEs using 
the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) Common 
Toxicity Criteria for Adverse Events (CTCAE), version 4.0. Safety assessments also include 
laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. 
 
EFFICACY: 
 
The responses to treatment assessed using the IWG consensus criteria (Phase I) and the IWG 
MRT and ELN Response Criteria (Phase II) will be tabulated by dose level and visit. The 
number and percentage of patients achieving the response will be provided for each response 


 
 
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level. The objective response rate (the percentage of patients with confirmed CR, PR, or CI 
during the treatment period) and its 95% exact binomial confidence interval will be provided 
by dose level. Quality of life assessed using the MF SAF during Phase I or MPN-SAF 
(MPN-10) during Phase II will be summarized by dose level and visit. Change in spleen size 
by magnetic resonance imaging (MRI; computed tomography [CT] scan for patients not able 
to tolerate MRI) for the Phase 2 portion will be summarized for the cohort. 
 
PHARMACOKINETIC/PHARMACODYNAMIC AND QUALITY OF LIFE: 
 
Pharmacokinetic parameters to be estimated include observed maximum concentration 
(Cmax), time to maximum plasma concentration (Tmax), area under the plasma 
concentration-time curve (AUC), terminal elimination half-life (t1/2), and accumulation 
ratio (R). Pharmacodynamic parameters include Janus kinase 2 (JAK2) V617F allele burden, 
phosphorylated signal transducer and activator of transcription 3 (phospho-STAT3), and 
cytokine levels.  
Quality of life will be assessed using the Myelofibrosis Symptom Assessment Form (MF 
SAF) or Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF (MPN-10)]. 
 
STATISTICAL ANALYSES: 
 
Continuous variables will be summarized with descriptive statistics, including the number of 
observations, arithmetic mean, standard error/deviation, median, minimum, and maximum 
values. Frequency counts and percentage will be provided for categorical data. 
 
Adverse events will be summarized by dose level. Clinical laboratory evaluations at each 
visit and change from baseline (Cycle 1 Day 1) will be summarized by dose level. A 
laboratory value shift table will be provided. Vital signs and ECG parameters at each 
assessment time will be summarized by dose level. Other safety variables and their changes 
from baseline (when applicable) will be summarized by dose level at each of the scheduled 
assessment times. 
 
Plasma concentrations of NS-018 and its metabolites will be summarized by dose level with 
descriptive statistics. Individual patient and mean plasma concentrations of NS-018 and its 
metabolites will be plotted versus time.  In addition, the relationship between plasma 
concentrations of NS-018 and its metabolites and each efficacy and toxicity outcome 
measure as well as any biomarker endpoints will be explored. 
 
Pharmacodynamic parameters including JAK2 V617F allele burden, phospho-STAT3, 
cytokine levels and their changes from baseline will be summarized by dose level and listed. 
The relationship between NS-018 dose level and JAK2 or phospho-STAT3 levels over time 
will be explored. 
 
Responses to treatment assessed using the IWG consensus criteria (Phase I) and the IWG 
MRT and ELN Response Criteria (Phase II) will be tabulated with the number and 
percentage of patients for each response level. The objective response rate (the percentage of 
patients with confirmed complete or partial responses during the treatment period) and its 


 
 
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95% exact binomial confidence interval will be provided by dose level. Quality of life 
assessed using the MF SAF (Phase I) or MPN-SAF (MPN-10) (Phase II) will be summarized 
by dose level and visit.  
 
SITES: Multisite in the United States 
SPONSOR: 
 
NS Pharma, Inc. 
140 E Ridgewood Ave, 2nd Floor 
Paramus, New Jersey 07652 
 
 
PPD


 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................... 2 
SYNOPSIS 3 
TABLE OF CONTENTS ....................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................... 11 
1 
INTRODUCTION AND BACKGROUND INFORMATION ..................... 13 
1.1 
Background ....................................................................................................... 13 
1.2 
Rationale ........................................................................................................... 13 
1.2.1 
Summary of non-clinical studies ........................................................................ 13 
1.2.2 
Speculation from non-clinical study results ....................................................... 16 
2 
STUDY OBJECTIVES AND HYPOTHESES .............................................. 18 
2.1 
Study Objectives ............................................................................................... 18 
2.1.1 
Phase 1 ............................................................................................................... 18 
2.1.2 
Phase 2 ............................................................................................................... 18 
3 
STUDY DESIGN .............................................................................................. 18 
3.1 
Summary of Study Design ............................................................................... 18 
4 
STUDY POPULATION .................................................................................. 19 
4.1 
Inclusion Criteria ............................................................................................. 19 
4.2 
Exclusion Criteria ............................................................................................ 20 
4.3 
Patient Enrollment ........................................................................................... 21 
4.4 
Patient Discontinuation ................................................................................... 21 
5 
STUDY PROCEDURES .................................................................................. 22 
5.1 
Assessment Schedule – Phase 1 ....................................................................... 22 
5.1.1 
Phase 1: Screening (Day -14 to Day 0) .............................................................. 22 
5.1.2 
Phase 1: Cycle 1, Day 1 ..................................................................................... 22 
5.1.3 
Phase 1: Cycle 1, Days 8, 15, and 22 (±2 days) ................................................. 23 
5.1.4 
Phase 1: Cycles 2, 3, and 4, Day 1 (±3 days) ..................................................... 23 
5.1.5 
Phase 1: Cycles 2, 3, and 4, Day 15; Cycles 5 and 6, Days 1 and 15 (±3 days) 24 
5.1.6 
Phase 1: Cycle 7 and 10, Day 1, (±1 week) ....................................................... 24 
5.1.7 
Phase 1: Cycle 8, 9 11 and 12 Day 1(±3 days) .................................................. 24 
5.1.8 
Phase 1: Cycle 13, Day 1 and Day 1 of every 3 cycles thereafter (±1 week) .... 25 
5.1.9 
Phase 1: End of Study Assessments ................................................................... 25 
5.1.10 
Phase 1: Follow-up ............................................................................................. 25 
5.2 
Assessment Schedule – Phase 2 ....................................................................... 26 
5.2.1 
Phase 2: Screening (Day -14 to Day 0) .............................................................. 26 
5.2.2 
Phase 2: Cycle 1, Day 1 ..................................................................................... 26 


 
 
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5.2.3 
Phase 2: Cycle 1, Day 8 (±2 days) ..................................................................... 27 
5.2.4 
Phase 2: Cycle 1, Day 15 (±2 days) ................................................................... 27 
5.2.5 
Phase 2: Cycle 1, Day 22 (±2 days) ................................................................... 27 
5.2.6 
Phase 2: Cycle 2, 3, and 4, Day 1 (±3 days) ...................................................... 27 
5.2.7 
Phase 2: Cycles 2, 3, and 4, Day 15; Cycles 5 and 6, Days 1 and 15 (±3 days) 28 
5.2.8 
Phase 2: Cycle 7 and 10 Day 1 (±1 week) ......................................................... 28 
5.2.9 
Phase 2: Cycle 8, 9, 11 and 12 Day 1 (±3 days) ................................................ 29 
5.2.10 
Phase 2: Cycle 13, Day 1 and Day 1 of every 3 cycles thereafter (±1 week) .... 29 
5.2.11 
Phase 2: End of Study Assessments ................................................................... 29 
5.2.12 
Phase 2: Follow-up ............................................................................................. 30 
6 
TREATMENTAND RESTRICTIONS .......................................................... 30 
6.1 
Treatment.......................................................................................................... 30 
6.1.1 
Treatment Regimen, Dosage, and Duration ....................................................... 30 
6.1.2 
Compliance Control ........................................................................................... 35 
6.2 
Study Restrictions ............................................................................................ 36 
6.2.1 
Concomitant Medications .................................................................................. 36 
7 
INVESTIGATIONAL PRODUCT ................................................................. 37 
7.1 
Clinical Trial Material ..................................................................................... 37 
7.2 
Pharmaceutical Formulation(s) ...................................................................... 37 
7.3 
Administration ................................................................................................. 37 
7.4 
Labeling and Packaging .................................................................................. 37 
7.5 
Dispensing Procedures and Storage Conditions ........................................... 37 
7.5.1 
Dispensing Procedures ....................................................................................... 37 
7.5.2 
Storage Conditions ............................................................................................. 38 
8 
SAFETY ASSESSMENTS .............................................................................. 38 
8.1 
Adverse Events ................................................................................................. 38 
8.1.1 
Collection of Adverse Events............................................................................. 38 
8.1.2 
Definition of Adverse Events ............................................................................. 38 
8.1.3 
Assessment of Adverse Events .......................................................................... 38 
8.1.4 
Recording Adverse Events ................................................................................. 40 
8.2 
Serious Adverse Event Reporting - Procedure for Investigators ................ 41 
8.3 
Exposure In Utero During Clinical Studies ................................................... 42 
8.4 
Laboratory Assessments .................................................................................. 42 
8.5 
Vital Signs ......................................................................................................... 43 
8.6 
Electrocardiograms .......................................................................................... 43 
8.7 
Physical Examinations ..................................................................................... 43 
9 
EFFICACY ASSESSMENTS ......................................................................... 44 
9.1 
Treatment Response......................................................................................... 44 
9.2 
Spleen Size Assessment .................................................................................... 44 
9.3 
Bone Marrow Assessment ............................................................................... 44 


 
 
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PHARMACODYNAMIC AND PHARMACOKINETIC ASSESSMENTS
 ............................................................................................................................ 44 
10.1 
Pharmacodynamic Assessments ..................................................................... 44 
10.1.1 
JAK2 V617F Allele Burden Assessment ........................................................... 44 
10.1.2 
Phospho-STAT3 Assessment ............................................................................. 44 
10.1.3 
Cytokine Assessment ......................................................................................... 45 
10.2 
Pharmacokinetic Assessment .......................................................................... 45 
11 
Other Assessments ........................................................................................... 46 
12 
STATISTICS .................................................................................................... 46 
12.1 
Sample Size Determination ............................................................................. 47 
12.2 
Analysis Populations ........................................................................................ 47 
12.2.1 
Safety Population ............................................................................................... 47 
12.2.2 
Pharmacokinetic Population .............................................................................. 48 
12.2.3 
Pharmacodynamic Population ............................................................................ 48 
12.2.4 
Efficacy Population ............................................................................................ 48 
12.3 
Demographic and Baseline Characteristics ................................................... 48 
12.4 
Efficacy Analyses .............................................................................................. 48 
12.5 
Safety Analyses ................................................................................................. 48 
12.6 
Pharmacokinetic Analyses............................................................................... 49 
12.6.1 
Relationship between PK data and endpoints .................................................... 49 
12.7 
Pharmacodynamic Analyses ........................................................................... 49 
13 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ....................... 49 
13.1 
Data Quality Assurance ................................................................................... 49 
13.1.1 
Database Management and Quality Control ...................................................... 50 
13.2 
Case Report Forms and Source Documentation ........................................... 50 
13.2.1 
Data Collection................................................................................................... 51 
13.3 
Access to Source Data ...................................................................................... 51 
13.4 
Data Processing ................................................................................................ 52 
13.5 
Archiving Study Records ................................................................................. 52 
13.6 
Good Clinical Practice ..................................................................................... 52 
13.7 
Informed Consent ............................................................................................ 52 
13.8 
Protocol Approval and Amendment .............................................................. 53 
13.9 
Safety Review Committee ................................................................................ 53 
13.10 
Duration of the Study ...................................................................................... 54 
13.11 
Premature Termination of the Study ............................................................. 54 
13.12 
Confidentiality .................................................................................................. 54 
13.13 
Publication Policy ............................................................................................. 55 
14 
List of Study Personnel .................................................................................... 55 
14.1 
Sponsor .............................................................................................................. 55 


 
 
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14.2 
Contract Research Organization .................................................................... 55 
14.3 
Drug Safety ....................................................................................................... 55 
15 
REFERENCES ................................................................................................. 56 
16 
SUPPLEMENT ................................................................................................ 57 
16.1 
Investigator’s Agreement ................................................................................ 57 
Appendix A:  Schedule of Procedures ................................................................................. 58 
Appendix B1:  Primary Myelofibrosis Definition .............................................................. 62 
Appendix B2:  Post-Polycythemia Vera Myelofibrosis Definition ................................... 63 
Appendix B3:  Post-Essential Thrombocythemia Myelofibrosis Definition .................... 64 
Appendix C:  International Prognostic Scoring System for Primary Myelofibrosis ..... 65 
Appendix D:  Eastern Coopertive Oncology Group (ECOG) Performance Status........ 66 
Appendix E:  Prohibited and Cautioned Medications – Specific Cytochrome P450 
Substrates and Inhibitors/Inducers ................................................................ 67 
Appendix F:  New York Heart Association (NYHA) Classification of Heart Failure .... 69 
Appendix G:  Clinical Laboratory (Safety) Tests .............................................................. 70 
Appendix H:  National Cancer Institute Common Toxicity Criteria for Adverse Events
 ............................................................................................................................ 71 
Appendix I:  International Working Group Concensus Criteria for Treatment 
Response in Myelofibrosis with Myeloid Metaplasia .................................... 72 
Appendix J:  Myelofibrosis Symptom Assessment Form .................................................. 74 
Appendix K:  Revised response criteria for Myelofibrosis:  International Working 
Group-Myeloproliferative Neoplasms Research and treatment (IWG-MRT) 
and European LeukemiaNet (ELN) consensus report .................................. 75 
Appendix L:  Myeloproliferative Symptom Assessment Form (MPN-SAF) (MPN-10) . 78 


 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area under the plasma concentration time curve 
BID 
“bis in die" Latin - twice a day 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CAD 
Clinically active dose 
CFR 
Code of Federal Regulations 
CI 
Clinical improvement 
Cmax 
Maximum concentration 
CR 
Complete remission 
CrCl 
Creatinine clearance 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
Coefficient of variation 
CYP 
Cytochrome p450 
DLT 
Dose-limiting toxicity 
DRL 
Drug Reference List 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELN 
European LeukemiaNet 
ET 
Essential thrombocythemia 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IND 
Investigational New Drug (application) 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IWG 
International Working Group 
IWG-MRT 
International Working Group for Myelofibrosis Research and 
Treatment 
JAK2 
Janus kinase 2 
Ki 
inhibitory constant 


 
 
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LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Myelofibrosis 
MF SAF 
Myelofibrosis Symptom Assessment Form 
MM 
multiple myeloma 
MPN 
Myeloproliferative neoplasm 
MPN-SAF 
Myeloproliferative Neoplasm Symptom Assessment Form 
 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute  
NOAEL 
no observed adverse effect level 
PD 
Pharmacodynamic; progressive disease 
PK 
Pharmacokinetic 
PMF 
Primary myelofibrosis 
PR 
Partial response 
PV 
Polycythemia vera 
QD 
Once daily 
QTcB 
Bazett’s correction of the QT interval formula 
SAE 
Serious adverse event 
SD 
Stable disease 
STAT 
Signal transducer and activator of transcription 
STD10 
Severely toxic dose in 10% of the animals 
t1/2 
Half-life 
TEAE 
Treatment emergent adverse event 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 


 
 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Nippon Shinyaku has developed a novel Janus kinase 2 (JAK2) inhibitor, 
NS-018, for the treatment of patients with myeloproliferative neoplasm (MPN). 
MPN, including polycythemia vera (PV), essential thrombocythemia (ET), and 
myelofibrosis (MF), is a clonal hematopoietic stem cell malignancy 
characterized by the abnormal proliferation and survival of one or more myeloid 
cell types. 
 
Until recently the molecular etiology of MPN remained elusive. However, 
understanding was greatly expanded when a somatic point mutation of JAK2 
tyrosine kinase (JAK2 V617F) was described in more than 90% of PV patients 
and about 50% of ET and MF patients in 2005. 1 , 2 , 3  JAK2 V617F is a 
constitutively activated kinase that activates the JAK/signal transducer and 
activator of transcription (STAT) signaling pathway and dysregulates cell 
growth and function. Another point mutation, in the thrombopoietin receptor, 
whose signaling is known to be mediated by JAK2, has been identified in 1% to 
5% of ET and MF patients. These findings suggest that aberrant JAK2 
activation is responsible for the molecular pathogenesis of MPN. 
 
The clinical courses of PV and ET are relatively indolent with a fairly long life 
expectancy. Polycythemia vera can be managed by treatment with phlebotomy 
and hydroxyurea and ET by treatment with low-dose aspirin and hydroxyurea. 
Myelofibrosis can arise de novo as primary myelofibrosis (PMF) or can develop 
as a terminal stage of PV (post-PV MF) or ET (post-ET MF). Myelofibrosis has 
a progressive clinical course and is associated with a shorter life expectancy, 
with median survival after diagnosis of about 5 years. Patients with MF have 
anemia, splenomegaly, or constitutional symptoms such as weight loss and 
fatigue. Since the only currently available curative therapy for MF is 
hematopoietic stem cell transplantation, it is hoped that alternative therapies that 
will ameliorate the clinical symptoms of MF can be developed. 
1.2 
Rationale 
1.2.1 
Summary of non-clinical studies 
JAK2 associates with the cytoplasmic domain of the erythropoietin receptor, 
thrombopoietin receptor, and several kinds of cytokine receptors in 
hematopoietic cells, and plays an essential role in intracellular signal 
transduction. JAK2 V617F is an activated JAK2 which constitutively 
phosphorylates downstream molecules such as STATs, signal transducer and 
activator of transcription, activates multiple signaling pathways and leads to cell 
proliferation, survival and anti-apoptosis. Cells expressing JAK2 V617F 
acquired 
cytokine-dependent 
growth 
ability 
and 
erythropoietin-hyper-
responsiveness.1  Mice transplanted with bone marrow cells expressing JAK2 
V617F developed a closely resembled feature of PV pathology including a 
striking 
elevation 
of 
hematocrit, 
leukocytosis, 
splenomegaly, 
and 


 
 
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reticulinfibrosis in the bone marrow.4 A line of JAK2 V617F transgenic mice 
progressed into a myelofibrosis-like disease including anemia, bone marrow 
fibrosis, splenomegaly and shortened life time. 5  Although JAK2 V617F 
mutation is probably the most frequent genetic alteration in MF, additional 
mutations have been detected in exon 12 of JAK2 (F537-K539delinsL, 
H538QK539L, K539L, etc.)6and in the FERM (Four-point-one, Ezrin, Radixin, 
Moesin) domain of JAK2 (R430Q)7 among JAK2 V617F negative patients. 
Likewise, mutations in the thrombopoietin receptor such as W515L/K, were 
identified in a small population of MF patients. Ligand-independent activation 
of mutated thrombopoietin receptor results in a constitutive activation of JAK2 
kinase. Moreover, excess production of inflammatory cytokines is believed to 
relate to constitutional symptoms of splenomegaly and a hypermetabolic state in 
MF. Interleukin-6, whose signal is mediated by JAK2, was notably elevated in 
MPN patients especially during progression of MF to acute myelogenous 
leukemia, and ET and PV to MF.8 This evidence collectively indicates that up-
regulated JAK2 signaling is of importance in the development of MF pathology, 
regardless of the presence of specific genetic alterations, and that there is a 
strong rationale for the application of JAK2 inhibitors for MF treatment. 
 
NS-018 is an orally available, potent and specific JAK2 inhibitor. NS-018 is a 
potential therapeutic agent for the treatment of MF, is expected to suppress the 
aberrant proliferation of bone marrow cells which express activated JAK2.NS-
018 demonstrated a potent in vivo effect on the prolongation of life and the 
reduction of splenomegaly at low dosages in a JAK2 V617F-bearing mouse 
model. Therefore, NS-018 can be expected to have specificity for activated 
JAK2 and a wide therapeutic range in vivo, providing a satisfactory margin of 
safety between its efficacy and its toxicity. 
 
The following is a summary of the key findings in the areas of nonclinical 
studies for NS-018.9 
 
Pharmacology 
• NS-018 inhibited JAK2 kinase with IC50values of subnanomolar range at 
both ATP = Km and ATP = 1 mmol/L, with selectivity for JAK2 over 
JAK1, JAK3, and Tyk2 kinases. 
• NS-018 showed potent antiproliferative activity against JAK2-driven cell 
lines such as BaF3/JAK2V617F with IC50 values of around 100 nmol/L 
and showed only minimal cytotoxicity against non-target cells. 
• NS-018 significantly prolonged survival at doses of over 6.25 mg/kg twice 
daily (bid) and reduced splenomegaly at dosages over 1.5 mg/kg bid in a 
mouse BaF3/JAK2V617F leukemia model. 
• NS-018 inhibited IL-6-induced STAT3 phosphorylation in a dose-
dependentmanner in MM cell lines such as PCM6, U266 and RPMI8226, 
and inhibitedthe IL-6-induced proliferation of PCM6 cells with an IC50 
value of140 nmol/L. 
 


 
 
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Safety Pharmacology 
• NS-018 had no effect on the central nervous system or the respiratory 
system of conscious male rats at doses up to 100 mg/kg. 
• NS-018 inhibited human ether-a-go-go-related gene (hERG) currents in 
human embryonic kidney cells (HEK293) in a concentration-dependent 
manner with an IC50of 0.6 mol/L. 
• Single doses of NS-018 up to 80 mg/kg in conscious dogs had no 
biologically significant effect on blood pressure, heart rate, or 
electrocardiogram (ECG) parameters, but caused loose stool at 5 mg/kg or 
more, and vomiting and/or diarrhea at 20 mg/kg or more. 
 
Pharmacokinetics and Metabolism 
• The bioavailability of NS-018 after a single oral administration to fasting 
male rats was 8.63%, and the bioavailability of NS-018 after a single oral 
administration to overnight fasting male dogs was 50.8%. 
• 
14C-NS-018 was well absorbed after a single oral administration to male 
and female rats. 
• The extent of binding of 14C-NS-018 to serum protein in vitro was more 
than 95% in rats, dogs, monkeys, and humans. 
• The distribution study of 14C-NS-018 in pigmented rats suggested there 
was an affinity of drug-related materials for melanin. 
• NS-018 was converted to several metabolites in hepatic microsomes and 
cryopreserved hepatocytes from preclinical species and humans, and 
human specific metabolites were not detected. 
• After a single intravenous and oral administration of 14C-NS-018 to male 
rats, radioactivity was excreted mainly into the feces. Following a single 
intravenous administration to bile duct-cannulated male rats, only a 
relatively small portion (approximately 6% of the dose) was reabsorbed to 
undergo enterohepatic recycling. 
• The effect of NS-018 on human cytochrome P450 enzymes (CYP) 
isoforms revealed that NS-018 inhibited CYP1A2 potently (IC50value of 
0.65 µmol/L) and moderately inhibited CYP3A4, CYP2C8, CYP2C9, 
CYP2C19, and CYP2D6.The Ki values were assayed for CYP1A2 and 
CYP3A4 and were 0.428 µmol/L and 1.66 µmol/L. A time-dependent 
inhibitory effect was also seen for CYP3A4. NS-018 also induced 
CYP3A4.CYP3A4 and CYP2D6 were considered to be mainly involved in 
the metabolism of NS-018. 
• NS-018 did not interact with P-glycoprotein (P-gp) as a substrate but 
interacted as an inhibitor. 
 
Toxicology 
• Hematological changes attributable to the pharmacological effect of NS-
018 were observed in a 4-week repeated-dose oral toxicity study in rats. 
Those changes were almost recovered at the end of the 4-week recovery 
period. One animal in the 150 mg/kg group died. 


 
 
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• Hematological, renal and gastrointestinal tract changes were also observed 
in a 4-week repeated-dose oral toxicity study in dogs. All 6 animals in the 
150 mg/kg group died. 
• In the 4-week repeated-dose studies, the maximum tolerated dose (MTD) 
of NS-018 was 50 mg/kg/day in both rats and dogs.  No observed adverse 
effect level (NOAEL) was determined to be 15mg/kg/day in male rats. 
The severely toxic dose in 10% of rats (STD10 of rats) was 150 mg/kg and 
the highest non-severely toxic dose (HNSTD) in dogs was 50 mg/kg/day. 
• In the 13-week repeated dose studies, the MTD of NS-018 was 30 
mg/kg/day in rats and 50 mg/kg/day in dogs, respectively. NOAEL was 
not determined in both rats and dogs. 
• NS-018 did not induce gene mutations. 
• NS-018 induced numerical aberration in the in vitrochromosomal 
aberration test. On the contrary, NS-018 did not induce structural 
chromosome aberration. 
• NS-018 increased the incidence of micronucleated immature erythrocytes 
in the in vivo micronucleus assay in rats, whereasNS-018 did not cause 
deoxyribonucleic acid (DNA) damage in the liver or peripheral blood cells 
in the rat comet (single-cell gel electrophoresis) assay. 
• NS-018 did not induce phototoxic response in the in vitro 3T3 NRU photo 
toxicity test. 
1.2.2 
Speculation from non-clinical study results 
Based on the nonclinical studies, the first-in-patient clinical trials will be 
conducted to evaluate the safety, tolerability, pharmacokinetics and clinical 
efficacy of NS-018. 
 
NS-018 is a competitive inhibitor of CYP1A2 and a non-competitive inhibitor 
of CYP3A4, and an inducer of CYP3A4 (based on an increase in activity of 
more than 40% at 1 µmol/L) and a moderate inducer of CYP1A2, as is 
presented in the following tables. 
 
IC50 and Ki values and inhibition type of NS-018 for each CYP isoforms: 
CYP Isoform
IC50 (µmol/L) 
Ki(µmol/L) 
Inhibition type
CYP1A2 
0.648 
0.428 
Competitive 
CYP2A6 
>50 
- 
- 
CYP2B6 
23.5 
- 
- 
CYP2C8 
4.05 
1.38 
Competitive 
CYP2C9 
5.31 
2.81 
Competitive 
CYP2C19 
5.77 
2.86 
Competitive 
CYP2D6 
6.63 
1.74 
Competitive 
CYP2E1 
>50 
- 
- 
CYP3A4 (midazolam) 
7.46 
- 
- 
CYP3A4 (testosterone) 
1.61 
1.66 
Noncompetitive 
-: no data 
 
 
 


 
 
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NS-018 potential to induce CYP1A2 and CYP3A4 activity. 
Phenacetin O-deethylase activities of NS-018: 
0.1 µmol/L 
322.5% vehicle 
3.7% positive control 
1 µmol/L 
1774.7% vehicle 
27.6% positive control 
3 µmol/L 
1094.9% vehicle 
16.4% positive control 
Testosterone 6β-hydroxylase activities of NS-018: 
0.1 µmol/L 
131.7% vehicle 
8.1% positive control 
1 µmol/L 
319.8% vehicle 
56.2% positive control 
3 µmol/L 
154.8% vehicle 
14.0% positive control 
Phenacetin O-deethylase for a substrate of CYP1A2 
Testosterone 6β-hydroxylase for a substrate of CYP3A4 
 
Plasma Cmax levels following repeated oral administration of well tolerated 
doses of NS-018 of 150 mg/kg/day in the rat (Report B091357) 10  and 
50 mg/kg/day in the dog (Report B091358),11 were approximately 15 (M)-20 (F) 
µmol/L and 4.5 (M)-5.1 (F) µmol/L, respectively, and are within the range of 
concentrations considered likely to inhibit or induce CYP1A2 and/or 3A4 
activity.  Therefore, the use of concomitant medications that are substantially 
metabolized by CYP1A2 and CYP3A4 should be cautioned as described in 
Section 4.2. 
 
While NS-018 was determined to be metabolized by CYP3A4 and CYP2D6 
from the study using the human P450-expressing microsomes, CYP3A4 was 
considered to be mainly involved in the metabolism of NS-018 from the result 
of the chemical inhibition study. In the investigation of inhibitory effects on the 
metabolism of NS-018 after addition of specific inhibitors of each P450 isoform 
to human liver microsomes, only ketoconazole (an inhibitor of CYP3A4) 
inhibited the formation of metabolites and the disappearance of NS-018. The 
percentage of inhibition on the disappearance of NS-018 was 53.6% for 
CYP3A4.12Therefore, the use of concomitant medications known to be strong 
inhibitors or inducers of  CYP3A4 should be cautioned as described in Section 
4.2. 
 
The starting dose of NS-018 was selected based on the results of 4-week 
repeated dose, daily administration, oral gavage toxicity studies conducted in 
rats and dogs. The STD10 of rats was 150 mg/kg (estimated human equivalent 
dose was 24.2 mg/kg) and the HNSTD in dogs was 50 mg/kg (the estimated 
human equivalent dose was 27.8 mg/kg). Taking into account the human 
equivalent dose of 1/10 of the STD10 of rats and 1/6 of the HNSTD in dogs, the 
starting dose in this first-in-human study was determined to be 75 mg. 
 
Dose conversion: Rat to Human 
Animal Dose 
Human Equivalent Dose 
Human Equivalent Dose of 1/10 STD10
150 mg/kg 
24.2 mg/kg 
2.42 mg/kg (145.2 mg at 60 kg) 
STD10 = severely toxic dose to 10%  
 


 
 
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Dose conversion: Dog to Human 
Animal Dose 
Human Equivalent Dose 
Human Equivalent of 1/6 HNSTD 
50 mg/kg 
27.8 mg/kg 
4.63mg/kg (278 mg at 60 kg) 
HNSTD = highest non-severely toxic dose 
 
2 
STUDY OBJECTIVES AND HYPOTHESES 
2.1 
Study Objectives 
2.1.1 
Phase 1 
The primary objective of the Phase 1 portion of the study is to evaluate the 
safety, tolerability, and to determine the maximum tolerated dose (MTD), and 
clinically active dose (CAD, as defined in Section 6.1.1) of NS-018 when orally 
administered in patients with PMF, post-PV MF, or post-ET MF. 
 
The secondary objectives of the Phase 1 portion of the study are to determine 
the plasma PK, evaluate PD correlates, and evaluate preliminary efficacy of 
NS-018 in patients with PMF, post-PV MF, or post-ET MF. 
2.1.2 
Phase 2 
The primary objective of the Phase 2 portion of the study is to further evaluate 
the safety and efficacy of the selected dose(s) in patients with PMF, post-PV 
MF, or post-ET MF. 
 
The secondary objectives of the Phase 2 portion of the study are to further 
determine the plasma PK and evaluate PD correlates of NS-018 in patients with 
PMF, post-PV MF, or post-ET MF. 
3 
STUDY DESIGN 
3.1 
Summary of Study Design 
This is a Phase 1/2, open-label study of NS-018 in patients with PMF, 
post-PV MF, or post-ET MF. Patients in the first cohort will self-administer 
NS-018 orally at a starting dose of 75 mg daily. Doses will be increased in later 
cohorts based on safety data. Treatment will be administered continuously as 
daily therapy in cycles of 28 days in duration. 
 
Approximately 24 patients will be enrolled during the Phase 1 portion (treated 
with escalated doses in a standard 3+3 cohort design) and 20 patients will be 
enrolled during the Phase 2 portion (treated at the MTD). Consideration by the 
Safety Review Committee will also be given to suspending Phase 2 enrollment 
at the MTD, and instead adding the same total number of patients at a second 
dose level, the CAD. The expansion cohorts for the MTD and CAD, should they 
both be pursued, will not be concurrently open for enrollment. The two dose 
levels would instead be expanded sequentially. Consideration will also be given 
to enroll patients only at the CAD but not MTD level, based on the risk/benefit 
of therapy as judged by the investigator/medical monitor and sponsor.  
 


 
 
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For the purpose of scheduling procedures and evaluations, a treatment cycle is 
defined as 28 days. A patient may continue to receive treatment with NS-018 
until the patient experiences unacceptable toxicity that precludes any further 
treatment, disease progression, and/or as long as the patient is benefiting from 
treatment, at the discretion of the investigator. 
 
This study will be conducted at selected sites in the United States. 
4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
Patients meeting the following criteria will be eligible to participate in the study: 
1. Primary myelofibrosis, post-PV MF, or post-ET MF (As defined in 
Appendix B) that requires therapy, including patients with intermediate-1, 
intermediate-2, or high-risk MF according to the International Prognostic 
Scoring System (IPSS)13 (Appendix C), regardless of their JAK2 mutation 
status. Patients must have symptomatic palpable splenomegaly (at least 5 cm 
below the left costal margin in the mid-clavicular line by physical 
examination).For the Phase 2 portion, MF patients must have received prior 
JAK2 
inhibitor 
therapy, 
and 
been 
found 
to 
be 
intolerant, or 
refractory/relapsed from prior JAK2 inhibitor therapy, based on investigator 
assessment. 
2. ≥18 years old. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤3 
(see Appendix D). 
4. Estimated life expectancy of ≥12 weeks. 
5. Male or non-pregnant, non-lactating female patients. Male and female 
patients who are fertile and their partners must agree to use one of the 
following methods of contraception from screening through 90 days 
following discontinuation of study drug. 
• Complete abstinence from sexual intercourse 
• Double-barrier method (condom with spermicide in conjunction with 
the use of an intrauterine device [IUD] or diaphragm) 
• Tubal ligation or vasectomy (surgical sterilization) 
6. Negative serum or urine pregnancy test within 7 days prior to the first dose 
of study drug (if patient is a female of childbearing potential). 
7. Serum creatinine of ≤ 1.5 ×the upper limit of normal (ULN) OR estimated 
creatinine clearance (CrCl) ≥40 ml/min/1.73 m2 calculated using the 
Cockcroft and Gault equation:  
 
CrCl (mL/min) = [(140-age (years)) x weight (kg)] / (serum creatinine  
  
 
(mg/dL) x 72) 
For females, multiply result by 0.85 
 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤3 × ULN and total bilirubin ≤ 1.5 × ULN. If the total bilirubin is elevated 


 
 
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between 1.5 x and 3 x ULN, patients with a direct bilirubin ≤1.5 X ULN are 
eligible during the Phase 2 portion. 
8. Adequate bone marrow reserve, as demonstrated by: 
• Absolute neutrophil count (ANC) >1000/µL and 
• Platelet count ≥25,000/µL without the assistance of growth factors or 
platelet transfusions. 
9. QTcB≤480 msec. 
10. No MF-directed treatment for at least 2 weeks prior to initiation of NS-018, 
including any use of corticosteroids for Myelofibrosis symptom or blood 
count management. Low dose corticosteroids ≤ 10 mg/day prednisone or 
equivalent is allowed for non-myelofibrosis purposes. 
11. No treatment with any investigational agent or anticancer agents within 2 
weeks prior to initiation of NS-018. 
12. Able to provide written informed consent prior to enrollment into the study. 
4.2 
Exclusion Criteria 
Patients are excluded from participation in the study if any of the following 
criteria apply: 
1. Active, uncontrolled systemic infection. 
2. Patients with any unresolved toxicity (regardless of organs) greater than 
Grade 1 from previous anticancer therapy. 
3. Prior treatment with JAK2 inhibitors that necessitated discontinuation 
specifically due to gastrointestinal toxicity. 
4. Potentially curative therapy is available: 
• Candidates for hematopoietic stem cell transplant in which transplant 
is an available and viable option and of higher priority than this 
study are excluded; 
• If the patient has declined hematopoietic stem cell transplant, has no 
donor for transplant, or in the judgment of the investigator is not 
suitable for transplant, the patient may be enrolled. 
5. Currently taking medication that is substantially metabolized by cytochrome 
P450 (CYP) 1A2 or CYP3A4 (see Appendix E) or taking medication known 
to be strong inhibitors or inducers of CYP3A4 (see Appendix E).   
6. Patients with a serious cardiac condition within the past 6 months such as 
uncontrolled arrhythmias, myocardial infarction, angina or heart disease as 
defined by the New York Heart Association (NYHA) Class III or IV (see 
Appendix F). 
7. Pregnant or lactating. 
8. Radiation therapy for splenomegaly within 6 months prior to study entry 
(screening). 
9. Splenectomy (applicable to patients enrolling in the Phase 2 portion of the 
study only). 
10. Known HIV positive status. 
11.  Known active hepatitis, or a history of viral hepatitis B or hepatitis C 
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12. Other concurrent disease and/or medical condition, which, in the judgment 
of the investigator, would prevent the patient’s participation. 
13. Patients diagnosed with another malignancy, unless they are disease free. 
Patients with early stage squamous cell carcinoma of the skin, basal cell 
carcinoma of the skin, or cervical intraepithelial neoplasia may be eligible 
for participation at the investigator’s discretion. 
14. Patients who have had surgery (other than placement of vascular access and 
bone marrow biopsy) within 4 weeks of study entry (screening), or patients 
with incomplete recovery from any prior surgical procedures. 
15. Patients actively receiving a concurrent investigational agent. 
16. Unwilling or unable to comply with the protocol. 
4.3 
Patient Enrollment 
When a patient has met the study requirements and is ready to be enrolled in the 
study, the site will send a Patient Enrollment Request Form to PAREXEL 
(Billerica, MA). PAREXEL will input the patient’s assigned dose cohort onto 
the form and send the form back to the site. The site will treat the patient at the 
assigned dose. 
4.4 
Patient Discontinuation 
Patients will be discontinued from the study under the following circumstances: 
• Disease progression or no clinical benefit after 6 cycles; 
• Patient’s physician considers a change of therapy would be in the best 
interest of the patient; 
• Patient requests discontinuation; 
• Continued unacceptable toxicities despite optimal treatment or dose 
reduction; 
• Need for any treatment not allowed by the protocol; 
• Non-compliance; and 
• Female patients who become pregnant during the study or who fail to use 
adequate birth control if applicable. (See Section 8.3 for more information 
regarding pregnancies).  
Patients who are discontinued will be asked to undergo the end of study 
procedures within 30 days after the last dose of study drug or within 30 days 
after withdrawal from the study, as outlined in Section 5.1.8 for the Phase 1 
portion and Section 5.2.10 for the Phase 2 portion. 
 
 


 
 
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5 
STUDY PROCEDURES 
5.1 
Assessment Schedule – Phase 1 
5.1.1 
Phase 1: Screening (Day -14 to Day 0) 
• Signed, written informed consent; 
• Medical history including concurrent baseline conditions. Document 
concomitant medications used within 14 days prior to study drug 
administration and blood products transfused within 3 months prior to study 
drug administration; 
• Complete physical examination including weight and spleen size by clinical 
assessment (palpation) (must be done within 7 days prior to Cycle 1, Day 1); 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature); 
• ECOG Performance Status; 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• Serum or urine pregnancy test for female patients of childbearing potential 
(must be done within 7 days prior to Cycle 1 Day 1); 
• Electrocardiogram (ECG) - triplicate; QTcB must be ≤480 msec, locally 
read for eligibility determination and centrally read for safety analysis; 
• Bone marrow assessment by aspiration and biopsy, according to standard 
practice at the site, (within 28 days prior to the first dose  of study drug) 
• Determine if the patient meets the inclusion/exclusion criteria. 
5.1.2 
Phase 1: Cycle 1, Day 1 
• Review eligibility criteria and laboratory test results; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
obtained before the first dose of study drug is taken; 
• ECOG Performance Status (may be obtained within 24 hours prior to study 
drug administration); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G) (may be obtained within 24 hours prior to study drug 
administration);  
• ECG – triplicate (pre-dose and approximately 2, 4, 6, and 8 hours post-dose; 
centrally read); 
• Obtain blood samples for PK assessment (sampling time points are pre-dose 
and approximately 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose); 
• JAK2 V617F allele burden (pre-dose may be obtained within 24 hours prior 
to study drug administration); 
• Phospho-STAT3 (pre-dose and approximately 3 and 6hours post-dose) 
(pre-dose may be obtained within 24 hours prior to study drug 
administration); 
• Cytokine level(pre-dose only; may be obtained within 24 hours prior to 
study drug administration); 
• Myelofibrosis Symptom Assessment Form (MF SAF) questionnaire (may be 
obtained within 24 hours prior to study drug administration); 


 
 
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• Distribute study drug and instruct patient regarding completion of the study 
drug dosing diary (may be done within 24 hours prior to study drug 
administration); 
• Assessment of AEs using the National Cancer Institute (NCI) Cancer 
Therapy Evaluation Program (CTEP) Common Toxicity Criteria for 
Adverse Events (CTCAE), version 4.0 (published 28 May 2009) (see 
Appendix H) (may be obtained within 24 hours prior to study drug 
administration and following study drug administration); and 
• Concomitant medication notation (may be obtained within 24 hours prior to 
study drug administration). 
5.1.3 
Phase 1: Cycle 1, Days 8, 15, and 22 (±2 days) 
• Directed physical examination including weight and spleen size by 
palpation; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature; 
pre-dose); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• ECG – triplicate (Day 8 only; pre-dose and approximately 2 hours post-
dose; centrally read); 
• Obtain blood samples for PK assessment (Day 8 only; sampling time points 
are pre-dose and approximately 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose); 
• Phospho-STAT3 (Day 8 only; pre-dose and approximately 3 and 6hours 
post-dose);  
• Review patient study drug dosing diary for compliance; 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.1.4 
Phase 1: Cycles 2, 3, and 4, Day 1 (±3 days) 
• Directed physical examination including weight and spleen size by 
palpation; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature; 
pre-dose); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G);  
• Serum or urine pregnancy test (female patients of childbearing potential 
only); 
• ECG – triplicate (at Cycle 2, pre-dose and approximately 2 hours post-dose, 
centrally read; at Cycles 3 and 4, pre-dose, locally read); 
• Obtain blood sample for PK assessment (Cycle 2 only; sampling time points 
are pre-dose and approximately 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose); 
• Bone marrow assessment (Cycle 4 only); 
• Response assessment using the International Working Group (IWG) 
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metaplasia, for the IWG for Myelofibrosis Research and Treatment 
(IWG-MRT); 
• JAK2 V617F allele burden if mutation present prior to start of therapy 
(Cycle 2 and Cycle 4, pre-dose); 
• Phospho-STAT3 (Cycle 2 only: pre-dose and approximately 3 and 6 hours 
post-dose; – refer to study lab manual for subset of patients to which this 
applies); 
• Cytokine (pre-dose); 
• MF SAF (Cycle 2 and Cycle 4, pre-dose); 
• Review patient study drug dosing diary for compliance and distribute study 
drug; 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.1.5 
Phase 1: Cycles 2, 3, and 4, Day 15; Cycles 5 and 6, Days 1 and 15 (±3 days) 
• Hematology and serum chemistry are to be obtained at the referring/local 
doctor’s office and the results faxed to the study site. 
5.1.6 
Phase 1: Cycle 7 and 10, Day 1, (±1 week) 
If a patient remains on study drug beyond 4 cycles, he/she will only be required 
to return to the clinic every 3 months  
• Directed physical examination including weight and spleen size by 
palpation; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature; 
pre-dose); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• ECG – triplicate (pre-dose, locally read); 
• Bone marrow assessment (pre-dose), Cycle 7 only; 
• Response assessment (IWG-MRT); 
• JAK2 V617F allele burden if mutation present prior to start of therapy 
(pre-dose); 
• MF SAF (pre-dose); 
• Review patient study drug dosing diary for compliance and distribute study 
drug, Cycle 7 only; 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.1.7 
Phase 1: Cycle 8, 9 11 and 12 Day 1(±3 days) 
• Hematology and serum chemistry are to be obtained at the referring/local 
doctor’s office and faxed to the study site, unless the patient is scheduled for 
a site visit. 


 
 
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5.1.8 
Phase 1: Cycle 13, Day 1 and Day 1 of every 3 cycles thereafter (±1 week) 
• Directed physical examination including weight and spleen size by 
palpation; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature; 
pre-dose); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• ECG – single reading (pre-dose, locally read);  
• Bone marrow assessment (pre-dose) Cycle 13 only, then annually; 
• Response assessment (IWG-MRT); 
• JAK2 V617F allele burden if mutation present prior to start of therapy 
(pre-dose); 
• MF SAF (pre-dose); 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.1.9 
Phase 1: End of Study Assessments 
The following procedures will be performed within 30 days after the last dose of 
study drug or within 30 days after withdrawal from the study: 
• Complete physical examination including weight and spleen size clinical 
assessment; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature); 
• ECOG Performance Status; 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
•  
• ECG – triplicate or single reading if Cycle 13 and thereafter (locally read); 
• Response assessment (IWG-MRT); 
• MF SAF; 
• Collect any unused study drug and review patient study drug dosing diary 
for compliance (if applicable); 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
 
All efforts will be made to complete the end of study visit for early termination 
patients however review of laboratory tests obtained from referring/local 
doctor’s office and a follow-up phone call to the patient may take place at a 
minimum for those patients refusing to return to the study site. 
5.1.10 
Phase 1: Follow-up 
If an unresolved AE was observed at the end of study visit, patients must be 
followed until the event resolves, until the event is judged stable and not 
expected to resolve completely, or until the patient begins alternative treatment. 


 
 
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5.2 
Assessment Schedule – Phase 2 
5.2.1 
Phase 2: Screening (Day -14 to Day 0) 
• Signed, written informed consent; 
• Medical history including concurrent baseline conditions. Document 
concomitant medications used within 14 days prior to study drug 
administration and blood products transfused within 3 months prior to study 
drug administration; 
• Complete physical examination including weight and spleen size by 
palpation (within 7 days prior to Cycle 1, Day 1); 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature); 
• ECOG Performance Status; 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• Serum or urine pregnancy test for female patients of childbearing potential 
(must be done within 7 days prior to Cycle 1 Day 1); 
• ECG – triplicate. QTcB must be ≤480 msec locally read for eligibility 
determination and central reading for safety analysis; 
• Bone marrow assessment by aspiration and biopsy, according to standard 
practice at the site(within 28 days prior to first dose  of study drug)  
• Spleen size measurement by magnetic resonance imaging (MRI; computed 
tomography [CT] scan for patients not able to tolerate MRI) within 14 days 
prior to study drug administration. Imaging will be transmitted to a central 
imaging center for central reading; 
• Determine if the patient meets the inclusion/exclusion criteria. 
5.2.2 
Phase 2: Cycle 1, Day 1 
• Review eligibility criteria and laboratory test results; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
obtained before the first dose of study drug is taken; 
• ECOG Performance Status (may be obtained within 24 hours prior to study 
drug administration); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G) (may be obtained within 24 hours prior to study drug 
administration);  
• ECG – triplicate (pre-dose and approximately 2, 4, 6, and 8 hours post-dose; 
centrally read); 
• Obtain blood samples for PK assessment (sampling time points are pre-dose 
and approximately 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose); 
• JAK2 V617F allele burden (pre-dose may be obtained within 24 hours prior 
to study drug administration); 
• Phospho-STAT3 (pre-dose and approximately 2 and 3hours post-dose) (pre-
dose may be obtained within 24 hours prior to study drug administration); 
• Cytokine level(pre-dose only; may be obtained within 24 hours prior to 
study drug administration); 


 
 
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• MPN SAF (MPN-10) (may be obtained within 24 hours prior to study drug 
administration); 
• Distribute study drug and instruct patient regarding completion of the study 
drug dosing diary (may be done within 24 hours prior to study drug 
administration); 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H) (may be obtained within 24 hours prior to 
study drug administration and following study drug administration); and 
• Concomitant medication notation (may be obtained within 24 hours prior to 
study drug administration). 
5.2.3 
Phase 2: Cycle 1, Day 8 (±2 days) 
• Laboratory tests (hematology, serum chemistries, as listed in Appendix G) 
• ECG – triplicate; pre-dose and approximately 2 hours post-dose; centrally 
read); 
• Review patient study drug dosing diary for compliance; 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.2.4 
Phase 2: Cycle 1, Day 15 (±2 days) 
• Directed physical examination, including weight and spleen size by 
palpation; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• ECG – triplicate (pre-dose and approximately 2 hours post-dose; centrally 
read); 
• Obtain blood samples for PK assessment (pre-dose and approximately 2 
hours post-dose); 
• Phospho-STAT3 (pre-dose and approximately 2 and 3hours post-dose);  
• Review patient study drug dosing diary for compliance; 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.2.5 
Phase 2: Cycle 1, Day 22 (±2 days) 
• Hematology and serum chemistry are to be obtained at the referring/local 
doctor’s office and faxed to the study site. 
5.2.6 
Phase 2: Cycle 2, 3, and 4, Day 1 (±3 days) 
• Directed physical examination including weight and spleen size by 
palpation; 
• Spleen size measurement by MRI (CT scan for patients not able to tolerate 
MRI) (Cycle 4 only). Imaging will be transmitted to a central imaging center 
for central reading; 


 
 
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• Vital signs (blood pressure, pulse, respiratory rate, and temperature); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G);  
• Serum or urine pregnancy test (female patients of childbearing potential 
only); 
• ECG – triplicate (Cycle 2: pre-dose and approximately 2 hours post-dose, 
centrally read; Cycle 3 and 4: pre-dose, locally read); 
• Obtain blood sample for PK assessment (Cycle 2 only; sampling time points 
are pre-dose and approximately 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose); 
• Bone marrow assessment (Cycle 4 only); 
• Response assessment (IWG-MRT and ELN); 
• JAK2 V617F allele burden if mutation present prior to start of therapy 
(Cycle 2 and Cycle 4, pre-dose); 
• Phospho-STAT3 (Cycle 2 only: pre-dose and approximately 2 and 3 hours 
post-dose;); 
• Cytokine (pre-dose); 
• MPN SAF (MPN-10) (Cycle 2 and Cycle 4, pre-dose); 
• Review patient study drug dosing diary for compliance and distribute study 
drug; 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.2.7 
Phase 2: Cycles 2, 3, and 4, Day 15; Cycles 5 and 6, Days 1 and 15 (±3 days) 
• Hematology and serum chemistry are to be obtained at the referring/local 
doctor’s office and faxed to the study site. 
5.2.8 
Phase 2: Cycle 7 and 10 Day 1 (±1 week) 
If a patient remains on study drug beyond 4 cycles, he/she will only be required 
to return to the clinic every 3 months.  
• Directed physical examination including weight and spleen size by 
palpation; 
• Spleen size measurement by MRI (CT scan for patients not able to tolerate 
MRI). Imaging will be transmitted to a central imaging center for central 
reading; 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• ECG – triplicate (pre-dose only; locally read); 
• Bone marrow assessment, Cycle 7 only; 
• Response assessment (IWG-MRT and ELN); 
• JAK2 V617F allele burden if mutation present prior to start of therapy 
(pre-dose); 
• MPN SAF (MPN-10) (pre-dose); 
• Review patient study drug dosing diary for compliance and distribute study 
drug, Cycle 7 only; 


 
 
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• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.2.9 
Phase 2: Cycle 8, 9, 11 and 12 Day 1 (±3 days) 
• Hematology and serum chemistry are to be obtained at the referring/local 
doctor’s office and faxed to the study site, unless the patient is scheduled for 
a site visit. 
5.2.10 
Phase 2: Cycle 13, Day 1 and Day 1 of every 3 cycles thereafter (±1 week) 
• Directed physical examination including weight and spleen size by 
palpation; 
• Spleen size measurement by MRI (CT scan for patients not able to tolerate 
MRI). Cycle 13 and after completion of months 18 and 24 treatment cycles 
(i.e. Cycle 19 and 25).  Imaging will be transmitted to a central imaging 
center for central reading;  After 24 treatment cycles, MRI will be performed 
as clinically indicated; however is not required to be transmitted to a central 
imaging center for central reading. 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature); 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• ECG – single reading (pre-dose only; locally read); 
• Bone marrow assessment (pre-dose) Cycle 13 only, then annually; 
• Response assessment (IWG-MRT and ELN); 
• JAK2 V617F allele burden if mutation present prior to start of therapy 
(pre-dose); 
• MPN SAF (MPN-10) (pre-dose); 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
5.2.11 
Phase 2: End of Study Assessments 
The following procedures will be performed within 30 days after the last dose of 
study drug or within 30 days after withdrawal from the study: 
• Complete physical examination including weight and spleen size by 
palpation; 
• Spleen size measurement by MRI (CT scan for patients not able to tolerate 
MRI) if not done within the past 8 weeks. 
• Vital signs (blood pressure, pulse, respiratory rate, and temperature); 
• ECOG Performance Status; 
• Laboratory tests (hematology, serum chemistries, and urinalysis, as listed in 
Appendix G); 
• ECG – triplicate or single reading if Cycle 13 or thereafter (locally read); 
• Response assessment (IWG-MRT and ELN); 
• MPN SAF (MPN-10); 


 
 
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• Collect any unused study drug and review patient study drug dosing diary 
for compliance, if applicable; 
• Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) (see Appendix H); and 
• Concomitant medication notation. 
 
All efforts will be made to complete the end of study visit for early termination 
patients however review of laboratory tests obtained from referring/local 
doctor’s office and a follow-up phone call to the patient may take place at a 
minimum for those patients refusing to return to the study site. 
5.2.12 
Phase 2: Follow-up 
If an unresolved AE was observed at end of study visit, patients must be 
followed until the event resolves, until the event is judged stable and not 
expected to resolve completely, or until the patient begins alternative treatment. 
 
6 
TREATMENTAND RESTRICTIONS 
6.1 
Treatment 
6.1.1 
Treatment Regimen, Dosage, and Duration 
Patients will be treated at the dose cohort level to which they are assigned. All 
study drug will be self-administered orally. NS-018 will be self-administered 
2 hours or more after the last meal and at least 1 hour before the next meal. 
 


 
 
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The dose levels planned and the numbers of patients in each dose level are 
presented below.  
 
Once Daily (QD) Cohort  [completed] 
Twice Daily (BID) Cohort 
Cohort 
NS-018Total 
Daily Dose(mg) 
No. of Patients 
Per Cohort 
Cohort 
NS-018 Total 
Daily Dose(mg) 
No. of Patients 
Per Cohort 
Phase 1 
 
 
Phase 1 
 
 
QD 1# 
75 
3-6 
 
 
 
QD 2# 
125 
3-6 
 
 
 
QD 3# 
200 
3-6 
BID 1# 
200 (100×2) £ 
3-6 
QD 4# 
300 
3-6 
 
－ 
－ 
 
－ 
－ 
BID 2# 
400 (200×2) £ 
3-6 
 
－ 
－ 
BID 3# 
600 (300×2) £ 
3-6 
 
－ 
－ 
BID 4#§ 
800 (400×2) £ 
3-6 
Phase 2 
MTD or lower Up to 20 patients 
MTD = maximum tolerated dose. 
£ BID dosing must be administered 12 hours apart 
#  If a DLT is experienced at any dose level, an intermediate cohort at a lower dose may be considered, as 
recommended by Safety Review Committee 
§ Additional cohorts at doses > 400 mg BID (800 mg/day) may be considered by the Sponsor if agreed by 
the Safety Review Committee after review of PK, PD, and safety data. The maximum planned increase in 
dose between cohorts will be 200 mg as the total daily dose (e.g.,  the dose level above 400 mg BID will 
not exceed  500 mg BID ) 
 
 
During the study, a Safety Review Committee will review data from each cohort 
and may make dosing schedule changes based on the data review. The Safety 
Review Committee is described in detail in Section 13.9. 
 
In the Phase 1 portion of the study, sequential cohorts of 3 to 6 patients will be 
treated with escalating doses until the MTD is established (see Section 6.1.1.3). 
The first patient in each cohort must be observed for at least 7 days of dosing 
with NS-018. If there is no clinically significant toxicity observed in that 
patient, enrollment in the cohort may continue. If a significant toxicity occurs, 
including any possible dose-limiting toxicity (DLT, see Section 6.1.1.2), the 
Safety Review Committee must meet and determine whether additional patients 
may be entered at that dose or an intermediate cohort at a lower dose should be 
considered. Each cohort can be assessed after at least 3 patients have completed 
28 days of study drug dosing. 
 
The Safety Review Committee can make dosing schedule changes (twice daily 
dosing rather than once daily dosing; intermediate dose levels if toxicity occurs 
that does not rise to the level of a DLT) based on pharmacodynamic, 
pharmacokinetic, and safety review. If twice daily dosing requires evaluation, 
dosing would start at one total daily dose level below the last once per day dose 
level that was declared safe.  For example, when 300 mg QD was declared safe, 


 
 
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the starting dose for BID dosing would be 100 mg twice daily, 12 hours apart 
[representing a total daily dose 200 mg]). 
 
Should BID dosing commence during the Phase I portion of the study, the SRC 
will meet after the last patient in that cohort has completed 28 days of dosing to 
assess the safety of that dosing schedule.  Should the BID cohort be declared 
safe, the next BID cohort may begin. However, during the Phase 1 escalation 
portion of study, intrapatient schedule changes are not permitted (i.e., patients 
who start QD dosing regimen must remain on QD dosing and patients who start 
on BID dosing must remain on BID dosing). 
 
If DLTs are seen in the 75 mg cohort, a cohort, labeled -1 and dosed at 50 mg, 
may be considered by the Safety Review Committee. Cohorts at doses >400 mg 
BID(800 mg/day) may be considered by the Sponsor if agreed by the Safety 
Review Committee after review of PK, PD, and safety data. The maximum 
planned increase in dose between cohorts will be 200 mg as the total daily dose 
(e.g.,  the dose level above 400 mg BID will not exceed 500 mg BID). 
 
Once a cohort is declared safe, patients treated at lower doses in earlier cohorts 
can be considered for intrapatient dose escalation. Intrapatient dose escalation is 
permissible in individual patients if the patient has received at least 3 months of 
study drug at a given dose and has not experienced any Grade 3 or 4 drug-
related toxicity and no evidence of significant clinical efficacy and the next 
highest dose cohort has already been declared safe by the Safety Review 
Committee.  Intrapatient dose escalation depends on the total daily dose and the 
confirmation of safety based on QD and/or BID dose regimen at a dose level. 
For example a patient at 100mg BID can increase by up to 200 mg BID only 
when 200 mg BID is declared safe by the Safety Review Committee. In the 
event that intrapatient dose escalation would result in a patient escalating more 
than one dose at a time, the eligibility of the patient for dose escalation would be 
reviewed and the dose level determined by the investigator and the medical 
monitor.  
 
After intrapatient dose escalation, patients will return to the study site after 
1 month of treatment at the higher dose to undergo physical examination 
(including assessment of spleen size by palpation) and safety laboratory tests 
(hematology and chemistry). Patients will return to 3-month visit schedule after 
this visit. 
 
When the MTD is reached, the Phase 2 portion of the study will commence. 
Additional patients will be added at the MTD level to confirm tolerability and 
explore efficacy, for a total of 20 patients. Consideration by the Safety Review 
Committee will also be given to suspending Phase 2 enrollment at the MTD, 
and instead adding the same total number of patients at a second dose level, the 
CAD. The CAD is defined as a dose level below the MTD with a clinically 
significant response rate and an acceptable toxicity profile as determined by the 


 
 
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investigator/medical monitor and sponsor. The expansion cohorts for the MTD 
and CAD, should they both be pursued, will not be concurrently open for 
enrollment. The two dose levels would instead be expanded sequentially. 
Consideration will also be given to enroll patients only at the CAD but not MTD 
level, based on the risk/benefit of therapy as judged by the investigator/medical 
monitor and sponsor. After Phase 2 has started, patients who are continuing 
treatment from the Phase 1 portion of the study are able to change to the Phase 2 
dose as intrapatient dose escalation, and based on risk/benefit as judged by the 
investigator. A change of schedule is allowed, such as a change from a QD 
Phase 1 dose to a BID Phase 2 dose. Since a patient could potentially be 
escalated by more than one dose upon crossing over from Phase 1 to the Phase 2 
dosing schedule, the eligibility of the patient for dose escalation would be 
reviewed and the dose level determined by the investigator and the medical 
monitor. A patient must receive at least 3 months of study drug at the Phase I 
dose and not experience any Grade 3 or 4 drug-related toxicity before being 
escalated to the Phase 2 dosing schedule. 
 
During the Phase 2 portion of the study, the Safety Review Committee will meet 
when a DLT-equivalent AE occurs, in order to determine whether additional 
patients may be enrolled at the same dose level or at a lower dose thereafter.  In 
addition, the Safety Review Committee will meet when the number of patients 
completing Cycle 1 reaches 10 to review the pooled safety information to 
determine if further enrollment is warranted. Any DLTs that occur at a dosing 
schedule will be evaluated separately. 
 
6.1.1.1 
Dose Reductions/Delays 
Patients who experience a DLT, as defined in Section 6.1.1.2, must have study 
drug administration interrupted: 1) when a Grade 4 drug related toxicity returns 
to ≤Grade 1 or to baseline within 4 weeks of study drug interruption, the 
investigator may recommence treatment, but at one dose level below that at 
which the toxicity occurred; 2) when a Grade 3 drug related toxicity returns to 
≤Grade 1 or to baseline within 4 weeks of study drug interruption, the 
investigator may recommence treatment at one dose level below that at which 
the toxicity occurred, or after discussion with the medical monitor, at the same 
dose at which the toxicity occurred. Discussion on the appropriateness of the 
patient continuing in the study will also include an evaluation of the current 
clinical response. 
 
At each step, the investigator must carefully evaluate the relevant risks and 
benefits to the patient of continued study participation. A second dose reduction 
can be considered by the investigator if a second significant toxicity occurs, to 
one further cohort dose below. Patients whose baseline dose has been reduced 
for toxicity cannot be dose escalated back to the prior dose. 
 


 
 
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Study drug administration may be interrupted for clinically significant toxicities 
of ≥Grade 1 that do not meet DLT criteria, at the discretion of the investigator. 
Once the toxicity has resolved to Grade 0 or 1, or to baseline level within 4 
weeks of study drug interruption, study drug may be resumed at either the same 
dose or one dose level below, at the discretion of the investigator.  Furthermore, 
subjects who experience Grade 4 life-threatening non-hematological toxicity 
will not be eligible for further treatment, unless reviewed by the Safety Review 
Committee and deemed appropriate for continued follow up and possible re-
initiation of study drug. 
 
Antidiarrheal or antiemetic therapy must be administered before interrupting 
therapy for Grade 1 or 2 nausea, vomiting, and/or diarrhea. 
 
Patients whose dose is reduced will continue the regular schedule of 
assessments. 
 
Patients requiring a >4 week interruption in study drug administration should be 
withdrawn from the study, unless reviewed by the Safety Review Committee 
and deemed appropriate for continued follow up and possible re-initiation of 
study drug. 
 
These guidelines for dose reductions or delays also apply to patients in Phase 2 
who experience a drug related toxicity 
 
6.1.1.2 
Definition of Dose-Limiting Toxicity 
A DLT is defined as any one or more of the following events that is unrelated to 
underlying disease, intercurrent illness, or concomitant medications: 
 
• Grade 4 neutropenia, thrombocytopenia, anemia, or lymphopenia 
• Grade 3 or 4 hematologic toxicity other than the above  
• Grade 3 or 4 non-hematologic toxicity, 
 
For nausea, vomiting, and/or diarrhea to be considered a DLT, the event must 
persist for at least 72 hours despite the use of an optimal antiemetic or 
antidiarrheal regimen. The optimal antiemetic regimen is to be determined by 
each investigator and should at a minimum include a 5-HT3 antagonist. The 
optimal antidiarrheal regimen is to be determined by each investigator and 
should at a minimum include Imodium®(Loperamide hydrochloride) or 
Lomotil®(diphenoxylate hydrochloride and atropine sulfate). Grade 3 nausea, 
vomiting, and/or diarrhea will not be considered a DLT in patients who did not 
receive optimal treatment with antiemetics or antidiarrheals.  
 
Important medical events other than those listed above may be considered a 
DLT based upon appropriate medical judgment and discussion by the Safety 
Review Committee (e.g., the same clinically significant toxicity not qualifying 


 
 
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as a DLT, but observed in multiple patients, or chronic Grade 2 toxicity that 
persists for more than 4 weeks despite interruption of therapy). 
6.1.1.3 
Definition of Maximum Tolerated Dose 
The MTD is defined as the dose at which ≤1 of 6 patients experience a DLT, 
with the next higher dose having at least 2 patients experiencing a DLT. 
 
Rules for Determination of MTD 
Number of Patients 
Experiencing DLT During 
Study Treatment  
Action 
0/3 
Escalate to the next higher dose level.  
1/3 
Up to 3 additional patients will be added before treating patients at a 
higher dose. If none of the additional patients experience a DLT, the 
dose will be escalated. If one of the additional patients has a DLT, 
the MTD will have been exceeded and 3 additional patients will be 
added at the previous dose to determine the MTD and recommended 
Phase 2 dose.  
2/3 
If 2 of the first 3 patients at a dose level experience a DLT, the MTD 
will have been exceeded and 3 additional patients will be added at 
the previous dose to determine the MTD and recommended Phase 2 
dose.  
DLT = dose-limiting toxicity; MTD = maximum tolerated dose. 
 
6.1.2 
Compliance Control 
Patient compliance will be monitored by assessing the tablet count from the 
drug packages returned at each visit. Patients will complete a study drug dosing 
diary daily that will document the time of day they took their study drug. Tablet 
counts will be compared by the site to the dosing diary to further assess 
compliance and aid patient education regarding compliance. Documentation on 
the electronic Case Report Form (eCRF) will account for patient compliance 
during each cohort. Patients will be instructed to return any unused study drug 
and packaging when attending clinic visits or if the patient is discontinued 
before the study is complete.  
 
Patients who take <80% of the expected prescribed regimen will be counseled 
on the importance of taking the study drug appropriately. If compliance is <80% 
during the first month of therapy, the patient will be counseled, remain on study 
drug and will follow the study assessment schedule. The patient will be included 
in all final study analysis populations (See Section 12.2), however the patient 
will not be included in the data from each cohort that is reviewed by the Safety 
Review Committee to determine dosing schedule changes. In the event that a 
patient’s compliance is <80% during the first month of therapy, an additional 
patient will be enrolled in the cohort and their data will be included in the cohort 
review by the Safety Review Committee as well as in all final study analysis 
populations. 


 
 
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6.2 
Study Restrictions 
6.2.1 
Concomitant Medications 
Any medication taken within 14 days of study drug administration will be 
considered a concomitant medication. The site will also enter the patient’s prior 
therapies for MF. Patients taking medications chronically should be maintained 
on the same dose and dosing schedule, if medically feasible. 
 
Necessary supportive measures for optimal medical care will be given 
throughout the study, including intravenous antibiotics to treat infections, blood 
components, antidiarrheals, and antiemetics. Additional care will be 
administered as indicated by the treating physician and the patient’s medical 
need. 
No 
concomitant 
cytotoxic 
therapy, 
whether 
conventional 
or 
investigational, will be allowed during this study. All concomitant medications 
and supportive therapy must be recorded in the eCRF. 
 
Routine prophylactic use of growth factors (G-CSF, GM-CSF, and 
erythropoietin) or high dose steroids (>10 mg/day of prednisone or prednisone 
equivalent) is not permitted. Therapeutic use may be considered at the treating 
physician’s discretion in patients who develop complications secondary to 
cytopenias (e.g., overt sepsis). 
 
Blood products can be administered as needed. 
 
The potential for drugs which are metabolized by cytochrome p450 enzymes 
being affected by NS-018 is considered possible.  The plasma concentration of 
these drugs may increase or decrease when administered concomitantly with 
NS-018. 
 
Patients currently taking medication that is substantially metabolized by 
cytochrome P450 (CYP) 1A2 or CYP3A4 (see Appendix E) are not eligible for 
this study.  Every effort should be made to change these medications to 
acceptable alternatives to allow patient enrollment. 
 
Patients taking strong CYP3A4 inducers or strong CYP3A4 inhibitors (see 
Appendix E) who cannot be safely switched to an acceptable alternative are 
excluded from the study.  
 
If a patient requires administration of a medication that is substantially 
metabolized by CYP1A2 or CYP3A4 or requires the administration of a strong 
CYP3A4 inhibitor after enrollment, and is benefiting from study treatment, the 
NS-018 dose will be decreased by 50%. When the course of treatment with a 
medication that is substantially metabolized by CYP1A2 or CYP3A4 or is a 
strong CYP3A4 inhibitor has been completed, the patient will resume their 
previous dose of NS-018 beginning the next day. 
 


 
 
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Use of moderate or weak CYP3A4 inducers or moderate or weak CYP3A4 
inhibitors (see Appendix E) is discouraged (alternative therapies should be 
considered), but does not disqualify the patient from study participation and 
does not require dose modification. 
 
No other drugs that directly treat myelofibrosis are allowed during this study. 
No other investigational agents and anticancer agents are permitted while on 
study. Herbal medications should be discontinued and not initiated while 
participating in the study. 
 
7 
INVESTIGATIONAL PRODUCT 
7.1 
Clinical Trial Material 
NS-018 will be supplied by NS Pharma. 
 
The lot numbers and expiration dates (if available) of the drugs supplied will be 
recorded in the final report. 
7.2 
Pharmaceutical Formulation(s) 
NS-018 is provided in 25 mg and 100 mg film-coated tablets. The tablet 
contains 25 mg or 100 mg of NS-018 drug substance and the following inactive 
ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose 
sodium, hydroxypropyl cellulose, and magnesium stearate. 
7.3 
Administration 
The patient will be instructed to take study drug 2 hours or more after the last 
meal and at least 1 hour before the next meal. When the twice daily (BID) 
dosing schedule is initiated, NS-018 doses must be administered at least 12 
hours apart. 
7.4 
Labeling and Packaging 
Open-label supplies will have a label indicating the number of tablets, storage 
conditions, directions for use, and sponsor study number and identification, as 
well as appropriate cautionary language for investigative material. Each bottle 
will contain 40 tablets. The labels will include space for the patient number and 
initials to be entered by the investigator.  
7.5 
Dispensing Procedures and Storage Conditions 
7.5.1 
Dispensing Procedures 
NS-018 will be dispensed to patients in high density polyethylene bottles with 
polypropylene caps containing 40 tablets. NS-018 will be dispensed at Cycle 1 
Day 1 and all other applicable visits. 
 
At each visit, patients will bring the bottles of study drug dispensed to calculate 
study drug compliance. 
 
Patients will be instructed not to split, crush, or chew tablets. 


 
 
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7.5.2 
Storage Conditions 
NS-018 tablets should be stored away from light at 2 to 8 °C. 
 
Study drug must be stored in a pharmacy or a locked and secure storage facility, 
accessible only to those individuals authorized by the investigator to dispense 
the investigational drug. 
 
8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
8.1.1 
Collection of Adverse Events 
It is responsibility of the investigator to collect all AEs (both serious and 
non-serious) derived by spontaneous, unsolicited reports of patients, by 
observation and by routine open questionings e.g., "How have you felt since I 
last saw you?" 
8.1.2 
Definition of Adverse Events 
An AE is any untoward medical occurrence that occurs in a patient or clinical 
investigation subject administered a pharmaceutical product, and which does not 
necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including abnormal 
laboratory finding), symptom, or disease temporally associated with the use of 
an investigational product, whether or not considered related to the product. 
 
Progression of disease is considered an efficacy outcome parameter and should 
not be captured as an AE. 
 
All AEs, including intercurrent illnesses, occurring during the study will be 
documented in the eCRF. Concomitant illnesses, which existed before entry into 
the study, will not be considered AEs unless they worsen during the treatment 
period.  All AEs, regardless of the source of identification (e.g., physical 
examination, laboratory assessment, ECG, reported by patient), must be 
documented. 
 
Pre-existing conditions will be recorded in the eCRF on the Medical History or 
appropriate page.   
 
A treatment-emergent AE (TEAE) will be defined as an AE that begins or that 
worsens in severity after at least one dose of study drug has been administered. 
8.1.3 
Assessment of Adverse Events 
Each AE will be assessed by the investigator with regard to the following 
categories. 


 
 
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8.1.3.1 
Seriousness 
A serious AE (SAE) is defined as an AE that meets any of the following 
criteria: 
• Results in death; 
• Is life-threatening; 
NOTE: The term “life-threatening” in the definition of “serious” refers to 
an event in which the patient was at risk of death at the time of the event. 
It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization; 
NOTE: In general, hospitalization for treatment of a pre-existing 
condition(s) that did not worsen from baseline is not considered an AE 
and should not be reported as an SAE. 
• Results in disability/incapacity; 
• Is a congenital anomaly/birth defect; or 
• Is an important medical event. 
NOTE: Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered SAEs when, 
based upon appropriate medical judgment, they may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalizations, or the development of drug dependency. 
8.1.3.2 
Intensity 
Investigators should assess the severity of AEs according to CTCAE (see 
Appendix H).  In general, CTCAE v4.0 Severity Grades are: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated; 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; 
Grade 3: 
Severe 
or 
medically 
significant 
but 
not 
immediately 
life-threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care; 
Grade 4: 
Life-threatening consequences; urgent intervention indicated; 
Grade 5: 
Death related to AE. 
8.1.3.3 
Causality 
The causal relationship of the AE to study drug will be described as follows: 
• Probable: the AE: 
o Follows a reasonable temporal sequence from administration of 
the study drug. 
o Could not be reasonably explained by the patient’s clinical state, 
environmental or toxic factors or other therapies administrated to 
the patient. 
o Disappears or decreases on cessation or reduction in dose of the 
study drug. 


 
 
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o Follows a known pattern of response to the study drug. 
o Reappears or worsens upon rechallenge. 
 
• Possible: the AE: 
o Follows a reasonable temporal sequence from administration of 
the study drug. 
o Could be reasonable explained by the patient’s clinical state, 
environmental or toxic factors or other therapies administrated to 
the patient. 
o Follows a known pattern of response to the study drug. 
 
• Unlikely: the AE 
o Does not follow a reasonable temporal sequence from 
administration of the study drug. 
o Could be reasonably explained by the patient’s clinical state, 
environmental or toxic factors or other therapies administrated to 
the patient. 
o Does not follow a known pattern of response to the study drug. 
o Does not reappear or worsen upon rechallenge. 
 
• Not related: 
o The AE does not meet the above criteria. 
o There is sufficient information that the etiology of the AE is not 
related to the study drug. 
8.1.4 
Recording Adverse Events 
Patients should be instructed to report any AE that they experience to the 
investigator. Investigators should assess for AEs at each visit. Adverse events 
occurring during the clinical study and the follow-up period should be recorded 
in the eCRF. To capture the most potentially relevant safety information during 
a clinical study, it is important that investigators record accurate AE terms in the 
eCRF.  
 
In addition to the above AEs, patients will be instructed to report any changes in 
skin or vision in order to assess possible phototoxicity of NS-018. During the 
periodic safety monitoring, investigators should be reminded to inquire of the 
patients about any changes in their skin or vision. 
 
Investigators are required to document all AEs occurring during the clinical 
study, commencing with the first dose of NS-018 and including the protocol-
defined post-treatment follow-up period in the eCRF. The AEs occurring 
following the signature of the informed consent, but prior to the first dose of 
NS-018 will not be reported as AEs unless the event is related to a study 
procedure. This information (events occurring following the signature of the 
informed consent but prior to the first dose of NS-018, and not related to a study 
procedure) will be collected within the medical history section of the eCRF. It is 


 
 
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also important to record all AEs that result in permanent discontinuation of NS-
018, whether serious or non-serious. 
 
All AEs occurring after any administration of NS-018 will be followed until the 
event resolves, until the event is judged stable and not expected to resolve 
completely, or until the patient begins alternative treatment. 
 
All AE reports should contain a brief description of the event, date and time of 
onset, date and time of resolution, intensity, treatment required, relationship to 
study drug, action taken with the study drug, outcome, and whether the event is 
classified as serious. 
8.2 
Serious Adverse Event Reporting - Procedure for Investigators 
Initial Reports 
All SAEs occurring from the time of the administration of the first dose of study 
drug until 30 days following the last administration of study drug must be 
reported to PAREXEL within 24 hours of the knowledge of the occurrence 
(this refers to any AE that meets any of the aforementioned serious criteria). 
Serious AEs that the investigator considers related to study drug occurring after 
the 30-day follow-up period will also be reported to PAREXEL. Events that 
occur after signing consent that are considered related to a required study 
procedure will also be captured as AEs/SAEs. 
 
To report the SAE, fax the completed SAE report form to PAREXEL (fax 
number listed below) within 24 hours of awareness. PAREXEL safety personnel 
are available for SAE reporting on a 24-hour basis. Reports are reviewed during 
normal business hours. 
 
Safety Contact Information: 
PAREXEL International 
1 Federal Street 
Billerica, MA 01821-3559 
 
SAE Contact Information: 
 
 
 
 
Serious AEs should be reported to the reviewing Institutional Review Board 
(IRB) according to individual requirements. A copy of that report must be 
retained at the investigative site and filed in the investigator Site File. 
 
The sponsor will notify FDA and all participating investigators in an IND safety 
report of any adverse experience associated with the use of the drug that is both 
serious and unexpected or of potentially serious risks from clinical trials or any 
other source, as soon as possible, but no later than 15 calendar days after the 
PPD


 
 
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sponsor receives the safety information and determines that the information 
qualifies for reporting. 
 
Follow-Up Reports 
The investigator must continue to follow the patient until the SAE has subsided, 
or until the condition becomes chronic in nature, stabilizes (in the case of 
persistent impairment), or the patient dies. Within 48 hours of receipt of new 
information, the updated follow-up SAE report form, along with any supporting 
documentation (e.g., laboratory test reports, patient discharge summary, or 
autopsy reports), should be faxed to PAREXEL clinical safety personnel. 
8.3 
Exposure In Utero During Clinical Studies 
The sponsor has a responsibility to monitor the outcome of pregnancies where 
there has been maternal exposure to the study drug.  
 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the 
study drug may have interfered with the effectiveness of a contraceptive 
medication. 
 
Elective abortions without complications should not be handled as AEs, unless 
they were therapeutic abortions (see below). Hospitalization for normal delivery 
of a healthy newborn should not be considered a SAE. 
 
All pregnancies must be reported by the investigator to the sponsor on the initial 
pregnancy report form within 24 hours after becoming aware of the pregnancy. 
The investigator must follow up and document the course and the outcome of all 
pregnancies even if the patient was discontinued from the study or if the study 
has finished. 
 
All outcomes of pregnancy must be reported by the investigator to the sponsor 
on the pregnancy outcome report form within 30 days after he or she has gained 
knowledge of the normal delivery or elective abortion. 
 
Any SAE that occurs during pregnancy (including SAEs occurring after last 
administration of study drug) must be recorded on the SAE report form 
(e.g., maternal serious complications, spontaneous or therapeutic abortion, 
ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, or birth 
defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs 
 
If a female partner of a male study patient who has been exposed to the study 
drug becomes pregnant, the pregnancy and outcome of pregnancy should be 
monitored. 
8.4 
Laboratory Assessments 
Safety laboratory assessments (hematology, chemistry, and urinalysis) will be 
performed locally at each center’s laboratory by means of their established 


 
 
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methods. Before starting the study, the investigator will supply the sponsor with 
a list of the normal ranges and units of measurement. 
8.5 
Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of 
Procedures (Appendix A): 
• Blood pressure (systolic and diastolic; mmHg); 
• Heart rate (beats per minute); 
• Body temperature (°C, oral); 
• Respiration rate (breaths per minute). 
8.6 
Electrocardiograms 
To determine whether NS-018 causes prolongation of the QTc interval, 12-lead 
ECG tracings will be collected as outlined below from all patients treated with 
NS-018: 
• Screening (locally read for eligibility determination; centrally read for 
analysis); 
• Cycle 1 Day 1: pre-dose and 2, 4, 6, and 8 hours after administration of 
NS-018; centrally read; 
• Cycle 1 Day 8 (Phase 1 and Phase II), Cycle 1 Day 15 (Phase 2): pre-
dose and 2 hours after administration of NS-018; centrally read; 
• Cycle 2 Day 1: pre-dose and 2 hours after administration of NS-018; 
centrally read; and 
• Cycle 3 Day 1, Cycle 4 Day 1, Cycle 7 Day 1 and every 3 cycles 
thereafter and End of Study: pre-dose; locally read.  
 
All ECGs up to Cycle 13 will be taken in triplicate about 1 minute apart and the 
median QTc value will be evaluated at the respective study site for inclusion 
criterion 10 (Section 4.1), for compliance with study protocol-defined 
procedures and safety.  After Cycle 13, all ECGs will be single reading only. 
 
When time points for ECG measurements coincide with the time points for 
pharmacokinetic sampling, triplicate ECG collection should take place 
immediately prior to the collection of the plasma sample for pharmacokinetics.  
 
All ECGs will be read locally and/or centrally. The ECGs for central reading 
will be sent after local reading; transmission will not be done immediately. 
Details regarding the ECG collection and reading will be provided in the study 
reference manual. 
 
Following the analysis of the PK data from the first cohort of patients, the ECG 
schedule may be modified so that tracings are taken around the time of peak 
plasma concentrations. 
8.7 
Physical Examinations 
Physical examinations, including weight and spleen size, will be performed in 
accordance with the Schedule of Procedures (Appendix A).  


 
 
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9 
EFFICACY ASSESSMENTS 
9.1 
Treatment Response 
Efficacy will be assessed using the IWG-MRT14during the Phase I portion of the 
study and IWG-MRT and ELN15 during the Phase II portion of the study.  The 
criteria are provided in Appendix I. 
9.2 
Spleen Size Assessment 
In the Phase 1 portion of the study, spleen size will be assessed clinically, by 
palpation. 
 
In Phase 2, spleen size will be assessed by palpation and by MRI (CT scan for 
patients not able to tolerate MRI), which will be transmitted to the central 
reading center and read centrally. Details regarding the MRI/CT protocol will be 
provided in the study reference manual. 
9.3 
Bone Marrow Assessment 
Bone marrow will be assessed by aspiration and biopsy, according to standard 
practice at the site.  
 
10 
PHARMACODYNAMIC AND PHARMACOKINETIC ASSESSMENTS 
Instructions for the processing, handling, and shipment of samples for central 
analysis will be provided in the study reference manual. 
10.1 
Pharmacodynamic Assessments 
10.1.1 
JAK2 V617F Allele Burden Assessment 
The intended time points for JAK2 V617F allele burden assessment in both the 
Phase 1 and Phase 2 portion of the study are specified below. 
 
• Cycle 1 Day 1: pre-dose; 
• Cycle 2 Day 1: pre-dose (if mutation present prior to start of therapy); 
• Cycle 4 Day 1: pre-dose (if mutation present prior to start of therapy); 
and 
• Cycle 7 Day 1 and every 3 cycles thereafter: pre-dose (if mutation 
present prior to start of therapy). 
10.1.2 
Phospho-STAT3 Assessment 
The intended time points for Phospho-STAT3 assessment are specified below 
for each phase of the study. 
 
Phase 1: 
• Cycle 1 Day 1: pre-dose and approximately 3 and 6 hours after 
administration of NS-018 ; 
• Cycle 1 Day 8: pre-dose and approximately 3 and 6 hours after 
administration of NS-018 ; 


 
 
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• Cycle 2 Day 1: pre-dose and approximately 3 and 6 hours after 
administration of NS-018 ; 
 
Phase 2:  
• Cycle 1 Day 1: pre-dose and approximately 2 and 3 hours after 
administration of NS-018 ; 
• Cycle 1 Day 15: pre-dose and approximately 2 and 3 hours after 
administration of NS-018 ; 
• Cycle 2 Day 1: pre-dose and approximately 2 and 3 hours after 
administration of NS-018 ; 
 
10.1.3 
Cytokine Assessment 
The intended time points for cytokine assessment in both the Phase 1 and Phase 
2 portions of the study are specified below. 
 
• Cycle 1 Day 1: pre-dose 
• Cycle 2 Day 1: pre-dose 
• Cycle 3 Day 1: pre-dose 
• Cycle 4 Day 1: pre-dose 
 
Additional analysis of excess plasma PD samples may be performed for other 
pharmacodynamic marker evaluations. 
 
10.2 
Pharmacokinetic Assessment 
Blood samples will be obtained for PK assessments to analyze NS-018 and its 
metabolites. The intended time points are specified below for each phase of the 
study. 
 
Phase 1: 
• Cycle 1 Day 1: pre-dose and approximately 0.5, 1, 2, 3, 4, 6, 8, and 
24 hours after administration of NS-018; 
• Cycle 1 Day 8: pre-dose and approximately 0.5, 1, 2, 3, 4, 6, and 8 hours 
after administration of NS-018; and 
• Cycle 2 Day 1: pre-dose and approximately 0.5, 1, 2, 3, 4, 6, 8, and 
24 hours after administration of NS-018. 
 
Phase 2: 
• Cycle 1 Day 1: pre-dose and approximately 0.5, 1, 2, 3, 4, 6, 8, and 
24 hours after administration of NS-018; 
• Cycle 1 Day 15: pre-dose and approximately 2 hours after administration 
of NS-018; and 
• Cycle 2 Day 1: pre-dose and approximately 0.5, 1, 2, 3, 4, 6 and 8 hours 
after administration of NS-018. 
 


 
 
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Pharmacokinetic parameters to be estimated include observed maximum 
concentration (Cmax), time to maximum plasma concentration (Tmax), area 
under the plasma concentration-time curve (AUC), terminal elimination half-life 
(t1/2), and accumulation ratio (R). 
 
A twice daily dosing schedule may be initiated based on results from PK 
analysis. 
 
Additional analysis of excess plasma PK samples may be performed for the 
further understanding of drug metabolites and for the understanding of drug 
levels of concomitant medications which might have effected levels (or 
interfered with measurement) of the experimental product. 
 
11 
OTHER ASSESSMENTS 
During the Phase I portion of the study, the Myelofibrosis Symptom Assessment 
Form (MF SAF, see Appendix J) will be completed at baseline and repeated at 
Cycle 2 Day 1 and Cycle 4 Day 1 and every 3 months thereafter, including End 
of Study.  
 
During the Phase II portion of the study, the Myeloproliferative Neoplasm 
Symptom Assessment Form [MPN SAF(MPN-10), see Appendix L] will be 
completed at baseline and repeated at Cycle 2 Day 1 and Cycle 4 Day 1 and 
every 3 months thereafter, including End of Study.  
 
Analysis of urine samples from patients in the Phase 2 portion of the study 
(C1D1, Pre-Dose and Single point, 100ml, 2-6 hours post dose on Cycle 2 Day 
1, first 6 patients) will be performed for the further understanding of drug 
metabolites and for the understanding of drug levels of concomitant medications 
which might have effected levels (or interfered with measurement) of the 
experimental product. 
 
12 
STATISTICS 
Additional statistical analyses, other than those described in this section, may be 
performed if deemed appropriate. A description of the statistical analysis 
performed on the study data will be outlined in the Statistical Analysis Plan. 
 
Each phase of this study will be analyzed separately. All tables, figures and 
listings will therefore be separated by study phase. 
 
Interim analyses of PK, PD, and safety data from the Phase 1 portion of the 
study will be conducted after the MTD has been established.   
 


 
 
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An analysis of all existing PK, PD, and safety data from the Phase 2 portion of 
the study will be conducted 6 months after the last patient is enrolled in this part 
of the study.   
 
The complete analysis of all study data will be contained in the clinical study 
report at the end of the study.   
12.1 
Sample Size Determination 
Approximately 24 patients will be enrolled during the Phase 1 portion (treated 
with escalated doses in a standard 3+3 cohort design) and 20 patients will be 
enrolled during the Phase 2 portion (treated at the MTD). In the Phase 1 portion, 
additional cohorts at doses >400 mg BID(800 mg/day) may be considered by 
the Sponsor if agreed by the Safety Review Committee after review of PK, PD, 
and safety data; if additional cohorts are considered the total number of patients 
in Phase 1 may increase beyond the approximately 24 projected patients. The 
maximum planned increase in dose between cohorts will be 200 mg as the total 
daily dose (e.g.,, the dose level above 400 mg BID will not exceed  500 mg 
BID). Consideration by the Safety Review Committee will also be given to 
suspending Phase 2 enrollment at the MTD, and instead adding the same total 
number of patients at a second dose level, the CAD. The expansion cohorts for 
the MTD and CAD, should they both be pursued, will not be concurrently open 
for enrollment. The two dose levels would instead be expanded sequentially. 
Consideration will also be given to enroll patients only at the CAD but not MTD 
level, based on the risk/benefit of therapy as judged by the investigator/medical 
monitor and sponsor.  
 
The probability of observing at least one event with a prevalence rate of e.g. 
30% is greater than 99% in the Phase 2 portion. 
 
Probabilities for observing at least one event/one response for other scenarios 
are presented in the table below: 
 
Prevalence rate / 
Response rate 
Probability of observing at least one AE / one response 
Phase 2 portion (N=20) 
5 % 
64,2 % 
10 % 
87,8 % 
15 % 
96,1 % 
20 % 
98,8 % 
30 % 
> 99,9 % 
 
12.2 
Analysis Populations 
12.2.1 
Safety Population 
The Safety Population consists of all patients who receive at least one dose of 
study drug. 


 
 
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12.2.2 
Pharmacokinetic Population 
The PK Population includes all patients who receive at least one dose of study 
drug and have at least one evaluable PK profile.  
12.2.3 
Pharmacodynamic Population 
The PD Population includes all patients who receive at least one dose of study 
drug and have baseline and at least one post-baseline PD assessment.  
12.2.4 
Efficacy Population 
The Efficacy Population includes all patients who receive at least one dose of 
study drug and have baseline and at least one post-baseline efficacy assessment. 
12.3 
Demographic and Baseline Characteristics 
Baseline and demographic characteristics will be summarized by dose level. 
Continuous variables will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum). Categorical variables 
will be summarized with frequency tables.  
12.4 
Efficacy Analyses 
Since the primary objective of this study is to evaluate the safety, tolerability, 
MTD, and clinically active dose of NS-018 in patients with PMF, post-PV MF, 
or post-ET MF, no formal hypothesis testing will be performed for efficacy 
parameters. Efficacy analysis will be based on the Efficacy Population. 
 
The responses to treatment assessed using the IWG consensus criteria(Phase I) 
and the IWG MRT and ELN Response Criteria (Phase II)will be tabulated by 
dose level and visit. The number and percentage of patients achieving the 
response will be provided for each response level. The objective response rate 
(the percentage of patients with confirmed complete remission (CR), partial 
response (PR), or clinical improvement (CI) during the treatment period) and its 
95% exact binomial confidence interval will be provided by dose level. Quality 
of life assessed using the MF SAF (Phase I) or MPN SAF (MPN-10) (Phase II) 
will be summarized by dose level and visit. Change in spleen size by MRI (CT 
scan for patients not able to tolerate MRI) for the Phase 2 portion will be 
summarized for the cohort.  
12.5 
Safety Analyses 
All safety analyses will be based on the Safety Population. Adverse events, vital 
sign measurements, clinical laboratory information, ECG measurements, and 
concomitant medications will be summarized by dose level. 
 
Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) classification system. The severity of all AEs will be 
graded according to the NCI CTEP CTCAE version 4.0. A summary of all AEs 
will be provided by system organ class and preferred term. The same summaries 
will be performed for Grade 3/4 AEs and drug-related AEs. Listings will be 
presented for SAEs, Grade 3/4 AEs, and AEs leading to discontinuation from 
the study. 


 
 
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Clinical laboratory evaluations at each visit and change from baseline (Cycle 1 
Day 1) will be summarized by dose level. A laboratory value shift table will be 
provided. Vital signs and ECG parameters at each assessment time will be 
summarized by dose level. Other safety variables and their changes from 
baseline (when applicable) will be summarized by dose level at each of the 
scheduled assessment times. 
12.6 
Pharmacokinetic Analyses 
Blood samples for PK analysis of NS-018 and its metabolites will be collected 
at designated study visits. All PK analyses will be based on the PK population. 
 
Plasma concentrations of NS-018 and its metabolites will be summarized 
descriptively by dose level and time point of collection. Summary statistics 
including number of patients, arithmetic mean, geometric mean, geometric CV, 
standard deviation, minimum, maximum, median, coefficient of variation, and 
standard error of the mean will be presented. Individual patient and mean 
plasma concentrations of NS-018 and its metabolites will be plotted vs. time in 
linear and log-linear scale.  
 
Derived PK parameters will be listed and summarized using the same measures 
as for the plasma concentrations of NS-018 and its metabolites. 
12.6.1 
Relationship between PK data and endpoints 
The relationship between plasma concentrations of NS-018 and its metabolites 
and each efficacy and toxicity outcome measure as well as any biomarker 
endpoints will be explored. The details will be outlined in the Statistical 
Analysis Plan.  
12.7 
Pharmacodynamic Analyses 
All PD analyses (JAK2 V617F allele burden, phospho-STAT3, and cytokine 
levels) will be based on the PD Population. JAK2 V617F allele burden and 
phospho-STAT3 values and cytokine levels at each time point and changes from 
baseline will be summarized descriptively by dose level and listed. The 
relationship between NS-018 dose level and JAK2 V617F allele burden or 
phospho-STAT3 levels over time will be explored. 
13 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
13.1 
Data Quality Assurance 
The sponsor will conduct a site visit to verify the qualifications of each 
investigator, inspect the site facilities, and inform the investigator of 
responsibilities and the procedures for ensuring adequate and correct 
documentation. 
 
The investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the study 
for each study participant. All information recorded on the eCRF/electronic data 


 
 
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capture (EDC) system for this study must be consistent with the patients’ source 
documentation (i.e., medical records). 
13.1.1 
Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each 
study center using eCRF. Data from external sources (such as laboratory data) 
will be imported into the database. Once the eCRF clinical data have been 
submitted to the central server at the independent data center, corrections to the 
data fields will be captured in an audit trail. The reason for change, the name of 
the person who performed the change, together with the time and date will be 
logged to provide an audit trail.  
 
If additional corrections are needed, the responsible monitor or data manger will 
raise a query in the EDC application. The appropriate staff at the study site will 
answer queries sent to the investigator. The name of the staff member 
responding to the query, and time and date stamp will be captured to provide an 
audit trail. Once all source data verification is complete and all queries are 
closed, the monitor will freeze the eCRF. 
 
The specific procedures to be used for data entry and query resolution using the 
eCRF/EDC system will be provided to study sites in a training manual. In 
addition, site personnel will receive training on the eCRF/EDC system. 
 
13.2 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the CRFs or EDC 
system promptly. All source documents from which eCRF/EDC entries are 
derived should be placed in the patient’s medical records. Measurements for 
which source documents are usually available include laboratory assessments, 
and ECG recordings.  
 
Data that will be entered directly into the eCRF/EDC system (i.e., for which 
there is no prior written or electronic record of data, such as Quality of Life 
assessments) are considered to be source data. 
 
The original eCRF/EDC entries for each patient may be checked against source 
documents at the study site by the site monitor.  
 
After review by the site monitor, completed eCRF/EDC entries will be 
uploaded. Instances of missing or uninterpretable data will be discussed with the 
investigator for resolution.  
 
The specific procedures to be used for data entry and query resolution using the 
eCRF/EDC system will be provided to study sites in a training manual.  In 
addition, site personnel will receive training on the eCRF/EDC system. 


 
 
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13.2.1 
Data Collection 
The investigators (and appropriately authorized staff) will be given access to an 
online web-based EDC) system which is 21 Code of Federal Regulations (CFR) 
Part 11 compliant. This system is specifically designed for the collection of the 
clinical data in electronic format. Access and right to the EDC system will be 
carefully controlled and configured according to each individual’s role 
throughout the study. In general, only the investigator and authorized staff will 
be able to enter data and make corrections in the eCRFs. 
 
The eCRF should be completed for each patient included in the study and 
should reflect the latest observations on the patients participating in the study. 
Therefore, the eCRFs are to be completed as soon as possible during or 
immediately after the patient’s visit or assessment. The investigator must verify 
that all data entries in the eCRF are accurate and correct. If some assessments 
cannot be done, or if certain information is unavailable, not applicable or 
unknown, the investigator should indicate this in the eCRF.  
 
Computerized data-check programs and manual checks will identify any clinical 
data discrepancies for resolution. Corresponding queries will be loaded into the 
system and the site will be informed about new issues to be resolved on-line. All 
discrepancies will be solved on-line directly by the investigator or by authorized 
staff. Off-line edit checks will be done to examine relationships over time and 
across panels to facilitate quality data. 
 
After completion, the investigator will be required to electronically sign off the 
clinical data 
 
Data about all study drug dispensed to the patient and any dosage changes will 
be tracked on the eCRF.  
13.3 
Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, 
compare EDC/eCRF entries and individual patient’s medical records, assess 
drug accountability, and ensure that the study is being conducted according to 
pertinent regulatory requirements. EDC/eCRF entries will be verified with 
source documentation. The review of medical records will be performed in a 
manner to ensure that patient confidentiality is maintained. 
 
Checking of the eCRF/EDC entries for completeness and clarity, and cross-
checking with source documents, will be required to monitor the progress of the 
study. Moreover, Regulatory Authorities of certain countries, IRBs, Institutional 
Ethics Committees (IECs), and/or the sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit 
inspections. Direct access to source data will be required for these inspections 
and audits; they will be carried out giving due consideration to data protection 
and medical confidentiality. The investigator assures the sponsor of the 
necessary support at all times. 


 
 
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13.4 
Data Processing 
All data will be entered by site personnel into the eCRF/EDC system (as 
detailed in Section 13.2.1). 
 
The data-review and data-handling document, to be developed during the 
initiation phase of the study, will include specifications for consistency and 
plausibility checks on data and will also include data-handling rules for obvious 
data errors. Query/correction sheets for unresolved queries will be sent to the 
study monitors for resolution with the investigator. The database will be updated 
on the basis of signed corrections.  
 
Previous and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Reference List (DRL), which employs the 
Anatomical Therapeutic Classification (ATC) classification system. Medical 
history/current medical conditions and AEs will be coded using the MedDRA 
terminology. 
 
Previous and concomitant diseases as well as AEs will be coded with MedDRA. 
 
The versions of the coding dictionaries will be provided in the Clinical Study 
Report. 
13.5 
Archiving Study Records 
According to International Conference on Harmonization (ICH) guidelines, 
essential documents should be retained for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 
2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. However, these documents should be retained for a 
longer period if required by the applicable legal requirements. 
13.6 
Good Clinical Practice 
Good Clinical Practice (GCP) is an international ethical and scientific quality 
standard for designing, conducting, recording, and reporting studies that involve 
human subjects. Compliance with this standard provides public assurance that 
the rights, safety, and well-being of study subjects are protected, consistent with 
the principles that have their origin in the Declaration of Helsinki, and that the 
clinical study data are credible. 
13.7 
Informed Consent 
Before each patient is admitted to the study, informed consent will be obtained 
from the patient (or his/her legally authorized representative) according to the 
regulatory and legal requirements of the participating country. This consent 
form must be dated and retained by the investigator as part of the study records. 
The investigator will not undertake any investigation specifically required only 
for the clinical study until valid consent has been obtained. The terms of the 


 
 
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consent and when it was obtained must also be documented in the eCRF/EDC 
system. 
 
If a protocol amendment is required, the informed consent form may need to be 
revised to reflect the changes to the protocol. If the consent form is revised, it 
must be reviewed and approved by the appropriate IEC/IRB, and signed by all 
patients subsequently enrolled in the study as well as those currently enrolled in 
the study. 
13.8 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents 
will be approved by the IEC/IRB/Competent Authorities, in accordance with 
local legal requirements. The sponsor must ensure that all ethical and legal 
requirements have been met before the first patient is enrolled in the study. 
 
This protocol is to be followed exactly. To alter the protocol, amendments must 
be written, receive approval from the appropriate personnel, and receive 
IRB/IEC/Competent 
Authority 
approval 
prior 
to 
implementation 
(if 
appropriate). Following approval, the protocol amendment(s) will be submitted 
to the Investigational New Drug application (IND) under which the study is 
being conducted.  
 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be communicated to the investigator by PAREXEL or NS 
Pharma. All protocol amendments will undergo the same review and approval 
process as the original protocol. A protocol amendment may be implemented 
after it has been approved by the IRB, unless immediate implementation of the 
change is necessary for patient safety. In this case, the situation must be 
documented and reported to the IRB within 5 working days. 
 
Administrative changes (not affecting the patient benefit/risk ratio) may be 
made without the need for a formal amendment. All amendments will be 
distributed to all protocol recipients, with appropriate instructions. 
13.9 
Safety Review Committee 
A Safety Review Committee, consisting of the actively recruiting investigators, 
the medical monitor overseeing the study for NS Pharma and a NS Pharma 
representative will meet to evaluate each cohort. If clinically significant toxicity 
occurs in the first patient in any cohort during their first 7 days of NS-018 
dosing, the Safety Review Committee will meet and determine dosing for future 
patients. The Safety Review Committee must review each cohort before patients 
can be enrolled into the next cohort. The Safety Review Committee can make 
dosing schedule changes (twice daily dosing rather than once daily dosing; 
intermediate dose levels if toxicity occurs that does not rise to the level of a 
DLT) based on pharmacodynamic, pharmacokinetic, and safety review. If twice 
daily dosing requires evaluation, dosing would start at one total daily dose level 
below the last once per day dose level that was declared safe. 


 
 
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If DLTs are seen in the 75 mg cohort, a cohort, labeled -1 and dosed at 50 mg, 
may be considered by the Safety Review Committee. Cohorts at doses >400 mg  
BID(800 mg/day)may be considered by the Sponsor if agreed by the Safety 
Review Committee after review of PD, PK, and safety data. The maximum 
planned increase in dose between cohorts will be 200 mg as the total daily dose 
(e.g., the dose level above 400 mg BID will not exceed 500 mg BID). 
 
Should BID dosing commence during the Phase I portion of the study, the SRC 
will meet after the last patient in that cohort has completed 28 days of dosing to 
assess the safety of that dosing schedule.  Should the BID cohort be declared 
safe, the next BID cohort may begin.  BID cohorts and QD cohorts may enroll 
simultaneously provided the previous lower dose of each cohort type has been 
declared safe by the SRC. 
 
During the Phase 2 portion of the study, the Safety Review Committee will meet 
when a DLT-equivalent AE occurs, in order to determine whether additional 
patients may be enrolled at the same dose level or at a lower dose thereafter.  In 
addition, the Safety Review Committee will meet when the number of patients 
who have completed Cycle 1 reaches 10 to review the pooled safety information 
to determine if further enrollment is warranted. 
13.10 
Duration of the Study 
A patient may continue to receive treatment with NS-018, administered 
continuously as daily therapy in cycles of 28 days duration, until the patient 
experiences unacceptable toxicity that precludes any further treatment, disease 
progression, and/or as long as the patient is benefiting from treatment, at the 
discretion of the investigator. 
13.11 
Premature Termination of the Study 
NS Pharma has the right to terminate the participation of either an individual 
site or the study at any time. Reasons for terminating the study include, but are 
not limited to, the following: 
1. Incidence or severity of AEs in this or other studies which indicates a 
potential health hazard to patients; 
2. Patient enrollment is unsatisfactory; 
3. Data recording is inaccurate or incomplete; or 
4. Investigator does not adhere to the protocol or applicable regulatory 
guidelines in conducting the study. 
13.12 
Confidentiality 
All study findings and documents will be regarded as confidential. The 
investigator and members of his/her research team must not disclose such 
information without prior written approval from the sponsor. 
 
The anonymity of participating patients must be maintained. Patients will be 
identified on the eCRF/EDC system and other documents submitted to the 


 
 
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55 
Amendment10: 21Apr2015 
sponsor by their patient number, initials and/or birth date, not by name. 
Documents not to be submitted to the sponsor that identify the patient (e.g., the 
signed informed consent) must be maintained in confidence by the investigator. 
13.13 
Publication Policy 
By signing the study protocol, the investigator agrees with the use of results of 
the study for the purposes of national and international registration, publication 
and information for medical and pharmaceutical professionals. If necessary, 
Regulatory Authorities will be notified of the investigator's name, address, 
qualifications and extent of involvement. 
 
An investigator shall not publish any data (poster, abstract, paper, etc.) without 
having consulted with the sponsor in advance.  Details are provided in a 
separate document. 
 
14 
LIST OF STUDY PERSONNEL 
14.1 
Sponsor 
NS Pharma, Inc. 
140 E Ridgewood Ave, 2nd Floor 
Paramus, NJ 07652 
 
 
14.2 
Contract Research Organization 
PAREXEL International 
195 West Street 
Waltham, MA 02451 
 
 
 
14.3 
Drug Safety 
PAREXEL International 
1 Federal Street  
Billerica, MA  01821-3559
 
 
 
PPD
PPD
PPD
PPD


 
 
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Amendment10: 21Apr2015 
15 
REFERENCES 
 
                                                 
1 James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A Unique clonal 
JAK2 
mutation 
leading 
constitutive 
signaling 
causes 
Polycythemia 
vera. 
Nature. 
2005;434:1144-48. 
2Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of function 
mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 2005;352:1779-90. 
3 Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation 
of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-61. 
4Wering G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG. Expression of Jak2V617F 
cause a Polycythemia vera-like disease with associated Myelofibrosis in a murine bone marrow 
transplant model. Blood. 2006;107:4274-81. 
5Shide K, Shimoda HK, Kumano T, Karube K, Kameda T, Takenaka K, et al. Development of 
ET, primary Myelofibrosis and PV in mice expressing JAK2 V617F. Leukemia. 2008;22:87-95. 
6 Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Path MRC, et al. JAK2 exon 12 mutations 
in polycythemia vera and idiopathic erythrocytosis. N. Engl. J. Med. 2007;356:459-68. 
7Aranaz P, Ormazabal C, Hurtado C, Erquiaga I, Calasanz MJ, Garcia-Delgado M, et al. A new 
potential oncogenic mutation in the FERM domain of JAK2 in BCR/ABL1-negative and V617F 
negative chronic myeloproliferative neoplasms revealed by a comprehensive screening of 17 
tyrosine kinase coding genes. Cancer Genet.Cytogenet. 2010;199:1-8. 
8Panteli KE, Hatzimichael EC, Bouranta PK, Katsaraki A, Seferiadis K, Stebbing J, et al. Serum 
interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic 
myeloproliferative diseases. Br. J. Haematol. 2005;130:709-15. 
9NS-018 Investigator Brochure. 
10Final Report for Study No.B091357:  A 4-week repeated dose oral gavage toxicity study of 
NS-018 (MPD-657) in rats followed by a 4-week recovery period.  Mitsubishi Chemical 
Medience Corporation.  Ibaraki, Japan.Oct 2010. 
11Final Report for Study No.B091358: A 4-week repeated dose oral gavage toxicity study of 
NS-018 (MPD-657) in beagle dogs.  Mitsubishi Chemical Medience Corporation.  Ibaraki, 
Japan.Oct 2010. 
12Final Report for Study No.BP-MPD-100726: Identification of human P450 isoforms involved 
in metabolism of NS-018.  Nippon Shinyaku Co, Ltd. Kyoto, Japan.  Nov 2010. 
13Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis 
in myelodysplastic syndromes.Blood. 1997;89:2079-2088. 
14Tefferi A, Barosi G, Mesa R, et al. International Working Group (IWG) consensus criteria for 
treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis 
Research and Treatment (IWG-MRT). Blood. 2006;108:1497-1503. 
 
15 Emanuel R, Tefferi A, Cervantes, F, Mesa R, et al. Revised response criteria for 
Myelofibrosis:  International Working Group-Myeloproliferative Neoplasms Research and 
treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood, 2013 122: 
1395-1398 
 
 


 
 
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Amendment10: 21Apr2015 
16 
SUPPLEMENT 
16.1 
Investigator’s Agreement 
By signing below I agree that: 
 
I have read this protocol. I approve this document and I agree that it contains all 
necessary details for carrying out the study as described. I will conduct this 
study in accordance with the design and specific provision of this protocol and 
will make a reasonable effort to complete the study within the time designated. I 
will provide copies of this protocol and access to all information furnished by 
NS Pharma to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study product and study 
procedures. I will let them know that this information is confidential and 
proprietary to NS Pharma and that it may not be further disclosed to third 
parties. I understand that the study may be terminated or enrollment suspended 
at any time by NS Pharma, with or without cause, or by me if it becomes 
necessary to protect the best interests of the study patients. 
 
I agree to conduct this study in full accordance with Food and Drug 
Administration Regulations, Institutional Review Board/Ethic Committee 
Regulations and ICH Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
_____________________________ 
 
____________________ 
Investigator’s Signature  
 
 
Date 
 
 
 
_____________________________ 
Investigator’s Name 


 
 
 
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APPENDIX A:  SCHEDULE OF PROCEDURES 
Schedule of Procedures – Phase 1 
Study Phase 
Screening 
Treatment Period – Phase 1 
Visit Timingp 
Day -14 to 
Day 0 
Cycle 1 
Day 1 
Cycle 1 
Days 8, 15, and 22 
Cycles 2, 3, and 4 
Day 1 
Cycle 7, Day 1 and 
every 3 cycles 
thereafter 
End of Studyo 
Visit Window 
 
 
±2 days 
±3 days 
±1 week 
 
Study Procedure 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Confirm/review eligibility criteria 
X 
X 
 
 
 
 
Medical history 
Xa 
 
 
 
 
 
Physical examination
Xb 
 
Xk 
Xk 
Xk 
Xb 
Vital signs 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
ECOG Performance Status 
X 
Xf 
 
 
 
X 
Clinical laboratory (see table next page)
Xd 
Xd,f 
Xd 
Xd 
Xd 
Xd 
Pregnancy test (serum or urine) 
X 
 
 
X 
 
 
12-lead electrocardiogram 
Xe 
Xh 
Xl (Day 8 only) 
Xm 
Xm 
Xm 
Bone marrow assessment
Xq 
 
 
X (Cycle 4 only) 
Xr 
 
Response assessment (IWG-MRT) 
 
 
 
X 
X 
X 
Pharmacokinetic sampling 
 
Xi 
Xi (Day 8 only) 
Xi (Cycle 2 only) 
 
 
JAK2 V617F allele burden
 
Xf 
 
Xn (Cycles 2 and 4) 
Xn 
 
Phospho-STAT3 
 
Xf,j 
X j (Day 8 only) 
Xj (Cycle 2only ) 
 
 
Cytokines 
 
Xf 
 
X 
 
 
MF SAF 
 
Xf 
 
X g  (Cycles 2 and 4) 
X g 
X 
Study drug dispensation 
 
Xf 
 
X 
X 
 
Diary dispensation 
 
Xf 
 
X 
 
 
Collect unused study drug 
 
 
 
 
 
X 
Compliance check 
 
 
X 
X 
X 
X 
Adverse events 
 
Xf 
X 
X 
X 
X 
Concomitant medications 
 
Xf 
X 
X 
X 
X 
a 
Including concomitant medications within 14 days prior to study drug administration, blood products transfused within 3 months prior to study drug administration, and concurrent baseline conditions. 
b 
Complete physical examination including weight and spleen size by clinical assessment (palpation). At screening, must be done within 7 days prior to Cycle 1, Day 1 (first dose). 
c 
Blood pressure, pulse, respiratory rate, and temperature; pre-dose during treatment. 
d 
Hematology includes erythrocytes, MCV, MCH, neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, leukocytes, hemoglobin and hematocrit. Serum chemistry includes BUN, LDH, 
creatinine, uric acid, total protein, albumin, glucose, total bilirubin, magnesium, alkaline phosphatase, AST, ALT, chloride, sodium, and potassium. Serum chemistry will also include amylase and lipase in 
the first 2 cycles. Urinalysis includes pH, protein, glucose, ketone, bilirubin, blood, and nitrite.  
e 
For eligibility determination, locally read; Median QTc must be ≤480 msec.  Centrally read for safety analysis. 
f 
Pre-dose; may be obtained within 24 hours prior to study drug administration. Adverse Events on Cycle 1, Day 1 will also be collected post-dose. 
g 
Pre-dose. 
h 
Pre-dose and 2, 4, 6, and 8 hours post-dose; centrally read. 
i 
Sampling times are pre-dose and approximately 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. Cycle 1, Day 8 will not include 24 hour time point). 


 
 
 
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j 
Pre-dose and approximately 3 and 6 hours post-dose.. 
k 
Directed physical examination including weight and spleen size by palpation. 
l 
Pre-dose and approximately 2 hours post-dose; centrally read. 
m Cycle 2: pre-dose and approximately 2 hours post-dose, in triplicate and centrally read. Cycles 3 and thereafter: pre-dose, in triplicate and locally read. After Cycle 13, single reading and locally read 
n 
If mutation present prior to start of therapy; pre-dose only. 
o 
Within 30 days after the last dose of study drug or within 30 days after withdrawal from the study. 
p 
For the purpose of scheduling procedures and evaluations, a treatment cycle is defined as 28 days. 
q 
Within 28 days prior to the first dose  of study drug 
r 
Every 6 months after Cycle 7 and annually after Cycle 13 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CBC=complete blood chemistry; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
JAK2=Janus kinase 2; LDH=lactate dehydrogenase; MF SAF=Myelofibrosis Symptom Assessment Form; STAT3=signal transducer and activator of transcription 3. 
 
 
Schedule of Safety Laboratory Procedures by Cycle (Site and Local Evaluations) – Phase 1 
Cycle 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Day 
1 
8 
15 
22 
1 
15 
1 
15 
1 
15 
1 
15 
1 
15 
1 
1 
1 
1 
1 
1 
1 
Site visit 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Local visit 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Local visit laboratory procedures at the indicated visits include: hematology (erythrocytes, MCV, MCH, neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, leukocytes, hemoglobin and 
hematocrit) and serum chemistry (BUN, LDH, creatinine, uric acid, total protein, albumin, glucose, total bilirubin, magnesium, alkaline phosphatase, AST, ALT, chloride, sodium, and potassium).  Serum 
chemistry will also include amylase and lipase in the first 2 cycles.  
Results should be faxed to the study site. 
 
 
 


 
 
 
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Schedule of Procedures – Phase 2 
Study Phase 
Screening 
 
Treatment Period – Phase 2 
Visit Timingq 
Day -14 to  
Day 0 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2, 3, and 4, 
Day 1 
Cycle 7, Day 1|and 
every 3 cycles 
thereafter 
End of Studyo 
Visit Window 
 
 
±2 days 
±2 days 
±3 days 
±1 week 
 
Study Procedure 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Confirm/review eligibility criteria 
X 
X 
 
 
 
 
 
Medical history 
Xa 
 
 
 
 
 
 
Physical examination
Xb 
 
 
Xl 
Xl 
Xl 
Xb 
Spleen size assessed by MRI (CT scan for 
patients not able to tolerate MRI) 
 
Xc 
 
 
 
 
 
X (Cycle 4 only) 
 
Xu 
 
Xp 
Vital signs 
Xd 
Xd 
 
Xd 
Xd 
Xd 
Xd 
ECOG Performance Status 
X 
Xh 
 
 
 
 
X 
Clinical laboratory (see table next page)
Xe 
Xe,h
Xe 
Xe 
Xe 
Xe 
Xe 
Pregnancy test (serum or urine) 
X 
 
 
 
 
 
 
12-lead electrocardiogram 
Xf 
Xi 
Xm 
Xm 
Xm 
Xm 
Xm 
Pharmacokinetic sampling 
 
Xj 
 
Xj 
Xj (Cycle 2 only) 
 
 
Urine PK 
 
Xs 
 
 
Xs (Cycle 2 only) 
 
 
Bone marrow assessment
Xr 
 
 
 
X (Cycle 4 only) 
Xt 
 
Response assessment (IWG-MRT and ELN) 
 
 
 
 
X 
X 
X 
JAK2 V617F allele burden
 
Xh
 
 
Xn(Cycles 2 and 4) 
Xn 
 
Phospho-STAT3 
 
Xh,k 
 
Xk 
Xk (Cycle 2 only) 
 
 
Cytokines 
 
Xh 
 
 
X 
 
 
 MPN SAF (MPN-10) 
 
Xh 
 
 
Xg (Cycles 2 and 4) 
X g 
X 
Study drug dispensation 
 
Xh 
 
 
X 
X 
 
Diary dispensation 
 
Xf 
 
 
X 
 
 
Compliance check 
 
 
X 
X 
X 
X 
X 
Adverse event 
 
Xh 
X 
X 
X 
X 
X 
Concomitant medication 
 
Xh 
X 
X 
X 
X 
X 
a 
Including concomitant medications within 14 days prior to study drug administration, blood products transfused within 3 months prior to study drug administration, and concurrent baseline conditions. 
b 
Full physical examination including weight and spleen size by clinical assessment (palpation). At screening, must be done within 7 days prior to Cycle 1, Day 1 (first dose). 
c 
All MRI/CT scans will be transmitted for central reading. 
d 
Blood pressure, pulse, respiratory rate, and temperature; pre-dose during treatment. 
e 
Hematology includes erythrocytes, MCV, MCH, neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, leukocytes, hemoglobin; and hematocrit. Serum chemistry includes BUN, LDH, 
creatinine, uric acid, total protein, albumin, glucose, total bilirubin, magnesium, alkaline phosphatase, AST, ALT, chloride, sodium, and potassium. Serum chemistry will also include amylase and lipase in 
the first 2 cycles. Urinalysis includes pH, protein, glucose, ketone, bilirubin, blood, and nitrite (no urinalysis at C1D8). At Cycle 1, Day 15, single point, 100mL urine samples 2-8 hours post-dose should 
be included for at least 3 patients. 
f 
For eligibility determination, locally read; Median QTc must be ≤480 msec. Centrally read for safety analysis. 
g 
Pre-dose. 


 
 
 
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h 
Pre-dose; may be obtained within 24 hours prior to study drug administration. Adverse Events on Cycle 1, Day 1 will also be collected post-dose. 
i 
Pre-dose and 2, 4, 6, and 8 hours post-dose; centrally read. 
j 
Sampling times for Cycle 1 Day 1 and Cycle 2 Day 1 are pre-dose and approximately 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose; (Cycle 1, Day 1 includes 24 hour post-dose).  Sampling times for Cycle 1 Day 
15 are pre-dose and approximately 2 hours post-dose. 
k 
Pre-dose and approximately 2 and 3 hours post-dose. 
l 
Directed physical examination including weight and spleen size by palpation. 
m Cycle 1, Day 8&15 and Cycle 2, pre-dose and 2 hours post-dose; in triplicate and centrally read; Cycle 3 and thereafter, pre-dose only, in triplicate and locally read. After Cycle 13, single reading and 
locally read 
n 
Pre-dose JAK2 V617F allele burden, if mutation was present prior to start of therapy. 
o 
Within 30 days after last dose of study drug or within 30 days after withdrawal from the study. 
p 
If not done within the previous 8 weeks. 
q 
For the purpose of scheduling procedures and evaluations, a treatment cycle is defined as 28 days. 
r 
Within 28 days prior to the first dose  of study drug 
s 
Single point collection (100mL) Pre-dose on Cycle 1 Day 1 and 2-6 hours post dose on Cycle 2 Day 1 
t 
Every 6 months after Cycle 7 and annually after Cycle 13 
u 
On day 1 of cycles 7, 10, and 13, and after completion of months 18 and 24 treatment cycles (i.e. Cycle 19 and 25).   
 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CBC=complete blood chemistry; CT=computed tomography; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; JAK2=Janus kinase 2; LDH=lactate dehydrogenase; MPN SAF (MPN-10) =Myeloproliferative  Neoplasm Symptom Assessment 
Form; MRI=magnetic resonance imaging; STAT3=signal transducer and activator of transcription 3. 
 
Schedule of Safety Laboratory Procedures by Cycle (Site and Local Evaluations) – Phase 2 
Cycle 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Day 
1 
8 
15 
22 
1 
15 
1 
15 
1 
15 
1 
15 
1 
15 
1 
1 
1 
1 
1 
1 
1 
Site visit 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Local visit 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Local visit laboratory procedures at the indicated visits include: hematology (erythrocytes, MCV, MCH, neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, leukocytes, hemoglobin; and 
hematocrit) and serum chemistry (BUN, LDH, creatinine, uric acid, total protein, albumin, glucose, total bilirubin, magnesium, alkaline phosphatase, AST, ALT, chloride, sodium, and potassium). Serum 
chemistry will also include amylase and lipase in the first 2 cycles.  
Results should be faxed to the study site. 
 
 
 


 
 
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APPENDIX B1:  PRIMARY MYELOFIBROSIS DEFINITION 
 
 
 
2008 WHO Diagnostic Criteria for primary myelofibrosis (PMF) 
 
 
Diagnosis requires meeting all 3 major criteria and 2 minor criteria 
 
 
Major criteria 
1. 
Presence of megakaryocyte proliferation and atypia,* usually accompanied by 
either reticulin or collagen fibrosis, 
or, 
in the absence of significant reticulin fibrosis, the megakaryocyte changes 
must be accompanied by an increased bone marrow cellularity characterized 
by granulocytic proliferation and often decreased erythropoiesis (ie, prefibrotic 
cellular-phase disease) 
2. 
Not meeting WHO criteria for polycythemia vera,† BCR-ABL1–positive chronic 
myelogenous leukemia,‡ myelodysplastic syndrome,§ or other myeloid 
disorders 
3. 
Demonstration of JAK2 V617F or other clonal marker (e.g., MPLW515K/L), 
or, 
in the absence of the above clonal markers, no evidence that bone marrow 
fibrosis is secondary to infection, autoimmune disorder or other chronic 
inflammatory condition, hairy cell leukemia or other lymphoid neoplasm, 
metastatic malignancy, or toxic (chronic) myelopathies|| 
 
Minor criteria 
1. Leukoerythroblastosis¶ 
2. Increase in serum lactate dehydrogenase level¶ 
3. Anemia¶ 
4. Palpable splenomegaly¶ 
 
*Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and 
hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering. 
†Requires the failure of iron replacement therapy to increase hemoglobin level to 
the polycythemia vera range in the presence of decreased serum ferritin. Exclusion of 
polycythemiavera is based on hemoglobin and hematocrit levels. Red cell mass 
measurement is not required. 
‡Requires the absence of BCR-ABL1. 
§Requires the absence of dyserythropoiesis and dysgranulopoiesis. 
||It should be noted that patients with conditions associated with reactive 
myelofibrosis are not immune to primary myelofibrosis, and the diagnosis should be 
considered in such cases if other criteria are met. 
 
¶Degree of abnormality could be borderline or marked. 
 
 
Reference: Vardiman J, Thiele T, Arber D, et al. The 2008 revision of the World Health Organization 
(WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. 
Blood.2009; 114:937-951. 
 
 
 
 
 
 
 


 
 
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APPENDIX B2:  POST-POLYCYTHEMIA VERA MYELOFIBROSIS 
DEFINITION 
 
 
 
 
 
2008 IWG-MRT Diagnostic Criteria for post-polycythemia 
veramyelofibrosis (post-PV MF) 
 
 
Required criteria: 
1. 
Documentation of a previous diagnosis of polycythemia vera 
as defined by the WHO criteria 
2. 
Bone marrow fibrosis grade 2–3 (on 0–3 scale) 3 or grade 3–4 
(on 0–4 scale) 4,a 
 
Additional criteria (two are required): 
1. 
Anemiab or sustained loss of requirement of either phlebotomy 
(in the absence of cytoreductive therapy) or cytoreductive 
treatment for erythrocytosis 
2. 
A leukoerythroblastic peripheral blood picture 
3. 
Increasing splenomegaly defined as either an increase in 
palpable splenomegaly of ≥ 5 cm (distance of the tip of the 
spleen from the left costal margin) or the appearance of a 
newly palpable splenomegaly 
4. 
Development of ≥ 1 of three constitutional symptoms: >10% 
weight loss in 6 months, night sweats, unexplained fever 
(>37.5˚C) 
 
Abbreviations: IWG-MRT, International Working Group for Myelofibrosis 
Research and Treatment; LDH, lactate dehydrogenase; post-ET 
MF, post-essential thrombocythemiamyelofibrosis; post-PV MF, postpolycythemia 
veramyelofibrosis. 
aGrade 2–3 according to the European classification:3 diffuse, often 
coarse fiber network with no evidence of collagenization (negative 
trichrome stain) or diffuse, coarse fiber network with areas of 
collagenization (positive trichrome stain). Grade 3–4 according to the 
standard classification: 4 diffuse and dense increase in reticulin with 
extensive intersections, occasionally with only focal bundles of 
collagen and/or focal osteosclerosis or diffuse and dense increase in 
reticulin with extensive intersections with coarse bundles of collagen, 
often associated with significant osteosclerosis. 
bBelow the reference range for appropriate age, sex, gender and altitude 
considerations. 
 
 
Reference: Barosi G, Mesa RA, Thiele J, et al. Proposed criteria for the diagnosis of post-polycythemia 
vera and post-essential thrombocythemiamyelofibrosis: a consensus statement from the international 
working group for myelofibrosis research and treatment. Leukemia.2008; 22:437-438. 
 


 
 
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APPENDIX B3:  POST-ESSENTIAL THROMBOCYTHEMIA 
MYELOFIBROSIS DEFINITION 
 
 
 
 
 
2008 IWG-MRT Diagnostic Criteria for post-essential 
thrombocythemiamyelofibrosis (post-ET MF) 
 
 
Required criteria: 
1. 
Documentation of a previous diagnosis of essential thrombocythemia 
as defined by the WHO criteria 
2. 
Bone marrow fibrosis grade 2–3 (on 0–3 scale) 3 or grade 3–4 
(on 0–4 scale) 4,a 
 
Additional criteria (two are required): 
1. 
Anemiab and a ≥ 2 mg ml -1 decrease from baseline hemoglobin level 
2. 
A leukoerythroblastic peripheral blood picture 
3. 
Increasing splenomegaly defined as either an increase in 
palpable splenomegaly of ≥ 5 cm (distance of the tip of the 
spleen from the left costal margin) or the appearance of a 
newly palpable splenomegaly 
4. 
Increased LDH (above reference level) 
5. 
Development of ≥ 1 of three constitutional symptoms: >10% 
weight loss in 6 months, night sweats, unexplained fever 
(>37.5˚C) 
 
Abbreviations: IWG-MRT, International Working Group for Myelofibrosis 
Research and Treatment; LDH, lactate dehydrogenase; post-ET 
MF, post-essential thrombocythemiamyelofibrosis; post-PV MF, postpolycythemia 
veramyelofibrosis. 
aGrade 2–3 according to the European classification:3 diffuse, often 
coarse fiber network with no evidence of collagenization (negative 
trichrome stain) or diffuse, coarse fiber network with areas of 
collagenization (positive trichrome stain). Grade 3–4 according to the 
standard classification: 4 diffuse and dense increase in reticulin with 
extensive intersections, occasionally with only focal bundles of 
collagen and/or focal osteosclerosis or diffuse and dense increase in 
reticulin with extensive intersections with coarse bundles of collagen, 
often associated with significant osteosclerosis. 
bBelow the reference range for appropriate age, sex, gender and altitude 
considerations. 
 
 
Reference: Barosi G, Mesa RA, Thiele J, et al. Proposed criteria for the diagnosis of post-polycythemia 
vera and post-essential thrombocythemiamyelofibrosis: a consensus statement from the international 
working group for myelofibrosis research and treatment. Leukemia.2008; 22:437-438. 
 
 


 
 
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APPENDIX C:  INTERNATIONAL PROGNOSTIC SCORING 
SYSTEM FOR PRIMARY MYELOFIBROSIS 
 
The following table determines risk level using the International Prognostic Scoring 
System (IPSS) for PMF (primary myelofibrosis).  
 
Risk Level 
IPSS PMF Score 
Low risk 
0 
Intermediate risk 1 
1 
Intermediate risk 2 
2 
High risk 
≥3 
 
Factors identified as predictors of shortened survival were: 
• age >65 years, 
• presence of constitutional symptoms, 
• hemoglobin <10 g/dL, 
• leukocyte count >25x109/L, and 
• circulating blast cells ≥1%. 
 
 
Source: 
Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary 
myelofibrosis based on a study of the International Working Group for Myelofibrosis 
Research and Treatment. Blood 2009;113(13):2895-2901. 


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


 
 
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APPENDIX E:  PROHIBITED AND CAUTIONED MEDICATIONS – 
SPECIFIC CYTOCHROME P450 SUBSTRATES AND 
INHIBITORS/INDUCERS 
 
The tables below list many of the medications that are prohibited or cautioned. See the website for 
additional medications that may not be listed.  To view this website, hit CTRL+Click when your cursor is 
on top of this link:   (http://medicine.iupui.edu/clinpharm/ddis/table.asp). 
 
CYP1A2 and CYP3A4 Substrates 
(Drugs Substantially Metabolized by CYP1A2 or CYP3A4) 
Use of these drugs is prohibited 
CYP1A2 Substrates 
amitriptyline 
excessive caffeine 
clomipramine 
clozapine 
cyclobenzaprine 
duloxetine 
estradiol 
fluvoxamine 
haloperidol 
imipramine N-DeMe 
mexiletine 
naproxen 
olanzapine 
 
ondansetron 
phenacetin 
propranolol 
riluzole 
ropivacaine 
tacrine 
theophylline 
tizanidine 
triamterene 
verapamil 
warfarin 
zileuton 
zolmitriptan 
CYP3A4 Substrates 
Macrolide antibiotics including clarithromycin, erythromycin and telithromycin (not azithromycin) 
 
Benzodiazapines including alprazolam, diazepam, midazolam, and triazolam 
 
Immune modulators including cyclosporine and tacrolimus 
 
Antihistamines including astemizole, and chlorpheniramine. 
 
Calcium channel blockers including amlodipine, diltiazem, felodipine, lercanidipine, nifedipine, 
nisoldipine, nitrendipine, verapamil 
 
HMG CoA reductase inhibitors (Statins) including atorvastatin, cerivastatin, lovastatin, simvastatin (not 
pravastatin and rosuvastatin) 
 
Steroid 6beta-OH including estradiol, hydrocortisone, progesterone, and testosterone 
Miscellaneous: 
alfentanil 
aprepitant 
aripiprazole 
buspirone 
cafergot 
excessive caffeine 
cilostazol 
cocaine 
codeine N-demethylation 
dexamethasone 
dextromethorphan 
domperidone 
 
eplerenone 
fentanyl 
finasteride 
haloperidol 
LAAM 
lidocaine 
methadone 
nateglinide 
ondansetron 
pimozide 
propranolol 
quetiapine 
 
quinidine 
quinine 
risperidone 
salmeterol 
sildenafil 
sirolimus 
tamoxifen 
trazodone 
zaleplon 
ziprasidone 
zolpidem 


 
 
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CYP3A4 STRONG Inhibitors and Inducers 
Use of these drugs is prohibited 
CYP3A4 Inhibitors 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
telithromycin 
 
CYP3A4 Inducers 
rifampin 
St. John’s Wort 
 
CYP3A4 MODERATE Inhibitors and Inducers 
Use of these drugs is discouraged (alternative therapies should be considered) but does not 
disqualify patient participation in the study. 
CYP3A4 Inhibitors 
aprepitant 
diltiazem 
erythromycin 
fluconazole 
grapefruit juice  
verapamil 
 
CYP3A4 Inducers 
carbamazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
troglitazone 
 
 
 
 
 


 
 
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APPENDIX F:  NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION OF HEART FAILURE 
 
Class
Patient Symptoms
Class I 
(Mild)
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, or dyspnea (shortness of breath).
Class II 
(Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, or dyspnea.
Class III 
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea.
Class IV 
(Severe)
Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency 
at rest. If any physical activity is undertaken, discomfort is increased.
 
Source: http://www.merckmanuals.com/professional/sec07/ch074/ch074a.html#CEGDEIFG 
 
 


 
 
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APPENDIX G:  CLINICAL LABORATORY (SAFETY) TESTS 
 
Hematology: 
erythrocytes 
mean corpuscular volume (MCV) 
mean corpuscular hemoglobin (MCH)
neutrophils 
eosinophils 
basophils 
lymphocytes 
monocytes 
platelets 
leukocytes 
hemoglobin 
hematocrit 
Urinalysis: pH 
protein 
glucose 
ketone 
bilirubin 
blood 
nitrite 
Clinical chemistry: blood urea nitrogen (BUN) 
lactate dehydrogenase 
creatinine 
uric acid 
total protein 
albumin 
glucose 
total bilirubin 
magnesium 
amylase (first 2 cycles only) 
lipase (first 2 cycles only) 
Liver 
enzymes: 
alkalinephosphatase 
aspartateaminotransfer
ase (AST) 
alanineaminotransfera
se (ALT) 
Electrolytes: 
chloride 
sodium 
potassium 
 
 
Pregnancy test: 
Serum or urine, in women with childbearing potential 
 


 
 
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APPENDIX H:  NATIONAL CANCER INSTITUTE COMMON 
TOXICITY CRITERIA FOR ADVERSE EVENTS 
 
See the following website for NCI CTEP CTCAE version 4.0 (28 May 2009).  To view 
this website, hit CTRL+Click when your cursor is on top of this link: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
 
 


 
 
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APPENDIX I:  INTERNATIONAL WORKING GROUP 
CONCENSUS CRITERIA FOR TREATMENT RESPONSE IN 
MYELOFIBROSIS WITH MYELOID METAPLASIA 
 
1. Complete remission (CR) 
(1) Complete resolution of disease-related symptoms and 
signs including palpable hepatosplenomegaly. 
 
(2) Peripheral blood count remission defined as 
hemoglobin level at least 110 g/L, platelet count at least 
100 × 109/L, and absolute neutrophil count at least 
1.0 × 109/L. In addition, all 3 blood counts should be no 
higher than the upper normal limit. 
 
(3) Normal leukocyte differential including disappearance 
of nucleated red blood cells, blasts, and immature myeloid 
cells in the peripheral smear, in the absence of 
splenectomy.* 
 
(4) Bone marrow histologic remission defined as the 
presence of age-adjusted normocellularity, no more than 
5% myeloblasts, and an osteomyelofibrosis grade no 
higher than 1.  
2. Partial remission (PR) 
Requires all of the above criteria for CR except the requirement 
for bone marrow histologic remission. However, a repeat bone 
marrow biopsy is required in the assessment of PR and may or 
may not show favorable changes that do not however fulfill 
criteria for CR. 
3. Clinical improvement (CI) Requires one of the following in the absence of both disease 
progression (as outlined below) and CR/PR assignment (CI 
response is validated only if it lasts for no fewer than 8 weeks) 
 
(1) A minimum 2 -g/L increase in hemoglobin level or 
becoming transfusion independent (applicable only for 
patients with baseline hemoglobin level of less than 
100 g/L).  
 
(2) Either a minimum 50% reduction in palpable 
splenomegaly of a spleen that is at least 10 cm at baseline 
or a spleen that is palpable at more than 5 cm at baseline 
becomes not palpable.  
 
(3) A minimum 100% increase in platelet count and an 
absolute platelet count of at least 50,000 × 109/L 
(applicable only for patients with baseline platelet count 
below 50 × 109/L). 
 
(4) A minimum 100% increase in ANC and an ANC of at 
least 0.5 × 109/L (applicable only for patients with baseline 
absolute neutrophil count below 1 × 109/L). 


 
 
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4. Progressive disease (PD) 
Requires one of the following:|| 
 
(1) Progressive splenomegaly that is defined by the 
appearance of a previously absent splenomegaly that is 
palpable at greater than 5 cm below the left costal margin 
or a minimum 100% increase in palpable distance for 
baseline splenomegaly of 5-10 cm or a minimum 
50% increase in palpable distance for baseline 
splenomegaly of greater than 10 cm. 
 
(2) Leukemic transformation confirmed by a bone marrow 
blast count of at least 20%. 
 
(3) An increase in peripheral blood blast percentage of at 
least 20% that lasts for at least 8 weeks. 
5. Stable disease (SD) 
None of the above. 
6. Relapse 
Loss of CR, PR, or CI. In other words, a patient with CR or PR 
is considered to have undergone relapse when he or she no 
longer fulfills the criteria for even CI. However, changes from 
either CR to PR or CR/PR to CI should be documented and 
reported. 
* Because of subjectivity in peripheral blood smear interpretation, CR does not require absence 
of morphologic abnormalities of red cells, platelets, and neutrophils. 
 In patients with CR, a complete cytogenetic response is defined as failure to detect a 
cytogenetic abnormality in cases with a pre-existing abnormality. A partial cytogenetic 
response is defined as 50% or greater reduction in abnormal metaphases. In both cases, at 
least 20 bone marrow- or peripheral blood-derived metaphases should be analyzed. A major 
molecular response is defined as the absence of a specific disease-associated mutation in 
peripheral blood granulocytes of previously positive cases. In the absence of a 
cytogenetic/molecular marker, monitoring for treatment-induced inhibition of endogenous 
myeloid colony formation is encouraged. Finally, baseline and posttreatment bone marrow 
slides are to be stained at the same time and interpreted at one sitting by a central review 
process. 
 Transfusion dependency is defined by a history of at least 2 units of red blood cell 
transfusions in the last month for a hemoglobin level of less than 85 g/L that was not 
associated with clinically overt bleeding. Similarly, during protocol therapy, transfusions for a 
hemoglobin level of 85 g/L or more is discouraged unless it is clinically indicated. 
 In splenectomized patients, palpable hepatomegaly is substituted with the same measurements.
|| It is acknowledged that worsening cytopenia might represent progressive disease, but its 
inclusion as a formal criterion was avoided because of the difficulty distinguishing 
disease-associated from drug-induced myelosuppression. However, a decrease in hemoglobin 
level of 20 g/L or more, a 100% increase in transfusion requirement, and new development of 
transfusion dependency, each lasting for more than 3 months after the discontinuation of 
protocol therapy, can be considered disease progression. 
ANC = absolute neutrophil count; CR = complete remission; CI = clinical improvement; 
PD = progressive disease; PR = partial response; SD = stable disease. 
 
Source: 
Tefferi A, Barosi G, Mesa R, et al. International Working Group (IWG) consensus 
criteria for treatment response in myelofibrosis with myeloid metaplasia, for the 
IWG 
for 
Myelofibrosis 
Research 
and 
Treatment 
(IWG-MRT).Blood. 
2006;108:1497-1503. 


 
 
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APPENDIX J:  MYELOFIBROSIS SYMPTOM ASSESSMENT FORM 
 
The MF SAF is described in  
 
Mesa RA, Schwager S, Radia D, et al. The myelofibrosis symptom assessment 
form (MFSAF): An evidence-based brief inventory to measure quality of life 
and symptomatic response to treatment in myelofibrosis. Leukemia Research. 
2009;33:1199-1203. 


 
 
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APPENDIX K:  REVISED RESPONSE CRITERIA FOR 
MYELOFIBROSIS:  INTERNATIONAL WORKING GROUP-
MYELOPROLIFERATIVE NEOPLASMS RESEARCH AND 
TREATMENT (IWG-MRT) AND EUROPEAN LEUKEMIANET 
(ELN) CONSENSUS REPORT 
 
 
Response categories  
Required criteria (for all response categories, benefit must 
last for >12 wk to qualify as a response)  
Complete Response 
(CR) 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; 
<grade 1 MF† and  
Peripheral blood: Hemoglobin >100 g/L and <UNL; 
neutrophil count > 1 x 109/L and <UNL;  
Platelet count >100 x 109/L and <UNL; <2% immature 
myeloid cells‡ and  
Clinical: Resolution of disease symptoms; spleen and liver 
not palpable; no evidence of EMH  
Partial Response (PR) 
Peripheral blood: Hemoglobin >100 g/L and <UNL; 
neutrophil count >1 x 109/L and <UNL; platelet count >100 
x 109/L and  
<UNL; <2% immature myeloid cells‡ and  
Clinical: Resolution of disease symptoms; spleen and liver 
not palpable; no evidence of EMH or  
Bone marrow:* Age-adjusted normocellularity; <5% blasts; 
<grade 1 MF†, and peripheral blood: Hemoglobin >85 but 
<100 g/L  
and <UNL; neutrophil count >1 x 109/L and <UNL; platelet 
count >50, but <100 x 109/L and <UNL; <2% immature 
myeloid  cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver 
not palpable; no evidence of EMH  
Clinical improvement 
(CI)  
The achievement of anemia, spleen or symptoms response 
without progressive disease or increase in severity of 
anemia, thrombocytopenia, or neutropenia§  
Anemia response  
Transfusion-independent patients: a >20 g/L increase in 
hemoglobin level||  
Transfusion-dependent 
patients: 
becoming 
transfusion-
independent{ 
Spleen response#  
A baseline splenomegaly that is palpable at 5-10 cm, below 
the LCM, becomes not palpablepp or  
A baseline splenomegaly that is palpable at >10 cm, below 
the LCM, decreases by >50%** 
A baseline splenomegaly that is palpable at <5 cm, below 
the LCM, is not eligible for spleen response  
A spleen response requires confirmation by MRI or 
computed tomography showing >35% spleen volume 
reduction  
Symptoms response  
A >50% reduction in the MPN-SAF TSS††  


 
 
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Progressive disease‡‡  
Appearance of a new splenomegaly that is palpable at least 5 
cm below the LCM or  
A >100% increase in palpable distance, below LCM, for 
baseline splenomegaly of 5-10 cm or  
A 50% increase in palpable distance, below LCM, for 
baseline splenomegaly of >10 cm or  
Leukemic transformation confirmed by a bone marrow blast 
count of >20% or  
A peripheral blood blast content of >20% associated with an 
absolute blast count of >1 x 109/L that lasts for at least 2 
weeks  
Stable disease  
Belonging to none of the above listed response categories  
Relapse  
No longer meeting criteria for at least CI after achieving CR, 
PR, or CI, or  
Loss of anemia response persisting for at least 1 month or  
Loss of spleen response persisting for at least 1 month  
Recommendations for assessing treatment-induced cytogenetic and molecular changes  
Cytogenetic remission 
At least 10 metaphases must be analyzed for cytogenetic 
response evaluation and  
requires confirmation by repeat testing within 6 months 
window  
CR: eradication of a preexisting abnormality  
PR: >50% reduction in abnormal metaphases  
(partial response applies only to patients with at least ten 
abnormal metaphases at baseline)  
Molecular remission  
Molecular response evaluation must be analyzed in 
peripheral blood granulocytes and  
requires confirmation by repeat testing within 6 months 
window  
CR: Eradication of a pre-existing abnormality  
PR: >50% decrease in allele burden  
(partial response applies only to patients with at least 20% 
mutant allele burden at baseline)  
Cytogenetic/molecular 
relapse  
Re-emergence of a pre-existing cytogenetic or molecular 
abnormality that is confirmed by repeat testing  


 
 
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Source:  Tefferi A, Cervantes, F, Mesa R, et al. Revised response criteria for Myelofibrosis:  
International Working Group-Myeloproliferative Neoplasms Research and treatment (IWG-
MRT) and European LeukemiaNet (ELN) consensus report. Blood, 2013 122: 1395-1398 
 
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology-or 
imaging study-proven nonhepatosplenic EMH); LCM, left costal margin;  
UNL, upper normal limit.  
*Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central 
review process. Cytogenetic and molecular responses are not required for  
CR assignment.  
†Grading of MF is according to the European classification  
Thiele et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. 
Haematologica. 2005;90:1128.  
It is underscored that the consensus definition of a CR bone marrow is to be used only in those 
patients in which all other criteria are met, including resolution of leukoerythroblastosis.  
It should also be noted that it was a particularly difficult task for the working group to reach a 
consensus regarding what represents a complete histologic remission.  
‡Immature myeloid cells constitute blasts 1 promyelocytes 1 myelocytes 1 metamyelocytes 1 
nucleated red blood cells. In splenectomized patients, <5% immature  
myeloid cells is allowed.  
§See above for definitions of anemia response, spleen response, and progressive disease. Increase in 
severity of anemia constitutes the occurrence of new transfusion  
dependency or a >20 g/L decrease in hemoglobin level from pretreatment baseline that lasts for at 
least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is  
defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil 
count, according to the Common Terminology Criteria for Adverse Events  
(CTCAE) version 4.0. In addition, assignment to CI requires a minimum platelet count of >25000 x 
10(9)/L and absolute neutrophil count of >0.5 x 10(9)/L.  
||Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting the strict 
criteria for transfusion dependency at the time of study enrollment  
(see as follows), but have received transfusions within the previous month, the pretransfusion 
hemoglobin level should be used as the baseline.  
{Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of 
packed red blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of 
<85 g/L, in the absence of bleeding or treatment-induced anemia. In addition, the most recent 
transfusion episode must have occurred in  
the 28 days prior to study enrollment. Response in transfusion-dependent patients requires absence of 
any PRBC transfusions during any consecutive “rolling” 12-week  
interval during the treatment phase, capped by a hemoglobin level of >85 g/L.  
#In splenectomized patients, palpable hepatomegaly is substituted with the same measurement 
strategy.  
**Spleen or liver responses must be confirmed by imaging studies where a >35% reduction in spleen 
volume, as assessed by MRI or CT, is required. Furthermore,  
a >35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response regardless of 
what is reported with physical examination.  
††Symptoms are evaluated by the MPN-SAF TSS.17 The MPN-SAF TSS is assessed by the patients 
themselves and this includes fatigue, concentration, early satiety,  
inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is 
from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it  
can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). 
Symptoms response requires >50% reduction in the MPN-SAF TSS.  
‡‡Progressive disease assignment for splenomegaly requires confirmation my MRI or computed 
tomography showing a >25% increase in spleen volume from baseline.  
Baseline values for both physical examination and imaging studies refer to pretreatment baseline and 
not to posttreatment measurements.  


 
 
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APPENDIX L:  MYELOPROLIFERATIVE SYMPTOM 
ASSESSMENT FORM (MPN-SAF) (MPN-10) 
 
 
The MPN-SAF (MPN-10) is described in  
 
Emanuel, R.M.,Dueck, A.C., Geyer, H.L.,Kiladjian, J-J., Slot, S., Zweegman, S., .…Mesa, 
R.A. Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom 
Score: Prospective InternationalAssessment of an Abbreviated Symptom Burden 
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