Clinical trial NCT04281498
Conditions: Accelerated/Blast-phase Myeloproliferative Neoplasm Chronic-phase Myelofibrosis IDH2 Mutation
Keywords: Phase II Myelofibrosis Therapeutic Ruxolitinib Enasidenib IDH2
Sponsor: John Mascarenhas
Start date: 2021-01-14; Completion date: 2023-05-30
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The presence of IDH mutation is associated with worse survival in patients with myelofibrosis. Moreover IDH mutations are among the most frequently encountered events in MPNs that have progressed to acute myeloid leukemia. Ruxolitinib, a JAK1/2 inhibitor, and enasidenib an IDH2 inhibitor are effective and tolerable treatments for patients with myelofibrosis (MF) and acute myeloid leukemia (AML), respectively. The study team hypothesize that the combination of these agents in patients with MPN with an IDH2 mutation will improve the overall clinical response to therapy.

Detailed description:
At this time, there is no standard medical treatment for MPN-AP/BP and most patients with accelerated and blast phase MPN do not respond well to treatment This is a phase II open-label study to evaluate the safety and efficacy of combined ruxolitinib and enasidenib in patients with accelerated/blast-phase myeloproliferative neoplasm or chronic phase myelofibrosis with high risk features and IDH2 mutation.

Ruxolitinib (Jakafi/Jakavi) is FDA approved for myelofibrosis and was shown to reduce splenomegaly and improve symptoms. Enasidenib is a potent inhibitor of the IDH2 mutant enzyme and is FDA approved for relapsed refractory AML where it showed effectivity.

Pre-clinical studies indicate increased disease mitigating effects with the combination of enasidenib and ruxolitinib.

This study will enroll up to 32 patients. Ruxolitinib and enasidenib will be given orally in 28-day cycles.

Arms: arm 1: Ruxolitinib and Enasidenib combination therapy
Interventions: intervention 1: Ruxolitinib intervention 2: Enasidenib
Intervention descriptions: intervention 1: Patients who are on ruxolitinib will continue their current dose. Patients who are not on ruxolitinib will receive ruxolitinib dosing based on platelet count intervention 2: 50mg -100mg daily

Protocol documents:
Prot_SAP_000.pdf: 
A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib in Patients With 
Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis With 
an IDH2 Mutation 
John Mascarenhas, MD
NCT04281498
Document Date: Nov 10, 2021


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2 
Page 1 of 77 
10 Nov 2021 
Confidential 
IND #: 
144836 
IND Holder Name: 
John Mascarenhas, MD 
Funding Source:  
NCI P01(funding) 
Investigational Product (IP):  Enasidenib (AG-221) 
IP Provider: 
Celgene 
NCT#: 
NCT04281498 
Sponsor/Investigator 
John Mascarenhas, MD 
Icahn School of Medicine at Mount Sinai 
Tisch Cancer Institute,  
Division of Hematology/Oncology 
One Gustave L. Levy Place, Box 1079 
New York, New York 10029 
Tel: (212) 241-3417 
Email: john.mascarenhas@mssm.edu 
Study Co-Chairs: 
Raajit Rampal, MD PhD 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave, Box 443 
New York, NY 10065 
Tel: (212) 639-2194 
Fax: (212)-717-8550 
Email: rampalr@mskcc.org 
Michal Bar-Natan, MD 
Icahn School of Medicine at Mount Sinai 
Division of Hematology/Oncology 
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Tel: (212) 241-6772 
Fax: (212) 876-5276 
Email: michal.bar-natan@mssm.edu 
Co-Investigator: Biostatistician 
Heidi Kosiorek, MS 
Mayo Clinic Cancer Center 
Division of Health Sciences Research 
13400 E. Shea Blvd 
Scottsdale, AZ, USA 85259 
Tel : (480) 301-6415 
Email: Kosiorek.Heidi@mayo.edu 
Statistics and Data Center Email: 
DLARZmpnrcstats@mayo.edu 
Co-Investigator: Pathologist 
Mohamad Salama, MD  
Mayo Medical Laboratories 
3050 Superior Drive NW 
Rochester, MN 55901-1195 
Lab Phone: (507) 284-1143 
Email: salama.mohamed@mayo.edu 
Co-Investigator: Biorepository 
Rona Singer Weinberg, PhD 
MPN-RC Tissue Bank 
New York Blood Center 
310 East 67th Street 
New York, NY 10065 
Tel: (212) 570-3412 
Fax: (212) 570-3495 
Laboratory Tel: (212) 570-3412 
Laboratory Fax: (212) 570-3495 
Email: rweinberg@nybloodcenter.org 
Ruben Mesa, MD 
Mays Cancer Center at UT Health 
San Antonio MD Anderson 
7979 Wurzbach Road 
San Antonio, Texas 78229 
Tel: (210) 450-1406 
Fax: 210-450-1100 
Email: mesar@uthscsa.edu 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2 
Page 2 of 77 
10 Nov 2021 
Confidential 
1. TRIAL CENTERS
Mayo Clinic – Arizona 
Jeanne Palmer, MD 
13400 E Shea Blvd. 
Scottsdale, AZ 85259 
Tel: (480) 301-8335 
Fax:  (480) 301-4675 
Email:  Palmer.Jeanne@mayo.edu 
Icahn School of Medicine at Mount Sinai 
John Mascarenhas, MD 
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Tel: (212) 241-3417 
Fax: (212) 876-5276 
Email: john.mascarenhas@mssm.edu 
Princess Margaret Cancer Centre 
Vikas Gupta, MD, FRCP, FRCPath 
610 University Avenue 
Toronto, Canada, M5G 2M9 
Tel: (416) 946-4521 
Fax: (416) 946-6546 
Email: vikas.gupta@uhn.ca 
Wake Forest Baptist Health 
Rupali Roy Bhave, MD 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Tel: (336) 716-1808 
Fax: (336) 716-5687 
Email: rbhave@wakehealth.edu 
Memorial Sloan-Kettering Cancer Center 
Raajit Rampal, MD, PhD 
1275 York Ave, Box 443 
New York, NY 10065 
Tel: (212) 639-2194 
Fax: (212) 717-8550 
Email: rampalr@mskcc.org 
Cleveland Clinic – Taussig Cancer Center Institute 
Aaron Gerds, MD, MS 
2010 E 90th Street 
Cleveland, OH 44195 
Tel: (216) 445-9840 
Fax: (216) 444-9464 
Email: gerdsa@ccf.org 
Moffitt Cancer Center 
Andrew T. Kuykendall, MD 
Moffitt Cancer Center 
12902 Magnolia Drive 
Tampa, FL 33612 
Tel:  (813) 745-6841 
Email: Andrew.Kuykendall@moffitt.org 
Mays Cancer Center at UT Health San Antonio 
Ruben Mesa, MD 
7979 Wurzbach Road 
San Antonio, TX 78229 
Tel: (210) 450-1406 
Fax: (210) 450-1100 
Email: mesar@uthscsa.edu 
Roswell Park Comprehensive Cancer Center 
Amro Elshoury, MD 
Elm and Carlton Streets 
Buffalo, NY 14263 
Tel: (716)-845-6272 
Fax: (716)-845-3426 
Email: Amro.Elshoury@roswellpark.org 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 3 of 77 
 
 
10 Nov 2021 
Confidential 
 
 
MPN-RC Clinical Consortium (Project 4) 
John Mascarenhas, MD 
Icahn School of Medicine at Mount Sinai  
Division of Hematology/Oncology 
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Tel: (212) 241-3417 
Fax: (212) 876-5276 
Email: john.mascarenhas@mssm.edu 
 
Ruben Mesa, MD 
Mays Cancer Center at UT Health San Antonio 
MD Anderson 
7979 Wurzbach Road 
San Antonio, TX 78229 
Tel: (210) 450-1406 
Fax: (210) 450-1100 
Email: mesar@uthscsa.edu 
 
MPN-RC Central Coordinating Office 
Ronald Hoffman, MD 
Icahn School of Medicine at Mount Sinai  
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Tel: (212) 241-2297 
Fax: (212) 876-5276 
Email: ronald.hoffman@mssm.edu 
 
Monitoring and Adverse Event Reporting 
MPN-RC Data Monitor 
MPN-RC Central Coordinating Office 
Melissa Nashawati, MPA 
Tel: (210) 450-3955 
nashawati@uthscsa.edu 
 
Statistics and Data Center 
Amylou Dueck, PhD 
Mayo Clinic Cancer Center 
Division of Health Sciences Research 
13400 E. Shea Blvd 
Scottsdale, AZ, USA 85259 
Tel: (480) 301-6159 
Email: Dueck.Amylou@mayo.edu 
Statistics and Data Center Email: 
DLARZmpnrcstats@mayo.edu 
 
MPN-RC Tissue Bank 
Rona Singer Weinberg, PhD 
New York Blood Center 
310 East 67th Street 
New York, NY 10065 
Tel: (212) 570-3488 
Fax: (212) 570-3495 
Laboratory Tel: (212) 570-3412 
Laboratory Fax: (212) 570-3495 
E-mail: rweinberg@nybloodcenter.org 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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Confidential 
 
TABLE OF CONTENTS 
1. TRIAL CENTERS ........................................................................................ 2 
2. LIST OF ABBREVIATIONS AND TERMS ............................................. 8 
3. STUDY SCHEMA ....................................................................................... 11 
4. STUDY SUMMARY ................................................................................... 12 
6. 
SCIENTIFIC BACKGROUND AND RATIONALE ................................................................................ 15 
6.1 
Disease Background ..................................................................................................... 15 
6.2 
RUXOLITNIB .............................................................................................................. 17 
6.2.1 
Clinical Experience in myelofibrosis with ruxolitinib ........................................... 18 
6.3 
Enasidenib (AG-221) ................................................................................................... 19 
7. 
STUDY OBJECTIVES ........................................................................................................................... 21 
7.1 
Primary Objectives ...................................................................................................... 21 
7.2 
Secondary Objectives................................................................................................... 22 
7.3 
Exploratory Objectives ................................................................................................ 22 
8.0 
PATIENT ELIGIBILITY .................................................................................................................. 22 
8.1 
Inclusion Criteria ......................................................................................................... 22 
8.2 
Exclusion Criteria ........................................................................................................ 23 
9.0 
SUBJECT RECRUITING AND SCREENING ............................................................................. 24 
9.1 
Study-wide recruitment methods ............................................................................... 24 
10. 
TREATMENT DOSAGE AND ADMINISTRATION .................................................................................... 24 
10.1 
Dose Modification for non-hematological AE’s, clinically significant in the 
opinion of the treating physician .......................................................................................... 25 
10.1.1 
QT prolongation .................................................................................................... 25 
10.1.2 
 Abnormal Level of Liver Enzymes (Hyperbilirubinemia) ............................... 26 
10.2 
Dose modifications for hematological AE’s............................................................ 28 
10.3 
Dose Escalations ........................................................................................................ 28 
10.4 
Concomitant Medications/Treatments ................................................................... 29 
10.5 
IDH-Inhibitor Differentiation Syndrome (IDH-DS) ............................................. 29 
10.6 
Non-infectious Leukocytosis .................................................................................... 30 
10.7 
Discontinuation of Ruxolitinib AND ENASIDENIB ............................................. 30 
10.8 
Evaluation During Treatment/Intervention ........................................................... 30 
11. 
WHEN AND HOW TO WITHDRAW SUBJECTS ....................................................................................... 30 
11.1 
Data Collection and Follow-up for Withdrawn Subjects...................................... 31 
11.2 
DURATION OF FOLLOW-UP .............................................................................. 31 
11.3 
Removal of Patients from Protocol Therapy ......................................................... 32 
11.4 
Patient ACCRUAL ................................................................................................... 32 
12.0 
STUDY TIMELINES ......................................................................................................................... 32 
13.0 
STUDY ENDPOINTS ................................................................................................................................ 32 
13.1 
Primary Endpoint ..................................................................................................... 32 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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13.2 
Secondary Endpoints ................................................................................................ 32 
13.3 
Safety Endpoints ....................................................................................................... 33 
13.4 
Exploratory Endpoints ............................................................................................. 33 
14.0 
STUDY PROCEDURES..................................................................................................................... 33 
14.1 
Screening/Baseline Procedures ................................................................................ 33 
14.2 
Registration Procedures ........................................................................................... 34 
14.2.1 
 Site Registration with MPN-RC.......................................................................... 35 
14.3 
Informed Consent ..................................................................................................... 36 
14.4 
Data Management..................................................................................................... 36 
15. 
TREATMENT PERIOD ........................................................................................................................... 36 
15.1 
End of Treatment visit ............................................................................................. 37 
15.2 
End of Study Visit ..................................................................................................... 37 
16. 
ADVERSE EVENTS ................................................................................................................................ 39 
16.1 
Definitions OF ADVERSE EVENT ........................................................................ 40 
16.2 
SEVERITY OF ADVERSE EVENT ...................................................................... 40 
16.2.1 
 SERIOUS ADVERSE EVENTs (SAE) .............................................................. 40 
16.2.2 
 ADVERSE EVENTs OF SPECIAL INTEREST (AESI) ................................. 41 
16.3 
CAUSALITY ............................................................................................................. 41 
16.4 
DURATION .............................................................................................................. 42 
16.5 
Action Taken ............................................................................................................. 42 
16.6 
Outcome ..................................................................................................................... 42 
16.7 
Overdose .................................................................................................................... 42 
16.8 
Abnormal Laboratory Values ................................................................................. 42 
17. 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS ......................................................................... 43 
17. 1 
Steps to Determine if an Adverse Event Requires Expedited Reporting 
(WITHIN 24 hours) ............................................................................................................... 43 
17.2 
Expedited Reporting................................................................................................. 43 
17.3 
Reporting Guidelines for Pharmaceutical Partner ............................................... 45 
17.4 
MPN-RC Reporting of Suspected Unexpected Serious Adverse Reactions 
(SUSARs) to Regulatory Bodies and Ethics Committees ................................................... 46 
17.5 
MPN-RC Reporting of SUSARs .............................................................................. 46 
17.6 
Timelines for Reporting ........................................................................................... 46 
17.7 
How to Report Safety Events ................................................................................... 46 
18. 
DRUG INFORMATION .................................................................................................................... 47 
18.1 
RUXOLITINIB ......................................................................................................... 47 
18.1.1 
 Side Effects ............................................................................................................ 47 
18.2 
Enasidenib ................................................................................................................. 47 
18.2.1 
Side Effects ............................................................................................................. 47 
18.2.2 
 Study Drug Packaging and Labeling .................................................................. 48 
18.2.3 
 Study Drug Storage .............................................................................................. 48 
18.2.4 
 Receiving Drug Supply, Receipt and Storage .................................................... 48 
18.2.5 
 Return or Destruction of Study Drug ................................................................. 48 
18.3 
RISKS TO SUBJECTS ............................................................................................ 48 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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18.3.1 
 Reproductive Risks .............................................................................................. 49 
CORRELATIVES/ SPECIAL STUDIES ..................................................................................................... 49 
19.1 
Shipping instructions ................................................................................................ 49 
19.2 
Bone Marrow Biopsy SLIDEs Guidelines .............................................................. 50 
19.3 
Bone Marrow Aspirate Guidelines ......................................................................... 51 
19.4 
Peripheral Blood: (use sterile technique) ............................................................... 51 
19.5 
Nail Clippings ............................................................................................................ 51 
19.6 
Cytogenetic Analysis................................................................................................. 51 
19.6.1 
General Inclusion Criteria for Conventional Cytogenetics ............................... 52 
19.7 
Specimen Banking .................................................................................................... 52 
20. 
STATISTICAL CONSIDERATIONS .............................................................................................. 54 
STUDY DESIGN/STUDY ENDPOINTS ....................................................... 54 
20.1 
ACCELERATED / BLAST-PHASE COHORT .................................................... 55 
20.1.2 
 POWER AND SIGNIFICANCE LEVEL / PRECISION ................................. 55 
20.2 
CHRONIC MPN PHASE ........................................................................................ 55 
21. 
SAMPLE SIZE AND ACCRUAL ............................................................................................................... 56 
22. 
DATA ANALYSIS PLANS ....................................................................................................................... 56 
22.1 
Primary endpoint ...................................................................................................... 56 
22.2 
Secondary Endpoints ................................................................................................ 56 
22.3 
Exploratory/Correlative Endpoints ........................................................................ 56 
23. 
STUDY MANAGEMENT .................................................................................................................. 57 
23.1 
Conflict of interest .................................................................................................... 57 
23.2 
Institutional Review Board (IRB) Approval and Consent ................................... 57 
24. 
DATA MANAGEMENT AND MONITORING/AUDITING .......................................................................... 57 
24.1 
Data Monitoring Committee/Data Safety Monitoring Board (DMC/DSMB) .... 57 
24.2 
Medical Monitoring .................................................................................................. 58 
24.3 
Monitoring Plan and Period of Observation .......................................................... 58 
25. 
REGULATORY REQUIREMENTS ........................................................................................................... 58 
25.1 
Adherence to the Protocol ........................................................................................ 58 
25.2 
Emergency Modifications ........................................................................................ 58 
25.3 
Other Reportable New Information and Protocol Deviations/Violations ........... 58 
25.4 
Amendments to the Protocol ................................................................................... 59 
25.5 
Record Retention ...................................................................................................... 59 
26. 
OBLIGATIONS OF INVESTIGATORS ...................................................................................................... 59 
26.1 
Good Clinical Practice.............................................................................................. 59 
26.2 
Ethical Considerations ............................................................................................. 60 
26.3 
Patient Information and Informed Consent .......................................................... 60 
26.4 
Patient Confidentiality ............................................................................................. 60 
26.5 
Protocol Compliance ................................................................................................ 60 
26.6 
Management of Information.................................................................................... 61 
26.7 
Drug Accountability ................................................................................................. 61 
26.8 
Source Documents .................................................................................................... 62 
26.9 
Case Report Forms (CRF) ....................................................................................... 62 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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26.10 
Premature Closure of the Study .............................................................................. 63 
26.11 
Record Retention ...................................................................................................... 63 
26.12 
Data Management..................................................................................................... 63 
26.13 
QUALITY ASSURANCE ........................................................................................ 63 
27. WITHDRAWAL OF SUBJECTS ............................................................................................................ 64 
28. 
BREACH OF CONFIDENTIALITY ............................................................................................................ 64 
29. 
POTENTIAL BENEFITS TO SUBJECTS ....................................................................................... 64 
30. 
SHARING OF RESULTS WITH SUBJECTS ................................................................................. 64 
31. 
PRIOR APPROVALS ........................................................................................................................ 64 
32. 
ECONOMIC BURDEN TO SUBJECTS .......................................................................................... 65 
33. 
CONSENT PROCESS ........................................................................................................................ 65 
34. 
REFERENCES ................................................................................................................................... 66 
34.1 
Appendix A: Response criteria ................................................................................ 68 
34.2 
Appendix B: IWG-MRT and ELN response criteria ............................................ 69 
34.3 
Appendix C:  Medications Known to Prolong the QT Interval ........................... 70 
34.4 
Appendix D:  Guidance IDH-Inhibitor Differentiation Syndrome (IDH-DS) 
Guidance for Management of Differentiation Syndrome in Subjects with Hematologic 
Malignancies Treatedwith IDH-inhibitors .......................................................................... 71 
34.5 
Appendix E:  Eastern Cooperative Oncology Group (ECOG) Performance 
Score Ratings .......................................................................................................................... 74 
34.6 
Appendix F: Myelofibrosis Symptom Assessment FORM (MF-SAF) V4.0........ 75 
34.7 
Appendix G: New York Heart Association (NYHA) Class III or IV congestive 
heart failure ............................................................................................................................ 76 
34.8 
Appendix H: FDA Medwatch Form ....................................................................... 77 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Confidential 
LIST OF TABLES  
Table 1. Ruxolitinib initial dose for patients’ baseline platelet count by cohort……27 
Table 2a. Ruxolitinib Dose Adjustment for patients with accelerated and blast phase 
MF for NON-HEMATOLOGICAL AEs………………………………………………27 
Table 2b. Ruxolitinib Dose Adjustment for patients with chronic phase MF for 
thrombocytopenia or non-hematological AEs…………………………………………27 
Table 3a. Enasidenib Dose Adjustment for thrombocytopenia………………………28 
Table 3b. Enasidenib Dose Adjustment for non-hematological AE………………….28 
Table 4. Schedule of Events……………………………………………………………..38 
Table 5. Correlative Studies Sample Collection Schedule…………………………….53 
Table 6. Statistical Power………………………………………………………………..55 
Table 7.  CRF Form Submission Schedule……………………………………………..62 
2. LIST OF ABBREVIATIONS AND TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
ACS 
acute coronary syndrome 
ALT 
alanine aminotransferase (SGPT) 
AML 
acute myelogenous leukemia 
ASCT 
allogeneic stem cell transplantation 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the plasma concentration-time curve 
BCRP 
Breast Cancer Resistance Protein 
BID 
twice a day 
BM 
bone marrow 
BMF 
bone marrow failure 
BUN 
blood urea nitrogen 
C 
Cycle 
CBC 
complete blood count 
CBR 
complete blast response  
CFR 
Code of Federal Regulations 
CI 
clinical improvement 
CK 
creatine kinase 
Cmax 
maximum (peak) concentration 
CRF 
case report form 
CR 
complete response 
Cri 
complete response with incomplete recovery of counts 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events (Version 5.0) 
C#D# 
Cycle (number) Day (number) 
D, d 
day 
DEHP 
di(2-ethylhexyl)phthalate 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EOS 
end of study 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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2. LIST OF ABBREVIATIONS AND TERMS 
EOT 
end of treatment 
ET  
essential thrombocythemia 
FCBP 
Female of child bearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IMRA                      Interval Milestone Response Assessment 
IND 
Investigational New Drug 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
IV 
intravenous 
IWG/ELN 
International Working Group/European Leukemia Net 
IWG-MRT 
International Working Group for Myelofibrosis Research and treatment 
LVEF 
left ventricular ejection fraction 
MF 
myelofibrosis 
MPN 
myeloproliferative neoplasms 
MPN-RC 
Myeloproliferative Neoplasms Research Consortium 
MRI 
magnetic resonance imaging 
MUGA 
multi-grade acquisition 
NaCl 
sodium chloride 
ORR 
overall response rate 
OS                           overall survival 
PB 
peripheral blood 
PBR 
partial blast response 
PD 
progressive disease 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PMF 
primary myelofibrosis 
PO 
orally, by mouth 
PPHS 
Program for the Protection of Human Subjects 
PR 
partial response 
PV 
polycythemia vera 
QD 
once a day 
QT 
ECG interval between onset of QRS complex to end of the T wave (QT interval) 
QTc 
QT interval corrected for heart rate 
RBC 
red blood cell 
SAE 
serious adverse event 
SAF 
symptoms assessment form 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to peak plasma concentration 
TSS 
total symptoms score 
ULN 
upper limit of normal 
UPR/UPIRSO 
Unanticipated problem involving risk to subjects or others 
US 
United States 
Vd 
volume of distribution 
Vol 
volume 
WBC 
white blood cell 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 10 of 77 
 
 
10 Nov 2021 
Confidential 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 11 of 77 
 
 
10 Nov 2021 
Confidential 
3. STUDY SCHEMA 
 
 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Page 12 of 77 
 
 
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Confidential 
4. STUDY SUMMARY 
Title 
A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib (AG-221) 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or 
Chronic-phase Myelofibrosis with an IDH2 Mutation 
Short Title 
MPN-RC 119-The IDH2 Study 
Protocol Number 
TBD 
Phase 
Phase II 
Methodology 
Open-label 
Study Duration 
6 months; if response is met, subjects may enter the extension phase indefinitely. 
Study Center(s) 
Icahn School of Medicine at Mount Sinai, Mays Cancer Center at University of 
Texas San Antonio, Memorial Sloan-Kettering Cancer Center, Mayo 
Clinic-Arizona, Wake Forest Baptist Health, University of Kansas Cancer Center, 
Moffitt Cancer Center, University of Michigan, Cleveland Clinic Taussig Cancer 
Center Institute, Princess Margaret Cancer Centre, Cedars-Sinai Medical Center 
Objectives 
Primary Objectives 
• 
To estimate the efficacy of ruxolitinib and enasidenib combination 
therapy in patients with accelerated-phase and blast-phase disease.  
Efficacy will be defined as the proportion of patients who achieve a best 
leukemia response of: complete response (CR), Partial Response (PR), 
complete response with incomplete recovery of counts (CRi), as 
assessed by the modified 2013 International Working Group (IWG) 
Response Criteria. 
Secondary Objectives 
• 
To assess the efficacy of the combination of ruxolitinib with enasidenib 
in patients with accelerated-phase and blast-phase disease using 
complete (CBR) and partial blast response (PBR). 
• 
To assess the efficacy (CR, PR, Clinical Improvement) of the 
combination of ruxolitinib with enasidenib in patients with PMF, post-
PV MF, or post-ET MF in chronic phase and 4-9% blasts as assessed by 
the modified 2013 International Working Group (IWG) Response 
Criteria  
• 
To determine the safety of the combination of ruxolitinib and enasidenib 
based on the Common Terminology Criteria for Adverse Events version 
5.0 (CTCAE). 
• 
To assess the impact of the combination of ruxolitinib with enasidenib 
on the overall survival (OS) of advanced phase MPN patients 
Exploratory Objectives 
• 
To determine the impact of the combination of ruxolitinib with 
enasidenib in patients with PMF, post-PV MF, or post-ET MF, on 
patient quality of life as assessed by Myelofibrosis Symptom 
Assessment Form (MF-SAFv4.0). 
• 
To evaluate the pharmacodynamics of ruxolitinib and enasidenib when 
combined in this population. 
• 
To evaluate the effects of combined therapy on gene expression and 
global methylation status.  
• 
To explore changes in mutant allele burden and clonal architecture of 
disease. 
 
Number of Subjects 
32 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Diagnosis and Main 
Inclusion Criteria 
1. Subjects must be ≥ 18 years at the time of signing the Informed Consent 
Form (ICF). 
2. Understanding and voluntary signing an IRB-approved informed consent 
form. 
3. Diagnosis of:  
a. 
Accelerated-phase  (≥ 10% blasts in PB or BM) or blast-phase (≥ 20% 
blasts in PB or BM) myeloproliferative neoplasm (with history of prior 
myelofibrosis, polycythemia vera, or essential thrombocythemia) 
b. Previously treated patients with myelofibrosis with persistent disease 
or progressive disease (persistent or progressive splenomegaly, 
leukocytosis, anemia, or thrombocytopenia) with intermediate-1 or 
greater risk disease according to 2013 International Working Group 
(IWG) criteria, and 4-9% circulating blasts. 
4. Demonstration of an IDH2 mutation 
5. Platelet count >75,000X109/L for chronic phase myelofibrosis patients 
6. Prior therapy with either ruxolitinib or enasidenib is permitted, but not a 
combination of ruxolitinib and enasidenib.   
7. Patients with chronic phase myelofibrosis on ruxolitinib must be on the drug 
for at least 3 months and on a stable dose for at least one month. 
8. Subjects must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 to 2. ECOG 3 status will be allowed if attributable 
to MPN. 
9. Patients must have adequate organ function as demonstrated by the 
following: 
a. 
Direct bilirubin < 2.0mg/dL, unless due to Gilbert’s disease or current 
elevations in direct bilirubin associated with existing enasidenib use. 
b. Serum creatinine < 2.0 mg/dL. 
c. 
ALT and AST ≤ 3 x upper limit of normal (unless transaminitis is 
considered to be related to MF). 
10. Females of childbearing potential (FCBP) must have a negative serum or 
urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 
days prior to starting enasidenib and must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods 
of birth control, one highly effective method and one additional effective 
method AT THE SAME TIME, at least 4 weeks before she starts taking 
enasidenib. FCBP must also agree to ongoing pregnancy testing. Men must 
agree to use a condom during sexual contact with a female of child bearing 
potential even if they have had a successful vasectomy. All patients must be 
counseled at a minimum of every 28 days about pregnancy precautions and 
risks of fetal exposure. 
11. All study participants must be able to swallow oral medication.  
12. Ability to adhere to the study visit schedule and all protocol requirements.  
 
Study Product(s), Dose, 
Route, Regimen 
Ruxolitinib and enasidenib will be given orally in 28-day cycles.  Ruxolitinib dose 
will be given per protocol, enasidenib will be given at 100 mg daily on enrollment 
for patients with accelerated and blast phase myelofibrosis regardless of platelet 
count. Patients with chronic phase myelofibrosis will receive enasidenib at starting 
dose of 50mg daily for cycle 1. The dose of enasidenib will be increased to 100mg 
for cycle 2 if the platelet count stays above  50,000 at the end of cycle 1 (Table 3a) 
and no other therapy emergent SAE of grade >2 developed (except grade 2 
hyperbilirubinemia that is acceptable for dose escalation). 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Duration of administration 
Duration of treatment anticipated to be at least 6 months.  Responders will 
continue therapy indefinitely unless progression of disease occurs, toxicity 
warranting discontinuation of therapy is observed, or at the discretion of the 
treating physician.  
Statistical Methodology 
The primary endpoint of this study is best overall response, defined as partial 
response or better (CR+PR+Cri), and will be defined as the best response by 
Cycle 6 of combination therapy.  All patients meeting the eligibility criteria who 
have signed a consent form and have begun treatment will be evaluable for 
response. Any evaluable patient not meeting the definition for response will be 
deemed as having a non- response. 
 
The largest overall response rate where the proposed combination treatment 
regimen would be considered ineffective in this patient population is 5%, and the 
smallest response rate that would warrant subsequent studies with the proposed 
regimen is 25%. This is based on retrospective analysis applying the 2013 IWG 
Response Criteria to patients treated with ruxolitinib. A Simon’s two-stage 
minimax design will be employed to test the null hypothesis that the true overall 
response rate in this patient population is at most 5%. 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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6. 
SCIENTIFIC BACKGROUND AND RATIONALE 
6.1 
DISEASE BACKGROUND 
Myeloproliferative neoplasms 
Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are each 
clonal stem cell malignancies each of which are classified as Philadelphia chromosome negative 
myeloproliferative neoplasms (MPN) by the World Health Organization (WHO)2. A portion of patients 
with PV and ET can evolve to a clinical picture which resembles PMF (post- PV/ET MF). Post-PV/ET 
MF and PMF, collectively referred to as MF, have similar clinical phenotypes with a median age at 
diagnosis of 65 years3, 3,4. MF is characterized by severe constitutional symptoms, progressive 
hepatosplenomegaly, peripheral blood cytopenias often requiring transfusional support and an increased 
propensity for transformation to a clinical picture resembling acute leukemia, termed myelofibrosis in 
blast phase (MF-BP)5. Like chronic myeloid leukemia, the blast phase of the MPN is nearly always 
preceded by an accelerated phase (MF-AP). Patients with more than 10% blasts in the peripheral blood 
or bone marrow have a median survival of less than 12 months rendering such patients candidates for 
aggressive therapy and placing MF-AP squarely on the continuum of progression to blast phase (4.1). 
Approximately 10-20% of MF patients will transform to MF-BP during the first decade following 
diagnosis with a median overall survival at the time of transformation of 2.6 months4,6.In addition, a 
recent publication reports that patient with 5-9% of blasts (≥ 4-9% PB or ≥ 5-9% BM) have similar 
inferior outcome as patients with > 10% blasts as compare to patient with <4% circulating blasts7. 
The choice of appropriate treatment options for MF patients is currently based on the prognosis of the 
individual patient8. Several prognostic scoring systems that utilize various clinical parameters including 
age, leukocyte count, hemoglobin level, platelet count, monocyte count, peripheral blast count, presence 
of splenomegaly, constitutional symptoms and degree of bone marrow fibrosis (BMF) are helpful in 
predicting patient outcome4,9-11. Patients under the age of 65 without significant co-morbidities and 
intermediate/high risk disease by Lille classification or int-2/high risk by IWG-MRT PSS are considered 
candidates for reduced intensity conditioning stem cell transplant (RIC-SCT). Allogeneic stem cell 
transplant is the only modality that offers the potential for cure, although the risk of transplant related 
mortality (TRM) and the morbidity and mortality associated with graft versus host disease (GVHD) are 
considerable12. Patients older than 65 or with competing co-morbidities are considered not to be 
candidates for RIC-ASCT but rather candidates for therapies such as interferon-alfa, immunomodulatory 
agents (IMiDs) JAK2-TKIs or histone deacetylase inhibitors (HDACI). MF patients that either fail 
current experimental therapies or are ineligible due to limiting cytopenias often have no alternative 
treatment options other than agents including hydroxyurea, melphalan, thalidomide, lenalidomide and 
danazol that achieve response rates of 20-50%, but have not been shown to alter the natural progression 
of disease13,14.   
Activating mutations of the Janus Kinase 2 receptor tyrosine kinase (JAKV617F), the thrombopoietin 
receptor (MPL W515L/K) and Calreticulin (CALR)have been identified in many patients with MPNs. 
Approximately 50-60% of patients with MF carry the JAK2 mutations, 20-25% CALR mutations and 
5% MPL mutations15-20. Mutations in additional Sex Combs-Like 1 (ASXL1), Ten-Eleven translocation-
2 (TET2), serine/arginine-rich splicing factor 2 (SRSF2), U2AF1, IDH and others have also been 
discovered in MPN patients and can coexist independently of JAK2V617F21-24.The prognostic 
significance of these mutations remains uncertain. Some of the mutation are considered high risk 
mutations and confer worse OS25,26. Ruxolitinib (Small molecule inhibitor of JAK2) has been shown to 
produce durable clinical benefits in terms of spleen volume reduction and improvement in constitutional 
symptoms with an acceptable toxicity profile27,28. Based on the results of two phase III studies 
(COMFORT-I, COMFORT-II)27,28showing improvement in spleen size, symptom control and 
improvement in quality of life, ruxolitinib was approved for use in patients with intermediate or high-risk 
myelofibrosis by the FDA. There is also evidence of a benefit in overall survival (OS) in patients treated 
with ruxolitinib. An OS advantage (HR=0.58; 95% CI, 0.39-0.85, p=0.005) in treated patients compared 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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to historical controls has been reported29.In addition, an analysis of the COMFORT-I study confirmed 
that patients treated with ruxolitinib had an OS advantage compared with placebo (HR=0.58, 95% CI, 
0.36-0.95, p=0.03) with a median of 102 weeks of follow up30.Follow-up analysis of the COMFORT-II 
trial has also demonstrated an OS advantage for patients treated with ruxolitinib31. 
In comparison to de novo AML, MPN-BP is highly resistant to standard induction chemotherapy and 
responses, if achieved, are difficult to maintain.  A retrospective review of 2333 myelofibrosis patients 
from Mayo clinic identified 91 patients who met WHO criteria for MF-BP6. The median overall survival 
of the entire group was 2.6 months after leukemic transformation with a median survival of 3.9 months 
in those patients receiving AML-like induction therapy. No patient achieved a complete response (CR) 
with induction therapy.  In a retrospective study of 74 patients with BCR-ABL negative MPN-BP at the 
MD Anderson Cancer Center, the best outcomes were seen in those receiving allogeneic stem cell 
transplants either upfront or immediately after achieving a response to induction therapy32. The survival 
was the same (6-7 months) for those patients that received either standard AML induction-like therapy 
or low dose therapies such as gemtuzumab, azacytidine or decitabine. In this review, a CR/CRi rate of 
46% was obtained with induction therapy but the median time to relapse was only 5 months. The 
prognosis for MPN-BP is dismal with present therapeutic options and more effective therapies are 
required. 
IDH2 Mutations in MPN: The presence of IDH mutations has prognostic significance in patients with 
MPNs. IDH mutations are associated with an increased risk of leukemic transformation. Co-occurring 
mutations in IDH1/2 and JAK2V617F33are associated with significantly reduced leukemia-free 
survival25in MF patients. Finally, IDH1/2mutations are among the most frequently encountered events 
in MPNs that have progressed to AML33,34. These clinical observations suggest, as is the case with TET2 
mutations, that IDH mutations alter the disease biology of MPNs. Moreover, a recent meta-analysis has 
showed that the presence of IDH mutation is associated with worse survival in patients with 
myelofibrosis35. 
Preclinical Data: Development and characterization of a JaK2V617F-Idh2R140Q murine model of 
MPN: To create a faithful model of phenotypic cooperativity betweenIDH2andJAK2 mutations, 
conditional knock-in Idh2R140Q mice were crossed with Jak2V617F and Mx1-cre. Intraperitoneal 
injections of polyI:polyC were used to excise and induce expression of both mutant alleles in 
hematopoietic cells.  Mice expressing combined Idh2R140Q and Jak2V617F demonstrated 
splenomegaly, leukocytosis and polycythemia similar to that of Jak2V617F mice, at timed sacrifices at 
approximately 100 days. Histologically, these mice demonstrated disrupted splenic architecture with 
blast-like cells, not seen in Jak2V617F mice. Bone marrow cytospins demonstrated abnormal myeloid 
elements with a strongly elevated M:E ratio. These data indicate that combined mutant mice have a 
lethal myeloproliferative neoplasm with histological pre-leukemic features. Competitive transplants 
demonstrated that the presence of the Idh2 mutant improved the competitive capacity of the donor bone 
marrow regardless of Jak2 mutant status. Transplant recipients developed a phenotype very similar to 
primary mice including polycythemia and thrombocytosis. Notably, leukocytosis was greater in 
recipients of Idh2R140Q-Jak2V617F marrow in comparison to Jak2V617F marrow. Flow cytometric 
analysis of Idh2R140Q-Jak2V617F primary mice demonstrated expansion of the lineage negative Sca+ 
cKit+ (LSK) population. Preclinical evaluation of combined JAK1/2 inhibition and IDH2 inhibition: 
To test the therapeutic efficacy of combined JAK1/2 inhibition and mutant IDH2 inhibition, 
Idh2R140Q-Jak2V617F mice were treated with ruxolitinib (60mg/kg) and enasidenib (100mg /kg) twice 
daily by gavage for 21-28 days. Primary recipients of Idh2R140Q-Jak2V617F bone marrow treated with 
enasidenib showed reduction of plasma 2-hydroxyglutarate (an oncometabolite product of mutant IDH2) 
to the level of wild type mice (Figure 1A). Monotherapy with either enasidenib or ruxolitinib reduced 
splenomegaly, while combined treatment completely resolved splenomegaly (Figure 1B). Combined 
therapy with enasidenib and ruxolitinib normalized polycythemia and leukocytosis to a level not seen 
with monotherapy (Figure 1C,D).  In the spleen, cells identified morphologically as blasts are no longer 
present in single AG221 or combined treatment with AG221, but not ruxolitinib, resulted in reduction of 
CD34 immunohistochemical staining in cells with megakaryocyte morphology (Figure 1E, F), 
transplant assay was used to examine the effect of therapy with inhibitors on donor chimerism. In 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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comparing peripheral blood from individual mice before and after treatment, we observed that mice 
treated with either enasidenib or with combined enasidenib and ruxolitinib showed significant reductions 
in mutant donor chimerism; in contrast, mice treated with either ruxolitinib or vehicle showed significant 
expansion of the proportion of mutant derived clones.  These effects were not seen in mice transplanted 
with Jak2V617F-mutant cells demonstrating specificity for IDH2-mutant MPN cells. 
Figure 1: Treatment of Idh2R140Q Jak2V617F combined mutant mice with combined JAK2 and 
IDH2 inhibitor: 
 
6.2 
RUXOLITNIB 
JAKs play an important role in signal transduction following cytokine and growth factor binding to their 
receptors. In addition, JAKs activate a number of downstream pathways implicated in the proliferation 
and survival of malignant cells including the STATs (signal transducers and activators of transcription), 
a family of important latent transcription factors. Aberrant activation of JAKs has been associated with 
increased malignant cell proliferation and malignant cell survival in patients with Philadelphia 
chromosome negative MPD.  The finding that peripheral blood from myeloproliferative disease (MPD) 
patients is capable of forming erythroid and megakaryocyte colonies in the absence of exogenous factors 
(which signal through JAKs) suggests that cells from these patients are intrinsically different than normal 
cells.  Indeed, work from a number of laboratories led to the identification of multiple somatic mutations 
in genes associated with cytokine and growth factor signaling. These include a mutation in the pseudo-
kinase domain of JAK2V617F (amino acid 617, valine to phenylalanine) that results in constitutive 
activation of JAK2 and downstream STATs. This mutation was found in > 90% of all PV patients and 
(A) 2HG 
quantification in 
plasma 
(B) Spleen weights 
(C) Hematocrit levels  
(D)WBC count 
(E-F) representative 
images of stained 
sections of spleen 
tissue.  
(F) CD34+ straining. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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in approximately 50% of all ET and Myelofibrosis with Myeloid Metaplasia (MMM) patients. More 
recently, other mutations have been identified in MPD patients lacking the JAK2V617F mutation. For 
instance, additional activating mutations in JAK2, as well as a mutation in the thrombopoietin receptor 
(MPL) and calreticulin (CALR) result in constitutive ligand- independent JAK activation. Importantly, 
ectopic expression of each of these mutant genes has been demonstrated to be sufficient to cause MPN-
like syndromes in mice.  Moreover, even in MPN patients lacking a confirmed JAK2 mutation, the 
detection of STAT activation suggests dysregulated JAK activity. In fact, regardless of the mutational 
status of JAK2, the malignant cells expectedly retain their responsiveness to  JAK activating cytokines 
and/or growth factors; hence, they may benefit from JAK inhibition. These findings, in addition to the 
limited life span of these patients and lack of beneficial therapies for the treatment of PMF and post-
PV/ET MF, clearly support the use of a JAK inhibitor in these diseases. 
Ruxolitinib is a JAK1/2 inhibitor that is currently FDA-approved for the treatment of patients with 
intermediate and high-risk MF (as well as PV patients with inadequate response to or are intolerant of 
hydroxyurea). Ruxolitinib is a substituted pyrrolopyrimidine compound that acts as a potent and 
selective inhibitor of the Janus kinase family of enzymes. Ruxolitinib is a novel, potent, and selective 
inhibitor of the JAKs with modest selectivity for JAK2. Ruxolitinib potently (IC50 values < 5 nM) 
inhibits JAKs, yet it does not significantly inhibit (<30% inhibition) a broad panel of 26 other kinases 
when tested at 200 nM (approximately 100 times the average IC50 value for JAK enzyme inhibition). 
Moreover, in cell-based assays relevant to the pathogenesis of MPDs, such as JAK-STAT signaling and 
the growth of cytokine-dependent lines, ruxolitinib demonstrated excellent potency (IC50 values of 80-
141 nM). This effect was not due to general cytotoxicity, because ruxolitinib (up to 25 μM) had no 
significant effect on the growth of cytokine-independent cell lines transformed by the Bcr-Abl  
oncogene.  In addition, ruxolitinib inhibited JAK/STAT signaling and growth of a cell line expressing 
the JAK2 mutant variant (JAK2V617F) that has been implicated in the pathogenesis of the majority of 
Philadelphia chromosome negative MPN. Additional details as to the in vitro pharmacology of 
ruxolitinib may be found in the Clinical Investigator’s Brochure (IB). Ruxolitinib was evaluated in two 
mouse models where either a cytokine-dependent multiple myeloma cell line, INA-6, oracell line, BaF3, 
engineered to express JAK2V617F was inoculated. The ability of ruxolitinib to inhibit JAK pathway 
signaling as well as tumor cell survival and growth was assessed in vivo. In vitro cell biology 
experiments have demonstrated that the potency of ruxolitinib is very similar between the cytokine-
dependent INA-6 myeloma cells, with wild type JAKs, and the BaF3 cells expressing a clinically 
relevant mutant JAK2. As such, the in vivo studies described herein characterize the ability of 
ruxolitinib to inhibit wild type JAK2 (using the INA-6 xenograft model) and MPD-related mutant JAK2 
(using a mouse model of splenomegaly driven by cells expressing the mutant JAK2V617F). 
Treatment of mice with orally administered ruxolitinib resulted in a dose-dependent suppression of 
STAT3 phosphorylation and tumor growth in the cytokine-dependent INA-6 xenograft model at doses 
≥ 10mg/kg BID. Moreover, oral administration of ruxolitinib inhibited the dramatic splenomegaly in 
mice resulting from intravenous inoculation of the BaF3-JAK2V617F cells. Additional details as to the 
in vivo pharmacology of ruxolitinib may be found in the Clinical Investigator’s Brochure (CIB). In 
summary, pharmacological data obtained in both in vitro and in vivo model systems support the potential 
utility of orally administered ruxolitinib in the treatment of malignancies, including MPD such as PMF 
and Post-PV/ET MF. 
The chemical name of ruxolitinib phosphate is (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-
pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate. Ruxolitinib phosphate has a molecular formula 
of C17H21N6O4P and a molecular weight of 404.36. Ruxolitinib phosphate drug substance is a white 
to off-white powder and is referred to herein as ruxolitinib. 
6.2.1 CLINICAL EXPERIENCE IN MYELOFIBROSIS WITH 
RUXOLITINIB 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Ruxolitinib has been shown to produce durable clinical benefits in terms of spleen volume reduction and 
improvement in constitutional symptoms with an acceptable toxicity profile27,28. Based on the results of 
two Phase III studies (COMFORT-I, COMFORT-II)27,28 showing improvement in spleen size, symptom 
control and improvement in quality of life, ruxolitinib was approved for use in patients with intermediate 
or high-risk myelofibrosis by the FDA. There is also evidence of a benefit in overall survival (OS) in 
patients treated with ruxolitinib. An OS advantage (HR=0.58; 95% CI, 0.39-0.85, p=0.005) in treated 
patients compared to historical controls has been reported29. In addition, an analysis of the COMFORT-
I study confirmed that patients treated with ruxolitinib had an OS advantage compared with placebo 
(HR=0.58,95%CI, 0.36-0.95, p-0.03) with a median of 102 weeks of followup30. Follow-up analysis of 
the COMFORT-II trial has also demonstrated an OS advantage for patients treated with ruxolitinib31. 
6.3 
Enasidenib (AG-221) 
The IDH enzymes play critical roles in catalyzing the oxidative decarboxylation of isocitrate to produce 
carbon dioxide (CO2) and alpha-ketoglutarate (α-KG) enzyme in the citric acid cycle.  Of the two best 
characterized isoforms, IDH1 and IDH2, mutations in IDH2 have been found in approximately 15% of 
subjects with AML36,37.  The mutated proteins have a gain-of-function, neomorphic activity, catalyzing 
the reduction of α-KG to 2-HG while lacking the ability to synthesize isocitrate38.  The excess 
accumulation of 2-HG leads to inhibition of dioxygenase dependent enzymes such as ten-eleven 
translocation (TET) and Jumonji which are responsible for demethylating DNA and histones, 
respectively, the consequence of which results in an altered epigenetic state and impaired cellular 
differentiation39,40.   
Recurring mutations in IDH2 may be important for AML pathogenesis or disease progression41.  
Retrospective clinical data have revealed that the presence of IDH1 mutations is associated with a worse 
prognosis in younger cytogenetically-normal AML subjects and subjects with IDH2 mutations had a 
significantly lower complete response rate37.  In a retrospective study of 398 subjects < 60 years of age 
who were diagnosed with AML and randomly assigned to receive induction therapy with high-dose or 
standard dose daunorubicin, IDH2 mutations were in general associated with an improved overall 
survival42.  Prospective clinical studies will help further understand the impact mutations, co-mutations, 
and/or karyotype status have on disease outcomes in the presence of an IDH mutation. 
Enasidenib is a first-in-class, selective, potent inhibitor of the neomorphic activity of IDH2 mutant 
enzyme and has been shown to suppress 2-HG production in enzymatic, cell-based, and in vivo systems.  
Pharmacology studies support that suppression of 2-HG levels by enasidenib results in alterations of 
cellular downstream markers, leading to a release in the block of tumor cell differentiation. 
Enasidenib has rapid oral absorption, low to medium total body plasma clearance, and low to high 
volume of distribution. The half-lives range from 2.5 to 5.4 hours, and oral bioavailability was 
approximately 40% to 50% (free base) in toxicology species.  Enasidenib is metabolized by multiple 
cytochromes (CYPs) and uridine diphosphate (UDP)-glucuronosyl transferases (UGTs).  Enasidenib is 
a direct inhibitor for CYP2C8,2C9, 2C19 and 2D6, as well as UDP-glucuronosyl transferase 1 family, 
polypeptide A1 (UGT1A1). The N-dealkylated metabolite, AGI-16903 is also an inhibitor of CYP1A2, 
2C8 and 2C9.  Enasidenib and AGI-16903 are weak inducers of CYP3A4.  Preliminary results indicate 
that enasidenib increased 4β-hydroxycholesterol level in subjects, indicating CYP3A induction in 
patients.  Enasidenib is not a substrate, but is a potent inhibitor of P-glycoprotein (P-gp) and breast 
cancer resistance protein (BCRP).  In vitro, enasidenib is an inhibitor of organic anion transporter 
(OAT) 1, OATP1B1, OATP1B3, and organic cation transporter (OCT) 2, while AGI-16903 is an 
inhibitor of BCRP, OAT1, OAT3, OATP1B1, and OCT2.  AGI-16903 is also a substrate of P-gp and 
BCRP.  Clinical relevance of such in vitro interactions will be evaluated in humans as needed. 
The toxicity profile of enasidenib has been evaluated in repeat dose oral toxicity studies of up to 90 days 
in Sprague-Dawley rats, and cynomolgus monkeys and for 7 days in beagle dogs, and in the bacterial 
reverse mutation (Ames) and mammalian chromosomal aberration assays in vitro.  Enasidenib was 
neither mutagenic nor clastogenic.  Dose-limiting toxicities in rats after 28 days of dosing were 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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multifactorial and included gastrointestinal tract atrophy and erosions, lymphoid atrophy, degeneration, 
and necrosis, bone marrow hypocellularity and necrosis, skeletal muscle degeneration and necrosis, 
pancreas and kidney epithelial vacuolation, and adrenal cortical hemorrhage and necrosis.  After 
90 days of dosing, non-dosing limiting target organ toxicities in rats were limited to testes/epididymides 
and pancreas.  In monkeys, ulcerative inflammation in the large intestine was determined as the dose-
limiting toxicity.  No changes in cardiovascular functions were noted in monkeys; however coronary 
artery lesion (periarteritis) was observed at the dose associated with dose-limiting toxicity indicated 
above.  Findings in large intestine and coronary artery in monkeys were observed following 28 days of 
dosing.  Additional target organ toxicities secondary to decreased body weight and food consumption 
in monkeys included femur/tibia (either dysplasia or decreased thickness of physis), bone marrow 
(decreased cellularity), thymus (atrophy/involution), liver (cytoplasmic rarefaction) and pancreas 
(acinar cell degranulation).  In dogs, there were enasidenib dose-related prolonged heart rate-corrected 
QT (QTc) intervals, hypotension and increased heart rate.  These functional cardiovascular effects of 
enasidenib were the likely underlying causes of coronary artery lesions in dogs.   
As of 15 Apr 2016, data are available for 330 subjects from Study AG221-C-001 who have been 
administered enasidenib across 13 dosing cohorts up to a 650 mg daily dose, including both BID and 
QD dosing regimens.  Study AG221-C-002, a food effect study in healthy volunteers is complete. Study 
AG-221-CP-001, a pharmacokinetic (PK) and safety study in healthy male Japanese and Caucasian 
adult subjects, and Study AG-221-CP-002, a PK study to evaluate the metabolism and excretion and 
determine absolute bioavailability of enasidenib in healthy male adult subjects, are also complete.  
Study AG221-C-003, a Phase 1/2 dose escalation study, evaluated enasidenib at doses ≥ 100 mg daily 
in subjects with advanced solid tumors with an IDH2 mutation, including glioma, and in subjects with 
AITL with an IDH2 mutation. Doses up to 650 mg were well-tolerated. The expansion phase of AG221-
C-003 was canceled based on the Sponsor’s decision to focus on the relapsed refractory AML indication 
and not for any safety reason. Ongoing studies include a Phase 3 randomized study in subjects with R/R 
AML with IDH2 mutation (AG-221-AML-004), a Phase 1b/2 study in subjects with newly-diagnosed 
AML (AG-221-AML-005), and a Phase 1 study in subjects with newly diagnosed AML sponsored by 
Agios in collaboration with Celgene (AG120-221-C-001).  Study AG-221-C-005 is evaluating oral AG-
120 plus subcutaneous (SC) azacitidine and oral enasidenib plus SC azacitidine in subjects with newly 
diagnosed AML with IDH1 or IDH2 mutation, respectively, who are not candidates to receive intensive 
induction chemotherapy. Study AG120-221-C-001 is evaluating AG-120 or enasidenib in combination 
with induction and consolidation therapy in subjects with newly diagnosed AML with an IDH1 and/or 
IDH2 mutation. 
Data from Study AG221-C-001 showed that enasidenib was well-tolerated at total daily doses up to 650 
mg. The MTD was not reached in the dose escalation part of the AG221-C-001 study. Based on 
pharmacodynamic and efficacy data, the 100 mg daily dose was chosen for further development.  No 
meaningful differences in nature, incidence, or severity of the Adverse Events (AE) have been observed 
between subjects with R/R AML, previously untreated AML, or MDS. As of 15 Apr 2016, 93 deaths 
have been reported in Study AG221-C-001 either on study or within 28 days of the last dose of study 
treatment.  Deaths were attributed to complications of the underlying condition or disease progression, 
with an exception of 1 subject who experienced pericardial effusion complicated by fatal cardiac 
tamponade. Retrospective analysis of this case suggests that pericardial effusion was a likely sign of 
isocitrate dehydrogenase-differentiation syndrome (IDH-DS).  Serious adverse events (SAEs) reported 
in ≥ 5% of the study participants included febrile neutropenia in 79 (23.9%), pneumonia in 47 (14.2%), 
sepsis in 39 (11.8%), pyrexia in 28 (8.5%), leukocytosis in 27 (8.2%), IDH-DS in 24 (7.3%), lung 
infection in 21 (6.4%), acute renal failure in 18 (5.5%), tumor lysis syndrome (TLS) in 18 (5.5%), and 
fatigue in 17 (5.2%) subjects. 
The safety and tolerability of enasidenib has been evaluated in more than 440 subjects enrolled in 
clinical studies of subjects with hematologic malignancies or solid tumors and single-dose 
pharmacology studies in healthy volunteers, as of the data cutoff date for this IB (15 Apr 2016 for Study 
AG221-C-001 and 01 Jul 2016 for all other ongoing clinical studies).  In clinical studies, enasidenib 
overall was generally well tolerated, with a relatively low incidence of discontinuations due to AEs.  


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Specific adverse drug reactions (ADRs) to enasidenib were identified. Events of IDH-DS (similar to a 
syndrome observed with retinoic acid in acute promyelocytic leukemia), noninfectious leukocytosis, 
TLS, GI disturbances (such as nausea, diarrhea, vomiting, and associated dysgeusia and decreased 
appetite), and hyperbilirubinemia have been observed in subjects with hematologic malignancies. 
Gastrointestinal disturbances and hyperbilirubinemia have been also observed in subjects with solid 
tumors. IDH-DS and noninfectious leukocytosis are associated with enasidenib mechanism of action 
and generally decrease in incidence with time. 
Preliminary analysis of PK data in Study AG221-C-001 (as of 15 Apr 2016) from subjects with 
advanced hematologic malignancies up to the 650 mg QD dose level demonstrated high plasma 
exposures, a long mean plasma half-life of enasidenib after a single dose, high drug accumulation after 
multiple doses, and relatively high PK variability.  The mean time to Cmax (Tmax) ranged from 
approximately 1 to 24 hours when administered as a single dose 3 days before study treatment began.  
In a subset of IDH2 mutated AML subjects, correlation of drug exposure, 2-HG levels, and IDH2 
mutation site was evaluated.  A comparison of PK data between the 2 groups (R140Q and R172K) at 
the enasidenib 100-mg dose level indicated that the average steady state exposure level (AUC0-10 or 
Cmax) was similar. Enasidenib treatment decreased 2-HG levels in R140Q and R172K patients.  
Preliminary analysis showed no clear correlation between 2-HG suppression and clinical response to 
enasidenib. 
As of 15 Apr 2016 in Study AG221-C-001, the overall response rate (ORR) (defined as complete 
response [CR] + CR with incomplete neutrophil recovery [CRi] + morphologic CR with incomplete 
platelet recovery [CRp] + partial response [PR] + marrow CR [mCR] + morphologic leukemia free state 
[MLFS]) among the 113 subjects in the dose escalation phase was 45.1% with a median time to first 
response of 1.9 months and a median time to best response of 3.7 months.  Twenty-four of the 113 
subjects (21.2%) achieved a best response of CR, with a median time to CR of 3.8 months. Responses 
occurred in all dosing groups (30 mg BID to 650 mg QD). Of the 176 subjects with R/R AML in the 
combined Phase 1 part of the study, the ORR was 40.3%, with a median duration of response of 5.8 
months.  Thirty-four of the 176 subjects (19.3%) achieved a CR, with a median duration of CR of 8.8 
months. The ORR, CR, and median duration of response were similar in the subset of subjects who 
received the 100 mg daily dose compared with the total R/R AML population. Of the 71 responders 
among subjects with R/R AML, the median time to first response was 1.9 months and the median time 
to best response was 3.7 months.  The median times to first response and best response were similar in 
the subset of subjects who received the 100 mg daily dose.  At the time of data cutoff, median event-
free survival for subjects with R/R AML was 6.4 months (95% CI = 5.4, 7.5) and median overall 
survival was 9.3 months (95% CI = 8.2, 10.9). 
This study43 led to the Food and Drug Administration approval to enasidenib for the treatment of adult 
patients with relapsed or refractory acute myeloid leukemia with IDH2 mutation in August 2017. 
Please refer to the current version of the enasidenib IB for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and AE profiles of enasidenib. 
7. 
STUDY OBJECTIVES 
Ruxolitinib (also known as INCB018424), a JAK1/2 inhibitor, and enasidenib (AG-221, an IDH2 
inhibitor) are effective and tolerable treatments for patients with myelofibrosis (MF) and acute myeloid 
leukemia (AML), respectively. We hypothesize that the combination of these agents in patients with 
MPN with an IDH2 mutation will improve the overall clinical response to therapy without causing 
excessive toxicity. 
7.1 
PRIMARY OBJECTIVES 
• 
To estimate the efficacy of ruxolitinib and enasidenib combination therapy in patients with 
accelerated-phase and blast-phase disease.  Efficacy will be defined as the proportion of patients 
who achieve a best leukemia response of: complete response (CR), Partial Response (PR), 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 22 of 77 
 
 
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Confidential 
complete response with incomplete recovery of counts (Cri), as assessed by the modified 2013 
International Working Group (IWG) Response Criteria. 
7.2 
SECONDARY OBJECTIVES 
• 
To assess the efficacy of the combination of ruxolitinib with enasidenib in patients with 
accelerated-phase and blast-phase disease using complete (CBR) and partial blast response 
(PBR). 
• 
To assess the efficacy (CR, PR, Clinical Improvement) of the combination of ruxolitinib with 
enasidenib in patients with PMF, post-PV MF, or post-ET MF in chronic phase and 4-9% blasts 
as assessed by the modified 2013 International Working Group (IWG) Response Criteria  
• 
To determine the safety of the combination of ruxolitinib and enasidenib based on the Common 
Terminology Criteria for Adverse Events version 5.0 (CTCAE). 
• 
To assess the impact of the combination of ruxolitinib with enasidenib on the overall survival of 
advanced phase MPN patients.  
7.3 
EXPLORATORY OBJECTIVES 
• 
To determine the impact of the combination of ruxolitinib with enasidenib in patients with PMF, 
post-PV MF, or post-ET MF, on patient quality of life as assessed by the Myelofibrosis Symptom 
Assessment Form (MF-SAFv4.0). 
• 
To evaluate the pharmacodynamics of ruxolitinib and enasidenib when combined in this 
population. 
• 
To evaluate the effects of combined therapy on gene expression and global methylation status.  
• 
To explore changes in mutant allele burden and clonal architecture of disease. 
8.0 
PATIENT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and not meet any of the 
exclusion criteria to be registered to the study by the Central Office. Study treatment may not begin 
until a subject is registered. 
8.1 
INCLUSION CRITERIA 
1. Willing and able to adhere to the study visit schedule and all protocol requirements 
2. Subjects must be ≥ 18 years at the time of signing the Informed Consent Form (ICF). 
3. Diagnosis of: 
a. Accelerated-phase (≥ 10% blasts in PB or BM) or blast-phase (≥ 20% blasts in PB or BM) 
myeloproliferative neoplasm (with history of prior myelofibrosis, polycythemia vera, or essential 
thrombocythemia) 
b. Previously treated patients with myelofibrosis with persistent disease or progressive disease 
(persistent or progressive splenomegaly, leukocytosis, anemia, or thrombocytopenia) with 
intermediate-1 or greater risk disease according to 2013 International Working Group (IWG) 
criteria, and 4-9% circulating blasts. 
4. Demonstration of an IDH2 mutation. 
5. Platelet count  > 75,000 X 109/L for chronic phase myelofibrosis patients. 
6. Prior therapy with either ruxolitinib or enasidenib is permitted, but not a combination of ruxolitinib 
and enasidenib.   
7. Patients with chronic phase myelofibrosis on ruxolitinib must be on the drug for at least 3 months 
and on a stable dose for at least one month. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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8. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
ECOG 3 status will be allowed if attributable to MPN. 
9. Patients must have adequate organ function as demonstrated by the following: 
a. Direct bilirubin < 2.0mg/dL, unless due to Gilbert’s disease or current elevations in direct 
bilirubin associated with existing enasidenib use. 
b. Serum creatinine< 2.0 mg/dL. 
c. ALT and AST ≤ 3x upper limit of normal (unless transaminitis is considered to be related 
to MF). 
10. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with 
a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to starting enasidenib and must 
either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable 
methods of birth control, one highly effective method and one additional effective method AT 
THE SAME TIME, at least 4 weeks before she starts taking enasidenib. FCBP must also agree 
to ongoing pregnancy testing. Men must agree to use a condom during sexual contact with a female 
of child bearing potential even if they have had a successful vasectomy. All patients must be 
counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. 
11. All study participants must be able to swallow oral medication.  
8.2 
EXCLUSION CRITERIA 
1. Use of any other standard anti-neoplastic drug or growth factor (e.g., anagrelide, G-CSF, 
lenalidomide, thalidomide clofarabine) except hydroxyurea or experimental drugs, with the 
exception of ruxolitinib or enasidenib, less than 14 days or 5-half-lives, whichever is longer, prior 
to starting study therapy and/or lack of recovery from all toxicity (except for alopecia) from 
previous therapy to Grade 1 or better. 
a. Patients will be permitted to receive hydroxyurea while on study for up to a total of 3 cycles 
of combined therapy. 
2. Known prior clinically relevant hypersensitivity reaction to ruxolitinib or enasidenib. 
3. Prior therapy with enasidenib in combination with ruxolitinib. 
4. Concurrent 
use 
of 
strong 
inducers 
of 
CYP3A4 
(Rifampin, 
St. 
John’s 
Wort, 
Carbamazepine,  Phenytoin) and/or the following strong inhibitors of CYP3A4 (protease 
inhibitor containing HIV anti-retrovirals, cobicistat, clarithromycin, itraconazole, ketoconazole, 
nefazodone, and telithromycin) are prohibited.  Also prohibited are CYP2C9 substrate 
medications that have a narrow therapeutic range: phenytoin and warfarin. 
5. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent 
the subject from signing the informed consent form, which places the subject at unacceptable risk 
if he/she were to participate in the study or which confounds the ability to interpret data from the 
study. 
6. Lactating females. 
7. Active uncontrolled infections. 
8. Patients with active malignancy of other type than required for this study are not eligible with the 
exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in 
situ" of the cervix or breast. Patients with malignancies with indolent behavior such as prostate 
cancer treated with radiation or surgery can be enrolled in the study as long as they have a 
reasonable expectation to have been cured with the treatment modality received. 
9. Subject has significant active cardiac disease within 6 months prior to the start of study treatment, 
including New York Heart Association (NYHA) Class III or IV congestive heart failure (Appendix 
G) acute coronary syndrome (ACS); and/or stroke; or left ventricular ejection fraction (LVEF) < 
40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 
28 days prior to the start of study treatment. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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Confidential 
10. QTc interval (Fridericia’s correction [QTcF]) > 450 ms 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee to 
ensure that the patient qualifies for the trial. 
9.0 
SUBJECT RECRUITING AND SCREENING 
Patients will be recruited from the sites participating in the MPN-RC. It is expected that a maximum of 
32 patients will be recruited to this study. The estimated accrual rate is 2-3 patients per month. 
9.1 
STUDY-WIDE RECRUITMENT METHODS 
Potential research subjects will be identified by a member of the patient’s treatment or research teams. 
If the Investigator is a member of the treatment team, s/he will screen their patient’s medical records 
for suitable research study participants and discuss the study and their potential for enrolling in the 
research study. Potential subjects contacted by their treating physician will be referred to the 
Investigator/research staff of the study. The extent of the risks, benefits, toxicities/side effects, 
alternatives/options for treatment, financial costs/burdens, and the voluntary nature of the study will 
be explained to patients. All patients will be required to sign a written informed consent prior to being 
registered on this protocol. Every effort will be made to answer questions raised by patients and their 
families or advocates regarding the protocol and alternative therapies prior to asking a patient to sign 
the consent form. 
Patients of all races, both male and female, will be accepted into the protocol. 
10. 
TREATMENT DOSAGE AND ADMINISTRATION 
Patients who are on ruxolitinib will continue their current dose. Patients who are not on ruxolitinib 
will receive ruxolitinib per Table 1 dosing based on platelet count (modified package insert dosing). 
Enasidenib will be given at 100 mg daily on enrollment for patients with accelerated and blast phase 
myelofibrosis regardless of platelet count (this will be deemed Cycle 1). Patients with chronic phase 
myelofibrosis will receive Enasidenib at starting dose of 50 mg daily for cycle 1. The dose of 
Enasidenib will be increased to 100 mg for cycle 2 if the platelet count stays above 50,000 at the end 
of cycle 1 (Table 3a) and no other therapy emergent SAE of grade >2 developed (except grade 2 
hyperbilirubinemia that is acceptable for dose escalation). 
Ruxolitinib and enasidenib will be given orally in an outpatient setting unless the patient is being seen 
inpatient for another reason. Ruxolitinib and enasidenib will be given orally in 28-day cycles.  
Patients should fast 2 hours before and 1-hour post enasidenib. Ruxolitinib may be administered 
independent of fasting and may be given with enasidenib. All protocol mandated visits will be 
performed at one of the participating institutions. Patients will return to the treating institution at a 
minimum of weekly during Cycles 1 and 2, every 4 weeks for Cycles 3 and beyond. Additional clinic 
visits will be mandated according to the patient clinical condition and at the discretion of the treating 
provider. Patients will have an end of study visit for a safety follow-up at 30 days after their last dose 
of therapy. 
The dosages of ruxolitinib and/or enasidenib can be reduced, based on assessment of adverse events, 
if any occur, as described below in Section 10.1. Missed or vomited doses of ruxolitinib or enasidenib 
will not be made up. 
Twenty-eight days is considered one cycle of therapy. Attempts will be made to provide an adequate 
treatment period with the combination of at least 6 cycles, unless significant toxicity is observed, to 
account for delayed time to response observed with biologic agents. Responders will continue therapy 
indefinitely unless progression of disease occurs, toxicity warranting discontinuation of therapy is 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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Confidential 
observed, or at the discretion of the treating physician. Patients will have an end of study visit for a 
safety follow-up at 30 days after their last dose of therapy.  
10.1 DOSE MODIFICATION FOR NON-HEMATOLOGICAL AE’S, 
CLINICALLY SIGNIFICANT IN THE OPINION OF THE TREATING 
PHYSICIAN 
Based on available pharmacokinetic and drug metabolism data, ruxolitinib is mainly metabolized by 
CYP3A4 with additional contribution from CYP2C9. Enasidenib inhibits CYP2C9 and induces 
CYP3A4. Although no adjustment is recommended when ruxolitinib is co-administrated with 
CYP3A4 inducer, potential drug-drug interactions might occur. This study will be the first time 
ruxolitinib and enasidenib will be used in combination for this patient population. Therefore, the 
safety of the combination will be confirmed in the first six patients who accrue. If no more than one 
patient out of the initial six has a treatment-related Grade 3 or higher adverse event attributable to the 
study drugs, the combination therapy will be considered safe.  If more than one patient out of the 
initial six has limiting toxicity, the trial will be suspended, and the safety data will be further reviewed. 
If drug-related Grade 3 clinically relevant non-hematologic toxicity is attributable to one or both of 
the drugs (based on known adverse events profile), dose interruption of that particular drug(s) is 
mandatory. Patients who experience Grade 3 drug related clinically relevant non-hematological 
toxicity may be given a subsequent course one dose level below the previous course, but the patient 
must have recovered to Grade ≤1 before initiation of the next course. If attributable to ruxolitinib, 
dosing modifications in Tables 2a and 2b should be utilized. If attributable to enasidenib, dosing 
modification in Table 3b should be utilized. If a patient has drug-related clinically relevant Grade 4 
non-hematologic toxicity, he/she will be taken off study. The dose of therapeutic agents can be 
decreased, at the discretion of treating physician, for chronic Grade 2 non-hematologic toxicity. 
Additionally, ruxolitinib dosage may be adjusted if patients develop decline in Creatinine clearance 
(CrCl) as calculated by the Cockcroft- Gault equation as follows: Reduce ruxolitinib dose by one dose 
level for patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 
mL/min) if the patient is receiving a ruxolitinib dose of 10 mg BID or higher. (Per FDA package 
insert for ruxolitinib).  
Myelosuppression and cytopenias are expected outcomes of MF disease processes and MF treatments 
and per se will not constitute adverse events except as follows: hematologic toxicity will be 
considered Grade 4 neutropenia with fever that does not clinically resolve within 14 days in the setting 
of optimal interventions or Grade 4 thrombocytopenia with clinically-significant bleeding. Dose 
interruption of the drug to which the adverse event is attributable is required. Patients may be given 
a subsequent course one dose level below the previous course, but the patient must have recovered to 
grade ≤ baseline at study entry. The dose of therapeutic agents can be decreased, at the discretion of 
treating physician, for chronic Grade 3 hematologic toxicity. 
10.1.1 QT PROLONGATION 
QTc interval has been observed in dogs at relatively low doses of enasidenib. Prolonged QTc interval 
has not been seen in other animal species at high doses.  Subjects who experience prolongation of 
the heart-rate corrected QT interval, Fridericia’s correction (QTcF) to > 480 msec (Grade ≥ 2) while 
treated with enasidenib, should be promptly evaluated for causality of the QTc prolongation and 
managed according to the following guidelines: 
• 
Levels of electrolytes (potassium, calcium, and magnesium) should be checked and 
supplementation given to correct any values outside the normal range. 
• 
Concomitant medications should be reviewed and adjusted as appropriate for medication 
with known QT prolonging effects. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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• 
If no other cause is identified and the Investigator believes it is appropriate, particularly if 
QTc remains elevated (after above measures have been implemented, or as determined by 
the Investigator), investigational product may be interrupted, and an ECG should be 
rechecked in approximately 1 week after the QTc prolongation was first observed, or more 
frequently as clinically indicated. 
o If QTc has recovered or improved and the Investigator believes it is safe to do so, 
re-challenge with enasidenib should be considered if held. ECGs should be conducted 
at least weekly (e.g., at every scheduled visit) for 2 weeks following QTc 
reduction ≤ 480 msec. 
o If Grade 2 (QTcF> 480 and ≤ 500 msec), the dose of enasidenib may be reduced to a 
dose approved by the Study Chair without interruption of dosing. The enasidenib dose 
may be re-escalated to the prior dose in ≥ 14 days after QT prolongation has decreased 
to ≤ Grade 1. 
o If Grade 3 (QTcF> 500 msec), when QTc prolongation is first observed, hospitalization 
for continuous cardiac monitoring and evaluation by a cardiologist should both be 
considered. Dosing with enasidenib will be interrupted. If QTc returns to within 30 ms 
of baseline or < 450 msec within 14 days, treatment may be resumed at a reduced dose. 
The enasidenib dose cannot be re-escalated following dose reduction for Grade 3 QTcF 
prolongation unless the prolongation was associated with an electrolyte abnormality or 
concomitant medication. 
o If Grade 4 (QTcF> 500 msec or > 60 msec change from baseline with torsade de pointes 
or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia), 
subjects should be admitted to hospital when QTc prolongation is first observed for 
continuous cardiac monitoring and be discharged only after review by a cardiologist. 
Dosing with enasidenib should be permanently discontinued. 
10.1.2  
ABNORMAL LEVEL OF LIVER ENZYMES 
(HYPERBILIRUBINEMIA) 
Subjects with elevations in ALT ≥ 3-fold ULN, subjects will be monitored using the algorithm: 
• 
Repeat LFT (i.e., ALT, AST, total bilirubin, ALP, GGT) within < 3 days of the initial test. 
Follow-up 2-3 times weekly, and weekly when stable. 
• 
Perform additional diagnostic follow up: 
o Focused medical history, including review of prior history of liver or biliary disorders, 
concurrent 
symptoms, 
review 
of 
all 
concomitant 
medications 
(e.g., acetaminophen-containing medications, over-the-counter or herbal medications, 
nutritional supplements) including any changes in medications, detailed review of 
alcohol use. 
o Hepatitis serology (anti-HAV, HBsAg, anti-HBs, anti-HB core, anti-HCV, HCV RNA, 
EBV and CMV screen), and autoantibodies (e.g., ANA, anti-smooth muscle antibody). 
o Complete physical examination. 
o Liver ultrasound and follow-up imaging as appropriate. 
o Additional evaluation as appropriate (INR, PT). 
Hyperbilirubinemia generally decreased in frequency as enasidenib treatment continued. \ 
 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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 Table 1. Ruxolitinib initial dose for patients’ baseline platelet count by cohort* 
Cohort 
Plt>100 X109/L 
Plt 50-100 X109/L 
Plt 20-50 X109/L 
Plt<20 X109/L 
Blast/Accelerated 
Phase 
20 BID 
15 BID 
10 BID 
5 BID 
Chronic Phase 
15 BID 
10 BID** 
NA 
NA 
*Patients already receiving Ruxolitinib will begin trial at the dose they were on prior to combination therapy. 
**Chronic phase patients with platelet<75 will not be enrolled to the trial. 
Table 2a. Ruxolitinib Dose Adjustment for patients with accelerated and blast phase MF for NON-
HEMATOLOGICAL AEs* 
Dose level 
PATIENTS’ BASELINE PLATELET COUNTS 
Plt>100 X109/L 
Plt 50-100 X109/L 
Plt 20-50 X109/L 
Plt<20 X109/L 
+1 
25 BID 
20 BID 
NA 
NA 
0 
20 BID 
15 BID 
10 BID 
5 BID 
-1 
15 BID 
10 BID 
5 BID 
5QD 
-2 
10 BID 
5 BID 
5 QD 
Stop treatment 
-3 
5 BID 
5 QD 
Stop treatment 
 
-4 
5 QD 
Stop treatment 
 
 
-5 
Stop treatment 
 
 
 
* For patients with accelerated and blast phase MF, treatment will continue at the same dose regardless of platelet 
count. 
Table 2b. Ruxolitinib Dose Adjustment for patients with chronic phase MF for thrombocytopenia or non-
hematological AEs 
Dose level 
DOSE ADJUSTMENT FOR THROMBOCYTOPENIA 
 
Plt>100 X109/L 
Plt 50-100 X109/L 
Plt 20-50 X109/L 
DOSE ADJUSTMENT FOR NON-
HEMATOLOGICAL AEs 
+1 
20 BID 
15 BID 
N/A 
0 
15 BID 
10 BID 
5 BID* 
-1 
10 BID 
5 BID 
5 QD 
-2 
5 BID 
5 QD 
Stop treatment 
-3 
5 QD 
Stop treatment 
 
-4 
Stop treatment 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 28 of 77 
 
 
10 Nov 2021 
Confidential 
Table 3a. Enasidenib Dose Adjustment for thrombocytopenia 
MF chronic phase 
Cycle 1 
MF chronic phase 
Cycle 2 and above 
MF chronic phase 
Cycle 2 and above 
MF chronic phase 
Cycle 2 and above 
MF accelerated 
phase and blast 
phase 
Platelet >75X109/L 
Platelet > 50X109/L 
Platelet 35-50X109/L 
Platelet<35X109/L 
Any platelet count 
50mg 
100mg 
50mg 
Hold 
100mg 
Table 3b. Enasidenib Dose Adjustment for non-hematological AE 
Dose Level 
Enasidenib 
-1 
50 mg QD 
  0 
100 mg QD 
10.2 DOSE MODIFICATIONS FOR HEMATOLOGICAL AE’S 
For subjects receiving ruxolitinib and enasidenib, ruxolitinib dosages will be adjusted as detailed in 
Table 2a and Table 2b. 
For chronic phase MF, if platelets are reduced to <  20X109/L ruxolitinib should be stopped 
Ruxolitinib can be rechallenged at 5mg BID when platelets recover to >20X109/L, and enasidenib 
could be added the subsequent cycle as long as platelets recover to >50X109/L. 
Interrupt treatment for absolute neutrophil count (ANC) less than 0.5 X 109 /L. After recovery of 
ANC above 0.75 X 109 /L, dosing may be restarted; restart dosing at 5 mg per day lower than the dose 
prior to the treatment interruption. 
For patients with accelerated and blast phase MF, treatment will continue at the same dose regardless 
of platelet count or ANC. 
10.3 DOSE ESCALATIONS 
Patients may be escalated to the next higher dose level of ruxolitinib as per dose levels in Table 2a 
in the event that a patient’s platelet count increases, after Cycle 3 of combined therapy or in case of 
suboptimal response in the opinion if the investigator. Patients with chronic phase MF will escalate 
the dose of enasidenib from 50mg to 100 mg in cycle 2 and ongoing if platelet count stays above  
50,000 at the end of cycle 1 (Table 3a) and no other therapy emergent SAE of grade >2 developed 
(except grade 2 hyperbilirubinemia that is permitted). 
Dose of ruxolitinib and enasidenib cannot be simultaneously increased in the same cycle. Dose 
escalation is permitted if ALL of the following criteria are met: 
1. No dose reductions due to toxicity were required in the prior cycle 
2. No dose interruptions due to toxicity were required in the prior cycle 
3. The prior cycle was not delayed due to toxicity 
4. The current cycle is not delayed due to toxicity 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
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5. ANC ≥ 1.0 x 109/L 
6. The patient has sub-optimal benefit, defined as a failure to reduce palpable spleen length by at 
least 50% and/or suboptimal improvement in disease- related symptoms as assessed by the 
Investigator. 
7. No development of new on set transfusion dependency judged to be due to therapy 
10.4 CONCOMITANT MEDICATIONS/TREATMENTS 
All supportive measures consistent with optimal subject care will be given throughout the study.  
Concomitant medications will be captured in the Case Report Form (CRF) beginning at Screening. 
Packed red blood cell or platelet transfusions are allowed when necessary.  Growth factor use 
(including erythropoietin) is not allowed with the exception of the use of filgrastim (G-CSF) or 
pegfilgrastim, which is permitted ONLY when used to treat febrile neutropenia or in patients who 
have prolonged (one week or more) Grade 3-4 neutropenia, after approval from the Study Chair.  
Concurrent use of strong inducers of CYP3A4 (Rifampin, St. John’s Wort, carbamazepine, 
phenytoin) and/or the following strong inhibitors of CYP3A4 (protease inhibitor containing HIV anti-
retrovirals, cobicistat, clarithromycin, itraconazole, ketoconazole, nefadozone, and telithromycin) are 
prohibited.  Also prohibited are CYP2C9 substrate medications that have a narrow therapeutic range: 
phenytoin and warfarin.  
The following medications that are known to prolong QT interval are prohibited: amiodarone, arsenic 
trioxide, astemizole, azithromycin, bepridil, chloroquine, chlorpromazine, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, escitalopram, 
flecainide, 
halofantrine, 
haloperidol, 
ibutilide, 
levomethadyl, 
mesoridazine, 
methadone, 
moxifloxacin, pentamidine, pimozide, probucol, procainamide, quinidine, sevoflurane, sotalol, 
sparfloxacin, terfenadine, thioridazine, or vandetanib. 
Concomitant use of other cytotoxic chemotherapeutic agents (e.g. anagrelide) or other experimental 
drug or therapy while the subject is on study is prohibited, except for hydroxyurea.  
Patients will be permitted to receive hydroxyurea while on study for a total of 3 cycles of combined 
therapy to control leukocytosis and thrombocytosis at the discretion of the treating physician. 
Patients who enter study on hydroxyurea will be permitted to remain on hydroxyurea for a total of 3 
cycles of combined therapy. Patients who continue to require hydroxyurea after 3 cycles will be 
removed from study. 
Steroids are allowed for the treatment of IDH-Inhibitor Differentiation Syndrome (IDH-DS), if 
warranted, as standard of care. The use of chronic low-dose steroids to treat an underlying medical 
condition that is not a malignancy is permitted during the course of study treatment 
For patient’s requiring ant-fungal prophylaxis, intravenous micafungin is the preferred agent.  If 
micafungin is not feasible, the oral antifungal of choice would be posaconazole barring other patient 
specific factors that would preclude use of posaconazole.  
Given the solubility profile of enasidenib, the exposure can be much lower for subjects with elevated 
gastric pH.  Thus antacids, H2 blockers, or proton pump inhibitors should be used only if medically 
necessary and with at least 4 hours of elapsed time after enasidenib administration.   
As enasidenib is an inhibitor of UGT1A1, the metabolism of drugs that are substrates for UGT1A1, 
including ezetimibe, raloxifene and raltegravir, may be slowed, leading to increased exposure to these 
compounds.  Therefore, subjects on these drugs should be switched to lower doses or alternate 
therapies, if possible, or otherwise monitored for AEs associated with the respective products and 
elevations in bilirubin levels. 
10.5 IDH-INHIBITOR DIFFERENTIATION SYNDROME (IDH-DS) 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
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Subjects treated with enasidenib may develop signs and symptoms of a IDH-Inhibitor Differentiation 
Syndrome (IDH-DS).  This may include any of the following: unexplained fever, skin rash, 
leukocytosis, thrombocytosis, hypoxia, respiratory distress, interstitial pulmonary infiltrates, pleural 
and/or pericardial effusion, peripheral edema, weight gain, or clinical deterioration.  No single sign 
or symptom may be considered per se as diagnostic of the syndrome.  It is recommended that the 
prophylactic and therapeutic measures indicated below be undertaken at the earliest manifestations of 
suspected IDH-Inhibitor Differentiation Syndrome (IDH-DS): 
• 
Enasidenib may be held at the Investigator’s discretion, and must be held if severe symptoms 
persist after 48 hours of systemic steroid administration. 
• 
Prompt initiation of hydroxyurea at a suggested dose of 2 to 3 g PO two or three times daily. 
• 
Prompt administration of corticosteroids at a suggested dose of 10 mg of dexamethasone 
intravenously (IV) every 12 hours until the disappearance of symptoms and signs, and for a 
minimum of 3 days. 
• 
Initiation of furosemide per local standard practice, if clinically required. 
• 
Prompt initiation of leukapheresis, if clinically required. 
Once the signs and symptoms resolve and the subject’s clinical condition improves, enasidenib may 
be reinitiated.  The dose of enasidenib at re-initiation is to be discussed with the Study Chair. 
For more information See Appendix D. 
10.6 NON-INFECTIOUS LEUKOCYTOSIS 
Initiation of treatment with the differentiating agents may lead to rapid WBC expansion not associated 
with infectious process and not manifesting with the signs and symptoms of IDH-Inhibitor 
Differentiation Syndrome (IDH-DS) discussed above. 
In subjects with elevated WBC, prompt initiation of hydroxyurea is suggested, as per standard local 
practices (e.g., dose of 2 to 3 g PO twice or three times daily for WBC > 30 x 109/L). In case of severe 
leukocytosis (WBC >100 x 109/L), use of leukapheresis may be appropriate. Subject should be 
regularly monitored for changes in WBC count and for new signs and symptoms of infection or IDH-
Inhibitor Differentiation Syndrome (IDH-DS). 
10.7 DISCONTINUATION OF RUXOLITINIB AND ENASIDENIB 
Upon planned discontinuation of ruxolitinib it is recommended to taper off the drug over the course 
of 4-7 days and permissible to use prednisone daily during this period to blunt rebound of symptoms.  
Since patients will be on varying dosing regimens of ruxolitinib, investigators are urged to discuss 
the ruxolitinib taper plan with Study Chairs.  
If a patient has to have ruxolitinib held abruptly for the occurrence of adverse events (e.g. major 
bleeding, significant thrombocytopenia, etc.), then the ruxolitinib may be stopped WITHOUT a taper 
and a pulse of prednisone may be utilized if deemed necessary by the Investigator. 
Enasidenib  may be interrupted or stopped without tapering. 
10.8 EVALUATION DURING TREATMENT/INTERVENTION 
Baseline evaluations are to be conducted within 28 days of the first study drug administration, unless 
otherwise indicated within the Schedule of Assessments outlined in Table 4. All scheduled visits will 
have a ±7 days window unless otherwise stated or indicated within the Schedule of Assessments. 
11. 
WHEN AND HOW TO WITHDRAW SUBJECTS 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
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In accordance with the Declaration of Helsinki and the guidelines of the country of the participating 
MPN-RC Clinical Study Center, each subject is free to withdraw from the study at any time.  An 
Investigator also has the right to withdraw a subject from the study in the event of the patient suffering 
an intercurrent illness, adverse events, or other reasons concerning the health or well-being of the 
patient, or in the case of lack of cooperation by the patient. All serious adverse reactions need to be 
followed up until resolution and information returned to study coordinators. 
Should a subject decide to withdraw after administration of study drug, or should the Investigator 
decide to withdraw the subject, all efforts should be made to complete and report the observations up 
to the time of withdrawal as thoroughly as possible. A final evaluation, the reason for, and the date of 
withdrawal must be recorded on the CRF. The last visit for each subject will be defined as a study 
discontinuation/ end-of-study visit, which will occur 30 (±7 days) days after time of treatment 
withdrawal.  
Subjects with clinically significant abnormal laboratory values as determined by the Investigator or 
who have ongoing clinically significant treatment-related adverse events during their last scheduled 
clinical evaluation will be monitored and treated until resolution or stabilization is achieved; or, in 
the event that the subject’s condition is not likely to improve because of disease progression, until the 
cause of the abnormal test result or adverse event can be determined. 
11.1 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN 
SUBJECTS 
The reason for and date of withdrawal from study drug treatment; and the reason for and date 
of withdrawal from the study will be recorded on the case report form (CRF). If a subject 
withdraws consent, every attempt will be made to determine the reason. If the reason for 
withdrawal is an adverse event or a clinically significant abnormal laboratory test result, 
monitoring will continue until the event has resolved or stabilized, until the subject is referred 
to the care of a local health care professional, or until a determination of a cause unrelated to 
the study drug or study procedure is made. The specific event or test result(s) must be recorded 
on the CRF. All evaluations will be performed, according to the protocol, 30 days (±7 days) 
after the patient is withdrawn from treatment. 
Patients will continue to be followed for long term survival every 3 months by telephone 
encounter or medical record review to determine the following variables: alive versus deceased 
and type of current therapy. Patients will be followed for this long term survival data until death, 
confirmed lost to follow up, or a maximum of 1 year after end of treatment. 
A subject will be considered to be lost to follow-up if all of the following criteria have been 
met: 
1. More than three phone calls to the subject are unanswered. 
2. A next of kin is contacted and no information is available. 
3. The referring physician is contacted and no information is available. 
4. A telegram or certified letter is unanswered. 
11.2 DURATION OF FOLLOW-UP 
The patient will have an end of study visit at 30 days after discontinuation of the protocol 
treatment, with a window of ±7 days, to assess for AEs. 
Patients will continue to be followed for long term survival every 3 months by telephone 
encounter or medical record review to determine the following variables: alive versus deceased 
and type of current therapy. Patients will be followed for this long term survival data until death, 
confirmed lost to follow up, or a maximum of 1 year after end of treatment. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
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11.3 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
Patients will be removed from therapy when any of the criteria listed in When and How to 
Withdraw Subjects section apply. Notify the Principal Investigator and document the reason 
for study removal and the date the patient was removed in the Case Report Form. 
11.4 PATIENT ACCRUAL 
Subjects are considered evaluable as long as they have signed informed consent, are eligible 
for participation and started study treatment. The maximum sample size in the Phase II 
(accelerated/blast-phase) is 20 evaluable patients.  Allowing for enrollment of up to 2 additional 
patients to account for ineligibility, cancellation, major treatment violation, or other reasons , 
this study will enroll a maximum of 22 patients in the Phase II AP/BP cohort.  The maximum 
sample size in the chronic phase MPN is 9 evaluable patients.  Allowing for enrollment of up 
to 1 additional patient, this study will enroll a maximum of 10 patients in the descriptive chronic 
phase MPN cohort.  Therefore, a maximum total of 32 (22 +10) patients will be enrolled in the 
trial. 
12.0 STUDY TIMELINES 
 
Baseline evaluations are to be conducted within 30 days of the first study drug administration, unless 
otherwise indicated within the Schedule of Assessments outlined in Table 4.  All scheduled visits will 
have a ±7 days window unless otherwise stated or indicated within the Schedule of Assessments 
outlined below. 
Ruxolitinib and enasidenib will be given orally in 28- day cycles. Attempts will be made to provide an 
adequate treatment period with the combination of at least 6 cycles, unless significant toxicity is 
observed, to account for delayed time to response observed with biologic agents. Interval Milestone 
Response Assessment (IMRA) can be performed at the beginning of any cycle after cycle 1 if specific 
milestones are achieved that will prompt such an evaluation. Specific milestones that will prompt 
assessment consist of clearance of blasts from peripheral blood in accelerated/blast phase patients, 
which will prompt bone marrow aspirate and biopsy. In addition progression of disease (as determined 
by an increase in blasts in the peripheral blood - defined as doubling of blasts % and achieving more 
than 10% in the chronic phase patients at least 7 days apart) will prompt IMRA.  Responders will 
continue therapy indefinitely unless progression of disease occurs, toxicity warranting discontinuation 
of therapy is observed, or at the discretion of the treating physician. Patients will have an end of study 
visit for a safety follow-up at 30 days after their last dose of therapy. 
13.0 STUDY ENDPOINTS 
13.1 PRIMARY ENDPOINT 
• 
The proportion of treated accelerated-phase and blast-phase MPN patients (primary cohort) 
that achieve a best response of either complete response (CR), Partial Response (PR), or 
complete response with incomplete recovery of counts (CRi), when treated with the 
combination of ruxolitinib with enasidenib within 6 cycles of combined therapy. 
13.2 SECONDARY ENDPOINTS 
• 
To assess the efficacy of the combination of ruxolitinib with enasidenib in patients with 
accelerated-phase and blast-phase disease using complete (CBR) and partial blast response 
(PBR). 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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• 
The proportion of treated patients with MF-CP and 4%-9% circulating blasts  that achieve 
complete response (CR) Partial Response (PR), clinical improvement (CI) with the 
combination of ruxolitinib and enasidenib within 6 cycles of combined therapy.   
• 
To assess the impact of the combination of ruxolitinib with enasidenib on the overall 
survival of advanced phase MPN patients 
13.3 SAFETY ENDPOINTS 
• 
The proportion of patients developing treatment-emergent hematological and non-
hematological adverse events for the combination of ruxolitinib and enasidenib. 
13.4 EXPLORATORY ENDPOINTS 
• 
The proportion of patients who achieve improvement quality of life as assessed by the by 
the Myelofibrosis Symptom Assessment Form (MF-SAFv4.0) with the combination of 
ruxolitinib and enasidenib  
• 
Assess the pharmacodynamics of ruxolitinib and enasidenib when combined in this 
population. 
• 
Assess the effects of combined therapy on gene expression and global methylation status.  
• 
Assess changes in mutant allele burden and clonal architecture of disease. 
14.0 STUDY PROCEDURES 
Study Design 
This is a multicenter, Phase II trial designed to assess the effect of ruxolitinib and enasidenib 
combination in subjects with accelerated or blast-phase MPN and subjects with chronic phase Primary 
Myelofibrosis, Post Polycythemia Vera, or Post Essential Thrombocythemia Myelofibrosis (PMF, post-
PV MF, or post-ET MF) with 4-9% blasts. Patients will receive ruxolitinib and enasidenib orally on 
days 1-28 of a 28-day cycle.  
Specifically, a Phase II Simon min-max design will be conducted in accelerated or blast-phase MPN 
patients (20 patients) and a descriptive cohort of up to 9 chronic phase patients.   
Intervention 
Patients who meet eligibility criteria will be treated with ruxolitinib and enasidenib orally on days 1-28 
of a 28-day cycle. Cycles will be continued until the patient wishes to be removed from the study, 
unacceptable toxicity develops, disease progression, treating physician recommends removal, or 
termination of study occurs. 
14.1 SCREENING/BASELINE PROCEDURES 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
All screening procedures must be performed within 30 days prior to registration unless otherwise 
stated. The screening procedures include: 
• 
Patient Informed Consent 
Before a patient undergoes screening, a medically qualified member of the Study Team who has 
been specifically trained in the implementation of this Protocol during the Site Initiation Visit or 
thereafter, such as the Site Principal Investigator, any of the co-Investigators, or a Clinical 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Research Nurse must obtain documented consent from each potential patient prior to participating 
in a clinical trial. 
Consent must be documented by the patient’s dated signature or by the patient’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion. A copy of the signed and dated consent form should 
be given to the patient before participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the patient must receive the IRB/EC’s approval/favorable 
opinion in advance of use. The patient or his/her legal representative should be informed in a 
timely manner if new information becomes available that may be relevant to the patient’s 
willingness to continue participation in the trial. The communication of this information will be 
provided and documented via a revised consent form that captures the patient’s or legal 
representative’s dated signature. The informed consent will adhere to IRB/EC requirements, 
applicable laws and regulations and Sponsor requirements. 
• 
Demographics (age, gender, race, ethnicity) 
• 
Medical History (A medical history will be obtained by the Investigator or qualified designee. 
Medical history will include all active conditions, and any condition diagnosed within the prior 
10 years that are considered to be clinically significant by the Investigator. Details regarding the 
disease for which the patient has enrolled in this study will be recorded separately and not listed 
as medical history). 
• 
Prior Treatment Details (The Investigator, or qualified designee, will review all prior cancer 
treatments including systemic treatments, RT and surgeries) 
• 
Bone marrow biopsy and aspirate with cytogenetics and molecular genetic profiling for presence 
of JAK2 (or MPL or CALR mutation status in the case that no JAK2 mutation is detected) as well 
as IDH2 mutation status. Bone marrow biopsy obtained within 84 days prior to screening in the 
absence of disease modifying therapy may be used for determining eligibility. Mutational 
profiling may be carried out at local laboratories and does not require central laboratory 
confirmation. 
• 
Physical exam including vital signs, body weight and height, and spleen and liver measurements 
• 
Transfusion history for 3 months prior to Day 1 
• 
Review previous concomitant medications within 90 days of screening and all myeloproliferative 
neoplasms directed therapies since time of diagnosis 
• 
Complete Blood Count (CBC) with differentials (includes platelet count) 
• 
Chemistries (LDH, total and direct bilirubin, phosphorus, albumin, uric acid, Na, K, Cl, Mg, CO2, 
BUN, Cr, glucose (random), Ca, AST, ALT, Alk Phos, total protein) 
• 
Lipid Panel 
• 
Urinalysis 
• 
Pregnancy test, urine or blood, with a sensitivity of at least 50 mIU/mL (for FCBP only) 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
• 
ECG 
• 
Spleen volume assessment by CT scan or MRI 
• 
Cardiac function assessment (LVEF ) by ECHO or MUGA 
• 
Review patient eligibility criteria 
14.2 REGISTRATION PROCEDURES 
Only MPN-RC approved centers may participate and register patients to this study.  


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
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To register a potential participant, complete the Registration Form for the trial located at the study 
REDCap link provided by the Mayo Statistical Data Center.  This form confirms eligibility criteria 
and informed consent and contains basic demographic and clinical information.  Once eligibility is 
confirmed and informed consent has been obtained, registration of a patient in the trial can occur.  
After completion of this form, a unique patient ID will be assigned by the system.  An email 
notification will be sent to the MPN-RC Administrative and Statistical and Data Center core for each 
registered patient.   
14.2.1  
SITE REGISTRATION WITH MPN-RC 
Before an MPN-RC institution can enroll patients, protocol specific regulatory documents must 
be submitted to the MPN-RC Central Coordinating Office via E-mail (PDF file preferred) or 
fax: 
MPN-RC Central Coordinating Office 
Phone: (212) 241-9138 
Fax: (212) 876-5276 
MPNRC_ClinicalTrialCentralOffice@mssm.edu 
 
 
Required Protocol Specific Regulatory Documents (E-mailed by PDF format preferred): 
1. Submit a copy of IRB approval for MPN-RC 119 
2. Submit a copy of the IRB approved consent form for MPN-RC 119 
3. Submit a copy of the CV of the investigational pharmacist and Pharmacy license 
4. Submit a copy of the site’s drug destruction policy 
5. Submit a copy of a signed and dated CV and medical license of the Principal Investigator 
6. Submit a copy of Form FDA 1572 as completed by the Principal Investigator 
 
 
Before an MPN-RC institution can enroll patients, please contact the Clinical Central Office  
(e-mail: MPNRC_ClinicalTrialCentralOffice@mssm.edu), to ensure that a slot is available for 
enrollment prior to approaching a patient about possible participation in this trial. 
This 
study 
uses 
the 
MPN-RC 
on-line 
Patient 
Registration 
system 
(https://redcap2.mayo.edu/redcap/). Registration will be accepted only through use of the MPN-
RC database. Registration must occur prior to the initiation of therapy.  
Confirm eligibility criteria and complete the on-line Registration Worksheet.  
If the registering clinical research coordinator (CRC) requires assistance, he/she may 
consult the on-line help file located under the Help menu of the MPN-RC application or 
call the central office. 
When the patient is registered to MPN-RC 119, a patient identification number will be 
generated.  Registration will not be completed if eligibility requirements are not met for the 
selected trial. 
The registering institution will receive a Confirmation of Registration email from the 
database that should be printed and included in the patient chart. If a registering institution 
needs to correct the registration form, contact the MPN-RC Statistics and Data Center at 
Mayo (DLARZmpnrcstats@mayo.edu) and the Clinical Central Office: E-mail: 
MPNRC_ClinicalTrialCentralOffice@mssm.edu. 
Before Study Drug Shipment 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Before Study Drug can be shipped to the MPN-RC center to begin accruing patients, the above 
regulatory documents are required to be emailed to the MPN-RC Central Office to the attention 
of the Clinical Trials Manager, as noted above. 
14.3 INFORMED CONSENT 
The patient must be aware of the neoplastic nature of his/her disease, as well as of the expected life 
expectancy at his/her stage of disease. The patient must willingly consent after being informed of the 
procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side 
effects, risks, and discomforts. BRANY Institutional Review Board (or other local ethics committees 
for non-US sites) approval of this protocol and of its consent form is required. 
14.4 DATA MANAGEMENT 
After registration of a patient, additional case report forms in the study database will be available for 
completion according to the Schedule of Events (Table 4).  All clinical data and obtained specimens 
will be labeled with the patient ID assigned at registration for the entire duration of the subject’s 
participation.   
Data for all clinical variables will be stored in the REDCap database.  Access to the REDCap database 
will be limited to MPN-RC investigators and designees; users at each site will only be able to view 
the records pertaining to subjects enrolled at their particular site. 
15. 
TREATMENT PERIOD 
The subject must be enrolled into the study, at the latest 30 days from signing the ICF, following 
Sponsor review of eligibility. The Treatment Period begins at Cycle 1 Day 1 and ends at the 
End-of-Treatment Visit. During the Treatment Period, all subjects will be closely monitored for 
safety. Toxicities (AEs and laboratory abnormalities) will be evaluated and graded according to the 
CTCAE.  During this period the following assessments should occur:   
• 
Bone marrow biopsy and aspirate with cytogenetics and molecular genetic profiling for presence 
of JAK2 (or MPL or CALR mutation status in the case that no JAK2 mutation is detected) as well 
as IDH2 mutation status. This is done at C4 D1 (for all accelerated patients, may be done at the 
discretion of the Investigator for chronic phase patients), C7 D1 (for all patients), C10 D1(for 
accelerated phase patients, may be done at the discretion of the Investigator for chronic phase 
patients), and every 6 cycles, thereafter (for all patients). 
• 
Transfusion history will be collected on Day of each cycle 
• 
Pregnancy Test 
• 
A physical exam including a review of current medical conditions and medications  
• 
Vital signs (heart rate, breathing rate, blood pressure, temperature, weight, and height) 
• 
ECOG performance status 
• 
Adverse events and concomitant medications 
• 
Complete blood counts and serum chemistry 
• 
Spleen volume assessment by CT/MRI at C7 D1, and C10 D1 
• 
ECG, day 1 of each cycle until Cycle 7 
• 
Research blood sample collection 
• 
MF-SAFv4.0 questionnaire (paper or electronic) 
• 
Enasidenib administration 
• 
Medication diary collected and  new one dispensed 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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15.1 END OF TREATMENT VISIT 
The post-treatment period includes the time after the End of Treatment Visit until the End of Study 
Visit. This period is 30 days.  The following assessments should occur: 
• 
Bone marrow biopsy and aspirate with cytogenetics and molecular genetic profiling for presence 
of JAK2 (or MPL or CALR mutation status in the case that no JAK2 mutation is detected) as well 
as IDH2 mutation status. Mutational profiling may be carried out at local laboratories and does 
not require central laboratory confirmation. 
• 
Physical exam   
• 
Vital signs, body weight and height, and spleen and liver measurements 
• 
Concomitant medications and adverse events 
• 
CBC and differentials 
• 
Serum chemistry 
• 
ECG 
• 
Spleen volume assessment by CT scan or MRI 
• 
Research blood sample collection 
• 
MF-SAFv4.0 questionnaire (paper or electronic) 
15.2 END OF STUDY VISIT 
The visit is the mandatory safety follow-up visit and should be conducted approximately 30 days after 
the end of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first. All AEs that occur prior to the End of Study Visit should be recorded.  
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Table 4. Schedule of Events 
Procedure 
Screening 
Period 
Cycle1-2 
Cycle 3-6 
Cycle 7 and 
beyond 
End of 
treatment 
End of 
Study11 
Survival 
Follow Up 
Day 
15 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 1 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History 
(including prior 
MF-directed therapies) 
X 
 
 
 
 
 
 
 
 
 
Physical examination1 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Transfusion History 
X2 
X2 
 
 
 
X 
X 
X 
X 
 
Pregnancy test (for 
FCBP 
only)3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC and differentials 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
12-LeadECG14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Echo/MUGA 
X 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate 
and 
Biopsy
6,7 
X6 
 
 
 
 
X6,7 
X6,7 
 
X6 
 
Biospecimen 
Collection– 
Peripheral blood 
X12 
X12 
 
 
 
X12 
X12 
 
X12 
 
Adverse event 
evaluation 
 
X 
 
X 
 
X 
X 
X 
X 
 
Concomitant 
medications, 
therapies, and 
procedures evaluation 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Spleen Volume 
Assessment8 
X 
 
 
 
 
 
X8 
 
X 
 
Response Assessment 
 
 
 
 
 
 
X9, 13 
 
X 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Confidential 
 
1. 
Includes vital signs, weight, height and measurements of the spleen and liver.  Height is only required at screening. 
2. 
Subjects must have 3 months documented transfusion history prior to Day 1. 
3. 
Pregnancy test, urine or blood, with a sensitivity of at least 50 mIU/mL, within 10 – 14 days prior to and again within 24 hours of 
starting enasidenib; then every week x 4, then monthly for all FCBP with regular menstrual cycles, or every 2 weeks if irregular cycles. 
4. 
Includes sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, total bilirubin, alanine aminotransferase, , and 
glucose. Magnesium, , PT/PTT and INR need to only be done at screening. Lactate dehydrogenase uric Acid, phosphorus need to be 
checked day 1 of every cycle and in the EOS 
5. 
If not done within 3 days of Day 1. 
6. 
Bone Marrow Aspirate and Biopsy to be collected at baseline (within 84 days from screening is also permissible with permission from 
the Study Chair), Cycle 4 day 1 (at the discretion of the Investigator for chronic phase patients), Cycle 7 day 1, Cycle 10 day1(at the 
discretion of the Investigator for chronic phase patients), every 6 cycles, thereafter, and at the end of study visit. Peripheral blood draws 
may be used to perform JAK2 mutation testing if the bone marrow is not aspirable. 
7. 
May be omitted if so decided by the treating physician. Should be done to confirm complete response and when clinically indicated. 
8. 
CT scan or MRI to be performed at baseline, Cycle 7, Cycle 10, and at the end of study. 
9. 
Response assessments (IWG-MRT criteria 2013 and ELN revised response criteria ) should be after 6 cycles and every 3 - 6 cycles 
thereafter for the remainder of the study. 
10. Collect pill diaries and any unused study drug to review for compliance prior to each cycle through cycle 24. After cycle 24, review 
patient drug diaries for ruxolitinib and enasidenib at each protocol visit. 
11. The discontinuation visit will be considered as such on the date the patient is taken off treatment. The patient will have an end of study 
visit approximately 30 days after the end of trial treatment  to assess for AEs. 
12. Peripheral blood biomarker samples will be collected at screening, and day 1 of Cycle 1 -Cycle 7, every 3 cycles thereafter, and at the 
end of study, in conjunction with standard-of-care blood draws. Bone marrow aspirate samples will be collected whenever a bone 
marrow examination is scheduled to take place as designated in item 6 above.  
13. Interval Milestone Response assessment can be performed at the beginning of any cycle after Cycle 1 if specific milestones are achieved 
as specified in study timeline. 
14. ECGs done day 1 of each cycle until Cycle 7, ECGs should be done at EOS.\ 
15. Patients will continue to be followed for long term survival every 3 months by telephone encounter or medical record review to 
determine the following variables: alive versus deceased and type of current therapy. Patients will be followed for this long term 
survival data until death, confirmed lost to follow up, or a maximum of 1 year after end of treatment. 
 
16. 
ADVERSE EVENTS 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done 
to ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to allow for optimal 
monitoring of patient safety and care.  
All patients experiencing an adverse event, regardless of its relationship to study drug, will be 
monitored until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse event return to 
baseline;  
• 
any abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes observed; or 
Nail Clippings 
X 
 
 
 
 
 
 
 
 
 
Study drug dispensing10 
 
X 
 
 
 
X 
X 
 
 
 
MF-SAFv4.0 Survey 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival Data15 
 
 
 
 
 
 
 
 
 
X 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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death. 
16.1 DEFINITIONS OF ADVERSE EVENT 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or 
worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values, regardless of etiology.  Any worsening (i.e., any clinically significant adverse 
change in the frequency or intensity of a pre-existing condition) should be considered an AE. A 
diagnosis or syndrome should be recorded rather than the individual signs or symptoms of the diagnosis 
or syndrome 
16.2 SEVERITY OF ADVERSE EVENT 
All non-hematologic adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events version 5.0 (CTCAE). The CTCAE is available at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refere
nce_8.5x11.pdf 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
• 
Mild (Grade 1): the event causes discomfort without disruption of normal daily activities. 
• 
Moderate (Grade 2): the event causes discomfort that affects normal daily activities. 
• 
Severe (Grade 3): the event makes the patient unable to perform normal daily activities or 
significantly affects his/her clinical status. 
• 
Life-threatening (Grade 4): the patient was at risk of death at the time of the event. 
• 
Fatal (Grade 5): the event caused death. 
16.2.1  SERIOUS ADVERSE EVENTS (SAE) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Results in death. If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
• 
Is life-threatening. (The patient was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more severe.) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event 
Events not considered SAEs are hospitalizations for: 
1. A standard procedure for protocol therapy administration. However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be reported as 
an SAE. 
2. Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
3. The administration of blood or platelet transfusion as routine treatment of studied 
Indication.  However, hospitalization or prolonged hospitalization for a complication of 
such transfusion remains a reportable SAE. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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4. A procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable SAE. 
5. Hospitalization or prolongation of hospitalization for technical, practical, or social reasons, 
in absence of an AE. 
6. A procedure that is planned (i.e., planned prior to starting of treatment on study); must be 
documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE. 
7. An elective treatment of or an elective procedure for a pre-existing condition unrelated to 
the studied indication. 
8. Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
If an AE is considered serious, both the AE page/screen of the CRF and the MEDWATCH form 
must be completed.  For each SAE, the Investigator will provide information on severity, start 
and stop dates, relationship to IP, action taken regarding IP, and outcome. 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
o 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 hospitalization, or the development of drug dependency or drug 
abuse (21CFR312.32). 
Important medical events as defined above may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
investigator. 
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
16.2.2  ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring of patients and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product. 
AESIs for enasidenib include but are not limited to events with AESIs observed with enasidenib include 
those specified in the IB. 
16.3 CAUSALITY 
The Investigator must determine the relationship between the administration of IP and the occurrence 
of an AE/SAE as unrelated, possible, probable or definite as defined below. 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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• 
Possible – The AE may be related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
When a determination of possibly, probable or definite is used, the Investigator should also determine 
whether the suspected agent is ruxolitinib or enasidenib.  
16.4 DURATION 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the event. 
16.5 ACTION TAKEN 
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable (e.g., 
discontinuation, interruption of IP, as appropriate) and report if concomitant and/or additional 
treatments were given for the event. 
16.6 OUTCOME 
The Investigator will report the outcome of the event for both AEs and SAEs.  All SAEs that have not 
resolved upon discontinuation of the subject’s participation in the study must be followed until 
recovered (returned to baseline), recovered with sequelae, or death (due to the SAE). 
16.7 OVERDOSE 
Overdose, as defined for this protocol, refers to enasidenib and ruxolitinib dosing only (as applicable).   
On a per dose basis, an overdose is defined as the following amount over the protocol-specified dose of 
enasidenib and ruxolitinib assigned to a given patient, regardless of any associated adverse events or 
sequelae - PO any amount over the protocol-specified dose.  On a schedule or frequency basis, an 
overdose is defined as anything more frequent than the protocol required schedule or frequency.  .  
Complete data about drug administration, including any overdose, regardless of whether the overdose 
was accidental or intentional, should be reported.    
To date, doses of enasidenib up to 650 mg QD were well tolerated in clinical trials. No information is 
currently available regarding overdose with enasidenib. In the event of overdose with toxicity, 
supportive clinical care should be provided. 
16.8 ABNORMAL LABORATORY VALUES 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• 
results in discontinuation from the study; 
• 
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or 
• 
is judged to be of significant clinical importance, e.g., one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing condition. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion need to 
be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a part of 
a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If possible, the 
laboratory abnormality should be recorded as a medical term and not simply as an abnormal laboratory 
result (e.g., record thrombocytopenia rather than decreased platelet).  


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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Confidential 
17. 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS 
All adverse events must be recorded in the subject's medical records and on the Case Report 
Form from the time the subject signs informed consent until 30 days after the last dose of IP and those 
SAEs made known to the investigator at any time thereafter that are suspected of being related to IP.  
The onset and end dates, severity, duration, effect on study drug administration (e.g. 
discontinuation), relationship to study drug, and administration of any other drug(s) to treat this 
event will be recorded for each adverse event. The BRANY Institutional Review Board is 
charged with the responsibility of reviewing and maintaining records of all Serious Adverse 
Events occurring in patients who are participating in BRANY IRB approved research trials at 
BRANY sites. All SAEs must be reported to Celgene Drug Safety within 24 hours of the Investigator’s 
knowledge of the event by facsimile, or other appropriate method, using the SAE Report Form, or 
approved equivalent form. 
17. 1 STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES 
EXPEDITED REPORTING (WITHIN 24 HOURS) 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for 
Adverse Events version 5.0 (CTCAE).  
Step 2: Grade the adverse event using the NCI CTCAE v5.0. 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and is 
attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from administration 
of the agent. An adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information section of this protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
17.2 EXPEDITED REPORTING 
The Site must notify the Central Office and the local IRB within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study or within 30 days 
of the last administration of the study drug.  A Serious Adverse Event (SAE) MEDWATCH 
form must be completed by the Investigator and emailed to the MPN-RC Central Office within 
24 hours of learning of the SAE.  The Site Investigator will print and keep a copy of this SAE 
form on file at the study site.  Report serious adverse events by phone, email, or facsimile to 
the Data Monitor and Clinical Trials Manager: 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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MPN-RC Central Office Phone: (212) 241-4546  
Fax: (212) 876-5276  
Email: MPNRC_ClinicalTrialCentralOffice@mssm.edu 
 
Central Office personnel is responsible for reporting all SAEs to Celgene via MedWatch to 
drugsafety@celgene.com. 
At the time of the initial report, the following information should be provided: 
• 
Study name and IND# 
• 
Site name or site # 
• 
Subject ID number 
• 
A description of the event 
• 
Date of onset 
• 
Current status of patient  
• 
Whether study treatment was discontinued 
• 
CTCAE grade 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association between the event and study treatment (if related 
or not and if expected or not) 
Within the following 48 hours, the Investigator must provide further information about the 
serious adverse event in the form of a written narrative. This should include an updated Serious 
Adverse Event form, and any other diagnostic information that will assist the understanding of 
the event.  Significant new information on ongoing serious adverse events should be provided 
promptly to the Study Sponsor.  
• 
The site must notify the central IRB, BRANY, within 5 business days of “any unanticipated 
problems involving risk to subjects or others” (UPR/UPIRSO).  Copies of each report and 
documentation of IRB notification and receipt will be kept in the Clinical Investigator’s 
binder. The IRB should only be notified of a SAE if it meets the definition of “possibly, 
probably or definitely” related to the study drug, and is an “unexpected” event. 
The following events meet the definition of UPR: 
o Any new information that indicates a new or increased risk, or safety issue 
(e.g., Interim Analysis, Safety Monitoring report, publication, updated Sponsor Safety 
report), that indicates an unexpected change to the risk/benefit ratio for the research. 
o An Investigator Brochure, package insert, or device labeling is revised to indicate an 
increase or magnitude of a previously known risk or describes a new risk.  
o Withdrawal, restriction, or modification of a marketed approval of a drug, device, or 
biologic used in research protocol 
o Protocol deviation or violation that harmed subjects or others or that indicated subjects 
or others might be at increased risk of harm. 
o Complaint of subject that indicates subjects or others might be at increased risk of harm 
or at risk of a new harm 
o Any breach in confidentiality that may involve risk to the subject or others. 
o Any harm experienced by a subject or other individual that in the opinion of the 
Investigator is unexpected and at least probably related to the research procedures. 
For IND/IDE trials: The Regulatory Agencies (FDA) should be notified within 7 business days 
of any unexpected fatal or life-threatening adverse event with possible relationship to study 
drug, and 15 business days of any event that is considered: 1) serious, 2) unexpected, and 3) at 
least possibly related to study participation.   


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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Confidential 
The MPN-RC Data Center and Regulatory Coordinator will receive reports of SAEs through 
the Central Office. The MPN-RC as Study Sponsor shall notify the Regulatory Agencies by 
telephone or by facsimile transmission of any unexpected fatal or life-threatening experience 
associated with the use of the drug as soon as possible but no later than 7 calendar days from 
the Sponsor’s original receipt of the information(1-800-332-0178) of any unexpected fatal or 
life-threatening experience associated with the use of the drug as soon as possible but no later 
than 7 calendar days from the Sponsor’s original receipt of the information. All other 
unexpected, serious adverse events that are considered related to study treatment will be 
reported on a MedWatch form by the Study Sponsor to the Regulatory Agencies within 15 
calendar days.  If a previous adverse event that was not initially deemed reportable is later found 
to fit the criteria for reporting, the Study Sponsor will submit the adverse event in a written 
report to the FDA and Health Canada as soon as possible, but no later than 15 calendar days 
from the time the determination is made. 
17.3 REPORTING GUIDELINES FOR PHARMACEUTICAL PARTNER 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness 
of events of being related to enasidenib based on the Investigator Brochure.  In the United 
States, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32. 
Serious adverse events (SAE) are defined above.  The Central Office must inform Celgene in 
writing using a MEDWATCH 3500A form of any SAE within 24 hours of being aware of the 
event.  The written report must be completed and supplied to Celgene by facsimile within 24 
hours.  The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s).  Information not available at 
the time of the initial report (e.g., an end date for the adverse event or laboratory values received 
after the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required.  The Celgene tracking number (XX-XX-XX- PI-#####) and 
the institutional protocol number should be included on SAE reports (or on the fax cover letter) 
sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to Celgene 
should be attached to the SAE and retained with the patient records. 
Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and  Risk Management 
86 Morris Avenue 
Building S12 
Summit, New Jersey 07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
For any Canadian sub-sites: 
Celgene Inc.  
Drug Safety Department 
6755 Mississauga Road, Suite 600 
Mississauga, ON  L5N 7Y2 
Telephone: 289-291-4838 
Fax:  289-291-4820 
Email:  drugsafety-canada@celgene.com 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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Confidential 
17.4 MPN-RC REPORTING OF SUSPECTED UNEXPECTED SERIOUS 
ADVERSE REACTIONS (SUSARS) TO REGULATORY BODIES AND 
ETHICS COMMITTEES 
All suspected adverse reactions related to an investigational medicinal product (the tested IMP) 
which occurs in the concerned trial, and that are both unexpected and serious (SUSARs) are 
subject to expedited reporting. These events should be reported by the individual investigators 
to the MPN-RC. 
17.5 MPN-RC REPORTING OF SUSARS 
MPN-RC, or designee, should report all the relevant safety information previously described to 
the concerned Regulatory Agencies. MPN-RC or designee shall inform all investigators 
concerned of relevant information about SUSARs that could adversely affect the safety of 
subjects. All SUSAR reports will also be reported to the FDA and Health Canada. 
17.6 TIMELINES FOR REPORTING 
Fatal or life-threatening SUSARs 
The MPN-RC should notify the Regulatory Agencies as soon as possible but no later than 7 
calendar days after the Sponsor has first knowledge of the minimum criteria for expedited 
reporting. In each case relevant follow-up information should be sought and a report completed 
as soon as possible.  
Non-fatal and non-life-threatening SUSARs 
All other SUSARs and safety issues must be reported to the Regulatory Agencies as soon as 
possible but no later than 15 calendar days after the Sponsor has first knowledge of the 
minimum criteria for expedited reporting. Further relevant follow-up information should be 
given as soon as possible. 
17.7 HOW TO REPORT SAFETY EVENTS 
Minimum criteria for initial expedited reporting of SUSARs 
Information on the final description and evaluation of an adverse reaction report may not be 
available within the required time frames for reporting. For regulatory purposes, initial 
expedited reports should be submitted by the Sponsor within the time limits as soon as the 
minimum following criteria are met: 
a. a suspected investigational medicinal product, 
b. an identifiable subject (e.g. study subject code number), 
c. an adverse event assessed as serious and unexpected, and for which there is a reasonable 
suspected causal relationship, 
d. an identifiable reporting source, and, when available and applicable: 
i. 
a unique clinical trial identification number or the Sponsor's trial protocol code 
number) 
ii. 
a unique case identification (i.e. Sponsor's case identification number). 
Follow-up reports of SUSARs 
In case of incomplete information at the time of initial reporting, all the appropriate information 
for an adequate analysis of causality should be actively sought from the reporter or other 
available sources. The Sponsor should report further relevant information after receipt of 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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follow-up reports. In certain cases, it may be appropriate to conduct follow-up of the long-term 
outcome of a particular reaction. 
 
Routine Reporting 
All other adverse events, such as those that are expected or are unlikely or definitely not related 
to the study participation- are to be reported annually as part of regular data submission. 
18. 
DRUG INFORMATION 
All study treatments will be administered on an outpatient basis. No investigational or commercial 
agents or therapies other than those described herein may be administered with the intent to treat the 
patient's malignancy while they are on this study. 
18.1 RUXOLITINIB 
 
Ruxolitnib is a JAK inhibitor approved for the treatment of patients with MF. It will be dispensed 
commercially, and is available as tablets formulated in 5, 10, 15 and 20 mg strengths. In the US, a 25 
mg strength is also available. See the applicable product label (i.e., USPI, Canadian PM or the EMA 
SmPC) for more details. 
18.1.1  
SIDE EFFECTS 
Reported toxicity of ruxolitinib includes the following: 
• 
Hematologic adverse events include; anemia, thrombocytopenia and neutropenia, all of which are 
dose related effects. 
• 
Non-hematologic adverse events include; bruising, dizziness, headache, raised ALT, raised AST, 
hypercholesterolemia, urinary tract infections, weight gain, flatulence, herpes zoster, increase in 
systolic blood pressure, constipation, infection, including Tuberculosis 
18.2 ENASIDENIB  
Enasidenib tablets are available in 50-, 100-, 150- and 200-mg free-base equivalent strength tablets 
for oral administration.  Each tablet is formulated using excipients that are generally regarded as safe 
and are used in marketed drug products.  Celgene Corporation will supply 50-mg and 100-mg tablets. 
All tablets will be packaged in high density polyethylene (HDPE) bottles with a desiccant (silica gel) 
canister and child resistant closures with heat induction seal.  All tablets should be swallowed whole 
and should not be broken or chewed. 
Bottles of enasidenib tablets must be stored according to the package label.  The storage area should 
be secure and have limited access.  Enasidenib tablets will be monitored by the Sponsor for stability 
for the duration of the study. 
18.2.1  SIDE EFFECTS 
Reported  specific adverse drug reactions of enasidenib includes the following: 
• 
Hematologic adverse events include: neutropenia and leukocytosis 
• 
Non-hematologic adverse events include: IDH-DS  
TLS, GI disturbances (such as nausea, diarrhea, vomiting, and associated dysgeusia and 
decreased appetite), and hyperbilirubinemia.  


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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10 Nov 2021 
Confidential 
18.2.2  
STUDY DRUG PACKAGING AND LABELING 
Enasidenib tablets will be supplied in high density polyethylene (HDPE) bottles with a 
desiccant (silica gel) canister, a polyester coil, and child resistant closures with heat induction 
seal.  Packaging and labeling will be prepared to meet all regulatory requirements. 
18.2.3  
STUDY DRUG STORAGE 
Bottles of enasidenib tablets must be stored according to the package label. 
All study drug products must be stored in a secure, limited-access location and may be 
dispensed only by the Investigator or by a member of the staff specifically authorized by the 
Investigator. 
18.2.4  
RECEIVING DRUG SUPPLY, RECEIPT AND STORAGE 
Drug will be distributed from Celegene to each participating site. Tablets are to be stored 
according to guidance in drug label insert. 
18.2.5  
RETURN OR DESTRUCTION OF STUDY DRUG 
Destruction of any remaining study drug will occur according to Mount Sinai Investigational 
Drug Services’ standard operating procedures. 
18.3 RISKS TO SUBJECTS 
Adverse events listed in current investigational brochures research medications: 
Both ruxolitinib and enasidenib have known side effects profile in patients with myelofibrosis and AML 
respectively. Please refer to to the investigator brochures for detailed listings. 
Known potential side effects from Ruxolitinb in humans include the following:   
Hematologic: Anemia (72% to 96%; Grade 3: ≤34%; Grade 4: ≤ 11%), Thrombocytopenia (27% to 
70%; Grade 3: 5% to 9%; Grade 4: ≤4%), Neutropenia (3% to 19%; Grade 3: 5%; Grade 4: ≤2%) all of 
which are dose-related effects. 
Non-hematologic: Dizziness (15% to 18%), Headache (15% to 16%), Fatigue (15%), Insomnia (12%), 
Weakness (7%), Bruise (23%), Epistaxis (6%), Pruritus (14%), Increased serum cholesterol (17% to 
35%), Hypertriglyceridemia (15%). Diarrhea (15%), Abdominal pain (15%), Constipation (8%), 
Nausea (6%), Flatulence (5%), Vomiting. Increased serum ALT (25%; Grade 3: <1%), Increased serum 
AST (17% to 23%). Muscle spasm (12%); Weight gain (≤7%). Dyspnea (13%), Edema (8%), 
Hypertension (<6%). Infection including: Urinary tract infection (≤9%), Herpes zoster (2% to 6%), 
Nasopharyngitis (9%), Cough (8%).  
Known potential side effects from Enasidenib in humans include the following:   
Non-hematologic: IDH-DS (14%), Noninfectious leukocytosis (8.2%), TLS (5.5%), GI disturbances 
Nausea (50%), Diarrhea (43%), Decreased appetite (34%), Vomiting (34%), Dysgeusia (12%), 
Hyperbilirubinemia (81%). In addition, Febrile neutropenia (23.9%), Pneumonia (14.2%), Sepsis 
(11.8%), Pyrexia (8.5%), Lung infection (6.4%), Acute renal failure (5.5%), and Fatigue (5.2%) 
Based on available pharmacokinetic and drug metabolism data, there are no anticipated major adverse 
reactions that may manifest secondary to drug-drug interactions when enasidenib is utilized 
concomitantly with ruxolitinib; however, there is a potential for unforeseeable adverse events with  the 
combination.  


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 49 of 77 
 
 
10 Nov 2021 
Confidential 
18.3.1  
REPRODUCTIVE RISKS 
Patients should not become pregnant or father a baby while on this study. Women should not 
breastfeed a baby while on this study. Females of childbearing potential must either commit to 
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth 
control, one highly effective method and one additional effective method AT THE SAME TIME, at 
least 4 weeks before she starts taking study medications (enasidenib and ruxolitinib). Females of 
childbearing potential must also agree to ongoing pregnancy testing. Men must agree to use a condom 
during sexual contact with a female of child bearing potential even if they have had a successful 
vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy 
precautions and risks of fetal exposure.  
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within (4 months), are 
considered immediately reportable events.  IP is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or 
approved equivalent form. The female subject may be referred to an obstetrician-gynecologist (not 
necessarily one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
The Investigator will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.  
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any of 
the serious criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, 
or other appropriate method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form.   
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant while the 
male subject is on study treatment or within 4 months of the male subject’s last study treatment, the 
male subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. 
CORRELATIVES/ SPECIAL STUDIES 
Submission of samples for correlative studies is mandatory.  The correlative biomarker studies will 
evaluate a series of biomarkers at baseline (at study entry), and during treatment at each study visit, and 
either at the time of relapse/progression or at termination of study (that is off study drug for any reason). 
Please see Table 5 for various time points for collection of samples.   
19.1 SHIPPING INSTRUCTIONS 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 50 of 77 
 
 
10 Nov 2021 
Confidential 
Each site will provide the necessary shipping materials to package.Blood and bone marrow samples 
will be shipped at room temperature on the day  of  collection. All shipments must be sent by overnight 
courier for delivery before 10 AM or morning delivery the next day.   Nail may be sent with the ambient 
shipment on the day of collection.  Slides may be batched and shipped every 3 months. In general 
shipments cannot be received on Saturday.  For special arrangements, contact Dr. Weinberg prior to 
collection of tissue and shipment. 
 
Rona Singer Weinberg, Ph. D 
New York Blood Center 
310 East 67th Street, Room 2-44 
New York, New York 10065 
Phone: (212) 570-3488 
Fax: (212) 570-3495 
rweinberg@nybc.org 
Laboratory Phone: (212) 570-3412 
Laboratory Fax: (212) 570-3495 
MPDLab@nybc.org 
SAMPLES ARE ACCEPTED MONDAY-THURSDAY 9AM TO 5PM; FRIDAY 9AM TO 1PM. 
NOTE:SAMPLES CANNOT BE RECEIVED ON SATURDAY OR SUNDAY. CALL DR. WEINBERG 
BEFORE COLLECTING SAMPLES IF SPECIAL ARRANGEMENTS NEED TO BE MADE.   
Include a de-identified copy of the institutional bone marrow aspiration and biopsy report with your 
shipment to the NYBC in New York. This report must include MPN-RC patient ID number, 
differential cell counts on the marrow aspirate, if performed. Contact the central office with any 
questions. 
19.2 BONE MARROW BIOPSY SLIDES GUIDELINES 
The following samples are to be collected at screening, at baseline, at Cycle 4 Day 1 (at the discretion 
of the Investigator for chronic phase patients), at Cycle 7 Day 1, Cycle 10 Day 1 (at the discretion of 
the Investigator for chronic phase patients), after every 6 cycles thereafter, and at termination of study 
for any reason. Biopsies should be done to confirm complete response and when clinically indicated.  
The following bone marrow aspiration and biopsy specimens must be obtained and submitted to Dr. 
Rona Weinberg at the New York Blood Center:  
• 
three (3) air-dried, unstained bone marrow aspirate slides (if available) 
• 
four (4) unstained peripheral blood films (thin smears) 
• 
two (2) air dried unstained bone marrow biopsy touch preps for patients with no aspirate sample 
(these are made with 8 touches per slide – 4 horizontal touches in 2 rows on the slide) 
Additionally: 
• 
three (3) unstained paraffin-fixed bone marrow biopsy slides each containing at least 2 sections 
• 
one (1) stained H & E biopsy slide  
• 
one (1) biopsy slide stained for iron  
• 
one (1) biopsy slide stained with the silver for reticulin fibrosis stain should be submitted for 
confirmatory cytologic and cytochemical studies. These should be submitted together with the 
final institutional pathology, cytochemistry, and immuno-phenotyping reports (if possible) 
Bone marrow biopsy should be repeated if relapse occurs or transformation to MDS, or acute 
leukemia is suspected. 
There must be an adequate amount of marrow biopsy specimen in each smear.  The above 
requirements are considered minimal.   


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 51 of 77 
 
 
10 Nov 2021 
Confidential 
Identify each slide with the subject’s patient ID number, protocol number, time point, and type of 
sample.  
The histopathology slides may be batch shipped every 3 Months to Dr. Weinberg at the NY Blood 
Center. 
Identify each slide with the patient’s MPN-RC patient ID number, protocol number, time point, and 
type of sample.  
Include a de-identified copy of the institutional bone marrow aspiration and biopsy report with your 
shipment to the NYBC in New York. This report must include MPN-RC patient ID number, 
differential cell counts on the marrow aspirate, if performed. 
19.3 BONE MARROW ASPIRATE GUIDELINES 
Bone marrow aspirate samples will be collected for histopathology, biomarkers, and 
cytogenetics/FISH. For biomarkers and cytogenetics, obtain a total of  3-7 mL of aspirated bone 
marrow. Apirate samples collected for biomarkers will be sent to the NYBC on the day of 
collection. Aspirate samples collected for cytogenetics/FISH will be sent to each site’s local 
labs for analysis.  Samples are to be divided as follows: 
• 
2-5 mL of bone marrow aspirate in a green top, heparinized tube (BD catalog number 
366480)  
• 
1-2 mL of bone marrow aspirate for Cytogenetics  
In the event that a biopsy does not produce aspirate, additional perpipheral blood samples must 
be sent for cytogenetic/FISH analysis.  
19.4 PERIPHERAL BLOOD: (USE STERILE TECHNIQUE) 
Peripheral blood samples will be collected at screening, and day 1 of Cycle 1-Cycle 7, every 3 cycles, 
and at the end of study, in conjunction with standard-of-care blood draws. The total amount to be 
collected should not exceed 25cc (approximately 5 teaspoons).   Peripheral blood samples must be 
shipped ambient on the day of collection. 
• 
25 mL of blood: three ACD (yellow top) tubes (BD catalogue number 364606; 
8.5 mL tubes) 
19.5 NAIL CLIPPINGS 
Two to ten nail clippings are to be obtained from each patient during the initial entry onto the protocol. 
Clippings are to be placed in a paper envelope and the envelope is to be sealed.   The sealed envelope 
maybe stored and shipped at room temperature. 
19.6 CYTOGENETIC ANALYSIS 
Diagnostic and follow up cytogenetics will be performed by local institutional laboratories.  All 
karyotypes will be centrally reviewed (see below).  Samples are to be sent for cytogenetic analysis at 
screening, at cycle 4 day1, cycle 7 day 1, cycle 10 day 1,  every 6 cycles thereafter, and at termination 
of study for any reason.  JPEG or TIFF images must be uploaded into the MPN-RC REDCap database 
for each cytogenetic assessment.  To ensure uniformity of cytogenetic preparations all participating 
local laboratories must adhere to the following requirements established by the central karyotype review 
co-Investigator (Dr. Vesna Najfeld).  


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 52 of 77 
 
 
10 Nov 2021 
Confidential 
19.6.1 
GENERAL INCLUSION CRITERIA FOR CONVENTIONAL 
CYTOGENETICS 
1. Banding level 300 or more and structural aberrations are accepted at 400 or higher banding 
level or confirmed by FISH. 
2. Minimum requirements for baseline assessments:  From each patient, bone marrow (PV, 
ET) and or unstimulated PB (PMF) specimen must be set up into two, preferably three, 
different cultures (direct, 24 hrs. with and without marrow max media). Every effort should 
be made to obtain the growth of cells that are cytogenetically abnormal. 
3. 20 metaphase evaluated from two or more cell cultures or from marrow max culture only. 
4. Only G-banding of chromosomes is acceptable. Other banding methods are not acceptable. 
5. Analysis of cell at 300 band resolution, or low-quality banding, irrespective of the findings, 
to be complemented with FISH screening for subtle aberrations, including del(20)(q11q13) 
with D20S108 probe. 
6. ISCN 2009 must be used to describe the karyotype. 
7. Aberrations classified as clonal should be present in at least 2 cells by G-banding or 
confirmed by FISH. 
8. Unusual or novel findings should be fully characterized by FISH using appropriate probes. 
9. Three karyotypes (and metaphase cells) from each patient must be uploaded electronically 
into the MPN-RC REDCap database to document the stated cytogenetic diagnosis.  The 
karyotypes are uploaded either as TIFF or JPEG files. 
FISH studies, IF POSSIBLE and warranted in an individual case 
1. Case normal by G banding, if possible, ought to be screened for cryptic changes by 
interphase FISH using a MPN panel of 12 probes: CEP1(1q12)/1q21, 5p15.2/5q31(EGR1), 
CEP7/7q31, CEP8, CEP9/9p21, RB1 at 13q14, P53/CEP17, 20q12/D20S108. 
2. FISH studies are performed on BM or PB on interphase cells processed directly (no culture) 
using Abbott Molecular FISH probes. A minimum of 200 cells at baseline should be scored 
by two individuals. Image of FISH results should be uploaded as JPEG or TIFF file into 
the MPN-RC database. 
Central Karyotype Review: Vesna Najfeld, Ph.D., Director, Tumor Cytogenetics, Icahn 
School of Medicine, NY.  
One of the QC indicators is a proper entry and submission of cytogenetic forms and karyotypes 
by the institutional cytogenetic laboratories. If the local laboratory fails two consecutive 
specimens (poor quality of chromosome banding, missed abnormality, wrong ISCN 
nomenclature) or lack of entering cytogenetic results into MPN- RC, the laboratory will be 
informed, and the third failure will result in placing the local laboratory on probation and the 
institutional PI will be informed. If required, either the central lab in NY or other MPN-RC 
approved cytogenetic lab will perform the studies from the institution whose cytogenetic lab is 
placed on probation. 
For any questions please call Joe Tripodi PhD, Cytogenetic Research Coordinator, Mount Sinai 
Medical Center: 212 241-8801 or Dr. Vesna Najfeld at 212 241-8801. 
19.7 SPECIMEN BANKING 
Subject samples collected for this study will be retained at New York Blood Center. Specimens will 
be stored indefinitely or until they are used up. If future use is denied or withdrawn by the subject, 
best efforts will be made to stop any additional studies and to destroy the specimens. 
The MPN-RC Consortium’s Tissue Distribution Committee will be responsible for reviewing and 
approving requests for clinical specimen from potential research collaborators outside of the 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 53 of 77 
 
 
10 Nov 2021 
Confidential 
Consortium. Collaborators will be required to complete an agreement (a Material Transfer Agreement 
or recharge agreement) that states specimens will only be released for use in disclosed research.  
The specimens, DNA, and their derivatives may have significant therapeutic or commercial value. 
The Informed Consent form contains this information and informs the subject that there is the 
potential for financial gain by the Investigator or a collaborating researcher or entity. Genetic testing 
is a plan for future research. 
The following information obtained from the subject's medical record may be provided to research 
collaborators when specimens are made available:  
• 
Diagnosis  
• 
Collection time in relation to study treatment 
• 
Clinical outcome – if available 
• 
Demographic data 
Sampling times may be adjusted according to early trial results in order to optimize evaluation.  No 
additional samples will be collected without formal amendment to this protocol.  Detailed procedures 
for collection, handling, and shipment of samples will be provided in the study Laboratory Manual. 
Samples will be sent to special laboratories at the New York Blood Center for careful study and 
analysis where they will be store using a unique code.  The code linking the sample will be stored at 
Mount Sinai and known only to members of the research team at the Central Coordinating Office. 
Table 5. Correlative Studies Sample Collection Schedule 
 
Sample 
 
Baseline 
Cycle 1-6 
Day 1 
Cycle 4, 7, 
10, day 1 
and every 
3 cycles4 
End of 
study5 
Bone Marrow 
Aspirate 
Histopathology
1
 
Three (3) air dried unstained 
slides 
X 
 
X 
X 
Aspirate 
Cytogenetics
2
 
At local institution, upload 
data and karyotypes to the 
website
1
. 
If 
no 
aspirate, 
provide 
peripheral 
blood 
karyotypes.  
X 
 
X 
X 
Aspirate 
Biomarkers
3
 
2 to 5 mL of bone marrow 
aspirate in a green top, 
heparinized tube (BD catalog 
#366480) 
X 
 
X 
X 
Biopsy 
Histopathology
1
 
One (1) H&E stain 
X 
 
X 
X 
One (1) Iron stain 
X 
 
X 
X 
One (1) Silver impregnated 
reticulin stain 
X 
 
X 
X 
Three (3) Unstained paraffin-
fixed slides each with at least 
2 sections 
X 
 
X 
X 
 
 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 54 of 77 
 
 
10 Nov 2021 
Confidential 
 
Sample 
 
Baseline 
Cycle 1-6 
Day 1 
Cycle 4, 7, 
10, day 1 
and every 
3 cycles4 
End of 
study5 
If no aspirate, two (2)air dried 
unstained touch preps, 8 
touches/slide, 2 horizontal 
X 
 
X 
X 
Peripheral Blood 
Histopathology
1
 
Four (4) Unstained peripheral 
blood films, thin smears 
X 
 
X 
X 
Cytogenetics
2
 
If no BM aspirate karyotypic 
analysis
1
 
X 
 
X 
X 
Biomarkers
3
 
Three (3) ACD: yellow 
(BD# 364606; 8.5 mL) 
X 
X 
X 
X 
Other 
Nails
3
 
2 to 10 clippings 
(pre-treatment, at enrollment 
only) 
X 
 
 
 
 
1. 
All slides MUST BE LABELED properly. Labels are to include the patient’s ID number, protocol number, time of study 
(e.g., baseline), type of specimen (e.g., BM biopsy, BM aspirate, blood), type of stain (e.g., Iron, H& E).  For unstained 
slides, use a pencil to label the slides.  All slides are to be sent to Dr. Rona Weinberg at the NYBC in a labeled slide box.  
The label on the box is to include the patient’s ID, protocol number, and time of study.   
2. 
Cytogenetic analyses are performed as a standard of care.  Karyotypic analysis of unstimulated bone marrow after direct 
24 and 48 hours, if available, or peripheral blood shall be performed.  Karyotypic analysis using G-banding technology is 
required.  
3. 
All 
tissue 
samples 
must 
be 
registered 
via 
the 
MPN-RC 
on-line 
Patient 
Registration 
system 
(https://redcap2.mayo.edu/redcap/ the day they are collected and prior to shipment. All tubes, and envelopes (nails) 
must be labeled with patient’s ID number, protocol number, time of study (e.g. baseline), type of specimen (e.g. BM 
biopsy, BM aspirate, blood) and date of collection. 
4. 
BMB is optional for cycles 4 and 10 at the discretion of the Investigator for chronic phase patients 
5. 
At relapse/progression or termination of study drug (that is off study drug for any reason). 
Fresh blood and bone marrow are to be stored at ambient temperature and must be shipped 
on the day that they are collected. 
Nails are to be stored at ambient temperature and may be shipped with the fresh specimens or 
subsequently. 
All slides are to be shipped to the tissue bank laboratory in a labeled slide box. The label on the 
box is to include the patient’s ID, protocol number, and time point of study. Slides may be 
shipped in batches together with the local institution’s histopathology report, every 3 months.  
All slides are shipped to Dr. Rona Singer Weinberg at the address above. 
20. 
STATISTICAL CONSIDERATIONS 
STUDY DESIGN/STUDY ENDPOINTS  
This is a Phase II design to evaluate the efficacy of ruxolitinib and enasidenib combination therapy for 
accelerated or blast-phase MPN patients with IDH2 mutations.  The study will also include a descriptive 
cohort of up to 9 evaluable patients with chronic phase MPN and will utilize a Gehan design in this 
cohort.  This study will be the first time ruxolitinib and enasidenib will be used in combination for this 
patient population. Therefore, the safety of the combination will be confirmed in the first six patients 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 55 of 77 
 
 
10 Nov 2021 
Confidential 
who are enrolled in the study. If no more than one patient out of the initial six has a treatment-related 
Grade 3 or higher adverse event attributable to the study drugs, the combination therapy will be 
considered safe.  If more than one patient out of the initial six has a limiting toxicity the trial will be 
suspended, and the safety data will be further reviewed. 
20.1 ACCELERATED / BLAST-PHASE COHORT 
Primary endpoint:  The primary endpoint of this study is best overall response, defined as partial 
response or better (CR+PR+Cri), and will be defined as the best response within 6 cyclesof combination 
therapy. All patients meeting the eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for response. Any evaluable patient not meeting the definition for response 
will be deemed as having a non- response. 
Design:  The largest overall response rate where the proposed combination treatment regimen would be 
considered ineffective in this patient population is 5%, and the smallest response rate that would warrant 
subsequent studies with the proposed regimen is 25%. This is based on retrospective analysis applying 
the 2013 IWG Response Criteria to patients treated with ruxolitinib1. A Simon’s two-stage minimax 
design will be employed to test the null hypothesis that the true overall response rate in this patient 
population is at most 5%. 
Decision Rule:  Enter 13 patients into the study. If 0 responses are observed in the first 13 patients 
(Stage 1), we may consider this regimen ineffective in the patient population and the trial will close due 
to a lack of efficacy.  If 1 or more responses are observed in the first 13 evaluable patients, we will 
proceed to Stage 2 and enroll an additional 7 patients onto the study for a total of 20 patients.  After 
completion of both stages, if 3 or more responses out of the 20 patients are observed, the combination 
therapy will be considered promising for further investigation.  
20.1.2  
POWER AND SIGNIFICANCE LEVEL / PRECISION 
Assuming that the number of overall response is binomially distributed, the significance level is <0.10 
and the probability of declaring that this regimen warrants further studies (i.e., statistical power) under 
various response proportions can be tabulated as a function of the true response proportion as shown in 
the following table.  
Table 6. Statistical Power 
Accelerated / Blast-Phase MPN 
If the true response rate is… 
0.05 
0.10 
0.15 
0.20 
0.25 
Then the probability of early termination of the 
study is … 
0.51 
0.25 
0.12 
0.05 
0.02 
Then the probability of declaring that the 
regimen warrants further studies is… 
0.07 
0.32 
0.59 
0.79 
0.90 
20.2 CHRONIC MPN PHASE 
Primary endpoint:  The primary endpoint of this study is best overall response, defined as clinical 
improvement or better (CI+PR+CR) according to IWG-ELN criteria, and will be defined as the best 
response within 6 cycles of combination therapy. All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be evaluable for response. Any evaluable patient 
not meeting the definition for response will be deemed as having a non- response. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
Page 56 of 77 
 
 
10 Nov 2021 
Confidential 
Design: Based on a Gehan design, observation of at least 1 response out of 9 evaluable patients would 
indicate activity in this cohort.  This design has 90% power if the true response rate is 25%.   
21. 
SAMPLE SIZE AND ACCRUAL 
The maximum sample size in the Phase II (accelerated/blast-phase) is 20 evaluable patients.  Allowing 
for enrollment of up to 2 additional patients as replacements for unevaluable patients (ineligibility, 
cancellation, major treatment violation, or other reasons) , this study will enroll a maximum of 22 
patients in the Phase II AP/BP cohort.  The maximum sample size in the chronic phase MPN is 9 
evaluable patients.  Allowing for enrollment of up to 1 additional patient as replacement for 
unevaluable patients, this study will enroll a maximum of 10 patients in the descriptive chronic phase 
MPN cohort.  Therefore, a maximum total of 32 (22 +10) patients will be enrolled in the trial. 
The anticipated accrual rate is approximately 2-3 patients per month. Therefore, the accrual period 
for this study is expected to be 15 months. The primary analysis can begin approximately 21 months 
after the trial begins, i.e., as soon as the last patient has been observed for 6 cycles.  
22. 
DATA ANALYSIS PLANS 
22.1 PRIMARY ENDPOINT 
Overall response rate (ORR):  The overall response rate will be estimated by the number of 
patients that attain a response (defined above per cohort) by 6 cycles of combination therapy 
divided by the total number of treated eligible patients. A two-sided 95% confidence interval 
for the true overall response rate will be calculated according the exact binomial method.  
22.2 SECONDARY ENDPOINTS 
To additionally assess the efficacy of the combination of ruxolitinib with enasidenib in patients 
with accelerated or blast-phase disease after 6 cycles of combined therapy using complete 
(CBR) or partial blast response (PBR).  CBR  and PBR will be defined according to Appendix 
A.  This will be calculated similarly to the primary endpoint for the MPN-AP/BP cohort. 
To assess the efficacy of the combination of ruxolitinib with enasidenib in patients with PMF, 
post-PV MF, or post-ET MF in chronic phase and 4-9% blasts as assessed by the modified 2013 
International Working Group (IWG) Response Criteria, after 6 months of combined therapy. 
This will be calculated similarly to the primary endpoint for the MPN-AP/BP cohort.  
Adverse events:  All eligible patients that have been initiated treatment will be included in the 
calculation of adverse event rate(s). The maximum grade for each type of adverse event will be 
tabulated for each patient, and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study treatment will be taken into 
consideration.  Adverse events will be summarized overall and by cohort.  
Overall Survival (OS) will be defined as the time from first treatment with the 
ruxolitinib/enasidenib combination to death by any cause. Patients will be considered censored 
at the last known date alive, if death is not documented. OS will be estimated using the Kaplan-
Meier method. 
22.3 EXPLORATORY/CORRELATIVE ENDPOINTS 
• 
Patient-reported symptoms and quality of MF-SAFv4.0. 
The MF-SAF v4.0 will be scored using published scoring algorithms.  Patient-reported 
symptoms and quality of life (QOL) will be described at each time point using the mean, 95% 


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in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
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confidence interval, median, and range. Changes from baseline will also be described using the 
mean, 95% confidence interval, median and range, and assessed using paired t-tests or 
Wilcoxon signed-rank tests as appropriate. Graphical procedures will include plots of average 
values over time.  . 
• 
Biomarkers:  
Biomarkers will be described at each time point using the mean, 95% confidence interval, 
median, and range if continuous, or frequency and relative frequency if binary. Continuous 
changes from baseline will be described using the mean, 95% confidence interval, median and 
range, and assessed using paired t-tests or Wilcoxon signed-rank tests as appropriate.  Binary 
changes from baseline will be described using frequencies and relative frequencies and assessed 
using McNemar’s tests as appropriate.  Biomarker associations with response (IWG/ELN 
and/or bone marrow) will be primarily descriptive in nature given the small sample size. 
23. 
STUDY MANAGEMENT 
23.1 CONFLICT OF INTEREST 
Any research personnel who has a conflict of interest with this study (patent ownership, intellectual 
property, royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
declare their conflict of interest to the appropriate institutional review bodies. Local institutional conflict 
of interest policies will be followed for all research personnel associated with the research project.   
23.2 INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND 
CONSENT 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. The IRB must approve the consent form and protocol. 
In obtaining and documenting informed consent, the Investigator should comply with the applicable 
regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include 
all the relevant elements currently required by the FDA Regulations and local or state regulations. 
Once this essential information has been provided to the patient and the Investigator is assured that 
the patient understands the implications of participating in the study, the patient will be asked to give 
consent to participate in the study by signing an IRB-approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. A 
copy of the signed consent form should be provided to the patient. 
24. 
DATA MANAGEMENT AND MONITORING/AUDITING 
24.1 DATA MONITORING COMMITTEE/DATA SAFETY MONITORING 
BOARD (DMC/DSMB) 
This trial will be monitored by the MPN-RC Data Safety Monitoring Board according to the established 
Charter.   
An External Data and Safety Monitoring Board has been established. All members have experience and 
expertise in clinical trials. DSMB members are not directly involved in any phase of MPN-RC clinical 


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trials and they have no major financial or intellectual conflict of interest that would prevent them from 
objectively reviewing the interim data and providing advice to the Trials Steering Committees and the 
Clinical Advisory Group. They function independently of all other individuals, processes, and progress 
to ensure study integrity, monitor patient safety (providing quarterly safety reports), evaluate the results 
of interim analysis to assess efficacy, and make recommendations about protocol amendments and early 
termination to the Trials Steering Committees. The External Data Safety and Monitoring Board must 
meet at least two times a year. 
24.2 MEDICAL MONITORING 
It is the responsibility of the local institutional Principal Investigator to oversee the safety of the study 
at his/her site. This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan.  Medical monitoring will include a regular assessment of the number and type of 
serious adverse events. 
24.3 MONITORING PLAN AND PERIOD OF OBSERVATION 
The MPN-RC will monitor study progress on an on-going basis; this will include electronic and 
telephone correspondence between the central coordinating office and with individual investigators 
and/or their designees at other sites. 
The Sponsor or the Sponsor designees, “study monitors,” will monitor the study according to a 
predetermined monitoring plan (centrally and with on-site visits). The monitoring visit will provide the 
Sponsor with opportunity to: 
• 
Evaluate the progress of the study 
• 
Verify the accuracy and completeness of CRFs 
• 
Assure that all protocol requirements, applicable laws and/or regulations, and 
Investigator’s obligations are being fulfilled 
• 
Resolve any inconsistencies in the study records 
25. 
REGULATORY REQUIREMENTS 
See the Regulatory Requirements section for a listing of required regulatory documents.  All protocol 
amendments will be generated through and distributed by the MPN-RC Central Coordinating Office, 
which will also maintain records of IRB approval, amendments, SAEs, and annual reviews. 
25.1 ADHERENCE TO THE PROTOCOL 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study subject requires alternative treatment, the study shall be conducted exactly as described in the 
approved protocol.  
25.2 EMERGENCY MODIFICATIONS 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB approval.  
25.3 OTHER REPORTABLE NEW INFORMATION AND PROTOCOL 
DEVIATIONS/VIOLATIONS 


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In accordance with BRANY IRB requirements, the following information must be reported within five 
(5) business days: 
• 
Non-compliance with federal regulations governing human research or with the 
requirements or determinations of the IRB, or an allegation of such non-compliance. 
• 
Failure to follow the protocol due to the action or inaction of the Investigator or research 
staff. 
• 
Breach of confidentiality 
• 
Premature suspension or termination of the research by the Sponsor or Investigator.  
25.4 AMENDMENTS TO THE PROTOCOL 
Should amendments to the protocol be required, the amendments will be originated and documented by 
the Principal Investigator. It should also be noted that when an amendment to the protocol substantially 
alters the study design or the potential risk to the patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the IRB for approval 
prior to implementation.  
 
25.5 RECORD RETENTION 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that the Study Investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on Harmonization (ICH) region. 
In all other cases, study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 
26. 
OBLIGATIONS OF INVESTIGATORS 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The Principal 
Investigator must assure that all study site personnel, including Sub-Investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines 
regarding clinical trials both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring 
visits will be conducted and the Principal Investigator will provide access to his/her original records 
to permit verification of proper entry of data. At the completion of the study, all case report forms 
will be reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
26.1 GOOD CLINICAL PRACTICE 


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The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
Investigator should be thoroughly familiar with the appropriate use of the study drug as 
described in the protocol and Investigator’s Brochure.  Essential clinical documents should be 
maintained to demonstrate the validity of the study and the integrity of the data collected.  
Master files should be established at the beginning of the study, maintained for the duration of 
the study and retained according to the appropriate regulations. 
26.2 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
This protocol and any amendments should be submitted to a properly constituted independent 
EC or IRB, in agreement with local legal prescriptions, for formal approval of the study 
conduct.  The decision of the EC/IRB concerning the conduct of the study should be made in 
writing to the Investigator and a copy of this decision should be provided to the MPN-RC 
Central Office before commencement of this study.  The Investigator should provide a list of 
EC/IRB members and their affiliate to the MPN-RC Central Office. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form should be submitted with the protocol for review and approval by the 
EC/IRB for the study.  The consent of a subject, using the EC/IRB-approved consent form, 
must be obtained before a subject is allowed to participate.  This consent form must be signed 
by the subject or legally acceptable surrogate, and the Investigator obtaining the consent. 
26.3 PATIENT INFORMATION AND INFORMED CONSENT 
After the study has been fully explained, written informed consent should be obtained from 
either the patient or his/her guardian or legal representative prior to study participation. The 
method of obtaining and documenting the informed consent and the contents of the consent 
should comply with ICH-GCP and all applicable regulatory requirement(s). 
26.4 PATIENT CONFIDENTIALITY 
Information about study subjects should be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following: 
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
The patient has the right to revoke their authorization for use of their PHI. In the event that a 
subject revokes authorization to collect or use PHI, the Investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to 
obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 
26.5 PROTOCOL COMPLIANCE 


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in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
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The Investigator should conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority(ies). Changes 
to the protocol will require approval of the MPN-RC and written IRB approval/favorable 
opinion prior to implementation, except when the modification is needed to eliminate an 
immediate hazard(s) to patients.  The MPN-RC will submit all protocol modifications to the 
regulatory authority(ies) in accordance with the governing regulations. Any departures from 
the protocol must be fully documented in the source documents. 
26.6 MANAGEMENT OF INFORMATION 
The MPN-RC at Mount Sinai will maintain sponsorship authority at the Icahn School of 
Medicine at Mount Sinai School and all other participating sites. 
Eligibility criteria will be confirmed using the electronic CRF. All inclusion and exclusion 
criteria are listed; the Investigator is obliged to fill in all items. Subjects are enrolled in the 
study only if he/she fulfills all inclusion and no exclusion criteria. 
IRB approval for each site will be submitted to the MPN-RC Central Coordinating Office via 
e-mail (PDF file preferred) or fax: 
MPN-RC Central Coordinating Office 
Clinical Trials Manager 
MPN-RC Central Office 
Phone: (212) 241-4546 
Fax: (212) 876-5276 
Email: MPNRC_ClinicalTrialCentralOffice@mssm.edu 
Office hours: Monday through Friday 9AM to 5PM EST/EDT 
Upon receipt of these documents and confirmation of certification of the Study Investigators, 
the site will be granted access to the online registration system and case report forms. 
In addition, all protocol amendments will be generated through and distributed by the MPN-RC 
Central Coordinating Office, which will also maintain records of IRB approval, amendments, 
SAEs, and annual reviews. 
Serious adverse event reporting is detailed in the Reporting Requirement section of this 
protocol. 
Protocol deviations will be reported to the MPN-RC Data Monitor and CTM:  
CTM: Lonette Sandy 
Tel: (212) 241-4546 
Email: lonette.sandy@mssm.edu 
Office hours: Monday through Friday 9AM to 5PM (EST) 
 
Data Monitor: Melissa Nashawati 
Tel: (210) 450-3955 
Email: nashawati@uthscsa.edu 
Office hours: Monday through Friday 8:00AM to 5:00 PM (CT) 
The MPN-RC Principal Investigators will be notified as soon as possible (and within 7 days) 
of reporting and will be responsible for granting approval. 
The MPN-RC will monitor study progress on an on-going basis; this will include electronic and 
telephone correspondence between the central coordinating office and with individual 
investigators at other sites. 
26.7 DRUG ACCOUNTABILITY 


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in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
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Accountability for the study drug at all study sites is the responsibility of the site Principal 
Investigator.  The responsible Investigator at each participating center will ensure that the study 
drug is used only in accordance with this protocol, drug accountability records indicating the 
drug’s delivery date to the site, inventory at the site, use by each patient, and return.  
Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and patient numbers. Conditions of the excursion will be evaluated on a case by 
case basis and a memo indicating continued use or discontinuation of the drug product involved 
will be communicated. 
26.8 SOURCE DOCUMENTS 
Source data includes all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or  magnetic  media, x-rays,  subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
26.9 CASE REPORT FORMS (CRF) 
The study CRF is the primary data collection instrument for the study.  All data requested on 
the CRF must be recorded. The CRFs may be found online at the MPN-RC website at 
(https://redcap2.mayo.edu/redcap/). The CRF Form Submission schedule is listed below:  
Table 7.  CRF Form Submission Schedule 
MPN-RC 
#119 Form# 
MPN-RC #119 FORM 
NAME 
CRF SUBMISSION SCHEDULE 
00 
Recruitment Form 
At Registration 
01 
Baseline 
After Registration 
02 
Bone Marrow Report 
At required time points specified in 
Table 5. 
03 
Cytogenetic 
At required time points specified in 
Table 5. 
04 
Symptom Assessment Package 
At required time points specified in 
Table 4. 
05 
Drug Dosage form 
At required time points specified in 
Table 4. 
06 
Adverse Event form 
At occurrence of Adverse Event 
07 
Cycle 1-2 Day 1 CRF 
At Cycle 1-2 Day 1 
08 
Cycle 1-2 Day 8 CRF 
At Cycle 1-2 Day 8 
09 
Cycle 1-2 Day 15 CRF 
At Cycle 1-2 Day 15 
10 
Cycle 1-2 Day 22 CRF 
At Cycle 1-2 Day 22 
11 
Cycle 3+ everyDay 1 CRF 
At Cycle 3+ Day 1 


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MPN-RC 
#119 Form# 
MPN-RC #119 FORM 
NAME 
CRF SUBMISSION SCHEDULE 
12 
Off Treatment 
At time of treatment withdrawal  
13 
Off Study  
At time of off study, 30 days post 
treatment withdrawal 
26.10 PREMATURE CLOSURE OF THE STUDY 
This study may be prematurely terminated, if in the opinion of the MPN-RC Trial Steering 
Committee there is sufficient reasonable cause. Written notification documenting the reason 
for study termination will be provided to the Investigator by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to patients 
• 
Failure to enter patients at an acceptable rate 
• 
Insufficient adherence to protocol requirements 
• 
Insufficient complete and/or evaluable data 
• 
Plans to modify, suspend or discontinue the development of the study drug 
26.11 RECORD RETENTION 
It is the Investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These 
documents must be retained at least 2 years following completion of the last follow-up on 
patients on active study.  These documents should be retained for a longer period if required by 
an agreement with the Sponsor.  In such an instance, it is the responsibility of the Sponsor to 
inform the Investigator/institution as to when these documents no longer need to be retained. 
26.12 DATA MANAGEMENT 
Study data will be recorded and managed using the Research Electronic Data Capture 
(REDCap) system developed by Vanderbilt University.  Research Electronic Data Capture is a 
secure, web-based application designed to support data capture for research studies, 
providing:1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages; and 4) procedures for importing data from external 
sources.   
After IRB approval and site training, REDCap database access will be given to approved and 
trained individuals at each site.  Each user will have a unique username/password assigned by 
the REDCap administrator at Mayo Clinic (where the MPN-RC Statistical and Data Center 
Core is located).  
26.13 QUALITY ASSURANCE 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be monitored 
periodically throughout the study period and potential problems will be brought to the attention of the 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
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study team for discussion and action. Monthly teleconferences including the Principal Investigators 
and/or their designees from all sites will be held to expedite the reviews of toxicity and efficacy data. 
27. WITHDRAWAL OF SUBJECTS 
Treatment with study drugs is to be discontinued when any of the following occurs: 
• 
Lack of any response by 6 cycles of combined enasidenib and ruxolitinib therapy (any effort should 
be made to provide therapy to the patient in a safe way for at least 3-6 cycles for proper assessment 
of potential efficacy). 
• 
Adverse event(s) that, in the judgment of the Investigator, may cause severe or permanent harm or 
which rule out continuation of study drug 
• 
Withdrawal of consent 
• 
Lost to follow up 
• 
Toxicity requiring dose modification/treatment suspension, without recovery to baseline, in a 
patient with less than a CRi 
• 
Death 
 
The patient will have an end of study visit at 30 days after discontinuation of the protocol treatment 
±7 days to assess for AEs. 
28. 
BREACH OF CONFIDENTIALITY 
 
One of the risks is release of information from health or research records in a way that violates privacy 
rights. The investigators will protect records so that name, address, phone number, and any other 
information that identifies the participant will be kept private. It will be stated to the participant that the 
chance that this information will be given to an unauthorized individual without the participant’s 
permission is very small. 
29. 
POTENTIAL BENEFITS TO SUBJECTS 
We hypothesize that the combination of ruxolitinib and enasidenib in patients with MPN both in 
accelerate/blasts-phase as well as with high risk chronic phase myelofibrosis with an IDH2 mutation will 
improve the overall clinical response to therapy including complete response, partial response, complete and 
partial blasts response, symptomatic improvement and improvement in quality of  life. 
30. 
SHARING OF RESULTS WITH SUBJECTS 
Results of tests performed during the study will be shared with the subject. Results of biomarker 
correlates will not be shared.  
31. 
PRIOR APPROVALS 
Approval to commence research will be obtained initially at Mount Sinai through the usual protocol 
approval pathway including the Disease Focus Group, Resource Allocation and Evaluation, Protocol 
Review and Monitoring Committees. Once this is complete, the protocol will be submitted for an IND 
to the Food and Drug Administration.  The IND-approved protocol will then be submitted to the central 
SMART IRB (BRANY) for ethical and regulatory evaluation.  Once this is IRB approved the final 
contract (with budget) will be executed and a Site Initiation Visit (SIV) will be scheduled. This will 
then allow for Mount Sinai to activate the protocol and start enrollment. The BRANY approved protocol 
will be concurrently submitted for internal review at the other MPN-RC participating sites. SIVs will 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
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be scheduled at each site once the protocol is approved locally. This will be coordinated throughout the 
MPN-RC central office within Project 4.  
32. 
ECONOMIC BURDEN TO SUBJECTS 
There will be no additional costs to the subject to participate in the study beside the standard of care 
costs. Research related per patient costs will be covered by the MPN-RC and will be determined by 
Medicare Analysis review (MCA).   
33. 
CONSENT PROCESS 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their inclusion 
in the study. Participants will also be informed that they are free to withdraw from the study at any time. 
All participants must sign an IRB/PB-approved consent form indicating their consent to participate. 
This consent form meets the requirements of the Code of Federal Regulations and the Institutional 
Review Board/Privacy Board of each site. The consent form will include the following:  
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic studies.) 
4. The name of the Investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to withdraw from 
participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.   
Each participant and consenting professional will sign the consent form. The participant must receive a 
copy of the signed informed consent form. The consent process should be documented in the patients’ 
medical records. 
 
 


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in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
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34. 
REFERENCES 
1. 
Pieri L, Sant'Antonio E, Rumi E, et al. IWG-MRT 2013 Criteria-Based Assessment of Response 
Among 83 Patients with Myelofibrosis Treated with JAK Inhibitors: Experience of Two Centers. 
2015;126(23):1615-1615. 
2. 
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization 
classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. 
3. 
Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and 
survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County 
Study, 1976-1995. American journal of hematology. 1999;61(1):10-15. 
4. 
Dupriez B, Morel P, Demory JL, et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 
195 cases with a new scoring system. Blood. 1996;88(3):1013-1018. 
5. 
Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342(17):1255-1265. 
6. 
Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation in 
myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 
2005;105(3):973-977. 
7. 
Masarova L, Bose P, Newberry K, et al. Correlation between blast percentage in myelofibrosis and 
outcomes: A single-center experience. 2017;35(15_suppl):e18562-e18562. 
8. 
Mascarenhas J. Looking forward: novel therapeutic approaches in chronic and advanced phases of 
myelofibrosis. Hematology American Society of Hematology Education Program. 2015;2015:329-339. 
9. 
Cervantes F, Pereira A, Esteve J, et al. Identification of 'short-lived' and 'long-lived' patients at 
presentation of idiopathic myelofibrosis. British journal of haematology. 1997;97(3):635-640. 
10. 
Tefferi A, Huang J, Schwager S, et al. Validation and comparison of contemporary prognostic models 
in primary myelofibrosis: analysis based on 334 patients from a single institution. Cancer. 
2007;109(10):2083-2088. 
11. 
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. 
12. 
Mascarenhas J. Risk adapted approach to the treatment of primary myelofibrosis. In: 
Association EH, ed. Hematology Education. Vol 14.2009:192-199. 
13. 
Mesa RA. Myelofibrosis with myeloid metaplasia: therapeutic options in 2003. Current hematology 
reports. 2003;2(3):264-270. 
14. 
Hoffman R, Rondelli D. Biology and treatment of primary myelofibrosis. Hematology American 
Society of Hematology Education Program. 2007:346-354. 
15. 
Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human 
myeloproliferative disorders. Lancet (London, England). 2005;365(9464):1054-1061. 
16. 
Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative 
disorders. N Engl J Med. 2005;352(17):1779-1790. 
17. 
James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive 
signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-1148. 
18. 
Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in 
polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer 
cell. 2005;7(4):387-397. 
19. 
Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in 
myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390. 
20. 
Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms 
with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405. 
21. 
Carbuccia N, Murati A, Trouplin V, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. 
Leukemia. 2009;23(11):2183-2186. 
22. 
Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia 
vera, essential thrombocythemia and myelofibrosis. Leukemia. 2009;23(5):905-911. 
23. 
Schaub FX, Looser R, Li S, et al. Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can 
be a late event in the progression of myeloproliferative neoplasms. Blood. 2010;115(10):2003-2007. 
24. 
Tefferi A, Lasho TL, Finke CM, et al. Targeted deep sequencing in primary myelofibrosis. Blood 
advances. 2016;1(2):105-111. 
25. 
Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. 
Leukemia. 2013;27(9):1861-1869. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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26. 
Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and 
prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014;28(9):1804-
1810. 
27. 
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for 
myelofibrosis. N Engl J Med. 2012;366(9):799-807. 
28. 
Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy 
for myelofibrosis. N Engl J Med. 2012;366(9):787-798. 
29. 
Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis 
receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical 
controls. Blood. 2012;120(6):1202-1209. 
30. 
Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety and survival with ruxolitinib in patients with 
myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica. 
2013;98(12):1865-1871. 
31. 
Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from 
COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. 
Blood. 2013;122(25):4047-4053. 
32. 
Tam CS, Nussenzveig RM, Popat U, et al. The natural history and treatment outcome of blast phase 
BCR-ABL- myeloproliferative neoplasms. Blood. 2008;112(5):1628-1637. 
33. 
Tefferi A, Jimma T, Sulai NH, et al. IDH mutations in primary myelofibrosis predict leukemic 
transformation and shortened survival: clinical evidence for leukemogenic collaboration with 
JAK2V617F. Leukemia. 2012;26(3):475-480. 
34. 
Rampal R, Ahn J, Abdel-Wahab O, et al. Genomic and functional analysis of leukemic transformation 
of myeloproliferative neoplasms. Proceedings of the National Academy of Sciences of the United States 
of America. 2014;111(50):E5401-5410. 
35. 
Lee YC, Hsieh CC, Lee YL, Li CY. Molecular Markers and Prognosis of Myelofibrosis in the 
Genomic Era: A Meta-analysis. Clinical lymphoma, myeloma & leukemia. 2018;18(9):558-568. 
36. 
Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 
mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. 
Cancer cell. 2010;17(3):225-234. 
37. 
Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular 
subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group 
B study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2010;28(14):2348-2355. 
38. 
Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. 
Nature. 2009;462(7274):739-744. 
39. 
Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a 
hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer 
cell. 2010;18(6):553-567. 
40. 
Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block 
to cell differentiation. Nature. 2012;483(7390):474-478. 
41. 
Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid 
leukemia genome. N Engl J Med. 2009;361(11):1058-1066. 
42. 
Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute 
myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089. 
43. 
Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute 
myeloid leukemia. Blood. 2017;130(6):722-731. 
44. 
Luesink M, Jansen JH. Advances in understanding the pulmonary infiltration in acute promyelocytic 
leukaemia. British journal of haematology. 2010;151(3):209-220. 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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34.1 APPENDIX A: RESPONSE CRITERIA 
 
Complete Response 
As per 2013 IWG-MRT and ELN Criteria 
Partial Response 
As per 2013 IWG-MRT and ELN Criteria 
Clinical Improvement 
(CI) 
As per 2013 IWG-MRT and ELN Criteria 
Anemia Response 
As per 2013 IWG-MRT and ELN Criteria 
Spleen Response 
As per 2013 IWG-MRT and ELN Criteria 
Symptom Response 
As per 2013 IWG-MRT and ELN Criteria 
Progressive Disease 
After at least 3 cycles of combined therapy: 
• 
New splenomegaly that is palpable at least 5cm below the LCM 
• 
a ≥100% increase in palpable distance, below LCM, for baseline 
splenomegaly of 5-10cm or 
• 
a 50% increase in palpable distance, below LCM, for baseline 
splenomegaly of > 10cm 
• 
Progression from chronic-phase disease (< 10% blasts) to blast-phase 
(≥ 20% blasts) disease on two separate CBCs within 28 days 
• 
For patients in accelerated of blast phase disease at baseline, a doubling of 
the absolute blast count 
Stable Disease 
As per 2013 IWG-MRT and ELN Criteria 
Cytogenetic Remission 
As per 2013 IWG-MRT and ELN Criteria 
Molecular Remission 
• 
Complete 
Molecular 
remission: 
eradication 
of 
IDH2 
and 
JAK2/MPL/CALR mutations as assessed by both next-generation 
sequencing and digital PCR assays. 
• 
Partial Molecular remission: 50% reduction in mutant IDH2 and 
JAK2/MPL/CALR allele burden as assessed by next-generation sequencing 
Cytogenetic/Molecular 
Relapse 
As per 2013 IWG-MRT and ELN Criteria 
Complete Blast Response 
Absence of circulating peripheral blood blast count with residual features of 
chronic-phase MPN maintained for at least 28 consecutive days.   
Partial Blast Response  
Reduction to < 4% blast count in peripheral blood with residual features of 
chronic-phase MPN maintained for at least 28 consecutive days.   
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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34.2 APPENDIX B: IWG-MRT AND ELN RESPONSE CRITERIA 
 
 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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34.3 APPENDIX C:  MEDICATIONS KNOWN TO PROLONG THE QT 
INTERVAL 
 
amiodarone  
citalopram  
Escitalopram 
methadone  
sevoflurane 
astemizole 
clarithromycin  
Flecainide 
moxifloxacin 
sotalol 
azithromycin  
disopyramide 
Halofantrine 
pentamidine 
sparfloxacin 
bepridil 
dofetilide 
Haloperidol  
pimozide 
terfenadine 
chloroquine  
domperidone 
Ibutilide 
probucol 
thioridazine 
chlorpromazine  
droperidol 
Levomethadyl 
procainamide  
cisapride 
erythromycin  
Mesoridazine 
quinidine  
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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34.4 APPENDIX D:  GUIDANCE IDH-INHIBITOR DIFFERENTIATION 
SYNDROME (IDH-DS) GUIDANCE FOR MANAGEMENT OF 
DIFFERENTIATION SYNDROME IN SUBJECTS WITH HEMATOLOGIC 
MALIGNANCIES TREATEDWITH IDH-INHIBITORS 
The participating investigators/health care professionals are responsible for the appropriate 
evaluation and management of the safety related issues in subjects enrolled in the study. The 
approach outlined below for identifying and managing Differentiation Syndrome in patients 
treated with IDH inhibitors should be considered as guidance and therefore management of 
each case should be individualized, as appropriate. 
Introduction to IDH inhibitors Differentiation Syndrome  
The isocitrate dehydrogenase (IDH) mutation, found in up to 15% of subjects with AML36,37, leads to 
excess accumulation of 2-hydroxyglutarate (2-HG) that causes inhibition of dioxygenase dependent 
enzymes responsible for demethylation of DNA and histones, and consequently resulting in impaired 
bone marrow differentiation39,40. 
Direct inhibition of mutated protein activity by IDH inhibitor is intended to block abnormal production 
of the oncogenic metabolite 2-HG and impact clinical outcome through a variety of mechanisms that 
include restoration of differentiation of the malignant cells. 
In patients with hematologic malignancies, initiation of treatment with the differentiating agents, such 
as IDH inhibitors, and associated maturation of aberrant bone marrow, may alter the balance of the 
expression of adhesion molecules and chemoattractants (cytokines) that could mediate tissue infiltration 
by maturing blood cells44, associated with signs and symptoms of Differentiation Syndrome (DS).  
Signs and symptoms could include fever, dyspnea, edema/ weight gain, increased serum creatinine and, 
in some cases, clinical features consistent with the acute respiratory distress syndrome with associated 
bilateral pulmonary infiltrates, and pulmonary or pericardial effusions. Increases in white blood cell 
(WBC) count concurrent to DS has been observed, but by itself do not substantiate the syndrome.   
There is no pathognomonic clinical sign or laboratory test to diagnose DS. In some instances, clinical 
presentation of DScan be confounded by other medical condition(s), such as concurrent infections or 
heart failure. Consequently, diagnosis of DS is made by excluding other potential causes, rather than 
based on a specific set of signs and symptoms.  
To improve diagnostic and treatment practices for management of DS associated with treatment with 
IDH-inhibitors (IDH DS), data for adverse events meeting diagnostic criteria for DS will be reviewed 
and assessed by a Differentiation Syndrome Review Committee. 
Clinical Assessment of Subjects for signs and symptoms of IDH-inhibitors differentiation 
syndrome  
Due to the heterogeneity of clinical symptoms and differences in adverse events reporting practices 
(e.g., symptoms of suspected IDH DS reported in place of DS diagnosis), exact incidence of 
Differentiation Syndrome in subjects treated with IDH-inhibitors has not been determined. In the 
clinical trial conducted for Idhifa’s approval, at least 14 percent of patients experienced differentiation 
syndrome 
As it has been reported by the Study Investigators, IDH DS is more likely to manifest within 10 days to 
5 months after the start of treatment, or after re-initiation of the study drug following prolonged 
treatment interruption (e.g., >3 weeks) in subjects who are not in complete remission.  In some cases, 
symptoms re-appeared after cessation of treatment for the initial manifestation of IDH DS. 
Signs and Symptoms 
In clinical trials with IDH inhibitors, DS has been described in two categories of severity: 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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Severe IDH-Differentiation Syndrome  
Based on presence of any of the below listed factors, with, or without symptoms of moderate severity 
IDH DS  
• 
New or worsened progressive dyspnea; hypoxia with increasing demands for supplemental oxygen; 
respiratory distress, without definitive etiology or refractory to treatment for the initially suspected 
cause  
• 
Radiologic evidence of new or worsened bilateral pulmonary involvement (infiltrates or opacities) 
with or without presence of infection, refractory to treatment with anti-infectives (antibiotics, 
antivirals, antifungals) that was not attributed to another cause 
• 
Radiologic evidence of new or worsened pleural or pericardial effusion that has no definitive 
etiology or is refractory to treatment for the initially suspected cause. 
Moderate Severity IDH Differentiation Syndrome  
Based on presence of at least 2 of the below listed factors, in absence of signs of severe IDH DS 
• 
Unexplained fever ≥38○C (100.4○F)  
• 
New or worsened peripheral edema without definitive etiology, or rapid weight gain (e.g., > 5 kg/11 
pounds) 
• 
Rash of unknown origin 
• 
New or worsened bone pain or arthralgia without other clear etiology 
• 
Lymphadenopathy  
• 
Increase in serum creatinine (e.g., >2-fold from baseline) 
Conditions that may co-occur with differentiation syndrome 
• 
Commonly co-occur: Leukocytosis in the absence of an infectious process 
• 
Infrequently co-occur: Laboratory Tumor Lysis Syndrome (TLS), or TLS associated with increased 
serum creatinine level, in settings of rapidly increasing blood cell count (leukocytosis) 
• 
Rarely co-occur: Coagulopathy in the setting of increased blood cell count  
Management of subjects with suspected IDH inhibitors-differentiation syndrome  
Conditions consistent with signs and symptoms of IDH DS but refractory to treatment for the initially 
suspected cause(s), or that worsen within the first 48 hours after treatment initiation, should be managed 
as potential IDH DS. 
It is recommended that the measures indicated below are undertaken at the earliest manifestations of 
suspected IDH DS. 
• 
Patients with severe or rapidly progressing IDH DS should be hospitalized for continued 
observation 
• 
In case of uncertainty with the diagnosis, e.g. presence of less specific symptoms of moderate 
severity IDH DS, patients should be closely monitored, as condition may rapidly exacerbate 
• 
Corticosteroids should be promptly initiated at a suggested dose 10 mg of dexamethasone IV every 
12 hours until complete resolution of IDH DS, after which the dose can be progressively reduced 
in the next few days or weeks 
• 
The study drug may be withheld at the investigator’s discretion. Due to long half-life of the 
IDH-inhibitors, treatment interruption may not immediately reverse symptoms of IDH DS.  
Potential for drug-drug interaction between IDH inhibitor and treatments initiated for management 
of IDH DS should be considered, when making decisions about study drug treatment interruption.  
If interrupted, study drug treatment may be reinitiated at the original or reduced dose once the signs 
and symptoms resolve and the subject’s clinical condition improves. 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
Amendment 2  
 
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• 
If renal dysfunction or severe pulmonary symptoms requiring intubation or ventilator support 
persist for more than 48 hours after initiation of systemic corticosteroids, interrupt enasidenib 
treatment until signs and symptoms are no longer severe 
• 
In subjects with elevated WBC, prompt initiation of hydroxyurea is suggested, as per standard local 
practices (e.g., dose of 2 to 3g PO twice or three times daily for WBC >30x109/L) 
• 
In cases of severe leukocytosis, use of leukapheresis may be appropriate 
• 
For substantial fluid accumulation, initiation of furosemide may be appropriate, as per local 
standard practice 
• 
Pericardial effusion - a less common symptom of IDH DS - can be life threatening condition 
requiring urgent intervention 
• 
Subjects with increasing serum creatinine levels should be evaluated for TLS 
• 
Subjects experiencing rapid increase in peripheral blood cells should be monitored for disseminated 
intravascular coagulopathy and hemorrhages 
• 
Imaging techniques such as standard or high-resolution CT or chest X-ray are useful in establishing 
a diagnosis of IDH DS. However, chest X-ray is less sensitive in detecting early radiological signs 
of IDH DS associated changes. 
Immediate communication with the Study Co-Chairs is encouraged for guidance regarding treatment. 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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34.5 APPENDIX E:  EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE SCORE RATINGS 
 
At each clinic visit after the screening visit, the investigator will assess each subject’s ECOG 
performance status according to the following scale: 
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, e.g., 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 
 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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34.6 APPENDIX F: MYELOFIBROSIS SYMPTOM ASSESSMENT FORM 
(MF-SAF) V4.0 
Instructions:  The following questions refer to symptoms that you may experience as a result of your 
myelofibrosis.  Please read through and complete the questions below.  There are no right or wrong 
answers.  Please select the answer that best applies to you. 
1. During the past 7 days, how severe was your worst fatigue (weariness, tiredness)?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent  
 
 
 
 
 
 
  Worst Imaginable 
 
2. During the past 7 days, how severe were your worst night sweats (or feeling hot or flushed)?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent  
 
 
 
 
 
 
  Worst Imaginable 
 
3. During the past 7 days, how severe was your worst itching?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent  
 
 
 
 
 
 
  Worst Imaginable 
 
4. During the past 7 days, how severe was your worst abdominal discomfort (feel pressure or bloating)?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent  
 
 
 
 
 
 
  Worst Imaginable 
 
5. During the past 7 days, how severe was the worst pain under your ribs on your left side?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent  
 
 
 
 
 
 
  Worst Imaginable 
 
6. During the past 7 days, what was the worst feeling of fullness you had after beginning to eat?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent  
 
 
 
 
 
 
  Worst Imaginable 
 
7. During the past 7 days, how severe was your worst bone pain (not joint or arthritis pain)?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Absent  
 
 
 
 
 
 
  Worst Imaginable 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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34.7 APPENDIX G: NEW YORK HEART ASSOCIATION (NYHA) CLASS 
III OR IV CONGESTIVE HEART FAILURE 
 
 
Class 
Patient Symptoms 
I(Mild) 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, or dyspnea (shortness of breath). 
II(Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results 
in fatigue, palpitation, or dyspnea. 
III(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less-than-ordinary activity 
causes fatigue, palpitation, or dyspnea. 
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: Dolgin M, Fox AC, Devereaux RB. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th 
ed. Boston: Little Brown and Company; 1994 p.253-256. 
 
 
 


A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib 
in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-
phase Myelofibrosis with an IDH2 Mutation 
(Myeloproliferative Neoplasms Research Consortium [MPN-RC] 119) 
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34.8 APPENDIX H: FDA MEDWATCH FORM 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
 
 
 
 

ICF_001.pdf: 
A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib in Patients With 
Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis With 
an IDH2 Mutation 
John Mascarenhas, MD
NCT04281498
Document Date: 12/17/2021


Version A, B, C, D, E
Protocol # MPN-RC-119
Page 1 of 21
BIOMEDICAL RESEARCH ALLIANCE OF NEW YORK LLC
THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Form Version Date: 11 Nov 2021
STUDY INFORMATION:
Study Title: A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib in Patients with 
Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis with an IDH2 
Mutation (MPN-RC 119)
Principal Investigator: Michal Bar-Natan, MD
Physical Address: Ruttenberg Cancer Center, 1470 Madison Ave., New York, New York 10029
Mailing Address: Icahn School of Medicine at Mount Sinai, Hematology/Oncology,
One Gustave L. Levy Place, New York, NY 10029
Phone: 212-241-0481 
____________________________
SUMMARY OF THIS RESEARCH STUDY:
In medicine, there are many unanswered questions. A “research study” is when scientists try to answer 
a question about something that we don’t know enough about.  Participation in a research study may 
or may not directly help you or others. Participation is entirely voluntary. It is completely up to you 
whether or not you take part. You can also change your mind at any time and it will not affect your ability 
to get medical care within the Mount Sinai Health System  
The purpose of this research study is to test the effectiveness and safety of Enasidenib when used in 
combination with the standard of care drug Ruxolitinib and to find out how well it works in patients with 
either accelerated or blast phase myeloproliferative neoplasm or high risk Chronic-phase myelofibrosis 
and who have an IDH2 mutation. 
Myelofibrosis occurs when an enzyme called Janus Kinases (JAKs) affects the ability of blood stem 
cells to form the normal amounts of red and white blood cells and platelets. It is believed that overactive 
JAK signaling (with or without a JAK mutation) affects the normal production of blood stem cells from 
bone marrow. Blood stem cells are formed in the bone marrow.  The bone marrow of patients with 
myelofibrosis and MPN is extensively scarred because mutated blood stem cells produce mature cells 
that grow too quickly and take over the bone marrow. Scar tissue in the bone marrow affects the body’s 
ability to produce a normal level of blood cells.  People who have accelerated phase MPN or 
myelofibrosis have too few red blood cells and frequently have an enlarged spleen.  The spleen is often 
enlarged because blood cell production may have moved from bone marrow to the spleen. 
Standard treatment for people with myelofibrosis is Ruxolitinib.  Ruxolitinib is a treatment that targets 
JAK signaling. Ruxolitinib works by reducing the overactive signaling of the JAK to keep the production 
of blood cells controlled.  
Many patients who have myeloproliferative diseases have an IDH2 mutation.  Research indicates that 
MPN patients with the IDH mutation have a higher risk of their MPN transforming to acute leukemia.
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Enasidenib is an FDA approved drug for the treatment of patients with relapsed or refractory acute 
myeloid leukemia who have an IDH2 gene mutation. Enasidenib works by inhibiting the IDH2, reducing 
the levels of its product and helping your bone marrow grow normal mature blood cells.  
This study proposes that the combination of these two drugs in patients who have MPN and an IDH2 
mutation will improve the response to therapy. While many patients have received each of these drugs 
separately, they have not been given together before. 
Response to the combination of these two drugs will be measured based upon by a reduction of scar 
tissue forming in bone marrow, blood cell levels, reduction of spleen and liver size, recovery of blood 
cell formation in bone marrow, increase in quality of life, and reduction of other symptoms associated 
with MPN.  
Safety of this study will be measured by collecting data on side effects you may or may not experience.  
Possible side effects are detailed in another section of this document.
You are being asked to participate in this study because you have either a Myeloproliferative Neoplasm 
(MPN) in accelerate or blast phase or previously treated high-risk Chronic-phase myelofibrosis.  If not 
already known, you will be tested to see if you have the IDH2 mutation to determine if you qualify for 
participation. 
If you choose to participate, your participation will be as follow. Each cycle is 28 days.  Participation 
may last for  6 cycles and continue for further cycles until you no longer respond to the study regimen, 
have a side effect that prevents you from continuing the study regimen, you decide to no longer 
participate, or indefinitely if you have a good response to the study regimen.  
Visits during the first two cycles will be weekly and then will be every 4 weeks from cycle 3 and beyond. 
Visits will include lab work, ECG’s, physical exam, and the collection of blood and bone marrow 
samples.  During your participation in this study, you will be asked to maintain a drug diary, take surveys 
that will tell us about how you are doing and provide information about any side effects you may 
experience. At the end of your study participation, another visit is required after 30 days to see if you 
have any lingering side effects. 
The main risks to you if you choose to participate are abnormal blood counts, bleeding and bruising, 
dizziness, headache, urinary tract infections, weight gain, gas, shingles, increased blood pressure, 
constipation, other infections (including Tuberculosis), nausea, vomiting, decreased appetite, loss of 
taste, abnormal labs, fast or chaotic heartbeats, and differentiation syndrome (IDH-DS), and possible 
death.  Differentiation Syndrome is a side effect of Enasidenib. IDH-DS is condition that affects your 
blood cells and should be treated immediately.  Symptoms of IDH-DS include fever, cough, shortness 
of breath, rapid weight gain (more than 10 pounds in a week), swelling in the arms, legs, neck, groin, 
or underarms, and bone pain. There is more detailed risk information later in this consent. 
REPRODUCTIVE RISKS 
If you are a woman who is pregnant or planning to get pregnant, you cannot take part in this study 
because we do not know how the study regimen might affect a developing fetus. We will do a pregnancy 
test before you start the study regimen to make sure you are not pregnant. 
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CONCERNS FOR SEXUALLY ACTIVE MEN AND WOMEN: Women should not become pregnant and 
men should not father a baby while taking part in this study because we do not know how the study 
regimen/ procedures could affect a man's sperm (for some regimens/procedures, the concern may be 
that the sperm might be affected and in some cases, could be carried by the semen into the vagina and 
cause harm) or a fetus, if a woman becomes pregnant during the study.
A member of the research team is available to answer any questions you may have about this study. 
Please feel free to ask questions that you may have before you decide to participate. You may also 
take home an unsigned copy of this form to think about or discuss with family or friends before deciding.  
If you choose to participate, any new information that develops during this research study such as new 
risks or benefits will be given to you promptly. If you participate, you will be given a copy of this signed 
and dated form. 
If you are interested in learning more about participating in this study, please continue to read below.
____________________________
PARTICIPATION IN THIS RESEARCH STUDY:
This research study will be fully explained to you by a member of the study team. Feel free to ask all 
the questions you want before you make a decision about whether or not to participate.  Any new 
information that develops during this research study that might make you change your mind about 
participating will be given to you promptly.
You may qualify to take part in this research study because you have an IDH2 gene mutation and you 
have a diagnosis of one of the following: accelerated-phase myelofibrosis, blast phase myelofibrosis or 
chronic phase myelofibrosis with high-risk features. Myelofibrosis (MF) is an uncommon type of 
leukemia that affects your body’s normal production of blood cells.  The production of blood cells 
normally occurs in your body’s bone marrow, however, people with MF’s bone marrow is often scarred 
which leads to a lack of red blood cells which result in anemia, weakness, fatigue and an enlarged 
spleen.  A gene mutation named JAK2 is thought to be the reason why people develop myelofibrosis.  
____________________________
DISCLOSURE OF FINANCIAL INTERESTS:
Funds for conducting this research are provided to the Myeloproliferative Neoplasms Research 
Consortium (MPN-RC) through a grant provided by the National Cancer Institute (NCI).  Additional 
funds are being provided by Celgene and Incyte. Celgene will provide the study drug Enasidenib. 
Celgene will be providing Enasidenib to study participants. Incyte, the manufacturer of ruxolitinib or 
Jakafi, will also provide funds. Celgene and Incyte have a financial interest that could be affected by 
the outcome of the results of this research study.
Dr. John Mascarenhas (a Sub-Investigator in this study) receives financial compensation as an 
advisory board member for Celgene (provider of funds for this study and manufacturer of Enasidenib, 
a drug being investigated in this study). 
In addition, Dr. Mascarenhas receives financial compensation as a consultant for the Incyte 
Corporation (provider of funds for this study and manufacturer of Ruxolitinib, a drug being investigated 
in this study).
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If you have questions regarding paid relationships that your physician/researcher may have with 
industry, we encourage you to talk with him or her, or check for industry relationships posted on 
individual faculty pages on our website at http://icahn.mssm.edu/.
____________________________
LENGTH OF TIME AND NUMBER OF PEOPLE EXPECTED TO PARTICIPATE:
Your participation in this research study is expected to last at least six months unless you have a bad 
reaction to the study drug. If you respond well, then you can remain on the study regimen until either 
you decide you want to stop, or the physician decides that it is no longer safe or effective for you to 
receive the study drug, or the study closes.  
  
The number of people expected to take part in this research study at this site, the Icahn School of 
Medicine at Mount Sinai is 7. This study will also be conducted at 9 other sites. The total number of 
people expected to take part in this multi-site research study is 32.
DESCRIPTION OF WHAT’S INVOLVED:
If you agree to participate in this research study, the following information describes what may be 
involved.
No procedures may take place until you have agreed to participate in this study and signed this form. 
All procedures will take place at Ruttenberg Cancer Center unless otherwise specified.  
Screening:
•
Medical History and Physical Exam: A complete history and physical exam and manual 
measurement (in cm) of your liver and spleen, if palpable.  Your study doctor will ask you a series 
of questions. He or she will use a stethoscope (a device placed on your skin to allow the doctor to 
hear inside your body) to listen to your heart, lungs, and belly.  He or she will feel your entire body, 
including your neck, trunk, arms, and legs. 
•
Measurements of your vital signs: heart rate, breathing rate, blood pressure, temperature, weight, 
and height. 
•
You will be asked to provide information about your age, race, gender, and ethnicity.
•
You will be asked to provide information about your prior medical history including all active 
conditions and conditions you have been told you have within the last 10 years.  You will also be 
asked to provide information about what treatment, if any you have had for these conditions.
•
Current medications will also be reviewed.  It is important that you tell your study doctor about any 
medications you are currently taking or have taken within the last 30 days.  Please tell your study 
doctor about all medications including over-the-counter medications, vitamins, herbal medications, 
and alternative medicines. You may need to stop some of your medicines in order to be able to take 
part in this study. 
•
You will be asked about any transfusion history you have had within the last 3 months. 
•
Bone marrow aspiration/biopsy/cytogenetics/molecular genetic profiling.  Bone marrow aspiration, 
also called bone marrow sampling, is the removal be suction (through a needle placed into the bone) 
of fluid from the soft, spongy materials that lines the inside of most bones (marrow).  (Approx. 1 ½ 
tsp).  During a bone marrow aspiration/biopsy, an area of the hip is numbed and a needle is placed 
through the skin and into the hip bone. A small sample of the bone marrow and bone is withdrawn.  
The bone marrow will be examined to see if it is abnormal.  (If you have had a bone marrow biopsy 
within the last 90 days and we are able to get the results, you will not have to repeat one at 
 
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screening.) Your genes are in the cells of your body.  Genes make you different from anyone else.  
Some genes are responsible for inherited traits like hair and eye color.  Some genes affect the 
chances that a person will get a certain disease or how their body responds to drugs.  The purpose 
of testing for specific molecular profiling is to determine if you qualify for this research.  The bone 
marrow testing is normally done for patients with MPN. 
•
Blood samples (approximately 9 tsp blood) will be drawn from your vein for clinical and research 
purposes
•
Urine will be collected for standard of care urinalysis 
•
Pregnancy test (1 tsp of blood): Serum HCG for women of childbearing potential.  Women will not 
be allowed to participate if they are pregnant or nursing. 
•
Both men and women who are able to have children must agree to use 2 effective forms of birth 
control (hormonal or barrier method of birth control, or abstinence) from the time of screening 
through their participation in the study. 
•
Spleen volume assessment by Computed Tomography (CT) or Magnetic Resonance Imaging 
(MRI). 
•
Electrocardiogram (ECG): will be done to measure the electrical activity of your heart.  For this test, 
you will be asked to lie down while 12 sticky pads are applied to each of your arms, legs, and to 
your chest.  The ECG will last about five minutes. The ECG is being done for research purposes. 
•
Cardiac function assessment for research purposes will be done by having an ECHO or MUGA 
scan. 
•
Nail clippings: 2 clippings will only be gathered once (at screening visit) for research. Your nail 
clippings will provide normal material, like DNA, for comparison with the abnormal material from 
your blood and/or bone marrow.
If the screening exams, tests, and procedures show that you can continue in the study, and you choose 
to take part, then you will need the following tests and procedures during the study period outlined 
below. 
You are to start the first day of the study within 30 days of completing the screening procedures.  For 
the first two cycles that you are on the study, you will return to the clinical at least once a week for tests 
and to be seen by your study doctor.  You will be given study drugs and a drug diary at the beginning 
of each cycle. Each cycle is 28 days.  During these visits, do not forget to tell your study doctor if you 
start taking any new medicines, feel unwell or want to stop participation in this study for any reason. 
After the first two cycles, you will come in for visits once a month until you stop the study regimen for 
whatever reason.  A mandatory safety follow up visit will be done within 30 days after the end of the 
study regimen or before you start a new regimen, whichever comes first. 
Your study medications are both taken orally at home every day unless you are being seen in the clinic 
for a study visit.  If you are being seen in the clinic for a study visit, you will need to bring the study drugs 
with you to take in the clinic. You should fast 2 hours before and 1 hour after taking Enasidenib.  You 
do not need to fast when taking Ruxolitinib and you may take it at the same time you take Enasidenib. 
Days 1 and 8 of Cycles 1 and 2
•
A physical exam including a review of current medical conditions and medications you are taking. 
•
A pregnancy test for women of child-bearing potential.
•
Blood samples (approximately 5 tsp blood) will be drawn from your vein for clinical and research 
purposes. 
 
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o
NOTE: Research blood samples will drawn on day 1 only.
•
Electrocardiogram (ECG): will be done to measure the electrical activity of your heart.  
•
You will be asked to complete a brief survey about your symptoms.
Days 8 and 22 of Cycles 1 and 2
•
A pregnancy test for women of child-bearing potential.
•
Blood samples will be drawn from your vein for clinical purposes only.
•
Electrocardiogram (ECG): will be done to measure the electrical activity of your heart.  
•
You will be asked to complete a brief survey about your symptoms.
Day 1 of Cycles 3 through 6
•
A physical exam including a review of current medical conditions and medications you are taking. 
•
You will be asked to provide updated transfusion history. 
•
A pregnancy test for women of child-bearing potential.
•
Blood samples (approximately 5 tsp blood) will be drawn from your vein for clinical and research 
purposes
•
Electrocardiogram (ECG): will be done to measure the electrical activity of your heart.  
•
Bone marrow aspirate and biopsy is done at C4 D1 (for accelerated phase patients, may be done 
at the discretion of the Investigator for chronic phase patients). 
•
Study drug will be dispensed
•
You will complete a drug diary and return to your study doctor
•
You will return all unused medication and the bottles
•
You will be asked to complete a brief survey about your symptoms.
Day 1 of Cycle 7 and Beyond 
•
A physical exam including a review of current medical conditions and medications you are taking. 
•
You will be asked to provide updated transfusion history. 
•
A pregnancy test for women of child-bearing potential.
•
Blood samples (approximately 5 tsp blood) will be drawn from your vein for clinical and research 
purposes
•
Bone marrow aspirate and biopsy 
o
NOTE: This will be done at C7 D1 (for all patients), C10 D1 (for accelerated phase 
patients, may be done at the discretion of the Investigator for chronic phase patients), 
and every 6 cycles, thereafter (for all patients).
•
Electrocardiogram (ECG): will be done to measure the electrical activity of your heart.  
•
Spleen volume assessment by CT or MRI. 
o
NOTE: This will be done at cycle 7 day1, cycle 10 day 1 and every 6 cycles afterward. 
•
Study drug will be dispensed
•
You will complete a drug diary and return to your study doctor
•
You will return all unused medication and the bottles. You will be asked to complete a brief survey 
about your symptoms
Response to the study regimen will be done after 6 cycles of the study regimen and every 3-6 cycles 
afterwards for the remainder of participation on the study. The response to the study regimen will be 
determined based upon exams, tests, and/or procedures to determine whether you will be allowed to 
 
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continue in the study. If you are not allowed to continue in the study, the study doctor will discuss the 
reasons with you. 
End of Study Regimen
•
A physical exam including a review of current medical conditions and medications you are taking. 
•
You will be asked to provide updated transfusion history. 
•
A pregnancy test for women of child-bearing potential.
•
Blood samples will be drawn from your vein for clinical purposes only.
•
Electrocardiogram (ECG): will be done to measure the electrical activity of your heart.  
•
Spleen volume assessment by CT or MRI.  
•
You will return a completed drug diary to your study doctor
•
You will return all unused medication and the bottles
•
You will be asked to complete a brief survey about your symptoms
End of Study
•
A physical exam including a review of current medical conditions and medications you are taking. 
•
You will be asked to provide updated transfusion history. 
•
A pregnancy test for women of child-bearing potential.
•
Blood samples (approximately 5 tsp blood) will be drawn from your vein for clinical and research 
purposes
•
Bone marrow aspirate and biopsy NOTE: This will be done at cycle 6, cycle 9 and every 6 months 
afterward.
•
Electrocardiogram (ECG): will be done to measure the electrical activity of your heart.  
•
Spleen volume assessment by CT or MRI. NOTE: This will be done at cycle 6, cycle 9 and every 6 
months afterward. 
•
Response assessment
•
You will be asked to complete a brief survey about your symptoms
Survival Follow Up
After your End of Study visit, you will be asked to continue follow-up with your study doctor or the 
study coordinator every 3 months for up to 1-year. This period may be conducted by record review 
(including public records) and/or telephone contact with you, your family, or your treating physician (if 
appropriate). During the follow up, your doctor or the study coordinator will collect further data related 
to your health, for example, if you are taking any therapies following the clinical trial for your MPN-
associated disease. 
Early Termination Visit: 
If you are withdrawn from the study, or choose to withdraw from the study, you will be required to meet 
with your study doctor for a final evaluation of your symptoms and general health. The procedures will 
be the same at the End of Study Visit procedures.
Because this project involves the use of medications, it is necessary that we make a note of your 
participation in the electronic medical record. That way anyone treating you will be aware of your 
participation and may be able to avoid any unfortunate outcomes that could arise if your research 
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For Women:
Since you are participating in a research study that involves drugs or an experimental regimen with 
potential risks to a developing fetus, it is recommended, for your protection, that you not become 
pregnant for the duration of the study and for at least 4 months after the study. You should not participate 
if you are breastfeeding. You will be counseled on the risks of becoming pregnant at least once every 
28 days about pregnancy precautions and risks of fetal exposure. 
A blood pregnancy test will be done before you begin the study and will be repeated weekly for cycles 
1 and 2, then will be repeated at the beginning of each study cycle. Women of child bearing potential 
(WCBP), must have a negative serum (blood) pregnancy test at each of these tests and must 
agree to use adequate methods of birth control throughout the study. Therefore, practicing two forms 
of effective birth control at the same time is important at least 4 weeks before you begin taking the study 
medications and for 4 months after you stop taking Enasidenib and Ruxolitinib. No individual birth 
control is 100% effective. 
Recommended methods of birth control are:
•
The consistent use of an approved hormonal birth control (pill/patches, rings), 
•
An intrauterine device (IUD), 
•
Contraceptive injection (Depo-Provera), 
•
Double barrier methods (Diaphragm with spermicidal gel or condoms with contraceptive foam), 
•
Sexual abstinence (no sexual intercourse) or 
•
Sterilization.
If you are unsure whether the method of birth control you use is acceptable to use while participating in 
this study, you should ask your study doctor before you begin the study. If you are less than one year 
post-menopausal, there is the potential that you could become pregnant. If you or your partner becomes 
pregnant, or may be pregnant, at any time during the trial and up to 4 months after you stop taking the 
study drugs, it is important that you tell your study doctor immediately. The trial drug may be stopped, 
and a referral may be made to an obstetrician/gynecologist for follow-up. If you plan to become pregnant 
in the year following a clinical trial, speak with your study doctor. 
Should you become pregnant, regardless of the outcome, the sponsor may ask for information on your 
pregnancy, even if you are withdrawn from the study, your written consent will be obtained separately 
in the case that this happens.
For Men:
Since you are participating in a study that involves experimental drugs or an experimental regimen with 
potential risks to a developing fetus, it is you must use a condom and not impregnate a woman or donate 
sperm while you are taking the study drug, and for an additional 4 months after you stop taking the 
study This is because levels of the study drug may be present in the sperm and/or seminal fluid even 
after you stop taking the study drug. You are encouraged to tell your female partner(s) and/or their 
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Should a female partner of yours become pregnant while you are on the study regimen or in the 4 
months following the study regimen, you should notify the study doctor, and the pregnant female partner 
should be advised to call her healthcare provider immediately.
Clinically Relevant Research Results
Results of clinical tests performed during the study will be shared with the subject. Results of 
biomarker testing done on blood/tissues collected for research purposes will not be shared. 
USE OF YOUR DATA AND/OR SPECIMENS:
Your participation in genetic testing is a mandatory part of this study and may help to better understand 
which MF patients may benefit from the study drug in the future. If you do not want to participate in the 
genetic testing part of this study, then you cannot participate in this study.
Segments of the DNA called genes are responsible for passing particular traits such as eye color from 
parents to children. The genes which pass along your traits direct cells in your body to make proteins.  
Your genes are in the cells in your body. Genes make you different from anyone else. Some genes are 
responsible for inherited traits like hair and eye color. Some genes affect the chances that a person will 
get a certain disease or how their body responds to drugs.  The research on your biospecimens 
will/might include whole genome sequencing, which is genetic testing that looks at all of your genes 
(DNA). This study is being done to help researchers understand why people may react differently to the 
study drug and how the body uses the study drug.
The researchers would like to ask your permission to keep the data and specimens (like blood, tissue, 
hair, or any other body matter) collected from you during this study to use them in future research 
studies. Please tell us how we may use this material in future research studies. You should also know 
that it is possible that products may someday be developed with the help of your specimens and data, 
and there are no plans to share any profits from such products with you.
Some of which may play a role in the development of disease such as MF. The study of gene mutations 
and variations in genes may help scientist to predict which patients with MF are most likely to respond 
to specific regimens. In this study, genetic testing will be performed in order to learn more about factors 
which may predict response to the study drug. The doctors at Mount Sinai are working with other cancer 
researchers, are attempting to better understand the causes of myeloproliferative neoplasms and to 
develop improved methods for the diagnosis and treatment of these diseases.
As part of this research study, a small sample of your blood will be taken to look for these certain 
molecules in the blood called “biomarkers.” Because these extra blood and bone marrow samples will 
be collected at the same time as regularly scheduled blood and bone marrow tests, you will not undergo 
any additional procedures. These blood and bone marrow samples will be collected for research 
purposes only. You are also being asked to provide nail clippings. These samples will be used to test 
and analyze the behavior and activity of molecules (the smallest unit of a substance that can exist alone 
and retain the character of that substance) and genes (the basic biological unit of hereditary) that may 
change as by- products of the disease itself. Your nail clippings will provide normal material like DNA 
for comparison with the abnormal material from your blood and/or bone marrow. This information may 
provide us with a better understanding of what causes the disease and how to develop better 
 
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treatments. You will not receive the results from research on your sample. That study will only collect 
blood, bone marrow, and nail samples to determine genetic characteristics.
These samples will be sent to special laboratories at the New York Blood Center for careful study and 
analysis. Your samples will be sent to these laboratories using a unique code that does not identify you 
by name, address or social security number. Researchers with access to your samples will not be able 
to identify you. The code linking the sample to your name would be stored at Mount Sinai and known 
only to your doctor and a limited number of research personnel at Mount Sinai. The research will not 
have any effect on your care; therefore, the results of the genetic testing will not be placed into your 
medical records. If you discontinue from the trial, regardless of the reason (patient, investigator or 
sponsor decision), no further genetic samples will be collected. However, we will continue to use data 
previously generated from the genetic samples collected prior to the date of discontinuation.
These samples will be obtained at the following times:
•
Bone marrow biopsy and aspirate – before starting the study, at cycle 4 day 1, cycle 7 day1, 
cycle 10 day 1, every 6 cycles afterwards and at the end of study.
•
Research blood samples- before starting the study drug, on day 1 of cycles 1 through 7, then 
every 3 cycles afterwards and at the end of study. 
•
Nail clippings-at screening, before starting the study drug
The blood and bone marrow samples we collect would normally be obtained at these times while taking 
the study drug and/or routine follow-up. Blood and bone marrow samples, described in the “Description 
of What’s Involved” section, for this study will be drawn only when these samples are being obtained 
for clinical purposes. Therefore, you will not have to undergo any additional procedures to participate in 
this study.
Nail clippings will be obtained only before starting the study drug.
Any information derived directly or indirectly from the future research, as well as any patents, diagnostic 
tests, drugs, or biological products developed directly or indirectly as a result of this research, are the 
sole property of the Sponsor (and its successors, licensees, and assigns) and may be used for 
commercial purposes. You have no right to this property or to any share of the profits that may be 
earned directly or indirectly as a result of this research. However, in signing this form and donating a 
blood sample or tumor tissue specimen for future research, you do not give up any rights that you would 
otherwise have.
To do more powerful research, it is helpful for researchers to share information they get from studying 
human samples. They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. Researchers can then study the combined information to learn even 
more about health and disease. If you agree to take part in this study, some of your genetic and health 
information might be placed into one or more scientific databases. There are many different kinds of 
scientific databases; some are maintained by Mount Sinai or another institution, some are maintained 
by the federal government, and some are maintained by private companies. For example, the National 
Institutes of Health (an agency of the federal government) maintains a database called “dbGaP.” A 
researcher who wants to study the information must apply for permission to use the database. Different 
databases may have different ways of reviewing such requests. Researchers with an approved study 
may be able to see and use your information, along with that from many other people. Researchers will 
always have a duty to protect your privacy and to keep your information confidential, but there are risks 
associated with data collection and sharing. They are described in more detail in the risks section. 
 
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____________________________
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH:
If you decide to take part in this research study, you will be responsible for the following things: 
complying with requirements of the study, maintaining a study drug log, taking prescribed medications, 
reporting side effects, use of two effective birth control (condom, taking the pill, or barrier methods), and 
regular attendance at study visits.
____________________________
COSTS THAT MAY RESULT FROM PARTICIPATION:
Taking part in this research study may lead to added costs to you. 
Your or your insurance company will be responsible for the costs of all items and services during the 
research study that you would have received for your condition if you were not enrolled in this research 
study.  You or your insurance company will also be responsible for the costs of all services that occur 
during the research study that your physician believes are medically necessary to treat you. 
You will receive the study drug Enasidenib at no cost. Ruxolitinib will be charged to you or your 
insurance since this is medication you would most likely be treated with for your MPN. 
PAYMENTS THAT MAY RESULT FROM PARTICIPATION
You will not be paid for taking part in this study. 
You have the choice of participating in our travel reimbursement program.  You will be reimbursed up 
to $50 for your travel expenses for study visits from Screening through the core study period ending in 
cycle 6 and including the End of Study Regimen and End of Study visits. This will potentially include 15 
visits in total.  You will not be reimbursed for travel and time if you remain on the study drug beyond 
cycle 6.  
This reimbursement will be by check and you should receive it within 3 months of receipts submission. The 
following information will be required from you to receive the reimbursement:
•
Receipt of travel expenses
•
Mailing address
•
Social security number
Tax law may require Mount Sinai’s finance department to report the amount of payment you receive 
from your participation in this research to the Internal Revenue Service (IRS) or other agencies, as 
applicable.  Generally, this reporting would take place if you receive payments that equal $600 or more 
from Mount Sinai in a calendar year. You would be responsible for the payment of any tax that may be 
due. 
___________________________
POSSIBLE BENEFITS:
 
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It is important to know that you may not get any benefit from taking part in this research.  Others may 
not benefit either.  You may or may not benefit from participation in this research based upon if the 
treatment combination is effective for you. Your condition may not get better or may get worse during 
your participation in this study.  The knowledge learned from this research study may be helpful to other 
people with myeloproliferative disorders. However, no benefit, to you or others, can be promised 
because of your participation in this research. 
____________________________
REASONABLY FORESEEABLE RISKS AND DISCOMFORTS:
While on this research study, you are at risk for certain side effects associated with the study medication 
you will be taking. There may also be side effects that we can’t predict or that are unknown at this time 
which could be serious, permanent, or in some cases, result in death. Therefore, it is important that you 
communicate any and all symptoms that you experience to your study doctor. Medications can be given 
to you to make side effects less serious and less uncomfortable. If you do experience side effects, we 
can withhold or stop your study drug. Many side effects go away shortly after the drug is stopped, but 
in some cases, side effects can be serious, long lasting or permanent. You should also tell your study 
doctor about any other medications or supplements that you are taking.
Risks from the research
The investigators have designed this study learn about the safety and efficacy of the combination of 
Ruxolitinib and Enasidenib. The combination may have side effects that are worse than previously 
observed or that have not been previously observed in animals or humans. The new regimen may not 
improve your condition or disease, or it may make your condition or disease worse. 
Risks from the specific research procedures (drug(s), interventions, or procedures) 
The following section will describe the risks related to each your participation in this research study. 
You should talk to your study doctor about any side effects or other problems that you have while taking 
part in the study.
Side effects can range from mild to serious. Serious side effects are those that may require 
hospitalization, are life threatening or fatal (could cause death). The frequency that people experience 
a certain side effect can range from many (likely), few (less likely) or only one or two (rarely).
Risks and side effects related to Ruxolitinib
•
Laboratory abnormalities (decrease in red blood cells, decrease in platelet counts, decrease 
in white blood cells, increase in cholesterol levels, increase in liver enzymes) up to 90%
•
Bruising 23%,
•
Dizziness and headache 15-18%,
•
Urinary tract infections <9%,
•
Weight gain <7%,
•
Gas and constipation 5-8%,
•
Shingles 2-6%, 
•
Elevated blood pressure <6%, 
•
Infection – including Tuberculosis up to 10% and rare
 
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Risks and side effects related to Enasidenib
•
Isocitrate Dehydrogenase – Differentiation Syndrome (IDH-DS).  IDH-DS is a life-threating 
side effect that has occurred in about 19% of AML patients treated with Enasidenib with 5% 
of these cases as causing death. Reports of symptoms from IDH-DS have occurred as early 
as 10 days and up to 5 months after starting Enasidenib.   Patients should call your study 
doctor and go to the emergency room right away if any of the following symptoms occur 
while taking Enasidenib: 

Fever

Cough

Shortness of breath

Swelling of arms and legs

Swelling around the neck, groin, or underarm area, 

Fast weight gain of more than 10 pounds within a week

Bone pain

Dizziness of feeling lightheaded
•
Common side effect of Enasidenib include:
▪
Nausea and vomiting 34-50%
▪
Diarrhea 43%
▪
Yellowing of the skin or whites of the eyes 81%
▪
Decreased appetite 34%
Risks and Side Effects related to MRI Scans: 
•
Claustrophobia
•
Allergic reaction to contrast
•
Serious allergic reactions that can be life-threatening may occur
•
Death or serious injury due to movement of metals in the body. 
Other risks that can be seen with participating in any clinical trial include:
•
Risk of loss of private information; this risk always exists, but there are procedures in place 
to minimize the risk.
•
Since the study drug combination is for research, when taken alone or in combination with 
other medications (including alcohol or illegal substances), there may be other risks that 
are unknown. 
•
All drugs have a potential risk for allergic reaction, which if not treated promptly, could 
become life threatening.
•
There may be other side effects or risks that are not known at this time. Should information 
become available that may affect your participation in this research study, you will be 
informed. You can then decide if you wish to continue with your participation in the study. 
To limit the risks as much as possible you will be subject to medical supervision. It is your 
responsibility to report to the study doctor and staff all changes in your physical condition 
during the study. This is important for your safety. 
•
The risks of a blood draw include pain, bruising, and the slight possibility of infection at the 
place where the needle goes in.  Some people feel dizzy or may faint during or after a blood 
draw.
 
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•
In addition to these risks, this research may hurt you in ways that are not known.  The 
unknown risks might be minor or might be major (death).
Risks of Bone Marrow Aspirates
•
Severe pain, swelling, and infection 
Risks and Side Effects related to CT Scans: 
The level of risk depends on the number of scans performed, whether contrast dye is used, and the 
amount of radiation used for the specific scans. Contrast dye is not being used in this study. The 
radiation received from CT scans may increase your lifetime chance of getting cancer. Ask the study 
doctor or study staff about the risk from CT scans in this study.
This research study includes exposure to radiation from x-rays or gamma rays. This radiation exposure 
is for research purposes only and is in addition to any radiation needed for your medical care. X-rays 
and gamma rays from natural or medical sources can damage the genetic material (DNA) in your cells. 
At low radiation exposures, the body is usually able to repair the damage. Radiation risk is believed to 
be related to the total lifetime exposure. You should think about your own history of radiation exposure 
from tests (like x-rays or CT scans) in deciding about the radiation in this study. If you have questions 
about the total amount of radiation exposure you will be receiving, you should ask your doctor.
The estimated radiation exposure that you will get for this research study will be 22.55 mSv (an mSv is 
the scientific unit of measurement for whole body radiation dose). The greatest annual exposure (22.55 
mSv) is projected to be in year(s) 1. This exceeds the 6.2 mSv that the average person in the United 
States gets each year from both natural sources like the sun, outer space, air, food and soil, as well as 
from medical procedures. It is less than the 50 mSv of radiation that is allowed each year for people 
who are exposed to radiation in their jobs.
Other risks that can be seen with participating in any clinical trial include:
•
Risk of loss of private information; this risk always exists, but there are procedures in place to 
minimize the risk.
•
Since the study drug combination is for research, when taken alone or in combination with other 
medications (including alcohol or illegal substances), there may be other risks that are unknown.
•
All drugs have a potential risk for allergic reaction, which if not treated promptly, could become 
life threatening.
•
There may be other side effects or risks that are not known at this time. Should information 
become available that may affect your participation in this research study, you will be informed. 
You can then decide if you wish to continue with your participation in the study.
•
To limit the risks as much as possible you will be subject to medical supervision. It is your 
responsibility to report to the study doctor and staff all changes in your physical condition during 
the study. This is important for your safety.
•
The risks of a blood draw include pain, bruising, and the slight possibility of infection at the place 
where the needle goes in. Some people feel dizzy or may faint during or after a blood draw.
In addition to these risks, this research may hurt you in ways that are not known. The unknown risks
might be minor or might be major (death).
 
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•
If you are or become pregnant, this research may hurt your baby or your pregnancy in ways 
that are unknown. The unknown risks might be minor or might be major (death) for the 
pregnancy. You should not become pregnant or impregnate a woman while on this research 
study. Please read the acceptable methods of birth control found under the Description of 
What’s Involved section of this document.
•
Group Risks - Although we will not give researchers your name, we will give them basic 
information such as your race, ethnic group, and sex. This information helps researchers 
learn whether the factors that lead to health problems are the same in different groups of 
people. It is possible that such findings could one day help people of the same race, ethnic 
group, or sex as you. However, they could also be used to support harmful stereotypes or 
even promote discrimination. 
•
Privacy Risks - Your name and other information that could directly identify you (such as 
address, date of birth or social security number) will never be placed into a scientific 
database. However, because your genetic information is unique to you, there is a small 
chance that someone could trace it back to you. The risk of this happening is very small but 
may grow in the future.  Since the database includes genetic information, a break in security 
may also pose a potential risk to blood relatives as well as yourself. For example, it could be 
used to make it harder for you (or a relative) to get or keep a job or insurance.  If your private 
information was misused it is possible you would also experience other harms, such as 
stress, anxiety, stigmatization, or embarrassment from revealing information about your 
family relationships, ethnic heritage, or health conditions.
Side effects from this study will likely go away soon after you stop the study regimen.  In some cases, 
side effects can be long lasting or may never go away.  
Everyone taking part in the study will be watched carefully for any side effects.  However, the study 
doctors don’t know all the side effects that may happen.  Be sure to tell your study doctor immediately, 
about any side effect that you have while taking part in the study. 
The Sponsor has taken steps to safeguard your genetic testing information, so the risk of loss of 
confidentiality is small, however, if confidentiality is broken, results of genetic testing may become 
available to insurance carriers or employers. The knowledge of this information has the potential to lead 
to discrimination in employment or insurance. Someone with a known genetic condition indicating a 
susceptibility to develop a disease or condition might be denied a job or a promotion, or denied health 
or life insurance, because they are regarded as a health risks and therefore an economic risk. Carriers 
for a genetic disorder might be discriminated against and viewed as having the potential to have a child 
with a genetic condition.
There is a Federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this law 
makes it illegal for health insurance companies, group health plans, and most employers of over 15 
people to discriminate against you based on your genetic information. However, it does not protect you 
against discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance.
OTHER POSSIBLE OPTIONS TO CONSIDER:
 Your other choices may include: 
 
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• Getting treatment or care without being in a study 
• Taking part in another study, and 
• Getting no treatment 
If you decide that you don’t want any more active regimen, one of your options is called “comfort care.” 
Comfort care includes pain medication and other support. It aims to maintain your comfort and dignity 
rather than cure disease. Usually this care can be provided at home. 
If you think you might prefer comfort care, please discuss this with your family, friends and your doctor. 
Not participating in this research is an option. The researcher will discuss all your options with you.
___________________________
IN CASE OF INJURY DURING THIS RESEARCH STUDY:
For medical emergencies, call 911.  If you are injured or made sick from taking part in this research 
study, medical care will be provided. Generally, this care will be billed to you or your insurance in the 
ordinary manner and you will be responsible for all treatment costs not covered by your insurance, 
including deductibles, co-payments and coinsurance.  This does not prevent you from seeking payment 
for injury related to malpractice or negligence. Contact the investigator for more information.
For more information on clinical trials and medical insurance coverage, you can visit the National Cancer 
Institute’s website at: http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  Another way to 
get this information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.
No other compensation will be offered by the sponsors of this study, the Mount Sinai Health System 
Hospitals, or the Biomedical Research Alliance of New York. 
You are not waiving any legal right to seek additional compensation through the courts by signing this 
form. 
____________________________
ENDING PARTICIPATION IN THE RESEARCH STUDY:
Your participation in this study is voluntary.  You may refuse to take part in this study or once in the 
study you may stop at any time without any penalty. This will not affect your ability to receive medical 
care at any of the Mount Sinai hospitals or to receive any benefits to which you are otherwise entitled.
If you decide to stop being in the research study, please contact the Principal Investigator or the 
research staff and tell them if you want to leave the study. If you do decide to stop participation, please 
do not stop taking Ruxolitinib without consulting with your physician. Your physician may either 
prescribe a tapering dose of Ruxolitinib over 4-7 days to reduce a sudden increase in symptoms or 
prednisone to ensure you can safely stop taking this medication. Additionally, for your safety, if you 
leave the study early, you may be asked to return to the study doctor’s office for a final study visit. 
If you stop being in the research study, already collected information may not be removed from the 
research study database and will continue to be used to complete the research analysis.  You may be 
asked whether the study doctor can collect information from your routine medical care. If you agree, 
this data will be handled the same as research data. 
 
 
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If you decide you don’t want your samples and/or data to be used for research anymore, you can contact 
the researcher and ask to have your samples and/or data removed from future use. If any samples or 
data have already been shared without your identity, it won’t be possible to retrieve them because no 
one will know who you are. Samples and data that have already been used will not be affected by your 
decision. Any samples and/or data that are still linked to your identity by a code the researcher has will 
be withdrawn so that no future sharing of your samples and/or data will take place. If your samples have 
already been deposited in an external repository, the study team will request that your samples be 
removed.
Withdrawal without your consent: The study doctor, the sponsor or the institution may stop your 
involvement in this research study at any time without your consent. This may be because the research 
study is being stopped, the instructions of the study team have not been followed, the investigator 
believes it is in your best interest, or for any other reason. If specimens or data have been stored as 
part of the research study, they too can be destroyed without your consent.  More possible reasons for 
removal from the study include: you become ineligible for continued participation, side effects that 
warrant discontinuation of the study drug combination, you become pregnant, or your condition changes 
and you need treatment that is not allowed while you are taking part in the study 
If you leave the study before the planned final visit, you may be asked by the study doctor to have some 
tests or procedures done so that you can leave the study safely. 
____________________________
CONTACT INFORMATION:
If you have any questions, concerns, or complaints at any time about this research, or you think the 
research has harmed you, please contact the office of the research team and/or the Principal 
Investigator (PI), John Mascarenhas, MD at phone number (212) 241-6756. 
If you experience an emergency during your participation in this research, contact the PI and call 911 
or go to the emergency room.  
If you have any questions about your rights as a research subject or complaints regarding this research 
study, or you are unable to reach the research staff, you may contact a person independent of the 
research team at the Biomedical Research Alliance of New York Institutional Review Board at 516-318-
6877. Questions, concerns or complaints about research can also be registered with the Biomedical 
Research Alliance of New York Institutional Review Board at www.branyirb.com/concerns-about-
research.
___________________________
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION:
To the extent allowed by law, every effort will be made to keep your personal information confidential.
However, information from this study will be submitted to the study sponsor and to the U.S. Food and 
Drug Administration. It may be submitted to governmental agencies in other countries where the study
product may be considered for approval. Medical records, which identify you and the consent form 
signed by you, will be looked at by the sponsor or the sponsor’s representatives and may be looked at
by the FDA and other regulatory agencies, the Institutional Review Board, and the Biomedical Research
Alliance of New York. While these parties are aware of the need to keep your information confidential, 
 
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total confidentiality cannot be guaranteed. The results of this research project may be presented at 
meetings or in publications; however, you will not be identified in these presentations and/ or 
publications.
AUTHORIZATION TO USE AND DISCLOSE PERSONAL HEALTH INFORMATION
Federal regulations give you certain rights related to your health information. These include the right to 
know who will be able to get the information and why they may be able to get it. The study doctor must 
get your authorization (permission) to use or give out any health information that might identify you. If 
you choose to be in this study, the study doctor will get personal information about you. This may include 
information that might identify you. The study doctor may also get information about your health, 
including:
•
Past and present medical records
•
Research records
•
Records about phone calls made as part of this research
•
Records about your study visits
•
Information obtained during this research about laboratory test results
•
Results from diagnostic and medical procedures including but not limited to X-rays, physical
•
examinations and medical history
•
Billing records
Information about your health may be used and given to others by the study doctor and staff. They 
might see the research information during and after the study. Your information may be given to the 
sponsor of this research. “Sponsor” includes any persons or companies that are working for or with the 
sponsor or are owned by the sponsor. Information about you and your health which might identify you 
may be given to:
•
The U.S. Food and Drug Administration
•
Department of Health and Human Services agencies
•
Governmental agencies in other countries
•
Biomedical Research Alliance of New York (BRANY)
•
The Institutional Review Board
•
Accrediting agencies
•
Data safety monitoring boards
•
Health insurers and payers
•
MPN Research Consortium members for monitoring and analysis
Your personal health information may be further shared by the groups above. If shared by them, the 
information will no longer be covered by the U.S. federal privacy laws. However, these groups are 
committed to keeping your personal health information confidential. If you give permission to give your
identifiable health information to a person or business, the information may no longer be protected. 
There is a risk that your information will be released to others without your permission.
Information about you and your health that might identify you may be given to others to carry out the 
research study. The sponsor will analyze and evaluate the results of the study. In addition, people from 
the sponsor and its consultants will be visiting the research site. They will follow how the study is done, 
and they will be reviewing your information for this purpose. The information may be given to the FDA. 
It may also be given to governmental agencies in other countries. This is done so the sponsor can 
 
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receive marketing approval for new products resulting from this research. The information may also be 
used to meet the reporting requirements of governmental agencies.
In almost all disclosures outside of Mount Sinai, you will not be identified by name, social security 
number, address, telephone number, or any other direct personal identifier. Some records and 
information disclosed may be identified with a unique code number. The Principal Investigator will 
ensure that the key to the code will be kept in a locked file or will be securely stored electronically. The 
code will not be used to link the information back to you without your permission, unless the Institutional 
Review Board allows it after determining that there would be minimal risk to your privacy. The Certificate 
of Confidentiality obtained from the Department of Health and Human Services will not be used to 
prevent disclosure to local authorities of child abuse and neglect, or harm to self or others. It is possible 
that a sponsor or their representatives, a data coordinating office, or a contract research organization, 
will come to inspect your records. Even if those records are identifiable when inspected, the information 
leaving the institution will be stripped of direct identifiers.  Additionally, the Office of Human Subjects 
Protection (OHRP) of the Department of Health and Human Services as well as the Food and Drug 
Administration (FDA) will be granted direct access to your medical records for verification of the 
research procedures and data. They are authorized to remove information with identifiers if necessary 
to complete their task. By signing this document, you are authorizing this access. We may publish the 
results of this research. However, we will keep your name and other identifying information confidential.
This authorization does not have an expiration date. If you do not withdraw this authorization in writing, 
it will remain in effect indefinitely.
By signing this consent form, you are giving permission to use and give out the health information listed 
above for the purposes described above. You do not have to sign this consent form. If you choose not 
to sign this consent form, you will not be able to be in this research study. Your decision not to sign this 
consent form will not have any effect on your medical care and you will not lose any benefits or legal 
rights to which you are entitled. You have the right to review and copy your health information. However, 
if you decide to be in this study and sign this permission form, you may not be allowed to look at or copy 
your information until after the research is completed.
You may withdraw or take away your permission to use and disclose your health information at any 
time. You do this by sending written notice to the study doctor at the address on the front of this informed 
consent form. If you withdraw your permission, you will not be able to continue being in this study, but 
you will not have any penalty or loss of access to treatment or other benefits to which you are entitled. 
When you withdraw your permission, no new health information which might identify you will be 
gathered after that date. Information that has already been gathered may still be used and given to 
others. This would be done if it were necessary for the research to be reliable.
If you have not already received it, you will also be given The Hospital’s Notice of Privacy Practices that 
contains more information about how The Hospital uses and discloses your protected health 
information.
It is important for you to understand that once information is disclosed to others outside Mount Sinai, 
the information may be re-disclosed and will no longer be covered by the federal privacy protection 
regulations. However, even if your information will no longer be protected by federal regulations, where 
possible, Mount Sinai has entered into agreements with those who will receive your information to 
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If as part of this research project your medical records are being reviewed, or a medical history is being 
taken, it is possible that HIV-related information may be revealed to the researchers.  If that is the case, 
the following information concerns you.  If this research does not involve any review of medical records 
or questions about your medical history or conditions, then the following section may be ignored.  
_________________________________________________________________________________
Notice Concerning HIV-Related Information
HIV-related information that either is collected as part of the research or that may already exist in your 
medical record might be accessed for the research by the research staff and the study sponsor, but will 
not be shared with others without your authorization, unless federal or state law requires the disclosure. 
You have a right to request a list of people who may receive or use your HIV-related information without 
authorization. If you experience discrimination because of the release or disclosure of HIV-related 
information, you may contact the New York State Division of Human Rights or New York City 
Commission on Human Rights. These agencies are responsible for protecting your rights.
_____________________________________________________________________________________
Collection of Identifiable Private Information or Identifiable Biospecimens 
Identifiers might be removed from your identifiable private information or identifiable biospecimens. After 
such removal, the information or biospecimens could be used for future research studies or distributed 
to another investigator for future research studies without your additional informed consent (or consent 
from your legally authorized representative).
Certificate of Confidentiality: 
To further protect your privacy, the researchers have obtained a Certificate of Confidentiality from the 
Department of Health and Human Services. This is intended to ensure that your identity as a participant 
in this research study will not have to be disclosed as a result from a subpoena, for the purpose of 
identifying you in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings other than to the FDA or OHRP as identified above.
The research staff will not share any of your research information or biospecimens with anyone who is 
not a member of the research team, including any family members or friends, other than to those 
identified above. However, you should know that if we learn that you or someone else is threatened 
with serious harm, such as a child or an elderly person being abused, the investigators may notify the 
appropriate authorities if necessary to protect you or others.  A Certificate of Confidentiality does not 
prevent you or a member of your family from voluntarily releasing information about yourself or your 
involvement in this research. This means that you and your family must also actively protect your own 
privacy. If an insurer or employer learns about your research participation, and you agree that they can 
have your research information, then the researchers may not use the Certificate of Confidentiality to 
keep this information from them.
ADULT PARTICIPANT:
Your signature below documents your permission to take part in this research and to the use and 
disclosure of your protected health information. A signed and dated copy will be given to you.
 
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_________________________
_________________________
__________
__________
Signature of subject
Printed Name of Subject
Date
Time
PERSON EXPLAINING STUDY AND OBTAINING CONSENT:
_________________________
_________________________
__________
__________
Signature of consent delegate
Printed Name of consent delegate
Date
Time
WITNESS SECTION:
When a witness is required to observe the consent process, it should be documented below (for 
example, when subject is illiterate, visually impaired, or this document accompanies a short form 
consent).
My signature below documents that the information in the consent document and any other written 
information was accurately explained to, and apparently understood by, the subject, and that consent 
was freely given by the subject.
_________________________
_________________________
__________
__________
Signature of Witness
Printed Name of Witness
Date
Time
 
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