A Phase Ib/II, Single Center, Open-Label, Safety and Efficacy Study to Improve Anemia in Subjects on Enasidenib With Lower Risk Myelodysplastic Syndrome and Non-proliferative Chronic Myelomonocytic Leukemia Without an IDH2 Mutation
Phase: PHASE1
Conditions: Leukemia, Leukemia, Myeloid, Monocytic Leukemia
Sponsor: Tian Yi Zhang

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Protocol Director:  Tian Yi Zhang, MD 
 
 
23 Jul 2024 
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A Phase 1b/2, Single Center, Open-Label, Safety and Efficacy Study to 
Improve Anemia in Subjects on Enasidenib with Lower-risk 
Myelodysplastic Syndrome and Non-proliferative Chronic 
Myelomonocytic Leukemia without an IDH2 Mutation  
IRB-62692 
HEM0056 
NCT05282459 
IND-158157 
Version:  23 Jul 2024 
Initial SRC Approval Date:  17 September 2021 (for version 08 September 2021)  
Single-Center 
Stanford Cancer Institute 
875 Blake Wilbur Dr 
Stanford Medicine at Stanford University 
Stanford, CA  94305  
Stanford Medicine IND-holder, Principal Investigator, and Protocol Director 
Tian Yi Zhang, MD 
269 Campus Drive;  CCSR Bldg, Rm 1155  
Stanford Medicine at Stanford University MC 5156 
Stanford, CA, 94305 
Phone:  650-726-1484  /  Fax:  650-724-5203 
e-mail:  tzhang8@stanford.edu   

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Biostatistician 
Ying Lu 
Street address:  
Medical School Office Building (MSOB) 1265 Welch Road, X359 
Stanford University School of Medicine 
Stanford, California 94305-5464 
Phone: (650) 736-8300 (Office)   
e-mail: ylu1@stanford.edu   
 
 
 
Regulatory Information  
 
 
Study Agent:  
Enasidenib mesylate (Idhifa, AG-221)  
Manufacturer: 
Celgene Corporation 
IRB of Record:  
Administrative Panels on Human Subjects in Medical Research (“Stanford IRB”)  
IND Sponsor:  
Tian Yi Zhang, MD 
IND 
158157 
IND Cross-reference:  
IND-117631 
Funding Source:  
Celgene Corporation 

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STATEMENT OF COMPLIANCE  
SPONSOR-INVESTIGATOR STATEMENT 
I have read and agree to the study, as detailed by this protocol document.  I am aware 
of my responsibilities as an Investigator pursuant to the clinical trial protocol,  
the guidelines of Good Clinical Practice (GCP) 1, the Declaration of Helsinki 2, and the 
applicable Code of Federal Regulations (CFR) at Title 21 3 and Title 45§46 4, as well as 
my responsibilities as a Sponsor-Investigator and IND-holder under 21 CFR §312 or 
§812 3, as a ClinicalTrials.gov Responsible Party under 42 CFR§11 5 as promulgated 
pursuant to Section 801 of the Food and Drug Administration Amendments Act 
(FDAAA 801), and other applicable requirements of the participating institutions 
including the Stanford Cancer Institute, the Stanford Hospitals and Clinics, and/or the 
Stanford University Medical Center.  I agree to conduct the trial according to these 
regulations, guidelines, and requirements, and to appropriately direct and assist the 
participating staff under my authority, and ensure that all staff members are aware of, 
and trained in, their clinical trial responsibilities. 
All key study personnel have completed Human Subjects Protection Training.   
Site Principal Investigators are expected to assure that no deviation from, or changes to 
the protocol, will take place without prior agreement from the sponsor and documented 
approval from the Institutional Review Board (IRB) of record, except where necessary to 
eliminate an immediate hazard(s) to the trial subjects.   
Sponsor-Investigator's Name:  
Tian Yi Zhang, MD, PhD 
Name of Site:  
Stanford Cancer Institute or Stanford Hospitals and Clinics 
Stanford Medicine  
Stanford, California 
Principal Investigator's Signature: ____________________________  Date: _________ 
1  
FDA Guidance for Industry:  current revision of the International Conference on Harmonization (ICH) 
Good Clinical Practice Guidelines E6. 
2  
World Medical Association, Declaration of Helsinki   Ethical Principles for Medical Research Involving Human Patients. 
3  
United States Code of Federal Regulations (CFR), Title 21, “Food and Drugs.” 
4  
CFR, Title 45 “Public Welfare;”  Part 46 “Protection of Human Subjects.” 
5  
CFR, Title 42 “Public Health;” Part 11 “Clinical Trials Registration and Results Information Submission.”  

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Table of Contents 
PROTOCOL SYNOPSIS ............................................................................................................ 6 
PROTOCOL SCHEMA ............................................................................................................... 9 
LIST OF ABBREVIATIONS .......................................................................................................10 
1. 
INTRODUCTION ...............................................................................................................11 
1.1. 
Study Rationale ..........................................................................................................11 
1.2. 
Background.................................................................................................................11 
1.3. 
Potential Risks and Benefits .......................................................................................14 
2. 
STUDY DESIGN, OBJECTIVES, AND OUTCOMES .........................................................15 
2.1. 
Study Design ..............................................................................................................15 
2.2. 
Objectives ...................................................................................................................17 
2.3. 
ClinicalTrials.gov Registration, Outcomes, and Results ..............................................18 
3. 
SUBJECT SELECTION .....................................................................................................21 
3.1. 
Eligibility Criteria and Participant Eligibility Checklist ...................................................21 
3.2. 
Recruitment and Retention Procedures ......................................................................26 
3.3. 
Informed Consent Process ..........................................................................................26 
3.4. 
Registration and Enrollment ........................................................................................27 
4. 
STUDY INTERVENTION ...................................................................................................27 
4.1. 
Investigational Drug ....................................................................................................27 
5. 
TREATMENT PLAN ...........................................................................................................29 
5.1. 
Treatment Assignment ................................................................................................29 
5.2. 
Treatment Dose ..........................................................................................................29 
5.3. 
Treatment Schedule ....................................................................................................29 
5.4. 
Treatment Duration .....................................................................................................29 
5.5. 
Subject Medication Diary ............................................................................................30 
5.6. 
Dose Modifications and Dose-limiting Toxicities ..........................................................30 
5.7. 
Concomitant Medications, Procedures, and Supportive Care Guidelines ....................34 
5.8. 
Criteria for Removing Subjects from Study Intervention and/or Study .........................35 
5.9. 
Duration of Follow-Up .................................................................................................35 
5.10. 
Study Completion or Discontinuation .......................................................................36 
6. 
STUDY PROCEDURES AND ASSESSMENTS .................................................................37 
6.1. 
Study Procedures Table..............................................................................................37 

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6.2. 
Description of Procedures and Assessments ..............................................................39 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES ..................................................41 
7.1. 
Adverse Event Definitions ...........................................................................................41 
7.2. 
Classification of Adverse Events .................................................................................42 
7.3. 
Potential Adverse Events and Risks ...........................................................................46 
7.4. 
Adverse Event Monitoring and Collection ....................................................................46 
7.5. 
Adverse Events of Special Consideration ...................................................................47 
7.6. 
Adverse Event Reporting ............................................................................................48 
7.7. 
Adverse Event Records ..............................................................................................52 
8. 
CORRELATIVE / SPECIAL STUDIES ...............................................................................52 
8.1. 
Correlative Studies Background ..................................................................................52 
8.2. 
Laboratory Correlative StudiesCollection of Specimen(s) ............................................52 
9. 
REGULATORY CONSIDERATIONS AND DATA REPORTING .........................................53 
9.1. 
Institutional Review Board Approval of Protocol ..........................................................53 
9.2. 
Protocol Compliance and Deviations...........................................................................53 
9.3. 
Data and Safety Monitoring Plan .................................................................................54 
9.4. 
Data Management ......................................................................................................54 
9.5. 
Site Documentation and Management ........................................................................55 
9.6. 
FDA Oversight ............................................................................................................55 
10. 
STATISTICAL CONSIDERATIONS ................................................................................56 
10.1. 
Statistical Plan .........................................................................................................56 
10.2. 
Study Endpoints ......................................................................................................57 
10.3. 
Interim Analyses ......................................................................................................59 
10.4. 
Primary Analysis ......................................................................................................59 
10.5. 
Secondary Analysis .................................................................................................60 
10.6. 
Descriptive Statistics and Exploratory Data Analysis ...............................................61 
11. 
REFERENCES ...............................................................................................................63 
12. 
PROTOCOL HISTORY ..................................................................................................64 
13. 
APPENDICES ................................................................................................................68 
13.1. 
Appendix A.  References for Stanford Cancer Institute Policies & Practices ............68 
13.2. 
Appendix B.  Reference reports submitted for DSMC audit .....................................70 
 

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PROTOCOL SYNOPSIS  
Study Title 
A Phase 1b/2, Single Center, Open-Label Study to Evaluate Safety and Efficacy 
of Enasidenib to Improve Anemia in Subjects with Lower-risk Myelodysplastic 
Syndrome and Non-Proliferative Chronic Myelomonocytic Leukemia without a 
Mutation in IDH2  
Study Drug 
Enasidenib 
Study Description 
An early phase, investigator-sponsored clinical trial to determine if enasidenib is 
safe and effective in improving anemia and decreasing transfusion needs in 
subjects diagnosed with lower-risk myelodysplastic syndrome (MDS) or 
nonproliferative chronic myelomonocytic leukemia (CMML) without a mutation in 
isocitrate dehydrogenase type 2 (IDH2 wildtype).  Other objectives include 
assessment of improvements in platelet production and characterization of the 
mechanism of action of enasidenib in enhancing endogenous erythropoiesis. 
Study Phase 
Phase 1b/2  
Study Purpose 
Indication 
Treatment 
Low and intermediate risk MDS (including very low risk, low risk and intermediate 
risk MDS, defined by IPSS-R score ≤ 4.5) 
Nonproliferative CMML  
Primary 
Objective(s) 
To determine the efficacy (response rate) of enasidenib in improving anemia and 
decreasing RBC transfusion dependence. 
Primary 
Endpoint(s) 
Proportion of subjects achieving modified IWG 2018-defined hematological 
improvement-erythroid (HI-E). 
Secondary 
Objective(s) 
To determine the tolerability, safety and durability of the erythroid response and 
identify laboratory parameters as clinical markers of response. 
Secondary 
Endpoint(s) 
1. To determine the safety of enasidenib in subjects without IDH2 mutations 
using the type, incidence, severity of adverse events in accordance with the 
CTCAE v5.0.   
2. To determine the time to HI-E, defined as time from first dose of enasidenib 
to the first observed hemoglobin change meeting 2018 IWG HI-E criteria. 
3. To determine the duration of HI-E, defined as time from each recorded 
response of increase in hemoglobin meeting 2018 IWG HI-E criteria 
(Section 10.2.1.2) to loss of response.   
4. To determine the proportion of subjects who achieve a response defined by 
the modified 2018 IWG criteria for improvement of platelet count (HI-P).   

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Secondary 
Endpoint(s) 
(continued) 
5. To determine the proportion of subjects who achieve a response defined by 
the modified 2018 IWG criteria in improvement of neutrophils (HI-N).   
6. To determine the proportion of study subjects who are transfusion dependent 
achieving RBC transfusion independence (RBC-TI) for 8 weeks or longer. 
Sample Size 
42 to 48 
Eligibility Criteria 
1. 18 year or older. 
2. With the pathological diagnosis of lower-risk MDS or nonproliferative CMML. 
3. With diagnosis of anemia defined by the modified 2018 IWG criteria. 
4. Performance status of ECOG 0 to 2.   
Dose 
The phase 1b portion of the trial will have a starting dose of 100 mg daily and the 
recommended phase 2 dose (R2PD) will be determined (100 to 200 mg daily) for 
the phase 2 portion of the study.  “Cohort A” will be those subjects receiving 
100 mg enasidenib, and “Cohort B” will be those receiving 200 mg enasidenib.  
Within the Phase 2 part of the study, subjects will be stratified as Cohort 1 for 
subjects with lower-risk MDS and Cohort 2 for subjects with non-proliferative 
CMML.  For purposes of analysis and reporting, Phase 1b subjects with lower-risk 
MDS and nonproliferative CMML may be included within Cohorts 1 and 2, 
respectively.  
Treatment and 
Procedural 
Summary 
Each study subject will self-administer the enasidenib orally every day.  
Peripheral blood draws and bone marrow (BM) biopsies will be conducted 
according to timeline to assess for treatment response.   
Statistical 
Considerations 
Simon's two-stage design will be used for each of the disease cohorts of the 
study (MDS, CMML).  The null hypothesis that the true response rate is 
0.1 [Po = 0.1] will be tested against a one-sided alternative.  In the first stage, 
16 [n1] subjects will be accrued.  If there are 1 [r1] or fewer responses in these 
16 subjects, the study will be stopped.  Otherwise, 5 additional subjects will be 
accrued for a total of 21 [n].  The null hypothesis will be rejected if 5 [R2+1] or 
more responses are observed in 21 subjects.  This design yields a type I error 
rate of 0.0735 and power of 0.8 when the true response rate is 0.30. 
Study Duration 
This study is expected to take approximately 24 months to complete enrollment, 
with an additional 2to 6 months for follow up for the last subject enrolled onto the 
study.  Anticipate data analysis to completed in 3 months after study is 
completed. 

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Subject Duration 
If a study subject has not met criteria as a responder within the first 6 months of 
treatment, the subject will be considered a nonresponder and exit the study. 
If the study subject is believed to be deriving clinical benefit on enasidenib by the 
end of 12 months on study protocol by the PI, the subject may continue treatment 
after discussion with the study sponsor. 

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PROTOCOL SCHEMA 
 

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LIST OF ABBREVIATIONS  
AE 
Adverse event 
IRB 
Institutional Review Board 
AML 
Acute myeloid leukemia 
LTB 
Low transfusion burden 
ALT 
Alanine aminotransferase 
MDS 
Myelodysplastic syndrome 
AST 
Aspartate aminotransferase 
MCV 
Mean corpuscular volume 
BM 
Bone marrow 
NCI 
National Cancer Institute 
BRCP 
Breast cancer resistance protein 
NGS 
Next Generation Sequencing 
CBC 
Complete blood count 
NTD 
Nontransfused 
CD 
Cluster of differentiation 
OnCore 
OnCore Enterprise Research System  
CFR 
Code of Federal Regulations 
OS 
Overall survival  
CMML 
Chronic Myelomonocytic Leukemia  
OAT 
Organic anion transporter 
CR 
Complete response 
OATP 
organic anion transporter peptide 
CRF 
Case report / record form 
OCT 
organic cation transporter 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
PD 
Progressive disease 
CYP 
Cytochrome P450 
PCR 
Polymerase chain reaction 
DLT 
Dose-limiting toxicity 
PLT 
Platelet 
DSMB 
Data Safety Monitoring Board 
REDCap 
Research Electronic Data Capture 
DSMC 
Data Safety Monitoring Committee 
RBC 
Red blood cells 
ECOG 
Eastern Cooperative Oncology Group  
RDW 
Red cell distribution and width 
FDA 
Food and Drug Administration 
RR 
Response rate 
GCP 
Good Clinical Practice 
R/R 
Relapsed/Refractory 
HCT 
Hematopoietic cell transplant 
SAE 
Serious adverse event 
Hgb 
Hemoglobin 
SIN 
Subject identification number 
HI-E 
Hematological improvement - erythroid 
SRC 
Scientific Review Committee  
HI-N 
Hematological improvement - neutrophil 
Stanford 
IRB 
Administrative Panels on Human Subjects 
in Medical Research  
HI-P 
Hematological improvement - platelet 
TGF 
transforming growth factor  
HIV 
Human immunodeficiency virus 
TI 
Transfusion independence 
HTB 
High transfusion burden 
TTR 
Time to response 
HMA 
Hypomethylating agent 
UDP 
uridine diphosphate 
HSPC 
hematopoietic stem and progenitor cell 
UGT 
glucuronosyltransferase 
ICH 
Int’l Conference on Harmonization 
ULN 
Upper Limit of Normal 
ICMJE 
Int’l Committee of Medical Journal Editors  
WBC 
White blood cell 

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1. 
INTRODUCTION  
1.1. 
Study Rationale  
Both malignant and non-malignant causes of anemia are associated with substantial morbidity, 
high medical costs, and significant limitations in quality of life1.  Chronic transfusion dependence 
is especially prevalent in patients with hematologic malignancies2.  In addition to 
disease-directed treatments, a large percentage of patients will require supportive red blood cell 
(RBC) transfusions.  Chronic transfusion dependence frequently results in secondary 
morbidities such as iron overload and transfusion-related reactions.  Transfusion support may 
also be limited by lack of donor availability, especially in alloimmunized patients, and for patients 
with rare blood types1,2.  Therefore, strategies that enhance endogenous erythropoiesis are 
urgently needed to decrease transfusion rates and improve quality of life in an already 
vulnerable population. 
In the phase 1-2 clinical trial of enasidenib conducted in subjects with relapsed/refractory 
IDH2-mutated AML, the majority of subjects showed a decrease in their transfusion 
requirements or even became transfusion-independent with respect to red blood cells (RBC) 
and platelets3.  Most strikingly, this phenomenon occurred in subjects with stable disease and 
appeared to be independent of IDH2 mutation burden or serum 2-hydroxyglutarate (HG) levels.  
A similar result was subsequently reported for older subjects with newly-diagnosed 
IDH2-mutated AML in the subgroup analysis for the same clinical trial4.  A BM biopsy from an 
enasidenib-treated subject has also demonstrated erythroid hyperplasia and increased erythroid 
differentiation5.   
These important clinical observations prompted us to examine whether enasidenib can drive 
erythroid differentiation independent of IDH2 mutation status. 
1.2. 
Background 
1.2.1. Overview of study intervention 
This study will determine the safety, tolerability, and efficacy of enasidenib in improving anemia 
and decreasing transfusion needs in subjects with lower-risk MDS and non-proliferative CMML 
who are not on any other disease-directed therapy.  After conducting baseline laboratory 
studies, subjects will begin self-administration of enasidenib everyday continuously through 
each 28-day cycle.  Laboratory studies and bone marrow (BM) biopsies will be repeated at the 
indicated time points (see study schema) to assess response.   
1.2.2. Mechanism(s) of Action for enasidenib  
Enasidenib (Idhfa) is a first-in-class, selective, potent inhibitor of the neomorphic activity of IDH2 
mutant enzyme which is expressed in AML and other myeloid malignancies6.  Mutant IDH2 
enzyme activity produces the oncometabolite, 2-HG.  Pharmacology studies support 
enasidenib-mediated suppression of 2-HG, reduced abnormal histone hypermethylation, and 
restored myeloid differentiation6–8.   
In more recent studies, enasidenib robustly increased erythropoiesis of both wildtype cord blood 
and BM-derived stem and progenitor cells (HSPC) in a concentration-dependent manner.  This 
activity was independent of IDH2 mutant activity and involved increased globin chain synthesis9. 

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1.2.3. Non-clinical Background  
Enasidenib robustly increased erythropoiesis of both wildtype cord blood and BM-derived 
HSPCs in a concentration-dependent manner9.  The erythropoietic activity was specific to 
enasidenib and occurred independently of mutant and wildtype IDH2, as well as the 
oncometabolite D-2-hydroxyglutarate (D-2HG).  Effects of enasidenib on human HSPCs was 
mediated by protoporphyrin accumulation, driving heme production and erythroid differentiation 
in committed CD71+ HSPCs.   
1.2.3.1. 
Non-clinical and Clinical Pharmacokinetics  
Preliminary analysis of pharmacokinetics (PK) data (as of 15 April 2016) from subjects with 
advanced hematologic malignancies in Study AG221-C-001 up to the 650 mg QD dose level 
demonstrated high plasma exposures, a long mean plasma half-life of enasidenib in humans 
(137 hours; data on file:  clinical PK/phamacodynamics study report of enasidenib-MPK-001), 
high drug accumulation after multiple doses, and relatively high PK variability in subjects 
(coefficient of variation [CV]% = ~40%).  The median time to maximum plasma concentration 
(Tmax) ranged from approximately 1 to 48 hours when administered as a single dose on 
Day -3.  Metabolite AGI-16903 mean plasma exposure is less than 10% of parent enasidenib 
mean plasma exposure.  Preliminary analysis of pharmacodynamics data demonstrated that a 
daily dose of 100 mg QD suppressed 2-HG levels at Cycle 2 Day 1 in subjects with the IDH2 
R140 mutation (n = 66, median 92.8% inhibition [range 45.3% to 99.4%]) and in subjects with 
IDH2 R172 mutation (n = 22, median 27.6% inhibition [range -233.7% to 93.8%]), showing on 
target activity in subjects. 
1.2.3.1.1. 
Major Route of Elimination  
Enasidenib is metabolized by multiple cytochromes (CYPs) and uridine diphosphate 
(UDP)-glucuronosyltransferases (UGTs).  Enasidenib is a direct inhibitor for CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, as well as UDP-glucuronosyltransferase 
(UGT) 1A1.  The N-dealkylated metabolite, AGI-16903 is also an inhibitor of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19 and CYP2D6.  Enasidenib is an inducer of CYP2B6 and 
CYP3A4.  Preliminary results indicate that enasidenib increased 4β-hydroxycholesterol levels 
in subjects, indicating CYP3A induction.  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, organic anion transporting polypeptide 
(OATP) 1B1, 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. 
1.2.3.2. 
Non-Clinical Pharmacology and Toxicology Studies  
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; a 
battery of genetic toxicity assays including bacterial reverse mutation (Ames) and mammalian 
chromosomal aberration assays; in vitro and in vivo rat bone marrow micronucleus assay; 
embryo-fetal development toxicity studies in rats and rabbits; and in vitro phototoxicity assay 
using BALB/c-3T3 mouse fibroblasts in the presence of ultraviolet radiation.  Dose-limiting 
toxicities in rats after 28 days of dosing were multifactorial and included gastrointestinal tract 

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atrophy and erosions, lymphoid atrophy, degeneration, and necrosis, BM 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), BM (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.  Enasidenib was neither mutagenic nor clastogenic.  
Also, no phototoxicity potential of enasidenib was observed.  Enasidenib treatment was 
associated with abortion in rats and rabbits.  In rats, but not in rabbits, enasidenib treatment was 
associated with delayed fetal development (decreased fetal weight and skeletal ossification).  
Although no dedicated nonclinical study was conducted to assess enasidenib effects on fertility 
parameters, histopathologic changes in testes, epididymides, and ovaries in rats after repeated 
enasidenib dosing were suggestive of potential test article-related effects on male and female 
fertility. 
1.2.4. Clinical Experience  
Clinical assessment of enasidenib is largely based on Study AG221-C-001, an ongoing, 
single-arm, phase 1-2 study that evaluates the safety and efficacy of enasidenib in subjects 
with advanced hematologic malignancies with an IDH2 mutation7. 
The enasidenib study AG221-C-001 was completed with 345 subjects with an IDH2 mutation 
(who received at least 1 dose of the study drug), including 281 subjects with relapsed or 
refractory (R/R) AML, 214 of whom received enasidenib treatment with a total daily dose of 
100 mg, 38 subjects with previously untreated AML, and 17 subjects with myelodysplastic 
syndromes (MDS).  The mean duration of exposure was 7.1 months in the overall population. 
As of 01 Jul 2017, a total of 344 (99.7%) subjects experienced at least 1 treatment emergent 
adverse event (TEAE), and for 284 (82.3%) of these subjects, at least 1 TEAE was suspected 
by the investigator to be related to enasidenib.  Overall, 306 (88.7%) subjects had a TEAE that 
was Grade 3 or 4 in severity, 148 (42.9%) subjects had a treatment-related TEAE that was 
Grade 3 or 4 in severity, 276 (80.0%) subjects had a treatment emergent serious adverse event 
(TESAE), and 65 (18.8%) subjects had a TEAE leading to discontinuation.  No meaningful 
differences in nature, incidence, or severity of the adverse events (AEs) have been observed 
between subjects with relapsed or refractory AML, previously-untreated AML, or MDS. 
1.2.5. Importance of the Clinical Trial  
Determination of enasidenib to be an effective pro-erythroipoietic agent could greatly improve 
an unmet need in multiple myeloid malignancies such as MDS and CMML.  In addition, it may 

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open up new avenues of research in a new class of small molecules capable of increasing 
heme synthesis.   
1.3. 
Potential Risks and Benefits 
1.3.1. Known Potential Risks of Study Drug Enasidenib 
As of 1 July 2017, a total of 344 (99.7%) subjects experienced at least 1 treatment emergent 
adverse event (TEAE), and for 284 (82.3%) of these subjects, at least 1 TEAE was suspected 
by the investigator to be related to enasidenib.  Overall, 306 (88.7%) subjects had a TEAE that 
was Grade 3 or 4 in severity, 148 (42.9%) subjects had a treatment-related TEAE that was 
Grade 3 or 4 in severity, 276 (80.0%) subjects had a treatment emergent serious adverse event 
(TESAE), and 65 (18.8%) subjects had a TEAE leading to discontinuation.  No meaningful 
differences in nature, incidence, or severity of the adverse events (AEs) have been observed 
between subjects with relapsed or refractory AML, previously-untreated AML, or MDS. 
The following AEs were determined to be adverse drug reactions to enasidenib: gastrointestinal 
(GI) events (nausea (49.8%), diarrhea (43.1%), and vomiting (34.9%) and associated 
decreased appetite (33.5%) and dysgeusia, increased blood bilirubin (32.7%), differentiation 
syndrome, leukocytosis (23.1%), and tumor lysis syndrome (3.8%). 
Other commonly- reported TEAEs were disorders characteristic for subjects with 
hematologic malignancies:  blood and lymphatic system disorders, including 
anemia (31.6%) and febrile neutropenia (30.7%); respiratory disorders, including 
dyspnea (32.2%) and cough (30.7%); infections, including pneumonia (21.7%); as well as 
general disorders, including fatigue (42.6%), peripheral edema (29.0%), and 
pyrexia (29.0%), and metabolic disorders, including hypokalemia (27.0%). 
Thrombocytopenia, neutropenia, anemia, febrile neutropenia, and infections are commonly 
reported in subjects with AML and other hematologic malignancies, as could be expected in 
this population.  Data available to date do not suggest a myelosuppressive effect associated 
with enasidenib treatment.  Nonclinical data do not indicate myelosuppression with enasidenib, 
and laboratory data show that treatment with enasidenib did not lead to reduction in the blood 
cell counts. 
1.3.2. Known Potential Risks of Study Procedures  
Procedures associated with the study include phlebotomy and BM biopsy.  Known risks related 
to phlebotomy and BM biopsy are the same and include:  pain, redness, bleeding and infection 
of the procedure site.   
1.3.3. Known Potential Benefits of Enasidenib 
 
Reduced the level of the oncometabolite serum 2-HG levels in subjects with 
IDH2-mutant AML.   
 
In IDH2-mutated AML, elicited an overall response rate of 30.8%.   
 
Decreased transfusion requirements of AML subjects and smaller number of 
MDS subjects harboring an IDH2 mutation, including approximately 40% who became 
transfusion independent.   

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 
Decreased platelet transfusion requirements of AML and MDS subjects harboring an 
IDH2 mutation. 
2. 
STUDY DESIGN, OBJECTIVES, AND OUTCOMES  
2.1. 
Study Design  
2.1.1. Overall Design 
This is a phase 1b/2, open-label, single arm study to evaluate enasidenib, as a safe and 
effective therapy to improve anemia in subjects with lower-risk MDS and nonproliferative CMML.   
2.1.2. Primary Purpose of the Study  
Treatment:  to determine if enasidenib is an effective therapy to improve anemia in 
subjects with lower-risk MDS and nonproliferative CMML.   
Basic Science:  to characterize the mechanism of action of enasidenib and evaluate 
biochemical or clinical biomarkers which predict response.   
2.1.3. Study Cohorts  
 
This study includes a single arm for both the phase 1b and phase 2 portion.  The 
phase 2 portion will include 2 disease specific cohorts receiving identical treatment. 
 
The phase 1b portion will determine the tolerability and safety of enasidenib using an 
abbreviated 3 x 3 dose escalation schema at 2 dose levels (100 and 200 mg daily).  
Lower-risk MDS and nonproliferative CMML subjects will be screened and appropriate 
subjects enrolled consecutively at during phase 1b.  
 
Dose Level 1 will be 100 mg daily, and may be identified as Cohort A (may include 
patients from Cohorts 1 and 2).  
o If no dose-limiting toxicity (DLT) is observed in the first 3 Dose Level 1 subjects, the 
dose will escalate to 200 mg daily (Dose Level 2).   
o If 1 DLT is observed in the first 3 subjects at Dose Level 1, 3 more subjects will be 
enrolled.  If no DLTs are observed in these 3 additional subjects (total of 
6 Dose Level 1 subjects), the dose will escalate to Dose Level 2 (200 mg daily).   
o If ≥ 2 DLTs are observed in up to 6 Dose Level 1 subjects, the recommended 
phase 2 dose (RP2D) for the phase 2 portion of the study will be Dose Level 1 
(100 mg daily, the dose described in the current FDA-approved package insert).  
 
Dose Level 2 will be 200 mg daily, and may be identified as Cohort B (may include 
patients from Cohorts 1 and 2).  
o For Dose Level 2, if no DLT is observed in the first 3 subjects, 200 mg daily will be 
the RP2D.  
o If 1 DLT is observed in the first 3 subjects, 3 more subjects will be enrolled at 
Dose Level 2.  If no DLT is observed in these 3 additional subjects (total of 
6 Dose Level 2 subjects), Dose Level 2 will be the RP2D.  

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o If ≥ 2 DLT is observed these 3 additional subjects, Dose Level 1 will be the RP2D.  
All evaluable subjects (Dose Levels 1 and 2) in the phase 1b portion will be be 
included in the phase 2 analysis.   
 
The phase 2 portion of the study will include 2 disease cohorts receiving identical 
treatment.  Cohort 1 will enroll subjects with lower-risk MDS and Cohort 2 will enroll 
subjects with nonproliferative CMML.  Both cohorts will receive 100 mg QD dose during 
Cycle 1 which will be escalated to the established RP2D dose of enasidenib each cycle 
of treatment. Each cycle is  28 days in duration. 
 
The response criteria are specified below (Section 2.1.8).  If a study subject has not met 
criteria as a responder within the first 6 months of treatment, the subject will be 
considered a nonresponder and exit the study. 
 
If the study subject is believed to be deriving clinical benefit on enasidenib by the end of 
12 months on study protocol by the PI, the subject may continue treatment after 
discussion with the study sponsor.   
2.1.4. Scientific Justification for Study Design 
 
Enasidenib is a FDA-approved therapy for treatment of relapse and refractory AML with 
published real-world safety and tolerability data.  This study aims to repurpose its use for 
subjects with myeloid malignancies without IDH2 mutations, and the phase 1b portion of 
the study is aimed to demonstrate safety and tolerability of enasidenib in IDH2 wildtype 
patient population.   
 
The 2 disease cohorts included on the study (lower-risk MDS and nonproliferative 
CMML) were chosen for having extreme unmet needs, with no or very limited existing 
options, to improve anemia.   
 
Thus, enasidenib’s well-tolerated toxicity profile and availability as an once daily oral 
agent makes it an ideal candidate to repurpose as an erythropoietic agent.   
2.1.5. Treatment Assignment 
This study is an open label study.  Enrollment bias will be minimized by consecutive screening 
of all subjects who fit the diagnostic criteria seen at the Stanford Cancer Institute.  Screen 
failures will have specific documentation of what constituted as screen failures by the study 
exclusion criteria. 
2.1.6. Justification for Dose(s) 
Enasidenib is a FDA-approved drug to be used at 100 mg daily for the treatment of 
AML subjects with relapsed or refractory AML with IDH2 mutations.  Daily dosing from 50 mg to 
650 mg has been demonstrated to be safe and tolerable in Study AG221-C-001 (see 
Section 1.2.3.1).  The doses chosen in this study are based on this prior experience which 
determined this dosing range to be safe and well-tolerated. For the Phase 2, subjects will 
initially receive 100 mg dose which will be escalated to the established RP2D. Please also refer 
to Section 2.1.4.  Scientific Justification for Study Design.   

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2.1.7. End of Study Definition  
A study is considered completed when subjects are no longer being examined or the last 
subject’s last study visit has occurred.  A subject is considered to have completed the study if he 
or she has completed all phases of the study including the last visit or the last scheduled 
procedure shown in the Schedule of Events at Section 6.1 and 6.2. 
2.2. 
Objectives  
2.2.1. Primary Objectives 
The primary objective for the study is to determine the efficacy (response rate) of enasidenib in 
improving anemia and decreasing RBC transfusion dependence.  Study subjects on each arm 
of the study will be divided into 3 cohorts [nontransfused (NTD), low transfusion burden (LTB) 
and high transfusion burden (HTB)] based on transfusion needs, as partially defined by the 
modified 2018 IWG recommendations10:  
 
No. of RBC Units Transfused 
Time Period (weeks) 
NTD 
0 
16 
LTB 
3 to 7 
16 
HTB 
≥ 8 
16 
or ≥ 4 
8 
The proportion of study subjects in each arm of the study will be determined as the response 
rate.  The primary efficacy endpoint is to determine the proportional of study subjects will be 
achieving modified IWG 2018-defined hematological improvement-erythroid (HI-E), defined as 
follow: 
 
2018 IWG HI-E criteria 
Time Period 
(weeks) 
NTD 
≥ 2 consecutive Hb measurements ≥ 1.5 g/dL for a period of 
minimum 8 wk in an observation period of 16 to 24 wk 
compared to the lowest mean of 2 Hb measurements 
8 
LTD 
0 units of RBC transfusions 
8 
HTB 
≥ 4 unit reduction of RBC transfusions; or 
8 
≥ 50% reduction in units of RBC transfusion 
8 
2.2.2. Secondary Objectives  
• 
To determine the safety and tolerability of enasidenib in subjects without IDH2 
mutations. 
• 
To determine the duration of HI-E. 

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• 
To determine the time to HI-E. 
• 
To determine the proportion of subjects who achieve a response defined by the modified 
2018 IWG criteria in improvement of platelet count (HI-P, see Section 10.2.2.4). 
• 
To determine the proportion of subjects who achieve a response defined by the modified 
2018 IWG criteria in improvement of platelet count (HI-N, see Section 10.2.2.5). 
• 
To determine the frequency of RBC transfusions 
• 
To determine the proportion of study subjects who are transfusion dependent (LTD and 
HTB) achieving RBC transfusion independence (RBC-TI) for 8 weeks or longer 
2.3. 
ClinicalTrials.gov Registration, Outcomes, and Results  
2.3.1. Data Sharing Statement  
Pursuant to the International Committee of Medical Journal Editors (ICMJE), the following 
statement, regarding sharing of individual subject data (i.e., subject-level data) generated by 
interventional clinical trials, is provided. 
It is not planned that individual subject data, including data dictionaries, will be made 
publicly available.  Individual subject study data judged by the investigator to be 
pertinent to a subject’s understanding of their medical condition and treatment options 
will be shared with that subject.  Otherwise and as such, details of what, or when, or by 
what mechanism, data and/or documents will be shared, who would share such data, or 
for what purposes or analyses, are not available or not applicable.   
Although not individual subject data, pursuant to the requirements of 42CFR§11.48(a)(5) 
(if applicable), the final IRB-approved protocol document with statistical analysis will be made 
available in the ClinicalTrials.gov results record.   
2.3.2. Outcome Measures for ClinicalTrials.gov Results Reporting 
2.3.2.1. 
Primary Outcome (Outcome 1) 
• 
Title: Clinical Response:  Hematological Improvement - Erythroid (HI-E)  
• 
Description:  Clinical response was assessed as the number of participants achieving a 
hematological improvement - erythroid (HI-E).  Participants will be characterized and 

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stratified as nontransfused (NTD), low-transfusion burden (LTB) and high-transfusion 
burden (HTB), with response defined as follows.  
• NTD = ≥ 2 consecutive Hb measurements ≥ 1.5 g/dL for a period of minimum 8 week in 
an observation period of 16 to 24 week compared to the lowest mean of 2 Hb 
measurements 
• LTB = 0 units of RBC transfusions 
• HTB = ≥ 4 unit or ≥ 50% reduction in RBC transfusions 
The outcome will be reported as the number of participants by dose level (Cohort A or 
Cohort B) that achieve the response, a number without dispersion.  
• 
Time Frame: 16 weeks  
• 
Completion of Primary Outcome:  The study is expected to reach Primary Completion 
by 31 January 2024 (6 months after enrollment of last subject).   
2.3.2.2. 
Secondary Outcomes 
Outcome 2 
• 
Title:  Related Adverse Events 
• 
Description:  Toxicity will be assessed as the number of related non-serious adverse 
events and related serious adverse events (SAEs) reported by dose level (Cohort A or 
Cohort B) for the 12-cycle treatment period plus follow-up.  The outcome will be reported 
as numbers without dispersion. 
• 
Time Frame:  12 months.   
Outcome 3 
• 
Title:  Time to Hematological Improvement - Erythroid (HI-E)  
• 
Description:  Time to hematological improvement - erythroid (HI-E) will be assessed as 
the time from first dose of enasidenib to the first observed hemoglobin response.  
Participants will be characterized and stratified as nontransfused (NTD), low-transfusion 
burden (LTB) and high-transfusion burden (HTB), with response defined as follows.  
• NTD = ≥ 2 consecutive Hb measurements ≥ 1.5 g/dL for a period of minimum 8 weeks 
in an observation period of 16 to 24 weeks compared to the lowest mean of 2 Hb 
measurements 
• LTB = 0 units of RBC transfusions 
• HTB = ≥ 4 unit or ≥ 50% reduction in RBC transfusions 
The outcome will be reported as the number of participants by dose level (Cohort A or 
Cohort B) that achieve the response, a number without dispersion.  
• 
Time Frame:  16 weeks.   

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Outcome 4 
• 
Title:  Duration of Hematological Improvement - Erythroid (HI-E)  
• 
Description:  Duration of Hematological Improvement - Erythroid (HI-E) will be 
assessed as the time from recorded response to loss of response.  Participants will be 
characterized and stratified as nontransfused (NTD), low-transfusion burden (LTB) and 
high-transfusion burden (HTB), with response defined as follows.  
• NTD = ≥ 2 consecutive Hb measurements ≥ 1.5 g/dL for a period of minimum 8 weeks 
in an observation period of 16 to 24 weeks compared to the lowest mean of 2 Hb 
measurements 
• LTB = 0 units of RBC transfusions 
• HTB = ≥ 4 unit or ≥ 50% reduction in RBC transfusions 
The outcome will be reported as the number of participants by dose level (Cohort A or 
Cohort B) that achieve the response, a number without dispersion.  
• 
Time Frame:  16 weeks.   
Outcome 5 
• 
Title:  Clinical Response:  Hematological Improvement - Platelets (HI-P)  
• 
Description:  Clinical response for platelets was assessed as the number of participants 
achieving a hematological improvement - platelets (HI-P).  Participants will be 
characterized and stratified as platelets < or ≥ 20 x 109/L, with response defined as 
follows.  
• < 20 x 109/L = increase in platelets from < 20 x 109/L to > 20 x 109/L AND by ≥ 100% 
• ≥ 20 x 109/L = absolute increase in platelets of 30 x 109/L 
The outcome will be reported as the number of participants by dose level (Cohort A or 
Cohort B) that achieve the response, a number without dispersion.  
• 
Time Frame: 8 weeks  
Outcome 6 
• 
Title:  Clinical Response:  Hematological Improvement - Neutrophils (HI-N)  
• 
Description:  Clinical response for neutrophils was assessed as the number of 
participants achieving a hematological improvement - neutrophils (HI-N).  Response 
defined as an absolute increase in neutrophils > 0.5 x 109/L that is also an increase of 
≥ 100%.  
The outcome will be reported as the number of participants by dose level (Cohort A or 
Cohort B) that achieve the response, a number without dispersion.  
• 
Time Frame: 8 weeks  

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Outcome 7 
• 
Title:  Red Blood Cell (RBC) transfusion independence (RBC-TI)  
• 
Description:  Clinical response for red blood cells was assessed as the number of 
participants who were transfusion-dependent that achieve red blood cell (RBC) 
transfusion independence (RBC-TI) for 8 weeks or longer.  The outcome will be reported 
as the number of participants by dose level (Cohort A or Cohort B) that achieve the 
response, a number without dispersion.  
• 
Time Frame: 12 months  
3. 
SUBJECT SELECTION  
3.1. 
Eligibility Criteria and Participant Eligibility Checklist 
Inclusion and Exclusion Criteria are provided on the Eligibility Checklist which may be extracted 
from this document for use in screening potential subjects.   
The Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration (see Section 3.4 Registration / Enrollment).  The completed, signed, and dated 
checklist is retained in the subject’s record.  Screening results will be collectively documented 
on the Study Participant Log (see references in Appendix A).   

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Participant Eligibility Checklist 
I. 
Protocol Information  
Protocol Title: A Phase 1b/2, Single Center, Open-Label, Safety and Efficacy Study 
to Improve Anemia and Decrease Transfusion Dependency in 
Subjects on Enasidenib with Low-risk Myelodysplastic Syndrome and 
Non-proliferative Chronic Myelomonocytic Leukemia without an IDH2 
Mutation 
OnCore number: HEM0056 
Principal Investigator: Tian Yi Zhang, MD  
II. 
Subject Information  
Subject name / Unique ID: 
/ 
Gender  
  Male   
 Female   
III. 
Eligibility Criteria  
3.1.1. Inclusion Criteria  
Prospective Subject Must Meet 
ALL these Inclusion Criteria to be Eligible 
Yes No 
Supporting 
Documentation * 
1. Documented diagnosis of: 
1) MDS according to WHO/FAB classification that 
meets IRSS-R classification of low or 
intermediate risk disease; and a diagnosed as de 
novo or secondary MDS (MDS-RS eligible if 
refractory to or declined luspatercept therapy). 
OR  
2) Dysplastic (nonproliferative) CMML with WBC 
< 13.0/microL) 
 
 
 
2. No disease-modifying therapy (HMA, hydrea) within 
2 months of starting study 
 
 
 
3. Age ≥ 18 years of age 
 
 
 
4. ECOG ≤ 3 
 
 
 

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Prospective Subject Must Meet 
ALL these Inclusion Criteria to be Eligible 
Yes No 
Supporting 
Documentation * 
5. Negative for IDH2 mutation by NGS  
 
 
 
6. Meets AT LEAST ONE of the following hematologic 
parameters: 
a) Has symptomatic anemia defined as hemoglobin 
< 10.5 g/dL with any of the following. 
o Tachypnea 
o Shortness of breath 
o Fatigue 
o Malaise 
o Worsening of cardiovascular function 
o Asthenia 
o Dyspnea on exertion 
o Angina  
o Other subject symptoms the subject reports as 
being associated with being anemic. 
b) Thrombocytopenic with <100 K/uL platelets 
c) Absolute neutrophil count <1.50 K/uL 
 
 
 
7. Stated willingness to comply with all study 
procedures and availability for the duration of the 
study 
 
 
 
8. Ability to take oral medication and be willing to 
adhere to the medication regimen.   
 
 
 
9. Females of reproductive potential need to either 
commit to true abstinence from heterosexual contact 
or agree to use, and be able to comply with highly 
effective contraception without interruption, 28 days 
prior to starting enasidenib, during the study 
therapy, and for 30 days after last dose of 
enasidenib.   
 
 
 
10. For males of reproductive potential: agreement to 
use of condoms 
 
 
 

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Prospective Subject Must Meet 
ALL these Inclusion Criteria to be Eligible 
Yes No 
Supporting 
Documentation * 
11. Adequate organ function defined as: 
 
Hepatic function: total bilirubin ≤ 1.5 x ULN 
(unless attributable to Gilbert’s disease),  
AST or ALT ≤ 3 x ULN 
 
Renal function:  creatinine clearance 
≥ 30 mL/minute, calculated by Cockcroft-Gault 
formula 
 
 
 
12. Ability to understand and the willingness to sign the 
IRB-approved informed consent document. 
 
 
 
13. Women of childbearing potential must have negative 
urine or serum pregnancy test  
 
 
 
3.1.2. Exclusion Criteria 
Prospective Subjects Must NOT Meet  
ANY of These Exclusion Criteria  
Yes No 
Supporting 
Documentation * 
1. Less than 3 months of life expectancy 
 
 
 
2. Significant cardiac disease (NYHA Class IV 
congestive heart failure, or unstable angina or 
myocardial infarction within the last 6 months 
 
 
 
3. Harbor IDH2 somatic mutations by NGS 
 
 
  
4. Any uncontrolled bacterial, fungal, viral or other 
infection. 
 
 
 
5. No known HIV+ or active hepatitis B or C infection, 
defined as positive viral load for HBV or HCV or a 
positive surface antigen (HBsAg) test for hepatitis B. 
 
 
 
6. Have other causes of anemia:  deficiencies in iron, 
B12, folate; nutritional deficiencies related to gastric 
surgery, anorexia nervosa, excessive zinc 
supplementation; gastrointestinal bleed.  
If nutritional deficiencies can be corrected, potential 
subject can be rescreened and enrolled if 
nutritionally replete and still meets eligibility criteria.   
 
 
 

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Prospective Subjects Must NOT Meet  
ANY of These Exclusion Criteria  
Yes No 
Supporting 
Documentation * 
7. Any other medical history, including laboratory 
results, deemed by the Principal Investigator likely 
to interfere with their participation in the study, or to 
interfere with the interpretation of the results 
 
 
 
8. Pregnant or breast feeding 
 
 
 
* All subject files must include supporting documentation to confirm subject eligibility.   
V. 
Statement of Eligibility  
By signing this form of this trial I verify that this subject is: 
 
 eligible for participation in the study 
 
 ineligible for participation in the study  
Study Coordinator printed name: 
Date:  
Signature: 
 
Investigator printed name: 
Date:  
Signature: 
 
Triple-check reviewer printed name: 
Date:  
Signature: 

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3.1.3. Lifestyle Considerations 
During this study, subjects are asked to maintain a reasonably active life style with consistency 
and healthy diet.  It is recommended that subject take enasidenib at the same time every day 
but without restriction in relationship to meal times.   
3.1.4. Screen Failures 
Subjects consent to participate in the clinical trial, but who do not meet 1 or more 
Eligibility Criteria during the screening procedures are considered Screen Failures.  
Screen Failures will not be considered enrolled subjects, although they will be tracked on the 
Screening Log (with reason for ineligibility) and in the OnCore study management system.   
Screen failures, because of a reversible process (infections, change in ECOG, etc) may be 
rescreened and assigned the same sequence number and OnCore subject identifier as for the 
initial screening.   
3.2. 
Recruitment and Retention Procedures 
3.2.1. Recruitment  
Potential subjects may be identified by the following methods: 
• 
Review of the medical records of new or existing hematology subjects for potential 
subjects who meet eligibility criteria.   
• 
Internal referral by Stanford physicians.  Subject must consent to being contacted by 
study staff by referring physicians.  A study investigator and/or study coordinator will 
discuss the study with the subject during a subject visit or with a visit scheduled for the 
purpose of recruitment to the study. 
• 
Self-referral by subject after viewing study listing on ClinicalTrials.gov or the Stanford 
Clinical Trials website.   
• 
Referral by external physicians  
• 
Trial posting with ANCO (Association of Northern California Oncologists) 
• 
All male and female subjects will be offered the same options to participate in this study.  
Base on the local population of the study site, we anticipate 23 female and 22 male 
study subjects.  Based on the 2010 US Census Bureau data for the Bay Area, we 
anticipate 26 (58%) subjects of Caucasian ethnicity, 8 subjects of Hispanic ethnicity, 
3 subjects of Black ethnicity and 8 subjects of Asian ethnicity.  Community outreach to 
Eastbay community providers will help with recruitment of underserved and 
under-represented populations.   
3.3. 
Informed Consent Process  
Study   will provide written informed consent prior to the conduct of any study-specific 
procedures in accordance with institutional policies. 
 
Informed consent can be provided in the native language of the subject on request.  An 
audio or video translator can be made available if requested by subject.   

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 
Remote video consenting can be conducted if appropriate according to the local county 
guidelines for COVID19 directed social distancing.  Electronic signatures will be 
accepted.   
3.4. 
Registration and Enrollment  
3.4.1. Subject Registration Procedures 
All subjects who provide informed consent for this study will be registered in the Stanford 
OnCore Enterprise Research System database within 5 days of the date of consent, regardless 
of the outcome of any eligibility screening.  Subject identification numbers will be sequentially 
assigned for the entire study.  The information necessary to register a subject for the study is 
defined below.   
• 
A copy of the Subject Eligibility Checklist indicating that all criteria are met. 
The 3rd signature for eligibility confirmation will provided by the Stanford study team.   
To register study subjects, the study site will provide the above information to the designated 
Stanford representative(s) to obtain authorization.  The Stanford representative(s) will process 
the information and register study subjects in OnCore.   
Veronica de Santiago 
650-725-4047  
desantv1@stanford.edu   
Woo In (Yustina) Cho 
650-721-2443 
wooin@stanford.edu   
The Stanford study team, at the time of subject registration in OnCore, will provide a 
3rd signature on the Eligibility Checklist that confirms eligibility.  Once confirmed by Stanford and 
consented, the subject will be promptly registered in OnCore (within no more than 
5 business days).   
3.4.2. Subject Enrollment Procedures 
For this study, a subject is enrolled on the study when registered per Section 3.4.1; has meet 
eligibility per the screening procedures; and has been otherwise accepted into the study.   
4. 
STUDY INTERVENTION  
4.1. 
Investigational Drug  
4.1.1. Name(s) 
Enasidenib (Idhifa, AG-221) 
4.1.2. Dose and Administration 
In phase 1b portion of the study, subjects will participate dose escalation with a starting dose of 
100 mg.  Enasidenib will be self-administered orally and daily.  

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4.1.3. Regulatory Status of Enasidenib 
Enasidenib is approved for marketing in the United States as Idhifa, for the indication of 
relapsed and refractory AML harboring an IDH2 mutation.  The indication described in this study 
is considered investigational relative to the approved indications.  Regulatory authorization to 
conduct this study is pursuant to the IND submitted by Tian Yi Zhang, MD.     
Enasidenib Preparation, Handling, Storage, and Accountability 
4.1.3.1. 
Acquisition and Accountability 
Enasidenib will be delivered to and received by Stanford Investigational Drug Service (IDS) for 
storage.  Study staff will be in charge of picking up study drug to dispense to study subjects.  
Expired or return of unused products will be stored by IDS and returned to the Sponsor via 
FedEx.   
4.1.3.2. 
Formulation, Appearance, Packaging, and Labeling 
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. 
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. 
4.1.3.3. 
Storage and Stability 
Bottles of Enasidenib tablets must be stored according to the FDA package label, which include 
storage at room temperature (from 20°C to 25°C) and in the original bottle.  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.   
4.1.3.4. 
Preparation 
All tablets are packaged in sealed bottles and dispensed to subject to be self-administered as a 
whole tablet.  No special preparation is required by study staff or study subjects.  Investigational 
Agent Supply  
Enasidenib will be provided by Celgene Corporation.  Responsible contact:  
Name:  
Celgene Corporation 
Address 
86 Morris Avenue, Summit, New Jersey 07901 
Phone: 
718-938-1201  

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4.1.3.5. 
Investigational Agent Ordering 
The investigational drug will be ordered by email to responsible staff at the investigator site 
below.   
The mailing address and local contact phone number for the drug supplier contact facility is: 
Name  
Celgene Corporation 
Address 
86 Morris Avenue, Summit, New Jersey 07901 
Phone: 
718-938-1201  
The investigational agent, enasidenib, will be delivered to and managed by the Stanford 
Investigative Drug Service (IDS) (the Stanford investigational pharmacy).   
5. 
TREATMENT PLAN  
5.1. 
Treatment Assignment  
A unique study subject identifier will be assigned by the Principal Investigator for all eligible 
study subjects.  All study subjects in this single arm study, including two disease cohorts, will be 
assigned to the same treatment.   
5.2. 
Treatment Dose 
The phase 1b portion will use an abbreviated 3 x 3 dose-escalation schema.  Dose Level 1 will 
be 100 mg daily.  If no DLT is observed in the first 3 subjects, the dose will escalate to 200 mg 
daily (Dose Level 2).  If, in the first 3 subjects treated at Dose Level 1, 1 DLT is observed, 
3 more Dose Level 1 subjects will be enrolled.  If > 1 DLT is found at Dose Level 1, the 
recommended phase 2 dose (RP2D) will be 100 mg daily (Dose Level 1).  For Dose Level 2, if 
no DLTs is observed in the first 3 subjects treated at Dose Level 2, 200 mg daily will be the 
RP2D.  If 1 DLT is found, 3 more subjects will be enrolled.  If no DLTs are observed in these 
3 additional subjects, Dose Level 2 will be the RP2D.  If > 1 DLT is observed at Dose Level 2 in 
the first 6 subjects, Dose Level 1 will be the RP2D.  
In the phase 2 portion, Ph 2 cohorts will receive 100 mg in Cycle 1 followed by dose escalation 
to the established  RP2D dose of enasidenib in future cycles as tolerated. 
5.3. 
Treatment Schedule  
All study subjects will receive daily dosing the study drug.  All efforts should be made to 
administer enasidenib on all of the scheduled days of each 28-day treatment cycle.  A dose 
missed earlier in a day can be made up later that day as long as it is taken as soon as possible 
on the same day.  Any missed doses should not be taken beyond the last scheduled day of 
enasidenib administration, but should be returned by the subject for enasidenib accountability.   
5.4. 
Treatment Duration 
In subjects without disease progression or unacceptable toxicities, Enasidenib treatment is 
recommended for a minimum of 6 months to allow time for clinical responses.  If clinical benefit 
is seen, treatment continuation will be permitted at the Principal Investigator’s discretion and 
agreement from the sponsor, Celgene, to continue to provide the investigational agent.   

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5.5. 
Subject Medication Diary 
Enasidenib is being self-administered.  Each study subject will be given a medication diary to 
record parameters of daily administration of the investigational agent, including time taken and 
side effects.  This medication diary will be reviewed at each clinic visit (see Section 6.1 Study 
Schedule) to ensure compliance by the study staff. 
5.6. 
Dose Modifications and Dose-limiting Toxicities 
5.6.1 Overall, Grade 3 to 4 related adverse events (toxicities) will result in a treatment 
pause/discontinuation until the toxicity decreases to Grade ≤ 2 or baseline.  Dosing may be 
resumed with a 50% dose reduction from 200 mg QD to 100 mg QD, or 100 mg to 50 mg QD).  
Any subject who is unable to tolerate 50 mg QD of enasidenib should be discontinued from 
study treatment.  
Dosing may be interrupted for toxicity or nontoxicity related reasons deemed appropriate by the 
PI, such as reasons involving other underlying comorbidities or due to personal reasons of the 
subject. Pauses or delays in enasidenib for toxicity or nontoxicity reasons deemed appropriate 
by PI is allowed as long as dose modifications are followed per protocol (5.6.2). If 28 days or 
more of study drug administration interruption have occurred and patient is to restart the study 
drug, the patient’s schedule will reset to the CxD1 subsequent to nearest completed cycle. 
The DLT assessment period for each dose level is defined by any 28 days of continuous 
therapy at each dose level (100mg, 200mg). An evaluable subject is any subject that completes 
the DLT assessment period defined as above. 
 
Any probably or definitely related AE will be considered a DLT unless the event can be 
attributed to a concurrent process, the underlying disease process (MDS or CMML), or 
concomitant medications by the PI. 
 
Criteria for defining DLT are outlined in table below: 
Toxicity 
DLT Criterion 
Hematological  
Neutropenia 
• 
Febrile, CTCAE Grade ≥3. 
• 
CTCAE Grade ≥3 which does not resolve with dose 
modifications per protocol (5.6.2) 
Thrombocytopenia 
• 
CTCAE Grade ≥3 which does not resolve with dose 
modifications per protocol (5.6.2) 
Anemia 
• 
CTCAE Grade ≥3 which does not resolve with dose 
modifications per protocol (5.6.2) 
Nausea 
• 
CTCAE Grade ≥3 which does not resolve with dose 
modifications per protocol (5.6.2) 

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Renal/genitourinary 
CTCAE Grade ≥3 which does not resolve with dose 
modifications per protocol (5.6.2) 
 
5.6.2 Each toxicity will be addressed as specified below. 
If treatment is modified during the course of the study and benefit is demonstrated with a 
reduced level of dose, then that dose level should be maintained during the subsequent 
treatment cycles that are given unless toxicity develops.  If no benefit is demonstrated, however, 
enasidenib dose may be re-escalated back to the starting dose, provided that the starting dose 
is now tolerated without toxicity.   
a. Cytopenias 
Event 
Grade 
Action 
Neutropenia 
3 to 4 
• Stop enasidenib until toxicity is ≤ Grade 1 or has returned to 
baseline 
• Administer prophylactic anti-infectives as clinically indicated 
• Resume enasidenib with a 50% dose reduction.  If toxicity does not 
recur, can re-escalate enasidenib dose 
• If toxicity recurs after resuming enasidenib at a 50% dose 
reduction, decrease enasidenib to 25% of starting dose, if this 
dose is less than 50 mg daily, stop enasidenib permanently. 
Thrombocytopenia 
3 to 4 
• Stop enasidenib until toxicity is ≤ Grade 1 or has returned to 
baseline 
• Transfuse as clinically indicated or per standard of care 
• Resume enasidenib with a 50% dose reduction.  If toxicity does not 
recur, can re-escalate enasidenib dose 
• If toxicity recurs after resuming enasidenib at a 50% dose 
reduction, decrease enasidenib to 25% of starting dose, if this 
dose is less than 50 mg daily, stop enasidenib permanently. 
b. QT Prolongation 
• 
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: 
i. Levels of electrolytes (potassium, calcium and magnesium) should be checked 
and supplementation given to correct any values outside the normal range. 

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ii. Concomitant therapies should be reviewed and adjusted as appropriate for 
medication with known QT prolonging effects. 
iii. If no other cause is identified and the investigator believes it is appropriate, 
particularly if the QTcF remains elevated (after above measures have been 
implemented, or as determined by the investigator), enasidenib treatment may be 
interrupted, and an ECG should be rechecked in approximately 1 week after the 
QTcF prolongation was first observed or more frequently as clinically indicated. 
iv. If QTcF has recovered or improved and the investigator believes it is safe to do 
so, a re-challenge with enasidenib should be considered if held.  ECGs should be 
conducted at least weekly (eg, at every scheduled visit) for 2 weeks following 
QTcF reduction ≤ 480 msec. 
v. If Grade 2 (QTcF > 480 and ≤ 500 msec), the dose of enasidenib may be reduced 
without interruption of dosing.  The enasidenib dose may be re-escalated to the 
prior dose in ≥ 14 days after QTcF prolongation has decreased to ≤ Grade 1. 
vi. If this is the second occurrence of QT prolongation, administration of enasidenib 
should continue at a reduced dose (ie, the dose may not be re-escalated). 
vii. If Grade 3 (QTcF > 500 msec), hospitalization for continuous cardiac monitoring 
and evaluation by a cardiologist should both be considered.  Dosing with 
enasidenib will be interrupted.  If QTcF returns to within 30 msec 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. 
viii. 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 the hospital for continuous cardiac 
monitoring and discharged only after review by a cardiologist.  Dosing with 
enasidenib should be permanently discontinued. 
c. IDH Differentiation Syndrome 
• 
Subjects treated with enasidenib have experienced symptoms of differentiation 
syndrome, which can be fatal if not treated.  Symptoms may include fever, 
dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial 
effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, 
and hepatic or renal dysfunction.  If differentiation syndrome is suspected, initiate 
corticosteroid therapy and hemodynamic monitoring until symptom resolution. 
• 
If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids 
(eg, dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until 
improvement.  Taper corticosteroids after resolution of symptoms.  If severe 
pulmonary symptoms requiring intubation or ventilator support, and/or renal 
dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt 
enasidenib until signs and symptoms are no longer severe.  Hospitalization for close 
observation and monitoring of subjects with pulmonary and/or renal manifestation is 

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recommended.  Enasidenib can be resumed when signs and symptoms improve to 
Grade 2 or lower.  Measurements of hemoglobin changes during steroid treatment 
will not be used until predisone dose reaches 10mg daily or less.   
• 
Further information on diagnosis and treatment of IDH differentiation syndrome can 
be found in the current version of IDH differentiation syndrome guidance 
documents. 
d. Noninfectious Leukocytosis  
• 
Subjects with hematologic malignancies treated with enasidenib may experience 
rapid myeloid cell proliferation, presenting as an increase in WBC count without 
evidence of infection or signs of IDH differentiation syndrome. 
• 
If leukocytosis is identified during the screening period, standard of care work up 
(blood cultures, chest X-ray, urine analysis) will be conducted to rule out infectious 
etiologies.   
• 
Blood counts should be assessed for noninfectious leukocytosis (defined as WBC 
greater than 30 x 109/L) prior to the initiation of enasidenib and monitored at a 
minimum of every 2 weeks for at least the first 3 months during treatment.   
e. Tumor Lysis Syndrome  
• 
Subjects with hematologic malignancies treated with enasidenib may 
experience tumor lysis syndrome.  Manage any abnormalities promptly.  If 
enasidenib-related toxicity is Grade 3 or more, enasidenib dosing will be 
stopped until toxicity returns to ≤ Grade 1 or below.  Allopurinol will be 
prescribed as standard of care for any subject experiencing tumor lysis 
syndrome. 
f. Gastrointestinal Disorders  
• 
Appropriate monitoring and management of GI toxicities, including nausea, and 
vomiting will be done at every study visit. 
• 
For Grade 2 or 1 nausea, subjects will be given with antiemetics to be taken prior to 
enasidenib (30 to 60 minutes), as per standard of care. 
• 
For Grade 3 or 4 nausea, enasidenib will be dose reduced by 50% (from 200 mg to 
100 mg, or from 100 mg to 50 mg) until nausea is ≤ Grade 2.  Antiemetics will also 
be given, as per standard of care.   
g. Elevated Serum Bilirubin  
• 
Hyperbilirubinemia is induced by enasidenib inhibition of UGT1A1, the enzyme 
responsible for the metabolism of bilirubin (a condition similar to Gilbert’s 
syndrome). 
• 
Subjects with Gilbert’s syndrome genotype treated with enasidenib experienced 
earlier onset of bilirubin elevation following treatment initiation, as compared to 
subjects with normal UGT1A1 genotype.  With continuing treatment, maximum 
severity of bilirubin elevation was similar in subjects with Gilbert’s syndrome and 
subjects with normal UGT1A1 genotype.   

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• 
Subjects with increasing hyperbilirubinemia will undergo standard of care work up 
including but not limited to: fractionated evaluation of bilirubin, LDH, haptoglobin, 
abdominal ultrasound. 
• 
Other causes of hyperbilirubinemia (such as hemolysis, choledocholithiasis) will be 
treated accordingly as per standard of care. 
• 
Enasidenib dosing will not be stopped or modified for hyperbilirubinemia related to 
enasidenib as it does not cause pathophysiology.   
5.7. 
Concomitant Medications, Procedures, and Supportive Care Guidelines 
All prior and concomitant medications (prescription and non-prescription) taken and treatment 
procedures received from the 4-week period (i.e., 28 days) prior to starting study treatment up 
to 28 days after the last study treatment must be recorded on the appropriate eCRF page(s).  
Particularly, all prior anti-cancer treatments should be recorded regardless of discontinuation 
date of treatment. 
Prohibited Concomitant Medications or Procedures 
Systemic anti-cancer therapy (excluding hydroxyurea) is not permitted during the course of 
study treatment, unless ECG monitoring can be done during the time of concurrent use.  Use 
of the medications below with ECG monitoring will be documented in subject progress notes.  
Use of these medications will also be document as concomitant medications.   
• 
Corticosteroids, with the exception of topical cutaneous, ophthalmic, nasal, and 
inhalational steroids.  Note that short course steroid therapy will be permitted to treat 
co-morbidities such as IDH Differentiation Syndrome.  Steroids may temporarily 
increase hemoglobin levels, however, sustained steroid use has never been 
necessary to treatment enasidnib associated differentiation syndrome.  Hemoglobin 
increases after steroid use will not be used satisfy response criteria unless it has 
been sustained for at least 8 weeks from last day of steroid dose (the minimal 
duration of sustain responses according to the 2018 IWG HI-E).   
• 
The following medications that are known to prolong QT interval: 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 
• 
Sensitive CYP substrate medications that have a narrow therapeutic range: 
paclitaxel and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin 
(CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2) 
• 
The BCRP transporter-sensitive substrate rosuvastatin  
• 
Coadministration of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP3A4, 
and CYP1A2 substrates other than those listed in Section 2.1.3 should be used 
only if medically necessary 

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• 
Coadministration of P-gp or BCRP substrates, OAT, OATP1B and OCT2 substrates 
other than those listed in Section 2.1.3 should be used only if medically necessary 
(refer to Appendix C for a list of transporter substrates) 
• 
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 an inhibitor of UGT1A1, enasidenib may slow down the metabolism of drugs 
that are substrates for UGT1A1, such as irinotecan, ezetimibe, raloxifene, and 
raltegravir.  If this applies, especially in subjects who develop hyperbilirubinemia, it 
might be necessary to lower the doses for UGT1A1 substrates or switch to 
alternate therapies, or otherwise monitor for AEs associated with the respective 
products.   
5.8. 
Criteria for Removing Subjects from Study Intervention and/or Study 
Subjects are free to withdraw consent and discontinue participation in a study at any time 
without prejudice to further treatment.  The investigator may discontinue a subject from 
treatment intervention or the entire study for medical or administrative reasons.  The following 
reasons may lead to discontinuation from the study intervention or the entire study.   
• 
There is need for any treatment not allowed by the protocol 
• 
Disease progression 
• 
Toxicity precluding further study treatment 
• 
Withdrawal of consent 
• 
Study non-compliance 
• 
Becomes pregnant 
• 
Investigator discretion 
If the subject elects to withdraw consent from further treatment with the study intervention, or is 
withdrawn by the investigator, it will be confirmed and documented if the subject will consent to 
continue to be followed per protocol, if applicable.  The rationale for the investigator’s decision 
to discontinue treatment will be clearly documented.   
5.9. 
Duration of Follow-Up 
After completion of treatment (i.e., date of last treatment, subjects will be followed for 3 months 
after completion or removal from study or until death or until the start of a subsequent therapy, 
whichever occurs first.  If a subject is removed from study due to unacceptable adverse event(s) 
or toxicity, that subject will be followed and safety data collected for 90 days after their last dose 
or resolution or stabilization of the adverse event, whichever is longest, to the extent possible.  
Subjects that personally withdraw will be requested to attend an end of treatment visit, or 
otherwise receive a follow-up contact, unless specifically countermanded by the subject.   

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5.10. Study Completion or Discontinuation  
The study will be complete when the last study data, including all follow-up data, has been 
collected, and analysis is complete.  This is expected to occur when the last enrolled study 
subject has completed 6 months of follow-up and all studies have been completed (estimated to 
be 31 January 2024).  Studies to be completed include biobanking of PB and BM biopsy 
samples.  All follow-up must occur within the on-study follow-up period.  Subjects will no longer 
be followed or subject data collected once the study is complete per this section. 
Conditions may be discovered during the conduct of the study by the investigator, regulatory 
authorities, or other oversight bodies that indicate that the study should be terminated 
prematurely.  The reasons that may warrant termination include, but are not limited to: 
• 
The study is determined to be non-feasible, including inadequate accrual 
• 
Determination of unexpected, significant, and/or unacceptable risk to subjects 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Demonstration of efficacy that would warrant termination by the sponsor and investigator 
• 
Determination of futility 
• 
Business decision by the Principal Investigator, institution, or funding source 
Written notification will be provided by the investigator to Celgene Corporation and regulatory 
authorities as appropriate, including the IRB of record. 

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6. 
STUDY PROCEDURES AND ASSESSMENTS  
6.1. 
Study Procedures Table 

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Footnotes for Study Schedule 
1 Screening is done within 45 days of C1D1. 
2 All adverse events and SAEs will be recorded by the Investigator from the time the subject signs informed consent until 90 days after the last 
dose of IP or start of new treatment, and those SAEs made known to the investigator at any time thereafter that are suspected of being related 
to IP. 
3 Demographics will include age, sex/gender, self-reported ethnicity 
4 Height measurement is only required during screening.   
5 CBC with differential includes total white blood cell count with differential count of neutrophils, lymphocytes, monocytes, eosinophils, basophils, 
blast count, and immature granulocytes, hemoglobin, hematocrit, and platelet count.  If a CBC was obtained during screening and is more than 
14 days prior to C1D1, a repeat CBC and reticulocyte will be done on C1D1. 
6 CMP or complete metabolic panel includes: sodium, potassium, chloride, carbon dioxide, glucose, creatinine, blood urea nitrogen, calcium, total 
protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase. 
7 Conjugated bilirubin is synonymous with direct bilirubin. 
8 Iron studies include serum iron, ferritin, transferrin saturation. For patients who are approved to continue after 12 cycles of treatment, iron 
studies will no longer be collected after Cycle 12.  
9 Nutritional panel includes B12, methylmalonic acid, folate, TSH and free T3.  If TSH is abnormal, also obtain free T4. 
10 Biobanking samples include 25 mL of peripheral blood in EDTA tube and 15mL of bone marrow aspirate in EDTA tubes. *EOT biobanking is 
collected at the PI’s discretion. 
11 Bone marrow biopsy performed at screening includes: aspirate, biopsy, flow, iron stain, cytogenetics, hemeSTAMP for verification of diagnosis 
and risk stratification.   If a bone marrow biopsy was previously done and samples are available for biobanking, a biopsy is not required at time 
of screening. 
12 Subsequent bone marrow biopsies while on study protocol will only include: aspirate, biopsy, iron stain and biobanking. 
13 Bone marrow biopsy will be performed at the PI’s discretion taking the following into consideration: at time of loss of response, a change in the 
response (sudden increase or decrease), for subjects who respond late on the protocol such as Cycle 5 or Cycle 6 
14 Single ECG. 
15 B-HCG is only collected for  females of child bearing potential 
16 Magnesium is only collected through Cycle 4 Day 15 (+/-3 day) .

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6.2. 
Description of Procedures and Assessments 
6.2.1. Efficacy Assessments 
Informed Consent and Screening Period 
 
All subjects who are seen at Stanford Cancer Center with the diagnosis of MDS, CMML 
will be considered by the PI and offered participation in the study.   
 
PI or co-PI will explain the study to the potential study candidate verbally and in written 
format providing all the pertinent information (purpose of the study, procedures, risks, 
benefits and alternatives to study participation, etc.).  All study candidates will be given 
ample opportunity to ask questions and the PI will ensure all questions are answered 
satisfactorily. 
 
The potential candidates will be given the IRB approved consent form and given ample 
time to consider participation.  All questions pertaining to the consent will be answered 
satisfactorily.  If the candidates decided to become a subject, both the study subject, the 
PI (or co-PI) or study coordinator will sign the consent form.  A signed copy of the 
consent will be 1) given to the study subject; 2) scanned and retained in medical 
records;  3) distributed to the pharmacy and CTRU as per Stanford Cancer Clinical Trial 
Office (CCTO) Standard Operating Procedures; and 4) consent will be documented in 
the form of a progress note in the subject’s chart. 
 
The screening period will take place up to 45 days prior to or on first treatment day 
(Cycle 1 Day 1).  Each potential study candidate will undergo the following: 
o Informed consent form 
o Medical history and complete physical exam 
o Obtain vital signs/ECOG performance status 
o Monitoring of concurrent medications 
o Baseline safety labs: CBC with differential, Complete Metabolic Panel, 
magnesium level, reticulocyte count, erythropoietin level, B12, methylmalonic 
acid and folate level, serum iron, ferritin, transferrin saturation, TSH, T3, T4 
o Unless a prior bone marrow biopsy (conducted at Stanford or outside) is 
available for biobanking, diagnostic confirmation and next generation sequencing 
testing by Stanford Pathology, a baseline BM biopsy will be conducted, including: 
aspirate, core biopsy, cytogenetics, hemeSTAMP, iron stain to verify diagnosis 
and provide risk stratification. 
o HemeSTAMP (multigene panel to detect somatic mutations by next generation 
sequencing).   
 
Virtual visits maybe conducted for evaluation. 

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Treatment Period 
 
Baseline labs and studies will be collected during the screening period. 
 
On Cycle 1 Day 1, each study subject will: 
o Receive 28-day supply of enasidenib, a study diary 
o Begin to self-administer enasidenib orally.   
o Each subject will be counseled to take enasidenib at the same time daily, 
approximately 24 hours apart.   
o Each subject will also begin recording each dose and any additional side effects 
or concerns in the study diary.   
 
On Day 15 of the first 6 cycles (± 3 days), subjects will have laboratory evaluation for 
CBC with differential, CMP, conjugated/direct bilirubin and magnesium. *Magnesium is 
only required up until Cycle 4 Day 15 (+/-3 days).  
 
On the first days of each 28-day treatment cycle (Day 1, ± 3 days), each study subject 
will be evaluated by the PI or designate.  The following will be obtained/performed at 
each visit: 
o Study diary monitoring, medication review, adverse events reporting 
o Symptom-directed physical exam with ECOG performance status 
o Vital signs, including weight 
o Laboratory evaluation:  CBC with differential, CMP, magnesium*, 
conjugated/direct bilirubin, iron studies, erythropoietin level, and biobanking. 
*Magnesium is only required up until Cycle 4 Day 15 (+/-3 days). 
o Drug dispensing for the next cycle 
 
Virtual visits maybe conducted for evaluation. 
 
For patients who are approved to continue treatment after 12 cycles, patients will have 
labs drawn as clinically indicated.  Iron studies and erythropoietin are not required to be 
collected after Cycle 12. 
 
 
Final Study Visit  
 
Study subjects who withdraw from treatment due to progressive disease will be seen 
within 4 weeks of determination of progressive disease for a final visit (End of Study 
Visit).   
 
Study subjects who withdraw due to intolerance of treatment should be followed until all 
toxicities have resolved.   
 
All study subjects who withdraw for any reason other than progressive disease or 
treatment intolerance will be seen within 4 weeks of withdrawal for a final visit.  Subjects 
without progression of disease and intolerance of treatment will have their final study visit 
within 4 weeks of the Cycle 12 Day 28.   

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 
At the End of Study Visit, the following procedures will be performed: 
o Study diary and all remaining Enasidenib returned to study staff 
o Symptom-directed physical exam with ECOG performance status 
o Vital signs including weight 
o Laboratory evaluation: CBC with differential, CMP, reticulocyte count, 
conjugated/direct bilirubin, erythropoietin, iron studies 
o Biobanking per investigator discretion 
 
Virtual visits maybe conducted for evaluation. 
Follow-Up Period 
 
Study subjects with unresolved AEs or SAEs will continue to be followed for 90 days or 
until resolutions of AEs/SAEs, or until the start of a new therapy, whichever occurs first. 
6.2.2. Safety and Other Assessments 
 
Study subjects will be screened according the inclusion and exclusion criteria to ensure 
their baseline health and performance status is fit for study participation within 45 days 
of starting the study medication. 
 
All study subjects who have received at least one dose of the Enasidenib will be 
included for safety evaluation.   
 
A study diary will be used for each study subject to keep track of self-administered doses 
and prevent overdose. 
 
All concurrent medications will be evaluated continuously to prevent drug-drug 
interactions and potentiation of known side effects.  
 
All study subjects will have laboratory evaluation and BM biopsies conducted at baseline 
to verify diagnosis/eligibility based on diagnostic criteria.  Additionally, laboratory 
evaluation will be done according to schedule of events in Section 6.1.  
 
All study subjects of child bearing age will have a pregnancy test done at baseline (for 
female study subjects) and be counseled in depth regarding the use of birth control to 
minimize risk of in utero exposure (see Scheduled Events in Section 6.1).   
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar 
with the content of this section.  References for Stanford Cancer Institute adverse event (AE) 
policies and practices are provided in Appendix A.  
7.1. 
Adverse Event Definitions 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related.  An adverse event can be any unfavorable 
and unintended sign or symptom, including abnormal laboratory findings, or disease, that is 
temporally associated with the use of a drug, and does not imply any judgment about causality.  

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An adverse event 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.  An adverse reaction is any event that is caused by a drug or device, ie, 
possibly-, probably-, or definitely-related to the use of the drug or device.  
Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a 
pre-existing condition) should be considered an AE.  However, anticipated day-to-day 
fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study 
that do not worsen over time are not considered adverse events.  However, except as otherwise 
explicitly defined within this section, this also includes all events of clinical deterioration 
such as tumor relapse, recurrence, or upstaging, or new cancers.   
Abuse, withdrawal, sensitivity or toxicity to enasidenib should be reported as an AE.  An 
overdose, accidental or intentional, whether or not it is associated with an AE, should be 
reported.  Any sequela of an accidental or intentional overdose of enasidenib should be 
reported as an AE.  If the sequela of an overdose is a serious adverse event (SAE), both the AE 
page/screen of the CRF and the SAE Report 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. 
All subjects will be monitored for AEs during the study.  Assessments may include monitoring of 
any or all of the following parameters: the subject’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or findings from other tests 
and/or procedures. 
Serious adverse events (SAEs) are defined per the FDA definition at 21CFR§312.32(a) and 
ICH GCP E6.  An adverse event is considered "serious" if, in the opinion of the PD, investigator, 
or sponsor, it results in ANY of the following. 
• 
Death  
• 
Life-threatening adverse event with an actual and immediate risk of death 
[21CFR§312.32(a)]  
• 
Insubject hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• 
A congenital anomaly/birth defect  
• 
Event jeopardizes the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed here 
7.2. 
Classification of Adverse Events 
7.2.1. Severity of Event 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
Events not considered SAEs are hospitalizations for: 

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• 
A standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be reported as 
an SAE. 
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• 
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 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. 
• 
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• 
A procedure that is planned (ie, 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. 
• 
An elective treatment of or an elective procedure for a pre-existing condition unrelated to 
the studied indication. 
• 
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event.   
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to 
the NCI Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale: 
• 
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
• 
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may 
be needed; no or minimal medical intervention/therapy required 
• 
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 
• 
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable 
• 
Grade 5 = Death - the event results in death 
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 

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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. 
NCI CTCAE version 5.0 is used to assess the severity of adverse events in this study. 
7.2.2. Adverse Event Attribution to Intervention or Study  
For this study, all recorded AEs will be assessed on the basis of whether or not the AE was 
caused by / due to (ie, related) to the study intervention(s).  AEs, serious or otherwise, will be 
attributed by the PI or qualified designate to study treatment in accordance with the definitions 
below.   
The Investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected: A causal relationship of the adverse event to IP administration is unlikely or 
remote, or other medications, therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event. 
Suspected: There is a reasonable possibility that the administration of IP caused the adverse 
event.  ‘Reasonable possibility’ means there is evidence to suggest a causal relationship 
between the IP and the adverse event. 
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available. 
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event. 

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• Definitely Related.  There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out.  The clinical event, including an 
abnormal laboratory test result, occurs in a plausible time relationship to study 
intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals.  The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible.  The event must be pharmacologically 
or phenomenologically definitive, with use of a satisfactory rechallenge procedure if 
necessary. 
• Probably Related.  There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely.  The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other drugs 
or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge).  Rechallenge information is not required to fulfill this definition. 
• Potentially / Possibly Related.  There is some evidence to suggest a causal 
relationship (e.g., the event occurred within a reasonable time after administration 
of the trial medication).  However, other factors may have contributed to the event 
(e.g., the subject’s clinical condition, other concomitant events).  Although an 
adverse event may rate only as “possibly related” soon after discovery, it can be 
flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
These are 
treated as 
“Related” 
• 
Unlikely to be related.  A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study intervention administration makes a 
causal relationship improbable (e.g., the event did not occur within a reasonable 
time after administration of the study intervention) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the subject’s 
clinical condition, other concomitant treatments). 
• 
Not Related.  The adverse event is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely related to another 
etiology.  There must be an alternative, definitive etiology documented by the 
clinician. 
These are 
treated as 
“Not Related” 
In addition, for adverse events determined “Not Related” to the study intervention(s), the 
Principal Investigator or qualified designate will attribute the event to the study or procedures 
according to the definitions above.  Note that adverse events can be determined related to both 
the intervention(s) and/or the study / procedures.   
7.2.3. Expectedness of Event 
The PI or co-PI will also assess all recorded AEs on basis of event severity, frequency 
(if applicable/assessable), and the established product risk information described within the 
product Investigator Brochure; the FDA-approved product labeling (if an approved agent); 
and/or this protocol document, as to whether the events are “expected” or “not expected” 
relative to the study interventions and/or the study / procedures.   

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Note that unexpected adverse events may have reporting requirements as described elsewhere 
in this section.   
7.2.4. Time Period of Event Assessment and Follow-up 
All adverse events and SAEs will be recorded by the Investigator from the time the subject signs 
informed consent until 90 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.  AEs and SAEs will 
be recorded in the subject’s source documents.   
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption of IP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event. 
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).  For both AEs and SAEs, the Investigator will provide a record of the start and stop dates 
of the event. 
7.3. 
Potential Adverse Events and Risks 
Potential adverse events and risks were described at Section 1.3.1 Known Potential Risks.   
In addition, adverse events described by the enasidenib Investigator Brochure and the 
FDA-approved product labeling (package insert) of enasidenib considered anticipated, ie, 
not unexpected.  Events occurring at demonstrably higher frequency than described in the 
Investigator Brochure of the package insert should be considered adverse events, and handled, 
documented, and reported accordingly.  Procedural risks described in Section 1.3.1 are 
considered anticipated.   
7.4. 
Adverse Event Monitoring and Collection  
Untoward medical events experienced by a subject within 30 days of receiving enasidenib,  will 
be considered an AE, regardless of whether or not considered drug-related.  All events of 
disease progression or second cancer will be recorded as a SAE using the Preferred Term 
appropriate for the clinical finding.   
All adverse events Grade 1 and higher will be collected and recorded as AEs.  In addition, 
laboratory values without a requirement for intervention, clinical consequence, or outcome will 
not be considered AEs.   
7.4.1. Case Report Forms for Adverse Event Reporting  
Both SAEs and non-serious adverse events will be described in source documentation and 
listed on study-specific Case Report Forms (CRFs or eCRFs).  SAEs will be reported to the SCI 
DSMC, via submission to CCTO-Safety.  The event must be described on either the Stanford 
Cancer Institute SAE form (see references in Appendix A), or a study-specific form.  The 
Form FDA 3500A (see Section 7.6) for mandatory IND Safety Reports may be substituted.   
AEs will be recorded on a log (see references in Appendix A) providing the unique subject 
identifier, event preferred term, CTCAE body system, date of occurrence, date of resolution; and 

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type of resolution.  All signs, symptoms, significant laboratory findings, AND diagnoses should 
be recorded, regardless of relationship, except as described in this document.  A single 
“overarching” diagnosis should not be solely entered as the adverse event term in lieu of the full 
list of observed signs, symptoms, and significant laboratory findings, which may include the 
diagnostic preferred term.  Any pre-existing condition that worsens in severity/Grade or 
frequency should be recorded as a new adverse event, except as described in this document.   
Types of resolution are:  
• 
“Resolved,” i.e., to Grade 0 (or baseline if a pre-existing condition)  
• 
“Continuing” and stable (includes downgrades from a higher grade to a lower grade) 
• 
“Deceased” (due to any cause will on-study) 
• 
Lost-to-follow-up.   
7.4.2. Progressive Disease 
Progressive disease will be reported by the clinical signs or symptoms of disease progression.  
If the event is Grade 5 fatal and signs/symptoms of disease progression are not available / 
informative for the event, the CTCAE v5.0 preferred term “Disease Progress” may be used. 
7.5. 
Adverse Events of Special Consideration    
7.5.1. Second vs Secondary Malignancy 
7.5.1.1. 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  A second malignancy is by definition a serious adverse 
event (SAE), and will be recorded and reported accordingly.  
7.5.1.2. 
Secondary Malignancy 
In the context of a clinical study, a secondary malignancy is a cancer caused by chemotherapy, 
radiation, or the investigational agent/intervention.  A secondary malignancy is not considered a 
metastasis of the initial neoplasm, but nonetheless, a secondary malignancy is by definition a 
serious adverse event (SAE), and will be recorded and reported accordingly.  Secondary 
malignancies are usually described as one of the following: 
• 
Leukemia secondary to oncology chemotherapy [e.g., acute myelocytic leukemia (AML)]  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
By definition, secondary malignancies are adverse events that are both serious and related to 
the research, and should be anticipated to be an Unanticipated Problem (UP) and reported 
accordingly.  If also determined to be related to the study treatment, and not described by the 
Investigator Brochure or package insert as known to be associated with the study agent, the 
secondary malignancies may also necessitate Expedited Reporting to FDA, e.g., an 
IND Safety Report to the IND. 

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7.5.2. Progressive Disease 
Progressive disease will be reported by the clinical signs or symptoms of disease progression.  
If the event is Grade 5 fatal and signs/symptoms of disease progression are not available / 
informative for the event, the CTCAE v5.0 preferred term “Disease Progress” may be used. 
7.6. 
Adverse Event Reporting 
All adverse clinical experiences, whether observed by the investigator or reported by the 
subject, must be recorded, with details about the duration and intensity of each episode, the 
action taken with respect to the test drug, and the event’s outcome, including lab abnormalities.  
The investigator will evaluate each adverse experience for its relationship to the test drug and 
for its seriousness. 
The investigator will appraise all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator will provide details 
about the action taken with respect to the test drug and about the event’s outcome or lab 
abnormality. 
Reportable adverse events 
Based on relatedness (attribution) to the study agent; expectedness, severity (Grade 1 to 5), 
seriousness (Yes/No), or any other aspect of the investigation, will be reported as described 
below. 
• 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (eg, cough, runny nose, sneezing, sore throat; and head congestion 
should be reported as "upper respiratory infection").   
• 
Serious adverse events (SAEs) per the definition at 21CFR§312.32 will be reported to 
the sponsor-investigator within 24 hours of the knowledge of the event.  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 (such as via secure email with CRF/eCRF attached).   
• 
SAEs will be reported to the SCI Data and Safety Monitoring Committee (DSMC) by 
submitting the study-specific CRF or the Stanford Cancer Institute CRF for SAE 
reporting through secure email to CCTO-safety@stanford.edu at the time of the 
first notification to any of drug manufacturer Celgene Corporation;  the IRB of record;  or 
the IND (ie, FDA).  The SAE form must be signed by the investigator. 
• 
SAEs per 21CFR§312.32 will be reported by the IND-holder to the IND under which this 
study is being conducted within 7 days (for a life-threatening or fatal event) or 15 days 
(for other SAEs) of the IND-holder’s determination that the SAE meets the criteria for an 
IND safety report, ie, the event was serious, unexpected, and at least possibly-related to 
the study drug [a serious, unexpected, suspected adverse reaction (SUSAR)].  IND 
Safety Reports will be submitted to the IND using the MedWatch Form FDA 3500A for 
mandatory reporting.  IND Safety Reports will also be distributed to all participating 
Principal Investigators within 60 days.   
IND Safety Reports will be submitted to either the address specified in the IND 
Study May Proceed letter, any other address specified by the IND reviewers, or via the 

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Electronic Submissions Gateway (contact CCTO-Regulatory@Stanford.edu for 
electronic submission assistance), or via the CDER NextGen portal.   
• 
All SAEs per protocol will be reported will be reported by each clinical site to the IRB of 
record in the Continuing Review, and/or the Final Report.  IRB reporting format can be 
as an event line listing (such as the Adverse Event log), or as an aggregate listing or 
summary (such as an IND Annual Report or SAE listing for ClinicalTrials.gov).   
• 
All Unanticipated Problem (UPs) associated with the use of a drug, biologic, or device 
will be reported as follows. 
o Note that for the purposes of Stanford IRB Unanticipated Problem reporting, subjects 
are considered to be study subjects when consented, ie, events during screening 
and/or pre-treatment through that subject’s official end of study participation may 
qualify as reportable.   
o To the Stanford IRB, by the Stanford Protocol Director, if an adverse event meets the 
Stanford IRB’s current definition of an Unanticipated Problem (UP) as specified by 
the IRB document “Events and Information that Require Prompt Reporting to the 
IRB” (GUI-P13), per the timeframes defined therein.  Once the DSMC has received 
the SAE report via OnCore, the DSMC may also issue a report on the event, which 
may be also provided to the IRB.  See also Section 9.4 Data and Safety Monitoring 
Plan.  In addition to event triggered expedited UP reports, all UPs should be 
summarized in the Continuing Review, with, as applicable, a discussion of any 
change in assessment of risk (ie, different than previously described).   
Subsequent follow-up reports, whether to SAEs or UPs, will be reported as required by the 
receiving entities.   
Adverse events that are serious and unexpected suspected adverse reactions (i.e., serious, 
unexpected events are possibly, probably, or definitely-related to the study drug enasidenib), 
will be reported by the IND-holder on a MedWatch 3500A form as an IND Safety Report 
[21CFR§312.32] to the IND within 15 calendar days, or within 7 calendar days if the event is an 
unexpected fatal or life-threatening suspected adverse reaction.  The IND annual report as 
submitted by the IND-holder will include summaries of the collected AEs, as specified by 
21CFR§312.33.   
Serious adverse events (SAEs) will be reported to the IRB of record and to the DSMC in 
accordance with the applicable guidelines and regulations.   
All serious adverse events (SAEs) will be followed for 90 days after the last dose of the 
enasidenib, or until the SAE(s) is(are) resolved or stable, or until patient initiates a 
new/alternative therapy (including but not limited to growth factors, chemotherapy or bone 
marrow transplant), whichever occurs first.  
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the 
abnormality: 
• 
results in discontinuation from the study; 

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• 
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 platelets). 
Overdose 
Overdose, as defined for this protocol, refers to enasidenib dosing only (as applicable).   
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of > 240 mg (+20%) assigned to a given subject, regardless of any associated adverse 
events or sequelae. 
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. 
Pregnancy 
All female study subjects of reproductive potential will be advised to avoid becoming pregnant 
while receiving enasidenib (Idhifa) and to use effective contraception during treatment with 
enasidenib and for at least 2 months after the last dose.  Coadministration of enasidenib may 
increase or decrease the concentrations of combined hormonal contraceptives.  The clinical 
significance of this potential drug interaction is unknown at this time.  
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 (2 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. 

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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 
All male study subjects with female partners of reproductive potential will be advised to use 
effective contraception during treatment with enasidenib (Idhifa) and for at least 2 months after 
the last dose of enasidenib.  
If a female partner of a male subject taking investigational product becomes pregnant while the 
male subject is on study treatment or within 2 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. 
Expedited Reporting by Investigator to Celgene 
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 investigator must inform Celgene in 
writing using a Celgene SAE form or 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 subject records.   
Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management  
86 Morris Avenue 
Summit, New Jersey 07901 

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BMS Patient Safety fax number: 1-609-818-3804 
E-mail:  WorldWide.Safety@bms.com  
7.7. 
Adverse Event Records 
The investigator will retain adverse event source data, supporting documentation of attribution 
and seriousness, and copies of official adverse event reports or SAE CRFs, as well as 
documentation of informal communications (such as telephone calls or emails) in accordance 
with the current version of Stanford School of Medicine standard operating procedure SOP-005 
“Identifying and Reporting Adverse Events” (see Appendix 1).   
8. 
CORRELATIVE / SPECIAL STUDIES  
8.1. 
Correlative Studies Background 
8.1.1. Explore the identity of the target cell population of enasidenib 
Primary samples will be interrogated to determine which erythroid progenitor population 
enasidenib is acting upon to increase endogenous erythropoiesis.   
8.1.2. Explore the mechanism of enasidenib 
Samples from responders and nonresponders will be used for transcriptional studies to discern 
regulatory pathways influenced by enasidenib.   
8.1.3. Explore immune differentiation effects of enasidenib 
The immune repertoire of each subject at baseline and while receiving enasidenib will be 
interrogated. 
8.2. 
Laboratory Correlative StudiesCollection of Specimen(s) 
8.2.1. Collection of Specimens 
The following samples will be collected for each study subject concomitant to standard of care 
studies according to protocol.   
1) peripheral blood mononuclear cells;  
2) peripheral blood plasma;  
3) bone marrow aspirate mononuclear cells; 
4) bone marrow plasma.   
8.2.2. Handling and Storage of Specimens 
All samples collected will be processed in the laboratory of Dr Tian Yi Zhang, 
Principal Investigator at Stanford University and cryopreserved for future studies.  All samples 
biobanked for correlative studies will remain in the purview of Tian Yi Zhang and her team 
members and will be used for future studies, provided the subject has furnished their consent.  
A detailed log of all biobanked samples will be kept and provided for DSMC review upon 
request.   

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8.2.3. Coding of Specimens for Privacy Protection  
All biobanked samples will be given a unique identifier and only the identifier used for the purposes 
of correlative studies.  This allows complete de-identification of the primary samples.  All sample 
acquisition, handling and processing will follow HIPAA guidelines. 
9. 
REGULATORY CONSIDERATIONS AND DATA 
REPORTING  
9.1. 
Institutional Review Board Approval of Protocol 
This protocol, the proposed informed consent, and all forms of information related to the study 
that will be provided to the subjects (e.g., handouts, written instructions, diaries, advertisements 
used to recruit subjects) will be submitted, reviewed, and approved by the Stanford 
Administrative Panels on Human Subjects in Medical Research of the Research Compliance 
Office (ie, the Stanford IRB) and the Stanford Cancer Institute Scientific Review 
Committee (SRC) prior to initiation of the research.  Any changes made to the protocol will be 
submitted as a modification and will be approved by the IRB of record prior to implementation.  
This study will be conducted in accordance with the iteration of the protocol that is currently 
IRB-approved Stanford. 
9.2. 
Protocol Compliance and Deviations  
9.2.1. Compliance with the Protocol  
No deviation or changes from the procedures and process described by the IRB-approved 
protocol, except those necessary to eliminate an immediate hazard(s) to trial subjects, or when 
the change(s) involves only logistical or administrative aspects of the trial [e.g., change in study 
monitor(s), change of telephone number(s)], will be knowingly permitted without review and 
approval by the IRB of record. 
9.2.2. Protocol Deviations  
Any deviation from the IRB-approved protocol, including those that eliminate an immediate 
hazard or are administrative in nature, will be documented and explained in the study site file.  
In addition, any deviation from the approved protocol that meets the reporting requirements 
defined in the Stanford University HRPP Policy Guidance “Events and Information that Require 
Prompt Reporting to the IRB” GUI-P13 with be reported to the IRB within the defined 
timeframes.   
For all studies monitored by the Stanford Cancer Institute Data and Safety Monitoring 
Committee (DSMC) as defined in Section 9.4 Data and Safety Monitoring Plan, all deviations, 
exceptions, and/or violations of the protocol, as well as deviations, exceptions, and/or violations 
to applicable IRB policies and overarching regulations, will be reported to the Stanford Cancer 
Institute data Safety and Monitoring Committee (DSMC).  Accordingly, as the DSMC only 
reviews reports recorded in OnCore, such events will be promptly submitted in the OnCore 
record for the study, per the current SCI DSMC SOP.   

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9.3. 
Data and Safety Monitoring Plan 
The Principal Investigator is responsible for monitoring the conduct of the study including 
oversight of safety and protocol compliance.  On an ongoing basis, the Principal Investigator will 
review safety data and identify any changes to the research necessary to ensure the 
appropriate measures and monitoring necessary for subject safety.  In addition to the 
Principal Investigator’s safety monitoring role, the SCI DSMC will conduct data and safety 
monitoring activities for this study.   
9.3.1. Monitoring  
In addition to investigator self-monitoring (Section 9.3.1.1), the SCI DSMC will monitor 
study-related activities to determine whether the study has been conducted in accordance with 
the protocol, local standard operating procedures, FDA regulations, GCP, and SOPs.  In 
addition, the DSMC will regularly review serious adverse events and protocol deviations 
associated with the research to ensure the protection of human subjects.  Results of DSMC 
monitoring activities will be communicated to the investigator, who has the responsibility to 
provide such reports to the IRB of record and the appropriate regulatory authorities at the time 
of continuing review, or in an expedited fashion, as needed.  
9.3.1.1. 
Investigator Monitoring  
Pursuant to the Guideline for GCP, monitoring is defined as the act of overseeing the progress 
of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with 
the protocol, standard operating procedures (SOPs), GCP, and the applicable regulatory 
requirement(s).  
The Principal Investigator is responsible for self-monitoring the progress of the trial on a 
continuous basis.  Monitoring may be delegated to an appropriately-trained individual.  
Self-monitoring includes, but is not limited to, those items that will be reviewed during an audit 
(see also Section 9.5).  Routine monitoring by the Principal Investigator or designated clinical 
research coordinator will be conducted at an estimated frequency of not less than monthly. 
9.4. 
Data Management  
Source documents for all research data will be retained in accordance with all applicable 
regulations and institutional requirements for data retention.  These materials will be made 
available for monitoring and/or auditing by SCI DSMC, other monitoring body and/or regulatory 
agencies. 
9.4.1. Data Management Plan  
The data manager will manually enter data from Epic into a study-specific eCRF created in 
REDCap by the PI in conjunction with Stanford CCTO.  The PI will certify that the data are 
complete and accurate by applying an electronic signature to the eCRF.  The study specific 
REDCap database will be maintained by the CCTO with password-protected access limited to 
the study team of each clinical site.  Original source documents, including consent, clinical 
charts and hospital, laboratory, and pharmacy records will be kept in a desigated area on a 
secure floor, only accessible to the research team.   

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Study monitoring will be done by the PI and/or designated person(s) (i.e., data manager) in a 
timely manner to ensure that valid consent is obtained an documented; the per-protocol data is 
collected; records and dataases are maintained with adequate and accurate subject case 
histories; adverse events are reported; clinical protocol is maintained; and the study is 
conducted according to the established procedures of the IRB of record.   
Queries will be issued for any discrepant or missing data.  Query reports and study status will 
be reviewed by the PI monthly.  Any ongoing data management, documentation, or protocol 
related issues will be discussed during scheduled clinical research team conferences (or 
teleconferences).  Additional conferences/teleconferences will be arranged on an as needed 
basis.   
At study completion, data will be locked at after the last study visit has been completed which 
will be approximately 6 months after the enrollment of the last subject.   
9.5. 
Site Documentation and Management 
The following information will be maintained by the PI at Stanford Cancer Center. 
• 
Delegation of Authority Log, indicating study role, training date, on-study date, and 
off-study date  
• 
Financial Disclosure Forms and updates 
• 
Copies of all correspondence with the IRB of record, including all approval letters and 
approved template informed consent documents, in chronological order by date. 
• 
Copies of all correspondence with the local Scientific Review Committee, including 
approval letters, renewals, and other types of communication. 
• 
Study agent accountability log 
• 
Serious adverse event (SAE) log, documenting the subject, date, event, relatedness, 
follow-up, and outcome, with dates of communication to the IRB of record and 
Oncore/CCTO-Safety (Stanford site)  
• 
Log of Exceptions (ie, authorized by Stanford Investigator) and Log of 
Deviations (not authorized)  
• 
Log of Deviations (ie, excursions form the protocol not authorized by the Stanford 
investigator and approved by the IRB).  The Log of Deviations must be maintained in 
OnCore.  
• 
Laboratory documentation, including copies of local site CAP and CLIA certificates, 
State licenses, laboratory director CV and medical license, with laboratory normal 
values/reference ranges for all labs used in the study. 
• 
Printed, dated copy of roster for IRB of record, for each year of the study  
9.6. 
FDA Oversight 
9.6.1. Investigational New Drug (IND) Application Considerations 
IND required 
This study will be conducted under IND TBD, held by Tian Yi Zhang, MD.   

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9.6.1.1. 
Protocol Amendments  
The protocol will be conducted at all times according to the current version of the protocol as 
approved by the IRB of record.  IRB-approved protocol versions will be submitted to the IND as 
a Protocol Amendment:  Change in Protocol.   
9.6.1.2. 
IND Reports  
Information regarding the progress and status of this study will be submitted to IND TBD, in 
accordance to the content and format defined at 21CFR§312.32 (Safety Reports) and 
312.33 (Annual Reports).   
10. STATISTICAL CONSIDERATIONS  
10.1. Statistical Plan  
Cohort A will be considered to be those subjects receiving 100 mg enasidenib, and as Cohort B 
will be those receiving 200 mg. enasidenib.  Within the Phase 2 part of the study, subjects will 
be stratified as Cohort 1 for subjects with lower-risk MDS and Cohort 2 for subjects with non-
proliferative CMML, and will receive the dose level for Cohort A or Cohort B, depending on the 
results of the Pahs 1B portion of the study.  Although the outcome for Cohorts 1 and 2 after 
determination of the recommended phase 2 dose( RP2D) is the nominal intent of the study, 
results may be analyzed and/or reported to include subjects from Cohort A or Cohort B who 
receive the eventual the RP2D.  
Simon’s two-stage design will be used for each of the 2 disease cohorts of the study (ie, study 
phase 2).  The null hypothesis that the true response rate is 0.1 [P0] will be tested against a 
one-sided alternative.  In the first stage, 16 [n1] subjects will be accrued.  If there are 1 [r1] or 
fewer responses in these 16 [n1] subjects, the study will be stopped for futility.  Otherwise, 5 
additional subjects will be accrued for a total of 21 [n].  The null hypothesis will be rejected if 
5 [r2+1] or more responses are observed in 21 subjects.  This design yields a type I error rate of 
0.075 and power of 0.80 when the true response rate is 0.30.   
10.1.1. Method of Treatment Assignment 
This single arm study will use open label enrollment for two disease cohorts, lower-risk MDS 
and nonproliferative CMML.  Subjects from both disease cohorts will be screened and enrolled 
consecutively.   
10.1.2. Sample Size Determination 
Sample size is determined based on Simon’s two-stage design.  See statistical plan in above.   
10.1.3. Minimization of Bias 
 
Subjects are screened and enrolled in a consecutive manner which reduces selection 
bias by the investigators.   
 
Both male and female study subjects of 18 years of age are included in study. 
 
Independent adjudication for enrollment by a subinvestigator will be used as needed to 
reduce selection bias  

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 
Independent adjudication for DLT assessment by a subinvestigator will be used as 
needed to reduce bias. 
10.2. Study Endpoints  
10.2.1. Primary Endpoint 
10.2.1.1. Primary Objective / Outcome 
The primary objective for the study is to determine the efficacy (response rate) of enasidenib in 
improving anemia and decreasing RBC transfusion dependence.  Study subjects on each arm 
of the study will be based on their transfusion status at study entry according to the modified 
2018 IWG recommendations: 
 
# of RBC Units Transfused Time Period (weeks) 
NTD 
0 
16 
LTD 
3-7 
16 
HTB 
≥ 8 
16 
or ≥ 4 
8 
The proportion of study subjects in each disease specific cohort of the study will be determined 
as the response rate.   
10.2.1.2. Endpoint Definition for Primary Objective / Outcome 
The subject response to treatment is determined by modified IWG 2018-defined hematological 
improvement-erythroid (HI-E) as below.  For example, subjects with entry as NTD will require an 
improvement of hemoglobin by 1.5 g/dL in a 8-week period.   
 
2018 IWG HI-E criteria 
Time Period (weeks) 
NTD 
Hemoglobin increase ≤ 1.5g/dL 
8 
LTD 
0 units of RBC transfusions 
8 
HTB 
≥ 4 unit reduction of RBC transfusions; or  
≥ 50% reduction in units of RBC transfusion 
8 
The primary efficacy endpoint is the response rate defined as the proportion of study subjects 
achieving treatment response.   
10.2.1.3. Assessment Methods for Primary Objective / Outcome 
The hemoglobin and the number of transfusions for each study subject will be recorded from 
each laboratory evaluation during the course of the study.  The changes in these parameters 
will be used to assess the primary objective.  These parameters will be captured by the data 
manager and recorded in the EDC (REDCap).   

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10.2.1.4. Measurement Time Points for Primary Objective / Outcome 
The changes in hemoglobin and number of transfusions for each study subject will be calculated 
and evaluated every 4 weeks according to the modified 2018 IWG HI-E criteria by the principal 
investigator and/or a designated research team member. 
10.2.1.5. Response Review 
The responses for each study subject will be reviewed by the principal investigator monthly.  If a 
study subject has not met criteria as a responder within the first 6 months of treatment, the 
subject will be considered a nonresponder and exit the study.  If the study subject is believed to 
be deriving clinical benefit on enasidenib by the end of 12 months on study protocol by the PI, 
the subject may continue treatment after discussion with the study sponsor, until unacceptable 
toxicity, loss of response or closure of the protocol. Patients who are approved to continue 
treatment after 12 cycles will have routine lab draws as clinically indicated.  
10.2.2. Secondary Endpoints 
The secondary endpoints are as follows: 
1) To determine the safety of enasidenib in subjects without IDH2 mutations using the type, 
incidence, severity, and relatedness of adverse events in accordance with the 
CTCAE v5.0.   
2) To determine the time to HI-E, defined as time from first dose of enasidenib to the first 
observed hemoglobin change meeting 2018 IWG HI-E criteria (Section 10.2.1.2). 
3) To determine the duration of HI-E, defined as time from each recorded response of 
increase in hemoglobin meeting 2018 IWG-HI-E criteria (Section 10.2.1.2) to loss of that 
specific response.   
4) To determine the proportion of subjects who achieve a response defined by the modified 
2018 IWG criteria in improvement of platelet count (HI-P).   
Pre-treatment platelets 
(average value during the 16-week 
baseline monitoring period) 
2018 IWG HI-P 
Time Period 
(weeks) 
< 20 x 109/L 
increase from < 20 x 109/L to > 20 x 109/L 
and by at least 100% 
8 weeks 
≥ 20 x 109/L 
absolute increase of 30 x 109/L 
8 weeks 
5) To determine the proportion of subjects who achieve a response defined by the modified 
2018 IWG criteria in improvement of neutrophils (HI-N).   

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Pre-treatment neutrophils  
(average value during the 16-week 
baseline monitoring period) 
 
 
 
2018 IWG HI-P 
Time Period 
(weeks) 
Any 
 
 
At least 100% increase and an absolute 
increase > 0.5 x 109/L 
8 weeks 
6) To determine the proportion of study subjects who are transfusion dependent (LTD and 
HTB) achieving RBC transfusion independence (RBC-TI) for 8 weeks or longer. 
10.2.3. Exploratory Endpoints 
The following exploratory endpoints will be analyzed: 
 
Erythropoiesis indices and potential predicative biomarkers in the responders and 
nonresponders will be analyzed using logistic regression or Cox proportional hazard 
ratio.  
 
The frequency of hematopoietic and erythroid progenitors in responders and 
nonresponders will be compared using unpaired t-test.  
 
Correlation of mutation status of each study subject and their response to therapy will be 
performed using multivariable Cox regression analysis.  
 
Transcriptomic analysis and gene expression profiling will be performed to identify 
potential pathways targeted by enasidenib.  Differentially expression genes will be 
determined using a negative binomial model.  Gene ontology analysis will be performed 
using the PANTHER Gene ontology Consortium tool.   
10.3. Interim Analyses 
10.3.1. Stopping Rules 
An interim efficacy analysis will be provided after enrolling 16 evaluable subjects for each 
disease cohort which is the end of the first stage of the study.  In the first stage, 16 [n1] subjects 
will be enrolled.  If there are 1 [r1] or less responses in stage 1, the study will be stopped for 
futility. 
10.4. Primary Analysis  
10.4.1. Primary Analysis Population 
The primary efficacy population will include all subjects who have received at least one dose of 
enasidenib at the RP2D and with at least one post-baseline laboratory evaluation.   

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10.4.2. Primary Analysis Plan 
The response rate of subjects to enasidenib in improving hemoglobin and reducing 
RBC transfusion dependence will be analyzed using primary endpoint defined in 
Section 10.2.1.2.  Response assessments will be summarized tables to best display and reflect 
the variation, timing and duration of responses of individual subjects.   
10.5. Secondary Analysis 
10.5.1. Secondary Analysis Population 
Safety - The safety population will consist of all enrolled subjects who received at least 1 dose 
of any study treatment.  The safety population will be used for the analysis of safety data.   
All other secondary endpoints – The secondary analysis population will include all subjects 
who have received at least 1 dose of enasidenib at the RP2D and with at least 1 post-baseline 
laboratory evaluation.   
10.5.2. Secondary Analysis Plan 
Safety 
All adverse events will be recorded and tabulated.  Dose limiting toxicity will be noted.  Adverse 
events will be graded according to the CTCAE v5.0 and divided into those that are Grade 1 to 2 
and those that are Grade 3 or higher.  Serious adverse events will also be analyzed separately, 
as will adverse events leading to discontinuation of study drug or exit from study. 
Time to HI-E 
Time to HI-E for each study subject will be determined as the interval between day of first dose 
of enasidenib to meeting response criteria as defined in Section 12.2.1.2 
(2018 modified IWG HI-E).  Results will be summarized descriptively using the Kaplan-Meier 
method.   
Duration of HI-E  
The duration of response for HI-E for each study subject will be determined as the interval 
between the time of first response to loss of the response according to criteria as defined in 
Section 12.2.1.2 (2018 modified IWG HI-E).  Results will be summarized descriptively using the 
Kaplan-Meier method.   
Response rate of HI-P  
The response rate of subjects to enasidenib in improving platelet count and reducing platelet 
transfusion dependency will be analyzed using a repeated measures model using secondary 
endpoint defined in Section 10.2.2 (2018 IWG HI-P).  Response assessments will be 
summarized in spider plots to best display and reflect the variation, timing and duration of 
responses of individual subjects.   
Response rate of HI-N 
The response rate of subjects to enasidenib in improving neutrophil count will be analyzed using 
a repeated measures model using secondary endpoint defined in Section 10.2.2 

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(2018 IWG HI-P).  Response assessments will be summarized in spider plots to best display 
and reflect the variation, timing and duration of responses of individual subjects.   
Transfusion rate 
The transfusion rate is defined as the number of transfusions (red blood cells and platelets) 
received by each study subject during an 8-week period.   
Transfusion independence 
Transfusion independence will be defined as the proportion of study subjects (defined by their 
transfusion needs in Section 10.2.1.1) which become transfusion independent after receiving at 
least one dose of enasidenib.   
10.5.3. Sample Size 
Each disease cohort will be evaluated independently.  This study has an accrual goal of 
21 subjects for each disease cohort.  The sample size is determined using Simon’s two-stage 
design to achieve a power of 0.80 with a type I error rate of 0.075 to detect a true response rate 
of 0.30.  See statistical plan in Section 10.1 for details.   
10.5.4. Accrual estimates 
We expect the study to take 24 months to accrue for each arm of the study and the core study 
will be completed by the end of 24 months.  Accrual estimates are made to the best of the 
Principal Investigator’s knowledge prior to study opening.  The PI will review study accrual with 
Celgene every 6 to 12 months and revise the accrual estimates in the protocol accordingly.   
10.5.4.1. Sample size justification 
Sample size is justified by the power calculations above in Section 10.5.3.   
10.5.4.2. Effect size justification 
Based on historical data and our experience in taking care of subjects with lower-risk MDS and 
nonproliferative CMML, the expected true response rate on best supportive therapy as standard 
of care would be 0, since there are no spontaneous remissions.  Therefore, a conservative true 
response rate of 0.1 [P0] was chosen to achieve a power of 0.80 with a type I error rate of 0.075 
to detect a response rate of 0.3 [P1].  The response rate of 0.3 would be considered a robust 
response given constraints of resources.   
10.5.4.3. Criteria for future studies 
If the trial is not stopped early for futility, and if 5 or more responses are observed in 21 subjects 
in each disease cohort, then the null hypothesis will be rejected which supports further 
development of enasidenib in improving erythropoiesis.   
10.6. Descriptive Statistics and Exploratory Data Analysis 
All statistical analysis will be performed using Graph Pad Prism 8 or R studio.   
Qualitative background variables (sex, age, race/ethnicity) will be summarized using 
contingency tables.  Descriptive statistics, including frequency and confidence internals, will be 
used to describe the study population.  Comparison will be made using institutional and 
published historical data. 

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Exploratory endpoint analysis will including the following: 
 
Erythropoiesis indices and potential predicative biomarkers in the responders and 
nonresponders will be analyzed using logistic regression or cox proportional hazard 
ratio.  Erythropoiesis indices will include the following:  
Reticulocyte count 
Red cell distribution 
MCV 
Plasma erythropoietin level 
Plasma TGF beta family member levels 
Serum iron 
Transferrin saturation 
Ferritin 
 
The frequency of hematopoietic and erythroid progenitors in responders and 
nonresponders will be compared using unpaired t test.   
 
Correlation of mutation status of each study subject and their response to therapy will be 
performed using multivariable Cox regression analysis.   
 
Transcriptomic analysis and gene expression profiling will be performed to identify 
potential pathways targeted by enasidenib.  Differentially expression genes will be 
determined using a negative binomial model.  Gene ontology analysis will be performed 
using the PANTHER Gene ontology Consortium tool (ref).   

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11. REFERENCES  
1. Goodnough LT, Schrier SL.  Evaluation and management of anemia in the elderly: 
Evaluation and management of anemia in the elderly.  Am J Hematol.  2014:89:88-96. 
2. Gilreath JA, Rodgers GM.  How I treat cancer-associated anemia.  Blood.  
2020:136:801-813. 
3. Stein EM, et al.  Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.  
Blood.  2017;130:722-731. 
4. Pollyea DA, et al.  Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable 
remissions in older patients with newly diagnosed acute myeloid leukemia.  Leukemia.  
2019;33:2575-2584. 
5. Hagiya A, et al.  Bone Marrow Features in Patients With Acute Myeloid Leukemia Treated 
With Novel Targeted Isocitrate Dehydrogenase 1/2 Inhibitors.  World J Oncol.  
2019;10:226-230. 
6. Yen K, et al.  AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia 
Harboring Oncogenic IDH2 Mutations.  Cancer Discovery.  2017;7:478-493. 
7. Stein EM, et al.  Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.  
Blood.  2017;130:722-731. 
8. Amatangelo MD, et al.  Enasidenib induces acute myeloid leukemia cell differentiation to 
promote clinical response.  Blood.  2017;130:732-741. 
9. Dutta R, et al.  Enasidenib drives human erythroid differentiation independently of isocitrate 
dehydrogenase 2.  Journal of Clinical Investigation.  2020:130:1843-1849. 
10. Platzbecker U, et al.  Proposals for revised IWG 2018 hematological response criteria in 
patients with MDS included in clinical trials.  Blood.  2019;133:1020-1030. 

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12. PROTOCOL HISTORY 

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Version 
Date * 
Change Summary 
19 Aug 2021 Submission to SCI Scientific Review Committee (SRC) 
24 Aug 2021 Initial IND submission (courtesy rush) 
8 Sep 2021 SRC-approved version 
21 Sep 2021 Response to FDA comments.  IRB submission 
2 Sep 2022 
• Clarifies the previously stated study population vs the inclusion criteria (Synopsis and 
Section 3.1.1.1).  
• Adjusts upper limit of hemoglobin level from < 10.0 g/dL to < 10.5 g/dL, as part of the 
corresponding Inclusion Criteria (Section 3.1.1.6).  
• Removes prior treatment with iron chelation therapy as an Exclusion Criteria 
(Section 3.1.2.2).  
• Revises the Concomitant Medications list to allow the medications if the subject will also 
receive ECG monitoring during the period of concurrent use.  
• Updates study procedures and table from specifying unconjugated bilirubin to specifying 
conjugated or direct bilirubin (Sections 6.1 and 6.2). 
• Clarifies study procedures and table regarding TSH; free T3; and free T4 testing 
(Sections 6.1 and 6.2). 
• Omits redundant text in Section 7.6.  
• Corrects the Stanford eProtocol number throughout. 
• Populates protocol history table (Protocol History).  
• Other typographical and administrative corrections and updates 
9 Sep 2022 Corrects typographical error in Inclusion Criteria for creatinine clearance. 
9 November 
2022 
• 
Updates to the cohort descriptions 
• 
Protocol statement that the determination of the recommended phase 2 dose will be 
reported to the  SCI DSMC and SRC is omitted. 
7 December 
2022 
• 
Clarifies that virtual visits maybe conducted for evaluation. (Section 6.2.1) 
• 
Typographical correction on page 38 

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Version 
Date * 
Change Summary 
2 February 
2023 
• 
Updates language regarding dose interruptions. (Section 5.6.1) 
• 
Clarifies dose limiting criterion (Section 5.6.1) 
• 
Updates Study Procedure table to include +/- 3 window for Day 15 to be consistent with 
Treatment Period visit description in Section 6.2.1 (Table 6.1) 
• 
Corrects End of Study window in Study Procedure table to be consistent with +28-day 
in Final Study Visit description in Section 6.2.1 (Table 6.1) 
• 
Removes ECG procedure from Final Study Visit description in 6.2.1 to be consistent 
with Table 6.1 (Section 6.2.1) 
• 
Other typographical and administrative corrections and updates. 
6 April 2023 
• 
Omits IDH2 PCR testing requirement from eligibility criteria (Sections 3.1.1 and 3.1.2). 
• 
Updates study team contact information (Section 3.4.1). 
• 
Modifies visit nomenclature “Day 28+ 7 days” to “Day 1+/-3” and updates exams listed 
under Final Visit to be consistent with Study Procedures Table (6.2.1). 
• 
Clarifies duration of follow-up for participants and those that discontinue treatment for 
unacceptable adverse events or toxicity (Sections 6.2.1 and 5.9). 
• 
Expands screening window to 45 days (Sections 6.1: Footnote1, 6.2.1, and 6.2.2). 
• 
Clarifies that EOT biobanking collection is collected per investigator discretion                  
(Sections 6.1:Footnote 10 and 6.2.1). 
• 
Clarifies that a single ECG is captured at designated timepoints (Sections 6.1:                  
Footnote 14 and 6.2.1). 
• 
Clarifies that B-HCG is only collected for participants who are female of child bearing       
potential (Sections 6.1: Footnote15 and 6.2.1). 
• 
Updates magnesium collection requirement through Cycle 4 Day 15 (Sections 6.1:           
Footnote 16 and 6.2.1). 
• 
Removes IDH2 PCR testing requirement (Sections 6.1 and 6.2.1) . 
• 
Omits adverse events of special interest language not applicable to protocol (Section 
7.2) 
• 
Addition of language to note that all SAEs will be followed for up to 90 days after the 
last dose of the enasidenib, or until SAE(s) is (are) resolved or stable, or until patient 
initiates a new/alternative therapy (including but not limited to growth factors, 
chemotherapy or          bone marrow transplant), whichever is occurs first (Section 7.6). 
• 
Updates drug manufacturer patient safety reporting email and fax (Section 7.6). 
• 
Other typographical and administrative corrections and updates. 

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Version 
Date * 
Change Summary 
13 Jun2023 
• 
Changes the amount of blood and aspirate being collected for biobanking 
• 
Other typographical and administrative corrections and updates. 
15 Aug 2023 
• 
Eligibility inclusion criteria 6 has been updated to include patients presenting with 
thrombocytopenia and/or neutropenia. (Section 3.1.1) 
• 
Clarification to bone marrow biopsy requirements at screening (Section 6.2.1) 
• 
Clarification to laboratory requirements for those patients who continue therapy with 
enasidenib beyond twelve cycles. (6.1 Study procedure table and 10.2.1.5) 
• 
Other typographical and administrative corrections and updates. 
20 Mar 2024 
• 
 Update that Ph 2 cohorts will receive 100 mg in Cycle 1 followed by dose escalation to 
200 mg (RP2D) dose of enasidenib in future cycles as tolerated. (Section 2.1.3; Section 
2.1.6; and Section 5.2) 
• 
Removed Exclusion criteria that limits the use of erythropoietic agents and G-CSF 
within 20 days of study enrollment (Section 3.1.2) 
• 
Clarification to the patient’s study schedule in the setting of a dose interruption of 28 
days or more (Section 5.6) 
• 
Other typographical and administrative corrections and updates. 
23 Jul 2024 
• 
Revised language to clarify duration of AE follow-up period so it is consistent with 
language in Section 7.2.4 (Section 6, footnote 2) 
• 
Other typographical and administrative corrections and updates. 
* Latest date should match footer date of the current document 

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13. APPENDICES  
13.1. Appendix A.  References for Stanford Cancer Institute Policies & Practices 
Standard Operating Procedures (SOPs): 
 
Stanford School of Medicine standard operating procedure SOP-005 “Identifying and 
Reporting Adverse Events.”  This document is available on the Spectrum website.   
http://med.stanford.edu/spectrum/b4_research_quality/b4_3_standard_operating_procedures.html.   
 
SCI Scientific Review Committee (SRC) Policies and Procedures 
http://med.stanford.edu/content/dam/sm/cancer/documents/PRMSDocuments/SRC_SOP.pdf.   
 
Confirmation of Participant Eligibility in Clinical Trials 
http://med.stanford.edu/content/dam/sm/ccto/sunet_id_resources/regulatory_documents/sop/SOP_Participant_Eligibility_
Confirmation.pdf.   
 
SCI Institutional Data and Safety Monitoring Plan. 
http://med.stanford.edu/cancer/research/trial-support/dsmc.html.   
 
SCI Data Management in Clinical Investigations 
http://med.stanford.edu/content/dam/sm/ccto/sunet_id_resources/regulatory_documents/sop/SOP-Data%20Management.pdf.   
Logs and Forms: 
 
The SCI Adverse Event Log (editable): 
http://med.stanford.edu/content/dam/sm/ccto/sunet_id_resources/coordinator_documents/Adverse%20Event%20Log.pdf.   
 
SCI Serious Adverse Event Report Form (editable): 
http://med.stanford.edu/content/dam/sm/ccto/sunet_id_resources/coordinator_documents/SAE_CRF.pdf. 
 
Sample Study Participant Log (editable): 
http://med.stanford.edu/content/dam/sm/ccto/sunet_id_resources/coordinator_documents/Subject_Log_07.29.11.doc.   
Guidelines: 
 
SCI Guideline for Studies Relying on External Central or Single IRBs.   
http://med.stanford.edu/content/dam/sm/ccto/sunet_id_resources/regulatory_documents/NCTN%20Guideline_Studies_Re
lying_on_External_Central_or_Single_IRBs.pdf.   
Current Stanford University IRB policies and procedures: 
 
Stanford University Human Research Protection Program (HRPP) Policy Manual at:  
http://researchcompliance.stanford.edu/hs/hrpp/Documents/hrpp_entire.pdf.   

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 
Stanford University HRPP Policy Guidance Events and Information that Require Prompt 
Reporting to the IRB GUI-P13 at: 
http://humansubjects.stanford.edu/research/documents/Events-Info-Report-to-IRB_GUI03P13.pdf.   
 
Stanford University HRPP Unanticipated Problem reporting process is defined at 
Section 3.10, in the Human Research Protection Program (HRPP) Policy Manual 
http://researchcompliance.stanford.edu/hs/hrpp/Documents/hrpp_entire.pdf.   
Other regulatory documentation and resources 
 
Contact a Department of Biomedical Data Science (DBDS) biostatistician: 
https://redcap.stanford.edu/surveys/?s=7TTM3AELCT.   
 
The US FDA requirements for adverse event reporting for investigational drugs are 
defined at 21CFR§312.32(a) 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32. 
 
The Common Terminology Criteria for Adverse Events (CTCAE) version 5 are available 
at:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50, see 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5.0.xlsx OR 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x
11.pdf.   
 
The International Conference on Harmonization (ICH) Guideline on 
Good Clinical Practice (ICH GCP E6r1), including adverse event reporting, is available 
at: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf.   
These links may change from time to time, and will be updated in this template as needed.  Consult issuing 
authority as needed.   

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13.2. Appendix B.  Reference reports submitted for DSMC audit 
 
Delegation of Authority (DOR/DOA) log 
 
Statement of Investigator (FDA Form 1572) 
 
Electronic copies of source documents and CRFs, including signed informed consent 
forms, eligibility checklists with reviewer signatures  
 
Documents that are available in EPIC do not need to be and are not provided 
 
Direct access to electronic data capture EDC system is required for monitoring 
purposes, effective 9/21/2020 
 
Investigational Drug services (IDS) drug dispense log and report 
 
IDS Drug accountability records, temperature logs, drug orders, and shipment records 
 
Electronic copies of drug diary from each subject 
 
Protocol Deviation (PD) aggregate review deviations reported in EDC 
 
Documentation justifying the RP2D at the end of phase 1b portion of the study.   
 
Sample log documenting all samples collected for research purposes.