Clinical trial NCT02842827
Conditions: Acute Myeloid Leukemia Myelodysplastic Syndrome
Keywords: LSD1 High-risk Acute Myeloid Leukemia High-risk Myelodysplastic Syndrome
Sponsor: Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)
Start date: 2016-10-06; Completion date: 2018-10-30
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open label study of the dose and duration of an orally administered lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat, in patients with high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Some participants may also receive all-trans retinoic acid (ATRA; also known as tretinoin and Vesanoid®) in combination with bomedemstat. This study investigates the following:

* The safety and tolerability of bomedemstat with and without ATRA
* The pharmacodynamic effect of different doses of bomedemstat and treatment durations, as well as bomedemstat administered in combination with ATRA
* The pharmacokinetics of bomedemstat with and without ATRA

Detailed description:

Arms: arm 1: Participants receive bomedemstat 0.75 mg/kg/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment). arm 2: Participants receive bomedemstat 1.5 mg/kg/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment). arm 3: Participants receive bomedemstat 3 mg/kg/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment). arm 4: Participants receive bomedemstat 6 mg/kg/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment). arm 5: Participants receive bomedemstat 3 mg/kg/day orally plus tretinoin 45 mg/m\^2/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment). arm 6: Participants receive bomedemstat 6 mg/kg/day orally plus tretinoin 45 mg/m\^2/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment). arm 7: Participants receive bomedemstat 6 mg/kg/day orally plus tretinoin 45 mg/m\^2/day orally in 21-day cycles consisting of 14 days of treatment and 7 days of rest. Participants will receive up to 2 cycles (21-day cycles) for up to a total of up 42 days (28 days on treatment). arm 8: Participants receive bomedemstat 6 mg/kg/day orally for 21 days plus tretinoin 45 mg/m\^2/day orally in 28-day cycles consisting of 21 days of treatment and 7 days of rest. Participants will receive at least 1 cycle (28-day cycles) and will receive subsequent cycles at the discretion of the investigator.
Interventions: intervention 1: bomedemstat intervention 2: tretinoin
Intervention descriptions: intervention 1: oral administration intervention 2: oral administration

Protocol documents:
Prot_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Multi-Center, Open Label Study to Assess 
the Safety,Steady-State Pharmacokinetics 
and Pharmacodynamics of IMG-7289 with 
and without ATRA (Tretinoin) in Patients
with Advanced Myeloid Malignancies
NCT02842827
29-Aug-2017


PPD
PPD
PPD
PPD
PPD
PPD
PPD


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 2 of 127 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Multi-Center, Open Label Study to Assess the Safety, 
Steady-State Pharmacokinetics and Pharmacodynamics of 
IMG-7289 with and without ATRA (Tretinoin) in Patients 
with Advanced Myeloid Malignancies 
Protocol No.: 
IMG-7289-CTP-101 
Version and Date Final: 
Amendment 3:  29 August 2017 
Sponsor: 
Imago BioSciences, Inc.
2729 Debbie Court  
San Carlos, CA 94070 - USA  
Imago BioSciences, Ltd. 
Church Cottage 
28 Broadway 
Chilton Polden 
Somerset TA7 9DP  
United Kingdom 
Declaration of Investigator 
I confirm that I have read and understood this protocol, and agree to conduct the study as 
outlined in the protocol and other information supplied to me.  I agree to conduct the 
study in compliance with: all local legal and regulatory requirements, good clinical 
practice as described in the International Conference on Harmonization document 
“Guidance for Industry – E6 Good Clinical Practice:  Consolidated Guidance”; and the 
Declaration of Helsinki. 
_________________________________________________________________                               ____________________ 
Investigator Signature                                                                                               Date 
 
_________________________________________________________________                               ____________________ 
Investigator Name (Print)                                                                                               
 
PPD
PPD


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Table of Contents 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................ 9 
1.1 
List of Abbreviations ............................................................................................................................... 9 
2 
PROTOCOL SYNOPSIS ...............................................................................................................................14 
3 
INTRODUCTION ............................................................................................................................................31 
3.1 
Background Information .......................................................................................................................31 
3.2 
The Diseases to be Treated ..................................................................................................................31 
3.3 
Lysine (K)-Specific Demethylase 1 (LSD1) ..................................................................................31 
3.3.1 
Potential Clinical Scenarios when Treating with an LSD1 Inhibitor ............................33 
3.4 
Background to All-Trans Retinoic Acid (ATRA; tretinoin) Use in Acute Leukaemia ....35 
3.5 
Rationale for IMG-7289 and ATRA Combination Therapy .....................................................36 
3.6 
IMG-7289 Dose Justification ..............................................................................................................37 
3.6.1 
Rationale for and Safety of the Proposed IMG-7289 Starting Dose .............................37 
3.6.2 
Rationale for the IMG-7289 Dosing Schedule.....................................................................39 
3.7 
ATRA Dose and Duration in Non-APL AML ...............................................................................40 
4 
HYPOTHESIS AND OBJECTIVES .........................................................................................................40 
4.1 
Hypothesis .................................................................................................................................................40 
4.2 
Objectives ..................................................................................................................................................40 
4.2.1.1 
Primary ................................................................................................................................... 41 
4.2.1.2 
Secondary .............................................................................................................................. 41 
4.2.1.3 
Exploratoryɸ ......................................................................................................................... 41 
5 
INVESTIGATIONAL PLAN .......................................................................................................................41 
5.1 
Overview ...................................................................................................................................................41 
6 
STUDY POPULATION .................................................................................................................................45 
6.1 
Study Entry Criteria ...............................................................................................................................45 
6.1.1 
Inclusion Criteria ...........................................................................................................................45 
6.1.2 
Exclusion Criteria ..........................................................................................................................46 
6.2 
Patient Enrollment ..................................................................................................................................47 
6.3 
Patient Withdrawal .................................................................................................................................47 
6.4 
Replacement of dropouts ......................................................................................................................48 
6.5 
Guidelines ..................................................................................................................................................48 
6.6 
Prohibited Medications .........................................................................................................................49 
6.7 
Patients Who Terminate Early or Discontinue Study Medication...........................................49 
6.8 
Treatment Failure ....................................................................................................................................50 
7 
STUDY TREATMENT ..................................................................................................................................50 
7.1 
Formulation, Labeling, Packaging and Storage ............................................................................50 


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7.1.1 
Formulation .....................................................................................................................................50 
7.1.2 
Packaging and Labeling ..............................................................................................................50 
7.1.3 
Storage ..............................................................................................................................................50 
7.2 
Dispensing, Dosage and Duration by Study Phase, and Administration ...............................51 
7.2.1 
Dispensing .......................................................................................................................................51 
7.2.2 
Dosage and Duration of Treatment ..........................................................................................51 
7.2.2.1 
Dosage and Duration of Treatment During the Dose-finding Phase .................. 52 
7.2.2.2 
Provisional Sub-cohorts; Unacceptable Dose Limiting Toxicity is 
Demonstrated at the Ds ............................................................................................................................ 54 
7.2.2.3 
Dosing and Duration of Treatment During the Duration-finding Phase ........... 55 
7.2.3 
Administration ................................................................................................................................57 
7.2.3.1 
IMG-7289 Administration ............................................................................................... 57 
7.2.3.2 
ATRA Administration ....................................................................................................... 57 
7.2.4 
Missed Doses ..................................................................................................................................57 
7.2.4.1 
Missed IMG-7289 Doses ................................................................................................. 58 
7.2.4.2 
Missed ATRA Doses ......................................................................................................... 58 
8 
DATA SAFETY MONITORING COMMITTEE (DSMC) REVIEWS AND 
MANAGEMENT OF STUDY TOXICITIES ...................................................................................................58 
8.1 
Data Safety Monitoring Committee (DSMC) Reviews ..............................................................58 
8.2 
Management of Study Toxicities .......................................................................................................61 
8.2.1 
IMG-7289 Toxicity Definitions ................................................................................................62 
8.2.2 
IMG-7289 Dose Escalation, Combination Therapy and Duration Extension 
Decision Rules ..................................................................................................................................................63 
8.2.3 
IMG-7289 Maximum Tolerated Dose (MTD) and Duration (MTDu)ɸ ........................64 
8.3 
ATRA Toxicity ........................................................................................................................................64 
9 
STUDY ASSESSMENTS BY COHORT AND CYCLE ....................................................................64 
9.1 
All Cohorts - Informed Consent and Screening Period, Including Baseline ........................65 
9.1.1 
All Cohorts - Informed Consent and Screening Period .....................................................65 
9.1.2 
All Cohorts - Baseline Period (Days -21 to Day -1) ..........................................................66 
9.1.3 
All Cohorts - Enrollment ............................................................................................................67 
9.1.4 
All Cohorts - Last Day of Screening Period (Day -1) .......................................................67 
9.2 
All Cohorts - Cycle 1, Day 1 (Start of Treatment) .......................................................................68 
9.2.1 
All Cohorts - Cycle 1, Pre-Dose Day 1 ..................................................................................68 
9.2.1.1 
Cohort 1 Only – Cycle 1, Pre-Dose Day 1 ................................................................. 68 
9.2.2 
All Cohorts - Cycle 1, Dosing Day 1 ......................................................................................68 
9.2.3 
All Cohorts - Cycle 1, Post-IMG-7289 Dose Day 1 ..........................................................68 
9.2.3.1 
Cohort 1 Only - Cycle 1, Post-IMG-7289 Dose Day 1........................................... 68 


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9.3 
Cohort 1, Cycle 1 ....................................................................................................................................69 
9.3.1 
Cohort 1, Cycle 1 - Days 2, 3 and 5 (± 1 day for Days 3 and 5) ....................................69 
9.3.2 
§§Cohort 1, Cycle 1 - Day 6 ........................................................................................................69 
9.3.3 
Cohort 1, Cycle 1 - Pre-Dose Day 7 ........................................................................................70 
9.3.4 
Cohort 1, Cycle 1 - Dosing Day 7 ............................................................................................70 
9.3.5 
Cohort 1, Cycle 1 - Post-IMG-7289 Dose Day 7 ................................................................70 
9.3.6 
Cohort 1, Cycle 1 - Day 8 ...........................................................................................................70 
9.3.7 
Cohort 1, Cycle 1 - Days 9 and 11 (± 1 day) ........................................................................71 
9.3.8 
Cohort 1, Cycle 1 - Day 14* ......................................................................................................71 
9.4 
Cohort 1, Cycles 2, 3 and 4 ..................................................................................................................71 
9.4.1 
Cohort 1, Cycles 2, 3 and 4 - Pre-Dose Day 1 .....................................................................71 
9.4.1.1 
§§Cohort 1, Cycles 2 and 3 Only - Pre-Dose Day 1 ................................................. 72 
9.4.1.2 
Cohort 1, Cycles 2 and 4 Only – Pre-Dose Day 1 – Combination Therapy 
Patients Only (excluding Cohort 1χ) ................................................................................................... 72 
9.4.2 
Cohort 1, Cycles 2, 3 and 4 – Dosing Day 1 ........................................................................72 
9.4.3 
Cohort 1, Cycles 2, 3 and 4 - Post-Dose Day 1 ...................................................................72 
9.4.4 
Cohort 1, Cycles 2, 3 and 4 - Days 4, 9 and 11 (± 1 day) .................................................72 
9.4.5 
Cohort 1, Cycles 2, 3 and 4 - Day 6 ........................................................................................73 
9.4.6 
Cohort 1, Cycles 2, 3 and 4 - Days 7 and 14* (Day 14 ± 1 day) ....................................73 
9.4.6.1 
Cohort 1, Cycle 3 Only – Days 7 and 11 – Combination Therapy Patients Only
 
73 
9.4.6.2 
Cohort 1, Cycles 2 and 4 Only - Day 14 (± 1 day) .................................................. 74 
9.4.6.3 
Cohort 1, Cycle 4 Only - Day 14 (± 1 day) ................................................................ 74 
9.5 
Cohorts 3 and 3χ, Cycle 1 ....................................................................................................................74 
9.5.1 
Cohorts 3 and 3χ, Cycle 1 - Days 3, 5, 9, 11, 16 and 18 (± 1 day) ................................74 
9.5.2 
Cohorts 3 and 3χ, Cycle 1 - Day 13 .........................................................................................74 
9.5.3 
Cohorts 3 and 3χ, Cycle 1 - Days 7, 14 and 21* (± 1 day for Day 7) ...........................75 
9.6 
Cohorts 3 and 3χ, Cycle 2 ....................................................................................................................75 
9.6.1 
Cohorts 3 and 3χ, Cycle 2 - Pre-Dose Day 1 ........................................................................75 
9.6.2 
Cohorts 3 and 3χ, Cycle 2 - Dosing Day 1 ............................................................................76 
9.6.3 
Cohorts 3 and 3χ, Cycle 2 - Post Dose Day 1 ......................................................................76 
9.6.4 
Cohorts 3 and 3χ, Cycle 2 - Days 4, 10, 12, 16 and 18 (± 1 day) ..................................76 
9.6.5 
Cohorts 3 and 3χ, Cycle 2 - Days 7, 14 and 21* (± 1 day for Day 7) ...........................76 
9.6.5.1 
Cohorts 3 and 3χ, Cycle 2 - Day 21 Only ................................................................... 77 
9.7 
Cohorts 4 and 4χ, Cycle 1 ....................................................................................................................77 
9.7.1 
Cohorts 4 and 4χ, Cycle 1 - Days 3, 5, 9, 11, 17, 19, 23 and 25 (± 1 day)..................77 
9.7.2 
Cohorts 4 and 4χ, Cycle 1 - Day 20 .........................................................................................78 


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9.7.3 
Cohorts 4 and 4χ, Cycle 1 - Days 7, 14, 21 and 28* (± 1 day for Days 7 and 14) ...78 
9.7.3.1 
Cohorts 4 and 4χ, Cycle 1 - Day 28 Only ................................................................... 79 
9.8 
Cohorts 4 and 4χ, First Additional Cycle (Cycle 2) .....................................................................79 
9.8.1 
Cohorts 4 and 4χ, First Additional Cycle (Cycle 2) - Pre-Dose Day 1 ........................79 
9.8.2 
Cohorts 4 and 4χ, First Additional Cycle (Cycle 2) - Dosing Day 1 ............................80 
9.8.3 
Cohorts 4 and 4χ, First Additional Cycle (Cycle 2) - Post IMG-7289 Dose Day 1 .80 
9.8.4 
Cohorts 4 and 4χ, First Additional Cycle (Cycle 2) - Days 4, 10, 13, 18, 23 and 25 
(± 1 day) 80 
9.8.5 
Cohorts 4 and 4χ, First Additional Cycle (Cycle 2) - Days 7, 15, 21 and 28 (± 1 day 
for Days 7, 15 and 21) ....................................................................................................................................80 
9.8.5.1 
Cohorts 4 and 4χ, First Additional Cycle (Cycle 2) - Day 28 Only.................... 81 
9.9 
All Cohorts, All Additional Cycles ...................................................................................................81 
9.9.1 
All Cohorts, All Additional Cycles - Pre-IMG-7289 Dose Day 1 .................................81 
9.9.2 
All Cohorts, All Additional Cycles - Dosing Day 1 ...........................................................82 
9.9.3 
All Cohorts, All Additional Cycles - Post IMG-7289 Dose Day 1 ...............................82 
9.9.4 
All Cohorts, All Additional Cycles - Treatment Days 4, 10 and 18 (± 1 day; as 
applicable based on cycle length) ...............................................................................................................82 
9.9.5 
All Cohorts, All Additional Cycles - Treatment Days 7, 14 and 21 (± 1 day; as 
applicable based on cycle length) ...............................................................................................................82 
9.9.6 
All Cohorts, All Additional Cycles - Rest Days 2, and 4 (± 1 day) ..............................82 
9.9.7 
All Cohorts, All Additional Cycles - Rest Day 7 (± 1 day) .............................................83 
9.10 
Extended Rest Period (Rest Day 8 up to to Rest Day 56) ..........................................................83 
9.10.1 
Abbreviated Visit – Rest Days 9, 11, 16, 18, 23, 25, 31, 38, 45 and 52 (as applicable 
based on duration of rest; ±1 day) ..............................................................................................................83 
9.10.2 
Standard Visit – Rest Days 14, 21, 28, 35, 42, 49 and 56 (as applicable based on 
duration of rest; ± 2 days) .............................................................................................................................84 
9.11 
Suspected Relapse ..................................................................................................................................84 
9.12 
Follow-Up Period Visits .......................................................................................................................84 
9.12.1 
End of Treatment ...........................................................................................................................84 
9.12.2 
Pre-End of Study Visit .................................................................................................................85 
9.12.3 
End of Study/Early Termination Visit ....................................................................................85 
10 LABORATORY SAMPLING FOR SAFETY, PK AND PD ANALYSIS ...................................86 
10.1 
Laboratory Measures .............................................................................................................................86 
10.1.1 
Local Laboratory Measures........................................................................................................86 
10.1.2 
Central Laboratory Measures ....................................................................................................87 
10.2 
Pharmacokinetic Sampling ..................................................................................................................88 
10.2.1 
Cohort 1 PK Sampling Schedule ..............................................................................................88 
10.2.1.1 
Cohort 1, Cycle 1 PK Sampling Schedule .................................................................. 88 


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10.2.1.2 
Cohort 1, Cycle 1 or Cycle 2 Sampling Schedule .................................................... 88 
10.2.2 
Cohort 1, Pre-dose Drug Concentration (Cmin) Sampling Schedule ..............................88 
10.2.2.1 
Cohort 1, Cycles 2, 3 and 4 Cmin Sampling Schedule .............................................. 89 
10.2.2.2 
Cohort 1 - Sampling Windows ....................................................................................... 89 
10.2.3 
Cohorts 3, 3χ, 4 and 4χ ................................................................................................................89 
10.2.3.1 
Cohorts 3, 3χ, 4 and 4χ - Sampling Schedule ............................................................ 89 
10.2.3.2 
Cohorts 3, 3χ, 4 and 4χ - Sampling Windows ........................................................... 89 
11 SAFETY ..............................................................................................................................................................90 
11.1 
Pregnancy ..................................................................................................................................................90 
11.2 
Adverse Events ........................................................................................................................................90 
11.2.1 
Adverse Event Intensity ..............................................................................................................92 
11.2.2 
Adverse Event Relatedness ........................................................................................................92 
11.2.3 
Serious Adverse Events ...............................................................................................................93 
11.2.4 
Reporting Serious Adverse Events ..........................................................................................94 
11.2.5 
Medical Events of Interest (MEOIs) .......................................................................................95 
12 ANALYSIS AND STATISTICAL CONSIDERATIONS ..................................................................95 
12.1 
General Considerations .........................................................................................................................95 
12.2 
Power ..........................................................................................................................................................95 
12.3 
Treatment Assignment and Blinding ................................................................................................95 
12.4 
Study Endpoints ......................................................................................................................................96 
12.4.1 
Primary Endpoints.........................................................................................................................96 
12.4.2 
Exploratory Endpoints .................................................................................................................97 
12.5 
Safety and Tolerability Data ................................................................................................................98 
12.6 
Pharmacokinetics Data ..........................................................................................................................98 
12.7 
Pharmacodynamic Data ........................................................................................................................99 
13 STUDY ADMINISTRATION .....................................................................................................................99 
13.1 
Ethical Considerations ........................................................................................................................ 100 
13.2 
Participation Information Sheet/Consent Form (PISCF)......................................................... 100 
13.3 
Human Research Ethics Committee (HREC) ............................................................................. 100 
13.4 
Study or Site Termination ................................................................................................................. 100 
13.5 
Study Documentation and Record Keeping ................................................................................ 101 
13.6 
Study Monitoring Requirements ..................................................................................................... 101 
13.7 
Quality Assurance ................................................................................................................................ 101 
13.8 
Confidentiality ...................................................................................................................................... 102 
14 INVESTIGATOR REQUIREMENTS ................................................................................................... 103 
14.1 
Protocol Adherence ............................................................................................................................. 103 


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14.2 
Source Documentation ....................................................................................................................... 103 
14.3 
Direct Access to Source Documentation ...................................................................................... 103 
14.4 
Case Report Forms .............................................................................................................................. 103 
14.5 
Study Drug Accountability ............................................................................................................... 104 
14.6 
Disposal of Study Drug ...................................................................................................................... 104 
14.7 
Training of Staff ................................................................................................................................... 105 
14.8 
Clinical Study Report ......................................................................................................................... 105 
14.9 
Retention of Records .......................................................................................................................... 105 
15 REFERENCES ............................................................................................................................................... 106 
16 APPENDICES ................................................................................................................................................ 111 
16.1 
Schedule of Assessments (SoA) by Cohort and Cycle ............................................................ 111 
16.1.1 
Required General Visits:  All Patients, All Cohorts ........................................................ 111 
16.1.2 
SoA:  Cohort 1, Cycle 1 ........................................................................................................... 112 
16.1.3 
SoA:  Cohort 1, Cycles 2-4 ..................................................................................................... 113 
16.1.4 
SoA:  Cohorts 3 and 3χ, Cycle 1 ........................................................................................... 114 
16.1.5 
SoA:  Cohorts 3 and 3χ, Cycle 2 ........................................................................................... 115 
16.1.6 
SoA:  Cohorts 4 and 4χ, Cycle 1 ........................................................................................... 116 
16.1.7 
SoA:  Cohorts 4 and 4χ, First Additional Cycle ............................................................... 117 
16.1.8 
SoA:  All Cohorts, All Additional Cycles .......................................................................... 118 
16.1.9 
Extended Rest Period ................................................................................................................ 119 
16.2 
Diagnostic Classifications, Prognostic Scores, and Response Criteria ............................... 120 
 
 
 


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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
1.1 List of Abbreviations 
Abbreviation 
Definition 
<, ≤, >, ≥ 
less than, less than or equal to, greater than, greater than or equal to 
± 
plus  
6-MP 
6-mercaptopurine 
6-TG 
6-thioguanine 
7+3 
seven days of cytarabine and three days of an anthracycline, generally 
daunorubicin or idarubicin 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukaemia 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukaemia 
AsO3 
arsenic trioxide 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
ATRA 
all-trans retinoic acid; tretinoin; Vesanoid® 
AUC 
area under the drug concentration time curve
AUC0-24 
area under the drug concentration time curve from time zero to 24 hours post-
dose  
BMI 
body mass index 
BSA 
body surface area 
BUN 
blood urea nitrogen 
°C 
degrees Centigrade 
C 
cohort 
CBC 
complete blood count 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CL/F 
apparent total clearance of drug after oral administration 
Cmax 
maximum observed blood concentration 
Cmin 
minimum observed plasma concentration at 24 hours from last dose 
CNS 
central nervous system 
CR 
complete remission or response 
CRi 
complete remission or response, with incomplete recovery 
CRF 
case report form 


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Abbreviation 
Definition 
CSF2 
colony-stimulating factor 2 
CSF3 
colony-stimulating factor 3 
CXCR4 
chemokine (C-X-C motif) receptor 4 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
co-efficient of variation 
Cycle 
duration comprised by the dosing and rest period; also referred to as treatment 
cycle 
d 
day 
Di 
dose needed to inhibit normal myeloid haematopoiesis 
DIC 
Disseminated Intravascular Coagulation 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
Dp 
pharmacodynamic dose; the dose needed to effect desired pharmacodynamics 
changes in malignant cells 
Ds 
starting dose 
DSMC 
Data Safety Monitoring Committee 
DSMP 
Data Safety Monitoring Plan 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event free survival 
EOS 
end of study 
EOT 
end of treatment 
EPO 
erythropoietin 
ESC 
embryonic stem cell 
EVI-1 
ecotropic viral integration site 1 
°F 
degrees Fahrenheit 
FAB 
French American British 
FACS 
fluorescence-activated flow cytometry 
FC 
flow cytometry 
FISH 
fluorescent in-situ hybridisation 
FPFV 
first patient first visit 
Free base of 
IMG-7289 
N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazin-
1-yl)-1-oxopentan-2-yl]-4-(1H-1,2,3-triazol-1-yl)benzamide, free base 
g or gm 
gram 
g/dL 
gram per deciliter 
GCP 
good clinical practice 
G-CSF 
gram colony stimulating factor 
GFR 
glomerular filtration rate 


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Abbreviation 
Definition 
GGT 
gamma glutamyltransferase 
GI 
gastrointestinal 
GLP 
good laboratory practice 
GM-CSF 
granulocyte-macrophage colony stimulating factor 
GMP 
Good Manufacturing Practices 
GVHD 
graft versus host disease 
H 
histone 
HbF 
fetal haemoglobin 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agent 
HREC 
Human Research Ethics Committee 
HSC 
haematopoietic stem cell 
HSCT 
haematopoietic stem cell transplant 
IC 
inhibitory concentration 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL8 
Interleukin 8
IMG-7289 
N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino-1-(4-methylpiperazin-
1-yl)-1-oxopentan-2-yl}-4-(1H-1,2,3-triazol-1-yl)benzamide, bis-tosylate salt 
INR 
International normalized ratio 
IPF 
immature platelet fraction 
IPSS 
International Prognostic Scoring System 
IPSS-R 
IPSS-Revised 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IWG 
International Working Group 
K 
lysine 
KD 
knockdown  
KDM1A 
lysine-specific demethylase 1 
Kel 
elimination rate constant 
kg 
kilogram 
L 
liter 
LC/MS/MS 
liquid chromatography/mass spectrometry/mass spectrometry 
LDH 
lactate dehydrogenase 
LPLV 
last patient last visit 
LSC 
leukaemia stem cell 


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Abbreviation 
Definition 
LSD1 
lysine-specific demethylase 1 
LSDi 
LSD1 inhibition or inhibitors 
m2 
meters squared 
MAO 
monoamine oxidases 
MCH 
mean cell haemoglobin 
MCHC 
mean cell haemoglobin concentration 
MCV 
mean cell volume 
MDS 
myelodysplastic syndromes 
me 
methyl 
MEOI 
Medical Events of Interest 
mg 
milligram 
mg/kg 
milligram per kilogram 
mg/kg/d 
milligram per kilogram per day 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
mL/min 
milliliters/minute 
MPP 
multipotent progenitor 
MPN 
myeloproliferative neoplasias or neoplasms 
MPV 
mean platelet volume 
mRNA 
messenger RNA 
MTD 
maximally tolerated dose 
MTDu 
maximally tolerated duration 
MV4;11 
a human AML cell line 
NCI 
National Cancer Institute 
ng·hr/mL 
nanogram an hour per milliliter 
nM 
nanomolar 
NOD/SCID 
non-obese diabetic/severe combined immunodeficiency 
NPM1 
nucleophosmin 1 
OS 
overall survival 
p53 
tumour protein p53 
PD 
pharmacodynamics 
PE 
physical examination 
PFS 
progression free survival 
PI 
Principal Investigator (at each site responsible for patient care) 
PI 
Product Information document 
PISCF 
Participant Information Sheet/Consent Form 
PK 
pharmacokinetics 


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Abbreviation 
Definition 
PKAP 
Pharmacokinetic Analysis Plan 
PML 
promyelocytic leukaemia 
PML-RARα 
PML-retinoic acid receptor alpha 
PR 
partial remission or response 
PSA 
prostate specific antigen 
QD 
once daily 
RBC 
red blood cell 
RD 
resistant disease 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
standard deviation 
Sh 
short hair 
SOA 
schedule of assessments 
SOC 
standard-of-care 
SRM 
Study Reference Manual 
t1/2 
half-life 
t-AML 
treatment related AML 
Tmax 
time to maximum concentration 
TCP 
tranylcypromine 
TF 
transcription factor 
TPO 
thrombopoietin 
µL 
microliter 
µM 
micromolar 
VAF 
variant allele frequency 
Vz/F 
apparent volume of distribution during terminal phase after oral administration 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of child-bearing potential 
 
 


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2 
PROTOCOL SYNOPSIS 
Protocol Title:  A MULTI-CENTER, OPEN LABEL STUDY TO ASSESS THE SAFETY, PHARMACOKINETICS 
AND PHARMACODYNAMICS OF IMG-7289 WITH AND WITHOUT ATRA (TRETINOIN) IN PATIENTS WITH 
ADVANCED MYELOID MALIGNANCIES 
Protocol No:   IMG-7289-CTP-101 
Investigator/Study Centers:  Approximately 8 sites in Australia; additional sites and 
countries may be added as needed. 
Study Hypothesis and Objectives: 
Hypothesis:  IMG-7289 with and without all-trans retinoic acid (ATRA; tretinoin) is a safe 
and tolerable orally available agent when administered to patients with advanced myeloid 
malignancies including high risk acute myeloid leukaemia (AML) and high risk 
myelodysplastic syndromes (MDS); lysine-specific demethylase 1 (LSD1) inhibition (LSDi) 
by IMG-7289 will have a negative impact on leukaemic and dysplastic cells, an effect which 
may be further enhanced via synergistic mechanisms when administered in combination 
with ATRA.   
Objectives:  The following objectives will be evaluated in patients with advanced myeloid 
malignancies, including high risk AML and high risk MDS, treated with IMG-7289 with and 
without ATRA: 
Primary: 
 
Safety and tolerability 
 
Pharmacokinetics  
 
The adequacy of dose and duration in producing a pharmacodynamic effect 
Secondary: 
 
The association of plasma concentrations (Cmax and Cmin) and exposure (AUC) on 
haematopoiesis (both short+ and longer-termǂ measures) 
 
The kinetics of recovery of haematopoiesis for a given dose and for a given duration 
of dosing 
+Short term measures may include reticulocyte counts, absolute neutrophil counts (ANC), platelet 
volume. 
ǂLonger-term measures may include return of counts to baseline or better. 
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Investigational Drug:  The drug product is identified as IMG-7289, a bis-tosylate salt.   The 
free base of IMG-7289 is an irreversible inhibitor of LSD1.  The chemical name is:  N-[(2S)-
5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino-1-(4-methylpiperazin-1-yl)-1-
oxopentan-2-yl}-4-(1H-1,2,3-triazol-1-yl)benzamide, bis-tosylate salt. 
IMG-7289 will be supplied as capsules in multiple strengths.
Additional Medication:  Tretinoin (all-trans retinoic acid; ATRA; Vesanoid®) is an 
approved retinoid for the indication of induction of remission in acute promyelocytic 
leukaemia (APL; FAB classification AML-M3).  Chemically, tretinoin is 3,7-dimethyl-9-
(2,6,6-trimethylcyclohex-1-enyl) nona-2,4,6,8-all-trans-retinoic acid.   
Tretinoin is available as oval, soft gelatin capsules; one half of each capsule is opaque 
orange-yellow the other half opaque reddish brown.  One capsule strength will be 
provided:  10 mg.  The Product Information (PI) document will be provided to each 
Principal Investigator. 
Note:  Tretinoin will be referred to as ATRA throughout the remainder of this protocol. 
Study Population:  Approximately 40 patients, eighteen years of age or older, with high 
risk AML or high risk MDS (as defined in the Inclusion/Exclusion Criteria) will be treated.   
A minimum of 3 patients per cohort/sub-cohort are required to complete the entirety of 
Cycle 1 (i.e., the applicable dosing and rest periods).  All patients will be unique; no patient 
will be allowed to be dosed in more than one cohort.  Contingent on the number of prior 
DLTs within a cohort/sub-cohort, non-completers of Cycle 1 will be replaced. 
Note:  ‘Sub-cohort’ (generally) refers to different treatment arms within the dose-finding Cohort. 
Methodology:  This is a multi-center, open-label study evaluating the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of IMG-7289 administered orally once 
daily (QD), with and without ATRA, to patients with advanced myeloid malignancies.   
Accordingly, as a measure of precaution, a starting dose of 0.75 mg/kg QD, representing the 
estimated <IC10 for inhibiting human platelet production has been selected as the starting 
dose and designated the Ds.   
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The study consists of two phases in which IMG-7289 will be dosed with and without ATRA: 
the dose-finding phase, and the duration-finding phase.  During both phases, a Data Safety 
Monitoring Committee (DSMC) will review safety parameters, pharmacodynamic markers 
and pharmacokinetic parameters to draw conclusions around the safety and 
pharmacodynamic effect of differing doses, treatment regimens and dosing durations.  DSMC 
reviews are critical, as neither a new dose-finding sub-cohort, nor a duration-finding cohort 
may commence without DSMC review and recommendation to do so.  Refer to Section 8 for 
details pertaining to DSMC reviews, and management of study toxicities. 
phase, will be used to establish and confirm 
the IMG-7289 Di and the Dp in patients, as well as provide samples sufficient to establish the 
pharmacokinetic parameters of IMG-7289 at several dose levels and, with and without ATRA.  
Patients assigned to combination therapy will receive IMG-7289 in combination with ATRA.  
The second phase of the study, the duration-finding phase, will be used to identify the safety 
and clinical effects of IMG-7289 treatment for durations longer than 7 days as well as provide 
samples sufficient to establish drug concentrations at steady state, with and without ATRA.  
A DSMC review will be conducted after a minimum of 3 patients in a cohort/sub-cohort have 
completed Cycle 1 to determine the safety of each dose and different treatment durations, 
with and without ATRA.  The DSMC will also assess the impact of each dose on normal 
myeloid haematopoiesis, the PD impact of that dose on malignant cells, and whether a further 
cohort/sub-cohort in the respective phase is appropriate.  Changes in the clearance of IMG-
7289, with and without ATRA, based on drug concentrations at Cmin will be reviewed as 
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available.  As DSMC review of data continues throughout the study, the DSMC may also 
recommend a different cohort progression than is currently outlined in the protocol. 
Importantly, if a specific dose, treatment regimen or dosing duration is found by the DSMC 
to be associated with greater therapeutic benefit, patients that have fully completed their 
initially allowed IMG-7289 cycles and are receiving either a different dose, treatment 
regimen (i.e., IMG-7289 alone versus combination therapy) or dosing for a different dosing 
duration will be transitioned to the more optimal dose, treatment regimen or dosing 
duration at the start of their next cycle.  Such transition may occur more than once, as 
different doses, treatment regimens and dosing durations continue to be evaluated. 
Patients will be followed closely for both Adverse Events (AEs) and signs of toxicity by 
frequent monitoring of clinical signs and symptoms and by peripheral blood and urine 
analyses. Pharmacodynamic effects will also be closely monitored by frequent haematology 
assessments of peripheral blood and bone marrow aspirates and biopsies, as required.   
All patients will undergo End-of-Treatment (EOT), pre-End-of-Study (pre-EOS), and End-of-
Study (EOS) visits approximately 7, 14 and 28 days, respectively, after last Cycle last dose. 
Study Phases, Doses and Duration: 
Dose-Finding Phase:  Cohort 1 (via sub-cohorts, as needed) comprises the dose-finding 
Cohort.  Cohort 1 patients, including the combination therapy sub-cohorts, will be dosed with 
IMG-7289 for 7 days and initially allowed to receive up to 4 cycles of IMG-7289, provided 
IMG-7289 (with or without ATRA) continues to be tolerated. 
The IMG-7289 alone component of the dose-finding phase is summarized below. 
Sub-cohort 1a:  Dosing will begin on Day 1 at the Ds, 0.75 mg/kg/d IMG-7289 free base.  
Note:  Though not expected, contingencies are in place in the case that unacceptable toxicity 
is seen at the Ds and sub-cohorts at lower doses are required.  Please refer to Section 7.2.2.2.
Dose escalation will proceed in sub-cohorts (i.e., Sub-cohorts 1b, 1c, etc.) provided that: 
1. A minimum of 3 patients from the previous sub-cohort have completed Cycle 1, both 
the applicable dosing and rest periods 
2. The number of patients who experience DLT is within the guidelines (Section 8.2.2) 
3. DSMC review of the previous sub-cohort has determined that: 
a. The dose administered appears safe 
b. Further dose escalation is appropriate 
If the DSMC determines dose escalation should proceed, then additional sub-cohorts (Sub-
cohorts 1b, 1c, etc.) will be dosed with increasing doses as per below.   
Sub-cohort 1b:  Dosing will begin on Day 1 at 1.5 mg/kg/d IMG-7289 free base.   
Sub-cohort 1c:  Dosing will begin on Day 1 at 3 mg/kg/d IMG-7289 free base. 
There are two potential dose-escalation pathways for Sub-cohort 1d:  6 and 10 mg/kg/d.  
The dose to be administered in Sub-cohort 1d will be determined at the discretion of the 
DSMC.  Therefore, upon completion of a minimum of 3 patients in Cycle 1 of Sub-cohort 1c, 
the DSMC will assess the safety and pharmacodynamic effects of the earlier sub-cohorts, 
and reach consensus on: 
1. Whether dose escalation should proceed at all, and if so… 
2. Whether the appropriate escalation for Sub-cohort 1d is a doubling or a tripling of 
the 3 mg/kg/d dose administered in Sub-cohort 1c. 
Sub-cohort 1d: Dosing will begin on Day 1 at either 6 or 10 mg/kg/d IMG-7289 free 
base. 


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Sub-cohort 1e: Dosing will begin on Day 1 at 10 mg/kg/d IMG-7289 free base, if not 
previously administered in Sub-cohort 1d. 
If appropriate, an additional sub-cohort will commence at a 2x multiple of the last sub-
cohort’s dose, followed by further sub-cohorts with dose escalation continuing in such 
increments until the DSMC determines that no further dose escalation is anticipatedΩ.  Upon 
such confirmation, the combination therapy sub-cohorts will commence. 
ΩThe DSMC may revisit dose escalation after having progressed to combination therapy. 
If the DSMC determines a specific IMG-7289 dose is associated with greater therapeutic benefit, 
patients who have fully completed their initially allowed IMG-7289 treatment cycles and are at 
a different dose will be titrated to the more optimal dose at the start of their next cycle. 
The table below summarizes the IMG-7289 alone component of the dose-finding phase by 
sub-cohort, dose, dosing duration, rest period, and number of initially allowed IMG-7289 
cycles.   
Sub-
cohort 
IMG-7289 Dose 
(free base) 
IMG-7289 Cycle 
No. of Initial 
IMG-7289 
Cycles** 
Dosing Duration 
Rest Period*
1a 
0.75 mg/kg/d = Ds 
7 days 
7 days 
4 
1b 
1.5 mg/kg/d 
1c 
3 mg/kg/d 
1dɸ 
6 or 10 mg/kg/d 
1e*** 
10 mg/kg/d 
*The duration of the rest period may be adjusted based on an assessment by the DSMC that either 
a specific patient or an entire sub-cohort could benefit from an extended rest period.  This decision 
could be taken if there is no clear indication of the restoration of normal haematopoiesis in the 7 
day period or analysis of the pharmacokinetic parameters in the earlier sub-cohorts suggest the 
rest period duration requires adjusting; for example, if the half-life of IMG-7289 is unexpectedly 
long.  Investigators will be notified of any such change. 
**Additional cycles may be allowed, contingent on clinical benefit/patient response. 
ɸThe dose to be used in Sub-cohort 1d, either 6 mg/kg/d or 10 mg/kg/d, will be determined by the 
DSMC based on review of safety and pharmacodynamic data from earlier dose-finding sub-cohorts.
***If 10 mg/kg/d was not studied in Sub-cohort 1d, and if deemed appropriate by the DSMC, then 
10 mg/kg/d will be studied in Sub-cohort 1e.  If deemed appropriate by the DSMC, then additional 
sub-cohorts beyond Sub-cohort 1e will commence with up-titration of dosing continuing in such 
increments until the Dp is identified. 
The IMG-7289 administered in combination with ATRA component of the dose-finding 
phase is summarized below. 
Sub-cohort 1χ:  Dosing will begin on Day 1 with IMG-7289 (dose to be determined by 
the DSMC) dosed for 7 days on followed by 7 days off, in combination with ATRA 45 
mg/m2 per day dosed for 7 days on followed by 7 days off. 
Additional combination therapy sub-cohorts may follow (i.e., Sub-cohort 1Ѡ, Sub-cohort 1Ѵ, 
etc.) as the DSMC continues to review data on an ongoing basis, provided that: 
1. A minimum of 3 patients from the previous sub-cohort have completed Cycle 1, both 
the applicable dosing and rest periods 
2. The number of patients who experience DLT is within the guidelines (Section 8.2.2) 
3. DSMC review of the previous sub-cohort has determined that: 
a. The doses administered in combination appear safe 
b. Further combination therapy is appropriate 
If the DSMC determines combination therapy should proceed, then additional sub-cohorts will 
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Sub-cohort 1Ѡ:  Dosing will begin on Day 1 with IMG-7289 (dose to be determined 
by the DSMC) dosed for 7 days on followed by 7 days off, in combination with ATRA 
45 mg/m2 per day dosed for 21 daysƍ on followed by 7 days off. 
ƍPatient’s enrolled in Sub-cohort 1χ will continue their current treatment regimen until completion of 
their initially allowed treatment cycles and pending DSMC review of the sentinel patient in Sub-cohort 
1Ѡ, after which transition to the new (21 day ATRA) regimen may occur at the start of the next cycle. 
As DSMC review of data continues throughout the study, the DSMC may recommend 
extending the dosing duration of IMG-7289, reducing the ATRA dose and/or adjusting the 
ATRA dosing duration.  The IMG-7289 dose may be either increased or decreased to a dose 
studied in an earlier sub-cohort, or decreased to an intermediary dose, by the DSMC.   
If the DSMC determines combination therapy offers greater therapeutic benefit as compared to 
single agent IMG-7289 therapy, patients who have fully completed their initially allowed IMG-
7289 treatment cycles and are receiving a different treatment regimen (i.e., IMG-7289 alone) 
will be transitioned to combination therapy at the start of their next cycle. 
The table below summarizes the IMG-7289 in combination component of the dose-finding 
phase by sub-cohort, drug, dose, dosing duration, rest period, and number of initially allowed 
IMG-7289 cycles.   
Sub-
cohort 
IMG-7289 Dose 
(free base) 
IMG-7289 Cycle 
No. of Initial 
IMG-7289 
Cycles** 
Dosing Duration 
Rest Period*  
1χ 
TBD¥ 
7 days on 
7 days off 
4 
Administered in combination with 
ATRA§  45 mg/m2/d for 7 daysƍ on followed by 7 days off 
1Ѡß 
TBD¥ 
7 days on 
7 days off 
4 
Administered in combination with 
ATRA§  45 mg/m2/d for 21 days on followed by 7 days off 
*The duration of the rest period may be adjusted based on an assessment by the DSMC that either a 
specific patient or an entire sub-cohort could benefit from an extended rest period.  This decision 
could be taken if there is no clear indication of the restoration of normal haematopoiesis in the 7 day 
period or analysis of the pharmacokinetic parameters in the earlier sub-cohorts suggest the rest 
period duration requires adjusting; for example, if the half-life of IMG-7289 is unexpectedly long.  
Investigators will be notified of any such change. 
 **Additional cycles may be allowed, contingent on clinical benefit/patient response. 
¥The IMG-7289 dose for administration with ATRA will be determined by the DSMC based on ongoing 
review of safety and pharmacodynamic data. 
§The ATRA dose may be reduced or the dosing and/or rest period duration adjusted by the DSMC 
based ongoing review of safety and pharmacodynamic data. 
ßIf deemed appropriate by the DSMC, then additional sub-cohorts beyond 1Ѡ will commence.  
ƍPatient’s enrolled in Sub-cohort 1χ will continue their current treatment regimen until completion of 
their initially allowed treatment cycles and pending DSMC review of the sentinel patient in Sub-cohort 
1Ѡ, after which transition to the new (21 day ATRA) regimen may occur at the start of the next cycle. 
Upon DSMC confirmation that no further dose-finding sub-cohorts are anticipated, and 
safety permitting (the DSMC must have determined it safe to extend the duration of IMG-
7289 treatment), the study will progress to assess the effect of IMG-7289 dosing duration.  
Duration-Finding Phase:  Cohorts 3, 3χ, 4 and 4χ comprise the duration-finding cohorts.  
Patients will be dosed with IMG-7289 at the Dp* (determined by the DSMC) for either 14 or 
21 days, with or without ATRA.  The number of initially allowed IMG-7289 cycles differs by 
cohort, in conjunction with the duration of IMG-7289 dosing, to a total of 28 days IMG-7289 
dosing.  


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*May change as data from earlier sub-cohorts becomes available and different durations continue to 
be evaluated. 
There are two potential duration-extension pathways for the duration-finding cohorts:  
duration extension with IMG-7289 alone, or IMG-7289 administered in combination with 
ATRA.  Therefore, prior to opening a duration-finding cohort, the DSMC will assess the 
safety and pharmacodynamic effects of the earlier sub-cohorts, and reach consensus on: 
1. Whether it appears safe to extend the duration of IMG-7289 dosing 
2. Whether there appears to be greater therapeutic benefit with IMG-7289 dosed in 
combination with ATRA.  
Based on the above assessments, one of the below duration-finding cohorts will commence.
Cohort 3:  Dosing of IMG-7289 at the Dp will begin on Day 1 for a duration of 14 days.   
Cohort 3χ:  The above IMG-7289 regimen in combination with ATRA 45 mg/m2 per day for 
14 days. 
Cohorts 3 and 3χ will initially be allowed to receive 2 cycles of IMG-7289, provided IMG-
7289 (with or without ATRA) continues to be tolerated. 
The duration of dosing will be extended in subsequent cohorts provided that: 
1. A minimum of 3 patients from the previous cohort have completed Cycle 1, both the 
applicable dosing and rest periods 
2. The number of patients who experience DLT is within the guidelines (Section 8.2.2) 
3. DSMC review of the previous cohort has determined that: 
a. The duration of dosing appears safe 
b. Further duration extension is appropriate 
If the DSMC determines further duration extension is appropriate, then additional cohorts will 
be dosed with extending durations to determine if a more optimal duration can be identified; 
possible cohorts are outlined below. 
Cohort 4:  Dosing of IMG-7289 will begin on Day 1 for a duration of 21 days.   
Cohort 4χ:  The above IMG-7289 regimen in combination with ATRA 45 mg/m2 per day for 
21 days. 
Cohorts 4 and 4χ will initially be allowed to receive 1 cycle of IMG-7289. 
If the DSMC determines a specific dosing duration is associated with greater therapeutic 
benefit, patients who have fully completed their initially allowed IMG-7289 cycles and are at a 
different dosing duration will be transitioned to the more optimal dosing duration at the start 
of their next cycle. 
The table below summarizes the duration-finding phase by cohort, dosing duration, 
treatment regimen, rest period and number of initially allowed IMG-7289 cycles.  
Cohort 
IMG-7289 Dose 
(free base) 
IMG-7289 Cycle 
No. of Initial 
IMG-7289 
Cycles** 
Dosing Duration 
Rest Period* 
3 
Dp¥ 
14 days 
7 days 
2 
3χ 
The Cohort 3 IMG-7289 regimen, administered in combination with 
ATRA§  45 mg/m2/d for 14 days on followed by 7 days off 
4 
Dp¥ 
21 days 
7 days 
1 
4χ 
The Cohort 4 IMG-7289 regimen, administered in combination with 
ATRA§  45 mg/m2/d for 21 days on followed by 7 days off 


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*The duration of the rest period may be adjusted based on an assessment by the DSMC that either 
a specific patient or an entire cohort could benefit from an extended rest period.  This decision 
could be taken if there is no clear indication of the restoration of normal haematopoeisis in the 7 
day period or analysis of the pharmacokinetic parameters in Cohort 1 suggest the rest period 
duration requires adjusting.  Investigators will be notified of any such change. 
**Additional cycles may be allowed, contingent on clinical benefit/patient response. 
¥The IMG-7289 dose for administration will be determined by the DSMC based on ongoing review 
of safety and pharmacodynamic data.  
§The ATRA dose may be reduced or the dosing and/or rest period duration adjusted by the DSMC 
based ongoing review of safety and pharmacodynamic data. 
Throughout all phases of the study, if it appears that either a maximally tolerated dose (MTD) 
or maximally tolerated duration (MTDu) is reached (see Section 8.2.3), the DSMC will 
convene to evaluate further dose escalation, combination therapy and/or extended dosing 
duration.    
Dose reductions may be made in consultation with the Medical Monitor, should an adverse 
event (AE) requiring a dose reduction occur. 
Additional Cycles:  Upon completion of the number of initially allowed IMG-7289 cycles per 
sub-cohort, patients deriving clinical benefit and safely tolerating IMG-7289, as determined 
by the Principal Investigator, may continue to receive IMG-7289, with additional dose 
titration, treatment regimen and/or duration changes occurring in consultation with the 
Medical Monitor, until disease progression or unacceptable toxicity ensues.  During the 
additional cycle period, the rest period may be extended from the 7 day standard to a 
maximum of 56 days, but only after: 1) the patient has received a minimum of 28 IMG-7289 
doses; and, 2) consultation with or recommendation by the DSMC.  Such recommendation 
may be made for a variety of reasons including evidence of tumour reduction, marked 
hypocellularity in the marrow consistent with myelosuppression, or to enable the return of 
normal haematopoiesis.  For protocol purposes, a rest period extending beyond the 7 day 
standard will be referred to as the extended rest period (see Section 9.10). 
Patients who either fail to demonstrate stable disease, demonstrate progressive disease after 
achieving partial remission (PR) or stable disease, or relapse after achieving complete 
remission (CR), CR with incomplete recovery (CRi) or PR (see Table 14 and Table 15) are 
the equivalent of treatment failures, and will discontinue study drug and enter the follow-up 
period. 
Study Duration:  Screening procedures may commence up to 28 days prior to the start of 
treatment.  Depending on the duration of dosing in each cohort, patients may initially 
undergo four, three, two or one treatment cycles while on study to a total of approximately 
28 days of dosing, with Rest Periods between each cycle anticipated to last approximately 7 
days.  Patients should be followed for 28 days post last dose.  As such, the length of patient 
participation will vary by cohort.  For Cohort 1 this will be ~15 weeks from first patient-
first visit (FPFV) to last patient-last visit (LPLV),  for Cohort 3/3χ ~13 weeks, and for 
Cohort 4/4χ ~11 weeks.  As described above, additional cycles may be given, contingent on 
patient response. 
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Adverse events (AEs) will be assessed throughout the study after the first IMG-7289 dose 
to the End of Study visit (EOS).  AE frequency, causality, and severity will be evaluated as 
measures of safety and tolerability.  Febrile neutropenia admissions will also be assessed. 
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Clinical laboratory measures:  
Cycle 1 
 
Haematology with differential* will be performed at Screening, Baseline, pre-dose on 
Day 1, and approximately every 3 days.   
 
Coagulation* will be performed at Screening, Baseline, pre-dose on Day 1, and then at 
least once weekly throughout the study.  
 
Biochemistry* will be performed at Screening, Baseline, pre-dose on Day 1, and then as 
follows: 
o Cohort 1:  Days 3 and 7 of dosing, and Days 9, 11 and 14 of the rest period.   
o All other Cohorts, pending DSMC review of Cohort 1 data: 
 
If clinically significant trends are noted by the DSMC, or an opinion has not yet 
been formed, then either focused panels or full biochemistry will be performed 
at least twice weekly throughout the Cycle.   
 
If clinically significant trends are not noted by the DSMC, then full biochemistry 
panels will be performed at least once weekly throughout the Cycle.   
 
Urinalysis with microscopy will be performed at Screening, pre-dose on Day 1, and then 
at least once weekly throughout the study.   
 
Red Cell Haemoglobin F (HbF)** will be measured pre-dose on Day 1, at the end of 
dosing (sample timing will vary depending on the duration of the Cohort), and then on 
the last day of the rest period. 
 
Prostate Specific Antigen (PSA)** will be measured in males pre-dose on Day 1 and then 
on the last day of the rest period.  
*To be performed at EOT, pre-EOS, and EOS visits. 
**To be performed at EOT. 
Cycle 2 and beyond, all Cohorts 
 
Haematology with differential (diff) will be performed pre-dose on Day 1 and 
approximately every 3 days throughout the duration of the study, at the EOT, pre-EOS, 
and EOS visits, and upon suspicion of relapse.  
 
Coagulation will be performed pre-dose on Day 1 and then at least once weekly 
throughout the study, at the EOT, pre-EOS, and EOS visits and upon suspicion of relapse.
 
Biochemistry: Pending DSMC review of Cycle 1 data, biochemistry will be performed:  
o If clinically significant trends are noted by the DSMC, or an opinion has not yet been 
formed, then either focused panels or full biochemistry will be performed twice 
weekly throughout the Cycle.   
o If clinically significant trends are not noted by the DSMC, then full biochemistry 
panels will be performed at least once weekly throughout the Cycle.   
o At the EOT, pre-EOS, and EOS visits and upon suspicion of relapse. 
 
Urinalysis with microscopy will be performed pre-dose on Day 1 and then at least once 
weekly throughout the study, at the EOT, pre-EOS, and EOS visits and upon suspicion 
of relapse. 
 
HbF will be measured on the last day of the rest period of the final initially allowed 
Cycle for Cohorts 1 and 3 (i.e., Cohort 1 = Cycle 4, Day 14; Cohort 3/3χ = Cycle 2, Day 
21), and on Rest Day 7 of every other Cycle during the additional treatment phase in all 
Cohorts. 
 
PSA will be measured on the last day of the rest period of the final initially allowed Cycle 
for Cohorts 1 and 3 (i.e., Cohort 1 = Cycle 4, Day 14; Cohort 3/3χ = Cycle 2, Day 21), and 
on Rest Day 7 of every other Cycle during the additional treatment phase in all Cohorts.


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Effective Dose Assessment:  The DSMC will assess the impact of each dose on normal myeloid 
haematopoeisis, and the pharmacodynamic impact of each dose on malignant cells (see 
Study Endpoints Section 12.4).  This assessment will be made using a combination of 
pharmacodynamic and pharmacokinetic markers.  Indicators evaluated may include: 
peripheral white blood cell count, peripheral blast count, reticulocyte count, platelet count, 
bone marrow blast count, changes in immunophenotype, changes in variant allele frequency 
(VAF), changes in cytokine profiles, and changes in PSA.  These metrics will be evaluated in 
the context of PK parameters such as Cmax and AUC, as available.   
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Eligibility:  Patients must meet all applicable Inclusion and none of the Exclusion Criteria. 
Inclusion Criteria: 
1. Willing and able to sign the approved informed consent. 
2. Age: 18+ years old at Screening. 
3. Diagnosis (a., b., and c. required) of EITHER Acute Myeloid Leukaemia:  
a. By World Health Organization (WHO) criteria regardless of etiology, sub-type or 
treatment history.  
b. High risk AML* diagnosis in accordance with one of the following classifications: 
 
≥ 60 years of age with AML who are not candidates for (based on parameters 
such as performance scores, co-morbidities and cytogenetic studies), or have 
refused, standard chemotherapy 
 
18+ year old with de novo or secondary AML (MDS/AML or treatment-related 
(t)-AML) who are not expected to benefit from standard remission-induction 
chemotherapy (unfavorable cytogenetics)  
 
Relapsed/refractory AML after no more than 3 previous lines of chemotherapy, 
including hypomethylating agents, for whom no standard therapies are available
c. Eastern Cooperative Oncology Group (ECOG) performance status score ≤2. 
*All forms of AML (M0–M7) diagnosed by morphologic, histochemical or cell surface marker 
criteria. 
OR 
Myelodysplastic Syndromes: 
a. By WHO criteria regardless of sub-type. 
b. High Risk MDS diagnosis in accordance with one of the following classifications: 
 
MDS patients who have failed first-line therapy, demonstrated by resistance to, 
or relapse following a minimum of 4 cycles with a hypomethylating agent (HMA)
 
Treatment-related MDS, except if it is associated with favorable cytogenetics, and 
not a candidate for stem cell transplantation 
c. Either an International Prognostic Scoring System (IPSS) score equivalent to 
intermediate-2 risk or higher, or a Revised International Prognostic Scoring System 
(IPSS-R) score equivalent to intermediate risk or higher. 
4. Prior autologous stem cell transplant is allowed if a minimum of 3 months has elapsed 
from the time of transplant and the patient has recovered from transplant-associated 
toxicities. 
5. Prior allogeneic stem cell transplant is allowed, provided all of the following criteria are 
met: 
 
Transplant was >120 days prior to study enrollment 
 
No immunosuppressive medications have been taken for at least 1 month 
 
No active graft versus host disease (GVHD), excluding Grade 1 skin GVHD 
6. WBC ≤ 30 x 109/L (30,000/µL) for at least one week prior to first dose, with hydroxyurea 
use to achieve this value acceptable. 


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7. Platelet count ≥ 30 x 109/L (30,000/µL) prior to first dose, with transfusions to reach 
this limit acceptable. 
8. Life expectancy >12 weeks. 
9. Willing to discontinue all existing anti-neoplastic therapies (with the exception of 
hydroxyurea) for the 3 weeks prior to first dose of IMG-7289, total duration of dosing, 
and 1 week after last dose. 
10. Amenable to serial bone marrow evaluation, blood, and urine sampling during the study.
11. Able to swallow capsules. 
12. Agrees to use an approved method of contraception from Screening and until 28 days 
after the last administration of the study drug.  Agreed methods of contraception may 
include: condom; use of birth control pills, patches, implants or injections, diaphragm 
with vaginal spermicide, intrauterine device (IUD) and/or surgical sterilization 
(vasectomy or tubal ligation at least six months prior to dosing). Patients practicing 
abstinence must agree to use an approved method of contraception should they become 
sexually active during the study.   
Exclusion Criteria: 
1. Has received either: immunotherapy within <8 weeks; chemotherapy within <3 weeks 
(with the exception of hydroxyurea); radiation therapy to >30% of marrow-bearing bone 
within <2 weeks prior to starting study treatment; or, has not yet recovered from the 
effects of such therapies (excluding alopecia). 
2. Has undergone major surgery ≤4 weeks prior to starting study drug or has not recovered 
from side effects of such surgery. 
3. Has undergone any surgical procedure within 2 weeks, excluding minor procedures (i.e., 
skin biopsy or central venous catheter placement/removal) prior to starting study drug.
4. Scheduled haematopoietic stem-cell transplant. 
5. Current use of a prohibited medication including anticoagulants or platelet inhibitors or 
expected to require any of these medications (outside of such use permitted as per the 
Prohibited Medications section) during treatment with the investigational drug. 
6. Current use of monoamine oxidase A and B inhibitors (MAOIs). 
7. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to IMG-7289, LSD1 inhibitors, or ATRA that contraindicates 
participation. 
8. Uncontrolled active infection. 
9. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, 
disseminated intravascular coagulation, or CNS leukaemia.  
10. A concurrent second active and non-stable malignancy (patients with a concurrent 
second active but stable malignancy, such as non-melanoma skin cancers, are eligible). 
11. Known human immunodeficiency virus (HIV) infection or known active Hepatitis B or 
Hepatitis C virus infection. 
12. History of any illness/impairment of gastrointestinal (GI) function that might interfere 
with drug absorption (e.g., chronic diarrhea), confound study results or pose an 
additional risk to the patient by their participation in the study; patients with gastric 
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13. Refractory to platelet transfusion (but not excluding patients receiving HLA–matched 
platelets that increment appropriately). 
14. Evidence at the time of Screening of risk of bleed, including any one of the following: 
a. Activated partial thromboplastin time (aPTT) ≥ 1.3 x the local upper limit of normal
b. International normalized ratio (INR) ≥ 1.3 x the local upper limit of normal 
c. History of severe thrombocytopenia unrelated to AML, MDS or treatment for either 
d. Known bleeding disorder (e.g., dysfibrinogenemia, factor IX deficiency, haemophilia, 
Von Willebrand's disease, Disseminated Intravascular Coagulation [DIC], fibrinogen 
deficiency, or other clotting factor deficiency)  
e. Receiving therapeutic anticoagulation 
15. Evidence at the time of Screening of significant renal or hepatic insufficiency (unless due 
to haemolysis, or leukaemic infiltration) as defined by any one of the following local lab 
parameters: 
a. Calculated glomerular filtration rate (GFR) < 40 mL/min or serum creatinine > 1.5 x 
the local upper limit of normal 
b. Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥ 2 x the local 
upper limit of normal 
16. Use of an investigational agent within less than 14 days, or the equivalent of at least 
7 half-lives of that agent, whichever is the longer, prior to the start of study treatment. 
17. Pregnant or lactating females. 
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IMG-7289 Dose Limiting Toxicity (DLT): Dose Escalation, Combination Therapy and 
Duration Extension Decision Making Rules; and, Maximum Tolerated Dose (MTD), 
Maximum Tolerated Duration (MTDu):   
Adverse event intensity will be evaluated using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03, published 14 June 2010.   
Definitions: 
Haematologic Toxicity:  Haematologic values outside of the normal reference range are 
inherent features of AML and MDS, and are expected effects of many therapeutic attempts to 
manage these diseases.  The effects of IMG-7289 on normal myeloid haematopoiesis 
observed in non-clinical studies are expected in humans; these are pharmacodynamic effects 
of LSD1 inhibition by IMG-7289, thus are not regarded as adverse.  These events, with the 
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exceptions noted below, will not be considered DLTs.  Additional information pertaining to 
haematologic toxicity, DLTs, dose escalation/duration extension rules, and MTDs is provided 
in Section 8.2. 
Dose limiting toxicity (DLT):  Any one of the following AEs that occurs during the first cycle 
and is considered by the Investigator possibly, probably or definitely related to IMG-7289:   
 
A clinically significant bleeding event;  
 
Any Grade 4 or 5 non-haematologic adverse event;  
 
Any Grade 3 non-haematologic adverse event with failure to recover to Grade 1 
within 7 days of drug cessation, with the following exceptions: 
o ≥ Grade 3 nausea, vomiting or diarrhoea that responds to standard medical 
care 
o ≥ Grade 3 aesthenia lasting less than 14 days 
 
Any Grade 3 electrolyte abnormality unrelated to the underlying malignancy and 
persisting greater than 24 hours. 
Patients who experience a DLT may have their dose adjusted downward if the Medical 
Monitor and Principal Investigator deem it safe for the patient to continue on IMG-7289.  To 
ensure a minimum of 3 Cycle 1 completers, and contingent on the number of prior DLTs 
within the cohort, such patients may be replaced. 
Please consult the Medical Monitor for IMG-7289 dose modifications for the management of 
clinically significant changes in platelets, neutrophil counts, or other haematologic 
parameters. 
Expected toxicities based on non-clinical studies with IMG-7289 are reported in the latest 
edition of the Investigator’s Brochure.   
IMG-7289 Dose Escalation, Combination Therapy and Duration Extension Decision Rules:  
The DSMC will convene and review safety data after a minimum of 3 patients in a sub-
cohort/cohort have completed Cycle 1 (both the treatment and rest periods).  If 0-1 of 3 
patients experience a DLT, and if the DSMC deems safe, then dose escalation will proceed to 
the next higher dose with the opening of the applicable sub-cohort/cohort.  If 2 out of 3 
patients experience a DLT, then the safe dose has been exceeded, enrollment in the sub-
cohort/cohort will close and dose escalation cease.   
 The table below outlines these rules. 
Patients with DLT at a Given Dose  
Escalation Decision Rules* 
0-1 out of 3 
Open subsequent sub-cohort/next dose  
2 out of 3 
Dose escalation will be stopped 
*The above instruction applies in kind for combination therapy and duration extension decision 
making. 
As this study is not investigating the effects of cytotoxic agents, the 2 DLT/3 patient rule 
should provide an adequate safety margin to patients, while allowing escalation to doses that 
could offer greater therapeutic benefit.  This study design does not conform to the traditional 
3+3 dose escalation study which is based on pre-specified rules using actual observations of 
target events such as dose-limiting toxicity.  The traditional 3+3 design was developed in an 
era of cytotoxic drugs and is appropriate when the toxicity is directly proportional to 
exposure.  This study takes the alternative model-based approach more appropriate for a 
targeted, non-cytotoxic drug such as IMG-7289, in which there is no observed monotonic 
relationship between exposure and toxicity (Le Tourneau, et al., 2009). Specifically, this 


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study employs the dose-toxicity model developed in rat and dog relating the plasma 
concentration of drug 24 hours after last dose at steady state needed to inhibit platelet 
production, a process dependent on the activity of LSD1. 
Additionally, the DSMC may review safety data and, even in the absence of 2 DLTs, deem that 
the safe dose has been exceeded.  Were this to occur, dose escalation would cease. 
IMG-7289 Maximum Tolerated Dose (MTD) and Maximum Tolerated Duration (MTDu)ɸ: 
MTD:  The highest dose below or at which <2 out of 3 patients experiences DLT.   
MTDu:  The longest duration below or at which <2 out of 3 patients experiences DLT. 
ɸMTD and MTDu definitions also apply to combination therapy sub-cohorts. 
The MTD may not be reached in this study if the highest dose tested is found to be safe. 
ATRA Toxicity:  Decisions on IMG-7289 and ATRA dose interruption, reduction and re-
challenge due to observed toxicity will be made by the Investigator in consultation with 
Medical Monitor and DSMC. 
Expected toxicities for ATRA can be found in the PI. 


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3 
INTRODUCTION 
3.1 Background Information 
3.2 The Diseases to be Treated 
Acute myeloid leukaemia (AML) is a lethal haematologic malignancy resulting in the accumulation 
of abnormal myeloid blasts (CD13+ and CD33+) in the bone marrow (Estey, 2013).  These blasts 
interfere with normal haematopoiesis causing cytopenias, and accumulate in peripheral blood and 
infiltrate the lung and the central nervous system (CNS).  AML accounts for approximately 80% of 
all adult acute leukaemias with a median age at diagnosis of 67 years (Pollyea et al., 2011).  AML 
can arise de novo without a prior history of haematologic disease but can also evolve from other 
clonal myeloid disorders such as myelodysplastic syndromes (MDS) or myeloproliferative 
neoplasias (MPNs), or secondary to prior DNA-damaging treatment  (Lindsley et al., 2015). 
AML is a devastating and difficult disease to treat.  Despite intense efforts, the treatment for AML 
has changed very little in almost 40 years.   Standard-of-care (SOC) induction with intensive 
chemotherapy consists of seven days of cytarabine and three days of an anthracycline (“7+3”), 
generally daunorubicin or idarubicin, with many additional agents used specific to clinical sites.  
Patients attaining a complete remission (CR) are subject to additional cycles of high-dose 
cytarabine and/or haematopoietic stem cell transplantation (HSCT) (Dombret and Gardin, 2016; 
Cornelissen and Blaise, 2016).  The addition of other agents to SOC, however, has not proven to 
provide additional clinical benefit (Stein and Tallman, 2012).  Improved supportive care, as 
opposed to more effective treatment, has been the primary means for extending life in these 
patients.   
The five-year overall survival rate is approximately 25%, but closer to 10% for patients over 65 
years of age primarily because of co-morbidities, a disproportionate number of adverse genetic 
abnormalities, treatment-related mortality and unsuitability for HSCT (Pollyea et al., 2011; Roboz, 
2012).  While standard chemotherapy and bone marrow transplantation are curative in up to 40% 
of younger (<40) AML patients, most patients are not cured of their disease.  AML is, after all, a 
disease of older people (>60) and these patients are the most difficult to cure (Appelbaum et al., 
2006; Burnett, 2012; Burnett, 2013).   Although more than 60% of AML patients treated with 
standard therapy will achieve a CR, at least 70% of these patients will relapse (Burnett et al., 2012).   
A core objective of improving outcomes is the identification of novel target(s) ideally present in all 
malignant cells; the greatest need is for those with either resistant disease or who cannot endure 
intensive SOC treatment.  
3.3 Lysine (K)-Specific Demethylase 1 (LSD1) 
LSD1, also known as KDM1A, was first described as an enzyme that removes mono- and dimethyl 
groups from critical lysines (K), K4 and K9 in histone (H) H3 (Shi et al., 2004).  Methylation of 
histone H3K4 and H3K9 is a post-translational modification associated with changes in rates of 
gene transcription (Bannister and Kouzarides, 2011; Beisel and Paro, 2011).  By virtue of altering 
the local state of chromatin, LSD1 is an epigenetic regulator of gene expression.  The lysine (K) sites 


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on histone H3 and the degree of methylation on those sites (1, 2 or 3 methyl groups) are associated 
with specific functions, e.g., enhancers and super-enhancers are characterized by H3K4me1 marks, 
whereas H3K4me2 is more often found in the proximal promoters and enhancers of actively 
transcribed genes (Campos and Reinberg, 2009; Gardner et al., 2011; Rando, 2012).  The inhibition 
of LSD1 (LSDi) can result in an increase or decrease of specific messenger RNAs (mRNAs) 
dependent on those local chromatin marks and associated transcription factors (TFs).  
LSD1 is an essential gene; loss of LSD1 activity leads to early embryonic lethality (Wang et al., 2009; 
Foster et al., 2010).  The protein is also needed for regulating the balance between self-renewal and 
proliferation (Wang et al., 2007).  A conditional in vivo LSD1 knockdown (KD) using a doxycycline-
inducible short hairpin LSD1 (shLSD1) established LSD1 as a central regulator of short-term 
haematopoietic stem cells (HSCs) and progenitor cells (Sprussel et al., 2012).  An inducible LSD1 KD 
resulted in profound but reversible thrombocytopenia, neutropenia and anaemia; monocyte counts 
were increased.  LSD1 KD for 27 days led to an increase in circulating multipotent progenitors 
(MPPs) and HSCs, with a concomitant down-regulation of chemokine (C-X-C motif) receptor 4 
(CXCR4), without affecting the size of the quiescent long-term HSC pool (Sprussel et al., 2012).   
LSD1 plays a key role in regulating the progression from pluripotency to terminal differentiation 
and balancing self-renewal and proliferation (Adamo et al., 2011; Wang et al., 2007; Whyte et al., 
2012).  LSD1 is also required for normal cell cycle progress, differentiation and prevention of 
apoptosis (Wang et al., 2009; Foster et al., 2010; Whyte et al., 2012),.   
Over-expression of LSD1 mRNA and excess LSD1 protein have been observed in many tumour 
types, including poorly-differentiated neuroblastoma, squamous cell carcinoma, Ewing’s sarcoma, 
AML, neuroendocrine carcinomas and epithelial tumours such as breast, prostate, bladder, small 
cell lung and colon cancers (Metzger et al., 2005; Kahl et al., 2006; Schulte et al., 2009; Lim et al., 
2010).   The role of LSD1 in neoplasia has, however, been most thoroughly studied in AML.  LSD1 
activity is present in a high proportion of AML cells.  In one survey of newly diagnosed primary 
AML cells of multiple sub-types, LSD1 activity was elevated in 80% of cases; in primary AML cells 
from patients with refractory or relapsing disease, 100% of cases had elevated LSD1 activity (Lin et 
al., 2011).   Expression of LSD1 was highest in the minimally differentiated M1 sub-type of AML 
compared to other more morphologically differentiated sub-types (Rhodes et al., 2007; Wouters et 
al., 2009).  LSD1 gene expression is among the highest in immunophenotypically stem/progenitor 
populations of leukaemic cells (Goardon et al., 2011).  Similar findings in mouse model of AML 
confirm that LSD1 expression is correlated with immunophenotypically and functionally defined 
leukaemic stem cells (LSC) (Somervaille et al., 2009; Harris et al., 2012).    
Inhibition of LSD1 in AML cells de-represses or induces the expression of genes associated with 
differentiation including markers of monocytic maturation such as CD14 and CD86 (Huang et al., 
2009; Lynch et al., 2013).  This phenomenon of drug-induced differentiation is reminiscent of the 
effects of all-trans retinoic acid (ATRA) combined with arsenic trioxide (As2O3) on acute 
promyelocytic leukaemia (APL M3) cells: inducing the degradation of the onco-fusion protein 
promyelocytic leukaemia-retinoic acid receptor alpha (PML-RARα) relieves the block to 
differentiation (Lallemand-Breitenbach et al., 1999).  Indeed, LSD1 inhibition sensitizes non-APL 


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AML cells to differentiation by ATRA as well as reducing leukaemic stem cell potential (Schenk et al., 
2012).   
Non-clinical studies indicate that the maximal differentiation and cell killing of AML cells is a result 
of complete inhibition of the enzyme.  Accordingly, IMG-7289, an irreversible inhibitor, was 
developed to enhance the probability that LSD1 activity would be fully inactivated during drug 
exposure.  Additional reasons IMG-7289 was selected for clinical development include: its high 
potency, chemical stability and its half-life in plasma in non-clinical animal models. 
Irreversible inhibitors of LSD1 include tranylcypromine (TCP) which has been used for the 
treatment of depression for decades.  The targets of TCP therapy, however, are the monoamine 
oxidases (MAO). TCP inactivates LSD1 in a manner identical to its action on MAO-A and MAO-B 
because these three enzymes share a similar oxidative mechanism of action.  Despite the lack of 
specificity and low potency of TCP for LSD1, there are currently at least two actively recruiting 
clinical trials in which TCP is being used for the treatment of AML (NCT02273102 and 
NCT02261779).   TCP derivatives with improved specificity for LSD1 over MAO-A and MAO-B have 
recently been developed with the therapeutic purpose of inhibiting LSD1 activity in cancer – these 
include IMG-7289.  Other molecules in development include ORY-1001 identified by Oryzon 
Genomic SA and now being developed by Roche; and, GSK2879552, a molecule being developed by 
GlaxoSmithKline (NCT02177812) for the treatment of AML and for small cell lung cancer.  Both 
companies are presently recruiting AML patients for these studies, though no clinical results have 
been published.   
In summary, the scientific evidence available in the literature shows that inhibition of LSD1 offers 
the promise of targeting an enzyme that participates in many essential neoplastic functions in AML 
cells including self-renewal, a phenotype that characterizes the major reservoir of treatment-
resistant-cells, the leukaemic stem cell population.   The pathological process in MDS that leads to 
neoplastic transformation is similar in many aspects to the evolution of AML and hence is thought 
to be subject to the same therapeutic thesis.  That AML cells employ LSD1 in a similar fashion 
suggests that with continued inhibition the population of both leukaemic blasts and stem cells 
might be eroded and eventually eradicated.  These data, and the successful treatment of various 
animal models of AML through the inhibition of LSD1, is the foundation for taking development of 
the Imago molecule, IMG-7289, into clinical trials in the AML population. 
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3.4 Background to All-Trans Retinoic Acid (ATRA; tretinoin) Use in Acute Leukaemia 
The standard “7+ 3” treatment regimen can be expected to achieve a complete remission rate 
approximating 80%.  AML is, however, infrequently cured with chemotherapy.  The outstanding 
exception is acute promyelocytic leukaemia (APL) which, when treated with all-trans retinoic acid 
(ATRA) in combination with other agents such as As2O3, can achieve a cure rate approaching 90% 
(Wang and Chen 2008; Lo-Coco et al., 2013).  The primary mechanism by which ATRA is thought to 
achieve its therapeutic effects is by converting the fusion oncoprotein PML-RARα from a 
transcriptional repressor to a transcriptional activator and inducing its own proteolysis.  
Transcriptional activation drives myeloid differentiation, but that alone is not sufficient to clear 
leukaemic stem cells; ligand-induced degradation of this oncoprotein is more closely linked to 
clinical efficacy (de The’ et al., 2012; dos Santos et al., 2013).  Granulocytic differentiation can be 
induced at low ATRA doses, but higher doses are required to induce PML-RARα proteolysis and 
reduce the frequency of leukaemic stem cells (Nasr et al., 2008).  Thus, with APL, differentiation 
alone is not sufficient for cure.     
While ATRA as monotherapy induces haematologic remission in virtually all cases of APL, patients 
invariably relapse because of residual disease; a surviving population of leukaemic stem cells 
(Warrell et al., 1991) present at remission. This remnant of disease may be partially owing to 
inadequate exposure to ATRA.  Orally administered ATRA is rapidly metabolized with a plasma 
elimination half-life of 0.8 hours (Muindi et al., 1992b).   When administered over a period of as 
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little as a week, Cmax and exposure (AUC) are reduced by as much as 50% and 90%, respectively 
(Muindi et al., 1992a; Adamson et al., 1995).  That a liposomal formulation of the drug effected 
cures as monotherapy in treatment-naive APL patients supports the notion that ATRA exposure 
must attain, and remain, above a certain threshold to achieve maximal clinical effects (Tsimberidou 
et al., 2006).  
The activity of ATRA has been studied in non-clinical models of, non-APL AML.  Primary cells from 
AML patients over-expressing ecotropic viral integration site 1 (EVI-1) showed greater sensitivity 
to ATRA suggesting that this sub-group might benefit clinically were ATRA added to their regimen 
(Verhagen et al., 2016 Blood).  In cells carrying nucleophosmin 1 (NPM1) mutations, ATRA 
exposure significantly increased the proportion of annexin V-positive and CD11b+ cells, while 
inducing p53 (El Hajj et al., 2016).  The clinical benefit afforded by adding ATRA to standard 
chemotherapy has also been studied.  Two studies report no improvement with the addition of 
ATRA to a SOC regimen (Burnett et al., 2010; Nazha et al., 2013), while Schlenk and colleagues 
reported that relapse-free and overall survival at four years in AML patients older than 60 years 
were superior to standard chemotherapy when ATRA was added (Schlenk et al., 2004; Schlenk et 
al., 2009). 
3.5 Rationale for IMG-7289 and ATRA Combination Therapy    
The rationale for combining ATRA with an LSD1 inhibitor is based on enhanced anti-leukaemic 
activity observed by various groups.  ATRA does not abolish the self-renewal or engraftment of 
leukaemic stem cells, whereas LSD1 inhibitors have been shown to reduce self-renewal, induce 
differentiation, inhibit engraftment and promote cell death in leukaemia stem cells (Zheng et al., 
2007; Harris et al., 2012; Schenk et al., 2012).  A study of the combination of the non-specific LSD1 
inhibitor, tranylcypromine (TCP), and ATRA was active against AML cells in culture and impaired 
engraftment in patient-derived AML cells transplanted to non-obese diabetic/severe combined 
immunodeficiency (NOD/SCID) mice (Schenk et al., 2012).  In this combination study, the CD11b 
marker was induced and the percentage of cells undergoing apoptosis was enhanced compared to 
monotherapy. The proposed mechanism of this synergism is the collective induction and  
de-repression of genes needed for differentiation.  
In in vitro and in vivo studies, the LSD1 inhibitor IMG-7289 was synergistic with ATRA in inhibiting 
AML cell growth in culture.  In a mouse xenograft model implanting the human AML cell line 
MV4;11, the combination of ATRA and the free base of IMG-7289 inhibited the growth of tumour 
volume more than either agent alone.   
As discussed in Section 3.3, there are currently at least two actively recruiting clinical trials in 
which TCP (an irreversible inhibitor of LSD1) is being used for the treatment of AML 
(NCT02273102 and NCT02261779).  Compared to IMG-7289 with a mean IC50 for inhibiting LSD1 
of 10 nM, the IC50 for TCP against LSD1 in vitro is approximately 10 μM, a Cmax plasma concentration 
difficult to achieve with standard TCP dosing because of dose-limiting toxicity, but this has not 
dampened enthusiasm for the combination.  The dose of ATRA being used in these studies is 45 
mg/m2 daily given in divided doses, the same as for the treatment of APL.  


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As with ATRA treatment for APL, the doses of IMG-7289 and ATRA needed to induce AML cell death 
(apoptosis) and reduce leukaemic stem cell potential may be higher than those needed to induce 
differentiation. 
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3.7 ATRA Dose and Duration in Non-APL AML 
There are no clinical studies comparing doses of ATRA in the treatment of APL. The standard dose is 
45 mg/m2 per day in divided doses, though some reports suggest that a reduced dose of 25 mg/m2 is 
equally effective (Tallman and Altman 2009).  Daily dosing of ATRA is typically continued until 
complete remission (CR) by clinical measures has been achieved, as long as the patient is tolerating 
treatment well.  Patients who have received ATRA for at least two weeks but were discontinued 
because of toxicity even eventually achieved CR.  After the induction of CR, APL patients receive 
intermittent ATRA for up to 2 years to achieve a molecular remission.    
Though very low doses of ATRA in combination with IMG-7289 were needed to induce 
differentiation in cultured AML cells, higher exposure to ATRA than that needed for differentiation 
may be required to induce AML cell death (apoptosis) and potentially reduce the leukaemic stem 
cell pool.  Hence, in combination with IMG-7289, the proposed dose of ATRA is 45 mg/m2 per day 
divided into two doses. 
The objective of this phase of the study is to expose leukaemic cells to a combination of both IMG-
7289 and ATRA.  Non-clinical models had suggested the half-life of IMG-7289 was less than 24 
hours.  The PK parameters now available for the first four dose-finding sub-cohorts indicate a drug 
half-life of 4-5 days.  Thus, what was originally defined as the 7 day “rest” period is one during 
which patients are still exposed to IMG-7289 at or above the IC50 of the drug.  This degree of 
exposure has, however, been demonstrated to be well tolerated.  Thus, to match more closely the 
exposure of ATRA to IMG-7289, ATRA will be given at the planned dose of 45 mg/m2, but for 21 
days, followed by a rest period of 7 days.  This dosing schedule of ATRA is regarded as safe as it 
affords less exposure than standard recommended treatment regimens of ATRA for acute 
promyelocytic leukaemia in which 45-60 days of daily ATRA at 45 mg/m2 would be most common. 
4 
HYPOTHESIS AND OBJECTIVES 
4.1 Hypothesis 
IMG-7289 with and without all-trans retinoic acid (ATRA; tretinoin) is a safe and tolerable orally 
available agent when administered to patients with advanced myeloid malignancies including high 
risk AML and high risk MDS; LSDi by IMG-7289 will have a negative impact on leukaemic and 
dysplastic cells, an effect which may be further enhanced via synergistic mechanisms when 
administered in combination with ATRA. 
4.2 Objectives 
The following primary, secondary and exploratory objectives will be evaluated in patients with 
advanced myeloid malignancies, including high risk acute myeloid leukaemia and high risk 
myelodysplastic syndromes, treated with IMG-7289 with and without ATRA: 
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4.2.1.1 Primary 
 
Safety and tolerability 
 
Pharmacokinetics 
 
The adequacy of dose and duration in producing a pharmacodynamic effect 
4.2.1.2 Secondary 
 
The association of plasma concentrations (Cmax and Cmin) and exposure (AUC) on 
haematopoiesis (both short+ and longer-termǂ measures) 
 
The kinetics of recovery of haematopoiesis for a given dose and for a given duration of dosing 
4.2.1.3 Exploratoryɸ 
 
The impact of therapy on disease burden as measured by malignant-cell specific nucleic 
markers (DNA or mRNA)*   
 
The effect of treatment on the immunophenotype of leukaemic and dysplastic cells**  
 
The effect of treatment on cytokine profiles*** 
 
The relationship between genetic and cytogenetic aberrations in leukaemic cells on 
pharmacodynamic response 
 
The association of conventional clinical responses**** with molecular assessments of response 
+Short term measures may include reticulocyte counts, absolute neutrophil counts (ANC), platelet volume. 
ǂLonger-term measures may include return of counts to baseline or better. 
ɸSome or all may be analysed time and cost permitting. 
*Nucleic markers include tumour-specific transcripts and DNA mutations detected by sequencing.   
** Immunophenotyping by fluorescence-activated cell sorting or flow cytometry (FACS; FC).  
***Serum cytokine quantification.  
****Conventional clinical response parameters may comprise: CBC including platelets, red and white blood 
cell (RBC and WBC) and leukaemic blast cell counts; transfusion requirements; cellular composition of the 
bone marrow (% marrow blasts); and, markers of differentiation. 
5 
INVESTIGATIONAL PLAN 
5.1 Overview 
Note:  ‘Sub-cohort’ (generally) refers to different treatment arms within the dose-finding Cohort. 
This is a multi-center, open-label, multiple ascending dose- and duration-finding study assessing 
the safety, pharmacokinetics and pharmacodynamics of IMG-7289, with and without ATRA, in 
patients with advanced myeloid malignancies.   Following their consent, patients will undergo 
Screening to confirm eligibility.  A sufficient number of patients will be screened to enroll and treat 
approximately 40 patients with high risk AML/MDS.  Screening may commence up to 28 days prior 
to the start of IMG-7289 treatment on Day 1.  Patients meeting all applicable Inclusion and no 
Exclusion Criteria will be enrolled into the study and assigned to a Cohort.  All patients will be 
unique; no patient will be allowed to be dosed in more than one cohort.  Contingent on the number 
of prior DLTs within a cohort, non-completers of Cycle 1 will be replaced. 
Non-clinical studies indicate that the maximal differentiation and cell killing of AML cells is a result 
of complete inhibition of the enzyme.  The dose of IMG-7289 (free base) estimated to provide in 


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humans a plasma concentration sufficient to inhibit the LSD1 enzyme throughout the 24 hour dosing 
cycle has been designated the Di.  Non-clinical studies indicate that an oral dose resulting in a Cmin 
unbound plasma concentration at 24 hours post-dose of between 1 and 2 ng/mL of the free base of 
IMG-7289 is sufficient to fully inhibit LSD1 during the dosing cycle and hence, arrest normal myeloid 
haematopoiesis in mouse, rat and dog.  This concentration approximates the IMG-7289 concentration 
needed to inhibit LSD1 activity fifty percent (IC50) in vitro as well as the IC50 for killing cultured AML 
cells (6-9 nM free base).  Based on pharmacokinetic modeling, the IMG-7289 free base dose needed 
to achieve this concentration in humans at 24 hours is approximately 3 mg/kg.   The non-clinical and 
modeling data may not be precise enough to accurately predict the pharmacokinetic parameters in 
humans.   Accordingly, as a measure of precaution, a starting dose of 0.75 mg/kg QD representing the 
estimated <IC10 for inhibiting human platelet production has been selected as the starting dose and 
designated the Ds.   
The Ds of 0.75 mg/kg QD (free base) is likely to be below the Di, the dose anticipated to achieve an 
unbound plasma concentration of drug across the dosing interval sufficient to inhibit normal myeloid 
haematopoiesis.  If, as expected, normal myeloid haematopoiesis is not significantly affected at the 
Ds, then planned dose escalation in subsequent sub-cohorts above the Ds are intended to identify the 
Di.  Similarly, the Di may not be the equivalent of the dose needed to achieve the desired PD effects 
on malignant cells in high risk AML/MDS patients, a dose designated the Dp; the Dp, which will be 
determined by the DSMC, may be higher or lower than the Di.  NB: the Dp may vary based on the IMG-
7289 dose, treatment regimen (i.e., IMG-7289 alone versus combination therapy) or dosing duration.  
If the anticipated PD responses are not demonstrated at the Di, then titrations above or below the Di 
are intended to identify the Dp.  Any potential dose titrations will be made with appropriate 
consideration to safety.   
The study consists of two phases in which IMG-7289 will be dosed with and without ATRA:  the dose-
finding phase, using multiple ascending doses of IMG-7289; and the duration-finding phase, during 
which multiple IMG-7289 durations may be assessed.  During both phases, a Data Safety Monitoring 
Committee (DSMC) will convene to review safety parameters, pharmacodynamic markers and 
pharmacokinetic parameters to draw conclusions around the safety and pharmacodynamic effects of 
differing doses, treatment regimens and dosing durations.  DSMC reviews are critical, as neither a 
new dose-finding sub-cohort, nor a duration-finding cohort may commence without DSMC review 
and recommendation to do so.  Refer to Section 8 for details pertaining to DSMC reviews, DLT 
management, dose escalation/duration extension rules, and MTDs. 
At least three patients will enroll in each cohort/sub-cohort, with a minimum of 3 patients per 
cohort/sub-cohort required to complete the entirety of Cycle 1 (i.e., the applicable IMG-7289 dosing 
and rest periods).  Each dose-finding sub-cohort will include a sentinel patient to be dosed for 7 
days, the safety of which will be determined by the DSMC before the remainder of the sub-cohort is 
treated; duration-finding cohorts will not include sentinel patients.  Therefore, with the exception 
of a sentinel patient in each dose-finding sub-cohort, patients will be enrolled on a rolling basis.  As 
there is no evidence in non-clinical studies of acute toxicity with IMG-7289, even at extremely high 
doses, it is believed that one sentinel patient for each dose-finding sub-cohort is sufficient to 
establish the acute safety of IMG-7289 dosed with and without ATRA.  Since this study is not 


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investigating the effects of cytotoxic agents, enrolling patients on a rolling basis facilitates 
progression to later cohorts that could offer greater therapeutic benefit.  
Patients will be treated with IMG-7289 in cycles, each cycle comprised of one IMG-7289 dosing 
period followed by one rest period.  The number of initially allowed IMG-7289 cycles differs by 
cohort, as does the duration of IMG-7289 dosing.  Patients may initially undergo four (Cohort 1), 
two (Cohort 3/3χ) or one (Cohort 4/4χ) IMG-7289 treatment cycles while on study to a total of 
approximately 28 days of IMG-7289 dosing.  During the initially allowed IMG-7289 treatment cycles 
and regardless of the dosing duration, the rest period will remain at 7 days, unless assessment is 
made by the DSMC that either a specific patient or an entire cohort could benefit from an extended 
rest period.  This decision could be taken if there is no clear indication of the restoration of normal 
haematopoiesis in the 7 day period or analysis of the IMG-7289 pharmacokinetic parameters in the 
earlier sub-cohorts suggest the rest period duration requires adjusting.  As IMG-7289 treatment 
may lead to cytopenias, transfusions may be administered in accordance with standard institutional 
guidelines.   
The initial dose-finding phase of the study will be used to establish and confirm the IMG-7289 Di 
and the Dp in patients, as well as to provide samples sufficient to establish the pharmacokinetic 
parameters of IMG-7289 at several dose levels, with and without ATRA.  It is anticipated that dose 
escalation of IMG-7289 as well as IMG-7289 administered in combination with ATRA will proceed 
in sub-cohorts (i.e., Sub-cohort 1b, 1c, 1χ, 1Ѡ) in accordance with Section 7.2.2.1, following DSMC 
reviews as detailed in Section 8.1 and the rules outlined in Section 8.2.2.  (Note:  Though not 
expected, contingencies are in place in the case that unacceptable toxicity is demonstrated at the Ds 
and sub-cohorts at lower doses are therefore required.  Please refer to Section 7.2.2.2.)  The IMG-
7289 dosing duration and associated rest period will remain at 7 days dosing followed by a 7 day 
rest period throughout the entirety of the dose-finding phase (includes all sub-cohorts)*.   Patients 
will be initially allowed to receive up to 4 cycles of IMG-7289, provided that IMG-7289 (with and 
without ATRA) continues to be tolerated.        
Upon DSMC confirmation that no further dose-finding sub-cohorts are anticipated, and safety 
permitting (the DSMC must have determined it safe to extend the duration of IMG-7289 treatment), 
the duration-finding phase will commence.  The duration-finding phase will be used to identify the 
safety and clinical effects of IMG-7289 treatment for durations longer than 7 days as well as provide 
samples sufficient to establish drug concentrations at steady state, with and without ATRA.  Duration-
finding cohorts will be dosed with IMG-7289 at the Dp (determined by the DSMC), with or without 
ATRA.  The Dp may change as data from earlier sub-cohorts becomes available and different durations 
continue to be studied.  The duration of dosing will be extended in cohorts in accordance with Section 
7.2.2.3, following DSMC reviews as detailed in Section 8.1 and the rules outlined in Section 8.2.2; each 
dosing duration will be followed by a 7 day rest period*.  Patients will be initially allowed to receive 
2 cycles of 14 days IMG-7289 dosing for Cohorts 3/3χ, and 1 cycle of 21 days IMG-7289 dosing for 
Cohorts 4/4χ; each dosing duration will be followed by a 7 day rest period.* 
*The duration of the rest period may be adjusted based on an assessment by the DSMC that either a specific 
patient or an entire cohort could benefit from an extended rest period.  This decision could be taken if there is 
no clear indication of the restoration of normal haematopoiesis in the 7 day period or analysis of the 


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pharmacokinetic parameters in earlier cohorts (or sub-cohorts) suggest the rest period duration requires 
adjusting.  Investigators will be notified of any such change. 
Importantly, if the DSMC determines a specific dose, treatment regimen or dosing duration is 
associated with greater therapeutic benefit, patients who have fully completed their initially allowed 
cycles and are receiving a different dose, treatment regimen (i.e., IMG-7289 alone versus combination 
therapy) or dosing duration will be transitioned to the more optimal dose, treatment regimen or 
dosing duration at the start of their next cycle.  Such transition may occur more than once, as different 
doses, treatment regimens and dosing durations continue to be evaluated. 
Throughout all phases of the study, if it appears that either a maximally tolerated dose (MTD) or 
maximally tolerated duration (MTDu) is reached (see Section 8.2.3), the DSMC will convene to 
evaluate further dose escalation, combination therapy and/or extended dosing duration.   
Upon completion of the number of initially allowed IMG-7289 cycles per cohort, patients deriving 
clinical benefit and safely tolerating IMG-7289, as determined by the Principal Investigator, may 
continue to receive IMG-7289 with additional dose titration, treatment regimen and dosing duration 
changes occurring in consultation with the Medical Monitor until disease progression or 
unacceptable toxicity ensues.  During the additional cycle period, the rest period may be extended 
from the 7 day standard to a maximum of 56 days but only after: 1) the patient has received a 
minimum of 28 IMG-7289 doses; and, 2) consultation with or recommendation by the DSMC.  Such 
recommendation may be made for a variety of reasons including evidence of tumour reduction, 
marked hypocellularity in the marrow consistent with myelosuppression, or to enable the return of 
normal haematopoiesis.  For protocol purposes, a rest period extending beyond the 7 day standard 
will be referred to as the extended rest period (see Section 9.10). 
Patients who either fail to demonstrate stable disease, demonstrate progressive disease after 
achieving partial remission (PR) or stable disease, or relapse after achieving complete remission 
(CR), CR with incomplete recovery (CRi), or PR (see Table 14 and Table 15) are the equivalent of 
treatment failures, and will discontinue study drug and enter the follow-up period.   
Patients will be followed closely for both Adverse Events (AEs) and signs of toxicity by frequent 
monitoring of clinical signs and symptoms and by blood and urine analyses both during the IMG-
7289 treatment period and the rest period.  Pharmacodynamic effects will also be closely monitored 
by frequent haematology assessments of peripheral blood and bone marrow aspirates, as required. 
All patients will undergo End-of-Treatment (EOT), pre-End of Study (pre-EOS), and End-of-Study 
(EOS) visits approximately 7, 14, and 28 days, respectively, after last Cycle last dose.   
A detailed description by-cohort, by-cycle, of assessments to be performed is provided in Section 9.  
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6 
STUDY POPULATION 
6.1 Study Entry Criteria 
6.1.1 Inclusion Criteria 
Patients must meet all of the applicable criteria to be eligible for enrollment in this study: 
1. Willing and able to sign the approved informed consent. 
2. Age: 18+ years old at Screening. 
3. Diagnosis (a., b., and c. required) of EITHER Acute Myeloid Leukaemia:  
a. By World Health Organization (WHO) criteria regardless of etiology, sub-type or treatment 
history.  
b. High risk AML* diagnosis in accordance with one of the following classifications: 
 
≥ 60 years of age with AML who are not candidates for (based on parameters such as 
performance scores, co-morbidities and cytogenetic studies), or have refused, standard 
chemotherapy 
 
18+ year old with de novo or secondary AML (MDS/AML or treatment-related (t)-AML) 
who are not expected to benefit from standard remission-induction chemotherapy 
(unfavorable cytogenetics)  
 
Relapsed/refractory AML after no more than 3 previous lines of chemotherapy, including 
hypomethylating agents, for whom no standard therapies are available 
c. Eastern Cooperative Oncology Group (ECOG) performance status score ≤2. 
*All forms of AML (M0–M7) diagnosed by morphologic, histochemical or cell surface marker criteria. 
OR Myelodysplastic Syndromes: 
a. By WHO criteria regardless of sub-type. 
b. High Risk MDS diagnosis in accordance with one of the following classifications: 
 
MDS patients who have failed first-line therapy, demonstrated by resistance to, or relapse 
following a minimum of 4 cycles with a hypomethylating agent (HMA) 
 
Treatment-related MDS, except if it is associated with favorable cytogenetics, and not a 
candidate for stem cell transplantation 
c. Either an International Prognostic Scoring System (IPSS) score equivalent to intermediate-2 
risk or higher, or a Revised International Prognostic Scoring System (IPSS-R) score 
equivalent to intermediate risk or higher. 
4. Prior autologous stem cell transplant is allowed if a minimum of 3 months has elapsed from the 
time of transplant and the patient has recovered from transplant-associated toxicities. 
5. Prior allogeneic stem cell transplant is allowed, provided all of the following criteria are met: 
a. Transplant was >120 days prior to study enrollment 
b. No immunosuppressive medications have been taken for at least 1 month 
c. No active graft versus host disease (GVHD), excluding Grade 1 skin GVHD 


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6. WBC ≤ 30 x 109/L (30,000/µL) for at least one week prior to first dose, with hydroxyurea use to 
achieve this value acceptable. 
7. Platelet count ≥ 30 x 109/L (30,000/µL) prior to first dose, with transfusions to reach this limit 
acceptable. 
8. Life expectancy >12 weeks. 
9. Willing to discontinue all existing anti-neoplastic therapies (with the exception of hydroxyurea) 
for the 3 weeks prior to first dose of IMG-7289, total duration of dosing, and 1 week after last 
dose. 
10. Amenable to serial bone marrow evaluation, blood, and urine sampling during the study. 
11. Able to swallow capsules. 
12. Agrees to use an approved method of contraception from Screening and until 28 days after the 
last administration of the study drug.  Agreed methods of contraception may include: condom; 
use of birth control pills, patches, implants or injections, diaphragm with vaginal spermicide, 
intrauterine device (IUD) and/or surgical sterilization (vasectomy or tubal ligation at least six 
months prior to dosing). Patients practicing abstinence must agree to use an approved method of 
contraception should they become sexually active during the study. 
6.1.2 Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Has received either: immunotherapy within <8 weeks; chemotherapy within <3 weeks (with the 
exception of hydroxyurea); radiation therapy to >30% of marrow-bearing bone within <2 weeks 
prior to starting study treatment; or, has not yet recovered from the effects of such therapies 
(excluding alopecia). 
2. Has undergone major surgery ≤4 weeks prior to starting study drug or has not recovered from 
side effects of such surgery. 
3. Has undergone any surgical procedure within 2 weeks, excluding minor procedures (i.e., skin 
biopsy or central venous catheter placement/removal) prior to starting study drug. 
4. Scheduled haematopoietic stem-cell transplant. 
5. Current use of a prohibited medication including anticoagulants or platelet inhibitors or expected 
to require any of these medications (outside of such use permitted as per the Prohibited 
Medications section) during treatment with the investigational drug. 
6. Current use of monoamine oxidase A and B inhibitors (MAOIs). 
7. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically 
related to IMG-7289, LSD1 inhibitors, or ATRA that contraindicates participation. 
8. Uncontrolled active infection. 
9. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated 
intravascular coagulation, or CNS leukaemia.  
10. A concurrent second active and non-stable malignancy (patients with a concurrent second active 
but stable malignancy, such as non-melanoma skin cancers, are eligible). 


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11. Known human immunodeficiency virus (HIV) infection or known active Hepatitis B or Hepatitis 
C virus infection. 
12. History of any illness/impairment of gastrointestinal (GI) function that might interfere with drug 
absorption (e.g., chronic diarrhea), confound study results or pose an additional risk to the 
patient by their participation in the study; patients with gastric bypass surgery. 
13. Refractory to platelet transfusion (but not excluding patients receiving HLA–matched platelets 
that increment appropriately). 
14. Evidence at the time of Screening of risk of bleed, including any one of the following: 
a. Activated partial thromboplastin time (aPTT) ≥ 1.3 x the local upper limit of normal 
b. International normalized ratio (INR) ≥ 1.3 x the local upper limit of normal 
c. History of severe thrombocytopenia unrelated to AML, MDS or treatment for either 
d. Known bleeding disorder (e.g., dysfibrinogenemia, factor IX deficiency, haemophilia, 
Von Willebrand's disease, Disseminated Intravascular Coagulation [DIC], fibrinogen 
deficiency, or other clotting factor deficiency) or  
e. Receiving therapeutic anticoagulation 
15. Evidence at the time of Screening of significant renal or hepatic insufficiency (unless due to  
haemolysis, or leukaemic infiltration) as defined by any one of the following local lab parameters: 
a. Calculated glomerular filtration rate (GFR) < 40 mL/min or serum creatinine > 1.5 x the local 
upper limit of normal 
b. Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥ 2 x the local upper limit 
of normal 
16. Use of an investigational agent within less than 14 days, or the equivalent of at least 7 half-lives 
of that agent, whichever is the longer, prior to the start of study treatment. 
17. Pregnant or lactating females. 
6.2 Patient Enrollment 
A sufficient number of patients who fulfil the inclusion and exclusion criteria documented in 
Section 6.1 will be screened to ensure approximately 40 patients are enrolled and treated in this 
study.   As patients are screened and become eligible for the study, they will be assigned to the 
currently open cohort.  This process will be detailed in the Study Reference Manual (SRM).  
6.3 Patient Withdrawal 
In accordance with the Declaration of Helsinki, Good Clinical Practice (GCP), and International 
Conference on Harmonization (ICH) Guidelines and applicable regulations governing human 
subject protection, a subject has the right to withdraw from the study at any time for any reason.  
Subjects may also be removed from the study by the Sponsor or Investigator.   The reason for 
withdrawal, if given, will be provided to the Sponsor and documented on the CRF.  Patients will be 
requested to return for follow-up beginning with an End of Treatment visit as per Section 9.12.1. 
The Sponsor or Investigator may remove patients from the study for various reasons, including:  


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 
Taking another investigational medicinal agent during their involvement in the study  
 
Major violation of, or deviation from, study protocol procedures which, in the judgment of the 
Medical Monitor, could adversely affect the patient or the integrity of the study including 
missing more than 2 consecutive doses or other evidence of major non-compliance;  
 
Withdrawal from the study is, in the Investigator’s judgment, in the patient’s best interest; 
 
Experiencing a Dose Limiting Toxicity (DLT), as per Section 8.2.1. 
6.4 Replacement of dropouts 
A minimum of 3 patients per cohort/sub-cohort are required to complete the entirety of Cycle 1 
(including the applicable treatment and rest periods).  Contingent on the number of prior DLTs 
within a cohort/sub-cohort, non-completers of Cycle 1 will be replaced to ensure a minimum of 3 
patients complete Cycle 1 of each cohort/sub-cohort. 
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6.7 Patients Who Terminate Early or Discontinue Study Medication 
All patients who finish the study early, or who discontinue study medication will be requested to 
return for follow-up visits, beginning with an End of Treatment visit as detailed in Section 9.12.1.  If 
a patient refuses to enter follow up, perform an Early Termination visit as detailed in Section 9.12.3  
Patients who discontinue study medication due to a DLT will be asked to continue follow-up. 
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6.8 Treatment Failure 
Patients who either fail to demonstrate stable disease, demonstrate progressive disease after 
achieving partial remission or stable disease, or relapse after achieving CR, CRi or PR (see Table 14 
and Table 15) are the equivalent of treatment failures, and will discontinue study drug and enter 
the follow-up period. 
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7.2.2 Dosage and Duration of Treatment 
Throughout both the dose- and duration-finding phases, patients will be treated with IMG-7289 in 
cycles comprised by one IMG-7289 dosing period followed by one rest period.  Regardless of IMG-
7289 dosing duration, the rest period will remain at 7 days, unless assessment is made by the DSMC 
that either a specific patient or an entire cohort could benefit from an extended rest period.  This 
decision could be taken if there is no clear indication of the restoration of normal haematopoiesis in 
the 7 day period or analysis of the IMG-7289 PK parameters in earlier sub-cohorts suggest the rest 
period duration requires adjusting.  
Throughout all phases of the study, if it appears that either a maximally tolerated dose (MTD) or 
maximally tolerated duration (MTDu) is reached (see Section 8.2.3), a DSMC review will convene to 
evaluate further dose escalation, combination therapy and/or duration extensions. 
Please consult the medical monitor regarding dose modifications of IMG-7289 should an adverse 
event (AE) requiring a dose reduction occur, and also for the management of clinically significant 
changes in platelets, neutrophil counts, or other haematologic parameters. 
Details on dosage, combination therapy and duration of treatment by study phase are detailed in 
the sections below. 
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7.2.2.1 Dosage and Duration of Treatment During the Dose-finding Phase 
Details on the selection of and rationale for the starting dose can be found in Section 3.6.1.  Details 
on the rationale for IMG-7289/ATRA combination therapy can be found in Section 3.5.  Cohort 1 
(via sub-cohorts, as needed), the dose-finding cohort, is outlined below.     
Patients assigned to a dose-finding sub-cohort will receive 7 days of IMG-7289 dosing and be 
initially allowed to receive up to 4 cycles of IMG-7289, provided IMG-7289 (with or without ATRA) 
is tolerated. 
The IMG-7289 alone component of the dose-finding phase is summarized below. 
Sub-cohort 1a:  Dosing will begin on Day 1 at the starting dose (Ds), 0.75 mg/kg/d IMG-7289 
free base.   
It is anticipated that dose escalation will proceed in sub-cohorts in accordance with the below, 
following DSMC reviews as detailed in Section 8.1 and in accordance with the rules outlined in Section 
8.2.2.  (Note: though not expected, contingencies are in place in the case that unacceptable toxicity is 
demonstrated at the Ds and lower doses are therefore required.  Please refer to Section 7.2.2.2. 
If the DSMC determines that dose escalation should proceed, then additional sub-cohorts (Sub-cohorts 
1b, 1c, etc.) will be dosed with increasing doses as outlined below. 
Sub-cohort 1b:  Dosing will begin on Day 1 at 1.5 mg/kg/d IMG-7289 free base.     
Sub-cohort 1c:  Dosing will begin on Day 1 at 3 mg/kg/d IMG-7289 free base. 
There are two potential dose-escalation pathways for Sub-cohort 1d:  6 and 10 mg/kg/d.  The dose 
to be administered in Sub-cohort 1d will be determined at the discretion of the DSMC.   
Sub-cohort 1d: Dosing will begin on Day 1 at either 6 or 10 mg/kg/d IMG-7289 free base. 
Sub-cohort 1e:  Dosing will begin on Day 1 at 10 mg/kg/d IMG-7289 free base, if not previously 
administered in Sub-cohort 1d.    
Note:  If appropriate, an additional sub-cohort will commence at a 2x multiple of the last cohort’s 
dose, followed by further sub-cohorts with dose escalation continuing in such increments until the 
DSMC determines that no further dose escalation is anticipatedψ.  Upon such confirmation, the 
combination therapy sub-cohorts will commence.  
ψThe DSMC may revisit dose escalation after having progressed to combination therapy. 
If the DSMC determines a specific IMG-7289 dose is associated with greater therapeutic benefit, 
patients who have fully completed their initially allowed IMG-7289 treatment cycles and are at a 
different dose will be titrated to the more optimal dose at the start of their next cycle. 
The table below summarizes the IMG-7289 alone component of the dose-finding phase by sub-
cohort, dose, dosing duration, rest period and the number of initially allowed cycles.   


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Table 1: IMG-7289 Alone Dose-Finding Sub-cohorts, Including Doses for Escalation 
*The duration of the rest period may be adjusted based on an assessment by the DSMC that either a specific 
patient or an entire sub-cohort could benefit from an extended rest period.  This decision could be taken if 
there is no clear indication of the restoration of normal haematopoiesis in the 7 day period or on analysis of 
the pharmacokinetic parameters in the earlier sub-cohorts suggest the rest period duration requires 
adjusting; for example, if the half-life of IMG-7289 is unexpectedly long.  Investigators will be notified of any 
such change. 
**Additional cycles may be allowed, contingent on clinical benefit/patient response. 
ɸThe dose to be used in Sub-cohort 1d, either 6 mg/kg/d or 10 mg/kg/d, will be determined by the DSMC 
based on review of safety and pharmacodynamics data from earlier dose-finding sub-cohorts. 
***If 10 mg/kg/d was not studied in Sub-cohort 1d, and if deemed appropriate by the DSMC, then 10 
mg/kg/d will be studied in Sub-cohort 1e.  If deemed appropriate by the DSMC, then additional sub-cohorts 
beyond Sub-cohort 1e will commence with up-titration of dosing continuing in such increments until the Dp is 
identified. 
The IMG-7289 administered in combination with ATRA component of the dose-finding phase 
is summarized below. 
Sub-cohort 1χ:  Dosing will begin on Day 1 with IMG-7289 (dose to be determined by DSMC) 
dosed for 7 days on followed by 7 days off, in combination with ATRA 45 mg/m2 per day dosed 
for 7 days on followed by 7 days off.    
Additional combination therapy sub-cohorts may follow (i.e., 1Ѡ, 1Ѵ, etc.) as the DSMC continues to 
review data on an ongoing basis.  
If the DSMC determines combination therapy should proceed, then additional sub-cohorts will 
commence. 
Sub-cohort 1Ѡ:  Dosing will begin on Day 1 with IMG-7289 (dose to be determined by the DSMC) 
dosed for 7 days on followed by 7 days off, in combination with ATRA 45 mg/m2 per day dosed 
for 21 daysƍ on followed by 7 days off. 
ƍPatient’s enrolled in Sub-cohort 1χ will continue their current treatment regimen until completion of their 
initially allowed treatment cycles and pending DSMC review of the sentinel patient in Sub-cohort 1Ѡ, after 
which transition to the new (21 day ATRA) regimen may occur at the start of the next cycle. 
If the DSMC determines that combination therapy offers greater therapeutic benefit as compared to 
single agent IMG-7289 therapy, then patients who have fully completed their initially allowed IMG-
7289 treatment cycles and are receiving a different treatment regimen (i.e., IMG-7289 alone) will be 
transitioned to combination therapy at the start of their next cycle.   
Sub-cohort 
IMG-7289 Dose 
(free base) 
IMG-7289 Cycle 
No. of Initial 
IMG-7289 
Cycles** 
Dosing Duration 
Rest Period* 
1a 
0.75 mg/kg/d = Ds 
7 days 
7 days 
4 
1b 
1.5 mg/kg/d 
1c 
3 mg/kg/d 
1dɸ 
6 or 10 mg/kg/d 
1e*** 
10 mg/kg/d 


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The table below summarizes the IMG-7289 in combination component of the dose-finding phase by 
sub-cohort, dose, dosing duration, rest period, and number of initially allowed IMG-7289 cycles. 
Table 2:  Combination Therapy Component of the Dose-finding Cohort 
Sub-
cohort 
IMG-7289 Dose 
(free base) 
IMG-7289 Cycle 
No. of Initial 
IMG-7289 
Cycles** 
Dosing Duration 
Rest Period*  
1χ 
TBD¥ 
7 days on 
7 days off 
4 
Administered in combination with 
ATRA§  45 mg/m2/d for 7 daysƍ on followed by 7 days off 
1Ѡß 
TBD¥ 
7 days on 
7 days off 
4 
Administered in combination with 
ATRA§  45 mg/m2/d for 21 days on followed by 7 days off 
*The duration of the rest period may be adjusted based on an assessment by the DSMC that either a specific 
patient or an entire cohort could benefit from an extended rest period.  This decision could be taken if there is 
no clear indication of the restoration of normal haematopoiesis in the 7 day period or analysis of the 
pharmacokinetic parameters in the earlier sub-cohorts suggest the rest period duration requires adjusting; for 
example, if the half-life of IMG-7289 is unexpectedly long.  Investigators will be notified of any such change. 
**Additional cycles may be allowed, contingent on clinical benefit/patient response. 
 ¥The IMG-7289 dose for administration with ATRA will be determined by the DSMC based on ongoing review 
of safety and pharmacodynamic data. 
§The ATRA dose may be reduced or the dosing and/or rest period duration adjusted by the DSMC based on 
ongoing review of safety and pharmacodynamic data. 
ßIf deemed appropriate by the DSMC, then additional sub-cohorts beyond 1Ѡ will commence. 
ƍPatient’s enrolled in Sub-cohort 1χ will continue their current treatment regimen until completion of their 
initially allowed treatment cycles and pending DSMC review of the sentinel patient in Sub-cohort 1Ѡ, after 
which transition to the new (21 day ATRA) regimen may occur at the start of the next cycle. 
Upon DSMC confirmation that no further dose-finding sub-cohorts are anticipated, and safety 
permitting (the DSMC must have determined it safe to extend the duration of IMG-7289 treatment), 
the study will progress to assess the effect of IMG-7289 dosing duration. 
7.2.2.2 Provisional Sub-cohorts; Unacceptable Dose Limiting Toxicity is Demonstrated at 
the Ds 
Although unlikely, it is possible that unacceptable toxicity may be seen at the Ds; the Ds could also 
be the maximum tolerated dose.  To address this possibility, and though not anticipated, the below 
contingencies are in place in the event that the DSMC determines that the starting dose is too high.  
Upon such determination, the enrollment of additional cohorts at lower doses will be necessary.  All 
procedures and rules (i.e., sentinel patient, DSMC reviews, number of DLTs, progression to duration 
finding cohorts, etc.) remain applicable to these additional lower dose cohorts throughout the 
study.  
Sub-cohort 1z will enroll the standard 3 patients at 0.375 mg/kg/d.  If unacceptable toxicity occurs 
(DLT in 2 out of 3 patients), then Sub-cohort 1y will enroll 3 patients at the reduced dose of 0.1875 
mg/kg/d.   


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Table 3:  Provisional Sub-cohorts to Initiate if Unacceptable Toxicity is Demonstrated at the 
Ds 
*The duration of the rest period may be adjusted based on an assessment by the DSMC that either a specific 
patient or an entire sub-cohort could benefit from an extended rest period.  This decision could be taken if 
there is no clear indication of the restoration of normal haematopoiesis in the 7 day period or on analysis of 
the pharmacokinetic parameters in the earlier sub-cohorts suggest the rest period duration requires 
adjusting; for example, if the half-life of IMG-7289 is unexpectedly long.  Investigators will be notified of any 
such change. 
**Additional cycles may be allowed, contingent on clinical benefit/patient response. 
7.2.2.3 Dosing and Duration of Treatment During the Duration-finding Phase 
The rationale for the IMG-7289 dosing schedule can found in Section 3.6.2.  The duration-finding 
cohorts (Cohorts 3, 3χ, 4 and 4χ) will be dosed at the IMG-7289 Dp (determined by the DSMC) for 
either 14 or 21 days, with or without ATRA.  The Dp may change as data from earlier sub-cohorts 
becomes available and different durations continue to be evaluated; the length of dosing will be 
extended by cohort as described below and summarized in Table 4.  The number of initially 
allowed IMG-7289 cycles differs by cohort, as does the duration of IMG-7289 dosing. The duration-
finding cohorts are outlined below. 
It is anticipated that duration extension will proceed in cohorts in accordance with the below, 
following DSMC reviews as detailed in Section 8.1 and in accordance with the rules outlined Section 
8.2.2.  Of note, there are two potential duration-extension pathways for the duration-finding 
cohorts which will be determined at the discretion of the DSMC. 
Cohort 3:  Dosing of IMG-7289 at the Dp will begin on Day 1 for a duration of 14 days.   
Cohort 3χ:  The above IMG-7289 regimen in combination with ATRA 45 mg/m2 per day for 14 days. 
Cohorts 3 and 3χ patients will initially be allowed to receive 2 cycles of IMG-7289, provided they 
continue to tolerate IMG-7289 (with or without ATRA). 
If the DSMC determines that duration extension should proceed, then additional cohorts will be dosed 
with extending durations; possible cohorts are outlined below. 
Cohort 4:  Dosing of IMG-7289 will begin on Day 1 for a duration of 21 days.   
Cohort 4χ:  The above IMG-7289 regimen in combination with ATRA 45 mg/m2 per day for 21 days. 
Cohort 4 and 4χ patients will initially be allowed to receive 1 cycle of IMG-7289. 
Sub-
cohort 
IMG-7289 Dose 
(free base) 
IMG-7289 Cycle 
No. of Initial 
IMG-7289 
Cycles** 
Dosing 
Duration 
Rest Period* 
1y 
0.1875 mg/kg/d 
7 days 
7 days 
4 
1z 
0.375 mg/kg/d 
1a 
0.75 mg/kg/d = Ds 


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If the DSMC determines that a specific dosing duration is associated with greater therapeutic benefit, 
then patients who have fully completed their initially allowed IMG-7289 treatment cycles and are at a 
different dosing duration will be transitioned to the more optimal dosing duration at the start of their 
next cycle. 
The table below summarizes the duration-finding phase by cohort, dosing duration, treatment 
regimen, rest period and number initially allowed IMG-7289 treatment cycles. 
Table 4:  Duration-finding Cohorts, Including Durations for Extension 
Cohort 
IMG-7289 Dose 
(free base) 
IMG-7289 Cycle 
No. of Initial 
IMG-7289 
Cycles** 
Dosing Duration 
Rest period* 
3 
Dp¥ 
14 days 
7 days 
2 
3χ 
The Cohort 3 IMG-7289 regimen, administered in combination with 
ATRA§  45 mg/m2/d for 14 days on followed by 7 days off 
4 
Dp¥ 
21 days 
7 days 
1 
4χ 
The Cohort 4 IMG-7289 regimen, administered with 
ATRA§  45 mg/m2/d for 21 days on followed by 7 days off 
*The duration of the rest period may be adjusted based on an assessment by the DSMC that either a 
specific patient or an entire cohort could benefit from an extended rest period.  This decision could be 
taken if there is no clear indication of the restoration of normal haematopoiesis in the 7 day period or 
analysis of the pharmacokinetic parameters in Cohort 1 suggest the rest period duration requires 
adjusting.  Investigators will be notified of any such change. 
**Additional cycles may be allowed, contingent on clinical benefit/patient response. 
¥The IMG-7289 dose for administration will be determined by the DSMC based on ongoing review of safety 
and pharmacodynamic data. 
§The ATRA dose may be reduced or the dosing and/or rest period duration adjusted by the DSMC based 
ongoing review of safety and pharmacodynamic data. 
Additional Cycles:  Upon completion of the number of initially allowed IMG-7289 cycles per cohort, 
patients deriving clinical benefit and safely tolerating IMG-7289, as determined by the Principal 
Investigator, may continue to receive IMG-7289 beyond the number of initially allowed IMG-7289 
treatment cycles, specifically:  4 cycles of 7 days IMG-7289 dosing for Cohort 1 patients; 2 cycles of 
14 days IMG-7289 dosing for Cohort 3/3χ patients; and, 1 cycle of 21 days IMG-7289 dosing for 
Cohort 4/4χ patients.  Additional dose titration, treatment regimen or dosing duration changes may 
occur in consultation with the Medical Monitor, until disease progression or unacceptable toxicity 
ensues.  During the additional cycle period, the rest period may be extended from the 7 day standard 
to a maximum of 56 days but only after: 1) the patient has received a minimum of 28 IMG-7289 doses; 
and, 2) consultation with or recommendation by the DSMC.  Such recommendation may be made for 
a variety of reasons including evidence of tumour reduction, marked hypocellularity in the marrow 
consistent with myelosuppression, or to enable the return of normal haematopoiesis.  For protocol 
purposes, a rest period extending beyond the 7 day standard will be referred to as the extended rest 
period (see Section 9.10). 


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Patients who either fail to demonstrate stable disease, demonstrate progressive disease after 
achieving partial remission or stable disease, or who relapse after achieving CR, CRi or PR (see Table 
14 and Table 15) are the equivalent of treatment failures and will discontinue study drug and enter 
the follow-up period. 
7.2.3 Administration 
Appropriately trained personnel of the study site will provide instruction pertaining to study drug 
administration and supervise the administration of the study drug on any day that it is taken in the 
clinic.  With the exception of the Day 1 visits, and other visits where either PK or samples for Cmin 
drug concentrations will be collected, it is not required that study drug be taken in the clinic; this 
will be determined based on the patient’s regular daily dosing time.  When applicable, the date and 
time of each administration in the clinic will be recorded in the source notes. 
Initial IMG-7289 dosing will be based on the patient’s weight on Day 1.  If during the course of the 
study, the patient’s weight differs from the weight used for Day 1 by more than 10%, the amount of 
IMG-7289 dispensed should be corrected per the dose chart provided to sites.   Initial ATRA dosing 
will be based on the patient’s body surface area calculated from height at Screening and weight on 
Day 1.  In cases where using weight measured on Day 1 is impractical for pharmacy dispensing, a 
weight taken as close to Day 1 as possible, e.g., Screening Visit or Baseline Visit may be used as long 
as the source data is clear on which weight has been used. 
7.2.3.1 IMG-7289 Administration 
Patients should be instructed to: 
 
Take their IMG-7289 in the morning once daily, at approximately the same time (suggest 
that patient select their dosing time with consideration given to fasting requirements) for 
the requisite dosing duration 
 
Swallow their IMG-7289 capsules whole, with a glass of water 
 
Take IMG-7289 on an empty stomach (fast for 1 hour prior to and 30 minutes after dose)   
Patients may have clear liquids prior to their dose, and following study drug administration. 
7.2.3.2 ATRA Administration 
Patients should be instructed to: 
 
Take their ATRA twice daily, split into two equal doses for the requisite dosing duration 
 
Take their ATRA doses during or immediately after a meal, at about the same time each day  
 
Swallow their ATRA capsules whole, with a glass of water 
 
Take their second dose of ATRA approximately 12 hours after their first dose   
7.2.4 Missed Doses 
Patients who miss more than 2 consecutive doses may be removed from the study at the discretion 
of the Sponsor.   


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7.2.4.1 Missed IMG-7289 Doses 
Patients who do not take their IMG-7289 dose at the usual required time should take it immediately 
upon noting that it was not taken; the patient should not take the dose more than 12 hours after the 
usual dosing time.  If a patient misses a dose, they should not take two doses the following day, but 
should notify their study coordinator and continue with their normal daily dose the following day.   
7.2.4.2 Missed ATRA Doses 
Patients who do not take their ATRA dose at the usual required time should take it immediately 
upon noting that it was not taken; however, if it is within 3 hours of their next scheduled dose time, 
the patient should not take the dose.  If a patient misses a dose, they should not take double the 
dose at the next dosing time, but should notify their study coordinator and continue with their 
twice daily dosing the following day.   
8 
DATA SAFETY MONITORING COMMITTEE (DSMC) REVIEWS AND 
MANAGEMENT OF STUDY TOXICITIES 
8.1 Data Safety Monitoring Committee (DSMC) Reviews 
Safety will be monitored throughout the study in accordance with a Data Safety Monitoring Plan 
(DSMP) by a DSMC constituted by, at a minimum: the Imago BioSciences Principal Medical Monitor, 
a Principal Investigator and an Independent designee, an AML clinical trials specialist with 
extensive clinical experience.  To ensure a quorum of 3 members at all meetings, an alternate DSMC 
member will also routinely attend Safety Reviews, and participate when needed.   
During all phases, the DSMC will review safety parameters, pharmacodynamic (PD) markers and 
pharmacokinetic (PK) parameters to form conclusions around the safety and pharmacodynamic 
effect of differing doses, treatment regimens and dosing durations.  DSMC reviews are critical, as 
neither a new dose-finding sub-cohort, nor a duration-finding cohort may commence without DSMC 
review and recommendation to do so.  The DSMC will assess:  the safety of each dose and dosing 
duration, with and without ATRA.  The DSMC will also assess: any clinically significant biochemistry 
trends; the impact of each dose on normal myeloid haematopoiesis; the PD impact of each dose on 
malignant cells, and whether further cohorts/sub-cohorts in each respective phase are appropriate.   
Data from each cohort/sub-cohort will be reviewed by the DSMC after a minimum of 3 patients in a 
cohort/sub-cohort have completed Cycle 1 and prior to dosing the next cohort/sub-cohort.  Safety 
data to be evaluated, may include:  clinical laboratory results, ECGs [ECGs required in the first 9 
patients only as there have been no non-clinical cardiovascular findings; if clinically meaningful 
trends in ECGs are noted, then the DSMC will make a recommendation as to the appropriate action 
to be taken (i.e., cardiologist consult, additional ECG requirements, etc.]; physical examination and 
vital sign measurements; and AEs/DLTs/Medical Events of Interest (MEOIs).  A combination of PD 
and PK markers will be evaluated, as available, and may include:  peripheral white blood cell count; 
peripheral blast count; reticulocyte count; platelet count; bone marrow blast count; expected 
changes in immunophenotype; changes in VAF, changes in cytokine profiles; and, changes in PSA 
(males only).  These metrics will be evaluated in the context of PK parameters such as changes in 


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the clearance of IMG-7289 (with and without ATRA) based on drug concentrations at Cmin, Cmax and 
AUC, as available.   
The DSMC is responsible for providing recommendations regarding the conduct of the study and 
guidance to Investigators to ensure the safety and well-being of all participating patients.   
To avoid repetition in this section, additional DSMC responsibilities are detailed below: 
 
Rest period duration (see Section 9.10, Extended Rest Period):   
o During the initially allowed IMG-7289 treatment cycles, the rest period will remain at 7 
days in duration, unless assessment is made by the DSMC that there is no clear 
indication of the restoration of normal haematopoiesis in the 7 day period or analysis of 
the IMG-7289 PK parameters in earlier sub-cohorts suggest the rest period duration 
requires adjusting.  Consideration of adjustments to the rest period duration will be 
based on an assessment that either a specific patient or an entire cohort could benefit 
from an extended rest period. 
o During the additional cycle period, the rest period may be extended from the 7 day 
standard to a maximum of 56 days, but only after: 1) the patient has received a 
minimum of 28 IMG-7289 doses; and, 2) consultation with or recommendation by the 
DSMC.  Such recommendation may be made for a variety of reasons including evidence 
of tumour reduction, marked hypocellularity in the marrow consistent with 
myelosuppression, or to enable the return of normal haematopoiesis. 
 
Cohort/sub-cohort progression:  In both the dose-finding and duration-finding phases, 
more than one pathway is available for cohort progression.  In these instances, 
determination will be made by the DSMC on the most appropriate path for progression.  
Additionally, as DSMC review of data continues throughout the study, the DSMC may a 
recommend a different cohort progression than is currently outlined in the protocol. 
 
Doses for use in a cohort/sub-cohort:   
o The DSMC will determine the IMG-7289 dose(s) for use in combination therapy 
cohorts/sub-cohorts and any duration-finding cohorts. The DSMC may determine (in 
the presence or absence of DLTs) that use of an IMG-7289 dose not pre-specified in the 
protocol is appropriate; for example, that a dose-finding sub-cohort of 1 mg/kg/d be 
studied were the dose of .75 mg/kg/d assessed as potentially too low and 1.5 mg/kg/d 
potentially too high.   
o 
As DSMC review continues throughout the study, the DSMC may recommend reducing 
the ATRA dose and/or adjusting the ATRA dosing duration. 
 
Transition of patients to a different dose, treatment regimen or dosing duration:  
Importantly, if a specific dose, treatment regimen or dosing duration is found to be 
associated with greater therapeutic benefit, patients who have fully completed their initially 
allowed cycles and are receiving a different dose, treatment regimen (i.e., IMG-7289 alone 
versus combination therapy) or dosing duration will be transitioned to the more optimal 


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dose, treatment regimen or dosing duration at the start of the next cycle.  Such transition 
may occur more than once, as different doses, treatment regimens and dosing durations 
continue to be evaluated. 
DSMC responsibilities will remain in effect until the study has ended. 
DSMC reviews during the IMG-7289 alone component of the dose-finding phase are detailed 
below. 
The DSMC will assess the safety of each sentinel patient before the remainder of the sub-cohort is 
treated. Each dose sub-cohort will be separated by approximately one week to allow for completion 
and analysis of appropriate safety assessments required for provision to the DSMC.  Dose escalation 
(see Section 7.2.2.1) will proceed in sub-cohorts (i.e., Sub-cohort 1b, 1c) provided that: 
1. A minimum of 3 patients from the previous sub-cohort have completed Cycle 1, both the 
applicable dosing and rest periods 
2. The number of patients who experience DLT is within the guidelines (see Section 8.2.2) 
3. DSMC review of the previous cohort has determined that: 
a. The dose administered appears safe 
b. Further dose escalation is appropriate  
There are two potential dose-escalation pathways for Sub-cohort 1d:  6 and 10 mg/kg/d.  The dose 
to be administered in Sub-cohort 1d will be determined at the discretion of the DSMC.  Therefore, 
upon Cycle 1 completion of a minimum of 3 patients in Sub-cohort 1c, the DSMC will assess the 
safety and pharmacodynamic effects of the earlier sub-cohorts, and reach consensus on: 
1. Whether dose escalation should proceed at all, and if so…  
2. Whether the appropriate escalation for Sub-cohort 1d is a doubling or a tripling of the 3 
mg/kg/d dose administered in Sub-cohort 1c. 
Post DSMC confirmation that no further dose escalation is anticipated, the combination therapy 
cohort will be enrolled.     
DSMC reviews during the IMG-7289 in combination with ATRA component of the dose-finding 
phase are detailed below. 
Combination therapy (see Section 7.2.2.1) will proceed in sub-cohorts (i.e., Sub-cohort 1Ѡ, 1Ѵ, etc.) 
provided that: 
1. A minimum of 3 patients from the previous sub-cohort have completed Cycle 1, both the 
applicable dosing and rest periods 
2. The number of patients who experience DLT is within the guidelines (Section 8.2.2) 
3. DSMC review of the previous sub-cohort has determined that: 
a. The doses administered in combination appear safe 
b. Further combination therapy is appropriate 


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Upon DSMC confirmation that no further dose-finding sub-cohorts are anticipated, the DSMC will also 
make a determination of whether it is safe to extend the dosing duration, to determine whether 
longer durations are associated with greater therapeutic benefit.  The study will then progress to 
assess the effect of IMG-7289 dosing duration. 
DSMC reviews during the duration-finding phase are detailed below. 
During the duration-finding phase, the DSMC will assess whether the longer duration of IMG-7289 
dosing, with and without ATRA, at the Dp is safe and associated with greater therapeutic benefit using 
a combination of PD and PK markers.  Each duration cohort will be separated by approximately one 
week to allow for completion and analysis of appropriate safety assessments required for provision 
to the DSMC.   
There are two potential duration-extension pathways for the duration-finding cohorts:  duration 
extension with IMG-7289 alone, or IMG-7289 administered in combination with ATRA.  Therefore, 
prior to opening a duration-finding cohort, the DSMC will assess the safety and pharmacodynamic 
effects of the earlier sub-cohorts, and reach consensus on: 
1. Whether it appears safe to extend the duration of IMG-7289 dosing 
2. Whether there appears to be greater therapeutic benefit with IMG-7289 dosed in 
combination with ATRA.  
Based on the above assessments, one of the duration-finding cohorts will commence. 
The duration of dosing (see Section 7.2.2.3) will be extended in subsequent cohorts provided that: 
1. A minimum of 3 patients in the previous cohort have completed Cycle 1, both the applicable 
dosing and rest periods 
2. The number of patients who experience DLT is within the guidelines (see Section 8.2.2) 
3. DSMC review of the previous cohort has determined that: 
a. The duration of dosing appears safe 
b. Further duration extension is appropriate 
Throughout all phases of the study, if it appears that either a maximally tolerated dose (MTD) or 
maximally tolerated duration (MTDu) is reached (see Section 8.2.3), the DSMC will convene to 
evaluate further dose escalation, combination therapy and/or extended dosing duration. 
8.2 Management of Study Toxicities 
Adverse event intensity will be evaluated using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03, published 14 June 2010. 
Dose-limiting toxicity and dose escalation and duration extension decision rules are defined in 
Sections 8.2.1 and 8.2.2 below.  Expected IMG-7289 toxicities based on non-clinical studies are 
reported in the latest available edition of the Investigator’s Brochure.  Expected ATRA toxicities are 
reported in the Product Information (PI) document. 


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8.2.1 IMG-7289 Toxicity Definitions 
Haematologic Toxicity: Haematologic values outside of the normal reference range are inherent 
features of AML and MDS, and are expected effects of many therapeutic attempts to manage these 
diseases.   These effects will not be considered DLTs.   
Both genetic knockdown (KD) of LSD1 mRNA and pharmacologic inhibition of LSD1 show that the 
loss of LSD1 activity arrests the production of mature red cells, platelets and granulocytes while 
over-producing monocytes (Sprussel et al., 2012; Kerenyi et al., 2013).  Production of cells of 
lymphoid lineage, B and T cells is unimpaired indicating that LSD1 has very cell-specific functions 
and its inhibition also has very specific effects.  LSD1 inhibition in AML cells causes the induction of 
monocytic differentiation markers, as well as a reduction of self-renewal potential of leukaemic 
cells, eventually resulting in apoptosis of treated cells.  Thus, the anaemia, thrombocytopenia, 
neutropenia and monocytosis attending LSD1 inhibition, as observed in animals treated with IMG-
7289, reflect primary pharmacodynamic effects.  The kinetics of anaemia, thrombocytopenia, and 
neutropenia following complete LSD1 inhibition are a function of the lifespan of the individually 
affected cell types.  Over the course of LSD1 inhibition, platelet and neutrophil counts are the most 
affected, reflecting their short mean lifespans of approximately seven and twelve days, respectively.  
Recovery of peripheral counts is reversible, rapid, and temporarily overshoots baseline values.  At 
lower doses, the effects on haematopoiesis are much less pronounced suggesting that a modicum of 
residual LSD1 activity is sufficient to support some blood cell formation.  Thus, both the duration of 
LSD1 inhibition as well as the degree of inhibition are critical to the pharmacodynamic effects on 
myeloid lineages. 
The intended dosing plan for high risk AML/MDS patients is predicated on the supposition that 
LSD1 must be maximally inhibited to achieve the greatest therapeutic benefit.  The concentrations 
of LSD1 inhibitors such as IMG-7289 (free base) used to achieve maximal effects on growth, 
differentiation and apoptosis in vitro with primary patient-derived AML cells as well as AML cell 
lines are similar to concentrations that in vivo inhibit red cell, platelet and granulocyte production.  
It is therefore expected that high risk AML/MDS patients will require treatment at doses sufficient 
to induce profound thrombocytopenia and neutropenia.  These drug-induced but reversible 
cytopenias can be managed clinically as needed with platelet and red cell transfusions as well as 
broad-spectrum antibiotics in the case of febrile neutropenia, as are already standard practices in 
the routine management of AML/MDS patients receiving intensive SOC chemotherapy. 
The effects of IMG-7289 on normal myeloid haematopoiesis observed in non-clinical studies are 
expected in humans; these are pharmacodynamic effects of LSD1 inhibition by IMG-7289, thus are 
not regarded as adverse.  These events, with the exceptions noted below, will not be considered DLTs.   
Dose Limiting Toxicity (DLT):  DLT is defined as any one of the following AEs that occurs during 
the first cycle of therapy and is considered by the Investigator to be possibly, probably or definitely 
related to IMG-7289. 
 
A clinically significant bleeding event;  
 
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 
Any Grade 3 non-haematologic adverse event with failure to recover to Grade 1 within 7 days 
of drug cessation, with the following exceptions: 
o ≥ Grade 3 nausea, vomiting or diarrhoea that responds to standard medical care 
o ≥ Grade 3 aesthenia lasting less than 14 days 
 
Any Grade 3 electrolyte abnormality unrelated to the underlying malignancy and persisting 
greater than 24 hours. 
Patients who experience a dose limiting toxicity (DLT) will have their dose adjusted downward if the 
Medical Monitor and Principal Investigator deem it safe for the patient to continue on IMG-7289.  To 
ensure a minimum of 3 Cycle 1 completers, and contingent on the number of prior DLTs within the 
sub-cohort/cohort, such patients may be replaced. 
Any patient that experiences a DLT that results in discontinuation of IMG-7289 therapy may begin 
alternative therapy after a one week washout period and if their physician deems this safe and 
appropriate regarding the resolution of the DLT. 
Please consult the Medical Monitor for IMG-7289 dose modifications for the management of clinically 
significant changes in platelets, neutrophil counts, or other haematologic parameters. 
Expected toxicities based on non-clinical studies with IMG-7289 are reported in the latest edition of 
the Investigator’s Brochure.   
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Additionally, the DSMC may review safety data and, even in the absence of 2 DLTs, deem that the 
safe dose has been exceeded.  Were this to occur, dose escalation would cease.  
Table 5:  IMG-7289 Dose Limiting Toxicity and Escalation Decision* 
Patients with DLT at a Given Dose 
Escalation Decision Rules 
0-1 out of 3 
Open subsequent sub-cohort/next dose 
2 out of 3 
Dose escalation will be stopped 
*The above instruction applies in kind for combination therapy and duration extension decision making. 
8.2.3 IMG-7289 Maximum Tolerated Dose (MTD) and Duration (MTDu)ɸ 
The MTD is defined as the highest dose below or at which <2 out of 3 patients experience DLT.  If 
unacceptable toxicity occurs (DLT in 2 out of 3 patients) at the reduced dose of 0.375 mg/kg/d, 
then the dose will be further reduced to the 0.1875 mg/kg/d dose.  In this study, the MTD may not 
be reached if the highest dose tested is found to be safe (that is, DLT in <2 out of 3 patients).   
The above instruction applies in kind for the MTDu. 
ɸMTD and MTDu definitions also apply to combination therapy sub-cohorts. 
8.3 ATRA Toxicity 
Decisions on IMG-7289 and ATRA dose interruption, reduction and re-challenge due to observed 
toxicity will be made by the Investigator in consultation with Medical Monitor and DSMC. 
Expected toxicities for ATRA can be found in the Product Information (PI) document. 
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10 LABORATORY SAMPLING FOR SAFETY, PK AND PD ANALYSIS 
Blood, bone marrow and/or their contents may be retained for future exploratory studies. 
The amount of blood collected from each patient for safety, PK and PD assessments will vary by 
Cohort due to differing PK sampling requirements, treatment durations, and DSMC assessment of 
biochemistry trends as either clinically significant or not clinically significant.  The average of the 
blood volumes, which vary by institution, is provided below for each cohort.  
Sub-cohort 1a: Approximately 539 mL blood over ~15 weeks  
Sub-cohort 1b*#: Approximately 478 mL blood over ~15 weeks  
Cohort 3/3χ#: Approximately 322 mL blood over ~13 weeks  
Cohort 4/4χ#: Approximately 267 mL blood over ~11 weeks  
The number of bone marrow aspirates and biopsies, and therefore the total volume required, will 
vary by Cohort due to differing treatment durations, and the number of Cycles allowed.  For each 
sample time-point, approximately 2-3 mL of bone marrow sample is required.  Estimates, by cohort, 
are provided below.  
 
Sub-cohort 1*:  4 samples and approximately 8-12 mL bone marrow over ~15 weeks 
Cohort 3/3χ:  3 samples and approximately 6-9 mL bone marrow over ~13 weeks 
Cohort 4/4χ:  3 samples and approximately 6-9 mL bone marrow over ~11 weeks 
*Applies to all sub-cohorts. 
#Figures based on standard biochemistry evaluations; if clinically significant trends are noted by 
the DSMC, these numbers will increase by Cohort (1, 3/3χ, or 4/4χ respectively), as follows:   63, 49, 
and 28 mL.  
Note:  The above blood volume, and bone marrow sampling time-points and volume, includes all 
Screening assessments and each study visit up to and including the EOS.  Not included, however, are 
any additional cycles that a patient may be allowed to receive if clinical benefit is observed nor the 
extended rest period. 
10.1 Laboratory Measures 
Details on the laboratory assessments performed throughout the study are provided below by 
category of tests (i.e., biochemistry, haematology with manual differential, etc.).  Details on the 
specific laboratory assessments required at each visit are located in Section 9 and in schematic 
form in Appendix 16.1.  When each category of test is required, at a minimum, the following clinical 
laboratory determinations (or their equivalent) will be performed. 
10.1.1 Local Laboratory Measures 
Biochemistry: Sodium, potassium, magnesium, chloride, bicarbonate, glucose, calculated creatinine 
clearance (by Cockcroft-Gault method) and/or serum creatinine, uric acid, phosphate, total calcium, 
anion gap, urea or blood urea nitrogen (BUN), triglyceride, cholesterol, albumin, protein, total 
bilirubin, conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, gamma 


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glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
transaminase (AST), lactate dehydrogenase (LDH).  At specified time-points, Prostate Specific 
Antigen (PSA) will also be measured in males.   
Haematology (with manual differential): Haemoglobin, red blood cell count (RBC) (including 
nucleated RBC), red cell distribution width (RDW), haematocrit, mean corpuscular volume (MCV), 
mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), 
platelets, mean platelet volume (MPV), immature platelet fraction (IPF), white cell count, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, promyelocytes, 
myelocytes, blasts and Auer rods.  At specified time-points, haemoglobin F (HbF) will also be 
measured. 
Coagulation: Prothrombin time (PT), activated partial thromboplastin time (aPTT) and 
International normalized ratio (INR). 
Urine Pregnancy Test: For WOCBP, a urine pregnancy testing kit will be utilized.   
Urinalysis: Leucocyte esterase, nitrites, urobilinogen, protein, pH, blood, specific gravity, ketones, 
bilirubin, glucose and microscopic examination. 
Bone marrow sampling: Aspirate and biopsy samples are to be collected as per site procedure. 
Evaluation, will be performed centrally (see Section 10.1.2); however, any locally available 
morphology, immunophenotyping, cytogenetic evaluations/ genetic interrogations performed on 
samples obtained at the same time-point as study samples, will also be reported in the eCRF.   
Sample Processing: Imago BioSciences will not provide either a laboratory manual or study 
supplies for the collection and handling of samples to be analysed locally – with the exception of 
urine pregnancy test kits for sites that cannot provide these.  Local laboratory standard procedures 
should be followed at each site. 
10.1.2 Central Laboratory Measures 
Immunophenotyping - peripheral blood: Fluorescence-activated cell sorting or flow cytometry 
(FACS; FC), will be performed using 4 mL blood per required time-point.  Baseline, end of the 
dosing period, and EOT and EOS visit peripheral blood samples will be routinely analysed; however, 
samples collected at other time-points may not be analysed unless the bone marrow sample is 
inadequate for immunophenotyping (note: sample may also be used for genomic testing if bone 
marrow sample is inadequate).  A standardized panel and gating will be used. 
Cytokines:  A 8.5 mL blood sample, per required time-point, for cytokine profiles may be quantified, 
via appropriate methods. 
Bone marrow:  A 2-3 mL bone marrow sample for central analysis must be collected from the first 
pull, whenever possible, and no later than the third.  A 1-2 cm section of trephine bone marrow 
sample for central analysis must also be collected.  Measures to be performed centrally include:  
immunophenotyping by FACS or FC, genomic analysis, and morphology review using 5 site 
prepared slides.  Fluorescent in-situ hybridization may also be performed, cost permitting.  A blood 
film must also be provided for review in conjunction with the marrow sample.  For selected 


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samples, if the marrow sample is inadequate, then immunophenotyping or genomic testing will be 
performed using peripheral blood.  
Genomic Testing:  If there is sufficient sample volume, then approximately 1-2 mL bone marrow 
aspirate will be used for analysis of mutant allele burden over the course of IMG-7289 treatment.; if 
sample volume is insufficient, then peripheral blood collected for immunophenotyping purposes 
may be used.  At Baseline and EOT, 10 mL blood will be collected for analysis.  Genomic sample 
collection, handling, storage, and analysis will conform to all applicable national guidance and 
regulations.   
Sample Processing: Imago BioSciences will provide a laboratory manual documenting the 
collection and handling of samples to be analysed centrally.  Additional supplies may be provided, 
dependent on the analyte to be measured and the supplies needed. 
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11 SAFETY 
The Investigator is responsible for monitoring the safety of patients who have been enrolled in this 
study.   
Once an Investigator determines a patient is a treatment failure (see Section 6.8) or if the patient is 
withdrawn from treatment early due to a Dose Limiting Toxicity, the patient should discontinue 
study treatment and undergo all follow-up procedures, beginning with an End of Treatment Visit 
(see Section 9.12.1).   
11.1 Pregnancy  
Every effort should be made to prevent pregnancy throughout the entire duration of participation 
in this study.  All patients of reproductive potential involved in the study are required to use 
effective methods of contraception during the study and for 28 days after the last IMG-7289 dose.  
Female patients will be instructed to notify the Investigator immediately if they discover they are 
pregnant; male patients will be instructed to notify the Investigator immediately if they discover 
that their sexual partner is pregnant.  Pregnancy data during the study will be reported in an 
expedited manner using the Pregnancy Report Form and following the SAE reporting process (see 
Section 11.2.4).  It will be necessary to collect detailed information on the course of any pregnancy 
occurring in a patient on study, including pregnancies in the partners of male patients, assuming 
consent to do so is provided.  If the outcome and/or a complication of the pregnancy meets serious 
criteria (i.e., miscarriage or congenital anomaly/birth defect), then it should be reported as an SAE 
using the SAE/ MEOI Report Form. 
Pregnant patients will discontinue study medication for the duration of the pregnancy.  The 
pregnancy will be followed by the Investigator and the outcome of the pregnancy will be reported 
to the Pharmacovigilance group as per the Study Reference Manual (SRM).   
It is not known whether IMG-7289 can affect reproductive capacity, and the direct effects of IMG-
7289 and the indirect effects of prior IMG-7289 exposure on fetal development are also unknown.     
It is well documented that ATRA can cause deformities to the unborn fetus.  Patients who are taking 
the combination therapy will be provided with this information.   
All patients will be encouraged to discuss contraception and pregnancy concerns with their 
physician in advance of becoming pregnant.  Full disclosure of a patient’s participation in this study 
to their general practitioner is strongly recommended. 
11.2 Adverse Events  
The Investigator is responsible for monitoring the safety of patients who have enrolled in the study 
and for accurately documenting and reporting information as described in this section. Patients will 
be instructed to report to the Investigator any AE that they experience.  Investigators will ask about 
the occurrence of AEs at each visit.  Investigators are required to document all AEs occurring during 
the clinical study, commencing with the first dose of IMG-7289 through to the End of Study Visit 
(scheduled at 28 days post last IMG-7289 dose).  Adverse event recording will continue for patients 


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who discontinue study treatment early but remain in follow-up, until their End of Treatment, Pre-
End of Study and End of Study Visits have been completed. 
Note: Any medical event which occurs from the time of Informed Consent but prior to dosing with 
IMG-7289 must still be documented in the patient’s medical notes and will be recorded on the 
appropriate medical history CRF pages.  
Adverse events will be recorded on designated CRF pages. Each AE is to be characterised (i.e., 
verbatim term) and information provided regarding its seriousness, start and stop dates, intensity, 
outcome, and causal relationship with the study drug.  
An AE is any undesirable physical, psychological or behavioral effect experienced by a patient 
during participation in an investigational study, in conjunction with the use of the drug or biologic, 
whether or not product-related.  This includes any untoward signs or symptoms experienced by the 
patient from the time of first dose with IMG-7289 until completion of the study. 
Adverse events may include, but are not limited to: 
 
Subjective or objective symptoms spontaneously offered by the patient and/or 
observed by the Investigator or medical staff 
 
Findings at physical examinations 
 
Laboratory abnormalities of clinical significance 
Progression of underlying malignancy is not reported as an AE if it is consistent with the suspected 
progression of the underlying cancer. Clinical symptoms of progression may be reported as AEs if 
the symptom cannot be determined as exclusively due to the progression of the underlying 
malignancy or does not fit the expected pattern of progression for the disease under study. If there 
is any uncertainty about an AE being due to only the disease under study, it should be reported as 
an AE. 
It is important that Investigators record accurate AE terms on CRFs.  Wherever possible, a specific 
disease or syndrome rather than individual associated signs, symptoms or laboratory parameter 
will be identified by the Investigator and recorded on the CRF.  However, if an observed or reported 
sign, symptom or laboratory parameter is not considered a component of a specific disease or 
syndrome by the Investigator, or is atypical, it should be recorded as a separate AE on the CRF. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of the 
investigational product are not considered AEs after treatment unless they reoccur after the patient 
has recovered from the preexisting condition or in the opinion of the Investigator they represent a 
clinically significant exacerbation in intensity or frequency.   
Clinical significance is defined as any variation in signs, symptoms, or testing that has medical 
relevance and may result in an alteration in medical care.  The Investigator will continue to monitor 
the patient until the assessment returns to Baseline or until the Investigator determines that 
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11.2.1 Adverse Event Intensity 
Adverse event intensity will be evaluated using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03, published 14 June 2010. For AEs 
not included in the NCI CTCAE, the Investigator will be required to assess the intensity of the 
adverse drug/biologic experience using the following categories and associated guidelines:   
 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL* 
 
Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL** 
 
Grade 4:  Life-threatening consequences; urgent intervention indicated 
 
Grade 5:  Death related to AE.   
Note 1: A semi-colon indicates ‘or’ within the description of the grade. 
Note 2: Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
11.2.2 Adverse Event Relatedness 
The Investigator will make a judgment regarding whether or not, in his/her opinion, the AE was 
related to study drug.  The Investigator will also evaluate any changes in laboratory values, make a 
determination as to whether the change is clinically significant, and whether or not the change(s) 
were related to study drug.  However, even if the Investigator feels there is no relationship to the 
study drug, the AE or clinically significant laboratory abnormality MUST be recorded on the CRF.  
Below are guidelines for relationship assessment: 
 
Unrelated: There was no relationship of the adverse event to the use of the drug or 
biologic. This may include, but is not limited, to the adverse experience being an 
expected outcome of a previously existing or concurrent disease, concomitant 
medication or procedure the subject experienced during their treatment period.  
 
Remote/Unlikely: Adverse events which are judged probably not related to the 
drug or biologic.  
 
Possible: There was no clear relationship of the adverse event to the use of the drug 
or biologic; however, one cannot definitively conclude that there was no 
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 
Probable: While a clear relationship to the drug or biologic cannot be established, 
the event is associated with an expected adverse event (per the current 
Investigator Brochure or DSMC findings) or there is no other medical condition or 
intervention which would explain the occurrence of such an experience.  
 
Definite: The relationship of the use of the drug or biologic to the experience is 
considered definitively established. 
If a causal relationship is considered probable, possible, or definite by the Investigator, the AE is 
considered to be “related” for purposes of regulatory reporting. If a causal relationship is 
considered remote/unlikely or unrelated, the AE is considered “unrelated” for purposes of 
regulatory reporting.   
11.2.3 Serious Adverse Events 
Serious adverse events will be reportable from the time the time of first dose through the End of 
Study Visit (scheduled for approximately 28 days post last IMG-7289 dose) or until the Investigator 
and Imago BioSciences determine that follow-up is no longer necessary.  Serious adverse events 
that are suspected to be drug related will be reported even if they occur when the patient is no 
longer on the study.   
An SAE is any AE that results in any of the following outcomes: 
 
Death¥ 
 
Life-threatening experience 
 
Required or prolonged inpatient hospitalisation¥ 
 
Persistent or significant disability/incapacity 
 
Congenital anomaly 
 
Important medical events that, based upon appropriate medical judgment, may 
jeopardise the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Life-threatening experience. Any adverse event that places the patient, in the view of the 
reporter, at immediate risk of death from the adverse event as it occurred, i.e., does not include an 
adverse event that had it occurred in a more severe form, might have caused death. 
Required or prolonged inpatient hospitalisation. The adverse event resulted in an initial 
inpatient hospitalisation or prolonged an existing hospitalisation of the patient. If a patient is 
hospitalised as part of the clinical use of the product, a period of normal hospitalisation will be 
outlined in the protocol or by the judgment of the Investigator. Hospitalisations longer than this 
period will be prolonged hospitalisations. 
Persistent or significant disability/incapacity. An adverse event that resulted in a substantial 
disruption of a person’s ability to conduct normal life functions. 
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judged to have resulted in the congenital anomaly/birth defect. 
Important medical events. Adverse events that may not result in death, be life-threatening, or 
require hospitalisation may be considered a serious adverse event when, based upon appropriate 
medical judgment, may jeopardise the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Important medical events or 
interventions may be considered an SAE based upon medical judgment of the Investigator.   
¥Note:  Hospitalization consistent with progression of underlying malignancy should NOT be 
reported as an SAE.  An SAE with an outcome of death solely due to progression of the underlying 
malignancy does not need to be reported as an SAE. 
11.2.4 Reporting Serious Adverse Events  
SAEs will be reported promptly, using the SAE/MEOI Report Form, once the Investigator 
determines that the event meets the protocol definition of an SAE.  The Investigator or designee will 
report the SAE within 24 hours of his/her becoming aware of these events regardless of 
relationship of the SAE to the use of study drug, in accordance with the instructions in the Study 
Reference Manual. The Investigator will always provide an assessment of relatedness at the time of 
the initial report as described in Section 11.2.2.  The SAE Report will always be completed as 
thoroughly as possible with all available details of the event within the designated time frames. 
Copies of relevant patient records, autopsy reports, and other documents may be requested.   
If the Investigator does not have all information regarding an SAE, he/she will not wait to receive 
additional information before reporting the SAE. The SAE Report will be updated when additional 
information is received within 24 hours of receipt of such information. 
Important:  For fatal and life-threatening events, the Sponsor’s Medical Responsible Person should 
be contacted immediately.  A death occurring during the study or information related to such 
occurrence that comes to the attention of the Investigator during the study must be reported 
immediately to the Sponsor.   
Contact numbers will be provided to the site, with a detailed SAE reporting procedure to be 
included in the Study Reference Manual (SRM), before any patients are consented. 
Table 7:  Serious Adverse Event Reporting Contact Details 
Australia Safety (phone/fax) 
Worldwide Safety (toll - phone/fax) 
Additionally, the Human Research Ethics Committee (HREC)* must be notified in writing of any 
SAEs that require expedited reporting to Regulatory Authorities.  Depending upon regional 
requirements, it is the responsibility of either the Investigator or Imago BioSciences to notify the 
HREC.  All unexpected SAEs (i.e. not documented in the current version of the Investigator 
Brochure) that are suspected by the Investigator to be related to the use of the study treatment 
(deemed possibly, probably or definitely related) will be reported to appropriate regulatory 
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agencies by Imago BioSciences or their designee as soon as possible and within the timeframes 
specified in the various regions in which the study is to be conducted.  
* If additional countries are engaged outside of Australia, then for purposes of this protocol reference to HREC 
shall also be deemed reference to any other Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC). 
11.2.5 Medical Events of Interest (MEOIs) 
Medical Events of Interest (MEOI) are AEs that do not meet any criteria for an SAE but are 
nonetheless of particular interest in the context of this study.  Medical Events of Interest will be 
collected for all patients during the study period in an expedited manner using the SAE/MEOI 
Report Form and following the SAE reporting process (see Section 11.2.4).  Although these are non-
serious events, the Investigator will be asked to provide detailed initial information and follow-up 
to the Sponsor.  The Sponsor will periodically review the AE data and in some cases may escalate an 
AE to a MEOI.  Examples of MEOI and reporting times include, but are not limited, to the following: 
Table 8:  Examples of MEOI and Reporting Timelines   
MEOI 
Reporting Times 
Electrocardiogram QT corrected interval prolonged 481 - 500 ms 
Within 5  
business days 
 
12 ANALYSIS AND STATISTICAL CONSIDERATIONS 
12.1 General Considerations 
Detailed methodology for summary and statistical analyses of the data collected in this trial will be 
documented in a Statistical Analysis Plan (SAP).  Additionally, a Pharmacokinetic Analysis Plan 
(PKAP) will be prepared.  These documents may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis will also 
be reflected in a protocol amendment.  Additional statistical analyses other than those described in 
this section may be performed if deemed appropriate and included in the SAP/PKAP. 
12.2 Power 
This study is designed to make an assessment of the safety, tolerability, and single-dose 
pharmacokinetics of the capsule formulation of IMG-7289, with and without ATRA.  With the 
planned minimum number of patients per dose cohort/sub-cohort (N=3), the study is sufficiently 
powered to determine mean pharmacokinetic parameters.  When feasible, more patients will be 
added to each cohort/sub-cohort. 
12.3 Treatment Assignment and Blinding 
This is an open-label study.  The Investigators, other hospital personnel, patients and Sponsor will 
know the identity of the treatment.   


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Effort will be made, as appropriate, to maintain continuity of study staff who administer/evaluate 
various assessments at each site (i.e., physical examination, ECG, morphology review, etc.), in order 
to facilitate consistency of assessments within a patient. 
12.4 Study Endpoints 
12.4.1 Primary Endpoints 
 The safety and tolerability of IMG-7289 with and without ATRA will be assessed by the analysis 
of adverse events (AEs), as well as changes in physical examinations, vital signs and laboratory 
values as detailed below.  
o Monitoring of Adverse Events (AEs) including determination of dose limiting toxicities 
(DLTs), medical events of interest (MEOIs), serious adverse events (SAEs), and AEs.  AEs 
will be assessed in terms of onset, duration, seriousness, severity, and causality, using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.03.  Deaths and other serious adverse events (SAEs) will also be evaluated and 
will be collected on a separate case report form (CRF).   
o Changes in physical examinations, vital signs and laboratory values will also be evaluated 
and assessed.  Information on the timing of these assessments is presented in Section 9.  
The following laboratory tests will be conducted: 
 
Complete blood counts (CBC) and differential 
 
Coagulation 
 
Chemistry panel including LFTs (AST, ALT, INR, total bilirubin, gamma 
glutamyltransferase (GGT), and albumin) 
 
Urinalysis with microscopy 
 
Electrocardiograms 
 Pharmacokinetic (PK) parameters will be determined using serial blood sampling at specified 
time points to determine PK effects of IMG-7289 with and without ATRA. Non-compartmental 
methods of analysis will be used to determine PK parameters following oral dosing of patients in 
Cycle 1. The following endpoints will be calculated: observed maximum concentration (Cmax), the 
time at which Cmax occurred (Tmax), the area under the concentration-time curve from time 0 to 24 
hours post-dose (AUC0-24), the apparent total clearance of drug after oral administration (CL/F), 
the apparent volume of distribution during terminal phase after oral administration (Vz/F) the 
terminal disposition phase half-life (t1/2), and the elimination rate constant (kel).  
 The adequacy of IMG-7289 dose and duration, with and without ATRA, in producing a 
pharmacodynamic effect will be determined using serial blood and bone marrow sampling 
throughout the course of treatment. Responses will be documented according to 
revised/modified International Working Group (IWG) Response Criteria – Cheson et al. 2003 for 
AML and Cheson et al. 2006 for MDS.  Measures of response will be assessed by blood counts and 
simultaneous examination of the bone marrow for percentage of bone marrow blasts, as well as 


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cytogenetics and molecular studies of bone marrow mononuclear cells.  
 Pharmacodynamic (PD) measurements will be obtained from serial blood, bone marrow, and 
urine sampling at specified time points to describe the PD effects of IMG-7289 with and without 
ATRA. The following endpoints may be analyzed: CCI
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12.5 Safety and Tolerability Data 
Demographics will be tabulated and summarized. Medical and surgical history data at Screening will 
be listed, as will Physical Examination data (including height and weight) at Screening, and at 
subsequent visits.  All characteristics at Baseline such as age, weight, height, vital signs (resting heart 
rate, semi-supine systolic/diastolic blood pressure, respiratory rate and temperature), and ECG 
parameters will be tabulated and summarized. 
All patients receiving at least one dose of IMG-7289 will be included in the safety analysis.   
Laboratory values outside the laboratory normal ranges will be summarized and assessed for change 
from Day 1 and trends indicating a safety signal.   
Treatment-emergent adverse events will be coded using the most updated version of Medical 
Dictionary for Regulatory Activities (MedDRA) available to the Sponsor at the time of study 
initiation (up-versioning will not occur) and summarized by cohort for the number of patients 
reporting the AE and the number of AEs reported.  A by-patient AE data listing including (but not 
limited to) verbatim term, coded term, cohort, severity, and relationship to treatment will be 
provided.  
Concomitant medications will be listed by patient and coded using the most updated version of 
WHO drug dictionary available to the Sponsor at the time of study initiation (up-versioning will not 
occur).  Medical history will be listed by patient. 
Descriptive statistics (arithmetic mean, standard deviation (SD), sample size, CV (coefficient of 
variation), median, minimum, maximum, and number) will be calculated for quantitative safety 
data as well as for the differences to baseline, when appropriate.  In addition, a shift table 
describing out of normal range shifts will be provided for clinical laboratory results, and ECG 
tracings.  Chi-square (χ2), Fisher exact, and Kruskal-Wallis tests may be used to assess the 
significance of differences in baseline patient characteristics.  For safety and tolerability, missing 
data including those not obtained because of death will be the last value carried forward. 
12.6 Pharmacokinetics Data 
For the determination of the pharmacokinetic parameters, the concentrations of IMG-7289 will be 
measured in all patients in Cohort 1, Cycle 1 using a validated assay method.  These samples are 
labeled PK in the protocol.  Pharmacokinetic parameters will be tabulated and summarized.  The 
concentration-time profiles for each patient and the mean concentration-time profile will be plotted. 
For Cohort 1, Cycles 2, 3 and 4 and all other Cohorts, samples will be collected at the specified times 
for the determination of drug concentrations, which will be used 
to correlate pharmacodynamic effects with free drug concentrations.   
Pharmacokinetic parameters will be calculated for all patients who partake in Cohort 1, intensive PK 
testing, of the study using standard non-compartmental methods as described below. 
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The following single dose pharmacokinetic parameters for IMG-7289 will be determined from the 
time and concentration data: 
AUC0–24: 
The area under the concentration versus time curve will be calculated using the linear 
trapezoidal rule from the zero time-point to the 24 hour time-point concentration. 
Cmax: 
The maximum observed concentration will be obtained directly from the concentration 
time profile. 
tmax:  
The time to maximum concentration will be obtained by inspection. If the maximum 
concentration occurs at more than one time point, the first is chosen. 
kel:  
The terminal elimination rate constant will be obtained from the slope of the line, fitted 
by linear least squares regression, through the terminal points of the log (base e) 
concentration-time profiles. 
t½: 
The half-life will be calculated by the equation t½ = 0.693/kel. 
CL/F: 
Apparent total clearance of drug after oral administration. 
Vz/F: 
Apparent volume of distribution during terminal phase after oral administration. 
Statistical analysis will be performed on the pharmacokinetic parameters using validated statistical 
software (i.e., WinNonlin, Pharsight Inc.).  
Descriptive statistics (mean, standard deviation and coefficient of variation) will be calculated for all 
pharmacokinetic parameters. 
12.7 Pharmacodynamic Data  
Measuring the activity IMG-7289 (with or without ATRA) has in producing a pharmacodynamics 
response (PD) is a secondary objective.  There are two PD responses of interest.  The first, the effect 
of the drug(s) on normal myeloid haematopoiesis, which will be measured by standard peripheral 
blood counts.  The second, the PD effect on a heterogeneous population of leukaemic cells.
Chi-square (χ2), Fisher exact, and Kruskal-Wallis tests may be used to assess the significance of 
differences in haematologic and pharmacodynamics markers among the dose-finding and duration-
finding cohorts.  If applicable, event free survival (EFS), and overall survival (OS) will be calculated 
using the Kaplan-Meier method. 
13 STUDY ADMINISTRATION 
The names, titles, and addresses of the Investigators and study personnel are listed in the Site 
Contacts list in a Study Reference Manual for Protocol IMG-7289-CTP-101 and are available from 
Imago BioSciences. 
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13.1 Ethical Considerations 
This research will be carried out in accordance with the protocol, US Code of Federal Regulations, 
GCP, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration of Helsinki, and 
the ICH harmonized tripartite guideline regarding GCP (E6 Consolidated Guidance, April 1996). 
13.2 Participation Information Sheet/Consent Form (PISCF) 
A sample PISCF document will be provided to each site.  No major deviations may be made from the 
sample PISCF other than country- or region-specific formatting or legal requirements.  Imago 
BioSciences and its advisors will review the site specific draft PISCF before it is finalised, and the 
final HREC-approved document must be provided to Imago BioSciences for regulatory purposes. 
The PISCF must be signed by the patient or the patient’s legal guardian before his or her 
participation in the study.  A copy of the PISCF must be provided to the patient or the patient's legal 
guardian.  If required by local procedure a second original of the PISCF may be provided to the 
patient or the patient’s legal guardian.  If applicable, it will be provided in a certified translation of 
the local language. 
An original signed PISCF must remain in each patient’s study file and must be available for 
verification by study monitors at any time. 
13.3 Human Research Ethics Committee (HREC) 
This protocol, the PISCF, relevant supporting information and all types of patient recruitment or 
advertisement information must be submitted to HREC* for review and must be approved before 
the study is initiated.  Any amendments to the protocol must also be approved, where necessary, by 
the HREC prior to implementing changes in the study. 
The Investigator is responsible for keeping the HREC apprised of the progress of the study and of 
any changes made to the protocol as deemed appropriate, but in any case at least once a year.  The 
Investigator must also keep the HREC informed of any AEs, according to the HREC policy. 
* If additional countries are engaged outside of Australia, then for purposes of this protocol reference to HREC 
shall also be deemed reference to any other Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC). 
13.4 Study or Site Termination 
The End-of-Trial date is considered to be the date of Database Lock.  
If Sponsor, an Investigator, or regulatory authorities discover conditions during the study that 
indicate that the study or related activities at a particular site should be terminated, this action may 
be taken after appropriate consultation between Sponsor and the Investigator.  Conditions that may 
warrant study or site termination include but are not limited to: 
1. The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
2. Patient recruitment is unsatisfactory 


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3. Data recording is inaccurate or incomplete 
4. Investigator(s) do not adhere to the protocol or applicable regulatory guidelines in 
conducting the study 
5. GCP is not being maintained or adequately followed 
6. Administrative reasons 
7. Reasons unrelated to the study. 
Study or site termination and follow-up will be performed in compliance with the conditions set 
forth in 21 Code of Federal Regulations (CFR) Section 312 and/or other national and local 
regulations, as applicable, and in compliance with the principles set forth in International 
Conference on Harmonisation (ICH) Good Clinical Practices (GCPs), including ICH E6, and ethical 
principles established by the Declaration of Helsinki. 
13.5 Study Documentation and Record Keeping 
13.6 Study Monitoring Requirements 
Monitoring and auditing procedures developed by Imago BioSciences will be followed in order to 
comply with ICH Good Clinical Practice (GCP) guidelines.  On-site checking of the CRFs for 
completeness and clarity, cross checking with source documents, and clarification of administrative 
matters will be performed.  Monitoring visits will consist of site qualification visits, periodic visits 
during the study period, and site close-out visits.   
The Investigator will permit authorised representatives of Imago BioSciences and the respective 
national or local authorities to inspect facilities and records relevant to this study. 
Imago BioSciences or its designee will monitor the study.  Monitoring will be done by personal 
visits from representatives of Imago BioSciences (site monitors) who will review the CRFs and 
source documents.  The site monitors will ensure that the investigation is conducted according to 
protocol design and regulatory requirements by frequent communications (letter, email, telephone, 
and fax). 
All unused study materials are to be returned to Imago BioSciences or its designee after the clinical 
period of the trial has been completed, or be disposed of at the site according to institutional 
policies but not prior to the approval of the Sponsor and with appropriate documentation.   
13.7 Quality Assurance 
The study will be initiated and conducted under the sponsorship of Imago BioSciences.  IMG-7289 
and clinical supplies will be supplied by Imago BioSciences.  Representatives of Imago BioSciences 
will monitor the study to verify study data, medical records, worksheets, and CRFs are in 
accordance with current International Conference on Harmonisation (ICH) GCPs and the respective 
local and national government regulations and guidelines. 


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The Investigator will contact the Sponsor immediately if contacted by a regulatory agency about an 
inspection at his or her center. The purpose of Sponsor audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according to 
the protocol, ICH/GCP guidelines, and any applicable regulatory requirements. 
13.8 Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and disclosure to 
third parties other than those noted below is prohibited. 
The patient’s identifying information will not leave the clinical site at which they are recruited.  The 
patient will be identified on all study documentation using a code number and their initials (where 
it is lawful to collect such information). 
Information obtained during the conduct of this study will be collected, processed, and transmitted 
to or for the benefit of Imago BioSciences in accordance with the applicable regulations and 
principles of confidentiality for each participating country.  Information contained therein will be 
maintained in accordance with applicable law protecting patient privacy, including the provisions 
of 46 CFR Part 164 promulgated under the Health Insurance Portability and Accountability Act 
(HIPAA) and may be inspected by the clinical researcher, the researcher’s staff, Sponsor and its 
representatives, partners, advisors, affiliates, successors, and clinical research contractors and 
subcontractors to check, process, evaluate, and use the information collected during the study.  The 
patient PISCF (or a separate data protection consent form if required locally) will be used to obtain 
participant consent to authorise transfer and processing of data consistent with applicable law.  
Processing, evaluation, or use of the information will be performed by a health professional for 
medical purposes and/or by those operating under a duty of confidentiality that is equivalent to 
that of a health professional.  Information obtained from the study will likely be used by Imago 
BioSciences or its affiliates or successors in connection with the development of study drug, 
including possible filing of applications with governmental authorities for marketing approval, and 
for other pharmaceutical and medical research purposes.  The study Investigator is obliged to 
provide Sponsor with complete test results and all data developed in this study.  This information 
may be disclosed to other physicians who are conducting similar studies and to the applicable 
regulatory authorities as deemed necessary by Imago BioSciences.  Patient-specific information 
may be provided to other appropriate medical personnel only with the patient’s permission, as 
necessary and in accordance with other applicable privacy laws and regulations protecting patient 
health information.   
To ensure compliance with the ICH GCP guidelines, data generated by this study must be available 
for inspection upon request by representatives of the appropriate national and local authorities, 
Imago BioSciences, and the HREC for each study site. 
The raw dataset will be available to Imago BioSciences on completion of the study.  Imago 
BioSciences will actively pursue publication of the results.  The Lead/Coordinating Investigator will 
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conditions of the Clinical Trial and Confidentiality Disclosure Agreements.  The Lead/Coordinating 
Investigator, with the agreement of Imago BioSciences, will co-ordinate the principal publication of 
the data arising from the study.  Patient names and other personal data relating to an identified or 
identifiable patient (such as photographs, audio, videotapes, or other factors specific to physical, 
physiological, mental, economic, cultural, or social identity), may not be disclosed in any publication 
without prior written authorisation, in compliance with patient privacy law, from Imago 
BioSciences and the patient. 
14 INVESTIGATOR REQUIREMENTS 
14.1 Protocol Adherence 
Each Investigator must adhere to the protocol as detailed in this document and agrees that any 
changes to the protocol must be approved by Imago BioSciences’s authorised representative in 
writing prior to seeking approval, where necessary, from the HREC.  Each Investigator will be 
responsible for allowing only those patients who have met all protocol eligibility criteria to be 
enrolled.   
Modifications to the protocol should not be made without agreement of the Investigators and Imago 
BioSciences.  Changes to the protocol will require written HREC approval / favorable opinion prior 
to implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients.  The HREC may provide expedited review and approval/favorable opinion for minor 
change(s) in ongoing trials that have the approval/favorable opinion of the HREC.  The Investigator 
will submit all protocol modifications to the HREC in accordance with the governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact Sponsor, if circumstances permit, to discuss the planned 
course of action.  Any departures from the protocol must be fully documented in the CRF and 
source documentation. 
14.2 Source Documentation 
The Investigator must maintain detailed records of all study participants who are enrolled in the 
study or who undergo screening. Source documents include patient medical records and 
Investigator’s patient study files, as well as all test results.  Information required for study purposes 
and any data recorded in the eCRF must be supported by appropriate source documentation. 
14.3 Direct Access to Source Documentation 
The Investigator will ensure that the Sponsor, HREC and regulatory authorities will have direct 
access to all trial-related sites, source data/documents, and reports for the purpose of monitoring 
and auditing (ICH[E6] 5.1.2 & 6.10).  This includes electronic source data.   
14.4 Case Report Forms 
Case report forms (or an electronic data capture system) will be provided to each investigational 
site for the collection of all study data for enrolled patients, with the exception of data that may be 
captured externally to the site (i.e., central laboratory data).  Study site personnel will record the 


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data in the source documentation and enter it on the CRF within, on average, 5 business days of the 
study visit, while carefully reviewing all information recorded for accuracy and consistency.  Any 
required data printouts should be filed in the patient’s source data, i.e., ECG tracings, laboratory 
reports, etc. and signed/dated by appropriately designated investigational site personnel as a true 
copy of the original. 
A clinical study monitor will review the CRFs and compare the content to the source data. 
The CRFs for each patient must be reviewed and signed by the Investigator.  This should be done as 
soon as possible after the patient has completed the study and all data queries have been resolved.   
14.5 Study Drug Accountability 
Accountability for study drug at the trial site is the responsibility of the Investigator.  The 
Investigator will ensure that study drug is used only in accordance with this protocol.  Where 
allowed, the Investigator may choose to assign some of the drug accountability responsibilities to a 
pharmacist or other appropriate individual.  Drug accountability records indicating the drugs’ 
delivery date to the site, inventory at the site, use by each patient, and return to Imago BioSciences 
(or disposal of the drug, if approved by Imago BioSciences) will be maintained by the clinical site.  
These records will adequately document that the patients were provided the drugs and doses as 
specified in the protocol and should reconcile all study drugs received from Imago BioSciences.  
Accountability records will include dates, quantities, batch/serial numbers, expiry dates (if 
applicable), and patient numbers.  Imago BioSciences or its designee will review drug 
accountability at the site on an ongoing basis during monitoring visits. 
A Per Patient Dispensing Log must be kept current and contain the following information: 
 
The identification of the patient to whom the drug was dispensed; 
 
The date(s), lot numbers and quantity of the drug dispensed to the patient; 
 
The date(s), lot numbers and quantity of drug returned by the patient 
A “Per Lot” Inventory must be maintained, and both the Per Patient and Per Lot Logs must be 
available for inspection by the study monitor during the study.   
14.6 Disposal of Study Drug 
All unused study drug will be retained at the site until inventoried by Imago BioSciences / designee.  
All unused or expired study drug will be returned to Imago BioSciences or its designee or, if 
authorised by Imago BioSciences, will be disposed of at the study site and the disposal will be 
appropriately documented.  Records shall be maintained by the Investigator of any such alternate 
disposition of the test drug.  These records must show the identification and quantity of each unit 
disposed of, the method of destruction (taking into account the requirements of local law), and the 
person/company who disposed of the test substance.  Such records must be submitted to the 
sponsor and copies on file in the Investigator’s Site File.  All material containing study drug will be 
treated and disposed of as hazardous waste in accordance with governing regulations. 


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14.7 Training of Staff 
The PI is responsible for the conduct of the study at this study site, including delegation of specified 
study responsibilities, and training of study staff.  The PI shall ensure that the study is carried out in 
accordance with the protocol, ICH/GCP guidelines, and regulations. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and other 
staff).  He or she will ensure that appropriate training relevant to the study is given to all of these 
staff, and that any new information of relevance to the performance of this study is forwarded to 
the staff involved. 
14.8 Clinical Study Report 
The Coordinating or Lead Investigator will be designated to sign any interim clinical study 
reports and the final clinical study report at the end of this study.  The signatory Lead 
Investigator will be identified by the Sponsor in advance of study completion. 
14.9 Retention of Records 
Records and documents pertaining to the conduct of this study, including CRFs, source documents, 
consent forms, laboratory test results, and medication inventory records, must be retained by the 
Investigator in accordance with locally applicable regulatory requirements, and in any event for a 
period of at least 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the investigational 
product.  No study records shall be destroyed without notifying Sponsor and giving Sponsor the 
opportunity to take such study records or authorizing in writing the destruction of records after the 
required retention period. 
 
 


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16 APPENDICES 
16.1 Schedule of Assessments (SoA) by Cohort and Cycle 
16.1.1 Required General Visits:  All Patients, All Cohorts 
 
Visit Name
Screen
Informed Consent
X
Medical History
Xa
X
Inclusion/Exclusion
X
Complete PE (incl vital signs)
X
X
X
X
Limited PE (incl vital signs)
X
X
Height
X
12-lead ECG
Xb
Concomitant Medications
Adverse Event Collection
BM Asp and Biopsy Sample
X
c
X
ch
X
c
X
c
Phone patient - fasting reminder
X
Haematology with Diff
X
Xi
X
X
X
X
Coagulation (PT/PTT/INR)
X
Xi
X
X
X
X
Biochem.
X
Xi
X
X
X
X
Urinalysis with Microscopy
X
X
X
X
X
Urine Pregnancy Test (WOCBP)
X
X
X
X
X
PSA (males)
X
HbF
X
Immunophenotyping by FC -  PB
X
Xe
Xe
X
Immunophenotyping by FC -  BM
X
X
X
X
BM Morphology Review
X
X
X
X
Genomic Analysis 
Xd
Xf
Xf
Xg
h Unless BM sample has been obtained for study purposes in the last 10 days or is due in the next 3 days are part of the normal study cycles
i If Screening and Baseline performed on the same day, duplicate sampling is not required.  
e PB sample may be used for either immunophenotyping or genomics, if the BM sample is inadequate for analysis purposes
d Germline, BM and PB sample required, with BM and PB collected on the same day whenever possible; germline sample(s) can be obtained any 
time during the screening period including baseline and pre-dose Day 1  (Note:patients that have previously provided a saliva sample under earlier 
protocol versions will be requested to provide additional germline samples at a future visit)
b Performed only in the first 9 patients to receive IMG-7289
f Only BM sample required for genomic analysis
g BM and PB sample required for genomic analysis
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; D, day; Diff, differential; ECG, electrocardiogram; EOS, End of Study; EOT, End of 
Treatment; FC, flow cytometry; HbF, hemoglobin F; incl, including;PB, peripheral blood; PD, pharmacodynamic; PE, physical examination; PK, 
pharmacokinetic; PSA, prostate-specific antigen; PT, prothrombin time; PTT, partial thromboplastin time; WOCBP, women of child-bearing potential
c Aspirate is to be obtained from the first pull whenever possible, and no later than the third
LOCAL LAB SAMPLING:
CENTRAL LAB SAMPLING:
Suspected 
Relapse
EOS/Early 
Termination
Visit Date
Days -28 to  
-1
Days -21 to 1
EOT
Pre-EOS
Baseline
Day -1
a Medical history includes documentation of WHO diagnosis criteria, ECOG or IPSS (-R) scores, and transfusions in the previous 15 days


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16.1.2 SoA:  Cohort 1, Cycle 1 
  
Visit Name
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Medical History
X
Verify Patient Eligibility
X
Complete PE (incl vital signs)
X
X
X
Limited PE (incl vital signs)
X
X
X
X
X
12-lead ECG
X
a
X
a
Concomitant Medications
Adverse Event Collection
Phone patient-Time of dose/fasting
X
gh
Haematology with Diff
X
X
X
X
X
X
X
X
Coagulation (PT/PTT/INR)
X
X
X
Biochem
.
X
X
X
X
X
X
Urinalysis with Microscopy
X
X
X
Urine Pregnancy Test (WOCBP)
X
X
X
HbF
X
X
X
PSA (males)
X
X
Full PK Sampling 
X
b
X
b
X
c
X
dh
X
eh
X
eh
X
eh
X
eh
Immunophenotyping by FC - PB
X
Cytokine Analysis
X
X
X
Dispensing
X
Dosing
X
f
X
f
X
f
X
f
X
f
X
f
X
f
Accountability/Collect Returns
X
X
X
X
Dispensing
X
X
k
Dosing
X
i
X
i
X
i
X
i
X
i
X
i
X
i
X
ik
X
ik
X
ik
X
ik
X
ik
X
ik
X
ik
Accountability/Collect Returns
X
X
X
X
X
a  2 hours post dose (±30 min); performed only in the first 9 patients to receive IMG-7289
c  24 hours (±1 hour) post Day 1 IMG-7289 dose and pre-IMG-7289 dose Day 2 
g Exact time of dose on Day 6 (IMG-7289 and ATRA, if applicable) to be collected from patient and recorded in the source notes; patient should also be 
reminded to fast prior to Day 7 visit and that Day 7 morning dosing (IMG-7289 and ATRA, if applicable) will occur in the clinic
h Performance of Day 7 through 14 PK sampling may be deferred to Cycle 2, if needed
i Patients should take their ATRA in the morning and the evening at approximately the same time every day
k Patients receiving 21 days continuous dosing with ATRA will continue to dose during the IMG-7289 rest period
Day
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; D, day; Diff, differential; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; FC, 
flow cytometry; HbF, hemoglobin F; incl, including;PB, peripheral blood; PD, pharmacodynamic; PE, physical examination; PK, pharmacokinetic; PSA, prostate-
specific antigen; PT, prothrombin time; PTT, partial thromboplastin time; WOCBP, women of child-bearing potential
b  Samples to be collected pre-IMG-7289 dose (within 60 min prior to dosing), and 1, 2 and 3 hours post-IMG-7289 dose (±10 min)
d  Samples to be collected:  pre-IMG-7289 dose (within 60 min prior to dosing), 0.5 (±3 min), 1, 2, 3, 4 (±10 min) and 8 hours (±30 min) post IMG-7289 dose
e  24 hours (±1 hour) and approximately 48, 96 and 168 hours post Day 7 IMG-7289 dose
f  Patients should take their IMG-7289 in the morning at approximately the same time every day
ATRA (if applicable):
Treatment Period (D = Day)
Rest Period
Pre- Dose D1
Day
IMG-7289:
LOCAL LAB SAMPLING:
CENTRAL LAB SAMPLING: 
Visit Date


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16.1.3 SoA:  Cohort 1, Cycles 2-4  
 
Visit Name
1
2
3
4
5
6
7
8
9
10
11
12
13
14h
Complete PE (incl vital signs)
Xb
X
X
Limited PE (incl vital signs)
X
X
X
Concomitant Medications
Adverse Event Collection
BM Asp and Biopsy Sample
Xac
Phone patient-Time of dose/fasting
Xi
Haematology with Diff
X
X
X
X
X
X
Coagulation (PT/PTT/INR)
Xb
X
X
Biochem – CS trends noted
X
X
X
Biochem – standard
Xb
X
X
Urinalysis with Microscopy
Xb
X
X
Urine Pregnancy Test (WOCBP)
Xb
X
X
HbF
Xm
PSA (males)
Xm
Drug Concentration Sample
Xd
Xe
Full PK Sampling k
Xek
Xk
Xk
Xk
Xk
Immunophenotyping by FC - PB
X
Xcf
Immunophenotyping by FC - BM
Xc
BM Morphology Review
Xc
Genomic Analysis - BM
Xc
Dispensing
X
Dosing
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Accountability/Returns
X
X
Dispensing
X
Xo
 
Dosing
Xn
Xn
Xn
Xn
Xn
Xn
Xn
Xno
Xno
Xno
Xno
Xno
Xno
Xno
Accountability/Collect Returns
Xp
X
X
Xo
c  In Cycles 2 and 4 ONLY, BM and associated analyses will be performed
e  24 hours post Day 6 IMG-7289 dose and prior to next IMG-7289 dose (±1 hour)
Visit Date
LOCAL LAB SAMPLING:
CENTRAL LAB SAMPLING:
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; CS, Clinically Significant; D, day; Diff, differential; ECG, electrocardiogram; EOS, End of Study; EOT, 
End of Treatment; FC, flow cytometry; HbF, hemoglobin F; incl, including; NCS, Not Clinically Significant; PB, Peripheral Blood; PD, pharmacodynamic; PE, 
physical examination; PK, pharmacokinetic; PSA, Prostate Specific Antigen; PT, prothrombin time; PTT, partial thromboplastin time; WOCBP, women of child-
bearing potential
b  If test was performed the calendar day prior to Day 1, as part of a previous Cycle, it does not need to be repeated; for physical examination - limited 
physical examination should be performed instead
IMG-7289:
a  Samples to be drawn within ± 2 days of the end of rest period but prior to dosing in next cycle.  Aspirate is to be obtained from the first pull whenever 
possible, and no later than the third.
ATRA (if applicable):
Treatment Period (D = Day)
Rest Period
Pre- Dose D1
Day
Day
g Patients should take their IMG-7289 in the morning at approximately the same time every day
d In Cycle 2 for all patients; also to be collected in Cycle 3 IF Day 7 through 14 PK was deferred to Cycle 2
f  PB sample may be used for either immunophenotyping or genomics, if the BM sample is inadequate for analysis purposes
h If the patient is completing the study, this visit will be replaced by the EOT visit
i Exact time of dose on Day 6 (IMG-7289 and ATRA, if applicable) to be collected from patient and recorded in the source notes; patient should also be 
reminded to fast prior to Day 7 visit and that Day 7 morning dosing (IMG-7289 and ATRA, if applicable) will occur in the clinic
k If Cycle 1 Day 7 through14 PK was deferred to Cycle 2
m In Cycle 4 ONLY
n If applicable patients should take their ATRA in the morning and the evening at approximately the same time every day
o In Cycle 3 ONLY, patients receiving 21 days continuous dosing with ATRA will continue to dose and return ATRA during the IMG-7289 rest period 
p In Cycles 2 and 4 ONLY, patients receiving 21 days continous dosing with ATRA will return medication from the previous cycle.  


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16.1.4 SoA:  Cohorts 3 and 3χ, Cycle 1 
 
Visit Name
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Medical History
X
Verify Patient Eligibility
X
Complete PE (incl vital signs)
X
X
X
X
Limited PE (incl vital signs)
X
X
X
X
X
X
Concomitant Medications
Adverse Event Collection
Phone patient-Time of dose/fasting
Xc
Haematology with Diff
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/PTT/INR)
X
X
X
X
Biochem – CS trends noted
X
X
X
Biochem – standard
X
X
X
X
Urinalysis with Microscopy
X
X
X
X
Urine Pregnancy Test (WOCBP)
X
X
X
X
HbF
X
X
X
PSA (males)
X
X
Drug Concentration Sample
Xa
Immunophenotyping by FC - PB
X
Cytokine Analysis
X
X
X
Dispensing
X
X
Dosing
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Accountability/Returns
X
X
X
X
X
X
Dispensing
X
X
Dosing
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Accountability/Returns
X
X
X
X
X
X
Treatment Period (D = Day)
Rest Period
Pre- Dose D1
a  24 hours post Day 13 IMG-7289 dose (±1 hour), pre-IMG-7289 dose Day 14
c  Exact time of dose on Day 13 (IMG-7289 and ATRA, if applicable) to be collected from patient and recorded in the source notes; patient should also be reminded to fast prior to Day 14 visit and that Day 14 
morning dosing (IMG-7289 and ATRA, if applicable) will occur in the clinic
d  Patients should take their ATRA in the morning and the evening at approximately the same time every day
Day
Day
LOCAL LAB SAMPLING:
CENTRAL LAB SAMPLING: 
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; CS, Clinically Significant; D, day; Diff, differential; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; FC, flow cytometry; HbF, 
hemoglobin F; incl, including; NCS, Not Clinically Significant; PB, Peripheral Blood; PD, pharmacodynamic; PE, physical examination; PK, pharmacokinetic; PSA, prostate-specific antigen; PT, prothrombin time; 
PTT, partial thromboplastin time; WOCBP, women of child-bearing potential
Visit Date
IMG-7289:
b  Patients should take their IMG-7289 in the morning, at approximately the same time every day
ATRA (If applicable):


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 115 of 127 
16.1.5 SoA:  Cohorts 3 and 3χ, Cycle 2  
 
Visit Name
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21e
Complete PE (incl vital signs)
Xb
X
X
X
Limited PE (incl vital signs)
X
X
X
X
X
Concomitant Medications
Adverse Event Collection
BM Asp and Biopsy Sample
Xa
Haematology with Diff
X
X
X
X
X
X
X
X
X
Coagulation (PT/PTT/INR)
Xb
X
X
X
Biochem – CS trends noted
X
X
X
X
Biochem – standard
Xb
X
X
X
Urinalysis with Microscopy
Xb
X
X
X
Urine Pregnancy Test (WOCBP)
Xb
X
X
X
HbF
X
PSA (males)
X
Drug Concentration Sample
X
Immunophenotyping by FC - PB
X
Xc
Immunophenotyping by FC - BM
X
BM Morphology Review
X
Genomic Analysis - BM
X
Dispensing
X
X
Dosing
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Accountability/Returns
X
X
X
X
X
Dispensing
X
X
Dosing
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Accountability/Returns
X
X
X
X
X
Treatment Period (D = Day)
Rest Period
Pre- Dose D1
Day
a  Samples to be drawn within ± 2 days of the end of rest period but prior to dosing in next cycle; Aspirate is to be obtained from the first pull whenever possible, and no later than the third
Day
LOCAL LAB SAMPLING:
CENTRAL LAB SAMPLING: 
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; CS, Clinically Significant; D, day; Diff, differential; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; FC, flow cytometery; HbF, 
hemoglobin F; incl, including; NCS, Not Clinically Significant; PB, Peripheral Blood; PD, pharmacodynamic; PE, physical examination; PK, pharmacokinetic; PSA, prostate-specific antigen; PT, prothrombin 
time; PTT, partial thromboplastin time; WOCBP, women of child-bearing potential
e If the patient is completing the study, this visit will be replaced by the EOT visit
f  Patients should take their ATRA in the morning and the evening at approximately the same time every day
d Patients should take their IMG-7289 in the morning, at approximately the same time every day
b  If test was performed the calendar day prior to Day 1, as part of a previous Cycle, it does not need to be repeated; for physical examination, limited physical examination should be performed instead
Visit Date
IMG-7289:
c  PB sample may be used for either immunophenotyping or genomics, if the BM sample is inadequate for analysis purposes
ATRA (If applicable):


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 116 of 127 
16.1.6 SoA:  Cohorts 4 and 4χ, Cycle 1 
 
Visit Name
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28e
Medical History
X
Verify Patient Eligibility
X
Complete PE (incl vital signs)
X
X
X
X
X
Limited PE (incl vital signs)
X
X
X
X
X
X
X
X
Concomitant Medications
Adverse Event Collection
BM Asp and Biopsy Sample
Xa
Phone patient-Time of 
dose/fasting
Xf  
Haematology with Diff
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/PTT/INR)
X
X
X
X
X
Biochem – CS trends noted
X
X
X
X
Biochem – standard
X
X
X
X
X
Urinalysis with Microscopy
X
X
X
X
X
Urine Pregnancy Test (WOCBP)
X
X
X
X
X
HbF
X
X
X
PSA (males)
X
X
Drug Concentration Sample
Xb
X
Immunophenotyping by FC - PB
X
Xc
Immunophenotyping by FC - BM
X
Cytokine Analysis
X
X
X
BM Morphology Review
X
Genomic Analysis - BM
X
Dispensing
X
X
X
Dosing
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Accountability/Returns
X
X
X
X
X
X
X
X
X
Dispensing
X
X
X
Dosing
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Accountability/Returns
X
X
X
X
X
X
X
X
X
d Patients should take their IMG-7289 in the morning, at approximately the same time every day
f  Exact time of dose on Day 20 (IMG-7289 and ATRA, if applicable) to be collected from patient and recorded in the source notes; patient should also be reminded to fast prior to Day 21 visit and that Day 21 morning dosing (IMG-7289 and ATRA, if 
applicable) will occur in the clinic
g Patients should take their ATRA in the morning and the evening at approximately the same time every day
b  24 hours post Day 20 IMG-7289 dose (±1 hour), pre-IMG-7289 dose Day 21
a  Samples to be drawn within ± 2 days of the end of rest period but prior to dosing in next cycle; Aspirate is to be obtained from the first pull whenever possible, and no later than the third
c  PB sample may be used for either immunophenotyping or genomics, if the BM sample is inadequate for analysis purposes
e If the patient is completing the study, this visit will be replaced by the EOT visit
Pre- Dose 
D1
Day
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; CS, Clinically Significant; D, day; Diff, differential; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; FC, flow cytometry; HbF, hemoglobin F; incl, including; NCS, Not Clinically 
Significant; PB, Peripheral Blood; PD, pharmacodynamic; PE, physical examination; PK, pharmacokinetic; PSA, prostate-specific antigen; PT, prothrombin time; PTT, partial thromboplastin time; WOCBP, women of child-bearing potential
Treatment Period (D = Day)
Rest Period
Day
LOCAL LAB SAMPLING:
Visit Date
IMG-7289:
CENTRAL LAB SAMPLING: 
ATRA (If applicable):


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 117 of 127 
16.1.7 SoA:  Cohorts 4 and 4χ, First Additional Cycle 
 
Visit Name
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
e
Verify Continued Patient Eligibility
X
f
Complete PE (incl vital signs)
X
b
X
X
X
X
Limited PE (incl vital signs)
X
X
X
X
X
X
Concomitant Medications
Adverse Event Collection
BM Asp and Biopsy Sample
X
a
Haematology with Diff
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/PTT/INR)
X
b
X
X
X
X
Biochem – CS trends noted
X
X
X
X
X
Biochem – standard
X
b
X
X
X
X
Urinalysis with Microscopy
X
b
X
X
X
X
Urine Pregnancy Test (WOCBP)
X
b
X
X
X
X
Immunophenotyping by FC - PB
X
X
c
Immunophenotyping by FC - BM
X
BM Morphology Review
X
Genomic Analysis - BM 
X
Dispensing
X
X
X
Dosing
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
X
d
Accountability/Returns
X
X
X
X
X
X
X
Dispensing
X
X
X
Dosing
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
X
g
Accountability/Returns
X
X
X
X
X
X
X
Treatment Period (D = Day)
Rest Period
LOCAL LAB SAMPLING:
CENTRAL LAB SAMPLING: 
Visit Date
Pre- Dose 
D1
Day
Day
f  Post completion of Cycle 1, verification of continued patient eligibility includes confirming the patient qualifies for additional cycles (based on PI assessment of safety and clinical benefit)
g Patients should take their ATRA in the morning and the evening at approximately the same time every day
a  Samples to be drawn within ± 2 days of the end of rest period but prior to dosing in next cycle; Aspirate is to be obtained from the first pull whenever possible, and no later than the third
IMG-7289:
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; CS, Clinically Significant; D, day; Diff, differential; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; FC, flow cytometry; HbF, hemoglobin F; incl, including; NCS, Not Clinically 
Significant; PB, Peripheral Blood; PD, pharmacodynamic; PE, physical examination; PK, pharmacokinetic; PSA, prostate-specific antigen; PT, prothrombin time; PTT, partial thromboplastin time; WOCBP, women of child-bearing potential
d Patients should take their IMG-7289 in the morning, at approximately the same time every day
b  If test was performed the calendar day prior to Day 1, as part of a previous Cycle, it does not need to be repeated; for physical examination, limited physical examination should be performed instead
c  PB sample may be used for either immunophenotyping or genomics, if the BM sample is inadequate for analysis purposes
e If the patient is completing the study, this visit will be replaced by the EOT visit
ATRA (If applicable):


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 118 of 127 
16.1.8 SoA:  All Cohorts, All Additional Cycles 
Visit Name
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
R1
R2
R3
R4
R5
R6
R7
f
Verify Continued Patient Eligibility
X
g
Complete PE (incl vital signs)
X
b
X
X
X
X
Concomitant Medications
Adverse Event Collection
BM Asp and Biopsy Sample
X
ad
Haematology with Diff
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/PTT/INR)
X
b
X
X
X
X
Biochem – CS trends noted
X
X
X
X
X
Biochem – standard
X
b
X
X
X
X
Urinalysis with Microscopy
X
b
X
X
X
X
Urine Pregnancy Test (WOCBP)
X
b
X
X
X
X
HbF
X
d
PSA (males)
X
d
Immunophenotyping by FC - PB
X
de
Immunophenotyping by FC - BM
X
d
BM Morphology Review
X
d
Genomic Analysis - BM 
X
d
Dispensing
X
X
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Accountability/Returns
X
X
X
X
X
Dispensing
X
X
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
h
X
h
X
h
X
h
X
h
X
h
X
h
Accountability/Returns
X
h
X
X
X
X
X
d Only to be performed EVERY OTHER Cycle
e PB sample may be used for either immunophenotyping or genomics, if the BM sample is inadequate for analysis purposes
Rest Period
g Verification of continued patient eligibility includes confirming the patient qualifies for each additional cycle (based on PI assessment of safety and clinical benefit)
h Patients receiving 21 days continuous dosing with ATRA, with IMG-7289 in 7 on/7 off cycles will continue to dose during the IMG-7289 rest period in every other cycle. ATRA will be returned on Day 1 of the alternate cycle. 
f  If the patient is completing the study, this visit will be replaced by the EOT visit
c Only to be performed in the FIRST additional Cycle
LOCAL LAB SAMPLING:
CENTRAL LAB SAMPLING: 
IMG-7289:
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; CS, Clinically Significant; D, day; Diff, differential; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; FC, flow cytometry; HbF, hemoglobin F; incl, including; NCS, Not Clinically 
Significant; PB, Peripheral Blood; PD, pharmacodynamic; PE, physical examination; PK, pharmacokinetic; PSA, prostate-specific antigen; PT, prothrombin time; PTT, partial thromboplastin time; WOCBP, women of child-bearing potential
a  Samples to be drawn within ± 2 days of the end of rest period but prior to dosing in next cycle; Aspirate is to be obtained from the first pull whenever possible, and no later than the third
b  If test was performed the calendar day prior to Day 1, as part of a previous Cycle, it does not need to be repeated; for physical examination, limited physical examination should be performed instead
Visit Date
Pre- Dose 
D1
Day
Day
Treatment Period (D = Day)
ATRA (If applicable):


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 119 of 127 
16.1.9 Extended Rest Period 
 
 
 
Visit Name
Concomitant Medications
Adverse Event Collection
Complete Physical Examination
X
X
BM Asp and Biopsy Sample
X
b
Haematology with Diff
X
X
X
Coagulation (PT/PTT/INR)
X
X
Biochem
.
X
X
Urinalysis with Microscopy
X
X
Urine Pregnancy Test (WOCBP)
X
X
Immunophenotyping by FC -  PB
X
c
Immunophenotyping by FC -  BM
X
b
BM Morphology Review
X
d
Genomic Analysis 
X
bcd
b Aspirate is to be obtained from the first pull whenever possible, and no later than the third
c PB sample may be used for either immunophenotyping or genomics, if the BM sample is inadequate for 
analysis purposes
d BM and PB sample required for genomic analysis
Abbreviated Visita
RD 9, 11, 16, 18, 23, 25, 
31, 38, 45, 52
Visit Date
LOCAL LAB SAMPLING:
CENTRAL LAB SAMPLING:
Standard Visits
RD 14, 21, 35, 42, 49
RD 28, 56
Asp, aspirate; Biochem, biochemistry; BM, bone marrow; Diff, differential; FC, flow cytometry; PB, peripheral 
blood; PT, prothrombin time; PTT, partial thromboplastin time; RD, rest day; WOCBP, women of child-
bearing potential
a Conducted as appropriate based on the duration of the extended rest period  


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
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Amendment 3, 29Aug2017 
Page 120 of 127 
16.2 Diagnostic Classifications, Prognostic Scores, and Response Criteria 
Table 9:  2016 WHO Classification System for AML and Related Precursor Neoplasms, and Acute Leukaemias of Ambiguous 
Lineage (Arber et al., 2016) 
Acute myeloid leukaemia with recurrent genetic 
abnormalities 
-AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
-AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
-APL with PML-RARA* 
-AML with t(9;11)(p21.3;q23.3); MLLT3-KM2A† 
-AML with t(6;9)(p23;q34.1); DEK-NUP214 
-AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM 
-AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1 
-Provisional entity: AML with BCR-ABL1 
-AML with mutated NPM1 
-AML with biallelic mutations CEBPA 
-Provisional entity: AML with mutated RUNX1 
Acute myeloid leukaemia with myelodysplasia-related changes‡ 
Therapy-related myeloid neoplasms§ 
Acute myeloid leukaemia, not otherwise specified 
(NOS) 
-Acute myeloid leukaemia with minimal differentiation 
-Acute myeloid leukaemia without maturation 
-Acute myeloid leukaemia with maturation 
-Acute myelomonocytic leukaemia 
-Acute monoblastic/monocytic leukaemia 
-Pure erythroid leukaemia 
-Acute megakaryoblastic leukaemia 
-Acute basophilic leukaemia 
-Acute panmyelosis with myelofibrosis 
Myeloid sarcoma 
Myeloid proliferations related to Down syndrome 
-Transient abnormal myelopoiesis (TAM) 
-Myeloid leukaemia associated with Down syndrome 


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Amendment 3, 29Aug2017 
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Acute leukaemias of ambiguous lineage 
-Acute undifferentiated leukaemia 
-Mixed phenotype acute leukaemia with t(9;22)(q34.1;q11.2); BCR-ABL1ǁ 
-Mixed phenotype acute leukaemia with t(v;11q23); KMT2A rearranged 
-Mixed phenotype acute leukaemia, B/myeloid, NOS 
-Mixed phenotype acute leukaemia, T/myeloid, NOS 
For a diagnosis of AML, a marrow blast count of ≥ 20% is required, except for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv(16) or t(16;16) 
and some cases of erythroleukaemia. 
*Other recurring translocations involving RARA should be reported accordingly: for example, AML with t(11;17)(q23;q12); ZBTB16-RARA; AML with 
t(11;17)(q13;q12); NUMA1-RARA; AML with t(5;17)(q35;q12); NPM1-RARA; or AML with STAT5BRARA (the latter having a normal chromosome 17 on conventional 
cytogenetic analysis). 
†Other translocations involving MLL should be reported accordingly: for example, AML with t(6;11)(q27;q23); MLLT4-MLL; AML with t(11;19)(q23;p13.3); MLL-
MLLT1; AML with t(11;19)(q23;p13.1); MLL-ELL; AML with t(10;11)(p12;q23); MLLT10-MLL. 
‡More than 20% blood or marrow blasts AND any of the following: previous history of myelodysplastic syndrome (MDS), or myelodysplastic/ myeloproliferative 
neoplasm (MDS/MPN); myelodysplasia-related cytogenetic abnormality (see below); multilineage dysplasia; AND absence of both prior cytotoxic therapy for 
unrelated disease and aforementioned recurring genetic abnormalities; cytogenetic abnormalities sufficient to diagnose AML with myelodysplasia-related changes 
are: 
- Complex karyotype (defined as 3 or more chromosomal abnormalities). 
- Unbalanced changes: -7 or del(7q); -5 or del(5q); i(17q) or t(17p); -13 or del(13q); del(11q); del(12p) or t(12p); del(9q); idic(X)(q13). 
- Balanced changes: t(11;16)(q23;p13.3); t(3;21)(q26.2;q22.1); t(1;3)(p36.3; q21.1); t(2;11)(p21;q23); t(5;12)(q33;p12); t(5;7)(q33;q11.2); 
t(5;17)(q33;p13); t(5;10)(q33;q21); t(3;5)(q25;q34). 
§Cytotoxic agents implicated in therapy-related haematologic neoplasms: alkylating agents; ionizing radiation therapy; topoisomerase II inhibitors; others. 
ǁBCR-ABL1–positive leukaemia may present as mixed phenotype acute leukaemia, but should be treated as BCR-ABL1–positive acute lymphoblastic leukaemia. 
Table 10:  Eastern Cooperative Group Performance Status for AML Patients 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house 
work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 


Imago BioSciences, Inc. 
 
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Amendment 3, 29Aug2017 
Page 122 of 127 
Table 11:  2016 WHO Classification System for Myelodysplastic Syndromes (Arber et al., 2016) 
Disease 
Dysplastic 
lineages 
Cytopenias* 
Ring sideroblasts  
as % of marrow 
erythroid elements 
Blood Findings 
Bone Marrow 
Findings 
Cytogenetics by conventional 
karyotype analysis 
MDS with single lineage 
dysplasia (MDS-SLD) 
1 
1 or 2 
<15%/<5% ϯ 
<1% blasts no 
Auer rods 
<5% blasts 
no Auer rods 
Any, unless fulfills all criteria for 
MDS with isolated del(5q) 
MDS with multilineage 
dysplasia (MDS-MLD) 
2 or 3 
1-3 
<15%/<5%ϯ 
<1% blasts no 
Auer rods 
<5% blasts  
no Auer rods 
Any, unless fulfills all criteria for 
MDS with isolated del(5q) 
MDS with ring sideroblasts 
(MDS-RS) 
 
 
 
 
 
 
MDS-RS and single lineage 
dysplasia (MDS-RS-SLD) 
1 
1 or 2 
≥15%/≥5%ϯ 
<1% blasts no 
Auer rods 
<5% blasts  
no Auer rods 
Any, unless fulfills all criteria for 
MDS with isolated del(5q) 
MDS-RS and multilineage 
dysplasia (MDS-RS-MLD) 
2 or 3 
1-3 
≥15%/≥5%ϯ 
<1% blasts no 
Auer rods 
<5% blasts  
no Auer rods 
Any, unless fulfills all criteria for 
MDS with isolated del(5q) 
MDS with isolated del(5q) 
1-3 
1-2 
None or any 
<1% blasts no 
Auer rods 
<5% blasts  
no Auer rods 
del(5q) alone or with 1 additional 
abnormality except -7 or del(7q) 
MDS with excess blasts  
(MDS-EB) 
 
 
 
 
 
 
MDS with excess blasts-1 
(MDS-EB-1) 
0-3 
1-3 
None or any 
2-4% blasts no 
Auer rods 
5-9% blasts  
no Auer rods 
Any 
MDS with excess blasts-2 
(MDS-EB-2) 
0-3 
1-3 
None or any 
5-19% blasts or 
Auer rods 
10-19% blasts 
or Auer rods 
Any 
MDS, unclassified (MDS-U) 
 
 
 
 
 
 
With 1% blasts 
1-3 
1-3 
None or any 
=1% blasts‡  
no Auer rods 
<5% blasts  
no Auer rods 
Any 
With single lineage dysplasia 
and pancytopenia 
1 
3 
None or any 
<1% blasts no 
Auer rods 
<5% blasts  
no Auer rods 
Any 
Based on defining cytogenetic 
abnormality 
0 
1-3 
<15%§ 
<1% blasts no 
Auer rods 
<5% blasts  
no Auer rods 
MDS-defining abnormality 
Provisional entity: Refractory 
cytopenia of childhood 
1-3 
1-3 
None 
<2% blasts 
<5% blasts 
Any 
*Cytopenias defined as: haemoglobin, <10 g/dL; platelet count, <100 x 109/L; and absolute neutrophil count, <1.8 x 109/L. Rarely, MDS may present 
with mild anemia or thrombocytopenia above these levels. PB monocytes must be <1 x 109/L  
ϯ If SF3B1 mutation is present.  
‡One percent PB blasts must be recorded on at least 2 separate occasions.  
§Cases with $15% ring sideroblasts by definition have significant erythroid dysplasia, and are classified as MDS-RS-SLD. 


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 123 of 127 
Table 12:  International Prognostic Scoring System (IPSS) and Risk Categories for Myelodysplastic Syndrome 
PROGNOSTIC CHARACTERISTICS 
POINTS 
0 
0.5 
1 
1.5 
2 
Cytogenetic risk categorya 
Good 
Intermediate 
Poor 
 
 
Blasts in bone marrow 
<5% 
5-10% 
 
11-20% 
21–30% 
Cytopeniasb 
0 or 1 
2 or 3 
 
 
 
aGood: normal, –Y, del(5q), or del(20q) as single abnormalities; Intermediate: abnormalities other than good or poor; Poor: complex, 3 or more abnormalities, abnormal 
chromosome 7. 
bEach of the following cytopenia counts as a value of 1:  haemoglobin < 10 g/dl; absolute neutrophil count (ANC) < 1,500×109/L; platelet count less than 100,000×109/L 
IPSS Risk Category 
Score 
Low 
0 
Intermediate-1 
0.5-1.0 
Intermediate-2
1.5-2.0
High 
> 2.0 
Table 13:  Revised International Prognostic Scoring System (IPSS-R) and Risk Categories for Myelodysplastic Syndromes 
PROGNOSTIC CHARACTERISTICS 
POINTS 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetic risk categorya 
Very good 
 
Good 
 
Intermediate 
Poor 
Very poor 
Blasts in bone marrow, % 
≤2 
 
>2%–5% 
 
5%–10% 
>10% 
 
Haemoglobin, g/dl 
≥10 
 
8–<10 
<8 
 
 
 
Platelet count, ×109/l 
≥100 
50–<100 
<50 
 
 
 
 
Absolute neutrophil count, ×109/l 
≥0.8 
<0.8 
 
 
 
 
 
aVery good: –Y and del(11q) as single abnormalities; good: normal, del(5q), del(12p) and del(20q) as single abnormalities, double abnormalities including del(5q); 
intermediate: del(7q), +8, +19, i(17q) and any other single abnormalities, any other double abnormalities; poor: −7 and inv(3)/t(3q)/del(3q) as single abnormalities, 
double abnormalities including −7/del(7q), complex (3 abnormalities); very poor; >3 abnormalities. 
IPSS-R Risk Category
Score
Very low 
≤1.5 
Low 
>1.5–3 
Intermediate 
>3–4.5 
High
>4.5–6
Very high 
> 6 


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 124 of 127 
Table 14  Response criteria in AML 
Category 
Definition 
Complete remission (CR)* 
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil 
count > 1.0 x 109/L (1000/µL); platelet count > 100 x 109/L (100 000/µL); independence of red cell transfusions 
CR with incomplete recovery 
(CRi) 
All CR criteria except for residual neutropenia (< 1.0 x 109/L [1000/µL]) or thrombocytopenia (< 100 x 109/L [100 
000/µL]) 
Morphologic leukaemia-free 
state (MLFS) 
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; no haematologic 
recovery required 
Partial remission (PR) 
Relevant in the setting of phase 1 and 2 clinical trials only; all haematologic criteria of CR; decrease of bone marrow 
blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50% 
Cytogenetic CR (CRc) 
Reversion to a normal karyotype at the time of morphologic CR (or CRi) in cases with an abnormal karyotype at the 
time of diagnosis; based on the evaluation of 20 metaphase cells from bone marrow 
Molecular CR (CRm) 
 A reduction in the frequency to below 0.01% in one or more alleles of AML-associated genes known to be 
somatically mutated in the patient 
Stable Disease (SD) 
Failure to achieve a response (CR, CRi, MLFS, PR, CRc or CRm) but not meeting Progressive Disease criteria for a 
period of more than 8 weeks. 
Progressive Disease (PD) 
Patient previously had partial remission or stable disease. For those with 5% to 66% bone marrow blasts at nadir, a 
>50% increase in bone marrow blast count percentage from the nadir and percentage is ≥20%; and for those with 
≥67% bone marrow blasts at nadir, a doubling of the nadir absolute peripheral blood blast count with a final 
absolute peripheral blood blast count >10 x 109/L. 
Treatment failure 
 
   Resistant disease (RD) 
Failure to achieve CR or CRi (general practice; phase 2/3 trials), or failure to achieve CR, CRi, or PR (phase 1 trials); 
only includes patients surviving ≥ 7 days following completion of initial treatment, with evidence of persistent 
leukaemia by blood and/or bone marrow examination 
   Death in aplasia 
Deaths occurring ≥ 7 days following completion of initial treatment while cytopenic; with an aplastic or hypoplastic 
bone marrow obtained within 7 days of death, without evidence of persistent leukaemia 
   Death from   
indeterminate cause 
Deaths occurring before completion of therapy, or < 7 days following its completion; or deaths occurring ≥ 7 days 
following completion of initial therapy with no blasts in the blood, but no bone marrow examination available 
Relapse¶ 
Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or development of extramedullary disease 
Definitions of response criteria are based primarily on those given by Cheson et al. 2003.  Stable and Progressive Disease included for analysis purposes.  


Imago BioSciences, Inc. 
 
Protocol IMG-7289-CTP-101 
IMG-7289 
 
Amendment 3, 29Aug2017 
Page 125 of 127 
*All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an aspirate with spicules; if ambiguous, 
consider repeat exam after 5 to 7 days; flow cytometric evaluation may help to distinguish between persistent leukaemia and regenerating normal 
marrow; a marrow biopsy should be performed in cases of dry tap, or if no spicules are obtained; no minimum duration of response required. 
¶In cases with low blast percentages (5-10%), a repeat marrow should be performed to confirm relapse. Appearance of new dysplastic changes should 
be closely monitored for emerging relapse. In a patient who has been recently treated, dysplasia or a transient increase in blasts may reflect a 
chemotherapy effect and recovery of haematopoiesis. Cytogenetics should be tested to distinguish true relapse from therapy-related MDS/AML. 
 


Imago BioSciences, Inc. 
 
 
Protocol IMG-7289-CTP-101  
IMG-7289 
 
 
Amendment 3, 29Aug2017 
Page 126 of 127 
Table 15:  Response Criteria for MDS 
Category 
Response Criteria (responses must last at least 4 weeks) 
Complete remission 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines* 
Persistent dysplasia will be noted*† 
Peripheral blood‡ 
Hgb ≥ 11 g/dL 
Platelets ≥ 100 x 109/L 
Neutrophils ≥ 1.0 x 109/L† 
Blasts 0% 
Partial remission 
All CR criteria if abnormal before treatment except: 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CR† 
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment† 
Peripheral blood: if HI responses, they will be noted in addition to marrow CR† 
Stable disease 
Failure to achieve at least PR, but no evidence of progression for > 8 wks 
Failure 
Death during treatment or disease progression characterized by worsening of cytopenias, increase in percentage of 
bone marrow blasts, or progression to a more advanced MDS FAB subtype than pretreatment 
Relapse after CR or PR 
At least 1 of the following: 
Return to pretreatment bone marrow blast percentage 
Decrement of ≥ 50% from maximum remission/response levels in granulocytes or platelets 
Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
Cytogenetic response 
Complete:  Disappearance of the chromosomal abnormality without appearance of new ones 
Partial:  At least 50% reduction of the chromosomal abnormality 
Disease progression 
For patients with: 
Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts 
5%-10% blasts: ≥ 50% increase to > 10% blasts 
10%-20% blasts: ≥ 50% increase to > 20% blasts 
20%-30% blasts: ≥ 50% increase to > 30% blasts 
Any of the following: 
At least 50% decrement from maximum remission/response in granulocytes or platelets 
Reduction in Hgb by ≥ 2 g/dL 
Transfusion dependence 


Imago BioSciences, Inc. 
 
 
Protocol IMG-7289-CTP-101  
IMG-7289 
 
 
Amendment 3, 29Aug2017 
Page 127 of 127 
Category 
Response Criteria (responses must last at least 4 weeks) 
Survival 
Endpoints: 
Overall: death from any cause 
Event free: failure or death from any cause 
PFS: disease progression or death from MDS 
DFS: time to relapse 
Cause-specific death: death related to MDS 
To convert haemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10. 
MDS indicates myelodysplastic syndromes; Hgb, haemoglobin; CR, complete remission; HI, haematologic improvement; PR, partial remission; FAB, French-
American-British; AML, acute myeloid leukaemia; PFS, progression-free survival; DFS, disease-free survival. 
*Dysplastic changes should consider the normal range of dysplastic changes (modification). 
†Modification to IWG response criteria. 
‡Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of response, as long as they recover to the 
improved counts of the previous course. 
  

SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Multi-Center, Open Label Study to Assess 
the Safety,Steady-State Pharmacokinetics 
and Pharmacodynamics of IMG-7289 with 
and without ATRA (Tretinoin) in Patients
with Advanced Myeloid Malignancies
NCT02842827
09-November-2017


Source Document Number: FORM 694.01 
 
Effective Date:  13-Apr-2015 
DCN # 1372 
 
 
Document Title: Statistical Analysis Plan Template  
 
Page 1 of 26 
 
Imago BioSciences 
Protocol #: IMG-7289-CTP-101 
 
A Multi-Center Open Label Study to Assess the Safety, Steady-State Pharmacokinetics 
and Pharmacodynamics of IMG-7289 with and without ATRA (Tretinoin) in Patients 
with Advanced Myeloid Malignancies 
 
Statistical Analysis Plan 
 
Version 2.0 
Document last saved: 9-Nov-2017 9:29 AM 
 
Prepared for: 
 Imago BioSciences, Inc. 
 2729 Debbie Court 
 San Carlos, CA 94070 
 
Prepared by: 
 
           
            Novella Clinical 
 
1700 Perimeter Park Dr. 
 
Morrisville, NC  27560 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


Imago Biosciences / Protocol: IMG-7289-CTP-101 
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Statistical Analysis Plan v2.0 
 
 
 
 
 
 
 
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This plan conforms to all International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH)  
guidelines, including E3 (Structure and Content of Clinical Study Reports) and  
E9 (Statistical Principles for Clinical Trials). 


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CONTENTS 
I.Introduction ............................................................................................................................ 5 
A. Background ............................................................................................................. 5 
B. Protocol and Amendment History .......................................................................... 6 
II.Protocol Hypothesis and Objectives ..................................................................................... 7 
A. Hypothesis............................................................................................................... 7 
B. Primary .................................................................................................................... 7 
C. Secondary ................................................................................................................ 7 
D. Exploratory ............................................................................................................. 8 
III.Study Endpoints ................................................................................................................... 8 
A. Primary .................................................................................................................... 8 
B. Exploratory ............................................................................................................. 9 
IV.Study Design ...................................................................................................................... 10 
A. Design Overview .................................................................................................. 10 
B. Study Population ................................................................................................... 13 
C. Sample Size Predictions ........................................................................................ 14 
D. Treatment Randomization ..................................................................................... 14 
E. Assessment Schedule ............................................................................................ 14 
V.Interventions........................................................................................................................ 14 
A. Clinical Trial Material........................................................................................... 14 
B. Study Procedures .................................................................................................. 14 
VI.General Analytical Considerations .................................................................................... 15 
A. Data Sources ......................................................................................................... 15 
B. Definition of Baseline ........................................................................................... 15 
C. Missing Data ......................................................................................................... 15 
D. Display and Imputation Methods for Missing Dates ............................................ 16 
E. Multiple Study Centers ......................................................................................... 17 
F. Covariate Adjustment in Primary Analysis .......................................................... 17 
G. Sample Size Reassessment ................................................................................... 17 
H. Interim Analyses or Timing of Analyses .............................................................. 17 
I. Multiple Comparisons ........................................................................................... 17 
J. Analysis Populations ............................................................................................. 17 
K. Data Display Characteristics ................................................................................. 18 
VII.Patient Accountability ...................................................................................................... 18 
A. Patient Characteristics ........................................................................................... 19 
B. Disposition ............................................................................................................ 19 
C. Protocol Deviations ............................................................................................... 20 
VIII.Efficacy Analysis ............................................................................................................ 20 
A. Response ............................................................................................................... 20 


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IX.Safety Analysis .................................................................................................................. 21 
A. Adverse Events ..................................................................................................... 21 
B. Other Safety Parameters ....................................................................................... 23 
X.Additional Analysis............................................................................................................. 23 
A. Pharmacodynamics ............................................................................................... 23 
B. Exposure ............................................................................................................... 24 
C. Prior and Concomitant Medications ..................................................................... 24 
D. Prior and Concomitant Transfusions .................................................................... 25 
E. Prior and Concurrent Cancer Chemotherapy ........................................................ 25 
XI.Pharmacokinetic Analyses ................................................................................................. 25 
XII.References ........................................................................................................................ 25 


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I. 
Introduction 
 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Imago Biosciences, Inc. Protocol IMG-7289-CTP-101 [A 
Multi-Center, Open Label Study to Assess the Safety, Steady-State Pharmacokinetics and 
Pharmacodynamics of IMG-7289 with and without ATRA (Tretinoin) in Patients with 
Advanced Myeloid Malignancies].  The purpose of this plan is to provide specific guidelines 
from which the analysis will proceed.  Any deviations from these guidelines will be 
documented in the clinical study report (CSR). 
 
A. Background 
 
Acute myeloid leukaemia (AML) is a lethal haematologic malignancy resulting in the 
accumulation of abnormal myeloid blasts (CD13+ and CD33+) in the bone marrow 
(Estey, 2013).  These blasts interfere with normal haematopoiesis causing cytopenias, 
and accumulate in peripheral blood and infiltrate the lung and the central nervous 
system (CNS).  AML accounts for approximately 80% of all adult acute leukaemias 
with a median age at diagnosis of 67 years (Pollyea et al., 2011).  AML can arise de 
novo without a prior history of haematologic disease but can also evolve from other 
clonal myeloid disorders such as myelodysplastic syndromes (MDS) or 
myeloproliferative neoplasias (MPNs), or secondary to prior DNA-damaging 
treatment  (Lindsley et al., 2015). 
 
AML is a devastating and difficult disease to treat.  Despite intense efforts, the 
treatment for AML has changed very little in almost 40 years.   Standard-of-care 
(SOC) induction with intensive chemotherapy consists of seven days of cytarabine 
and three days of an anthracycline (“7+3”), generally daunorubicin or idarubicin, with 
many additional agents used specific to clinical sites.  Patients attaining a complete 
remission (CR) are patient to additional cycles of high-dose cytarabine and/or 
haematopoietic stem cell transplantation (HSCT) (Dombret and Gardin, 2016; 
Cornelissen and Blaise, 2016).  The addition of other agents to SOC, however, has 
not proven to provide additional clinical benefit (Stein and Tallman, 2012).  Improved 
supportive care, as opposed to more effective treatment, has been the primary means 
for extending life in these patients.   
  
LSD1, also known as KDM1A, was first described as an enzyme that removes mono- 
and dimethyl groups from critical lysines (K), K4 and K9 in histone (H) H3 (Shi et 
al., 2004).  Methylation of histone H3K4 and H3K9 is a post-translational 
modification associated with changes in rates of gene transcription (Bannister and 
Kouzarides, 2011; Beisel and Paro, 2011).  By virtue of altering the local state of 
chromatin, LSD1 is an epigenetic regulator of gene expression.  The lysine (K) sites 
on histone H3 and the degree of methylation on those sites (1, 2 or 3 methyl groups) 
are associated with specific functions, e.g., enhancers and super-enhancers are 
characterized by H3K4me1 marks, whereas H3K4me2 is more often found in the 


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proximal promoters and enhancers of actively transcribed genes (Campos and 
Reinberg, 2009; Gardner et al., 2011; Rando, 2012).  The inhibition of LSD1 (LSDi) 
can result in an increase or decrease of specific messenger RNAs (mRNAs) 
dependent on those local chromatin marks and associated transcription factors (TFs).  
 
In summary, the scientific evidence available in the literature shows that inhibition of 
LSD1 offers the promise of targeting an enzyme that participates in many essential 
neoplastic functions in AML cells including self-renewal, a phenotype that 
characterizes the major reservoir of treatment-resistant-cells, the leukaemic stem cell 
population.   The pathological process in MDS that leads to neoplastic transformation 
is similar in many aspects to the evolution of AML and hence is thought to be patient 
to the same therapeutic thesis.  That AML cells employ LSD1 in a similar fashion 
suggests that with continued inhibition the population of both leukaemic blasts and 
stem cells might be eroded and eventually eradicated.  These data, and the successful 
treatment of various animal models of AML through the inhibition of LSD1, is the 
foundation for taking development of the Imago molecule, IMG-7289, into clinical 
trials in the AML population. 
  
The rationale for combining ATRA with an LSD1 inhibitor is based on enhanced 
anti-leukaemic activity observed by various groups.  ATRA does not abolish the self-
renewal or engraftment of leukaemic stem cells, whereas LSD1 inhibitors have been 
shown to reduce self-renewal, induce differentiation, inhibit engraftment and promote 
cell death in leukaemia stem cells (Zheng et al., 2007; Harris et al., 2012; Schenk et 
al., 2012).  A study of the combination of the non-specific LSD1 inhibitor, 
tranylcypromine (TCP), and ATRA was active against AML cells in culture and 
impaired engraftment in patient-derived AML cells transplanted to non-obese 
diabetic/severe combined immunodeficiency (NOD/SCID) mice (Schenk et al., 
2012).  In this combination study, the CD11b marker was induced and the percentage 
of cells undergoing apoptosis was enhanced compared to monotherapy. The proposed 
mechanism of this synergism is the collective induction and de-repression of genes 
needed for differentiation.  
  
The protocol for Study IMG-7289-CTP-101 describes the general approach to 
analysis of data from the study.  This analysis plan describes additional detail needed 
to complete such an analysis. 
 
B. Protocol and Amendment History 
   
This Statistical Analysis Plan (SAP) is based on Amendment 2 of the Protocol.   
 
Version 
Approval Date 
Salient Changes, if any* 
Protocol 
05 April 2016 
 
Amendment 1 
29 June 2016 
 


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Amendment 2 
19 January 2017 
 
Amendment 3 
29Aug2017 
(1) Change “The adequacy of dose and duration 
in producing a pharmacodynamic effect” from a 
secondary to a primary objective 
(2) Include additional combination therapy sub-
cohorts in dose-finding phase 
(3) Remove Cohort 2 and add combination 
therapy cohorts in the duration-finding phase 
(4) Add Stable and Progressive Disease 
Response Criteria for AML patients 
(5) Remove Medical Events of Interest (MEOIs) 
categories 
(6) Increase the number of patients 
* Changes expected to require accommodation in analysis plan. 
 
This SAP will govern the analysis of data from this study.  The plan may be modified 
until database lock.  Any deviations from the analysis plan, including any after the 
time of treatment database lock, will be documented as such in the study report.   
 
II. 
Protocol Hypothesis and Objectives 
 
A. Hypothesis 
 
The protocol (Section 4.1) lists the following hypothesis:  IMG-7289 with and 
without all-trans retinoic acid (ATRA; tretinoin) is a safe and tolerable orally 
available agent when administered to patients with advanced myeloid malignancies 
including high risk AML and high risk MDS; LSDi by IMG-7289 will have a 
negative impact on leukaemic and dysplastic cells, an effect which may be further 
enhanced via synergistic mechanisms when administered in combination with ATRA. 
 
B. Primary 
 
The protocol (Section 4.2) lists the following primary objectives:   
 Safety and tolerability 
 Pharmacokinetics 
 The adequacy of dose and duration in producing a pharmacodynamic effect 
 
C. Secondary 
 
The protocol (Section 4.2) lists the following secondary objectives: 
 The association of plasma concentrations (Cmax and Cmin) and exposure (AUC) 
on haematopoiesis (both short and longer-term measures)  
 The kinetics of recovery of haematopoiesis for a given dose and for a given 
duration of dosing 


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III. 
Study Endpoints 
 
A. Primary 
 
The safety and tolerability of IMG-7289 with and without ATRA will be assessed by 
the analysis of adverse events (AEs), as well as changes in physical examinations, 
vital signs and laboratory values as detailed below.  
 Monitoring of Adverse Events (AEs) including determination of dose limiting 
toxicities (DLTs), medical events of interest (MEOIs), serious adverse events 
(SAEs), and AEs.  AEs will be assessed in terms of onset, duration, 
seriousness, severity, and causality, using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 
4.03.  Deaths and other serious adverse events (SAEs) will also be evaluated 
and will be collected on a separate case report form (CRF).   
 Changes in physical examinations, vital signs and laboratory values will also 
be evaluated and assessed.  Information on the timing of these assessments is 
presented in Protocol Section 9.  The following laboratory tests will be 
conducted: 
 
Complete blood counts (CBC) and differential 
 
Coagulation 
 
Chemistry panel including LFTs (AST, ALT, INR, total 
bilirubin, gamma glutamyltransferase (GGT), and albumin) 
 
Urinalysis with microscopy 
 
Electrocardiograms 
CCI




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IV. 
Study Design 
 
A. Design Overview  
 
This is a multi-center, open-label, multiple ascending dose- and duration-finding 
study assessing the safety, pharmacokinetics and pharmacodynamics of IMG-7289, 
with and without ATRA, in patients with advanced myeloid malignancies.   
Following their consent, patients will undergo Screening to confirm eligibility.  A 
sufficient number of patients will be screened to enroll and treat approximately 40 
patients with high risk AML/MDS.  Screening may commence up to 28 days prior to 
the start of IMG-7289 treatment on Day 1.  Patients meeting all applicable Inclusion 
and no Exclusion Criteria will be enrolled into the study and assigned to a Cohort.  
CCI


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All patients will be unique; no patient will be allowed to be dosed in more than one 
cohort.  Contingent on the number of prior DLTs within a cohort, non-completers of 
Cycle 1 will be replaced. 
 
The study consists of two phases in which IMG-7289 will be dosed with and without 
ATRA:  the dose-finding phase, using multiple ascending doses of IMG-7289; and 
the duration-finding phase, during which multiple IMG-7289 durations may be 
assessed.  During both phases, a Data Safety Monitoring Committee (DSMC) will 
convene to review safety parameters, pharmacodynamic markers and 
pharmacokinetic parameters to draw conclusions around the safety and 
pharmacodynamic effects of differing doses, treatment regimens and dosing 
durations.  DSMC reviews are critical, as neither a new dose-finding sub-cohort, nor a 
duration-finding cohort may commence without DSMC review and recommendation 
to do so.  Refer to Protocol Section 8 for details pertaining to DSMC reviews, DLT 
management, dose escalation/duration extension rules, and MTDs. 
  
At least three patients will enroll in each sub-cohort/cohort with a minimum of 3 
patients required to complete the entirety of Cycle 1 (i.e., the applicable IMG-7289 
dosing and rest periods).  Each dose-finding sub-cohort will include a sentinel patient 
to be dosed for 7 days, the safety of which will be determined by the DSMC before 
the remainder of the sub-cohort is treated; duration-finding cohorts will not include 
sentinel patients.  Therefore, with the exception of a sentinel patient in each dose-
finding sub-cohort, patients will be enrolled on a rolling basis.  As there is no 
evidence in non-clinical studies of acute toxicity with IMG-7289, even at extremely 
high doses, it is believed that one sentinel patient for each dose-finding sub-cohort is 
sufficient to establish the acute safety of IMG-7289 dosed with and without ATRA.  
Since this study is not investigating the effects of cytotoxic agents, enrolling patients 
on a rolling basis facilitates progression to later cohorts that could offer greater 
therapeutic benefit. 
 
Patients will be treated with IMG-7289 in cycles, each cycle comprised of one dosing 
period followed by one rest period.  The number of initially allowed IMG-7289 
cycles differs by cohort, as does the duration of IMG-7289 dosing.  Patients may 
initially undergo four (Cohort 1), two (Cohort 3/3χ) or one (Cohort 4/4χ) IMG-7289 
treatment cycles while on study to a total of approximately 28 days of IMG-7289 
dosing.  During the initially allowed IMG-7289 treatment cycles and regardless of the 
dosing duration, the rest period will remain at 7 days, unless assessment is made by 
the DSMC that either a specific patient or an entire cohort could benefit from an 
extended rest period.  This decision could be taken if there is no clear indication of 
the restoration of normal haematopoiesis in the 7 day period or analysis of the IMG-
7289 pharmacokinetic parameters in the earlier sub-cohorts suggest the rest period 
duration requires adjusting.  As IMG-7289 treatment may lead to cytopenias, 
transfusions may be administered in accordance with standard institutional guidelines. 
  


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The initial dose-finding phase of the study will be used to establish and confirm the 
IMG-7289 Di and the Dp in patients, as well as to provide samples sufficient to 
establish the pharmacokinetic parameters of IMG-7289 at several dose levels, with 
and without ATRA.  It is anticipated that dose escalation of IMG-7289 as well as 
IMG-7289 administered in combination with ATRA will proceed in sub-cohorts (i.e., 
Sub-cohort 1b, 1c, 1χ, 1Ѡ  in accordance with Protocol Section 7.2.2.1, following 
DSMC reviews as detailed in Protocol Section 8.1 and the rules outlined in Protocol 
Section 8.2.2.  (Note:  Though not expected, contingencies are in place in the case  
that unacceptable toxicity is demonstrated at the Ds and sub-cohorts at lower doses 
are therefore required.  Please refer to Protocol Section 7.2.2.2.)  The IMG-7289 
dosing duration and associated rest period will remain at 7 days dosing followed by a 
7 day rest period throughout the entirety of the dose-finding phase (includes all sub-
cohorts).   Patients will be initially allowed to receive up to 4 cycles of IMG-7289, 
provided that IMG-7289 (with and without ATRA) continues to be tolerated.        
 
Upon DSMC confirmation that no further dose-finding sub-cohorts are anticipated, 
and safety permitting (the DSMC must have determined it safe to extend the duration 
of IMG-7289 treatment), the duration-finding phase will commence.  The duration-
finding phase will be used to identify the safety and clinical effects of IMG-7289 
treatment for durations longer than 7 days as well as provide samples sufficient to 
establish drug concentrations at steady state, with and without ATRA.  Duration-
finding cohorts will be dosed with IMG-7289 at the Dp (determined by the DSMC), 
with or without ATRA.  The Dp may change as data from earlier sub-cohorts becomes 
available and different durations continue to be studied.  The duration of dosing will 
be extended in cohorts in accordance with Protocol Section 7.2.2.3, following DSMC 
reviews as detailed in Protocol Section 8.1 and the rules outlined in Protocol Section 
8.2.2; each dosing duration will be followed by a 7 day rest period.  Patients will be 
initially allowed to receive 2 cycles of 14 days IMG-7289 dosing for Cohorts 3/3χ, 
and 1 cycle of 21 days IMG-7289 dosing for Cohorts 4/4χ; each dosing duration will 
be followed by a 7 day rest period. 
 
Importantly, if the DSMC determines a specific dose, treatment regimen or dosing 
duration is associated with greater therapeutic benefit, patients who have fully 
completed their initially allowed cycles and are receiving a different dose, treatment 
regimen (i.e., IMG-7289 alone versus combination therapy) or dosing duration will be 
transitioned to the more optimal dose, treatment regimen or dosing duration at the 
start of their next cycle.  Such transition may occur more than once, as different 
doses, treatment regimens and dosing durations continue to be evaluated. 
 
Throughout all phases of the study, if it appears that either a maximally tolerated dose 
(MTD) or maximally tolerated duration (MTDu) is reached (see Protocol Section 
8.2.3), the DSMC will convene to evaluate further dose escalation, combination 
therapy and/or extended dosing duration.  


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Upon completion of the number of initially allowed IMG-7289 cycles per cohort, 
patients deriving clinical benefit and safely tolerating IMG-7289, as determined by 
the Principal Investigator, may continue to receive IMG-7289 with additional dose 
titration, treatment regimen and dosing duration changes occurring in consultation 
with the Medical Monitor until disease progression or unacceptable toxicity ensues.  
During the additional cycle period, the rest period may be extended from the 7 day 
standard to a maximum of 56 days but only after: 1) the patient has received a 
minimum of 28 IMG-7289 doses; and, 2) consultation with or recommendation by the 
DSMC.  Such recommendation may be made for a variety of reasons including 
evidence of tumour reduction, marked hypocellularity in the marrow consistent with 
myelosuppression, or to enable the return of normal haematopoiesis.  For protocol 
purposes, a rest period extending beyond the 7 day standard will be referred to as the 
extended rest period (see Protocol Section 9.10). 
 
Patients who either fail to demonstrate stable disease, demonstrate progressive 
disease after achieving partial remission (PR) or stable disease, or relapse after 
achieving complete remission (CR), CR with incomplete recovery (CRi), or PR (see 
Protocol Table 14 and Protocol Table 15) are the equivalent of treatment failures, and 
will discontinue study drug and enter the follow-up period.   
 
Patients will be followed closely for both Adverse Events (AEs) and signs of toxicity 
by frequent monitoring of clinical signs and symptoms and by blood and urine 
analyses both during the IMG-7289 treatment period and the rest period.  
Pharmacodynamic effects will also be closely monitored by frequent haematology 
assessments of peripheral blood and bone marrow aspirates, as required. 
 
All patients will undergo End-of-Treatment (EOT), pre-End of Study (pre-EOS), and 
End-of-Study (EOS) visits approximately 7, 14, and 28 days, respectively, after last 
Cycle last dose.   
 
A detailed description by-cohort, by-cycle, of assessments to be performed is 
provided in Protocol Section 9.  Additionally, a by-cohort schema of assessments is 
included in Protocol Section 16.1, Schedule of Assessments.    
 
B. Study Population 
 
The patient population will consist of men and women age 18 or older who have been 
diagnosed with either high-risk Acute Myeloid Leukaemia or Myelodysplastic 
Syndrome.  Eligible patients who have signed informed consent must not have had 
prior treatments within a specified period of time and must have meet pre-specified 
laboratory values for selected parameters, in addition to multiple other required 
eligibility criteria. 
 




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VI. 
General Analytical Considerations 
 
The statistical analyses will be reported using summary tables, figures, and data 
listings.  Unless otherwise noted, all statistical testing will be two-sided with 
significance being p < 0.05.  Continuous variables will be summarized with means, 
standard deviations, medians, minimums, and maximums.  Categorical variables will 
be summarized by counts and by percentage of patients in corresponding categories. 
As appropriate and where specified, continuous and categorical variables will be 
evaluated using the Student t-test, ANOVA, Wilcoxon rank sum, Fisher’s exact, or χ2 
tests.  As appropriate and where specified, summary tables will be presented by 
cohort, and may also include a “Total” or “All Patients” summary.  
 
The analyses described in this plan are considered a priori, in that they have been 
defined prior to database lock. If any post-hoc analyses are performed they will be 
defined and reported in the CSR. 
 
All analyses will be performed using SAS statistical analysis software (SAS, 
SAS/GRAPH and SAS/STAT; version 9.3 or higher of SAS for Windows [SAS 
Institute Inc; Cary, NC, USA]). 
 
A. Data Sources 
 
All data are collected via electronic case report forms (eCRFs) through remote data 
entry.  Section 13.7 of the protocol describes data quality assurance. 
 
B. Definition of Baseline 
 
For analysis purposes, baseline is defined as the last assessment prior to the first dose 
of study drug.   Cycle 1 Day 1 is the first day a patient receives study drug.  For most 
measurements, baseline assessments will be taken pre-dose on Cycle 1 Day 1.  If pre-
dose assessments on Day 1 are not available, the most recent prior assessment closest 
to Day 1 may be substituted in some cases, and unless otherwise specified.  For local 
laboratory data, baseline data will be obtained during the screening period (Days -28 
to 1).  All other baseline data will be collected on Days -21 to 1. 
 
C. Missing Data 
 
For safety and tolerability, missing data, including those not obtained because of 
death, will be the last value carried forward. 
 
If CTCAE Grade is missing, the event is assumed to be ‘Severe’ (grade 3). If AE 
relatedness is missing, the event is assumed to be ‘possibly’ related. 
 
Otherwise, missing data will not be replaced with imputed values.  When relevant, 
sections below will address how missing data will be handled for the particular 
analyses.  


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D. Display and Imputation Methods for Missing Dates 
 
Every effort will be made to query missing dates.  However, partial dates are allowed 
on the eCRF for Adverse Event (AE) onset and resolution dates (only month and year 
are required), Concomitant Medication (CM) start and stop dates (only year is 
required), and Prior and Concurrent Cancer Chemotherapy (PCTHX) start and stop 
dates (only year is required).  
 
Per protocol, Adverse Events (AEs) are captured in the eCRF commencing with the 
first dose of IMG-7289 through to the End of Study Visit (scheduled for 
approximately 28 days post last IMG‐7289 dose).  For records with missing AE onset 
day, the following procedure will be employed for use in determining whether the AE 
is treatment-emergent: 
 AE onset dates with missing day will be assumed to occur on the first day of 
the non-missing month, except for AEs occurring in the first month of 
dosing, in which case the date will be the first day of dosing. 
Additionally, if for some reason the start date of an AE is partially or completely 
missing and the end date of the AE does not indicate that the AE occurred prior to the 
first dose of IMG-7289, then the determination of treatment-emergent status will be 
based on the following: 
 If the start date is completely missing, then the AE is treatment-emergent. 
 If the start year is the same as the year of the first dose of study drug and the 
start month is the same or after the month of the first dose of study drug, then 
the AE is treatment-emergent. 
 If the start year is after the year of the first dose of study drug, then the AE is 
treatment emergent. 
For records with a missing CM or PCTHX start and/or stop day or month, the 
following procedure will be employed for use in determining whether the therapy 
(i.e., medication or chemotherapy) is prior or concomitant/concurrent: 
 Therapy start dates with a missing day and non-missing month will be 
assumed to occur on the first day of the non-missing month, except for 
therapies occurring in the first month of dosing, in which case the date will be 
the first day of dosing. 
 Therapy start dates with a missing day and month will be assumed to occur on 
the first day of the non-missing year (i.e., January 1), except for medications 
occurring in the first year of dosing, in which case the date will be the first 
day of dosing.   
 Therapies that are not marked as ongoing, and have a stop date with a missing 
day and non-missing month will be assumed to occur on the last day of the 
non-missing month. 


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 Therapies that are not marked as ongoing, and have a stop date with a missing 
day and month will be assumed to occur on the last day of the non-missing 
year (i.e. December 31). 
For the listings, AE, CM and PCTHX dates will be listed as collected in the eCRF. 
All other data will be reported as they are collected.  No imputation methods will be 
used to replace missing data unless otherwise stated in this document.    
 
Partial transfusion start dates are not permitted, and thus assumptions should not be 
needed to determine if the transfusion was prior to the first dose of IMG-7289.  
 
E. Multiple Study Centers 
 
There will be no adjustment for multiple study centers in the analysis. 
 
F. Covariate Adjustment in Primary Analysis 
 
There will be no adjustment in the analysis for covariates.  
 
G. Sample Size Reassessment 
 
No sample size reassessment is planned for this study. 
 
H. Interim Analyses or Timing of Analyses 
 
The Data Safety Monitoring Committee (DSMC) will review safety parameters, 
pharmacodynamic markers, and pharmacokinetic parameters to draw conclusions 
around the safety and pharmacodynamic effect of differing doses, treatment regimens 
and dosing durations. DSMC reviews are critical, as neither a new dose-finding sub-
cohort, nor a duration-finding cohort may commence without DSMC review and 
recommendation to do so.  Refer to Protocol Section 8 for details pertaining to DSMC 
reviews, and management of study toxicities. 
 
I. Multiple Comparisons 
 
No control for the effect of multiple comparisons is planned.  
 
J. Analysis Populations  
 
Two analysis populations will be defined for use with various analyses.   
 
1. Safety Population 
 
All enrolled patients who received at least one dose of IMG-7289 will be 
included in the Safety population.   
 


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2. Efficacy Population 
 
All enrolled patients who received at least one dose of IMG-7289 and have 
disease assessment at baseline (Bone Marrow Aspirate/Biopsy and 
Haematology).  Patients having no post-baseline response assessment will be 
defined as NE (Not Evaluable).  
 
K. Data Display Characteristics 
 
Data displays produced for this study will include three types—summary tables, data 
listings, and figures.  Unless stated otherwise, data listings will be produced for all 
recorded data.  In general, there will be one set of data displays encompassing 
patients in both the dose-finding phase and duration-finding phases.  Summary tables 
will include columns for each cohort, and the ordering of these cohorts will be 
defined in the tables, listings, and figures (TLF) shells document.  Summary tables 
will be produced as specified in the following sections.  Additional data listings will 
be produced for outcome measures that involve extensive procedures to derive the 
analyzed outcomes.   
 
Data listings will simply list the data that are either recorded on the CRF or derived 
for each patient.  In general, they will be ordered by cohort, site, patient number, and 
time of assessment, unless otherwise specified in the display shell.  When expedient, 
additional levels of ordering hierarchy may reflect subsets of assessments within 
patient.  Data listings will not display patient initials. 
 
Summary tables will display summary statistics calculated for each cohort, and for all 
patients combined, unless described otherwise in the following sections, or in the 
display shells. For most summary tables, the cohorts will be presented in a column, 
and the summary statistics of interest will be presented in rows.  
 
Descriptive statistics (arithmetic mean, standard deviation (SD), sample size, median, 
minimum, maximum, and number) will be calculated for quantitative safety data as 
well as for the differences to baseline, when appropriate.  In addition, shift tables for 
laboratory values with respect to normal range (low, normal, high) will be 
summarized; and overall laboratory and ECG result shift from baseline (Normal, 
Abnormal clinically significant (CS), and Abnormal non-clinically significant (NSC) 
will be summarized.   
Chi-square (χ2), Fisher exact, and Kruskal-Wallis tests may be used to assess the 
significance of differences in haematologic and pharmacodynamics markers among 
the dose-finding and duration-finding cohorts.  If applicable, event free survival 
(EFS), and overall survival (OS) will be calculated using the Kaplan-Meier method. 
 
VII. Patient Accountability 
 


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A. Patient Characteristics 
 
Demography.  Data collected about the following patient characteristics at the 
screening/baseline visit will be listed and summarized for the safety population: 
 
 Disease diagnosis (i.e., AML or MDS) 
 Age.  Age will be calculated as the number of years elapsed between birth 
date and the date of informed consent, adjusted for whether the birthday has 
passed as of the day of the screening visit.  (This corresponds to the typical 
calculation of age a person would use in conversation.) 
 Sex at birth 
 Ethnicity 
 Race 
 Height 
 Weight 
 Body Mass Index (BMI) 
 
AML Baseline Disease History.  Baseline history will be summarized and listed. 
 AML type 
 Genetic Classification 
 WHO Classification 
 ECOG Performance Status 
 
MDS Baseline Disease History.  Baseline history will be summarized and listed. 
 MDS type 
 WHO Classification 
 IPSS-R Risk 
 IPSS Risk 
 
Medical History.  Medical Histories will be listed. 
 
Prior Disease Treatment.  Data from prior disease treatments will be summarized and 
listed: 
 Prior Radiation Therapy 
 Prior Cancer Related Surgeries/Procedures 
 Prior Transplants 
 Prior Cancer Chemotherapy 
 
B. Disposition 
 
Disposition.  Patient disposition data will be summarized for the Safety Population by 
cohort.  Summaries will include: the numbers of patients enrolled, the number of 
patients in each analysis population, and the number of patients that either completed 


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the study or prematurely withdrew from study participation.  Treatment completion 
will be indicated by the response “Yes” (they completed their initially allowed cycles) 
on the End of Treatment form.  Any other non-missing response on this form will be 
counted as a premature withdrawal. 
 
Premature withdrawals from treatment in each cohort group will be further 
characterized as the number of patients who ended treatment of IMG-7289 
prematurely and the number of patients who ended treatment of ATRA prematurely 
for each of the reasons listed in the eCRF End of Treatment (EOT) form and in the 
corresponding summary display shell. 
 
Premature withdrawals from the study in each cohort group will be characterized as 
the number of patients who permanently discontinued from the study for each of the 
reasons listed in the eCRF Study Discontinuation (EOS) form and in the 
corresponding summary display shell.  
 
C. Protocol Deviations 
 
Protocol deviations and waivers will be provided in a listing. 
 
VIII. Efficacy Analysis 
 
A. Response 
 
The primary objective, the adequacy of IMG-7289 dose and duration with and 
without ATRA in producing a pharmacodynamic effect, will be determined using 
serial blood and bone marrow sampling throughout the course of treatment with 
responses documented according to revised/modified International Working Group 
(IWG) Response Criteria – Cheson et al. 2003 for AML and Cheson et al. 2006 for 
MDS as described in Protocol Section 16.2.  Response is to be assessed each time a 
bone marrow aspirate or biopsy is performed, with the exception of baseline.  All 
available response data will be listed.  The visit overall response per patient, as 
determined by the Investigator, and recorded on the eCRF, will be listed and 
summarized for each cohort, using the Efficacy Population.  
The best response of each AML patient will be programmatically selected based on 
the following order: Complete Remission (CR), CR w/Incomplete Recovery (CRi), 
Morphologic Leukaemia-Free State (MLFS), Partial Remission (PR), Cytogenetic CR 
(CRc), Molecular CR (CRm), Stable Disease (SD), Resistant Disease (RD), Relapse 
(Rel), Progressive Disease (PD), Death from Indeterminate Cause (DInd), Death in 
Aplasia (DiA), and Not Evaluable.  The best response of each MDS patient will be 
programmatically selected based on the following order: Complete Remission (CR), 
Partial Remission (PR), Marrow CR (CRm), Cytogenetic Response (CyR), Stable 
Disease (SD), Relapse After CR or PR (Rel), Disease Progression (DP), Failure: 
Disease Progression (FDP), Survival (Sur), Failure: Death During Treatment (FDDT), 
and Not Evaluable.   


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Objective response in AML includes Complete remission (CR), CR with incomplete 
recovery (CRi), Morphologic leukamia-free state, Partial remission (PR), Cytogenetic 
CR (CRc), and Molecular CR (CRm) and Stable Disease (SD); while objective 
response in MDS includes Complete remission (CR), Partial remission (PR), Marrow 
CR, or Cytogenetic response (CyR) and Stable Disease (SD).  Objective response rate 
(ORR) is the proportion of responders with AML or MDS. ORR and its Fisher exact 
95% confidence interval will be presented. 
Additionally, the Kaplan-Meier method will be used to analyze event-free survival 
(EFS) and overall survival (OS); Summaries will present the number (%) of subjects 
with events, the number (%) of subjects without events (censored), the median (95% 
CI) survival, and the probability of 6-month survival.  OS is defined as the time 
interval between treatment start date and death date, and OS will be censored at the 
last date known alive.  EFS is defined as the time interval between the date of 
treatment start and date of resistance, relapse, progression, or death.  For subjects that 
do not have an event, EFS will be censored at the date of last tumor assessment prior 
to any concurrent cancer chemotherapy and transfusion.  
 
IX. 
Safety Analysis 
 
The safety and tolerability of IMG-7289 with and without ATRA will be assessed by the 
analysis of adverse events (AEs), as well as changes in physical examinations, vital signs, 
laboratory values and ECGs as detailed below, using the Safety Population.  
A. Adverse Events 
 
The AEs reported on the eCRFs will be coded using the latest version of MedDRA 
available to the sponsor at the time of study initiation (up-versioning will not occur), 
associating lower-level terms with preferred terms and system organ classes (SOC) 
by the primary hierarchy.  The tables will display counts and percentages of subjects 
who reported at least one AE in each system organ class represented in the AE data.  
Within each system organ class, the tables will display the counts and percentages of 
subjects reporting at least one AE, as designated by the preferred terms.  
 
In any given category (e.g., SOC or preferred term) a patient will be counted only 
once.  If a patient has the same AE on multiple occasions, only the highest toxicity 
grade will be used. Similarly, only the most related event will be used.  Percentages 
will be based on the number of patients in the subgroup of patients being tabulated 
and not the number of events.  Summaries that are displayed by system organ class 
and preferred terms will be ordered by descending order of incidence of system organ 
class and preferred term within each system organ class. 
 
Treatment-emergent adverse events will be summarized.  Only those events with an 
onset date on or after the date on which IMG-7289 was first dispensed, and within 28 
days of last IMG-7289 treatment are to be recorded on the AE eCRF; therefore, all 
reported AEs are expected to be treatment-emergent.  However, if eCRF completion 


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guidelines change, or are not followed adequately, treatment-emergent events will be 
identified programmatically per the above definition, using imputed start date. 
 
Severity of AEs will be reported using the NCI CTCAE grades (v4.03) where Grade 
1 is Mild, Grade 2 is Moderate, Grade 3 is Severe, Grade 4 is Life-Threatening, and 
Grade 5 is Fatal.    
 
CCI






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D. Prior and Concomitant Transfusions 
 
Prior transfusions are defined as those with a transfusion start date from the 15 days 
prior to Screening up to the first IMG-7289 dose.  Concomitant transfusions are 
defined as those with a transfusion start date on or after the date of the first IMG-7289 
dose.  
 
Prior and concomitant transfusions will be listed and summarized. 
 
E. Prior and Concurrent Cancer Chemotherapy 
 
Prior chemotherapy, which is ended before the first IMG-7289 dose, will be 
summarized with other prior treatment or therapy.  Prior and concurrent 
chemotherapy will be listed by cohort and by patient. 
 
XI. 
Pharmacokinetic Analyses 
 
Pharmacokinetic data are not within the scope of this SAP.  Analysis details are 
provided in the protocol and in a separate Pharmacokinetic Analysis Plan. 
 
 
XII. References 
 
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Beisel, C., Paro, R., 2011. Silencing chromatin: comparing modes and mechanisms. 
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Campos, E.I., Reinberg, D., 2009. Histones: annotating chromatin. Annu Rev Genet 
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Cheson, B.D., Bennett, J.M., Kopecky, K.J., Bu¨chner, T., Willman, C.L., Estey, 
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