A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects With IPSS Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) That is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Sponsor: Geron Corporation

Official Title: 
A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent 
Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndrome 
(MDS) that is Relapsed/Refractory to Erythropoiesis- Stimulating Agent 
(ESA) Treatment 
NCT Number: 
NCT02598661 
Document Date: 
Protocol Version 8.0: 13 December 2022 

1 
Status: Final, Date: 13 December 2022 
Geron Corporation* 
Clinical Protocol 
A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS 
Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) that is Relapsed/Refractory 
to Erythropoiesis- Stimulating Agent (ESA) Treatment    
Protocol 63935937MDS3001 Amendment 8/USA-1; Phase 2/3 
 GRN163L (imetelstat)  
*As of protocol amendment 3, the term “sponsor”, as used throughout this protocol, refers to Geron
Corporation.  Prior to protocol amendment 3, this study was sponsored by Janssen Research &
Development or its related legal entities.
This compound is being investigated in Phase 2/3 clinical studies. 
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312). 
EudraCT NUMBER: 2015‐002874‐19 
Status: 
Final 
Date: 
13 December 2022 
Prepared by: Geron Corporation 
Local Amendment to: Protocol 63935937MDS3001 Global Amendment 8, 30 November 2022 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. 

GRN163L (imetelstat) 
 
 
 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
LIST OF ATTACHMENTS ............................................................................................................................ 5 
LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 5 
PROTOCOL AMENDMENTS ....................................................................................................................... 6 
SYNOPSIS .................................................................................................................................................. 40 
TIME AND EVENTS SCHEDULES ............................................................................................................ 46 
ABBREVIATIONS ...................................................................................................................................... 59 
1. 
INTRODUCTION ................................................................................................................................ 61 
1.1. 
Background .................................................................................................................................... 61 
1.1.1. 
Telomeres and Telomerase ........................................................................................................ 61 
1.1.2. 
Imetelstat .................................................................................................................................... 61 
1.1.3. 
Myelodysplastic Syndromes ....................................................................................................... 62 
1.1.4. 
Treatment Options for Myelodysplastic Syndromes ................................................................... 63 
1.1.5. 
Clinical Experience with Imetelstat in Myeloproliferative Neoplasms and MDS ......................... 65 
1.2. 
Overall Rationale for the Study ...................................................................................................... 68 
1.3. 
Benefit-risk Assessment: COVID-19 .............................................................................................. 69 
2. 
OBJECTIVES AND HYPOTHESES .................................................................................................. 70 
2.1. 
Objectives ...................................................................................................................................... 70 
2.2. 
Hypothesis ..................................................................................................................................... 71 
3. 
STUDY DESIGN AND RATIONALE ................................................................................................. 71 
3.1. 
Overview of Study Design .............................................................................................................. 71 
3.2. 
Study Design Rationale .................................................................................................................. 76 
3.3. 
Rationale for the Extension Phase ................................................................................................. 79 
4. 
SUBJECT POPULATION .................................................................................................................. 80 
4.1. 
Inclusion Criteria ............................................................................................................................ 80 
4.2. 
Exclusion Criteria ........................................................................................................................... 82 
4.3. 
Prohibitions and Restrictions ......................................................................................................... 84 
5. 
TREATMENT ALLOCATION AND BLINDING ................................................................................. 84 
5.1. 
Treatment Allocation ...................................................................................................................... 84 
5.2. 
Blinding and Unblinding ................................................................................................................. 84 
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 85 
6.1. 
Dose Modifications ......................................................................................................................... 87 
6.1.1. 
Dose Modifications for Hematologic Toxicities ........................................................................... 87 
6.1.2. 
Dose Modifications for Non-hematologic Toxicities, Excluding Hepatic Toxicities..................... 88 
6.1.3. 
Dose Modifications for Liver Function Test Elevations and Hepatic Adverse Events ................ 88 
6.1.4. 
Dose Modifications for COVID-19 Symptoms or Positivity (any Grade) .................................... 89 
6.2. 
Infusion-Related Reactions ............................................................................................................ 90 
7. 
TREATMENT COMPLIANCE ............................................................................................................ 91 
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 92 
8.1. 
Prestudy Therapy ........................................................................................................................... 92 
8.2. 
Premedication ................................................................................................................................ 92 

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8.3. 
Concomitant Medications ............................................................................................................... 92 
9. 
STUDY EVALUATIONS .................................................................................................................... 93 
9.1. 
Study Procedures (Part 1 and Part 2) ............................................................................................ 93 
9.1.1. 
Overview ..................................................................................................................................... 93 
9.1.2. 
Blood Volume ............................................................................................................................. 94 
9.1.3. 
Screening Phase and Predose ................................................................................................... 95 
9.1.4. 
Treatment Phase ........................................................................................................................ 97 
9.1.5. 
Posttreatment Phase (Follow-Up) .............................................................................................. 98 
9.1.6. 
Extension Phase ......................................................................................................................... 99 
9.2. 
Endpoints ..................................................................................................................................... 100 
9.2.1. 
Primary Efficacy Endpoint......................................................................................................... 100 
9.2.2. 
Secondary Endpoints ................................................................................................................ 100 
9.2.3. 
Exploratory ................................................................................................................................ 101 
9.3. 
Efficacy ......................................................................................................................................... 101 
9.3.1. 
Evaluations ............................................................................................................................... 101 
9.4. 
Pharmacokinetics and Immunogenicity ....................................................................................... 103 
9.4.1. 
Sample Collection and Handling .............................................................................................. 103 
9.4.2. 
Analytical Procedures ............................................................................................................... 103 
9.4.3. 
Pharmacokinetic Parameters ................................................................................................... 104 
9.4.4. 
Immunogenicity Assessments .................................................................................................. 104 
9.5. 
Biomarkers ................................................................................................................................... 104 
9.6. 
Patient Reported Outcomes (Part 2 Only) ................................................................................... 106 
9.7. 
Medical Resource Utilization (Part 2 Only) .................................................................................. 108 
9.8. 
Safety Evaluations ....................................................................................................................... 108 
9.8.1. 
Clinical Laboratory Tests .......................................................................................................... 109 
9.8.2. 
Electrocardiogram ..................................................................................................................... 111 
9.8.3. 
Vital Signs ................................................................................................................................. 111 
9.8.4. 
Physical Examination ................................................................................................................ 111 
9.8.5. 
ECOG Performance Status ...................................................................................................... 111 
9.9. 
Sample Collection and Handling .................................................................................................. 111 
10. 
SUBJECT COMPLETION/WITHDRAWAL ..................................................................................... 112 
10.1. 
Completion ................................................................................................................................... 112 
10.2. 
Discontinuation of Study Treatment ............................................................................................. 112 
10.3. 
Withdrawal from the Study ........................................................................................................... 112 
10.3.1. 
Withdrawal from the Use of Samples in Future Research ....................................................... 113 
11. 
STATISTICAL METHODS ............................................................................................................... 113 
11.1. 
Analysis Populations .................................................................................................................... 113 
11.2. 
Subject Information ...................................................................................................................... 113 
11.3. 
Sample Size Determination ......................................................................................................... 114 
11.4. 
Efficacy Analyses ......................................................................................................................... 114 
11.5. 
Pharmacokinetic Analyses ........................................................................................................... 116 
11.6. 
Immunogenicity Analyses ............................................................................................................ 116 
11.7. 
Pharmacokinetic/Pharmacodynamic Analyses ............................................................................ 116 
11.8. 
Biomarker Analyses ..................................................................................................................... 116 
11.9. 
Medical Resource Utilization Analyses (Part 2 only) ................................................................... 117 
11.10. Safety Analyses ........................................................................................................................... 117 
11.11. Independent Data Monitoring Committee .................................................................................... 118 
11.12. Independent Hepatic Expert Committee ...................................................................................... 119 
11.13. Independent Review Committee .................................................................................................. 119 
12. 
ADVERSE EVENT REPORTING .................................................................................................... 119 
12.1. 
Definitions .................................................................................................................................... 119 
12.1.1. 
Adverse Event Definitions and Classifications ......................................................................... 119 
12.1.2. 
Attribution Definitions ................................................................................................................ 120 

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12.1.3. 
Severity Criteria ........................................................................................................................ 121 
12.2. 
Special Reporting Situations ........................................................................................................ 121 
12.3. 
Procedures ................................................................................................................................... 122 
12.3.1. 
All Adverse Events .................................................................................................................... 122 
12.3.2. 
Serious Adverse Events ........................................................................................................... 123 
12.3.3. 
Adverse Events of Interest ....................................................................................................... 124 
12.3.4. 
Pregnancy ................................................................................................................................. 125 
12.4. 
Contacting Sponsor Regarding Safety ......................................................................................... 125 
13. 
PRODUCT QUALITY COMPLAINT HANDLING ............................................................................ 125 
13.1. 
Procedures ................................................................................................................................... 126 
13.2. 
Contacting Sponsor Regarding Product Quality .......................................................................... 126 
14. 
STUDY DRUG INFORMATION ....................................................................................................... 126 
14.1. 
Physical Description of Study Drug(s) ......................................................................................... 126 
14.2. 
Packaging .................................................................................................................................... 126 
14.3. 
Labeling ........................................................................................................................................ 126 
14.4. 
Preparation, Handling, and Storage ............................................................................................. 127 
14.5. 
Drug Accountability ...................................................................................................................... 127 
15. 
STUDY-SPECIFIC MATERIALS ..................................................................................................... 127 
16. 
ETHICAL ASPECTS ....................................................................................................................... 128 
16.1. 
Study-Specific Design Considerations ......................................................................................... 128 
16.2. 
Regulatory Ethics Compliance ..................................................................................................... 129 
16.2.1. 
Investigator Responsibilities ..................................................................................................... 129 
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................. 129 
16.2.3. 
Informed Consent ..................................................................................................................... 130 
16.2.4. 
Privacy of Personal Data .......................................................................................................... 131 
16.2.5. 
Long-Term Retention of Samples and Use of Data for Additional Future Research ............... 132 
16.2.6. 
Country Selection ..................................................................................................................... 132 
17. 
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 132 
17.1. 
Protocol Amendments .................................................................................................................. 132 
17.2. 
Regulatory Documentation .......................................................................................................... 133 
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 133 
17.2.2. 
Required Prestudy Documentation ........................................................................................... 133 
17.3. 
Subject Identification .................................................................................................................... 134 
17.4. 
Source Documentation ................................................................................................................. 134 
17.5. 
Case Report Form Completion .................................................................................................... 134 
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 135 
17.7. 
Record Retention ......................................................................................................................... 135 
17.8. 
Monitoring .................................................................................................................................... 136 
17.9. 
Study Completion/Termination ..................................................................................................... 137 
17.9.1. 
Study Completion ..................................................................................................................... 137 
17.9.2. 
Study Termination ..................................................................................................................... 137 
17.10. On-Site Audits .............................................................................................................................. 137 
17.11. Use of Information and Publication .............................................................................................. 138 
REFERENCES .......................................................................................................................................... 140 
 

GRN163L (imetelstat) 
 
 
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Status: Final, Date: 13 December 2022 
  
 
LIST OF ATTACHMENTS 
Attachment 1: 
World Health Organization (WHO) 2008 Classification (Used in Part 2) ................. 143 
Attachment 2: 
French-American-British (FAB) Cooperative Group Classification .......................... 144 
Attachment 3: 
International Prognostic Scoring System (IPSS) for Myelodysplastic 
Syndrome ................................................................................................................. 145 
Attachment 4: 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale ............ 146 
Attachment 5: 
International Working Group (IWG) Response Criteria 2006 ................................... 147 
Attachment 6: 
Functional Assessment of Cancer Therapy − Anemia-Related Effects (FACT-
An©) .......................................................................................................................... 149 
Attachment 7: 
EuroQol 5-Dimension Questionnaire (EQ-5D-5L) .................................................... 152 
Attachment 8:   
QUALMS Questionnaire ........................................................................................... 155 
Attachment 9: 
PGIC Questionnaire ................................................................................................. 157 
Attachment 10:   
Anticipated Events .................................................................................................... 158 
Attachment 11:   
Ventricular Repolarization (QTc) Substudy .............................................................. 159 
 
LIST OF IN-TEXT TABLES AND FIGURES  
TABLES 
Table 1: 
Time and Events Schedule for Part 1 (Open-label, Imetelstat Treatment) ............................... 46 
Table 2: 
Time and Events for Part 1 Pharmacokinetic / Immunogenicity Sampling 
(Amendment 2) ......................................................................................................................... 49 
Table 3: 
Time and Events Schedule for Part 2 Main Study (Double-blind, Randomized 2:1, 
Imetelstat or Placebo Treatment) ............................................................................................. 50 
Table 4:  
Time and Events for Part 2, Main Study Pharmacokinetic / Immunogenicity Sampling ........... 56 
Table 5 
Time and Events Schedule for Extension Phase ..................................................................... 57 
Table 6:   Dose Titration ............................................................................................................................ 87 
Table 7: 
Dose Modifications for Grade 3 Hematologic Toxicities ........................................................... 87 
Table 8: 
Dose Modifications for Grade 4 Hematologic Toxicities ........................................................... 88 
Table 9: 
Dose Modifications for Grade 3 and 4 Non-hematologic/Non-hepatic Toxicities ..................... 88 
Table 10: Dose Modifications for Liver Function Test Elevations and Hepatic Adverse Events .............. 88 
Table 11: Management of Infusion-Related Reactions ............................................................................ 91 
Table 12: Volume of Blood to be Collected from Each Subject - Part 1 and Part 2 Main Study .............. 94 
Table 13: Volume of Blood to be Collecfted from Each Subject – Extension Phase ................................ 95 
Table 14  Time and Events Schedule for Part 2 Ventricular Repolarization Substudya ........................... 163 
Table 15 
ECG and PK Assessments for Part 2 Ventricular Repolarization Substudy .......................... 166 
Table 16: Volume of Blood to be Collected from Each Subject in the Ventricular Repolarization 
Substudy ................................................................................................................................. 168 
 
FIGURES 
Figure 1:  Survival According to Intensity of Red Blood Cell Transfusion Requirement ........................... 63 
Figure 2: 
Schematic Overview of the Study: Part 1 and Main Study of Part 2 ........................................ 75 
Figure 3 
Overview of the Extension Phase Following Amendment 8 ..................................................... 76 
 
 
 

GRN163L (imetelstat) 
 
 
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PROTOCOL AMENDMENTS 
Protocol Version  
Issue Date 
Original Protocol 
29 July 2015 
Amendment 1 
31 May 2016 
Amendment 2 
31 Aug 2017 
Amendment 3 
18 April 2019 
Amendment 4 
23 March 2020 
Amendment 5 
29 June 2020 
Amendment USA-1 
03 September 2020 
Amendment 6 USA-1 
01 April 2021 
Amendment 7 USA-1 
02 September 2021 
Amendment 8 USA-1 
13 December 2022 
 
Amendments are listed beginning with the most recent amendment. 
Amendment 8 (13 December 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
 
The overall reason for the amendment:  
• 
To add an extension phase to allow continued treatment for those subjects who are benefitting from 
imetelstat, and to continue long-term monitoring of safety, overall survival, and disease progression for 
all subjects who remain in follow-up 
• 
Revise unblinding language and End of Study definition. 
• 
To revise exclusion criteria for the Ventricular Repolarization (QTc) substudy. 
• 
Additional changes were made to provide clarifications and other minor edits. 
Applicable Section(s) 
Description of Change(s) 
Synopsis (Objectives and Hypotheses), (Overview of 
Study Design), (Dosage and Administration), 
Section 3.1 (Overview of Study Design) 
• 
Added primary objective for the Extension 
Phase evaluating the long-term safety, OS, 
and disease progression, including progression 
to AML in transfusion dependent subjects 
with low or intermediate-1 risk MDS that is 
relapsed/refractory to ESA treatment receiving 
imetelstat. 
• 
Added Extension Phase information for drug 
administration, evaluations, timeframe, and 
analysis 
• 
Text was updated to the QTc substudy text to 
say 45 evaluable subjects will be enrolled and 
that subjects who are not evaluable may be 
replaced, indicating that > 45 subjects may be 
enrolled if subjects need to be replaced. 
• 
Revised End of Study definition to account for 
addition of Extension Phase 
• 
Added text that, with Protocol Amendment 8, 
subjects in Part 1 will complete participation 
in the study as Part 1 will have already met the 
duration of follow-up defined for the 
Extension Phase 

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Status: Final, Date: 13 December 2022 
  
Table 3 (Time and Events Schedule for Part 2, Main 
Study) 
The following updates were included: 
• 
Chemistry panel for LFT investigations (local 
laboratory): Comments edited to add text in 
alignment with Section 9.8. 
• 
Medical Resource Utilization: Comments 
edited to add text in alignment with 
Section 9.7 and updated to no longer require 
Long-term Survival Follow-up. 
Table 5 (Time and Events Schedule-Extension Phase) 
Added Table for Extension Phase Time and Events 
Schedule 
Synopsis (Overview of Study Design), Section 3.1 
(Overview of Study Design), Section 9.1.6 (Extension 
Phase), Section 11.12 (Independent Hepatic Expert 
Committee) 
Added text to clarify that Hepatic Expert Committee 
review of AEs and LFT abnormalities will continue in 
the Extension Phase. 
Section 2.1 (Objectives) 
Added primary objective for the Extension Phase 
evaluating the long-term safety, OS, and disease 
progression, including progression to AML in 
transfusion dependent subjects with low or 
intermediate-1 risk MDS that is relapsed/refractory to 
ESA treatment receiving imetelstat. 
Section 3.1 (Overview of Study Design-Schematic) 
Added Figure 3 depicting Extension Phase 
Section 3.2 (Study Design Rationale), Section 5.2 
(Blinding) 
• 
Clarified study blinding and added 
‘Unblinding’ to section title. 
• 
Added text to clarify that subjects, 
investigators, and study team members will be 
unblinded after primary efficacy analysis. 
Section 3.3 (Rationale for the Extension Phase) 
Section added to describe rationale for adding 
Extension Phase 
Synopsis (Dosage and Administration), Section 6 
(Dosage and Administration), Section 7 (Treatment 
Compliance) 
Text regarding guidelines for drug administration and 
dose modification in Extension Phase was added 
Section 7 (Treatment Compliance) 
Text that the guidelines for study drug administration 
and data collection continue in the Extension Phase 
Section 8.3 (Concomitant Medication)  
Text that recommendations for concomitant therapy 
continues in the Extension Phase 
Section 9.1.1 (Overview) 
• 
Text was added with Amendment 8 to add the 
Extension Phase 
• 
Blood volume table for Extension Phase 
added 
Section 9.1.6 (Extension Phase) 
Section added explaining Extension Phase procedures 
Table 3 (Time and Events for Part 2 Main Study); 
Section 9.7 (Medical Resource Utilization) 
Duration of collection of medical resource utilization 
data was updated to start from time of first dose and 
end at the End of Treatment visit. As the analysis will 
focus on the treatment emergent MRU, the duration of 
data collection has been changed from ending at start 
of subsequent therapy to end at EOT or 30 days after 
the last dose of study drug, whichever occurs later. 

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Section 9.8 (Safety Evaluations) 
Clarified that monthly laboratory assessments for 
Grade 1 and 2 elevations of LFTs only need to be 
collected until resolution to at least baseline or until the 
start of subsequent therapy, whichever comes first. 
Section 11 (Statistical Methods) 
Added text regarding final analysis for Extension Phase 
Section 11.4 (Efficacy Analyses) 
Text revised describing when the final analysis for the 
main study will be completed. 
Section 12.3.1 (All Adverse Events) 
Text added for continued collection of adverse event 
and pregnancy reporting in the Extension Phase 
Section 14.2 (Packaging) 
Text was added for drug packaging after the study is 
unblinded 
Section 15 (Study-Specific Materials) 
Bullet for Sample ICFs updated to include text that an 
updated ICF signature is needed for Extension Phase 
Section 17.3 (Subject Identification, Enrollment, and 
Screening Logs) 
Removed Enrollment and Screening Logs from section 
title to reflect the contents of the section 
Section 17.9.1 (Study Completion)  
Text revised to describe completion including 
Extension Phase 
Attachment 11 Ventricular Repolarization (QTc) 
substudy 
The following updates were included: 
• 
After consultation with an external expert 
cardiologist and discussion with the study 
steering committee, exclusion criteria #17 was 
updated to exclude subjects with a QTcF>490 
msec in the presence of a right bundle branch 
block or ventricular conduction delay (QRS 
>119 msec) in order to avoid unnecessary 
exclusion of elderly subjects with MDS who 
have modest QRS prolongation. In these 
subjects with modest QRS prolongation due to 
right bundle branch block or ventricular 
conduction delay, QTc variability is not 
increased and QTc remains a valid indicator 
of increased risk of Torsades de pointes 
arrhythmia (TdP). All complete left bundle 
branch blocks remain excluded. 
• 
Text was updated to say  
45 evaluable subjects will be enrolled and that 
subjects who are not evaluable may be 
replaced, indicating that > 45 subjects may be 
enrolled if subjects need to be replaced. 
• 
Text added that subjects in the QTc substudy 
may enter the Extension Phase after the 
primary analysis for the QTc substudy is 
reached and that subjects would be unblinded 
prior to entrance into Extension Phase. 
• 
Clarified the timepoint when the exposure-
response analysis (ie, the primary analysis) for 
the QTc substudy will take place. 
• 
Table 14: Chemistry panel for LFT 
investigations (local laboratory): comments 

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Status: Final, Date: 13 December 2022 
  
edited to add text in alignment with 
Section 9.8. 
• 
Removed “Note” at the bottom of the 
attachment. 
 
 

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Amendment 7 (02 September 2021) 
The overall reason for the amendment:  
• 
To modify the current Ventricular Repolarization (QTc) substudy in Part 2 to separate it from the main 
MDS3001 study. In Part 2, the main study will enroll 170 subjects, and the separate Ventricular 
Repolarization (QTc) substudy will enroll an additional 45 subjects.  The substudy will have broader 
eligibility criteria and fewer efficacy study evaluations in order to focus on the assessment of the 
relationship between the plasma concentrations of imetelstat and QTc interval changes. Data from this 
Ventricular Repolarization (QTc) substudy will not be included as part of the primary analysis of the 
efficacy and safety data from the main MDS3001 study.  
 
• 
Due to the extended recruitment period for the main study in Part 2, the primary efficacy and safety 
analysis from the main MDS3001 study is planned for 12 months (instead of 15 months) after the last 
subject is randomized in Part 2, as sufficient follow up information will be collected by that time to 
determine the benefit/risk of imetelstat in low risk, transfusion dependent MDS subjects. 
 
• 
Additional changes were made to provide clarifications on assessments, in particular for post-treatment 
assessments and for other minor clarifications 
Applicable Section(s) 
Description of Change(s) 
Synopsis (Overview of Study Design); Synopsis 
(Statistical Methods); Section 3.1 (Overview of Study 
Design) 
Updated the number of subjects in the study from 225 
to 270. Revised text to state that there is a main study 
of Part 2 and a Ventricular Repolarization substudy in 
Part 2.  Revisions were made to include details 
pertaining to the Ventricular Repolarization substudy.  
Time and Events Schedule (Part 1) (Table 1) 
The following updates were included: 
• 
Transfusion history and status, myeloid 
growth factor treatment: Updated to clarify 
that transfusion collection is needed until first 
transfusion in Posttreatment Follow-up. 
• 
BM aspirate, biopsy: Updated to no longer 
require in Posttreatment Follow-up 
• 
Response assessment: Updated to specify that 
assessment is only required at time of 
suspected PD in Posttreatment Follow-up. 
• 
INR (or PT) and aPTT:  Routine monitoring at 
Day 1 of each cycle was removed and 
guidance was provided to state that 
assessment is to be repeated during the study 
if subject has a Grade ≥3 bleeding event. 

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Status: Final, Date: 13 December 2022 
  
Time and Events Schedule (Part 2) (Table 3) 
The following key updates were included: 
• 
Table Title was updated to specify it is 
applicable to the Main Study of Part 2 
• 
12-lead ECG; Pharmacokinetic/ 
Immunogenicity samples: Comments edited to 
remove Ventricular Repolarization study 
(QTc) substudy language. 
• 
Transfusion history and status, myeloid 
growth factor treatment: Revised text to 
specify that transfusion and growth factor 
follow-up will continue until the first 
transfusion in post-treatment follow-up. 
• 
Text was added to clarify that the following 
assessments must be completed at each DE 
visit, specifically when the timing does not 
align with a Cycle Day 1 visit: Hematology 
(local laboratory), Hematology (central 
laboratory), Transfusion history and status, 
myeloid growth factor treatment. 
• 
BM aspirate, biopsy: Clarified text regarding 
requirements for BM assessment. Updated to 
no longer require in Posttreatment Follow-up 
• 
Response assessment: Updated to specify that 
assessment is only required at time of 
suspected PD in Posttreatment Follow-up. 
Included text to specify that CR, PR or mCR 
only to be assessed in subjects with >5% 
baseline bone marrow aspirate blasts.  
• 
INR (or PT) and aPTT (local laboratory): 
Modified assessment schedule because 
clinically significant changes to coagulation 
laboratory parameters in imetelstat treated 
subjects have not been found in Part 1 and in 
other recent studies.  Schedule modified to 
require assessments at Cycle 1 Day 1 and 
repeat during study if subject has a Grade ≥3 
bleeding event (instead of at each cycle). 
• 
BM aspirate for cytogenetics (central 
laboratory): Clarified text regarding 
requirements for cytogenetic assessments. 
• 
BM aspirate for RNA Seq or CyTOF (if 
feasible); Mutation Analysis:  The timing of 
the assessment was clarified to include RNA 
Seq or Cytof at the time of mCR was added. 
• 
Text was added to state that the following 
assessments in post-treatment follow-up will 
only be required until the start of subsequent 
therapy: MRU, FACT-An, EQ-5D-5L, 
QUALMS, PGIC 

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Status: Final, Date: 13 December 2022 
  
Table 4:  Time and Events for Part 2, Main Study 
Pharmacokinetic / Immunogenicity Sampling 
The following updates were included: 
• 
Table Title was updated to specify it is 
applicable to the Main Study of Part 2. 
• 
Footnote edited to remove Ventricular 
Repolarization study (QTc) substudy 
language. 
Section 2.1 (Objectives) 
For Secondary Objectives add clarifying text for the 
Qtc interval objective to state it will be reported 
separately from Part 2. 
Section 3.1 (Overview of Study Design);  
Figure 2: Schematic Overview of the Study 
Section 5.2 (Blinding) 
 
Updated text and figure to reflect modified Ventricular 
Repolarization substudy and to reflect clarification for 
required assessments as per Time and Events Table. 
Section 4.1 (Inclusion Criteria) 
The following updates were included: 
• 
Inclusion Criteria no. 8.1 removed the text 
“(ie, ≥1500/mm3)” 
• 
Inclusion Criteria no. 8.2 removed the text 
“(ie, ≥75,000/mm3)” 
Section 6.1.1. (Dose Modifications for Hematologic 
Toxicities) 
Updated to delete repetition and added clarifying text 
explaining that for Grade 3 or Grade 4 hematologic 
toxicities that are not considered related to imetelstat, 
the dose should still be held until recovery to ANC 1 x 
109/L and platelets 50 x 109/L. 
6.1.4. (Dose Modifications for COVID-19 Symptoms 
or Positivity (any Grade)) 
Modified COVID-19 language to include following 
local standard of care, local recommendations for 
quarantine, vaccination and/or potential dosing delays, 
and when it is acceptable to begin/resume study 
treatment after positive COVID-19 test or infection 
based on updated knowledge and guidance.  
Section 6.2 (Infusion-Related Reactions) 
Section 8.2 (Premedication) 
Added text to clarify premedication requirements, 
including guidance that specify premedications may 
be administered 1 hour prior to study drug infusion 
per local standard of care. 
Section 8.3 (Concomitant Medications) 
Added text that concomitant medication collection 
includes any vaccines including COVID-19 
vaccination.  
Modified text to explain that subjects receiving iron 
chelating agents should be assessed regularly for the 
need for dose reductions and/or continued use of iron 
chelating agents according to local prescribing 
information (eg, hold dose for ferritin levels 
<500 mcg/L) in order to reduce the potential risk of 
hepatic toxicity. 
Section 9 (Study Evaluation and all subsections) 
Updated to reflect modified Ventricular Repolarization 
substudy, clarification added for required assessments 

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as per Table of Events, and modification to the dose 
modifications for COVID-19. 
Sections 10.2 (Discontinuation of Study Treatment) 
Added and modified text to provide guidance regarding 
continuing treatment in exceptional cases when the 
subject is experiencing clinical benefit, and guidance to 
continue the subject in post-treatment follow-up if 
treatment is withdrawn. 
Section 10.3 (Withdrawal from the Study) 
Due to the modifications to the Ventricular 
Repolarization substudy, deleted the following text: A 
subject may withdraw from the Ventricular 
Repolarization substudy but continue participation in 
the main study (see Attachment 11). 
Section 11 (Statistical Methods) 
Added text to clarify that the analysis of ECG and 
concentration-QTc, as well as safety and limited 
efficacy in the Ventricular Repolarization substudy will 
be performed separately from the primary analysis of 
170 subjects in the main study of Part 2. 
Section 11.3 (Sample Size Determination) 
Number of subjects updated and approximate number 
of subjects for the Ventricular repolarization substudy 
in Part 2 was added.  
Section 11.4 (Efficacy Analyses) 
Clarified that the primary efficacy analysis is planned 
12 months (and no longer 15 months) after the last 
subject is randomized in Part 2. 
Section 11.13 (Independent Review Committee) 
Text added to clarify adjudicated investigator-assessed 
disease response and response for subjects with >5% 
baseline bone marrow aspirate blasts based on the 
central pathology reviewer’s assessment.  
Section 12.3.1 (All Adverse Events) 
Section 12.3.2 (Serious Adverse Events) 
Section 12.3.4 (Pregnancy) 
Clarified that the form for reporting adverse events, 
adverse events of interest, serious adverse events and 
pregnancies is called the “Serious Adverse 
Event/Adverse Event of Interest Form”. 
Section 16.1 (Study-Specific Design Considerations) 
• 
Updated the total blood volume to be collected 
from each subject from 629 mL to 569 mL for 
Part 2 due to the removal of the collection of 
coagulation factors at Day 1 of each cycle after 
Cycle 1. 
• 
Added in total blood volume to be collected 
from each subject from the modified 
Ventricular Repolarization substudy of Part 2 
as 361 mL. 

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Section 17.8 Monitoring 
Added that home healthcare visits may also occur if the 
subject is unable to be seen at the study site. 
Attachment 11 (Ventricular Repolarization (QTc) 
Substudy 
Attachment 11 was replaced with the modified 
Ventricular Repolarization substudy of Part 2 as agreed 
with the agency.  Key modifications include adjustments 
to the inclusion / exclusion criteria, time and events 
table, schedule of ECG and PK assessments, and 
unblinding activities. 
 
Amendment 6 USA-1 (01 April 2021) 
The overall reason for the amendment: To modify dose modification criteria for Liver Function Test 
Elevations and Hepatic Adverse Events to clarify the need to hold study drug, investigate the cause, and when to 
restart, stop, or dose reduce depending on the cause. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: To modify dose modification criteria for Liver Function Test Elevations and Hepatic Adverse Events 
6.1.3 Dose Modifications for Liver 
Function Test Elevations and Hepatic 
Adverse Event           
Renamed section “Dose Modifications for Liver Function Test 
Elevations and Hepatic Adverse Events” to clarify the items that fall 
under this category.    
Dose modifications were updated to clarify the criteria for holding 
study drug, and the actions that should be taken in these events.  
Modifications were made to Table 9 that decrease the number of 
times subjects are permitted to dose reduce due to Grade 3 or 4 ALT, 
AST, or bilirubin elevations, and Grade 3 or 4 hepatic adverse events 
prior to discontinuing treatment.  Added modification and stopping 
criteria for Grade 2 ALT or AST with concomitant Grade 2 bilirubin 
elevations.  Provided guidance on investigations into possible causes 
of liver function test elevations and hepatic adverse events and 
subsequent monitoring.   
 
Rationale: To add ALT or AST >3.0 x ULN WITH Bilirubin >2.0 x ULN as adverse event of interest  
9.8 Safety Evaluations 
Added ALT or AST >3.0 x ULN WITH Bilirubin >2.0 x ULN as 
adverse event of interest and added abbreviation (AEI).  Updated 
language for liver function test monitoring to align with new 
language in section 6.1.3. 
12.3.3.1 Elevated Liver Function Tests 
(LFTs)  
Added ALT or AST >3.0 x ULN WITH Bilirubin >2.0 x ULN as 
adverse event of interest 
Rationale: Updated section to recommend monitoring of concomitant medications while on study.  
8.3. 
Concomitant Medications 
Added language to adjust concomitant medications over the course 
of the study based on clinical status.  

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Amendment USA-1 (03 September 2020) 
The overall reason for the amendment: The country-specific amendment is based on feedback from the US 
Food and Drug Administration (FDA). 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Biochemical laboratory test values of bilirubin were clarified at the request of the FDA. 
4.1 Inclusion Criteria (Criterion 9.4.1) 
Added an upper limit for direct bilirubin for patients with Gilbert’s 
syndrome, ineffective erythropoiesis due to MDS, or hemolysis due 
to RBC transfusion. 
Rationale: Actions to be taken for Grade 3 or 4 LFT elevations and hepatic events were clarified at the request of 
the FDA. 
6.1.3 Dose Modifications for Hepatic 
Toxicities 
Added additional language to the dose modification language for 
hepatic toxicity to allow continuing treatment if another cause of 
transaminase or bilirubin elevation is clearly identified. 
 
Amendment 5 (29 June 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
 
The overall reason for the amendment: To clarify eligibility criteria/assessments and study procedures 
pertaining to Part 2 of the study. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: To clarify eligibility criteria/assessments 
4.1 Inclusion Criteria (Criterion 5.2.1) 
Added text to Inclusion Criteria no. 5 to further clarify the definition 
of MDS relapsed to ESA treatment (ie. to clarify that subjects must 
receive at least 8 weeks of ESA treatment at the protocol specified 
dose before meeting the definition of relapsed). 
4.1 Inclusion Criteria; 
9.8.1 Clinical Laboratory Tests 
• 
Added text to Inclusion Criteria no. 9.4 to allow bilirubin 
(total/direct) outside the specified range due to Gilbert’s 
syndrome, ineffective erythropoiesis due to MDS or in case 
of hemolysis due to RBC transfusions. 
• 
Added text to the serum chemistry panel to allow for 
additional testing to demonstrate eligibility if a subject with 
elevated bilirubin levels meets the revised criterion. 

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Applicable Section(s) 
Description of Change(s) 
4.2 Exclusion Criteria 
• 
Added text to Exclusion Criteria no. 2 to clarify that 
subjects who received an experimental or investigational 
drug within 30 days prior to Randomization will be 
excluded from participation. 
• 
Added text to Exclusion Criteria no. 5.2 to add thalidomide 
and thalidomide analogues to the list of prohibited prior 
treatment.  
• 
Added text to Exclusion Criteria no. 5.3 to specify receiving 
anti-MDS therapy within 4 weeks prior to Randomization 
as an exclusion criterion. 
Rationale: To clarify the study procedures 
Time and Events Schedule for Part 2 
(Table 3) 
• 
Informed consent: Added text regarding further clarification 
of screening procedures. 
• 
Hematology (local laboratory); hematology (central 
laboratory): Added text to clarify that tests should also be 
conducted pre-transfusion to ensure availability of pre-
transfusion Hb and platelet count data. 
• 
BM aspirate, biopsy: 
- 
Central cytogenetics results are required for eligibility 
confirmation, aligned with Inclusion Criteria no. 2.3. 
Clarified that local cytogenetic analysis may be 
performed per local standard of care. 
- 
Added text to clarify that a confirmatory BM should be 
performed 4 to 8 weeks after investigator-assessed CR, 
PR, or mCR, if clinically feasible. 
- 
Added cross-references to Section 9.3.1.3, 
Section 9.1.4, and Section 11.13. 
- 
Bone marrow assessments at the time of suspected 
HI-E (Hb) were removed. This is no longer required for 
study purposes and is not required for the confirmation 
of HI-E (HI-E evaluation is based upon Hb results and 
transfusion requirements per modified IWG 2006). 
Bone marrow will continue to be assessed at all other 
study time points as planned. Section 9.1.4 was revised 
accordingly. 
• 
Response assessment; hematology (central laboratory): 
Adjusted text to clarify that central hematology results will 
be used for calculation of hematologic improvement-
erythroid (HI-E) and local laboratory results should be used 
for investigator-assessed response evaluations. 
• 
Survival status and subsequent therapy: Adjusted text to 
clarify the time point of follow-up as at least every 12 to 16 
weeks; more frequently if needed. 
• 
Serum ferritin, transferrin saturation (local laboratory): 
Added text to clarify that total iron binding capacity and 
serum iron (Fe) may be performed to calculate transferrin 
saturation if transferrin saturation is not available at the site. 

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Applicable Section(s) 
Description of Change(s) 
• 
Hepatitis serologies: Added text to clarify that hepatitis 
testing is to establish a baseline, but subjects with positive 
results will not be excluded from study treatment unless the 
subject meets Exclusion Criteria no. 12 (active systemic 
hepatitis infection requiring treatment) (Section 4.2). The 
change here is to minimize the need for retesting if the 
screening period lasts >28 days (see Section 9.1.3 about the 
screening period). 
• 
Pharmacokinetic/Immunogenicity samples: Added cross-
references to Table 4 and Attachment 11 to clarify sample 
collection time points. 
• 
TA, TL and hTERT: Moved the row of information 
previously listed under Bone Marrow, to reflect that blood 
samples will be assessed. 
• 
Bone marrow (BM aspirate for cytogenetics [central 
laboratory]): Added text to align the screening cytogenetics 
timeframe with the remaining screening bone marrow 
assessments. 
Synopsis (Efficacy Evaluations); 
3.1 Overview of Study Design; 
9.1.4 Treatment Phase; 
9.3.1.3 Bone Marrow Assessment  
Adjusted and added text on BM assessments in alignment with other 
protocol sections. 
Synopsis (Pharmacokinetic and 
Immunogenicity Evaluations); 
Table 4 Time and Events for Part 2 
Pharmacokinetic/Immunogenicity 
Sampling; 
3.2 Study Design Rationale (Endpoints 
[Pharmacokinetic and Immunogenicity 
Evaluations]);  
9.4.1 Sample Collection and Handling; 
9.4.3 Pharmacokinetic Parameters 
Adjusted and added text on PK sample collection and PK evaluations 
in alignment with other protocol sections. 
6 Dosage and Administration (Study 
Drug [Imetelstat or Placebo]) 
Added text to clarify that site does not necessarily need to wait until 
the weight changes by 10% to recalculate the total dose. The total 
dose may be recalculated more frequently (eg, at each study visit) 
depending on local practice. 
6.1.3 Dose Modifications for Hepatic 
Toxicities 
Added text to allow for events that are not related to study drug and 
the underlying origin is known, and the subject may benefit from 
treatment with study drug. 
8.2 Premedication 
Added text to clarify the administration time of premedication. 
8.3 Concomitant Medications 
Added text to further clarify the allowed supportive care and 
medications prohibited during the study. 
9.1.2 Blood Volume (Table 11) 
Adjusted blood volumes in alignment with Table 3 (Time and Events 
Schedule). 

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Applicable Section(s) 
Description of Change(s) 
9.1.3 Screening Phase and Predose 
• 
Added text to clarify that the central MDS diagnosis 
confirmation will primarily be based upon the central 
pathology review of the bone marrow sample taken within 
12 weeks of Randomization. Supportive historic bone 
marrow samples and lab data (ie. hematology) are often 
useful to help support this diagnosis. 
• 
Added text on best practice if transfusion treatment and 
collection of screening labs coincide in the same subject. 
• 
Added text to clarify procedures to be followed in the event 
the screening period extends beyond 28 days (for example, 
if time is required for results and/or retesting). 
• 
Adjusted text in line with other sections of the protocol. 
9.1.4 Treatment Phase 
• 
Added text to clarify that the modified IWG 2006 will be 
used to assess subject response. 
• 
Added text to clarify that all disease assessments should be 
repeated relative to the time of initial assessment of CR and 
PR in order to confirm a CR or PR, if feasible, per modified 
IWG 2006 criteria. 
• 
Added text to clarify the purpose and feasibility of 
confirmatory bone marrow assessments to define the 
response. 
9.1.5 Posttreatment Phase (Follow-Up) 
Adjusted text to clarify the time period for the collection of 
transfusion data. 
9.3.1.2 Hemoglobin Assessment 
• 
Adjusted text to clarify the definitions of pretreatment Hb 
and HI-E response. 
• 
Adjusted and added text to clarify assessment and 
presentation of hematology data. 
• 
Adjusted text in line with other sections of the protocol. 
9.5 Biomarkers 
Adjusted text to clarify the collection of biomarker assessments. 
9.8.1 Clinical Laboratory Tests; 
Table 3 (Time and Events Schedule for 
Part 2); 
Table 11 (Volume of Blood to be 
Collected from Each Subject) 
• 
Added text to clarify if a site’s local laboratory does not 
assess the laboratory tests noted in Section 9.8.1, other 
laboratory tests may be performed to calculate the values to 
be assessed, for example: 
- 
Added total iron binding capacity and serum iron to 
calculate transferrin saturation if transferrin saturation 
is not available at the site. 
• 
Added urea to the serum chemistry panel as an alternative 
assessment if a site is unable to assess blood urea nitrogen. 
• 
Added text to clarify that hepatitis serologies may be 
performed by local or central laboratory. 

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Applicable Section(s) 
Description of Change(s) 
14.5 Drug Accountability 
Adjusted text to clarify that study drug administration, return of 
unused study drug, and study drug destruction on-site must be 
documented in the IWRS. 
15 Study-specific Materials 
Adjusted text to reflect that investigational product preparation 
instructions are presented in the Site Investigational Product Manual. 
17.3 Subject Identification, Enrollment, 
and Screening Logs 
Adjusted text in alignment with data protection requirements. 
Rationale: To clarify the secondary objectives and endpoints 
Synopsis (Objectives, Endpoints, 
Statistical Methods) 
2.1 Objectives (Secondary Objectives) 
3.2 Study Design Rationale (Endpoints) 
9.2.2 Secondary Endpoints 
11.4 Efficacy Analysis 
• 
Added text to clarify that mCR is being assessed as part of 
the secondary endpoints for disease response. 
• 
Updated Section 11.4 in alignment with objectives and 
endpoints. 
9.2.2 Secondary Endpoints 
Added text to clarify the time to 8-week RBC TI and the duration of 
the RBC TI. 
Rationale: To clarify adjudication of investigator-assessed disease response assessments 
11.13 Independent Review Committee 
Added text to establish an Independent Review Committee (IRC) to 
adjudicate investigator-assessed disease response (CR, PR, mCR, or 
cytogenetic response) based on the modified IWG 2006 criteria. 
Responsibilities, authorities and procedures will be detailed in a 
separate charter. 
Table 3 (Time and Events Schedule for 
Part 2 ); 
9.1.4 Treatment Phase 
9.3.1.2 Hemoglobin Assessment 
16.1 Ethical Aspects, Study-specific 
Design Considerations 
Added text in alignment with and/or cross-references to 
Section 11.13. 
Rationale: To clarify adverse event reporting 
12.1.1 Adverse Event Definitions and 
Classifications (Unlisted [Unexpected] 
Adverse Event/Reference Safety 
Information 
Added text to clarify responsibility for determination of 
expectedness/listedness of adverse events. 
12.2 Special Reporting Situations 
Added text to clarify reporting of special reporting situations that 
meet the criteria of a SAE.  
12.3.2 Serious Adverse Events 
Adjusted text in alignment of the current procedure for reporting of 
SAEs. 
Rationale: To provide clarifications on the Ventricular Repolarization substudy 

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Applicable Section(s) 
Description of Change(s) 
Attachment 11 (Ventricular 
Repolarization Substudy at Selected Sites 
[Study Design and Subject Population]) 
Adjusted text to clarify the expected numbers of subjects 
(approximately 30 and 15 subjects in the imetelstat and placebo 
groups, respectively) to account for the fact that the study is blinded. 
Rationale: To further clarify considerations regarding the COVID-19 pandemic 
1.3 Benefit-risk Assessment: COVID-19 
Added section to describe risk/benefit for COVID-19 instruction that 
was included as part of Protocol Amendment 4. 
6.1.4 Dose Modifications for COVID-19 
Symptoms or Positivity (any Grade) 
Added text to clarify recording of cases of confirmed, suspected, or 
exposed COVID-19 infection. 
17.8 Monitoring 
Added text to allow for remote monitoring. 
Rationale: To provide clarification of future research 
16.2.5 Long-term Retention of Samples 
and Use of Data for Additional Future 
Research 
Added text to outline the use of samples and data for future research. 
Rationale: Administrative changes and minor corrections were made 
Attachment 5 International Working 
Group (IWG) Response Criteria 2006 
Corrected wording under Erythroid response in alignment with 
protocol text. 
Attachment 10 Anticipated Events 
Wording updated in alignment with sponsor regulatory reporting 
procedures. 
Throughout the protocol 
• 
Changed “QTc” substudy to “Ventricular Repolarization” 
substudy for consistency. 
• 
Minor grammatical, formatting, or spelling changes were 
made. In addition, minor rewording or clarifications were 
added to improve the understanding of the content of the 
protocol. 
 
Amendment 4 (23 March 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, and healthy authority guidance 
on the COVID-19 pandemic. 
 
The overall reasons for the amendment: Amendment 4 is issued in consideration of the COVID-19 pandemic 
and includes guidelines for the management of subjects who have confirmed COVID-19 infection, have clinical 
signs and symptoms consistent with COVID-19 infection, or have been exposed to a person with confirmed 
COVID-19 infection. 
 

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Applicable Section(s) 
Description of Change(s) 
Rationale: To include guidance for subjects with symptoms or confirmed cases COVID-19 infection 
6.1.4 Dose Modifications for COVID-19 
symptoms or positivity (any Grade) 
Added subsection to the protocol to include dose modification 
guidance regarding COVID-19 for subjects on treatment. 
Rationale: To clarify evaluation at screening 
9.1.3 Screening Phase and Predose 
Added text to elucidate COVID-19 screening procedures and 
enrollment decisions as they pertain to COVID-19. 
Rationale: To clarify evaluation of physical examination 
9.8.4 Physical Examination; 
Table 3 Time and Events Schedule for 
Part 2 
Added text to elucidate monitoring, follow-up and reporting of 
clinical signs and symptoms of COVID-19 infection. 
Cross-reference to Section 9.8.4 was added in Table 3. 
Rationale: Administrative change 
Throughout the protocol 
Following recent move in location, the sponsor’s contact details 
were updated to Geron Corporation, 919 E. Hillsdale Blvd., Suite 
250, Foster City, CA 94404. 
 
Amendment 3 (18 April 2019) 
This amendment is considered to be substantial based on the on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
 
The overall reasons for the amendment: To update sponsorship change to Geron Corporation, to include 
efficacy and safety data from Part 1 of the study as a basis for starting Part 2 of the study, and to clarify study 
procedures and conduct. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: To reflect change of sponsorship as of protocol amendment 3 
Cover page, Synopsis, 6. Dosage and 
Administration, Investigator Agreement  
Change of sponsor name from Janssen Research & Development to 
Geron Corporation, including change of product designation. 
Rationale: To clarify the definitions of study entry for Part 1 and Part 2, Treatment Phase, and End of Study 
Throughout the protocol 
Clarified that study entry referred to Cycle 1 Day 1 for Part 1 (C1D1) 
and Randomization for Part 2. 
Clarified that the Treatment Phase will extend from C1D1 (Part 1) or 
Randomization (Part 2) until disease progression, or unacceptable 
toxicity, or withdrawal of consent (ie, deleted the mention of lack of 
response). 
Clarified that the End of Study is defined as 24 months after 
randomization of the last subject in Part 2 or anytime the sponsor 
terminates the study, whichever comes first. 

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Applicable Section(s) 
Description of Change(s) 
Rationale: To provide Part 1 data of the current study that support continuing with Part 2 
Synopsis (Overview of Study Design, 
Statistical Methods), 1.2. Overall 
Rationale for the Study, 3.1. Overview 
of Study Design, 3.2. Study Design 
Rationale, 11.3. Sample Size 
Determination 
Added information on the actual number of subjects evaluated in the 
completed Part 1 and clarified that data from Part 1 support 
continuing with Part 2. 
1.1.5. Clinical Experience with 
Imetelstat in Myeloproliferative 
Neoplasms and MDS  
Added a statement to mention that a comprehensive summary of the 
clinical data is provided in the Investigator’s Brochure (Edition 14). 
Added a summary of results from Part 1. 
Rationale: To clarify the study objectives and study endpoints 
Synopsis (Secondary Objectives, 
Exploratory Objectives, Endpoints), 
2.1. Objectives, 9.2.2. Secondary 
Endpoints, 9.2.3. Exploratory Endpoints, 
9.5. Biomarkers 
Clarified that the following secondary objectives (and associated 
endpoints) are only applicable to Part 2: 
• 
To assess the rate and amount of supportive care, including 
transfusion and myeloid growth factors. 
• 
To assess the effect of treatment on medical resource 
utilization. 
• 
To assess the effect of imetelstat on corrected QT (QTc) 
interval in a subset of subjects). 
Clarified that the following exploratory objective (and associated 
endpoint) is only applicable to Part 1:  
• 
To explore the effects of imetelstat on immune profiles 
through immunophenotyping. 
Clarified that TL samples are only collected at baseline. 
Rationale: To clarify the study procedures 
Time and Events Schedule (Table 3) 
• 
Added a row to clarify when the randomization is to occur. 
• 
Clarified that for subjects who stop treatment before 15 
months (instead of 12 months originally), the collection of 
transfusion data must be continued for a minimum of 15 
months (instead of 12 months originally) from 
Randomization. Added the mention that pre-transfusion Hb 
must be documented. 
• 
Clarified that for hematology performed at a local 
laboratory, hematology panel includes hemoglobin, platelet 
count, white blood cell count, ANC) and added that manual 
absolute peripheral blast count should be done prior to 
randomization and on D1 of each cycle only). 
• 
Added a row with hematology assessments performed at the 
central laboratory (with same timing of assessments as those 
performed in a local laboratory) and clarified that central 
laboratory will be used for HI-E assessments Hematology 
panel assessed in central laboratory will be hemoglobin, 
platelet count, white blood cell count and ANC. Manual 

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Applicable Section(s) 
Description of Change(s) 
absolute peripheral blast count for the central lab should be 
done prior to randomization and on C1 of each cycle only. 
• 
Clarified the procedure for the bone marrow aspirate and 
biopsy and the response assessment (central review). 
• 
Clarified that all other clinical laboratory assessments 
(chemistry, chemistry panel for LFT investigations, INR and 
aPTT, serum EPO level, serum ferritin, transferrin 
saturation, and B12/folic acid/reticulocytes) will be done at a 
local laboratory. 
• 
Added that serum or urine pregnancy test will be done on 
Day 1 of every cycle and at end of study. 
• 
Added that for the Ventricular Repolarization substudy, 
blood for PK samples will be collected on C1D1 prior to 
study drug administration through 24 hours after start of 
infusion. 
• 
Modified the timing of assessment for TA, TL, and hTERT: 
instead of having them assessed at CID1 predose only, TA 
and hTERT will be done at C1D1 predose, 24h post-dose, 
C1D8, C2D1, C2D8; TL will be done at baseline only. 
• 
Clarified the procedure for the BM aspirate for cytogenetics 
(central laboratory): Baseline aspirate should be obtained 
during screening and must be submitted to the central 
laboratory to confirm eligibility. Aspirate is required for all 
subjects with baseline abnormalities every 24 weeks after 
C1D1 at the time of suspected HI-E (Hb), PR, or CR and 
every 24 weeks thereafter up to and including suspected PD. 
Sample should be obtained at the time of suspected PD for 
all subjects irrespective of baseline status.  
• 
Modified the timing of assessment for mutation analysis to 
every 12 weeks after C1D1, at time of suspected response 
HI-E (Hb), PR or CR and at time of PD (instead of “at time 
of suspected HI-E [Hb], PR, CR, and PD”). 
• 
Deleted the assessment of immunophenotyping as it is no 
longer applicable to Part 2. 
Time and Events Schedule (Table 3), 
Figure 2, 9.1.4. Treatment Phase 
Clarified the time frame of the EOT visit (ie, 30 days ±3 days after 
the last dose). 
3.1. Overview of Study Design 
Added that subjects in Part 1 are not eligible to enroll in Part 2. 
Clarified that robust transfusion data will be collected for a minimum 
of 15 months from Randomization in Part 2 (instead of 12 months). 
Added that, for Part 2, central laboratory will be used for assessment 
of the HI-E response.  
3.1. Overview of Study Design, 
Figure 2, 6. Dosage and Administration  
Deleted statement mentioning that, for Part 1 and Part 2, if after 6 
months of treatment, a subject has not achieved hematologic 

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Applicable Section(s) 
Description of Change(s) 
improvement-erythroid (HI-E) or RBC TI for ≥8 weeks, further 
continuation of treatment should be discussed with the sponsor. 
3.2. Study Design Rationale 
(Pharmacokinetic and Immunogenicity 
Evaluations) 
Added that anti-drug antibodies will be assessed during the study.  
 
4.1. Inclusion Criteria (no. 2), 9.1.3 
Screening Phase and Predose 
Deleted that a copy of the local pathology report may suffice for 
central pathology review prior to randomization, with baseline bone 
marrow samples submitted as soon as possible during screening or 
after randomization. Replaced with a statement that central laboratory 
review is required to confirm diagnosis of MDS prior to 
randomization in Part 2. 
4.1. Inclusion Criteria (no. 10.2); 12.1.1. 
Adverse Events Definitions and 
Classifications; 12.2. Special Reporting 
Situations  
Added that women of childbearing potential must agree to be tested 
on Day 1 of every cycle and at end of study (30 days post last dose) 
as part of the inclusion criteria. 
Added that female subjects who become pregnant during the course 
of the study up to 30 day after the last dose or a female partner of a 
male subject who becomes pregnant up to 90 days of the last dose for 
the male subject. constitutes a medically important event to be 
reported as a serious adverse event. 
6. Dosage and Administration 
Deleted the statement that the sponsor may permit an extension to the 
hold of study drug to allow for further subject assessment with the 
possibility for restarting treatment. 
6.1.1, Dose modifications for 
Hematologic Toxicities, 6.1.2. Dose 
Modifications for Non-hematologic 
Toxicities, Excluding Hepatic 
Toxicities, 6.1.3. Dose Modifications for 
Hepatic Toxicities 
Clarified that actions should be taken for all Grade 3 or 4 events 
regardless of the relationship to study drug (ie, deleted the part 
mentioning “drug-related”) 
9.1.2. Blood Volume 
Clarified that immunophenotyping is only applicable to Part 1. 
Added an additional 5 mL blood sample for the central laboratory 
hematology (Part 2). 
Clarified that additional serum or urine pregnancy tests may be 
performed at the local laboratory. 
9.1.3 Screening Phase and Predose 
Clarified that the bone marrow aspirate or biopsy at screening must 
be of adequate quality for central review. 
9.1.5. Posttreatment Phase 
Deleted that follow up samples of bone marrow aspirate/biopsy must 
be submitted for central review at the time of suspected response, 
including HI-E (Hb), PR, CR, and at the time of suspected PD; 
however, local assessment will be used for treatment decisions. 
Changed the time period for the collection of transfusion data 
regardless of study drug discontinuation, progressive disease, or 
subsequent therapy (from a minimum of 12months to a minimum of 
15 months). 

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Applicable Section(s) 
Description of Change(s) 
9.6. Patient Reported Outcomes 
Clarified the process to be followed when questionnaires are 
conducted over a telephone call during the posttreatment period. 
9.7. Medical Resource Utilization 
Added that frequency of hospitalization will also be collected. 
Rationale: To clarify the use of central laboratory  
9.3 Efficacy, 9.3.1.2 Hemoglobin 
assessment, 9.3.1.3 Bone Marrow 
Assessment 
Added that, in Part 2, in addition to the local laboratory, a central 
laboratory will be used for all planned Hb assessments. Treatment 
decision may be based on the local laboratory; however, efficacy 
assessments will be based on the central laboratory. 
Deleted that local disease evaluations will be used for treatment 
decisions and clarified that bone marrow aspirate and biopsy must be 
available for submission for central pathology review prior to the 
Randomization in Part 2 to confirm diagnosis and eligibility for 
study. 
Deleted that a copy of the local pathology report (in English) must be 
submitted for diagnosis confirmation. 
9.8.1. Clinical Laboratory Tests 
Added the following text: “In addition, central laboratory will be 
utilized for hematology panel (hemoglobin, platelet count, white 
blood cell count, ANC and manual absolute peripheral blast count) 
and will be used for HI-E assessment. Local hematology panel may 
be used for treatment decision.” 
Added the following text: “In addition, the following hematology 
tests will be performed at the central laboratory: hemoglobin, platelet 
count, white blood cell count and ANC; and manual absolute 
peripheral blast count.” 
Rationale: To clarify the statistical section 
11.4. Efficacy Analyses 
Clarified that the primary efficacy analysis is planned 15 months (and 
no longer 12 months) after the last subject is randomized in Part 2. 
11.5. Pharmacokinetic Analyses 
Added that detailed pharmacokinetic analysis will be provided in a 
specific PK-statistical analysis plan. 
11.9. Medical Resource Utilization 
Analyses 
Clarified that this subsection is applicable to Part 2 only. 
Rationale: To align with new sponsor policies 
13. Product Quality Complaint Handling 
Deleted the statement mentioning that the sponsor has established 
procedures in conformity with regulatory requirements worldwide to 
ensure appropriate reporting of product quality complaint 
information; all studies conducted by the sponsor or its affiliates will 
be conducted in accordance with those procedures. 
16.2.4. Privacy of Personal Data 
Clarified that personal data collected during the study will be 
processed in compliance with the patient information and informed 
consent form and agreements with the sponsor. 

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Applicable Section(s) 
Description of Change(s) 
Clarified that the transfer of data to other entities or other countries 
will be done in compliance with applicable data privacy laws and 
regulations. 
Clarified how subjects can submit data privacy requests. 
17.11. Use of Information and 
Publication 
Deleted the statement mentioning that recruitment performance or 
specific expertise related to the nature and key assessment parameters 
of the study will be used to determine a coordinating investigator. 
Modified the duration during which investigators must withhold 
publications from 60 days to 90 days. 
Added that if an investigator wishes to publish information from the 
study, the confidentiality of sponsor’s information must be respected. 
Modified the duration during which the investigators must not submit 
for publication data derived from the individual study site from 
within 12 months to within 18 months of the availability of the final 
data. 
Rationale: To provide clarifications on the Ventricular Repolarization substudy 
Synopsis (Pharmacokinetic and 
Immunogenicity Evaluations), Time and 
Events Schedule (Table 3) 
Clarified that in Part 2, for subjects participating in the Ventricular 
Repolarization substudy, serial blood samples for pharmacokinetic 
evaluation will be collected at C1D1 at prespecified time points over 
24 hours, prior to and after start of infusion. 
3.2. Study Design Rationale 
(Pharmacokinetic and Immunogenicity 
Evaluations) 
Added that pharmacokinetic sampling will be performed in 30 
subjects in the Ventricular Repolarization substudy (Part 2). 
16.1. Study-Specific Design 
Considerations 
Added that subjects participating in the Ventricular Repolarization 
substudy are expected to have an additional 8 mL of blood draws due 
to increased intensity of sampling. 
Attachment 11 (Ventricular 
Repolarization Substudy at Selected 
Sites) 
Clarifications added on the approximate number of subjects that will 
be enrolled in the Ventricular Repolarization substudy.  
Added that efficacy, pharmacodynamic, biomarker and 
immunogenicity evaluations will be assessed in the main study and 
that cardiac-related adverse events will be reviewed by the Data 
Monitoring Committee on an ongoing basis. 
Clarified the activities specific to the Ventricular Repolarization 
substudy. 
Rationale: To add new references supported adding data from Part 1 
References 
Added references from Fenaux et al (2018), Steensma (abstract 
2018), and Williams (2017). 
Rationale: To provide a more recent WHO classification 
Attachment 1 (World Health 
Organization (WHO) 2008 
Classification) 
To update with 2008 classification. 

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Applicable Section(s) 
Description of Change(s) 
Rationale: Minor corrections were made 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made. In 
addition, minor rewording or clarifications were added to improve the 
understanding of the content of the protocol. 
 
Amendment 2 (31 Aug 2017) 
This amendment was considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: This amendment revised some aspects of study design and conduct 
following an analysis of Part 1, Week-24 data.  
 
Applicable Section(s) 
Description of Change(s) 
Rationale: In Part 1, no subject who received prior treatment with lenalidomide or a hypomethylating agent 
achieved transfusion independence, and a trend toward higher incidence of cytopenia was observed for these 
subjects.  
Synopsis (Overview of Study Design); 
3.1. Overview of Study Design; 
3.2. Study Design Rationale; 
5.1. Treatment Allocation 
Prior lenalidomide use was removed as a stratification factor for Part 
2.  
Synopsis (Subject Population) 
 
Clarification was added that beginning with this amendment, 
enrolled subjects will have non-del(5q) MDS and no prior exposure 
to either a hypomethylating agent or lenalidomide. 
3.2. Study Design Rationale 
 
Part 1 findings for 8-week TI were described for subjects with prior 
exposure to lenalidomide or a hypomethylating agent and for 
subjects with non-del(5q) MDS without prior exposure to either a 
hypomethylating agent or lenalidomide.  
4.2. Exclusion Criteria (no. 5) 
Exclusion criterion 5 was separated into 3 parts to exclude prior use 
of hypomethylating agents (Part 5.1), lenalidomide (Part 5.2), and to 
specify the minimum allowable interval following prior use of an 
ESA or any chemotherapy, immunomodulatory, or 
immunosuppressive therapy (Part 5.3). 
4.1. Inclusion Criteria (no. 13) 
 
Inclusion Criterion 13 was deleted. Previously, subjects with the 
del(5q) karyotype are eligible if they failed treatment with 
lenalidomide. 
4.2. Exclusion Criteria (no. 17) 
Inclusion Criterion 17 was added. Subjects with the del(5q) 
karyotype are excluded from the study. 
Rationale: Review of safety and efficacy data from the initial Part 1 cohort of 32 subjects showed better efficacy 
among subjects with non-del(5q) MDS without prior exposure to either a hypomethylating agent or lenalidomide. 
Part 1 of the study is expanded to include additional subjects with non-del(5q) MDS who have not received prior 
treatment with lenalidomide or a hypomethylating agent to further confirm the 7.5 mg/kg dose of imetelstat in 
this patient population. 
Synopsis (Overview of Study Design, 
Statistical Methods);  
3.1. Overview of Study Design;  
Enrollment in Part 1 will be expanded to include approximately 22 
additional subjects in the target population meeting the revised entry 
criteria. Total enrollment in Part 1 (initial cohort plus expanded 

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Description of Change(s) 
Figure 2 (Schematic Overview of the 
Study); 
11.3. Sample Size Determination 
 
cohort) will increase from up to 30 subjects to approximately 55 
subjects. Total study enrollment will increase from approximately 
200 subjects to approximately 225 subjects. If data from Part 1 for 
the target population continue to be supportive of a satisfactory 
benefit/risk profile, Part 2 of the study will be initiated. 
Rationale: In Part 1, dose escalation from 7.5 mg/kg to 9.4 mg/kg was not associated with improved transfusion 
independence. 
Synopsis (Dosage and Administration); 
Time and Events Table 1 and Table 3 
(Hematology); 
3.1. Overview of Study Design; 
Figure 2 (Schematic Overview of the 
Study);  
6. Dosage and Administration; 
6.1. Dose Modifications; 
9.3.1.2. Hemoglobin Assessment 
Dose escalation to 9.4 mg/kg and dose re-escalation following dose 
reduction is not permitted in Part 2. Text associated with dose 
escalation and re-escalation was deleted.  
Synopsis (Dosage and Administration); 
3.1. Overview of Study Design; 
Figure 2 (Schematic Overview of the 
Study);  
6. Dosage and Administration; 
6.1. Dose Modifications 
Clarification added that subjects whose dose was previously 
escalated (before Amendment 2) may continue at the 9.4 mg/kg 
dose. 
Rationale: Investigation of the potential effects of imetelstat on ventricular repolarization was added with a 
Ventricular Repolarization substudy to be performed in Part 2.   
Synopsis (Overview of Study Design); 
Time and Events Table 3 (12-lead ECG); 
3.1. Overview of Study Design; 
Figure 2 (Schematic Overview of the 
Study); 
4. Subject Population; 
9.1.2. Blood Volume; 
9.8.2. Electrocardiogram 
11.10. Safety Analyses 
(Electrocardiogram); 
Attachment 11 
Newly added Attachment 11 describes the Ventricular 
Repolarization substudy that will be performed at selected sites to 
characterize the effects of imetelstat treatment on QTc interval in 
Part 2.  
10.3. Withdrawal from the Study 
Text was added to indicate that subjects may withdraw from the 
Ventricular Repolarization substudy but continue participation in the 
main study. 
Rationale: In Part 1, the median prior RBC transfusion burden was approximately 6 units. Revising the 
stratification criteria is expected to allow the 2 treatment groups to be balanced for this variable. 
Synopsis (Overview of Study Design); 
3.1. Overview of Study Design; 
3.2. Study Design Rationale; 
5.1. Treatment Allocation 
The stratification factor prior RBC transfusion burden was changed 
from 4 or >4 units to ≤6 or >6 units RBC. 
Rationale: In Part 1, the study population was fairly well-balanced between the IPSS low (approximately 60%) 
and intermediate-1 risk (approximately 40%) subgroups. Response rates differed by IPSS subgroup, so 
stratification using IPSS criteria is expected to ensure balance for these subgroups within the 2 treatment groups. 

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Applicable Section(s) 
Description of Change(s) 
Synopsis (Overview of Study Design); 
3.1. Overview of Study Design; 
3.2. Study Design Rationale; 
5.1. Treatment Allocation 
IPSS risk group (low versus intermediate-1 risk) was added as a 
stratification factor. 
Rationale: Additional sampling is required to further characterize the pharmacokinetic profile for imetelstat.   
Synopsis (Pharmacokinetic and 
Immunogenicity Evaluations); 
Time and Events Table 2  
Beginning with Amendment 2, serial PK sampling was removed for 
Part 1, as data have been collected from adequate number of 
subjects. PK sampling time points for Cycle 1 Day 1 for all subjects 
in Part 1 were updated to better characterize kinetics after the end of 
infusion. An end-of-infusion PK sample was added for all cycles 
after Cycle 1 to assess potential longitudinal changes in exposure 
during treatment. Time points for immunogenicity evaluation were 
revised. 
Synopsis (Pharmacokinetic and 
Immunogenicity Evaluations); 
Time and Events Table 3 
(Pharmacokinetic/  
Immunogenicity samples); 
Time and Events Table 4 (Part 2 
Pharmacokinetic / Immunogenicity 
Sampling) 
PK and immunogenicity sampling in Part 2 is described in newly 
added Table 4. In Part 2, end-of-infusion blood samples will be 
collected for PK evaluation on Day 1 of all cycles. Pre-dose blood 
samples for immunogenicity evaluation will be collected on Day 1 of 
Cycle 1 and then every 3 cycles thereafter (Day 1 of Cycles 4, 7, 10, 
etc.). 
9.4.3. Pharmacokinetic Parameters 
Clarification was added that pharmacokinetic parameters based on 
serial sampling will be derived in Part 1. Descriptive statistics 
(geometric and arithmetic means, standard deviation, coefficient of 
variation [%]) will be provided to summarize imetelstat plasma 
concentrations at each sampling time point for both Part 1 and Part 2. 
Rationale: Addition of an Independent Central Pathology Review provides an impartial confirmation of disease 
status at baseline and following disease response.   
Synopsis (Efficacy Evaluations); 
Time and Events Table 3 (BM aspirate 
biopsy); 
3.1. Overview of Study Design;  
4.1. Inclusion Criteria (no. 2); 
9.1.3. Screening Phase and Predose; 
9.1.4. Treatment Phase;  
9.1.5. Posttreatment Phase; 
9.3.1.3. Bone Marrow Assessment 
Centralized review of bone marrow aspirate/biopsies is required in 
Part 2 for all subjects at screening, at the time of suspected response 
(ie, HI-E [Hb], CR, PR), and at the time of suspected PD. Treatment 
decisions will continue to be made based on the investigator’s 
assessment of local pathology review. 
Rationale: Study endpoints and objectives have been expanded following examination of Part 1 data and changes 
to the scope of study procedures. 
Synopsis (Secondary Objectives); 
Synopsis (Endpoints); 
2.1. Objectives; 
9.2.2. Secondary Endpoints; 
11.4. Efficacy Analyses 
Assessment of progression free survival (PFS) was added as a 
secondary objective. 
Synopsis (Secondary Objectives); 
Synopsis (Endpoints); 
2.1. Objectives; 
9.2.2. Secondary Endpoints 
Assessment of the effect of imetelstat on QTc interval in a subset of 
subjects was added as a secondary objective. 

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Applicable Section(s) 
Description of Change(s) 
11.5. Pharmacokinetic Analyses 
Text was revised: Descriptive statistics will be provided to 
summarize imetelstat plasma concentrations at each sampling time 
point for subjects undergoing serial pharmacokinetic sampling in 
Part 1 and the Ventricular Repolarization substudy in Part 2.  
Synopsis (Exploratory Objectives); 
Synopsis (Endpoints); 
Synopsis (Pharmacodynamic and 
Biomarker Evaluations); 
2.1. Objectives; 
3.2. Study Design Rationale; 
9.2.3. Exploratory; 
9.5. Biomarkers 
Evaluation of mutation changes during treatment was added to 
evaluation of baseline mutation status for the purpose of exploring 
the association with clinical response was added as an exploratory 
objective. 
Rationale: Clarification was added for document consistency, to aid interpretation of procedures, reflect 
experience gained in Part 1, and improve study quality.  
Title Page 
Janssen Pharmaceuticals NV was added to the sponsorship statement 
as a legal entity. 
Synopsis (Overview of Study Design); 
3.1. Overview of Study Design 
The following text was added: Enrollment into the study may be 
temporarily held between Part 1 and Part 2 while safety and efficacy 
data are analyzed. 
Synopsis (Endpoints); 
Synopsis (Pharmacodynamic and 
Biomarker Evaluations); 
9.2.3. Exploratory; 
9.5. Biomarkers (Cytogenetic Response) 
Clarification was added that cytogenetic assessment will include 
cytogenetic changes including response. 
Synopsis (Efficacy Evaluations) 
Clarification was added that symptom assessments will be based on 
patient-reported outcomes. 
Synopsis (Safety Evaluations) 
Unnecessary text was deleted: Additionally, an Independent Data 
Monitoring Committee will be commissioned to monitor safety data 
during Part 1 and Part 2 of the study. 
Synopsis (Pharmacokinetic and 
Immunogenicity Evaluations) 
Part 1 and Part 2 pharmacokinetic and immunogenicity evaluations 
were presented separately.  
Synopsis (Pharmacokinetic and 
Immunogenicity Evaluations; 
Pharmacodynamic and Biomarker 
Evaluations) 
Text addressing exposure-response relationships was simplified and 
moved from the Pharmacokinetic and Immunogenicity Evaluations 
section of the Synopsis to the Pharmacodynamic and Biomarker 
Evaluations section of the Synopsis. 
 
Time and Events Table 1, Table 3 
The window for survival follow-up during the Posttreatment Follow-
up Phase was changed from “every 16 weeks (±7 days)” to “every 
12-16 weeks”. 
Time and Events Schedule Table 1 (BM 
aspirate, biopsy; BM aspirate for RNA 
Seq or CyTOF   
Clarification was added that in addition to previous time points, bone 
marrow aspirate should be obtained at the time of suspected HI-E 
(Hb). 
Time and Events Table 1 and Table 3 
(Chemistry) 
Additional cross-reference to Section 9.8 was added. 

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Applicable Section(s) 
Description of Change(s) 
Time and Events Table 1 and Table 3 
“BM aspirate for cytogenetics”, “BM aspirate for RNA Seq or 
CyTOF”, “Immunophenotyping” will not be performed after the 
End-of-Treatment Visit.  
Time and Events Table 1, Table 3 (BM 
aspirate for cytogenetics); 
9.5. Biomarkers 
In Part 1, BM aspirate for cytogenetics is required for all subjects at 
the time of PD. Subjects with baseline abnormalities will also have 
BM aspirate at the time of suspected PR, CR, or HI-E (Hb) and 
every 24 weeks thereafter up to and including the time of PD. 
Time and Events Table 1, Table 3 
(Mutation analysis) 
Mutation analysis is required at the time of suspected response (CR, 
PR, HI-E [Hb]) or PD. 
Time and Events Table 3 
Post-screening assessments will occur at the time of suspected HI-E 
(Hb), PR, CR, PD, and as otherwise specified. 
Time and Events Table 1 and Table 3 
(Hematology); 
9.8.1. Clinical Laboratory Tests 
Clarification was added to the comment that if hematology tests are 
repeated on the day of the visit, the most recent results should be 
reviewed before dosing. 
Time and Events Table and Table 3 
(Response assessment) 
Bone marrow analysis is required at the time of suspected response 
or progression in addition to the analysis required every 24 weeks. 
Time and Events Table 1 and Table 3 
(Serum EPO level) 
An additional measurement of serum erythropoietin level is required 
at the first occurrence of suspected HI-E (Hb), PR, or CR. 
Subsequent measurement is not required if response further 
improves. 
Time and Events Table 1 and Table 3 
(serum ferritin, transferrin saturation) 
Serum ferritin and transferrin saturation were separated from other 
laboratory assessments and given a separate line in the Time and 
Events Schedules. In addition to screening assessments, serum 
ferritin and transferrin saturation will be measured on Day 1 of all 
cycles and at the EOT visit.  
Time and Events Table 1, Table 3 (TA, 
TL and hTERT); 
9.5. Biomarkers 
All subjects in Part 1 will have blood samples for TA, TL, and 
hTERT evaluation. Only predose Day 1 Cycle 1 blood samples will 
be collected in Part 2.   
Time and Events Table 2 
Clarification was added that the table only applies to Part 1. 
3.1. Overview of Study Design 
Clarification was added that 170 eligible subjects will be randomized 
in Part 2. 
3.1. Overview of Study Design; 
6. Dosage and Administration (Study 
Drug); 
6.1. Dose Modifications 
Text describing conditions under which dose re-escalation may occur 
was deleted, as re-escalation is not permitted in Part 2.  
3.2. Study Design Rationale 
“The time to AML progression” was rephrased as “the time to 
progression to AML”. 
4. Subject Population; 
4.2. Exclusion Criteria 
A NOTE stressing the importance of compliance with enrollment 
criteria was made more prominent by repositioned the text from the 
bottom of Section 4.2 to the bottom of Section 4. 
4.2 Exclusion Criteria (no. 4) 
Exclusion criterion 4 was revised to address prestudy restrictions on 
corticosteroid and growth factor treatment only. 
4.2. Exclusion Criteria (no. 16) 
A new exclusion criterion was added: Individuals previously 
diagnosed with IPSS intermediate-2 or high risk MDS are excluded 
from the study. 

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Applicable Section(s) 
Description of Change(s) 
4.2. Exclusion Criteria (no. 18) 
A new exclusion criterion was added: Subject with MDS/ 
myeloproliferative neoplasm (MPN) Overlap Syndrome. 
6. Dosage and Administration 
Clarification was added that the sponsor should be contacted before 
study drug is discontinued for subjects with study drug being held 
more than 28 days due to toxicity, if the subject is otherwise 
responding to treatment and the toxicity appears to be manageable.  
6.1.1 Dose Modifications for 
Hematologic Toxicities; Table 6; Table 7 
Text was added recommending contact with the sponsor before 
discontinuing treatment for Grade 3 or Grade 4 hematologic toxicity, 
particularly when the hematologic toxicity is asymptomatic. The 
following text was added as a footnote to the Dose Modification 
tables: “Note: Contact the sponsor to discuss the specific case before 
study drug is discontinued for hematologic toxicity”. 
8.3. Concomitant Medications 
Clarification was added that chemotherapy, including anticancer or 
hypomethylating agents, is prohibited during the study. 
9.1.2. Total Blood Volume (Table 11); 
16.1. Study-Specific Design 
Considerations 
The blood volume to be collected was updated to reflect revised 
study procedures. The total blood volume to be collected was 
changed from 486 mL to 555 mL. 
9.1.3. Screening Phase and Predose 
Text was updated to emphasize that only limited retesting of 
abnormal screening values is permitted.  
9.1.4. Treatment Phase  
Clarification was added that disease assessments should be 
performed for subjects with suspected disease progression or 
suspected response (eg, HI-E (Hb) in conjunction with recovery from 
cytopenias)  
9.2.2. Secondary Endpoints 
The definition of time to progression to AML was clarified as the 
interval from Study Day 1 to the date of AML diagnosis. 
9.3.1.2. Hemoglobin Assessment 
Part “i” of the definition of HI-E was revised as follows: 
Hematologic improvement-erythroid (HI-E) response is defined as i) 
a Hb rise of at least 1.5 g/dL above pretreatment level baseline, 
measured 28 days or more following the last RBC transfusion.  A 
definition of pretreatment Hb level was added. 
9.8.1. Clinical Laboratory Tests 
An Anemia Panel (including B12, folic acid, reticulocytes) was 
separated from Screening testing, as some or all of these tests may be 
repeated after screening. Serum erythropoietin, serum ferritin, and 
transferrin saturation were separated from other anemia tests to 
match the Time and Events Schedules. “Screening testing” was 
revised to “Pregnancy testing” and the pregnancy test was clarified 
as β-hCG. 
11.4. Efficacy Analyses 
Reference to the Hochberg procedure was deleted. 
11.7. Pharmacokinetic/ 
Pharmacodynamic Analyses 
Clarification was made that a population 
pharmacokinetic/pharmacodynamic analysis may be performed 
using nonlinear mixed-effects modeling if required, and that data 
may be combined with relevant Phase 1 and Phase 2 studies for the 
analyses. Exposure-response analysis for the Ventricular 
Repolarization substudy in Part 2 may be provided in a separate 
report. 
12.3.1. All Adverse Events 
Adverse event information will be collected until 30 days after the 
last dose of study drug (changed from completion of last study-

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Applicable Section(s) 
Description of Change(s) 
related procedure), for consistency with the Time and Events 
Schedule. The following text was added: Any adverse event thought 
to be potentially related to study drug must be reported to the 
sponsor irrespective of timing from the last dose of study drug. 
12.3.1. All Adverse Events; 
Attachment 10 
Text related to anticipated events was moved to Attachment 10, 
which identifies anticipated events associated with MDS and 
describes reporting and analysis procedures. Progressive disease of 
MDS was deleted as an Anticipated Event.  
14.5. Drug Accountability 
Text not applicable to the study was deleted. 
Rationale: Minor errors were noted 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made. 
 
Amendment 1 (31 May 2016) 
This amendment was considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: 1) To modify the eligibility criteria (MDS criteria, biochemistry 
inclusion and hepatitis exclusion criterion) for alignment across the imetelstat clinical program, based on advice 
from the Hepatic Expert Committee, consultations with Health Authorities, and MDS experts; 2) To add the 
QUALMS instrument, which is a newly validated MDS-specific measure of PRO; 3) To make clarifications 
throughout protocol based on questions received during execution of Part 1. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Protocol changes were requested following consultation with Health Authorities. 
Synopsis (Overview of Study Design); 
3.1. Study Design; 
3.2. Study Design Rationale 
(Randomization); 
5.1. Treatment Allocation 
The definition of “prior RBC transfusion burden” was revised to the 
maximum number of RBC units transfused over an 8-week period 
during the 16 weeks (changed from 12 weeks) prior to Study Entry. 
Synopsis (Population); 
4.1. Inclusion Criteria (no. 2) 
Eligible subjects must have a diagnosis of MDS based on WHO 
criteria. An MDS diagnosis based only on FAB classification 
(Attachment 2) is not permitted. 
Time and Events Schedule (Table 1, 
Table 2; Transfusion history); 
8.1. Prestudy Therapy; 
9.1.3. Screening Phase and Predose 
RBC transfusion history is required for the 16-week period before 
Study Entry (changed from 12 weeks).  
Time and Events Schedule (Table 1, 
Table 2; Transfusion history); 
3.1. Overview of Study Design; 
9.1.5. Posttreatment Phase; 
9.3.1.1. Transfusions 
Text was added to help ensure collection of robust transfusion data 
until treatment is stopped. For subjects who receive less than 12 
months of treatment, transfusion data will be collected for a 
minimum of 12 months from Study Entry. Text was added to Section 
9.3.1.1 describing transfusion data collection methods, including 
enhanced monitoring and continuous medical review. 
 

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Applicable Section(s) 
Description of Change(s) 
Time and Events Schedule (Table 1, 
Table 2; Transfusion history); 
9.1.5. Posttreatment Phase; 
9.3.1.1. Transfusions 
Clarification was added that during the Posttreatment Phase, 
transfusion information should be collected every 4 to 6 weeks. 
4.1. Inclusion Criteria (no. 4); 
 
The definition of “transfusion dependent” for determining study 
eligibility was revised to having received at least 4 RBC units over 
an 8-week period during the 16 weeks (changed from 12 weeks) 
prior to Study Entry.  
4.1. Inclusion Criteria (no. 6) 
To ensure subjects have adequate iron stores they must have 
transferrin saturation greater than 20% and (changed from either) 
serum ferritin greater than 400 ng/mL. 
4.1. Inclusion Criteria 
Inclusion criterion no. 13 was added. Subjects with the del(5q) 
karyotype are eligible if they have failed treatment with 
lenalidomide.  
11.4. Efficacy Analyses (Part 2) 
Clarification was added that subjects will not be considered 
transfusion independent in the absence of robust, continuous 
assessment of transfusion requirements during the observation 
period. 
Rationale: Eligibility criteria or study procedures were aligned with expert advisor recommendations and across 
the imetelstat clinical program.  
Time and Events Schedule (Table 2, BM 
aspirate, biopsy); 
9.3.1.3. Bone Marrow Assessment 
Requirement added that a sample of the bone marrow used for 
diagnostic confirmation must be available to submit for central 
pathology review, if requested. 
Time and Events (Table 1, Table 2; 
Hepatitis serologies) 
9.8.1. Clinical Laboratory (Viral 
hepatitis) 
Requirements for screening hepatitis serology were clarified. 
Hepatitis D serology is only required if the subject tests positive for 
the hepatitis B surface antigen (HBsAg).   
4.1. Inclusion Criteria (no. 9.4) 
Requirement added that total bilirubin must be ≤3 x ULN. 
Requirement for direct bilirubin was changed from ≤1.5 x ULN to 
≤2 x ULN. Patients with elevated bilirubin due to Gilbert’s 
syndrome may be eligible to participate in the study.  
4.2. Exclusion Criteria (no. 12) 
 
History of prior hepatitis infection was deleted as part of the 
exclusion criterion. Subjects with active systemic hepatitis infection 
requiring treatment are excluded (carriers of hepatitis virus are 
permitted to enter the study).  
Rationale: Additional PRO instruments have been identified for use in the study. 
Synopsis (Endpoints); 
9.2.2. Secondary Endpoints 
“Change from baseline in scores from FACT-An and EQ-5D-5L” 
was changed to “Assessment of QUALMS, FACT-An and EQ-5D-
5L.” 
Time and Events Schedule (Table 2, 
Efficacy Assessments); 
3.2. Study Design Rationale (Patient-
Reported Outcomes); 
9.1.3. Screening; 
9.1.5. Posttreatment Phase; 
9.6. Patient–Reported Outcomes 
QUALMS and PGIC were added to FACT-An and EQ-5D-5L for 
use in Part 2. When applicable, these are referred to collectively as 
PRO measures or PRO questionnaires.  

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Applicable Section(s) 
Description of Change(s) 
11.4. Efficacy Analyses (Part 2) 
A description of efficacy analyses related to QUALMS was added. 
Attachment 7; Attachment 8; Attachment 
9 
Attachment 7 (EQ-5D-5L) was updated. Attachments for QUALMS 
(Attachment 8) and PGIC (Attachment 9) were added. 
Rationale: The flexibility to use peripheral blood instead of bone marrow aspirate for cytogenetic testing will 
allow cytogenetic testing to occur when bone marrow aspiration is clinically unfeasible. Bone marrow aspirate is 
preferred to peripheral blood for cytogenetic assessment. The same sample type should be collected at screening 
and subsequent time points, if possible, because changes in cytogenetic findings may result for a given subject 
when different sample types are used. 
Time and Events Schedule (Table 1, 
Table 2; BM aspirate for cytogenetics);  
9.5 Biomarkers (Cytogenetic Analysis)  
Guidance was provided for when bone marrow aspiration yields a 
dry tap. Peripheral blood can be submitted if bone marrow aspirate 
cannot be collected. A consistent type of sample (peripheral blood or 
bone marrow aspirate) should be used throughout the study. 
Rationale: Clarification was added to aid interpretation of procedures, for consistency with other parts of the 
protocol, and to reflect experience gained during conduct of Part 1. 
Synopsis (Exploratory Objectives) 
The list of exploratory objectives was aligned with Section 2.1, 
Objectives. 
Synopsis (Overview of Study Design); 
3.1. Overview of Study Design; 
11.2. Subject Information 
The definition of “Study Entry” was clarified for Part 1 and Part 2 of 
the study. Study Day 1 is equivalent to Study Entry and is defined as 
the day of the first dose for subjects enrolled in Part 1 and the day of 
randomization for subjects enrolled in Part 2. In Section 3.1, specific 
reference to Study Entry as the day of the first dose was deleted, as 
the text is not specific to Part 1. 
Synopsis (Endpoints); 
9.2.2. Secondary Endpoints 
Secondary endpoints were revised as follows: “Rate and amount of 
transfusions” was revised to “amount and relative change in RBC 
transfusions,” and “dose of myeloid growth factors usage” was 
revised to “duration of myeloid growth factors usage.”  
Synopsis (Safety Evaluations); 
3.1. Overview of Study Design; 
11.11. Independent DMC; 
16.1. Study Design Considerations 
The independent DMC’s involvement in the study was extended to 
Part 1 in addition to Part 2.  
Synopsis (Pharmacokinetics); 
Time and Events Schedule (Table 1, 
Table 2; Pharmacokinetics) 
Pharmacokinetic sampling scheduled for Cycle 3 was moved to 
Cycle 4. Subsequent sampling was shifted accordingly. 
Time and Events Schedule (Table 1, 
Table 2; Study Entry) 
The row for Study Entry was deleted. 
Time and Events Schedule (Table 1, 
Table 2; Dispense/administer study 
drug); 
6. Dosage and Administration (Study 
Drug) 
Clarification was added that the body weight measurement collected 
at Screening is used for the initial dose calculation. Clarification was 
added that dosing should begin within 72 hours of enrollment (Part 
1) or randomization (Part 2) in IWRS. 
 
Time and Events Schedule (Table 1, 
Table 2; Hematology, BM aspirate, 
biopsy) 
Rows for “Hematology” and “BM aspirate, biopsy” were 
repositioned as Efficacy Assessments to keep together all evaluations 
required for response assessment.  

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Applicable Section(s) 
Description of Change(s) 
Time and Events Schedule (Table 1, 
Table 2: BM aspirate, biopsy; Response 
assessment; TA, TL, hTERT; BM 
aspirate for cytogenetics; 
Immunophenotyping) 
Clarification was added that samples are collected at the time of 
suspected PR, CR, and PD.  
Time and Events Schedule (Table 1, 
Table 2; Hematology, Chemistry) 
Screening hematology and chemistry tests should (changed from 
must) be performed within 14 days before Study Entry.  
Time and Events Schedule (Table 1, 
Table 2; Hematology);  
6.1.1. Dose Modification; 
9.1.4. Treatment Phase 
9.8.1. Clinical Laboratory Tests 
Text was added to emphasize that laboratory testing beyond required 
assessments in the Time and Events Schedules should be performed 
as clinically indicated. Weekly hematology follow-up is required 
after any Grade ≥3 thrombocytopenia or neutropenia that occurs 
during the treatment phase until values return to baseline. 
Time and Events Schedule (Table 1, 
Table 2; Hematology); 
6.1. Dose Modification; 
9.3.1.2. Hemoglobin Assessment 
Clarification added that “dose escalation” means “dose escalation to 
9.4 mg/kg.” 
Time and Events Schedule (Table 2; 
Hematology) 
Hematology assessments were added for the first visit of the 
Posttreatment Follow-up Phase. 
Time and Events Schedule (Table 1, 
Table 2; BM aspirate, biopsy) 
After baseline, BM assessments can be performed with a window of 
±7 days. Clarification was added that the every-24-week interval for 
BM aspirate assessment begins from C1D1 and that BM biopsy 
occurs annually (every 48 weeks) after C1D1. A cross-reference to 
additional BM sampling procedures was added. 
Time and Events Schedule (Table 1, 
Table 2; Response Assessment) 
Required evaluations for response assessment were added to the 
Comments column (peripheral blood and RBC transfusion 
requirements at all assessments; bone marrow analysis every 24 
weeks). A cross-reference to Section 9.1.5 was added for subjects 
who discontinue treatment for any reason other than disease 
progression. Clarification was added that the every-12-week interval 
for response assessment begins from C1D1 ±1 week.  
Time and Events Schedule (Table 1, 
Table 2; Chemistry) 
A cross-reference to Section 9.8.1 was added for additional detail on 
required clinical laboratory testing. 
Time and Events Schedule (Table 1, 
Table 2; Chemistry Panel for LFT 
investigations) 
Both the routine chemistry panel and LFT investigations chemistry 
panel are repeated weekly as required. Subjects with Grade 1 or 
Grade 2 elevations in AST, ALT, ALP, or bilirubin at the time of 
treatment discontinuation will continue to be tested monthly until 
resolution to at least baseline. 
Time and Events Schedule (Table 1, 
Table 2; INR (or PT) and aPTT; 
9.1.4. Treatment Phase; 
9.8.1. Clinical Laboratory Tests 
Text was added to clarify the requirement for additional coagulation 
assessments for subjects who experience a hemorrhagic event during 
the treatment phase.  
Time and Events Schedule (Table 1, 
Table 2; TA, TL, and hTERT) 
Clarification was added that blood samples are collected.  

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Applicable Section(s) 
Description of Change(s) 
Time and Events Schedule (Table 1, 
Table 2; BM aspirate for cytogenetics) 
Clarification was added that local cytogenetic analysis of BM 
aspirate is recommended for Screening (a sample must still also be 
submitted to the central laboratory). The baseline sample for the 
central laboratory may be collected either during Screening or before 
dosing on C1D1. Bone marrow aspirate is required “at time of 
suspected PR/CR and every 24 weeks thereafter up to and including 
PD” (changed from until PD). 
Time and Events Schedule (Table 1, 
Table 2; BM aspirate for RNA Seq or 
CyTOF) 
Text was added to allow collection of the baseline aspirate sample 
either during Screening or before dosing on C1D1. After baseline, 
BM assessments can be performed with a window of ±7 days. 
Time and Events Schedule (Table 3) 
Clarification was added to the first column that the Cycle 1, 22h – 
26h postdose time point may occur on Day 1 or Day 2. All Cycle 3 
sampling was changed to Cycle 4, with subsequent sampling revised 
from “Day 1 of Cycles 6, 9, etc.” to “Day 1 of Cycles 7, 10, etc.” 
Additional Serial Pharmacokinetic samples were added for Cycle 4, 
Day 1 at 2 hours and 3 to 6 hours. Additional Serial Pharmacokinetic 
and Sparse Pharmacokinetic samples were added for subjects who 
have a dose escalation to 9.4 mg/kg. Footnote “c” was added for the 
“Sparse Pharmacokinetic Blood Sampling” column. Footnote “d” 
clarified to indicate that the 2 h time points should correspond to a 
time point immediately before the end of infusion, including cases 
where infusion time extends beyond 2 hours. Footnote “f” was 
revised to reflect changes to sample collecting. 
3.1. Study Design; 
Figure 2 (Study Schematic); 
6. Dosage and Administration 
Guidance for discontinuation of study treatment for subjects with 
inadequate response after 6 months of treatment was aligned for Part 
1 and Part 2. 
3.1. Overview of Study Design; 
6. Dosage and Administration (Study 
Drug); 
6.1 Dose Modifications 
Clarification was added that dose re-escalation may (changed from 
will) be considered for subjects with improved tolerability after the 
dose had been reduced due to toxicity.  
4.1. Inclusion Criteria; 
4.2. Exclusion Criteria  
Bulleted sub-criteria for inclusion no. 5, inclusion no. 8, inclusion 
no. 9, and exclusion no. 9, were assigned numbers. The bulleted 
inclusion criterion regarding acceptable methods of birth control was 
assigned the number 10.1. The subsequent inclusion criterion 
regarding pregnancy testing was renumbered 10.2 (previously no. 
10). 
4.1. Inclusion Criteria (no. 5.4) 
“Serum EPO level” was clarified as “Endogenous serum EPO level”. 
4.2. Exclusion Criteria 
 
The following text was added to the “Note:” below the list of 
exclusion criteria: “The last laboratory result obtained prior to 
enrollment/randomization will be used to determine eligibility.”   
5.1. Treatment Allocation 
Clarification was added that that pre-transfusion Hb should be ≤9.0 
g/dL to count towards the 4-unit total, unless there is clinical 
rationale for transfusing at a higher Hb level. 

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Applicable Section(s) 
Description of Change(s) 
6. Dosage and Administration (Study 
Drug); 
6.1.1. Dose Modifications 
(Hematologic); 
6.1.2 Dose Modifications (Non-
hematologic); 
6.1.3. Dose Modifications (Hepatic) 
Clarification was added that the dose modification instructions 
provided in Tables 5 to 9 are applicable only when Grade 3 or Grade 
4 toxicities are present at the planned time of study drug 
administration on Day 1 of a dosing cycle. 
 
6.1. Dose Modifications  
Additional guidance was added to the Table 4 footnote. Subjects 
must receive 3 cycles of treatment at 7.5 mg/kg before escalation to 
9.4 mg/kg can be considered. Guidance was added to perform 
additional pharmacokinetic sampling per Table 3 when dose 
escalation to 9.4 mg/kg occurs. 
6.2. Infusion-Related Reactions (Table 9) 
Revised guidance was provided for management of Grade 2 
infusion-related reactions.   
9.1.1. Overview; 
9.8.2. Electrocardiogram 
The detailed recommendation for the order of study procedures was 
deleted. 
9.1.2. Total Blood Volume (Table 10); 
16.1. Study Design Considerations 
The total blood volume to be collected was increased by 16 mL due 
to additional pharmacokinetic sampling and expanded hepatitis 
testing. 
9.1.4. Treatment Phase 
Clarification was added that a window of ±3 days is allowed for 
visits to the clinic. 
9.1.5. Posttreatment Phase  
Clarification was added regarding continuation of response 
assessments when study drug is discontinued for reasons other than 
disease progression. Response assessment visits should continue per 
timing in the Time and Events Schedule or according to site standard 
practice through the time of disease progression or until the start of 
subsequent therapy, whichever comes first. Redundant reference to 
the Time and Events Schedule was deleted. 
9.3.1.2. Hemoglobin Assessment 
Clarification was added to the definition of HI-E that reduction in 
transfusion burden is a comparison to “prior RBC transfusion 
burden.”  
9.5. Biomarkers 
Text describing immunophenotype analysis was repositioned within 
the section. The subheading “Additional analysis” was changed to 
“BM aspirate for RNA Seq or CyTOF.” 
9.8.1. Clinical Laboratory Tests  
Clarification was added to the Serum Chemistry Panel (Routine) that 
total bilirubin with fractionation is required at screening. 
Fractionation is required post-screening if total bilirubin is abnormal.  
10.2. Discontinuation of Study Treatment 
Inadequate response after 6 months of treatment was deleted as a 
reason for study drug discontinuation. 
11.4. Efficacy Analyses (Part 1 and Part 
2) 
Additional detail was added to the description of planned efficacy 
analyses for Part 1 and Part 2.  
12.3.3. Adverse Events of Interest 
Adverse events of interest must be reported to the sponsor with 24 
hours of awareness (changed from will). Adverse events of interest 
must be reported irrespective of seriousness.  
References 
References 1 and 46 were added. Unused references were deleted. 
Citation numbering was revised accordingly. 

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Applicable Section(s) 
Description of Change(s) 
Rationale: Additional information regarding Study CP14B019 has become available.  
1.1.5. Clinical Experience; 
1.1.5.2.1. Hematologic Toxicities; 
1.1.5.2.3. Hepatotoxicity 
Information related to the MDS cohort in CP14B019 was added or 
updated based on currently available published literature. 
Rationale: Janssen Research & Development standard protocol text has been updated. 
Title Page 
Janssen Infectious Diseases BVBA has been deleted as one of the 
legal entities comprising Janssen Research & Development. 
4. Subject Population 
Clarification was added that waivers to required entry criteria are not 
permitted. 
12.2. Special Reporting Situations 
Exposure to a sponsor study drug from breastfeeding was added as 
an event that may require expedited reporting and safety evaluation. 
12.3.1. All Adverse Events 
Additional text was added describing Anticipated Events and the 
reporting process for serious Anticipated Events. 
16.2.2. IEC or IEB 
Clarification was made that IEC/IRB annual approval of the protocol 
will be obtained, where required. 
Rationale: Minor errors were noted 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made. 
 

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SYNOPSIS 
A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or 
Intermediate-1 Risk Myelodysplastic Syndrome (MDS) that is Relapsed/Refractory to Erythropoiesis-
Stimulating Agent (ESA) Treatment. 
Imetelstat (GRN163L) is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a 
potent specific inhibitor of telomerase. Telomerase inhibition leads to loss of a cancer cell’s ability to 
maintain telomere length (TL), resulting in cell-cycle arrest, apoptosis, or senescence. Imetelstat binds with 
high affinity to the template region of the ribonucleic acid (RNA) component of human telomerase reverse 
transcriptase (hTERT) and is a competitive inhibitor of telomerase enzymatic activity.2,24 Treatment of 
various cancer cells with imetelstat in vitro increases their sensitivity to radiation, decreases their 
clonogenic potential, and results in altered expression of stem-cell related genes. Clinical data in a small 
number of MDS subjects further indicate that treatment with imetelstat resulted in transfusion independence 
and other measures of hematologic improvement. 
OBJECTIVES AND HYPOTHESES 
Primary Objective 
Part 1: To evaluate the efficacy and safety of imetelstat in transfusion dependent subjects with low or 
intermediate-1 risk MDS that is relapsed/refractory to ESA treatment. 
Part 2: To compare the efficacy, in terms of red blood cell (RBC) transfusion independence (TI), of 
imetelstat to placebo in transfusion dependent subjects with low or intermediate-1 risk MDS that is 
relapsed/refractory to ESA treatment. 
Extension Phase: To evaluate the long-term safety, OS, and disease progression, including 
progression to AML in transfusion dependent subjects with low or intermediate-1 risk MDS that 
is relapsed/refractory to ESA treatment receiving imetelstat. 
Secondary Objectives (Part 1 and Part 2) 
• 
To assess the safety of imetelstat in subjects with MDS 
• 
To assess the time to RBC TI and duration of RBC TI 
• 
To assess the rate of hematologic improvement 
• 
To assess the rates of complete remission (CR), partial remission (PR), or marrow complete remission 
(mCR) 
• 
To assess overall survival (OS) 
• 
To assess progression free survival (PFS) 
• 
To assess time to progression to acute myeloid leukemia (AML) 
• 
To assess the rate and amount of supportive care, including transfusions and myeloid growth factors 
(Part 2 only) 
• 
To evaluate the pharmacokinetics and immunogenicity of imetelstat in subjects with MDS 
• 
To assess the effect of imetelstat treatment on patient-reported outcomes (PROs) 
• 
To assess the effect of treatment on medical resource utilization (Part 2 only) 
• 
To assess the effect of imetelstat on corrected QT (QTc) interval in subjects in the Ventricular 
Repolarization substudy (to be reported separately from Part 2) 

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Exploratory Objectives (Part 1 and Part 2) 
• 
To evaluate pharmacodynamic biomarkers such as telomerase activity (TA), TL and hTERT and to 
explore the association between baseline results and clinical response 
• 
To evaluate change of cytogenetic abnormalities and explore the association between baseline 
cytogenetic status and clinical response  
• 
To evaluate baseline mutational status and mutation changes during treatment for exploring the 
association with clinical response 
• 
To explore the effects of imetelstat on immune profiles through immunophenotyping (Part 1 only) 
• 
To evaluate the exposure-response relationship between pharmacokinetics and pharmacodynamic 
biomarkers, efficacy and safety  
Hypothesis 
The primary hypothesis is that imetelstat will improve the rate of RBC TI as compared to placebo in 
transfusion dependent subjects with low or intermediate-1 risk MDS that is relapsed/refractory to ESA 
treatment. 
OVERVIEW OF STUDY DESIGN 
This is a multicenter study of imetelstat in transfusion-dependent subjects with low or intermediate-1 risk 
MDS that is relapsed/refractory to ESA treatment (as per inclusion criteria). The study will consist of 
2 parts, and approximately 270 subjects will be enrolled. Part 1 was an open-label, single-arm design to 
assess the efficacy and safety of imetelstat, which enrolled 57 subjects. Part 2 is a double-blind, randomized, 
placebo-controlled design to compare the efficacy of imetelstat with placebo. In addition to the 
approximately 170 subjects to be enrolled in the main study in Part 2, approximately 45 subjects will be 
enrolled in a separate Ventricular Repolarization substudy. Subjects should be enrolled in the main study 
of Part 2 until enrollment is complete unless a subject is known to meet criteria that would make the subject 
ineligible for the main study (eg, del 5 q, prior HMA therapy). The sponsor has reviewed and assessed all 
available data in Part 1, including blood counts, transfusion requirement, tolerability, pharmacokinetic, and 
pharmacodynamic biomarker data. 
The futility criteria before Amendment 2 were defined as follows: If 4 or fewer subjects among 30 subjects 
in Part 1 achieve RBC TI lasting at least 8 weeks, the study will be stopped unless there is compelling 
clinical evidence of efficacy in one or more other endpoints (eg, transfusion reduction, erythroid 
improvement). Upon review of the efficacy and safety data observed with the 7.5 mg/kg dose among 
32 subjects in Part 1, a subset of 13 subjects was identified with higher hematologic response rates. These 
were subjects with non-del(5q) MDS and without prior exposure to either hypomethylating agents or 
lenalidomide. As of Amendment 2, Part 1 was expanded to include only subjects who meet these criteria, 
with the goal to confirm the safety and efficacy data seen in this subset and to re-confirm the dose. 
Twenty-five additional subjects with non-del(5q) MDS and without prior exposure to either 
hypomethylating agents or lenalidomide, so called target population, were enrolled for a total of 38 (from 
57 enrolled in Part 1). 
Since data from Part 1 for this target population show clinical benefit of treatment with imetelstat (see 
Section 3.2 for a summary of data from the 38 subjects in the target population), Part 2 of the study will be 
initiated in subjects with non-del(5q) MDS and without prior exposure to either hypomethylating agents or 
lenalidomide. Enrollment into the study was temporarily held between Part 1 and Part 2 while safety and 
efficacy data were analyzed. Subjects in Part 2 will be randomized in a 2:1 ratio to receive either imetelstat 
or placebo, respectively. Randomization will be stratified by prior RBC transfusion burden (≤6 or >6 units 
RBC) and by International Prognostic Scoring System (IPSS) risk group (low versus intermediate-1). Prior 

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RBC transfusion burden is defined as the maximum number of RBC units transfused over an 8-week period 
during the 16 weeks prior to Cycle1 Day 1 (C1D1) for subjects enrolled in Part 1 or the day of 
randomization for subjects enrolled in Part 2. Each part of the study will consist of 3 phases: 
• 
a Screening Phase of up to 28 days during which subject eligibility will be reviewed and approved 
by the sponsor prior to C1D1 (Part 1) or Randomization (Part 2); 
• 
a Treatment Phase that will extend from C1D1 (Part 1) or Randomization (Part 2) until disease 
progression, or unacceptable toxicity, or withdrawal of consent; and 
• 
a Posttreatment Follow-up Phase which will continue until death, loss to follow-up, withdrawal of 
consent, or the end of the study (whichever occurs first). The end of the main study is defined as 
24 months after the randomization of the last subject in the main study of Part 2.  
• 
An Extension Phase will begin after the end of the main study (24 months after the last subject was 
randomized in the main study of Part 2) and continue until subjects who entered from Part 2 of the 
main study participate in the study for at least 5 years from the first dose of imetelstat (including 
treatment and follow-up), or 3 years of post-treatment follow-up from the last dose of study 
treatment, whichever occurs later, or until death, withdrawal of consent, study termination, or until 
a subject is lost to follow-up. 
In Part 2, approximately 45 evaluable subjects (in addition to the approximately 170 subjects who will be 
enrolled in the main study) will be enrolled in a separate Ventricular Repolarization (QTc) substudy 
investigating the effects of imetelstat exposure on ventricular repolarization. Subjects who are not evaluable 
for the QTc substudy primary electrocardiograms (ECG) endpoint may be replaced with new subjects. 
Serial ECGs will be obtained with PK samples on Day 1 of Cycle 1 as indicated in Attachment 11. The 
cardiac safety analysis in regard to ECG and concentration QTc analysis in the substudy based on the 
additional 45 subjects will be performed separately from the primary analysis of 170 subjects in the main 
study (refer to Attachment 11 for further details). Subjects who have enrolled into the Ventricular 
Repolarization substudy of Part 2 prior to Protocol Amendment 7 will continue with the assessments as 
required for the main study. 
Subjects benefiting from imetelstat at the end of the main study (ie, 24 months after last subject randomized 
in the main study of Part 2) per investigator assessment may continue to receive imetelstat during the 
Extension Phase. Subjects in the Posttreatment Follow-up Phase of the main study will also continue in the 
Extension Phase for assessment of survival status, subsequent anticancer therapy, and monitoring of disease 
progression. Subjects will be followed in the Extension Phase for at least 5 years from the first dose of 
imetelstat in Part 2 of the main study (including treatment and follow-up), or 3 years of post-treatment 
follow-up from the last dose of study treatment, whichever occurs later, or until death, withdrawal of 
consent, study termination, or until a subject is lost to follow-up. During the Extension Phase, the 
Independent Hepatic Expert Committee (HEC) will be available to review all hepatic adverse events and 
liver function test abnormalities at least on a quarterly basis, or more frequently if needed. 
Subjects who are receiving imetelstat in the QTc substudy may also enter the Extension Phase after the 
clinical cut off for the primary analysis is reached for the QTc substudy (ie, after approximately 45 evaluable 
subjects have completed Cycle 2). Once the end of the Extension Phase is reached for subjects participating 
in the main study (as described above), the study will also end for the QTc substudy subjects who enter the 
Extension Phase. 
With Protocol Amendment 8, Part 1 of the study will close as all subjects in Part 1 have already discontinued 
treatment and the study will have already met the duration of follow-up defined for the Extension Phase 
(ie, at least 5 years from the first dose of imetelstat treatment, or 3 years of post-treatment follow-up from 

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the last dose of study treatment, whichever occurs later). Any Part 1 subjects remaining in follow-up will 
be discontinued from the study. Therefore, the Extension Phase does not apply to Part 1 subjects. 
SUBJECT POPULATION 
Key eligibility criteria include the following: ≥18 years of age; diagnosis of MDS according to World 
Health Organization criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to C1D1 
(Part 1) or Randomization (Part 2); IPSS low or intermediate-1 risk non-del(5q) MDS that is 
relapsed/refractory to ESA treatment; RBC transfusion dependent; an Eastern Cooperative Oncology Group 
(ECOG) Performance Status score of 0, 1 or 2; and no prior treatment with either a hypomethylating agent 
or lenalidomide. Eligibility criteria for the additional 45 subjects enrolled in the Ventricular Repolarization 
substudy of Part 2 are outlined in Attachment 11. 
DOSAGE AND ADMINISTRATION 
All subjects in Part 1 will receive imetelstat. Subjects in Part 2 will receive either imetelstat or placebo. The 
term 'Study Drug', as used in this protocol, refers to either imetelstat or placebo. 
The study drug is administered as an intravenous (IV) infusion. The starting dose of the study drug is 
7.5 mg/kg every 4 weeks. Subjects whose dose was previously escalated (before Amendment 2) may 
continue at the 9.4 mg/kg dose (Part 1 only). 
Guidelines for imetelstat dosage and administration for subjects who continue treatment during the 
Extension Phase will follow those described in the Treatment Phase. 
ENDPOINTS 
The primary efficacy endpoint of this study is the rate of RBC TI lasting at least 8 weeks. The 8-week RBC 
TI rate is defined as the proportion of subjects without any RBC transfusion during any consecutive 8 weeks 
starting from Study Day 1. 
The secondary endpoints of this study are: the safety of imetelstat in subjects with MDS; the rate of RBC 
TI lasting at least 24 weeks; the time to and duration of RBC TI; the rate of hematologic improvement, 
including hematologic improvement-erythroid; the rates of CR, PR, or mCR; OS; PFS; time to progression 
to AML; amount and relative change in RBC transfusions; rate and duration of myeloid growth factors 
usage; assessment of Quality of Life in Myelodysplasia Scale (QUALMS), Functional Assessment of 
Cancer 
Therapy-Anemia-Related 
Effects 
(FACT-An), 
and 
EuroQol-EQ-5D-5L 
(EQ-5D-5L); 
pharmacokinetic parameters (eg, Cmax, AUC0-t), and immunogenicity of imetelstat (eg, antibodies to 
imetelstat); and the medical resource utilization data including hospitalization, emergency room visits, 
hematology specialist visits, and ECG parameters including change in QTc interval for subjects enrolled in 
the Ventricular Repolarization substudy (Part 2 only). 
The exploratory endpoints of this study are: TA, and hTERT at baseline and the change from baseline, TL 
at baseline; the cytogenetic status at baseline and cytogenetic changes, including response; the mutation 
status at baseline; mutation changes during treatment; and the immune profiles at baseline and change from 
baseline (Part 1 only). 
EFFICACY EVALUATIONS 
Efficacy evaluations will include transfusion data, blood count assessments, limited physical examinations, 
bone marrow biopsy and aspirate for disease and cytogenetic assessments, and symptom assessment via 
PRO. In addition to local disease evaluations, which will be used for treatment decisions, in Part 2, an 
Independent Central Pathology Reviewer will review bone marrow assessments performed at baseline to 
confirm diagnosis throughout the duration of the main study. An Independent Review Committee will be 
established to adjudicate investigator-assessed disease response (CR, PR, mCR, or cytogenetic response). 

GRN163L (imetelstat) 
 
 
 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
44 
Status: Final, Date: 13 December 2022 
  
Patient-reported outcome questionnaires will be collected to provide an assessment of the subject’s 
functional status, well-being, and MDS symptoms over time and to provide estimates of utility to include 
in future cost effectiveness models. 
SAFETY EVALUATIONS 
Safety will be assessed by adverse events (AEs), physical examinations, clinical laboratory parameters, 
electrocardiograms, vital sign measurements, ECOG performance status, and concomitant medication 
usage. The sponsor will review the safety data on an ongoing basis. Additionally, an Independent Data 
Monitoring Committee (DMC) will be commissioned to monitor safety data during the study. All hepatic 
adverse events and liver function test abnormalities will also be reviewed at least on a quarterly basis, or 
more frequently if needed, by an Independent HEC throughout the study. 
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS 
Samples to assess both the plasma concentration (pharmacokinetics) of imetelstat and the generation of 
antibodies to imetelstat (immunogenicity) will be obtained. 
In Part 1, serial PK sampling on Cycle 1 Day 1 was completed before implementation of Amendment 2. 
Subjects will have an end-of-infusion blood sample collected on Day 1 of each cycle. Pre-dose blood 
samples for immunogenicity evaluation will be collected on Day 1 of Cycle 1 and then every 3 cycles 
thereafter (Day 1 of Cycles 4, 7, 10, etc.). 
In Part 2, blood samples will be collected for PK evaluation on Day 1 of Cycle 1 and then at prespecified 
time points thereafter as indicated in Table 4. Pre-dose blood samples for immunogenicity evaluation will 
be collected on Day 1 of Cycle 1 and then every 3 cycles thereafter (Day 1 of Cycles 4, 7, 10, etc.).  
In Part 2, for subjects participating in the Ventricular Repolarization substudy, serial blood samples for PK 
evaluation will be collected at C1D1 at prespecified time points, prior to and after start of infusion (SOI) as 
indicated in the schedule of events in Attachment 11. 
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS  
The exposure-response relationship for key efficacy and safety parameters will be evaluated. 
Blood and bone marrow samples will be collected to evaluate the mechanism of action of imetelstat and to 
determine cytogenetic and mutation changes, including response. Other markers may be assessed to 
evaluate potential inter-individual variability in clinical outcomes or identification of population subgroups 
that respond differently to treatment with imetelstat. 

GRN163L (imetelstat) 
 
 
 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
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Status: Final, Date: 13 December 2022 
  
STATISTICAL METHODS 
A total of approximately 270 subjects will be enrolled in the study (a total of 57 subjects were enrolled in 
Part 1, approximately 170 subjects are planned for the main study of Part 2, and approximately 45 subjects 
are planned for the Ventricular Repolarization substudy of Part 2 with Protocol Amendment 7). The initial 
cohort of 32 subjects enrolled into Part 1 was expanded with Protocol Amendment 2 to include 25 additional 
subjects who meet the revised entrance criteria, for 57 subjects in total for Part 1. 
On the basis of historical data, RBC TI rate is expected to be approximately 7.5% in subjects with low or 
intermediate-1 risk MDS without any active treatment. The RBC TI rate with imetelstat treatment is 
expected to be approximately 30% based on preliminary data from Study CP14B019. The futility criteria 
before Amendment 2 were defined as follows: If 4 or fewer subjects among 30 subjects in Part 1 
achieve RBC TI lasting at least 8 weeks, the study will be stopped unless there is compelling clinical 
evidence of efficacy in one or more other endpoints (eg, transfusion reduction, erythroid improvement). 
The assumption was that if the RBC TI rate of 30% with imetelstat treatment is true, the probability of 
passing the futility criterion would be 97%. 
Upon review of the efficacy and safety data observed with the 7.5 mg/kg dose among 32 subjects in the 
initial cohort of Part 1, a subset of 13 subjects was identified with higher hematologic response rates. These 
were subjects with non-del(5q) MDS and without prior exposure to either hypomethylating agents or 
lenalidomide. As of Amendment 2, Part 1 was expanded to include only subjects who meet these criteria, 
with the goal to confirm the safety and efficacy data seen in this subset and to re-confirm the dose. Twenty-
five additional subjects with non-del(5q) MDS and without prior exposure to either hypomethylating agents 
or lenalidomide were enrolled for a total of 38 (from 57 enrolled in Part 1) that met these criteria.  
Since data from Part 1 for this target population show clinical benefit of treatment with imetelstat 
(Section 1.1.5), Part 2 of the main study will be initiated in subjects with non-del(5q) MDS without prior 
exposure to either hypomethylating agents or lenalidomide. 
In the main study of Part 2, approximately 170 subjects will be randomized in a 2:1 ratio to receive either 
imetelstat or placebo. Using a 2:1 ratio randomization and a 2-group continuity corrected Chi-square test 
with 0.05 (2-sided) significance level, 150 subjects are needed to achieve a power of approximately 88% 
to detect the difference between a RBC TI rate of 30% in the imetelstat group and a RBC TI rate of 7.5% 
in the placebo group. After correction for a 10% drop-out rate, a total of approximately 170 subjects 
(115 subjects in the imetelstat group and 55 subjects in the placebo group) will be needed. The overall study 
power from Part 1 and Part 2 is approximately 85%. 
Efficacy data in Part 1 will be descriptively summarized based on the treated population. The proportion of 
subjects with 8-week RBC TI, 24-week RBC TI, CR, PR, mCR, hematologic improvement, and other 
binary endpoints will be summarized with percentage along with its 95% 2-sided exact confidence interval. 
Efficacy data in the main study of Part 2 will be compared between the imetelstat group and the placebo 
group based on the intent to treat population. Transfusion independence rates will be summarized with 
frequency and percentage along with a 2-sided 95% confidence interval for each treatment group. The 
comparison will be based on stratified Cochran-Mantel-Haenszel test adjusting for the stratification factors 
at a two-sided significance level of 0.05. 
Safety variables are to be tabulated by descriptive statistics. 
The ECG and concentration-QTc in the Ventricular Repolarization substudy as well as safety and limited 
efficacy based on the additional 45 evaluable subjects enrolled, will be performed separately from the 
primary analysis of 170 subjects in the main study of Part 2 (see Attachment 11). These data may only be 
available after the primary analysis of the main study of Part 2 has already been completed. 
 

GRN163L (imetelstat) 
 
 
  
 
 
 
 
 
 
 
 
 
Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
Status: Final, Date: 13 December 2022 
 
 
 
TIME AND EVENTS SCHEDULES 
Table 1: 
Time and Events Schedule for Part 1 (Open-label, Imetelstat Treatment) 
 
PHASE 
Screening 
Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment 
Follow-up 
Phase 
Study Procedures 
Comments 
Up to 28 days 
before first 
dose 
Cycle 1 
Day 1 
(predose) 
Cycle 1 
Day 8, 15, 22 
Cycle 2 
Day 1, 8, 15, 
22 
Cycle 3 until 
EOT 
Day 1 
EOT Visit 
within 30 
days after 
last dose 
Survival 
Follow-up 
Every 12-16 
weeks 
Screening 
Informed consent 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
Medical history and 
demographics 
 
X 
 
 
 
 
 
 
Study Medication Administration 
Dispense/administer study 
drug 
Refers to imetelstat (see Section 6) The screening weight is 
considered baseline for dose calculation. Recalculate dose if 
≥10% weight change from baseline. Dosing should begin within 
72 hours of enrollment in IWRS. 
 
X 
 
X (D1 only) 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
Physical exam (including 
weight) 
Full PE at screening; limited symptom-directed PE thereafter.   
X 
X 
 
X (D1 only) 
X 
X 
 
Vital signs 
Includes temperature, HR, SBP and DBP (preferably in a seated 
position). Measure and record prior to infusion. 
X 
X 
 
X (D1 only) 
X 
X 
 
12-lead ECG 
At screening, at C2D1 and as clinically indicated.  
X 
 
 
X (D1 only) 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
Transfusion history and 
status, myeloid growth 
factor treatment 
Assessment of RBC transfusion requirement 16 weeks prior to 
C1D1 and at each clinic visit until end of treatment. For subjects 
who stop treatment before 12 months, continue to collect 
transfusion data for a minimum of 12 months from C1D1. Sites 
should make every attempt to obtain complete information, 
including both in-patient and out-patient transfusions (see 
Section 9.3.1.1 for additional information).  
X 
X 
 
X (D1 only) 
X  
X 
X (every 4-6 
weeks) until 
first transfusion 
in 
Posttreatment 
Follow-up 
Hematology 
Screening tests should be within 14 days prior to C1D1. For 
C1D1, no need to repeat if the screening tests were performed 
within 5 days. Refer to the Inclusion Criteria (Section 4.1) for 
further details. After C1D1, tests must be performed within 48h 
before the scheduled visit. For all cycles, if tests are repeated 
on the day of the visit, the most recent results should be 
reviewed before dosing. Perform unscheduled weekly follow-up 
after any Grade ≥3 thrombocytopenia or neutropenia until 
values return to baseline.  
X 
X 
X 
X 
X 
X 
X (first visit if 
feasible) 
 
46 
 

GRN163L (imetelstat) 
 
 
 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
47 
Status: Final, Date: 13 December 2022 
Table 1 Continued: 
Time and Events Schedule for Part 1 (Open-label, Imetelstat Treatment) 
 
PHASE 
Screening 
Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment 
Follow-up 
Phase 
Study Procedures 
Comments 
Up to 28 
days before 
first dose 
Cycle 1 
Day 1 
(predose) 
Cycle 1 
Day 8, 15, 22 
Cycle 2 
Day 1, 8, 15, 
22 
Cycle 3 until 
EOT 
Day 1 
EOT Visit 
within 30 days 
after last dose 
Survival 
Follow-up 
Every 12-16 
weeks 
BM aspirate, biopsy 
All BM biopsies must be assessed for presence of fibrosis. A 
BM aspirate and biopsy with iron stain completed up to 12 
weeks prior to C1D1 may be used for sponsor confirmation of 
eligibility; otherwise BM biopsy and aspirate must be done at 
screening (within 28 days of C1D1). After baseline, BM 
assessments can be performed with a window of ±7 days. 
Following PR or CR, aspirate should be repeated 4 to 8 weeks 
later for confirmatory purposes. If assessment occurred within 
8 weeks of EOT a repeat is not required. See below for 
additional required BM sampling for biomarkers. 
X 
Aspirate: Every 24 weeks after C1D1, at time of suspected HI-E (Hb), PR, 
or CR, and every 24 weeks thereafter up to and including suspected PD  
Biopsy: annually (every 48 weeks after C1D1 in conjunction with BM 
aspirate) and at suspected PD 
 
Response assessment 
Per IWG 2006; see Attachment 5. Each response assessment 
requires assessment of peripheral blood and RBC transfusion 
requirements. Bone marrow analysis is required every 24 
weeks, with additional assessments at the time of suspected 
response or progression. If study drug is discontinued for any 
reason other than disease progression, refer to Section 9.1.5 
 
Every 12 weeks from C1D1 (±1 week) up to week 72, then every 24 weeks until suspected 
PD 
At suspected 
PD 
ECOG performance status  
See Attachment 4 
X 
X 
 
X (D1 only) 
X 
X 
 
Survival status and 
subsequent therapy 
Subsequent therapy collected throughout survival follow-up 
period. 
 
 
 
 
 
X 
X 
Clinical Laboratory Assessments 
Chemistry 
Screening tests should be performed within 14 days prior to 
C1D1. For C1D1, no need to repeat if Screening tests 
performed within 5 days. After C1D1, tests must be performed 
within 48h before the scheduled visit. Refer to Inclusion 
Criteria (Section 4.1) for further details. Refer to Sections 9.8 
and 9.8.1 for additional detail on required clinical laboratory 
testing.  
X 
X 
X 
X (D1 only) 
X 
X 
 
Chemistry panel for LFT 
investigations 
Includes GGT, chloride, bicarbonate, magnesium, and 
fractionated bilirubin. For subjects with AST, ALT, ALP or 
bilirubin Grade ≥3, repeat chemistry panel and LFT 
investigations panel weekly until bilirubin with fractionation is 
<3x ULN, and AST, ALT and ALP is <5x ULN. Subjects with 
Grade 1 or Grade 2 elevations in AST, ALT, ALP, or bilirubin at 
time of treatment discontinuation, continue to test monthly until 
resolution to at least baseline.  
 
 
 
If an adverse event of interest occurs 
 
INR (or PT) and aPTT 
With additional assessments performed during treatment 
phase if subject has a hemorrhagic event. 
X 
 
Repeat during study if subject has a Grade ≥3 bleeding event 
 
 
 
 
 

GRN163L (imetelstat) 
 
 
 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
48 
Status: Final, Date: 13 December 2022 
Table 1 Continued: 
Time and Events Schedule for Part 1 (Open-label, Imetelstat Treatment) 
 
PHASE 
Screening 
Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment 
Follow-up 
Phase 
Study Procedures 
Comments 
Up to 28 
days before 
first dose 
Cycle 1 
Day 1 
(predose) 
Cycle 1 
Day 8, 15, 22 
Cycle 2 
Day 1, 8, 
15, 22 
Cycle 3 until 
EOT 
Day 1 
EOT Visit 
within 30 days 
after last dose 
Survival 
Follow-up 
Every 12-16 
weeks 
Serum EPO level 
Only required during treatment at first suspected response. 
Repeat assessment is not required if response further 
improves. 
X 
At time of suspected HI-E (Hb), PR, CR 
Serum ferritin, transferrin 
saturation 
 
X 
X 
 
X (D1 only) 
X 
X 
 
B12 / folic acid / 
reticulocytes 
 
X 
 
 
 
 
 
 
Hepatitis serologies 
Comprehensive hepatitis serology panel A through E. Hepatitis 
D serology is only required if the subject tests positive for the 
hepatitis B surface antigen (HBsAg). 
X 
 
 
 
 
 
 
Serum or urine pregnancy 
test  
 
X 
 
 
 
 
 
 
Pharmacokinetics, Pharmacodynamics and Immunogenicity 
Pharmacokinetic / 
immunogenicity samples 
See Table 2, Part 1 PK Time and Events Schedule. If 
possible, anytime an IRR is observed, a blood sample should 
be drawn as soon as possible after the IRR for potential 
immune response and pharmacokinetic analysis. 
 
X 
 
X (D1 only) 
X (Cycle 4 then 
every 3 cycles) 
X 
X  
(first visit if 
feasible) 
TA, TL and hTERT 
All subjects in Part 1 will have predose and on treatment 
samples collected. 
 
X (predose and 
24h postdose) 
X (D8 only) 
X (D8 only) 
At time of suspected PR, CR, and PD 
 
Bone Marrow 
BM aspirate for cytogenetics 
Local cytogenetics results should be obtained for screening; 
samples must also be submitted to the central lab. The 
baseline aspirate sample for the central laboratory may be 
collected during Screening or before dosing on C1D1. After 
baseline, BM assessments can be performed with a window of 
±7 days. If BM aspiration yields a dry tap, see Section 9.5.  
X 
At the time of suspected PD for all subjects. For subjects with baseline 
abnormalities, also at the time of suspected PR, CR, or HI-E (Hb) and 
every 24 weeks thereafter up to and including suspected PD. Information 
will be provided to the sites on which subjects will need to have repeat BM 
aspirate samples. 
 
BM aspirate for RNA Seq or 
CyTOF 
Samples must be submitted to the central lab for all subjects if 
collection of the sample is feasible. The baseline aspirate 
sample may be collected during Screening or before dosing on 
C1D1. After baseline, BM assessments can be performed with 
a window of ±7 days. 
X 
At time of suspected HI-E (Hb), PR, CR, and PD 
 
Biomarkers 
 
 
 
 
 
 
 
Mutation analysis 
 
 
X 
At the time of suspected response (CR, PR, HI-E [Hb] or PD 
 
Immunophenotyping 
 
X 
 
X 
(D8 only) 
X (D8 only) 
At time of suspected PR, CR and PD 
 
Ongoing Subject Review 
 
 
 
 
 
Concomitant therapy 
 
X 
Continuous 
X 
 
Adverse events 
 
X 
Continuous 
X 
 
Abbreviations: BM=Bone Marrow; C=Cycle; CR=complete remission; CyTOF= cytometry by time of flight ; D=Day; DBP=diastolic blood pressure; EOT=end of treatment; EPO=erythropoietin; GGT=gamma-glutamyl transpeptidase;  
HI-E (Hb)=hematologic improvement-erythroid (hemoglobin); hTERT=human telomerase reverse transcriptase; HR=heart rate; INR=international normalized ratio; IRR=infusion-related reaction; IWRS=interactive web response 
system; PD=disease progression; PE=physical exam; PK=pharmacokinetic; PR=partial remission; PT=prothrombin time; SBP=systolic blood pressure; TA=telomerase activity; TL=telomere length; ULN=upper limit of normal  

GRN163L (imetelstat) 
 
 
 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
49 
Status: Final, Date: 13 December 2022 
Table 2: 
Time and Events for Part 1 Pharmacokinetic / Immunogenicity Sampling (Amendment 2)   
Study Day 
Pharmacokinetic Blood  
Sampling Time a 
Pharmacokinetic 
Blood Sampling  
Immunogenicity 
Evaluation c,d 
Cycle 1 Day 1 
0 (before start of infusion) 
 
X 
Cycle 1 Day 1 
2h b 
X 
 
Cycle 1 Day 1 
4-5h 
X 
 
Cycle 1 Day 1 
6h-7h 
X 
 
Day 1 of all 
subsequent cycles  
2h b 
X 
 
Day 1 of Cycles 4, 7, 
10, etc. 
0 (before the start of the 
infusion) 
 
X d 
End of Treatment 
during the visit 
X 
X d 
First Posttreatment 
Follow-up 
during the first visit 
X 
X d 
Abbreviations: h=hour; PK=pharmacokinetic  
a. 
All samples are collected at the time point relative to the START of the infusion. 
b. 
For the 2-hour time points (relative to the start of the infusion), the pharmacokinetic sample should be taken immediately 
before the end of the infusion (ie, this includes cases where infusion time is extended beyond 2 hours). 
c. 
An aliquot from the pharmacokinetic sample will be used to assess immunogenicity (separate blood draw not needed). If 
possible, anytime an IRR is observed, a blood sample should be drawn as soon as possible after the IRR for potential 
immune response and pharmacokinetic analysis. 
d. 
Beginning at Cycle 4, collect a sample at predose Day 1 and then predose every 3 cycles (Cycles 7, 10, etc.); at the EOT 
visit, and at the first posttreatment visit.  
Note: Ten subjects enrolled in Part 1 completed serial pharmacokinetic sampling before implementation of Amendment 2. The 
time points for serial PK sampling are provided in Amendment 1.   
 
 

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 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
50 
Status: Final, Date: 13 December 2022 
Table 3: 
Time and Events Schedule for Part 2 Main Study (Double-blind, Randomized 2:1, Imetelstat or Placebo Treatment) 
 
PHASE 
Screening Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment Follow-
up Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomization 
Cycle 1 
Day 1 
(predose) 
Cycle 1 
Day 8, 
15, 22 
Cycle 2 
Day 1, 
8, 15, 
22 
Cycle 3 
until EOT 
Day 1 
EOT Visit 
30 ±3 days 
after last dose 
Survival Follow-up 
Every 12-16 weeks 
Screening 
 
 
 
 
 
 
 
 
Informed consent 
Refer to Section 9.1.3 for guidance regarding COVID-19 and further 
clarification of screening procedures. 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
X 
 
 
 
 
 
Medical history and 
demographics 
 
X 
 
 
 
 
 
 
Study Medication Administration 
Randomization 
Randomization will occur on C1D1 or up to 72h prior to study drug 
administration 
 
X  
 
 
 
 
 
Dispense/administer study 
drug 
Refers to Imetelstat or placebo (see Section 6). The screening 
weight is considered baseline for dose calculation. Recalculate dose 
if ≥10% weight change from baseline. Dosing should begin within 
72 hours of randomization in IWRS. 
 
X 
 
X (D1 
only) 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
Physical exam (including 
weight)  
Full PE at Screening; limited symptom-directed PE thereafter.   
Refer to Section 9.8.4 for guidance regarding COVID-19. 
X 
X 
 
X (D1 
only) 
X 
X 
 
Vital signs 
Includes temperature, HR, SBP and DBP (preferably in a seated 
position). Measured and recorded prior to infusion. 
X 
X 
 
X (D1 
only) 
X 
X 
 
12-lead ECG 
At screening, at C2D1 and as clinically indicated. 
X 
 
 
X (D1 
only) 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
Transfusion history and 
status; myeloid growth factor 
treatment 
Assessment of RBC transfusion requirement 16 weeks prior to 
Randomization and at each clinic visit until the end of treatment. 
Sites should make every attempt to obtain complete information, 
including both in-patient and out-patient transfusions (see Section 
9.3.1.1 for additional information). Pre-transfusion Hb must be 
documented. 
Note: if DE Visit does not align with a Cycle Day 1 visit, then 
transfusion data must be collected at the DE Visit. 
X 
X 
 
X (D1 
only) 
X  
X 
X (every 4-6 weeks) until 
first transfusion in 
Posttreatment follow-up 
 
 

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 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
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Status: Final, Date: 13 December 2022 
Table 3 Continued: 
Time and Events Schedule for Part 2 Main Study (Double-blind, Randomized 2:1, Imetelstat or Placebo Treatment) 
 
PHASE 
Screening Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment Follow-
up Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomization 
Cycle 1 
Day 1 
(predose) 
Cycle 1 
Day 8, 
15, 22 
Cycle 2 
Day 1, 
8, 15, 
22 
Cycle 3 until 
EOT 
Day 1 
EOT Visit 
30 ±3 days 
after last dose 
Survival Follow-up 
Every 12-16 weeks 
Hematology (local laboratory) 
Screening tests should be within 14 days prior to Randomization. For 
C1D1, no need to repeat if Screening tests performed within 5 days. 
Refer to Inclusion Criteria (Section 4.1) for further details. After C1D1, 
tests must be performed within 48h before the scheduled visit. For all 
cycles, if tests are repeated on the day of the visit, the most recent 
results should be reviewed before dosing. Perform unscheduled 
weekly follow-up after any Grade ≥3 thrombocytopenia or 
neutropenia until values return to baseline. Testing should be 
conducted pre-transfusion, if feasible. Hematology panel includes 
hemoglobin, platelet count, white blood cell count, ANC. Absolute 
peripheral blast count should be done prior to randomization and on 
D1 of each cycle only. 
Note: if DE Visit does not align with a Cycle Day 1 visit, then 
hematology (local) is required at the DE Visit. 
X 
X 
X 
X 
X 
X 
X (first visit if feasible) 
Hematology  
(central laboratory) 
Hematology panel assessed in central laboratory will be hemoglobin, 
platelet count, white blood cell count and ANC. Central hematology 
sample should also be collected pre-transfusion, if feasible. 
 
Manual absolute peripheral blast count for the central lab should be 
done prior to randomization and on D1 of each cycle only. 
 
Note: if DE Visit does not align with a Cycle Day 1 visit, then 
hematology (central) is required at the DE Visit. 
X 
X 
X 
X 
X 
X 
X (first visit if feasible) 
 
 

GRN163L (imetelstat) 
 
 
 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
52 
Status: Final, Date: 13 December 2022 
Table 3 Continued: 
Time and Events Schedule for Part 2 Main Study (Double-blind, Randomized 2:1, Imetelstat or Placebo Treatment) 
 
PHASE 
Screening Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment Follow-
up Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomization 
Cycle 1 
Day 1 
(predose) 
Cycle 1 
Day 8, 
15, 22 
Cycle 
2 
Day 1, 
8, 15, 
22 
Cycle 3 until 
EOT 
Day 1 
EOT Visit 
30 ±3 days 
after last dose 
Survival Follow-up 
Every 12-16 weeks 
BM aspirate, biopsy 
A BM aspirate and biopsy with iron stain completed up to 12 weeks 
prior to Randomization may be used for confirmation of eligibility 
(assessed both locally and centrally); otherwise BM biopsy and 
aspirate assessment must be done during screening. After baseline, 
BM assessments may be performed with a window of ±7 days. 
Following investigator-assessed CR, PR, or mCR, in subjects with 
>5% baseline bone marrow aspirate blasts, repeat aspirate 4 to 8 
weeks later for confirmatory purposes, if clinically feasible (also see 
Section 9.1.4). 
Central Pathology Review: Timely submission of all bone marrow 
samples (aspirate smear and bone marrow biopsy) to the 
Independent Central Pathology Reviewer is required for diagnostic 
confirmation. Local pathology assessments are used for treatment 
decisions. See below for additional required BM sampling for 
cytogenics and biomarkers. 
X 
Aspirate: Every 24 weeks after C1D1, at time of suspected PR, CR, or 
mCR and every 24 weeks thereafter up to and including suspected PD 
 
Biopsy: annually (every 48 weeks after C1D1 in conjunction with BM 
aspirate) and at suspected PD 
 
Response assessment 
Per modified IWG 2006; see Attachment 5 (see Section 11.13 for 
adjudication of assessments by independent review). Each response 
assessment every 12 weeks requires review of peripheral blood and 
RBC transfusion requirements. In addition, bone marrow analysis 
(including central review) is required every 24 weeks with additional 
assessments at the time of suspected response or progression. 
Investigators will use local laboratory and bone marrow results for 
response evaluations. If study drug is discontinued for any reason 
other than disease progression, refer to Section 9.1.5. See under 
Hematology (central laboratory) for hematology panel and peripheral 
blast count to be used for response assessment. 
Note: CR, PR or mCR only to be assessed in subjects with >5% 
baseline bone marrow aspirate blasts. 
 
Every 12 weeks from C1D1 (±1 week) up to week 72, then every 24 weeks 
until suspected PD 
At suspected PD 
ECOG performance status 
See Attachment 4 
X 
X 
 
X (D1 
only) 
X 
X 
 
 
 

GRN163L (imetelstat) 
 
 
 Clinical Protocol 63935937MDS3001 Amendment 8/USA-1 
 
53 
Status: Final, Date: 13 December 2022 
Table 3 Continued: 
Time and Events Schedule for Part 2 Main Study (Double-blind, Randomized 2:1, Imetelstat or Placebo Treatment) 
 
PHASE 
Screening Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment 
Follow-up Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomization 
Cycle 1 
Day 1 
(predo
se) 
Cycle 1 
Day 8, 
15, 22 
Cycle 2 
Day 1, 8, 15, 
22 
Cycle 3 until 
EOT 
Day 1 
EOT Visit 
30 ±3 days after 
last dose 
Survival Follow-up 
Every 12-16 weeks 
FACT-An 
See Attachment 6; At all visits, complete before any tests, 
procedures, dosing or other consultations are performed and before 
the subject is informed of any assessment results (eg, hemoglobin 
values), when possible.  
 
X 
 
X (D1 only) 
X 
X 
X 
(until start of 
subsequent therapy) 
EQ-5D-5L 
See Attachment 7; At all visits, complete before any tests, 
procedures, dosing or other consultations are performed and before 
the subject is informed of any assessment results (eg, hemoglobin 
values), when possible. 
 
X 
 
X (D1 only) 
X 
X 
X 
(until start of 
subsequent therapy) 
QUALMS 
See Attachment 8. At all visits, complete before any tests, 
procedures, dosing or other consultations are performed and before 
the subject is informed of any assessment results (eg, hemoglobin 
values), when possible. 
 
X 
 
X (D1 only) 
X 
X 
X 
(until start of 
subsequent therapy) 
PGIC 
See Attachment 9. At all visits, complete before any tests, 
procedures, dosing or other consultations are performed and before 
the subject is informed of any assessment results (eg, hemoglobin 
values), when possible. 
 
 
 
X (D1 only) 
X 
X 
X 
(until start of 
subsequent therapy) 
Survival status and 
subsequent anti MDS/AML 
therapy 
Survival status and subsequent therapy are planned to be collected 
at the EOT visit and throughout survival follow-up period at least 
every 12 to 16 weeks (data may be collected more frequently, if 
needed). 
 
 
 
 
 
X 
X 
Clinical Laboratory Assessments 
Chemistry (local laboratory) 
Screening tests should be performed within 14 days prior to 
Randomization. For C1D1, no need to repeat if Screening tests 
performed within 5 days. After C1D1, tests must be performed within 
48h before the scheduled visit. Refer to Inclusion Criteria (Section 
4.1) for further details. Refer to Sections 9.8 and 9.8.1 for additional 
detail on required clinical laboratory testing.   
X 
X 
X 
X (D1 only) 
X 
X 
 
Chemistry panel for LFT 
investigations (local 
laboratory) 
Includes GGT, chloride, bicarbonate, magnesium, and fractionated 
bilirubin. For subjects with AST, ALT, ALP or bilirubin Grade ≥3, 
repeat chemistry panel and LFT investigations panel weekly until 
bilirubin with fractionation is <3x ULN, and AST, ALT and ALP is <5x 
ULN. Subjects with Grade 1 or Grade 2 elevations in AST, ALT, ALP 
or bilirubin at time of treatment discontinuation should continue to 
have tests monthly until resolution to at least baseline grade or until 
the start of subsequent therapy, whichever comes first. 
 
If an adverse event of interest occurs 
 
INR (or PT) and aPTT (local 
laboratory) 
With additional assessments performed during treatment phase if 
subject has a hemorrhagic event. 
X 
 
 Repeat during study if subject has a Grade ≥3 bleeding event 
 
 
 
Serum EPO level (local 
laboratory) 
Only required during treatment at first suspected response. Repeat 
assessment is not required if response further improves. 
X 
At time of suspected HI-E (Hb), PR, CR 

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Table 3 Continued: 
Time and Events Schedule for Part 2, Main Study (Double-blind, Randomized 2:1, Imetelstat or Placebo Treatment) 
 
PHASE 
Screening 
Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment Follow-
up Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomization 
Cycle 1 
Day 1 
(predose) 
Cycle 1 
Day 8, 
15, 22 
Cycle 2 
Day 1, 8, 15, 
22 
Cycle 3 
until EOT 
Day 1 
EOT Visit 
30 ±3 days 
after last dose 
Survival Follow-up 
Every 12-16 weeks 
Serum ferritin, transferrin 
saturation (local laboratory) 
Total iron binding capacity and serum iron (Fe) may be performed to 
calculate transferrin saturation if transferrin saturation is not 
available at the site. 
X 
X 
 
X (D1 only) 
X 
X 
 
B12 / folic acid / reticulocytes 
(local laboratory) 
 
X 
 
 
 
 
 
 
Hepatitis serologies 
Comprehensive hepatitis serology panel A through E. Hepatitis D 
serology is only required if the subject tests positive for the hepatitis 
B surface antigen (HBsAg). If the subject screening window is 
>28 days (Section 9.1.3), hepatitis screening results may still be 
used to determine eligibility outside of the initial 28-day screening 
period provided the subject is asymptomatic and does not meet 
Exclusion Criteria no. 12 (Section 4.2). 
X 
 
 
 
 
 
 
Serum or urine pregnancy 
test 
 
X 
 
 
X (D1 only) 
X 
X 
 
Pharmacokinetics, Pharmacodynamics and Immunogenicity 
Pharmacokinetic/  
Immunogenicity samples 
See Table 4, Part 2 PK Time and Events Schedule. 
 
 
Refer to Table 4. 
TL 
Collection of samples for TL assessments will be done at baseline 
(C1D1) only. 
 
X 
(predose) 
 
 
 
 
TA, and hTERT 
Collection of samples for TA and hTERT assessments will be done 
at C1D1 predose, 24h post-dose, C1D8, C2D1, C2D8.  
 
 
X 
(predose and 
24h post-
dose) 
X  
(at D8 
only) 
X  
(at D1 
[predose] and 
D8 only) 
 
 
Bone Marrow  
BM aspirate for cytogenetics 
(central laboratory) 
Baseline aspirate for cytogenetics should be obtained during 
screening and must be submitted to the central laboratory to confirm 
eligibility. 
If results are available from cytogenetic assessment within 12 weeks 
prior to Randomization, or if aspiration yields a dry tap, peripheral 
blood sample (instead of a bone marrow sample) may be submitted 
for central cytogenetic assessment at screening. 
Central or local cytogenetics may be used for eligibility and 
stratification purposes. After baseline, BM assessments may be 
performed with a window of ±7 days. 
 
X 
 
Aspirate is required for all subjects with baseline 
abnormalities every 24 weeks after C1D1, at the time of 
suspected PR, or CR and every 24 weeks thereafter up to 
and including suspected PD. Sample should be obtained at 
the time of suspected PD for all subjects irrespective of 
baseline status. Information will be provided to the sites on 
which subjects will need to have repeat BM aspirate samples. 
 
BM aspirate for RNA Seq or 
CyTOF (if feasible) 
Samples must be submitted to the central lab for all subjects if 
collection of the sample is feasible. The baseline aspirate sample 
may be collected during Screening or before dosing on C1D1. After 
baseline, BM assessments can be performed with a window of ±7 
days. 
X 
At time of suspected PR, CR, mCR, and PD 
 
 
 

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Table 3 Continued: 
Time and Events Schedule for Part 2, Main Study (Double-blind, Randomized 2:1, Imetelstat or Placebo Treatment) 
 
PHASE 
Screening 
Phase 
Treatment Phase 
(4-week cycles ±3 days) 
Posttreatment Follow-up Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomizatio
n 
Cycle 1 
Day 1 
(predose) 
Cycle 1 
Day 8, 
15, 22 
Cycle 2 
Day 1, 8, 
15, 22 
Cycle 3  
Day 1 
until EOT 
 
EOT Visit 
30 ±3 days 
after last dose 
Survival Follow-up 
Every 12-16 weeks 
Biomarkers  
Mutation analysis 
 
 
X 
Every 12 weeks after C1D1, at time of suspected response  
HI-E(Hb), PR, mCR or CR and at time of PD   
 
Ongoing Subject Review 
Concomitant therapy 
 
X 
Continuous 
X 
 
Adverse events 
 
X 
Continuous 
X 
 
Medical Resource 
Utilization 
Data associated with medical encounters (not protocol specified), 
will be collected for all subjects throughout the study from the time 
of first dose until the EOT or 30 days after the last dose of study 
drug, whichever occurs later. 
 
Continuous 
X 
 
Abbreviations: AML = acute myeloid leukemia; BM=Bone Marrow; C=Cycle; CR=complete remission; CyTOF=cytometry by time of flight ; D=Day; DBP=diastolic blood pressure; EOT=end of treatment; EPO=erythropoietin; 
EQ-5D-5L=EuroQol-EQ-5D-5L; FACT-An= Functional Assessment of Cancer Therapy - Anemia-Related Effects; HI-E (Hb)=hematologic improvement-erythroid (hemoglobin); HR=heart rate; GGT= gamma-glutamyl 
transpeptidase; hTERT = human telomerase reverse transcriptase; INR=international normalized ratio; IRR=infusion-related reaction; IWRS=interactive web response system; mCR=marrow complete remission; 
MDS = myelodysplastic syndrome; PD=disease progression; PE=physical exam; PGIC= Patient Global Impression of Change; PK=pharmacokinetic; PR=partial remission; PT=prothrombin time; QUALMS= Quality of Life in 
Myelodysplasia Scale; SBP=systolic blood pressure; TA=telomerase activity; TL=telomere length; ULN=upper limit of normal 
 
 
 

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Table 4:  
Time and Events for Part 2, Main Study Pharmacokinetic / Immunogenicity Sampling 
Study Day 
Pharmacokinetic Blood  
Sampling Time a 
Pharmacokinetic 
Blood Sampling  
Immunogenicity 
Evaluation  
Cycle 1 Day 1 
0 (before start of infusion) 
 
X 
Cycle 1 Day 1 
2hb (end of infusion) 
X 
 
Cycle 1 Day 1 
4-5 h 
X 
 
Cycle 1 Day 1 
6-7 h 
X 
 
Day 1 of all 
subsequent cycles  
2h b (end of infusion) 
X 
 
Day 1 of Cycles 4, 7, 
10, etc. 
0 (before the start of the 
infusion) 
 
X  
If IRR is observed 
As soon as possible after 
IRR is observed 
X 
X c 
End of Treatment 
During the visit 
 
X 
First Posttreatment 
Follow-up, if feasible 
During the first visit 
 
X 
a. 
All samples are collected at the time point relative to the START of the infusion. 
b. 
For the 2-hour time points (relative to the start of the infusion), the pharmacokinetic sample should be taken immediately 
before the end of the infusion (ie, this includes cases where infusion time is extended beyond 2 hours). 
c. 
An aliquot from the pharmacokinetic sample will be used to assess immunogenicity (separate blood draw not needed). 
 

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Table 5 
Time and Events Schedule for Extension Phase 
Study Procedures 
Comments 
All Subjects 
Extended 
Treatment 
(4-week cycles 
± 3 days) 
EOT Visit  
30 ± 3 days 
after last dose 
Extended Follow-up 
(Every 16 weeks 
± 7 days from EOT 
Visit) 
Informed Consent 
All subjects must provide informed consent to enter the 
Extension Phase. This must occur before the first dose 
of imetelstat for subjects continuing treatment in the 
Extension Phase, or before the first extended follow-up 
assessment for subjects continuing in the Extended 
Follow-up Phase. 
X 
 
 
 
Dispense/administer study 
drug 
Refer to imetelstat Section 6 for dose modification 
requirements. Investigator should assess chemistry and 
hematology results prior to dosing. 
 
X (Day 1) 
 
 
Directed physical exam 
(including weight) 
Limited symptom-directed physical exam. 
Refer to Section 9.8.4 for guidance regarding COVID-19. 
 
X 
X 
 
Vital signs 
Includes temperature, heart rate, SBP, and DBP 
(preferably in a seated position). Measured and 
recorded prior to infusion. 
 
X 
X 
 
Transfusion status; 
 myeloid growth factor 
treatment 
Sites should make every attempt to obtain complete 
information, including both in-patient and out-patient 
transfusions (see Section 9.3.1.1 for additional 
information). Pre-transfusion Hb must be documented. 
 
X 
X 
X (until first 
transfusion in 
Extended Follow-up) 
Chemistry (local laboratory) 
Tests must be performed within 48 hours before the 
scheduled visit. Refer to Inclusion Criteria (Section 4.1) 
for further details. Refer to Sections 9.8 and 9.8.1 for 
additional detail on required clinical laboratory testing.   
 
X 
X 
 
Hematology (local 
laboratory) 
Tests must be performed within 48 hours before the 
scheduled visit. For all cycles, if tests are repeated on 
the day of the visit, the most recent results should be 
reviewed before dosing. Perform unscheduled weekly 
follow-up after any Grade ≥3 thrombocytopenia or 
neutropenia until values return to baseline. Testing 
should be conducted pre-transfusion, if feasible.  
Hematology panel includes hemoglobin, platelet count, 
white blood cell count, ANC. Absolute peripheral blast 
count should be done on D1 of each cycle. 
 
X 
X 
 

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Study Procedures 
Comments 
All Subjects 
Extended 
Treatment 
(4-week cycles 
± 3 days) 
EOT Visit  
30 ± 3 days 
after last dose 
Extended Follow-up 
(Every 16 weeks 
± 7 days from EOT 
Visit) 
Chemistry panel for LFT 
investigations (local 
laboratory) 
Includes GGT, chloride, bicarbonate, magnesium, and 
fractionated bilirubin. For subjects with AST, ALT, ALP 
or bilirubin Grade ≥3, repeat chemistry panel and LFT 
investigations panel weekly until bilirubin with 
fractionation is <3x ULN, and AST, ALT and ALP is <5x 
ULN. Subjects with Grade 1 or Grade 2 elevations in 
AST, ALT, ALP or bilirubin at time of treatment 
discontinuation should continue to have tests monthly 
until resolution to at least baseline grade or until the start 
of subsequent therapy, whichever comes first. 
 
If an adverse event of interest occurs 
 
INR (or PT) and aPTT 
(local laboratory) 
Additional assessments performed during treatment 
phase if subject has a hemorrhagic event. 
 
Repeat during study if subject has a 
Grade ≥3 bleeding event   
 
Serum or urine pregnancy 
test 
 
 
X 
X 
 
Concomitant Therapy 
 
 
X 
X 
 
Adverse Events 
Adverse events, including SAE, pregnancy, and AEI 
monitoring, will continue in the Extension Phase 
 
X 
X 
 
Survival Status and 
Subsequent Anti-MDS/AML 
Therapy 
Survival status and subsequent therapy are planned to 
be collected throughout the survival follow-up 
approximately 16 weeks (data may be collected more 
frequently, if needed). 
 
 
X 
X 
Disease Progression 
Follow-up 
Per modified IWG 2006; see Attachment 5. Data to be 
collected includes date of disease progression to AML, 
and any available supporting bone marrow, peripheral 
blast, and laboratory results. 
 
Continuous 
Until progression to 
AML 
AE = adverse event; AEI = adverse event of interest; AML = acute myeloid leukemia; DBP = diastolic blood pressure; EOT = end of treatment; IWG = International Working Group;  
MDS = myelodysplastic syndrome; q = every; SAE = serious adverse event; SBP = systolic blood pressure 
 
 

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ABBREVIATIONS 
AE 
adverse event 
AEI 
adverse events of interest 
aPTT 
activated partial thromboplastin time 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BM 
bone marrow 
CFU-MK 
colony-forming unit-megakaryocyte  
Cmax 
maximum plasma concentration 
CMML 
chronic myelomonocytic leukemia 
CR 
complete remission 
CRF 
case report form 
CSC 
circulating stem cells 
CyTOF 
cytometry by time of flight 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
EPO 
erythropoietin 
EQ-5D-5L 
EuroQol-EQ-5D-5L 
ESA 
erythropoiesis-stimulating agent 
ET 
essential thrombocythemia 
FAB 
French-American-British 
FACT-An 
Functional Assessment of Cancer Therapy - Anemia-Related Effects 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FDA 
Food and Drug Administration 
G-CSF 
granulocyte-colony stimulating factor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
β-hCG 
beta human chorionic gonadotropin 
Hb 
hemoglobin 
HEC 
Hepatic Expert Committee 
HI-E 
hematologic improvement-erythroid 
HIV 
human immunodeficiency virus 
HR 
heart rate 
hTERT 
human telomerase reverse transcriptase 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IPSS 
International Prognostic Scoring System 
IPSS-R 
Revised International Prognostic Scoring System 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee (see Section 11.13)  
IRR 
infusion-related reaction 
ITT 
intent to treat 
IV 
intravenous 
IWG 
International Working Group 
IWG 2006 
International Working Group Response Criteria 2006 
IWG-MRT 
International Working Group – Myeloproliferative Neoplasms Research and Treatment 
IWRS 
interactive web response system 
LFT 
liver function tests 
mCR 
Marrow complete remission 
MDS 
myelodysplastic syndrome(s) 

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MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
Modified IWG 2006 
Proposed modification of IWG 2006 response criteria in myelodysplasia 
NASH 
nonalcoholic steatohepatitis 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OS 
overall survival 
PD 
progressive disease / disease progression 
PE 
physical exam 
PFS 
progression free survival 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetics 
PQC 
product quality complaint 
PR 
partial remission 
pRBC 
packed red blood cell 
PRO 
patient-reported outcome(s) 
PT 
prothrombin time 
qRT-PCR 
quantitative real-time polymerase chain reaction  
QTcB 
QT interval by Bazett’s correction method 
QTcF 
QT interval by Fridericia’s correction method 
QUALMS 
Quality of Life in Myelodysplasia Scale 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAP 
statistical analysis plan 
SIPM 
Site Investigational Product Manual 
TA 
telomerase activity 
TI 
transfusion independence 
TIC 
tumor inducing cell 
TL 
telomere length 
TQT 
Thorough QT study 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WPSS 
WHO Classification-Based Prognostic Scoring System 
 
 
 
 

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1. 
INTRODUCTION 
For the most current comprehensive nonclinical and clinical information regarding imetelstat, 
including information on adverse drug reactions, refer to the latest version of the Investigator's 
Brochure (IB) and IB Addenda for imetelstat.25 
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document. 
1.1. 
Background 
1.1.1. 
Telomeres and Telomerase 
Telomeres consist of tandem repeats of the deoxyribonucleic acid (DNA) sequence TTAGGG, 
forming a T-loop structure to cap the ends of all mammalian chromosomes. Capping prevents 
chromosomal fusion and prevents their ends from being misinterpreted as DNA double-strand 
breaks.36 Normal somatic cells have relatively long telomeres (approximately 9 to 12 kilobases) 
and typically do not express detectable levels of telomerase. Telomeres shorten approximately 
50 to 120 nucleotides at each cell division.21,18 When telomeres get critically short, they can no 
longer cap the chromosome ends, thus destabilizing the T-loop and exposing a 3’ overhang which 
triggers a DNA damage signal, ultimately resulting in senescence, terminal differentiation, or 
apoptosis. Telomere loss is prevented by the presence of the enzyme telomerase, which consists 
of 2 essential components: the human telomerase ribonucleic acid (RNA) template (hTR) and the 
human telomerase reverse transcriptase (hTERT) catalytic subunit. Telomerase counters telomere 
loss by the addition of TTAGGG repeats to the chromosome ends.19 
1.1.2. 
Imetelstat 
Imetelstat (GRN163L) is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that 
acts as a potent specific inhibitor of telomerase. Telomerase inhibition leads to loss of a cancer 
cell’s ability to maintain telomere length (TL), resulting in cell-cycle arrest, apoptosis, or 
senescence. Imetelstat binds with high affinity to the template region of the RNA component of 
hTERT and is a competitive inhibitor of telomerase enzymatic activity.2,23 Treatment of various 
cancer cells with imetelstat in vitro increases their sensitivity to radiation, decreases their 
clonogenic potential, and results in altered expression of stem-cell related genes.12,20 
1.1.2.1. 
Rationale for use of Imetelstat in Myelodysplastic Syndrome 
Myelodysplastic syndrome (MDS) is characterized by clonal myeloproliferation that arises from 
malignant progenitor cell clones that have shorter telomeres and multiple clonal genetic 
abnormalities. Telomerase is highly activated and continually upregulated in malignant progenitor 
clones enabling continued and uncontrolled proliferation. While telomerase activity (TA) is 
generally undetectable in normal somatic cells, it is expressed in approximately 85% of human 
cancers as well as in cancer progenitor cells, which are believed to play a critical role in 
dysregulated cell growth and tumor metastasis.20 In MDS, TA and expression of hTERT, a key 
catalytic subunit of telomerase, are significantly increased as compared to healthy controls.4,5 
Myelodysplastic syndrome patients with high TA have been shown to have a significantly shorter 

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overall survival (OS) as compared to those with lower TA.17 In addition, the average TL has been 
shown to be significantly shorter in MDS patients as compared to healthy controls,30,40 and 
progression of the disease and conversion of MDS to acute myeloid leukemia (AML) are 
connected with progressive decrease in TL.43 Several studies showed that higher TA and hTERT, 
and shorter TL correlate with International Prognostic Scoring System (IPSS) risk score in 
MDS.5,38,52 In low risk MDS patients, in addition to other factors, short telomeres and high TA 
were also reported as poor prognostic features.37,51 Given the role of TA in preventing cell 
senescence and apoptotic cell death in immortalized cells such as tumor cells,24 inhibition of TA 
constitutes an attractive therapeutic approach in MDS. 
1.1.3. 
Myelodysplastic Syndromes 
Myelodysplastic syndromes constitute a heterogeneous form of blood cancer that primarily affects 
the elderly and are characterized by anemia and other cytopenias and a high risk of leukemic 
transformation.7 In routine clinical practice, MDS are suspected when an otherwise unexplained 
anemia is associated with other cytopenias, increased mean corpuscular volume, or increased red 
cell distribution width. Diagnosis requires bone marrow examination and cytogenetic studies. The 
bone marrow is typically hyperproliferative. The diagnosis is based on demonstration of erythroid, 
granulocyte, or megakaryocyte dysplasia in 10% or more of informative cells.50 The natural history 
of MDS includes transformation to AML in a proportion of patients. 
The standard prognostic tool in MDS is the IPSS, which classifies patients into low, intermediate-
1, intermediate-2, and high risk categories on the basis of the percentage of bone marrow blasts, 
the karyotype, and the number of cytopenias. The median survival rates for the low, intermediate-
1, intermediate-2, and high risk categories are estimated at 5.7, 3.5, 1.2, and 0.4 years, respectively. 
The estimated times for 25% to transform to AML by prognostic group are 9.4, 3.3, 1.1 and 0.2 
years, respectively.7,15 Other prognostic systems have also been described, namely the World 
Health Organization (WHO) Classification-Based Prognostic Scoring System (WPSS)35 and the 
Revised International Prognostic Scoring System (IPSS-R).16 The IPSS is more frequently 
referenced in clinical studies. Patients with low and intermediate-1 risk MDS are also often 
referred to as having “lower-risk” disease, whereas those with intermediate-2 and high risk MDS 
are referred to as patients with “higher-risk” disease. 
Many anemic patients with MDS eventually develop dependence on packed red blood cell (pRBC) 
transfusions.45 In a cohort of patients in Italy, the nonleukemic causes of death were: cardiac 
events, including cardiomyopathies and arrhythmias (50%); infection (30%); bleeding 
complications (8%); and liver cirrhosis (8%).34,35 Examination of these cases suggests that iron 
overload after chronic transfusions may be a contributing factor in the overall morbidity of the 
disease. The development of transfusion dependence and iron overload (as measured by serum 
ferritin) was associated with further worsening of OS and leukemia-free survival in addition to the 
known risk factors associated with MDS WHO subtype and cytogenetics.34 Further evaluations 
have indicated that a transfusion requirement of 2 units per month reduces the life expectancy of 
a patient with MDS by approximately 50% (Figure 1).33 The use of iron chelation therapy may 
ameliorate some of the consequences of iron overload. However, its use in this setting is not 
universal.49 

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Figure 1:  
Survival According to Intensity of Red Blood Cell Transfusion  
Requirement 
 
Survival of MDS patients according to the intensity of their RBC transfusion requirement, calculated as the number of packed red 
cell units per month (U PRC/4WK) (data obtained from 426 patients diagnosed with MDS according to WHO criteria at the IRCCS 
Policlinico San Matteo, Pavia, Italy, between 1992 and 2004). The between-group comparison was performed by applying a Cox 
proportional hazard regression model with time dependent covariates.34  
1.1.4. 
Treatment Options for Myelodysplastic Syndromes 
For most patients with IPSS low and intermediate-1 risk MDS, the initial approach to treatment 
remains supportive care, aimed at alleviating cytopenias. This can be accomplished through 
transfusions or the use of erythropoiesis-stimulating agents (ESAs) or other hematopoietic growth 
factors. Among anemic patients with low and intermediate-1 risk MDS and anemia treated with 
ESAs, approximately 40% will achieve an International Working Group (IWG) defined 
hematologic improvement for a median duration of 2 years. The Nordic MDS group has developed 
a model which identifies patients more likely to respond to ESAs. Those with low or absent 
transfusion requirement (<2 pRBC units/month) and a low serum erythropoietin level 
(<500 mU/mL) have a higher response rate than those with high transfusion needs 
(≥2 units/month) and elevated serum erythropoietin levels (≥500 mU/mL); 74% versus 7%, 
respectively.22 
Treatment options after ESA failure (primary resistance or relapse after a response) in patients 
who remain with a low or intermediate-1 IPSS score for MDS are limited. Most patients eventually 
require long-term RBC transfusions. Early ESA failure (no response to ESA or relapse within 
6 months) appears to be a marker of disease severity and is associated with frequent subsequent 
AML progression (12-20% over 5 years) and a median survival of approximately 3.5 years.9,28 
Lenalidomide is approved by both the United States Food and Drug Association (FDA) and the 
European Medicines Agency for the treatment of lower risk (IPSS low and intermediate-1), 
transfusion-dependent MDS patients with the del(5q) chromosomal abnormality. In Phase 2 and 

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Phase 3 registration studies, approximately 60% of subjects achieved durable (>24 weeks) 
independence from RBC transfusions. The median duration of response was approximately 
2 years. Myelosuppression (neutropenia 51-55%; thrombocytopenia 23-44%) was the most 
frequently reported Grade 3 or 4 toxicity.10,31 Phase 2 and Phase 3 studies have also been conducted 
in transfusion-dependent MDS subjects who did not have the del(5q) abnormality. Rates and 
durability of transfusion independence (TI) were lower than those observed in the cohorts with the 
del(5q). Approximately one-quarter of subjects (27%) who received lenalidomide achieved RBC 
TI, with median duration of response ranging from 33 to 41 weeks.39,41 In the placebo controlled 
Phase 3 study, only 3% of placebo-treated subjects achieved TI lasting at least 8 weeks. 
In contrast to lower-risk MDS, poorer OS and more rapid progression to AML that characterizes 
higher-risk MDS warrant the initiation of disease-modifying therapy. In this setting, 2 
hypomethylating agents (azacitidine or decitabine) are used as single agents. The postulated 
mechanism of action is the reversal of aberrant methylation of tumor suppressor genes that are 
common in higher-risk MDS.26,42 In a Phase 3 study in which decitabine was compared with 
supportive care, 17% of patients achieved complete remission (CR) or partial remission (PR) 
according to IWG criteria, and another 13% showed hematologic improvement.27 When 
azacitidine was evaluated in a randomized study of MDS subjects (higher-risk and lower-risk with 
significant cytopenias) and compared to supportive care, 14% of subjects achieved CR or PR and 
an additional 30% showed hematologic improvement based on IWG criteria.44 
These hypomethylating agents are also used in lower risk MDS patients with multiple cytopenias, 
frequently after failure of other agents. Low-dose decitabine has been evaluated in 2 Phase 2 
studies. In 1 study, decitabine was given at a dose of 20 mg/m2 for 3 days per 28-day cycle to 
65 subjects with lower risk MDS, of whom 22% achieved an IWG response (per modified IWG 
2006).14 In the other study, decitabine was administered at 3.5 to 7 mg/m2 1-3 times weekly to 
25 subjects, of whom 47% achieved an IWG response.32 
Oral azacitidine has been evaluated in 1 study of 41 subjects, of whom 48% had lower risk disease. 
Among the 32 enrolled subjects with MDS, 35% of previously treated and 60% of first-line-treated 
subjects had an overall response (CR, hematologic improvement, or RBC/platelet TI). This drug 
is being explored in the Phase 3 setting.13 

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1.1.5. 
Clinical Experience with Imetelstat in Myeloproliferative 
Neoplasms and MDS 
Study CP14B015 (Phase 2) was the first proof of concept study in hematological malignancies. 
Subjects with essential thrombocythemia (ET) who were resistant to, intolerant of or had refused 
conventional therapies were enrolled. Imetelstat induced and maintained hematologic responses in 
100% of the subjects, with 16 of 18 (89%) achieving a CR. Importantly, 7 of 8 subjects with the 
JAK2V617F mutation achieved partial molecular response with 72% to 96% reduction in allele 
burden.3 
An open-label, Phase 2 study (CP14B019) was conducted to evaluate the safety and efficacy of 
single-agent imetelstat in multiple dosing cohorts in 60 subjects with myelofibrosis (MF). 
Additional cohorts enrolled subjects with MDS (N=9) and blast-phase MF (N=9). Among the 
33 MF subjects treated with 9.4 mg/kg imetelstat every 3 weeks (Arm A) or 9.4 mg/kg imetelstat 
on Days 1, 8, 15, 22 and then every 3 weeks (Arm B), the median duration of treatment was 
8.6 months (range 1.4 to 21.7 months) as of December 2014. Twelve of the 33 subjects (36.4%) 
achieved an overall response (CR, PR, or clinical improvement) as defined by the 2013 
International Working Group-Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) criteria. Of note, 7 subjects were in remission (defined as CR+PR) including 
4 subjects with a CR. Additionally, 5 subjects (15.2%) had clinical improvement.48 The 9 subjects 
in the MDS cohort were given a starting imetelstat dose of 7.5 mg/kg every 4 weeks. Median age 
was 70 years; 78% were male. This was lower than the dose given to the MF subjects to minimize 
the risk for myelosuppression in subjects with an already compromised bone marrow. All were 
anemic (hemoglobin [Hb]<10 g/dL) and 8 of the 9 subjects were considered to be transfusion 
dependent prestudy (per modified IWG 2006 criteria for MDS). Baseline IPSS scores were 
intermediate-1 (7 subjects) and intermediate-2 (2 subjects). Seven of these subjects had received 
prior treatments, including 6 who previously received ESAs. Additional treatments received by 
less than one-third of the cohort included lenalidomide, a Janus kinase inhibitor, hydroxyurea and 
hypomethylating agents. 
As of 10 May 2015 (CP14B019), the median duration of treatment with imetelstat was 13.7 months 
(range 6.6-17.9). Three subjects who had been deemed transfusion dependent prestudy became 
transfusion independent during treatment, defined as not requiring transfusions for at least 
8 weeks.47 Among these 3 subjects, the transfusion independent interval started between Weeks 9 
and 14, and the durations of TI were 9, 24 and 28 weeks. Hemoglobin increase of ≥1.5 g/dL above 
baseline following a transfusion-free period of at least 28 days was achieved by 4 subjects and 
occurred at Weeks 16 (in 2 subjects), 19, and 32. Hemoglobin increase of ≥1.5 g/dL after a 
transfusion-free period of ≥14 days was also observed in 4 subjects at Weeks 12, 16, 17, and 21. 
Three subjects who met both criteria went on to become transfusion independent; 2 others had 
only transient increases in Hb. 
A comprehensive summary of the clinical data is provided in the Investigator’s Brochure 
(Edition 14).25  

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Data from Part 1 of the current study demonstrated activity of imetelstat in subjects with MDS 
with higher rates of red blood cell (RBC) TI in subjects with non-del(5q).11,46 In the initial cohort 
of 32 MDS subjects, RBC TI was observed in 11 (34%) subjects, with a higher rate of RBC TI in 
7 of the 13 (54%) subjects with non-del(5q) MDS and no prior lenalidomide or hypomethylating 
agent therapy. The study was amended to include only these subjects. As of the clinical cut-off 
date of 26 October 2018, 38 subjects (13 original and 25 additional) who had non-del(5q) MDS 
and no prior lenalidomide or hypomethylating agent therapy were enrolled and dosed with 
imetelstat. The median follow-up for the initial 13 subjects was 29.1 months and 8.7 months for 
the additional 25 subjects. The median number of treatment cycles was 8 (range, 1-34) and the 
median dose intensity was 6.9 mg/kg/cycle. The median baseline transfusion burden was 8 units/8 
weeks (range, 4-14 units). The 8-week and 24-week were 14/38 (37%) subjects, and 
10/38 (26%) subjects, respectively.  The median time to onset of RBC TI was 8.1 weeks (range 
0.1-33.1 weeks) and the median duration of RBC TI has not been achieved (17 weeks- not 
estimated [NE]). The mean relative reduction of RBC transfusion burden was 68%, and 8 subjects 
(21%) had responses by modified IWG 2006 criteria (complete remission [CR]+ marrow CR + 
partial remission [PR]). The 24-week RBC TI responses were accompanied by a Hb rise of 
≥3 g/dL.  The HI-E rate was 71%. 
1.1.5.1. 
Clinical Pharmacology of Imetelstat 
Single-dose kinetics showed dose dependent increases in exposure at the 6 mg/kg to 11.7 mg/kg 
range with half-life ranging from 4 to 5 hours. At the 6 mg/kg to 11.7 mg/kg range, imetelstat 
clearance appears to be independent of dose. The excretion and metabolism of imetelstat has not 
been evaluated in the clinical setting. However, it is anticipated that imetelstat is predominantly 
metabolized in systemic circulation and its component fragments are excreted mainly via the 
urinary tract, as observed for other oligonucleotides. 
1.1.5.2. 
Clinical Safety of Imetelstat  
A detailed summary of safety is provided in the Investigator’s Brochure (Edition 14).25 
1.1.5.2.1. 
Hematologic Toxicities 
Cytopenias, in particular thrombocytopenia, are dose-limiting in both single-agent imetelstat 
studies and when imetelstat is combined with other chemotherapy. The frequency and severity of 
all cytopenias, particularly thrombocytopenia and neutropenia, was associated with the dose 
intensity (dose and frequency of dosing) of imetelstat, concomitant administration with other 
cytotoxic agents, the number and nature of prior chemotherapy regimens to which subjects had 
been exposed, and low marrow reserve. 
In Study CP14B019 (as of the clinical cutoff date of 10 May 2015), among the 9 subjects with 
MDS, the incidence of treatment-emergent Grade 3 and Grade 4 thrombocytopenia was 22.2% and 
11.1%, respectively.47 Treatment-emergent Grade 3 and Grade 4 neutropenia occurred in 44.4% 
and 22.2% of the MDS subjects, respectively.25 None of the Grade 3 or Grade 4 hematologic events 
lasted ≥4 weeks and all demonstrated reversibility. Despite several subjects having nadir absolute 

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neutrophil count (ANC) values below 1.0 x 109/L, no serious infections were reported (data on 
file). 
The incidence of treatment-emergent Grade 3 and 4 thrombocytopenia in the MF cohort (n=33) 
was 27.3% and 21.2%, respectively. Twelve (36.3%) subjects with MF required dose reduction, 
and 2 discontinued following these events. One subject died after suffering intracerebral 
hemorrhage in the setting of Grade 4 thrombocytopenia and febrile neutropenia. The incidence of 
treatment-emergent Grade 3 and 4 neutropenia in the MF cohort was 20.5% and 12.8%, 
respectively. Seven subjects with MF required dose reduction following Grade 3 or 4 neutropenia, 
but none discontinued due to this event. Grade 3 treatment-emergent anemia occurred in 52.6% of 
subjects with MF; no Grade 4 treatment-emergent anemia was reported. 
In Part 1 of the current study, Grade 3 or higher neutropenia was observed in 34/57 enrolled 
subjects (59.6%). Grade 3 or higher thrombocytopenia was observed in 31/57 enrolled subjects 
(54.4%) and anemia in 10/57 enrolled subjects (17.5%). Most of the cytopenias were manageable 
with dose modifications and resolved in approximately 4 weeks. Three subjects (5.3%) had febrile 
neutropenia. In general, cytopenia was managed by cycle delays and dose reduction.11,46   
1.1.5.2.2. 
Non-Hematologic Toxicities 
In Study CP14B019, the incidence of severe (Grade 3 or greater) non-hematologic adverse events 
was low. Grade 3 or higher events that occurred in at least 5% of all eligible subjects treated (n=78) 
were: fatigue (9.0%), lung infection (7.7%), hyperkalemia (6.4%), and atrial fibrillation, 
hypotension and heart failure (5.1% for each). Within the MDS cohort, the following ≥Grade 3 
events occurred in 1 subject each: fatigue and aspiration. One subject had 3 cardiac events of Grade 
3 or higher [Grade 3 heart failure, Grade 3 hypotension, and Grade 5 (fatal) cardiac arrest]; this 
same subject also had other Grade 3 non-hematologic adverse events of duodenal ulcer, 
hyperglycemia, hypoalbuminemia and hypocalcemia.25 
In Part 1 of the study Grade 3 or higher treatment-emergent adverse events were reported in 46 of 
the 57 enrolled subjects (80.7%).  Increased liver enzymes were reported in 3 (5.3%), back pain in 
3 (5.3%), bronchitis, cellulitis, hyponatremia and iron overload in 2 (3.5%) subjects each.  Other 
events occurred in 1 subject only and no specific trends in adverse events was noted (data on file).25  
1.1.5.2.3. 
Hepatotoxicity 
The adverse events of concern in the clinical studies thus far have been liver function test (LFT) 
abnormalities or clinical hepatic adverse events. 
Among the 9 subjects with MDS, no Grade 3 or 4 LFT abnormalities were reported. The 
frequencies of Grade 1 or 2 abnormalities were: alanine aminotransferase (ALT) 67%, aspartate 
aminotransferase (AST) 67%, alkaline phosphatase (ALP) 33.3% and total bilirubin 11%.47 The 
CP14B019 study is ongoing and LFT monitoring continues. Reversibility of liver function test 
abnormalities was demonstrated. Following cessation of imetelstat in the ET/ polycythemia vera 
and multiple myeloma subjects, there were no new liver-related adverse events and the LFT 
abnormalities resolved in the majority of the subjects whose data were available. However, the 

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clinical significance and long-term consequences of the abnormal hepatic biochemistry findings 
with ongoing treatment remain unknown at this time. Severe hepatobiliary events, including acute 
hepatic failure and cirrhosis have been observed and relationship to imetelstat cannot be excluded. 
Among the 33 subjects with MF in Study CP14B019, worsening in AST (60.6%) is the most 
commonly reported treatment emergent LFT parameter, followed by ALP (57.6%), total bilirubin 
(48.5%), and ALT (42.4%). Most LFT abnormalities were Grade 1 and Grade 2, with only 3 
subjects experiencing Grade 3 events (2 subjects with ALP and 1 subject with total bilirubin). No 
subject had Grade 3 or higher AST or ALT elevation. No hepatic adverse events attributed to 
imetelstat in MF subjects were reported and no treatment discontinuations or delays were due to 
LFT abnormalities. 
In Part 1 of the study, there were no elevation of LFTs consistent with Hy’s Law in any of the 
enrolled subjects. Of the 38 subjects in the target population, 3 (8%) subjects had reversible Grade 
3 LFT elevations and none of the LFT increases were considered to be drug-related by an 
Independent Hepatic Expert Committee.  
1.2. 
Overall Rationale for the Study 
Limited treatment options are available for RBC transfusion dependent, IPSS low or intermediate-
1 risk MDS patients who are considered poor candidates for ESA treatment (due to having both 
high levels of endogenous erythropoietin [EPO] and transfusion dependency) or who have already 
received at least 1 prior treatment with an ESA without achieving or maintaining a response. The 
median survival for low-risk MDS patients for whom ESA treatment has failed is about 3.5 years, 
which is considerably shorter than predicted at the time of diagnosis. Therefore, there remains a 
highly unmet need for effective treatments for these patients. 
Imetelstat, a first-in-class telomerase inhibitor, with its novel mechanism of action, may provide 
clinical benefit to MDS patients. Imetelstat has a long half-life and is preferentially distributed in 
the bone marrow, spleen and plasma.  Imetelstat accumulates in bone marrow, has the ability to 
target circulating stem cells (CSCs) and tumor inducing cells (TICs), inhibits malignant 
megakaryocyte colony-forming unit (CFU-MK) in vitro, targets diseases with short TL, and has 
the ability to inhibit telomerase. All such properties are relevant to patients with MDS, as this 
disease state arises from malignant progenitor cell clones, is associated with short TLs and highly 
active telomerase. In addition, data from Study CP14B015 suggest that imetelstat can selectively 
inhibit neoplastic clonal proliferation in patients with ET and provide a rationale for evaluating 
imetelstat in patients with other myeloproliferative neoplasms and MDS. Clinical data from Study 
CP14B019 further indicate that treatment with imetelstat resulted in transfusion independence and 
other measures of hematologic improvement in subjects with MDS. 
Furthermore, as summarized in Section 1.1.5, clinical data from Part 1 show that treatment with 
imetelstat provides clinical benefit in this patient population which warrants further investigation 
of imetelstat in Low/Int-1 MDS patients.  

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1.3. 
Benefit-risk Assessment: COVID-19 
As a result of the COVID-19 pandemic, which began in Wuhan, China in December 2019 and 
became a global public health emergency in March 2020, changes to this MDS3001 protocol were 
made as an Urgent Safety Measure (USM) after careful review of regulatory guidelines and 
outreach to investigators and study coordinators at participating sites.  These changes with respect 
to COVID-19 were outlined in a Dear Investigator Letter (DIL) dated 18 March 2020 and added 
to the protocol as part of Protocol Amendment 4 (PA4).  
Given that the MDS3001 study enrolls subjects with cancer who are in need of treatment, the 
protocol allows subjects who are in screening or on active treatment to continue to receive 
potentially beneficial treatment if the investigator determines that the risk of potential exposure to 
COVID-19 (ie, as a result of travel to the site and considering any other co-morbidities or risk 
factors the subject may have) does not outweigh the potential benefit of receiving treatment. 
Therefore, in order to protect the safety of these subjects, PA4 includes enhanced ongoing 
monitoring for signs and symptoms of COVID-19 and exposure to COVID-19. In addition, there 
is guidance provided for withholding treatment for subjects who have tested positive, who show 
signs and/or symptoms of COVID-19, or who have potential exposure to COVID-19. Decisions to 
either initiate or continue study treatment are left to the discretion of the local investigators 
depending on the outcome of these COVID-19 assessments and the overall status of each 
individual subject. 
For enrollment of new subjects on the study, given that each site and/or country may be impacted 
differently during the COVID-19 pandemic and changes may occur at a rapid pace, through close 
communication with the sites, it was determined that the sites should follow their own institutional 
guidelines, as well as making individual risk assessments of their sites ability to enroll new subjects 
and, when needed, to hold enrollment of new subjects at their site. 
Therefore, the additional measures for COVID-19 monitoring and treatment management outlined 
in PA4 are designed to minimize the risk to subjects posed by COVID-19 while enabling them to 
continue to receive treatment for their cancer. However, as outlined in the protocol, the ultimate 
decision on the appropriate course of action and risk/benefit for each subject will be made by the 
local investigator. As further developments in the COVID-19 pandemic emerge, the sponsor will 
continually assess the need for any additional changes to the study conduct and implement, as 
appropriate. 
With the emergence of approved vaccines for COVID-19, investigators should discuss the benefit 
versus risk of COVID-19 vaccination prior to enrollment or while on study. 

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2. 
OBJECTIVES AND HYPOTHESES 
2.1. 
Objectives 
Primary Objectives 
Part 1: To evaluate the efficacy and safety of imetelstat in transfusion dependent subjects with 
low or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment. 
Part 2: To compare the efficacy, in terms of RBC TI, of imetelstat to placebo in transfusion 
dependent subjects with low or intermediate-1 risk MDS that is relapsed/refractory to ESA 
treatment. 
Extension Phase: To evaluate the long-term safety, OS, and disease progression, including 
progression to AML in transfusion dependent subjects with low or intermediate-1 risk MDS that 
is relapsed/refractory to ESA treatment receiving imetelstat. 
Secondary Objectives (Part 1 and Part 2) 
The secondary objectives of this study are: 
• 
To assess the safety of imetelstat in subjects with MDS 
• 
To assess the time to RBC TI and duration of RBC TI 
• 
To assess the rate of hematologic improvement 
• 
To assess the rates of CR, PR, and mCR 
• 
To assess OS 
• 
To assess progression free survival (PFS) 
• 
To assess time to progression to AML 
• 
To assess the rate and amount of supportive care, including transfusions and myeloid growth 
factors (Part 2 only) 
• 
To evaluate the pharmacokinetics and immunogenicity of imetelstat in subjects with MDS 
• 
To assess the effect of imetelstat treatment on patient-reported outcomes (PROs) 
• 
To assess the effect of treatment on medical resource utilization (Part 2 only) 
• 
To assess the effect of imetelstat on corrected QT (QTc) interval in subjects in the Ventricular 
Repolarization substudy (to be reported separately from Part 2) 
Exploratory Objectives (Part 1 and Part 2) 
The exploratory objectives of this study are: 
• 
To evaluate pharmacodynamic biomarkers such as TA, TL and hTERT and to explore the 
association between baseline results and clinical response 
• 
To evaluate change of cytogenetic abnormalities and explore the association between baseline 
cytogenetic status and clinical response  

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• 
To evaluate baseline mutational status and mutation changes during treatment for exploring 
the association with clinical response 
• 
To explore the effects of imetelstat on immune profiles through immunophenotyping (Part 1 
only) 
• 
To 
evaluate 
the 
exposure-response 
relationship 
between 
pharmacokinetics 
and 
pharmacodynamic biomarkers, efficacy, and safety   
2.2. 
Hypothesis 
The primary hypothesis is that imetelstat will improve the rate of RBC TI as compared to placebo 
in transfusion dependent subjects with low or intermediate-1 risk MDS that is relapsed/refractory 
to ESA treatment. 
3. 
STUDY DESIGN AND RATIONALE 
3.1. 
Overview of Study Design 
This is a Phase 2/3, multicenter study of imetelstat in transfusion-dependent subjects with low or 
intermediate-1 risk MDS that is relapsed/refractory to ESA treatment (see Inclusion Criterion 5, 
Section 4.1). The study will consist of 2 parts, and approximately 270 subjects may be enrolled 
(Figure 2). Part 1 was an open-label, single-arm design to assess the efficacy and safety of 
imetelstat, which enrolled 57 subjects. Part 2 is a double-blind, randomized, placebo-controlled 
design to compare the efficacy of imetelstat with placebo. In addition to the approximately 
170 subjects to be enrolled in the main study in Part 2, approximately 45 subjects will be enrolled 
in a separate Ventricular Repolarization substudy. Subjects should be enrolled in the main study 
of Part 2 until enrollment is complete unless a subject is known to meet criteria that would make 
the subject ineligible for the main study (eg, del 5 q, prior HMA therapy). See Figure 2 for 
schematic overview of the study. 
Part 1 was an open-label, single-arm design to assess the efficacy and safety of imetelstat. 
Fifty-seven subjects were enrolled in Part 1, including the expansion cohort, and were followed-
up for safety, hematologic improvement, and reduction in transfusion requirement. The sponsor 
has reviewed and assessed all available data in Part 1, including blood counts, transfusion 
requirement, tolerability, pharmacokinetics, and pharmacodynamic biomarker data. 
The futility criteria before Amendment 2 were defined as follows: If 4 or fewer subjects among 30 
subjects in Part 1 achieve RBC TI lasting at least 8 weeks, the study will be stopped unless there 
is compelling clinical evidence of efficacy in one or more other endpoints (eg, transfusion 
reduction, erythroid improvement). Upon review of the efficacy and safety data observed with the 
7.5 mg/kg dose among 32 subjects in Part 1, a subset of 13 subjects was identified with higher 
hematologic response rates. These were subjects with non-del(5q) MDS and without prior 
exposure to either hypomethylating agents or lenalidomide. As of Amendment 2, Part 1 was 
expanded to include only subjects who meet these criteria, with the goal to confirm the safety and 
efficacy data seen in this subset and to re-confirm the dose. Twenty-five additional subjects with 
non-del(5q) MDS and without prior exposure to either hypomethylating agents or lenalidomide, 

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so called target population, were enrolled for a total of 38 (from 57 enrolled in Part 1) that met 
these criteria. 
Since data from Part 1 for this target population show clinical benefit of treatment with imetelstat 
(see Section 3.2 for a summary of data from the 38 subjects in the target population), Part 2 of the 
study has been initiated in subjects with non-del(5q) MDS and without prior exposure to either 
hypomethylating agents or lenalidomide. Enrollment into the study was temporarily held between 
Part 1 and Part 2 while safety and efficacy data were analyzed. 
Part 2 is a double-blind, randomized design to compare the efficacy of imetelstat with placebo. 
Approximately 170 eligible subjects (non-del(5q); no prior lenalidomide or hypomethylating 
agents) will be randomized in a 2:1 ratio to receive either imetelstat or placebo, respectively in the 
main study. Randomization will be stratified by prior RBC transfusion burden (≤6 or >6 units 
RBC) and by IPSS risk group (low risk versus intermediate-1 risk). Prior RBC transfusion burden 
is defined as the maximum number of RBC units transfused over an 8-week period during the 
16 weeks prior to Randomization. In addition to the main study of Part 2, a Ventricular 
Repolarization substudy will enroll approximately 45 subjects to be randomized 2:1 to receive 
either imetelstat or placebo. 
Each part of the study will consist of 3 phases: a Screening Phase of up to 28 days during which 
subject eligibility will be reviewed and approved by the sponsor prior to C1D1 (Part 1) or 
Randomization (Part 2); a Treatment Phase that will extend from C1D1 (Part 1) or C1D1 (Part 2) 
until disease progression (PD), or unacceptable toxicity, or withdrawal of consent; and a 
Posttreatment Follow-up Phase which will continue until death, lost to follow-up, withdrawal of 
consent, or the end of the study (whichever occurs first). The end of the main study is defined as 
24 months after the randomization of the last subject in the main study of Part 2. The end of the 
study is defined as after all subjects have completed participation in the Extension Phase (at least 
5 years from the first dose of imetelstat in Part 2 of the main study, or 3 years of post-treatment 
follow-up from the last dose of study treatment, whichever occurs later, or until death, withdrawal 
of consent, study termination, or until a subject is lost to follow-up). 
Subjects enrolled in Part 1 will continue through the Part 1 treatment and posttreatment follow-up 
phases after initiation of Part 2.  Subjects enrolled in Part 1 of the study are not eligible to enroll 
in Part 2. 
For Part 2, an additional 45 evaluable subjects will be enrolled in a separate substudy investigating 
the effects of imetelstat exposure on ventricular repolarization. Details regarding the Ventricular 
Repolarization substudy, including eligibility criteria and study procedures (including Time and 
Events Table) for participating subjects are provided in Attachment 11. 
The term 'Study Drug', as used in this protocol, refers to either imetelstat or placebo in Part 2. Each 
treatment cycle will consist of 4 weeks (28 days). All subjects receiving study drug must be 
premedicated to prevent infusion reactions (see Section 6.2). The starting dose of the study drug 
is 7.5 mg/kg every 4 weeks. In Part 1 of the study, subjects whose dose was previously escalated 
(before Amendment 2) may continue at the 9.4 mg/kg dose. Study drug dose delay or reduction 

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for Grade 3 or Grade 4 toxicities will be instituted as per the instructions provided in Table 7, 
Table 8, Table 9, and Table 10. 
Supportive care, including transfusions or myeloid growth factors, is to be administered to all 
subjects as needed per investigator discretion and according to local standard practices. 
All study procedures will be conducted according to the Time and Event Schedules for Part 1 and 
Part 2 as per Table 1 and Table 3, respectively. Subjects who have enrolled into the Ventricular 
Repolarization substudy of Part 2 prior to Protocol Amendment 7 will continue the study 
assessments as required for the main study. Assessment of disease response and disease 
progression will be conducted based on the modified IWG Response Criteria 2006 for MDS 
(Modified IWG 2006),7 and robust transfusion data will be collected for all subjects (see Section 
9.3.1.1 for details). For Part 2, in addition to local disease response evaluations, which may be 
used for treatment decisions, an Independent Central Pathology Reviewer will review bone 
marrow assessments performed at screening to confirm diagnosis and eligibility at the time of each 
bone marrow assessment throughout the duration of the main study. Following investigator-
assessed CR, PR, or mCR, in subjects with >5% baseline bone marrow aspirate blasts, aspirate 
should be repeated 4 to 8 weeks later for confirmatory purposes, if clinically feasible. An 
Independent Review Committee (IRC) will be established to adjudicate investigator-assessed 
disease response (CR, PR, mCR, or cytogenetic response). Central laboratory results will also be 
used for assessment of the HI-E response. Safety evaluations will include adverse event 
monitoring, physical examinations, electrocardiogram (ECG) monitoring, clinical laboratory 
parameters (including hematology and chemistry), vital sign measurements, and Eastern 
Cooperative Oncology Group (ECOG) performance status. 
The sponsor will review the safety data on an ongoing basis to ensure the safety of the subjects 
enrolled in this study. In addition, all hepatic adverse events and LFT abnormalities will be 
reviewed at least on a quarterly basis, and more frequently if needed, by an Independent Hepatic 
Expert Committee (HEC) (see Section 11.12). An Independent Data Monitoring Committee 
(DMC) will be established for the study to monitor safety data. The DMC will meet periodically 
to review safety data and after the review, the DMC will make recommendations regarding the 
conduct of the study. The details will be provided in a separate independent DMC charter. Refer 
to Section 11.11, Independent Data Monitoring Committee, for additional details. 
Subjects benefiting from imetelstat treatment at the end of the main study (ie, 24 months after last 
subject randomized in the main study of Part 2) per investigator assessment may continue to 
receive imetelstat during the Extension Phase. All subjects in the Posttreatment Follow-up Phase 
of the main study will also continue in the Extension Phase for assessment of survival status, 
subsequent anticancer therapy, and monitoring of disease progression, including progression to 
AML (Table 5 and Figure 3). Subjects will be followed in the Extension Phase for at least 5 years 
from the first dose of imetelstat received in Part 2 of the main study (including treatment and 
follow-up), or 3 years of post-treatment follow-up from the last dose of study treatment, whichever 
occurs later, or until death, withdrawal of consent, study termination, or until a subject is lost to 

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follow-up. Subjects in the QTc substudy may also enter the Extension Phase after the clinical cut 
off for the primary analysis is reached for the substudy. 
During the Extension Phase, the Independent HEC will be available to review all hepatic adverse 
events and liver function test abnormalities at least on a quarterly basis, or more frequently if 
needed. 
With Protocol Amendment 8, Part 1 of the study will close as all subjects in Part 1 have already 
discontinued treatment and study will have already met the duration of follow-up defined for the 
Extension Phase (ie, at least 5 years from the first dose of imetelstat, or 3 years of post-treatment 
follow-up from the last dose of study treatment, whichever occurs later). Any subjects remaining 
in follow-up will be discontinued from the study. Therefore, the Extension Phase does not apply 
to Part 1 subjects. 
The study endpoints are listed in Section 9.2. 

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Figure 2: 
Schematic Overview of the Study: Part 1 and Main Study of Part 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. Supportive care, including transfusions or myeloid growth factors, is to be administered as needed per investigator discretion 
and according to local standard practices.  
b. Enrollment in Part 1 was expanded from up to 30 subjects to approximately 55 subjects in Amendment 2. 
c. Beginning with Amendment 2, dose escalation to 9.4 mg/kg is no longer permitted for subjects enrolled in Part 1. Part 1 
subjects whose dose was previously escalated (before Amendment 2) may continue at the 9.4 mg/kg dose. 
 
 
Part 1a,c 
28-day treatment cycle 
Imetelstat 7.5 mg/kg every 4 weeks (starting dose; refer to Section 6) 
Open-label, single-arm in approximately 55 subjectsb   
If data from Part 1 are supportive of a satisfactory benefit/risk profile, and it is unlikely that the futility 
criterion will be met, Part 2 will be initiated. 
Treatment Phase  
Imetelstat 7.5 mg/kg or Placebo 
28-day treatment cycle 
 
Until disease progression, unacceptable 
toxicity, or withdrawal of consent 
 
Treatment Phase  
Imetelstat 7.5 mg/kg or Placebo 
28-day treatment cycle 
After ≥ 2 cycles option to unblind per PI decision 
with sponsor discussion 
Part 2a 
Main Study 
Randomized, double blind, placebo controlled in approximately170 
subjects (2:1 imetelstat:placebo)  
End-of-Treatment Visit 
30 ±3 days after end of treatment 
Follow-up Phase  
Part 2 
Ventricular Repolarization 
Substudy 
Randomized, double blind, placebo 
controlled in approximately 45 
subjects  
(2:1 imetelstat:placebo) 

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Figure 3 
Overview of the Extension Phase Following Amendment 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Subjects randomized to the placebo arm in the main study will enter the Extended Follow-up Phase part of the Extension Phase. 
 
3.2. 
Study Design Rationale 
Myelodysplastic syndromes are characterized by clonal myeloproliferation that arises from 
malignant progenitor cell clones that have shorter telomeres and multiple clonal genetic 
abnormalities. Telomerase is highly activated and continually upregulated in malignant progenitor 
End of Main Study – Part 2 
Withdraw from study 
Extended Treatment 
Continue treatment until loss of 
benefit or unacceptable toxicity. 
Extended Follow-up for Survival Status 
End of Extension Phase (EP) 
Subjects will be followed in the EP for at least 5 years from the 
first dose of imetelstat received in Part 2 of the main study 
(including treatment and follow-up), or 3 years of post-treatment 
follow-up from last dose of study treatment, whichever occurs 
later, or until death, withdrawal of consent, study termination, or 
until a subject is lost to follow-up. 
Extension Phase (EP)* 
• Subjects who are benefitting from imetelstat treatment in the 
Treatment Phase of the Main Study may continue on treatment 
in the EP. 
• Subjects in the Posttreatment Follow-up Phase will enter the 
EP and continue in follow up.  
• Subjects who received imetelstat in the QTc substudy may 
enter the EP after the clinical cut off for the primary analysis 
timepoint is reached for the QTc substudy. 

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clones enabling continued and uncontrolled proliferation. While TA is generally undetectable in 
normal somatic cells, it is expressed in approximately 85% of human cancers as well as in cancer 
progenitor cells, which are believed to play a critical role in dysregulated cell growth and tumor 
metastasis.20 In MDS, TA and expression of hTERT are significantly increased as compared to 
healthy controls.4,5 Myelodysplastic syndrome patients with high TA have been shown to have a 
significantly shorter OS as compared to those with lower TA.17 In addition, the average TL has 
been shown to be significantly shorter in MDS patients as compared to healthy controls30,40 and 
progression of the disease and conversion of MDS to AML are connected with progressive 
decrease in TL.43 Several studies showed that higher TA and hTERT, and shorter TL correlate 
with IPSS risk score in MDS.5,38,52 In low risk MDS patients, short telomeres and high TA in 
addition to other factors were reported as poor prognostic features.37,51 Given the role of TA in 
preventing cell senescence and apoptotic cell death in immortalized cells such as tumor cells,24 
inhibition of TA constitutes an attractive therapeutic approach in MDS. 
Randomization and Treatment Groups  
This is a multicenter, 2-part, study to compare the efficacy of imetelstat to placebo in 
transfusion-dependent subjects who have MDS that is relapsed/refractory to ESA treatment. 
Part 1 of the study was an open-label single-arm design. Randomization will be used in Part 2 of 
the study to minimize bias in the assignment of subjects to treatment groups, to increase the 
likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. The 2:1 randomization scheme has been chosen 
to limit the number of subjects in the placebo group, to increase the likelihood of subjects receiving 
active treatment of imetelstat for low or intermediate-1 risk MDS, and to study safety of imetelstat 
in a larger cohort. 
Subjects will be stratified in the randomization process according to prior RBC transfusion burden 
(≤6 or >6 units RBC) and by IPSS risk group (low versus intermediate-1) to ensure equal 
distribution across treatment groups. Prior RBC transfusion burden is defined as the maximum 
number of RBC units transfused over an 8-week period during the 16 weeks prior to C1D1 (Part 1) 
or Randomization (Part 2). 
Blinded treatment will be used to minimize the potential influence of treatment assignment 
knowledge on clinical decision making, such as transfusion administration, and to reduce potential 
bias during data collection and evaluation of clinical endpoints; thus, ensuring the robustness and 
integrity of the study. The primary objective and secondary efficacy objectives of Part 2 of the 
main study are to compare RBC TI, time to RBC TI, and duration of RBC TI between the 
2 treatment groups (imetelstat and placebo). The use of the modified IWG 2006 criteria to assess 
disease progression is intended to promote uniformity across study centers. It is the intent that all 
subjects, investigators, and study team members, except some required project roles (eg, members 
associated with DMC and HEC), will remain blinded to treatment group assignment at least until 
the primary efficacy analysis (12 months after the last subject is randomized in the main study of 
Part 2). As of Protocol Amendment 8, subjects, investigators, and study team members will be 

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unblinded after primary efficacy analysis. Upon unblinding the subjects after the primary analysis, 
subjects on imetelstat may continue treatment per investigator discretion. Subjects on placebo may 
discontinue treatment and enter the posttreatment follow-up phase of the study. The investigator 
will discuss treatment options with subject’s discontinuing study treatment and record treatment 
selection as part of subsequent therapy. 
Study Population 
Limited treatment options are available for patients who are RBC transfusion dependent, who have 
IPSS low risk or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment whether 
because they have already received at least one prior treatment with an ESA without achieving or 
maintaining a response or have high levels of endogenous erythropoietin and are considered 
unlikely to respond. The median survival for low-risk MDS patients for whom ESA treatment has 
failed is about 3.5 years, which is considerably shorter than predicted at the time of diagnosis. 
Therefore, there remains a highly unmet need for effective treatments for these patients. 
Review of the data of Part 1 (Section 1.1.5) support further evaluation of imetelstat in subjects that 
are non-del(5q) and have not been previously treated with either a hypomethylating agent or 
lenalidomide, hence this represents the target population of Part 2 of the main study. 
Endpoints 
The primary endpoint of this main study is the proportion of subjects who achieve 8-week RBC 
TI, defined as absence of RBC transfusion during any consecutive 8-week period. Transfusion 
independence for 8 weeks is a clinically meaningful and robust endpoint which is included in the 
modified IWG 2006 response criteria and has been the basis for regulatory approvals. 
The rate of hematologic improvement-erythroid (HI-E) will provide further explanation of the 
hematologic response (as per modified IWG 2006 response criteria). The time to progression to 
AML and OS are important endpoints considering that the natural history of MDS includes 
transformation to AML in a proportion of patients. 
The depth of the response will be captured by assessment of CR, PR, and mCR per modified IWG 
2006 response criteria. The data from Study CP14B019 suggest the potential for disease 
modification and long-term benefit to patients. Duration of responses will be assessed. Subjects 
will be followed for OS. 
Pharmacokinetic and Immunogenicity Evaluations 
Pharmacokinetics of imetelstat have not been characterized in MDS patients. Intensive 
pharmacokinetic sampling analysis was performed in up to approximately 15 subjects in Part 1 
and will be performed in up to approximately 30 subjects (active treatment) in the Ventricular 
Repolarization substudy (Part 2). Along with sparse pharmacokinetic sampling in the remainder 
of subjects, this will allow for estimation of individual pharmacokinetic parameters and build a 
population pharmacokinetic model. The specific time points for measurement of imetelstat plasma 
concentrations are chosen to gather information about the pharmacokinetic properties of imetelstat. 
Anti-drug antibodies will be assessed during the study.  

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Biomarkers 
Based on the mechanism of action of imetelstat and results from preclinical and previous clinical 
studies, imetelstat is expected to cause TA inhibition, TL shortening and hTERT level reduction. 
Blood samples will be collected from all subjects to evaluate TA, TL, or hTERT RNA level 
changes as pharmacodynamic biomarkers. Karyotyping on bone marrow samples from all subjects 
in the main study (imetelstat and placebo) will be performed to evaluate cytogenetic response by 
assessing the reduction or depletion of clones with cytogenetic abnormalities. Blood and bone 
marrow samples from all subjects in the main study will be analyzed to characterize mutation 
status and mutation change, immunophenotyping, and perform RNA seq for evaluation of potential 
inter-individual variability in clinical outcomes or identification of population subgroups that 
respond differently to imetelstat. 
Patient-Reported Outcomes 
The Functional Assessment of Cancer Therapy − Anemia (FACT-An), is included in order to 
provide an assessment of the subject’s functional status, well-being, and symptoms over time. The 
Quality of Life in Myelodysplasia Scale (QUALMS)1 is a new MDS-specific health-related 
quality-of-life measure, and the Patient Global Impression of Change (PGIC) captures the patient’s 
perspective of improvement or decline in MDS over time. The EuroQol-EQ-5D-5L (EQ-5D-5L) 
assessment is included to provide estimates of utility to include in future cost effectiveness models. 
Imetelstat Dose and Regimen Selection 
In Study CP14B019, subjects with MDS received a starting imetelstat dose of 7.5 mg/kg every 
4 weeks. Subsequent doses were adjusted based on investigator assessment of toxicity and clinical 
response, resulting in individualized regimens that included 6.0 mg/kg, 7.5 mg/kg and 9.4 mg/kg 
every 4 weeks. In addition, neither prolonged thrombocytopenia nor neutropenia were observed in 
the MDS cohort. Based on the available data, a starting dose regimen of 7.5 mg/kg every 4 weeks 
demonstrated an acceptable safety profile and favorable efficacy that warrants further clinical 
investigation. Efficacy and safety data from Part 1 of the current study support the use of this 
dosing regimen in Part 2 of the study. 
3.3. 
Rationale for the Extension Phase 
Once the end of the main study has been reached (Section 17.9.1), accommodation must be made 
to allow subjects benefiting from imetelstat to continue treatment, until there is loss of benefit or 
unacceptable toxicity, as determined by the investigator according to local standard of care. 
Subjects will be followed in the Extension Phase for at least 5 years from the first dose of imetelstat 
received in Part 2 of the main study (including treatment and follow-up), or 3 years of  
post-treatment follow-up from the last dose of study treatment, whichever occurs later, or until 
death, withdrawal of consent, study termination, or until a subject is lost to follow-up. Subjects 
receiving imetelstat in the QTc substudy may also enter the Extension Phase after the clinical cut 
off for the primary analysis is reached for the substudy. It is anticipated that the Extension Phase 
will allow sufficient time for all subjects to receive adequate treatment and for collection of 
long-term survival data, and additional maturity of the survival data for a more precise estimate of 
OS. It is also anticipated that during this time the rate of observed deaths will reach approximately 

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65%, indicating a mature data set. Because sufficient efficacy data will have been collected during 
the main study to allow the planned final analysis for the main study, data collection during the 
Extension Phase will be limited to imetelstat treatment information (exposure), transfusion 
collection, survival status, routine safety reporting, laboratory assessments for safety monitoring, 
and disease progression including progression to AML. 
4. 
SUBJECT POPULATION 
Subject eligibility will be reviewed and approved by the sponsor prior to C1D1 (Part 1) or 
Randomization (Part 2) (as defined in Section 3.1). Screening will be performed within 28 days 
prior to C1D1 (Part 1) or Randomization (Part 2). 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections for Part 1 and main study of Part 2. 
For subjects participating in the Ventricular Repolarization substudy after Protocol Amendment 7 
(Part 2 only), the eligibility criteria are provided in Attachment 11. 
If there is a question about the inclusion or exclusion criteria below, the investigator should consult 
with the appropriate sponsor representative before C1D1 (Part 1) or Randomization (Part 2). 
Waivers are not allowed. 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
The last laboratory result obtained prior to enrollment/randomization will be used to determine 
eligibility. If a subject's status changes (including laboratory results or receipt of additional medical 
records) after screening but before C1D1 (Part 1) or Randomization (Part 2) (as defined in 
Section 3.1) such that he or she no longer meets all eligibility criteria, then the subject should be 
excluded from participation until all eligibility criteria have been met (retesting information in 
Section 9.1.3). Section 17.4, Source Documentation, describes the required documentation to 
support meeting the enrollment criteria. 
4.1. 
Inclusion Criteria 
Each potential subject must satisfy all of the following criteria to be entered in the study. 
1. Man or woman ≥18 years of age (or the legal age of consent in the jurisdiction in which the 
study is taking place); 
2. Criterion modified per Amendment 1. 
2.1. Criterion modified per Amendment 2.  
2.2.  Criterion modified per Amendment 3 
2.3  In Part 1, diagnosis of MDS according to WHO criteria confirmed by bone marrow 
aspirate and biopsy within 12 weeks prior to C1D1. A local laboratory report from this 
diagnostic bone marrow aspirate and biopsy must be reviewed and approved by the 
sponsor (Attachment 1).  
 
In Part 2, diagnosis of MDS according to WHO criteria confirmed by bone marrow 

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aspirate and biopsy within 12 weeks prior to Randomization (Attachment 1). A sample 
of the baseline bone marrow aspirate and biopsy must be submitted to the Independent 
Central Pathology Reviewer for diagnostic confirmation. Central laboratory review is 
required to confirm diagnosis prior to Randomization. 
3. IPSS low or intermediate-1 risk MDS (Attachment 3); 
4. Criterion modified per Amendment 1. 
4.1. RBC transfusion dependent, defined as requiring at least 4 RBC units transfused over 
an 8-week period during the 16 weeks prior to C1D1 (Part 1) or Randomization (Part 2) 
(defined in Section 3.1); pre-transfusion Hb should be ≤9.0 g/dL to count towards the 
4 units total; 
5. Has MDS that is relapsed/refractory to ESA treatment; as defined by meeting any one of the 
criteria below: 
5.1. Received at least 8 weeks of treatment with a minimum weekly dose of epoetin alfa 
40,000 U, epoetin beta 30,000 U or darbepoetin alfa 150 mcg (or equivalent agent/dose), 
without having achieved a Hb rise ≥1.5 g/dL or decreased RBC transfusion requirement 
by at least 4 units over 8 weeks 
5.2. Criterion 5.2 replaced by criterion 5.2.1 per Amendment 5. 
5.2.1 Transfusion dependence or reduction in Hb by ≥1.5 g/dL after hematologic improvement 
from at least 8 weeks of treatment with therapies outlined in inclusion criteria 5.1, in the 
absence of another explanation. 
5.3. Criterion 5.3 replaced by criterion 5.4 per Amendment 1. 
5.4. Endogenous serum EPO level >500 mU/mL; 
6. Criterion modified per Amendment 1. 
6.1. Adequate iron stores, defined as transferrin saturation greater than 20% and serum 
ferritin greater than 400 ng/mL, measured within the screening period, or adequate iron 
stores as demonstrated by recent (within 12 weeks prior to C1D1 [Part 1] or 
Randomization [Part 2]) bone marrow examination with iron stain 
7. ECOG performance status 0, 1 or 2 (Attachment 4); 
8. Hematology lab test values within the following limits: 
8.1. ANC ≥1.5 x 109/L independent of growth factor support (defined in Section 9.1.3) 
8.2. Platelets ≥75 x 109/L independent of platelet transfusion support (defined in Section 
9.1.3); 
9. Biochemical laboratory test values must be within the following limits: 
9.1. AST, ALT and ALP ≤2.5 times the upper limit of normal (x ULN) 
9.2. Serum creatinine ≤2.0 x ULN 
9.3. Criterion 9.3 replaced by criterion 9.4 per Amendment 1. 
9.4. Criterion 9.4 replaced by criterion 9.4.1 per Amendment 5. 
9.4.1 Total bilirubin ≤3 x ULN (unless due to Gilbert’s syndrome, ineffective erythropoiesis 
due to MDS, or hemolysis due to RBC transfusion) AND  

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Direct bilirubin ≤2 x ULN (unless due to Gilbert’s syndrome, ineffective erythropoiesis 
due to MDS, or hemolysis due to RBC transfusion, where a direct bilirubin value of 
≤3 x ULN or less than 1/3 of the total bilirubin value is acceptable); 
10.1.  Women of childbearing potential and practicing a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for subjects 
participating in clinical studies: eg, established use of oral, injected or implanted hormonal 
methods of contraception; placement of an intrauterine device or intrauterine system; barrier 
methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male 
partner sterilization (the vasectomized partner should be the sole partner for that subject); 
true abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
For females, these restrictions apply for 1 month after the end of dosing. Note: If the 
childbearing potential changes after start of the study (eg, woman who is not heterosexually 
active becomes active, premenarchal woman experiences menarche) a woman must begin a 
highly effective method of birth control, as described above; 
10.2. A woman of childbearing potential must have a negative serum (β-human chorionic 
gonadotropin [β-hCG]) or urine pregnancy test at screening and agree to be tested on Day 1 
of every cycle and at end of study (30 days post last dose); 
11. A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also 
not donate sperm during the study. For males, these restrictions apply for 3 months after the 
end of dosing. 
12. Each subject (or their legally acceptable representative) must sign an informed consent form 
(ICF) indicating that he or she understands the purpose of and procedures required for the study 
and are willing to participate in the study. 
13.  Criterion deleted per Amendment 2.  
4.2. 
Exclusion Criteria 
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1. Subject has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients (refer 
to the IB25); 
2. Criterion 2 modified per Amendment 5. 
2.1   Subject has received an experimental or investigational drug or used an invasive 
investigational medical device within 30 days prior to C1D1 (Part 1) or Randomization (Part 2) 
(defined in Section 3.1) or is currently enrolled in an investigational study; 
3. Prior treatment with imetelstat; 
4. Criterion modified per Amendment 2. 
4.1   Have received corticosteroids >30 mg/day prednisone or equivalent; or growth factor 
treatment within 4 weeks prior to  C1D1 (Part 1) or Randomization (Part 2); 

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5. Criterion modified per Amendment 2. 
5.1   Prior treatment with a hypomethylating agent (eg, azacitidine, decitabine); 
5.2   Criterion 5.2 replaced by criterion 5.2.1 per Amendment 5. 
5.2.1 Prior treatment with lenalidomide, thalidomide, or other thalidomide analogues; 
5.3   Criterion 5.3 replaced by criterion 5.3.1 per Amendment 5. 
5.3.1 Has received an ESA or any anti-MDS therapy, chemotherapy, immunomodulatory, or 
immunosuppressive therapy within 4 weeks prior to C1D1 (Part 1) or Randomization (Part 2) 
(8 weeks for long-acting ESAs); 
6. Prior history of hematopoietic stem cell transplant; 
7. Anemia attributed to factors other than MDS (including hemolysis, chronic renal failure, 
hepatitis, gastrointestinal bleeding); 
8. Major surgery within 4 weeks prior to C1D1 (Part 1) or Randomization (Part 2) (excluding the 
placement of vascular access and other minor surgical procedures); 
9. Diagnosed or treated for malignancy other than MDS, except: 
9.1. Malignancy treated with curative intent and with no known active disease present for 
≥3 years before C1D1 (Part 1) or Randomization (Part 2)   
9.2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease 
9.3. Adequately treated cervical carcinoma in situ without evidence of disease; 
10. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of C1D1 (Part 1) or 
Randomization (Part 2), or any Class 3 (moderate) or Class 4 (severe) cardiac disease as 
defined by the New York Heart Association Functional Classification; 
11. Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic 
infection requiring IV antibiotics; 
12. Criterion modified per Amendment 1. 
12.1. Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are 
permitted to enter the study), or known acute or chronic liver disease including 
cirrhosis; 
13. Females who are pregnant or are currently breastfeeding or planning to become pregnant while 
enrolled in this study or within 1 month after the end of dosing; 
14. Subject is a man who plans to father a child while enrolled in this study or within 3 months 
after the end of dosing; 
15. Any life-threatening illness, medical condition, or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, interfere with the imetelstat 
metabolism, or put the study outcomes at undue risk; Subject has any condition for which, in 
the opinion of the investigator, participation would not be in the best interest of the subject (eg, 
compromise the well-being) or that could prevent, limit, or confound the protocol-specified 
assessments; 

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16. Subject was previously assessed as having IPSS intermediate-2 or high risk MDS; 
17. Subject with del(5q) karyotype;  
18. Subject with MDS/myeloproliferative neoplasm Overlap Syndrome. 
4.3. 
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and restrictions 
during the course of the study to be eligible for participation: 
1. 
A woman of childbearing potential must remain on a highly effective method of birth 
control (see inclusion criteria) during the study. For females, these restrictions apply for 
1 month after the end of dosing. 
2. 
A man who is sexually active with a woman of childbearing potential must use an adequate 
method of birth control and all men must also not donate sperm during the study. For males, 
these restrictions apply for 3 months after the end of dosing. 
3. 
Section 8 details prestudy and concomitant therapies used in this study. 
5. 
TREATMENT ALLOCATION AND BLINDING 
5.1. 
Treatment Allocation 
Part 1:  Randomization will not be used in Part 1; all subjects will receive imetelstat. As Part 1 is 
an open-label design, blinding procedures are not applicable. 
Part 2:  Subjects will be randomly assigned 2:1 in Part 2 to receive either imetelstat or placebo. 
Randomization will be based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. Randomization will be stratified by prior 
RBC transfusion burden (≤6 or >6 units RBC) and by IPSS risk group (low versus intermediate-1). 
Prior RBC transfusion burden is defined as the maximum number of RBC units transfused over an 
8-week period during the 16 weeks prior to Randomization. Pre-transfusion Hb should be 
≤9.0 g/dL to count towards the 4 units total unless there is clinical rationale for transfusing at a 
higher Hb level. The interactive web response system (IWRS) will assign a unique treatment code, 
which will dictate the treatment assignment for the subject. The requestor must use his or her own 
user identification and personal identification number when contacting the IWRS and will then 
give the relevant subject details to uniquely identify the subject. 
5.2. 
Blinding and Unblinding 
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject. 
Data that may potentially unblind the treatment assignment (ie, study drug plasma concentrations) 
will be handled with special care to ensure that the integrity of the blind is maintained and the 
potential for bias is minimized. This may include making special provisions, such as segregating 

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the data in question from view by the investigators, clinical team, or others as appropriate until the 
time of database lock and unblinding. 
Under normal circumstances, the blind should not be broken until all subjects have completed the 
study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the treatment 
by contacting the IWRS. It is recommended that the investigator contact the sponsor or its designee 
if possible, to discuss the particular situation, before breaking the blind. Telephone contact with 
the sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the 
blind is broken, the sponsor must be informed as soon as possible. The date, time, and reason for 
the unblinding must be documented by the IWRS, in the appropriate section of the case report 
form (CRF), and in the source document. The documentation received from the IWRS indicating 
the code break must be retained with the subject’s source documents in a secure manner. Subjects 
who have had their treatment assignment unblinded should continue to return for scheduled 
evaluations and with sponsor approval may continue study drug. It is the intent that all subjects, 
investigators, and study team members, except some required project roles (eg, members 
associated with DMC and HEC), will remain blinded to treatment group assignment at least until 
the primary efficacy analysis (12 months after the last subject is randomized in the main study of 
Part 2). As of Protocol Amendment 8, subjects, investigators, and study team members will be 
unblinded after primary efficacy analysis. 
For subjects participating in the Ventricular Repolarization substudy (Part 2) after Protocol 
Amendment 7, additional information for unblinding is provided in Attachment 11. 
6. 
DOSAGE AND ADMINISTRATION 
The term ‘Study Drug’ refers to treatment with either imetelstat or placebo. 
Subjects may receive study drug until disease progression, unacceptable toxicity, or withdrawal of 
consent.  
Supportive Care 
All subjects will receive supportive care (including transfusions or myeloid growth factors) as 
needed per investigator discretion and according to local standard practices. Should an exceptional 
situation arise where it is deemed clinically necessary to give a transfusion for a Hb >11 g/dL, the 
reasons should be documented in the CRF. 
Study Drug (Imetelstat or Placebo) 
Imetelstat Sodium (GRN163L) for injection (imetelstat) is the investigational product in this study 
and will be provided by the sponsor. 
Placebo will be supplied by the sponsor. 

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Study drug will be administered as a 2-hour IV infusion (± 10 minutes) at a constant rate using an 
infusion pump. 
The baseline weight (ie, body weight determined at Screening) will be used to calculate the dose 
of study drug to the nearest 0.1 mg. The dose should be recalculated if there is a ≥ 10% weight 
change from baseline. Note that the total dose may be recalculated more frequently (eg, at each 
study visit) depending on local practice. Study drug will be administered IV on a 28-day cycle. 
The first dose of study drug should be administered within 72 hours of enrollment (Part 1) or 
randomization (Part 2) in IWRS. 
All subjects in Parts 1 and 2 will receive a starting dose of 7.5 mg/kg of study drug given IV every 
4 weeks. Subjects whose dose was previously escalated (before Amendment 2) may continue at 
the 9.4 mg/kg dose. Study drug dose delay or reduction for Grade 3 or Grade 4 toxicity will be 
instituted as needed, per the instructions provided in Table 7, Table 8, Table 9, Table 10, and Table 
11. Note that these instructions are intended for Grade 3 or Grade 4 toxicities observed at the time 
of the planned dose on Day 1 of the next cycle. These instructions are not applicable when 
toxicities occur mid-cycle and subsequently resolve to Grade <3 by the time of the next planned 
dose. 
The study drug may be held for up to 28 days from the expected start date of the scheduled cycle; 
a hold >28 days must be reviewed and approved by the sponsor. The study drug should be 
discontinued permanently if it cannot be restarted within 28 days due to toxicity. If the subject is 
exhibiting an otherwise positive clinical response to treatment and the toxicity appears to be 
manageable, contact the sponsor to discuss the specific case before study drug is discontinued.  
Treatment During the Extension Phase 
Dose modification guidelines provided in the following sections will continue in the Extension 
Phase. Subjects may receive treatment in the Extension Phase until there is loss of benefit or 
unacceptable toxicity, as determined by the investigator according to local standard of care. 

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6.1. 
Dose Modifications 
Study Drug dose modifications will be performed as described in Table 6. All dose modifications 
must be recorded in the Dosage Administration electronic case report form (eCRF). 
Table 6:   
Dose Titration 
Titration* 
Dose Regimen 
(imetelstat or equivalent volume of placebo) 
  0 
Starting dose 
7.5 mg/kg IV every 4 weeks 
-1 
Dose reduction #1 
6.0 mg/kg IV every 4 weeks 
-2 
Dose reduction #2 
(Minimum dose) 
4.7 mg/kg IV every 4 weeks 
Part 1 subjects whose dose was previously escalated (before Amendment 2) may continue at the 
9.4 mg/kg dose. 
6.1.1. 
Dose Modifications for Hematologic Toxicities 
For any occurrence of Grade ≥3 thrombocytopenia or neutropenia, additional weekly blood counts 
should be performed until there is a return to baseline values. For treatment of hematologic 
toxicities, granulocyte-colony stimulating factors (G-CSF) are permitted for neutropenia as well 
as blood transfusions for anemia or thrombocytopenia. 
The actions in Table 7 should be taken for Grade 3 hematologic toxicities present at the planned 
start of a dosing cycle. The actions in Table 8 should be taken for imetelstat-related Grade 4 
hematologic toxicities at the planned start of a dosing cycle. It is recommended to contact the 
sponsor before discontinuing treatment due to Grade 3 or Grade 4 hematologic toxicity, 
particularly when the hematologic toxicity is without clinical consequences. Note that for Grade 3 
or Grade 4 hematologic toxicities that are not considered related to imetelstat, the dose should still 
be held until recovery to ANC 1 x 109/L and platelets 50 x 109L. 
Table 7: 
Dose Modifications for Grade 3 Hematologic Toxicities 
Occurrence 
Action 
First 
Hold study drug until recovery to ANC 1.0 x 109/L and platelets 50 x 109/L*; may 
restart at most recent dose level 
Second 
Hold study drug until recovery to ANC 1.0 x 109/L and platelets 50 x 109/L*; restart at 
1 dose level lower 
Third 
Hold study drug until recovery to ANC 1.0 x 109/L and platelets 50 x 109/L*; restart at 
1 dose level lower 
Fourth 
Discontinue study drug** 
*For any other hematologic toxicities, the minimum counts for restarting should be at the Investigator’s discretion 
** Contact the sponsor to discuss the specific case before study drug is discontinued for hematologic toxicity 
 

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Table 8: 
Dose Modifications for Grade 4 Hematologic Toxicities 
Occurrence 
Action 
First 
Hold study drug until recovery to ANC 1.0 x 109/L and platelets 50 x 109/L*; restart at 
1 dose level lower 
Second 
Hold study drug until recovery to ANC 1.0 x 109/L and platelets 50 x 109/L*; restart at 
1 dose level lower 
Third 
Discontinue study drug** 
*For any other hematologic toxicities, the minimum counts for restarting should be at the Investigator’s discretion 
** Contact the sponsor to discuss the specific case before study drug is discontinued for hematologic toxicity 
6.1.2. 
Dose Modifications for Non-hematologic Toxicities, Excluding 
Hepatic Toxicities 
The actions in Table 9 should be taken for Grade 3 or 4 non-hematologic/non-hepatic toxicities 
present at the planned start of a dosing cycle. For nausea and vomiting, only Grade 3 or 4 events 
which persist despite optimal antiemetic therapy should be considered for dose modification. 
Table 9: 
Dose Modifications for Grade 3 and 4 Non-hematologic/Non-hepatic Toxicities 
Occurrence 
Action 
First 
Hold study drug until recovery to Grade ≤ 1 or baseline; restart at 1 dose level lower 
Second 
Hold study drug until recovery to Grade ≤ 1 or baseline; restart at 1 dose level lower 
Third 
Discontinue study drug 
6.1.3. 
Dose Modifications for Liver Function Test Elevations and 
Hepatic Adverse Events 
The actions in Table 10 should be taken for Grade 3 or 4 LFT elevations (AST, ALT and bilirubin), 
Grade 3 or 4 hepatic adverse events, and Grade ≥2 AST or ALT with Grade ≥2 bilirubin present 
at the planned start of a dosing cycle.  
Table 10: 
Dose Modifications for Liver Function Test Elevations and Hepatic Adverse Events 
Adverse Event 
Action to be taken 
Grade 3 or 4  
AST, ALT, or bilirubin 
 
For ALT or AST >8xULN or 
baseline, contact sponsor and 
consider discontinuing drug 
altogether 
• 
HOLD study drug and report as adverse event of interest (AEI) 
• 
Determine relatedness to study drug (i.e. extensive investigationa to 
determine an alternative likely cause(s) for the event) 
o 
If considered at least possibly related, after recovery to 
baseline, restart study drug at one dose level lower.  
o 
If not related, after recovery to baseline, restart study drug 
without dose reduction.  
• 
If the event recurs and is related, study drug should be discontinued 
 

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Adverse Event 
Action to be taken 
Grade 3 or 4   
hepatic adverse event 
 
• 
HOLD study drug and report as AEI 
• 
Determine relatedness to study drug (i.e. extensive investigationa to 
determine an alternative likely cause(s) for the event)  
o 
If considered at least possibly related, after recovery to 
baseline, restart study drug at one dose level lower.  
o 
If not related, after recovery to baseline, restart study drug 
without dose reduction.  
• 
If the event recurs and is related, study drug should be discontinued 
Grade ≥ 2 AST or ALT with 
concomitant Grade ≥2 bilirubin*  
 
*Subjects with Grade 2 bilirubin at 
study entry should have worsening 
bilirubin with concomitant Grade 2 
AST or ALT elevation 
 
• 
HOLD study drug and report as AEI 
• 
Determine relatedness to study drug (i.e. extensive investigationa to 
determine an alternative likely cause(s) for the event) 
o 
If considered at least possibly related, discontinue study drug  
o 
If not related, after recovery to baseline, study drug can be 
restarted at same dose 
 
If upon rechallenge the event recurs, study drug 
should be discontinued 
a Extensive investigation includes repeating liver enzyme and serum bilirubin tests with fractionation once or twice weekly until 
levels return to baseline.  Obtain additional tests to evaluate liver function, as appropriate (i.e., INR, albumin).  In addition, obtain 
a detailed history of symptoms, prior or concomitant disease, concomitant medications (including nonprescription herbal and 
dietary supplements), alcohol use, recreational drug use, special diets and environmental chemical agents.  The following should 
be ruled out: acute viral hepatitis types A, B, C, D and E; autoimmune or alcoholic hepatitis; nonalcoholic steatohepatitis 
(NASH); hypoxic/ischemic hepatopathy; and biliary tract disease and may require gastroenterology and hepatology consultations.  
Consider hepatology (or gastroenterology) consultation.  Document findings in the Imetelstat Questionnaire for Adverse Event of 
Interest eCRF. 
 
6.1.4. 
Dose Modifications for COVID-19 Symptoms or Positivity (any 
Grade) 
As of Amendment 4, due to the COVID-19 pandemic the following guidance must be followed 
for subjects on treatment: 
• 
Closely monitor for clinical signs and symptoms of COVID-19 (eg, fever, cough, shortness 
of breath, breathing difficulties). For more comprehensive overview on signs and symptoms 
please refer to guidance from the WHO and regional health authority guidance. 
• 
For subjects on treatment who have clinical signs and symptoms, if possible, perform 
COVID-19 testing according to local recommendations per local standard of care to assess 
COVID-19 status. Study treatment must be held for subjects who meet any of the following: 
− 
have confirmed COVID-19 infection based on testing 
− 
have clinical signs and symptoms consistent with COVID-19 infection in the absence of 
testing 
− 
do not have clinical signs and symptoms consistent with COVID-19 infection but have 
been exposed to a person with confirmed COVID-19 infection based on local 
recommendations for quarantine 

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• 
Study treatment can resume only after the subject has tested negative for COVID-19 according 
to local guidelines or, if testing was not performed, is asymptomatic (eg, no fever, no cough, 
no shortness of breath, no breathing difficulties) and it has been at least 14 days since start of 
symptoms. If a subject tests positive for COVID-19 while on study, treatment may 
begin/resume after 14 days from positive test and only after symptom free for at least 24 hours 
(smell and taste changes may linger and should not prevent from restarting treatment). 
• 
Cases of confirmed, suspected, or exposed COVID-19 infection leading to changes in study 
conduct or COVID-19 vaccination and/or potential dosing delays should be documented in 
the eCRF, as applicable. 
6.2. 
Infusion-Related Reactions 
All subjects receiving an infusion of study drug must be premedicated with an antihistamine 
(diphenhydramine 25 to 50 mg or equivalent) and a corticosteroid (hydrocortisone 100 to 200 mg 
or equivalent), either intravenously or orally. Premedications may be administered per local 
standard of care approximately 1 hour prior to study drug infusion.  If per Investigator’s discretion 
premedication(s) is/are contraindicated for a subject, modifications should be reviewed and 
approved by the sponsor’s Medical Monitor. It is recommended that subjects are monitored for at 
least 1 hour after the infusion has been completed. 
Subjects should be carefully observed during study drug infusions. Trained study staff at the clinic 
should be prepared to intervene in case of any infusion reactions. If an infusion-related reaction 
develops, then the infusion should be temporarily interrupted and the actions in Table 11 should 
be taken. If possible, an unscheduled blood sample to determine antibodies to imetelstat 
(immunogenicity) should be drawn as soon as possible after the infusion-related reaction for 
potential immune response analysis. 

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Table 11: 
Management of Infusion-Related Reactions 
Severity [per CTCAE 4.03] 
Recommended action 
Grade 1 
[Mild transient reaction; infusion 
interruption not indicated; intervention 
not indicated] 
• 
Evaluate and manage symptomatically as needed 
• 
May complete infusion if reaction remains mild, with stable vital signs 
and does not worsen to Grade 2 
Grade 2 
[Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications 
indicated for <=24 hrs] 
• 
Stop infusion 
• 
Manage symptomatically as needed 
• 
After recovery to Grade ≤1, resume infusion at half the previous rate for 
30 minutes 
− 
If no further symptoms occur, complete the infusion at the full dose 
rate 
− 
If the intensity of the adverse event returns to Grade 2 after restart of 
the infusion, then the procedure described in this section may be 
repeated at the investigator’s discretion. Should the intensity of the 
adverse event increase to Grade 2 for a third time, discontinue 
imetelstat for that cycle.  
Grade 3 
[Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical 
sequelae] 
• 
Stop infusion 
• 
Administer supportive care as indicated 
• 
Observe subject carefully until the resolution of the adverse event or until 
the intensity of the event decreases to Grade 1, at which point the 
infusion may be restarted at the investigator’s discretion. Upon restart, 
the infusion rate should be half of that used before the interruption. 
Subsequently, the infusion rate may be increased at the investigator’s 
discretion. 
− 
If the intensity of the adverse event returns to Grade 3 after restart 
of the infusion, then the procedure described in this section may be 
repeated at the investigator’s discretion. Should the intensity of the 
adverse event increase to Grade 3 for a third time, discontinue 
imetelstat 
Grade 4 
[Life-threatening consequences; urgent 
intervention indicated] 
• 
Stop infusion 
• 
Administer supportive care as indicated 
• 
Discontinue imetelstat 
 
7. 
TREATMENT COMPLIANCE 
Study drug will be administered by qualified site staff, and the details of each administration will 
be recorded in the eCRF. Additional details are provided in the Site Investigational Product Manual 
(SIPM) or equivalent document. 
These guidelines for study drug administration and data collection will continue in the Extension 
Phase. 

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8. 
PRESTUDY AND CONCOMITANT THERAPY 
8.1. 
Prestudy Therapy 
Prestudy therapies administered up to 30 days before C1D1 (Part 1) or Randomization (Part 2) 
must be recorded at screening. Transfusions up to 16 weeks prior to screening also must be 
recorded at screening. 
8.2. 
Premedication 
All subjects receiving an infusion of study drug must be premedicated with an antihistamine 
(diphenhydramine 25 to 50 mg or equivalent) and a corticosteroid (hydrocortisone 100 to 200 mg 
or equivalent), either intravenously or orally. Premedications may be administered per local 
standard of care approximately 1 hour prior to study drug infusion. If per Investigator’s discretion 
premedication(s) is/are contraindicated for a subject, modifications should be reviewed and 
approved by the sponsor’s Medical Monitor. It is recommended that subjects are monitored for at 
least 1 hour after the infusion has been completed. 
8.3. 
Concomitant Medications 
All recommendations regarding the use of concomitant therapy are applicable to the Extension 
Phase. 
Subjects should receive supportive care as clinically indicated. This includes blood product support 
(blood transfusions and use of myeloid growth factors [eg, granulocyte-colony stimulating factor], 
to be administered as needed per investigator discretion and according to local standard practices), 
iron chelation therapy, anti-diarrheals, anti-emetics, analgesics, antibiotic treatment, and treatment 
of other medical conditions. 
The following medications are prohibited during the study: ESA therapy, chemotherapy 
(anticancer/hypomethylating agents) including any anti-MDS therapy, immunomodulatory drugs 
(eg, lenalidomide), immunotherapy, experimental therapy, and radiotherapy. Systemic use of 
corticosteroids in excess of prednisone 20 mg/day or its equivalent for more than 10 days is 
prohibited unless reviewed and approved by the sponsor’s medical monitor. Long-term, chronic 
use of corticosteroids at any dose should also be reviewed and approved by the sponsor’s medical 
monitor. Corticosteroids used as premedication are permitted. The sponsor must be notified in 
advance (or as soon as possible thereafter) of any instances in which prohibited therapies are 
administered. 
Concomitant therapies (prescription or over-the-counter medications, including vaccines, 
vitamins, herbal supplements), including myeloid growth factors, transfusions, iron-chelation 
therapy, anti-infectives (antibacterials, antivirals, and antimycotics), steroids, anti-arrhythmics and 
other cardiac supportive therapy, anti-histamines, anti-emetics, anti-diarrheals, and anti-coagulants 
must be recorded throughout the study beginning with signing of the ICF to 30 days after the end 
of dosing or until the start of subsequent anticancer treatment, if earlier. Collection of concomitant 
medications includes any vaccinations received, including COVID-19 vaccination. Modification 
of an effective pre-existing therapy should not be made for the explicit purpose of entering a 

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subject into the study. Over the course of the study, concomitant therapy may need to be adjusted 
based on the subject’s clinical status. Subjects receiving iron chelating agents should be assessed 
regularly for the need for dose reductions and/or continued use of iron chelating agents according 
to local prescribing information (eg, hold dose for ferritin levels <500 mcg/L) in order to reduce 
the potential risk of hepatic toxicity. Concomitant therapies should be recorded beyond 30 days 
only in conjunction with new or worsening adverse events or serious adverse events that meet the 
criteria outlined in Section 12.3.2, Serious Adverse Events. 
9. 
STUDY EVALUATIONS 
9.1. 
Study Procedures (Part 1 and Part 2) 
The study procedures will be conducted in Part 1 and the main study of Part 2 as per the Time and 
Events Schedules included in the Synopsis. For the Ventricular Repolarization substudy of Part 2, 
refer to the Time and Events Table in Attachment 11. A subject can only participate in 1 part of 
the study. 
The term ‘study drug’ refers to treatment with imetelstat in Part 1 and treatment with imetelstat or 
placebo in Part 2. 
9.1.1. 
Overview 
The Time and Events Schedules for Part 1, the main study of Part 2, and the Ventricular 
Repolarization substudy of Part 2 (Table 1, Table 3, and Table 14, respectively) summarizes the 
frequency and timing of safety, efficacy, pharmacokinetic, immunogenicity and biomarker 
measurements as applicable for both Part 1 and Part 2. As of Amendment 8, an additional Time 
and Events Schedule was added for subjects who enter the Extension Phase (Table 5). Additional 
details for the Extension Phase is provided in Section 9.1.6. 
It is recommended that PRO assessments be completed before any tests, procedures, dosing, or 
other consultations for that visit to prevent influencing subject perceptions. Actual dates and times 
of assessments will be recorded in the source documentation and CRF. 

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9.1.2. 
Blood Volume 
The total blood volume collected is approximately 594 mL for Part 1 and 569 mL for Part 2 over 
the course of the study (see Table 12). 
Table 12: 
Volume of Blood to be Collected from Each Subject - Part 1 and Part 2 Main Study 
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Subject a 
Total Volume of 
Blood (mL) b 
Safety (including screening and posttreatment 
assessments) 
 
 
 
 - Hematology 
5 
28 e 
140 
- Prothrombin time (PT)/ international normalized ratio 
(INR) and activated partial thromboplastin time (aPTT) 
5 
2 
10 
 - Serum EPO level 
2 
1 
2 
 - Serum chemistry c 
10 
17 
170 
 - B12/folic acid/reticulocytes, serum ferritin (screening), 
transferrin saturation f 
5 
1 
5 
- Serum Ferritin (post-screening) 
5 
12 
60 
 - Hepatitis serologies 
13 
1 
13 
 - Serum β-hCG pregnancy tests 
2 
1 
2 
Pharmacokinetic/immunogenicity samples d 
2 
19 
38 
Part 1 Pharmacodynamics (TA, TL, hTERT) 
14.5 
5 
72.5 
Part 2 Pharmacodynamics (TL) 
6 
1 
6 
Part 2 Pharmacodynamics (TA, hTERT) 
8.5 
5 
42.5 
Part 1 Biomarkers (mutation analysis) 
5 
1 
5 
Part 2 Biomarkers (mutation analysis) 
5 
4 
20 
Biomarkers(immunophenotyping) – Part 1 only 
4 
4 
16 
Central laboratory hematology – Part 2 only 
5 
12 
60 
Approximate Total d 
 
 
 
 
 
 
594 mL (Part 1) 
 
 
 
 
 
 
569 mL(Part 2) 
a. 
Volumes below derived for median 12 cycle duration and includes end of treatment visit. 
b. Calculated as number of samples multiplied by amount of blood per sample.  
c. Serum chemistry includes basic liver function tests. An expanded panel of liver function tests may also be required for safety 
reasons. 
d. The blood volume associated with participation in the Ventricular Repolarization substudy is described in Attachment 11. 
e. Including 8 unscheduled blood samples for central testing, if required. 
f. 
Total iron binding capacity and serum iron (Fe) may be performed to calculate transferrin saturation if transferrin saturation is 
not available at the site. 
Note: An indwelling intravenous cannula may be used for blood sample collection.  
 
 
 

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In the Extension Phase, the total blood volume collected is approximately 325 mL (see Table 13). 
Table 13: 
Volume of Blood to be Collected from Each Subject – Extension Phase 
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Subject a 
Total Volume of 
Blood (mL) b 
Safety (including screening and posttreatment 
assessments) 
 
 
 
- Hematology 
5 
21 d 
105 
- Prothrombin time (PT)/ international normalized ratio 
(INR) and activated partial thromboplastin time (aPTT) 
5 
2 
10 
- Serum chemistry c 
10 
21 d 
210 
Approximate Total 
 
 
 
                325 mL  
 
 
 
 
 
 
 
a. 
Volumes below derived for median 12 cycle duration and includes end of treatment visit. 
b. Calculated as number of samples multiplied by amount of blood per sample.  
c. Serum chemistry includes basic liver function tests. An expanded panel of liver function tests may also be required for safety 
reasons. 
d. Including 8 unscheduled blood samples for additional testing, if required. 
 
Note: An indwelling intravenous cannula may be used for blood sample collection. 
 
Repeat or unscheduled samples (including an expanded panel of liver function tests) may be taken 
for safety reasons or for technical issues with the samples. 
Additional serum or urine pregnancy tests may be performed, at the local laboratory as determined 
necessary by the investigator or required by local regulation, to establish the absence of pregnancy 
at any time during the subject’s participation in the study. 
9.1.3. 
Screening Phase and Predose 
All subjects must sign an ICF prior to the conduct of any study-related procedures. Screening 
procedures other than bone marrow aspirate and biopsy will be performed up to 28 days before 
C1D1 (Part 1) or Randomization (Part 2) (see definition in Section 3.1). 
The bone marrow aspirate and biopsy must be performed within the screening period or up to 
12 weeks prior to C1D1 (Part 1) or Randomization (Part 2); however, the sample must be of 
adequate quality for central review. Assessments performed as part of the subject’s routine clinical 
evaluation and not specifically for this study need not be repeated after signed ICF has been 
obtained provided the assessments fulfill the study requirements and are performed within the 
specified timeframe prior to C1D1 (Part 1) or Randomization (Part 2). Central Pathology Review 
(Part 2): A sample of the baseline bone marrow aspirate and biopsy must be submitted to the 
Independent Central Pathology Reviewer for diagnostic confirmation prior to randomization. 
Central laboratory review is required to confirm diagnosis of MDS prior to randomization in 
Part 2. Supporting laboratory samples or results (eg, historic bone marrow slides, hematology 
results) may be requested by the central pathologist and/or sponsor to support the screening MDS 
diagnosis confirmation. Central pathology laboratory diagnosis confirmation is not required for 
subjects participating in the Ventricular Repolarization substudy after Protocol Amendment 7. 

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Laboratory tests noted in the inclusion criteria must be performed and the results within the limits 
specified in the inclusion criteria. Limited retesting of abnormal screening values that lead to 
exclusion are allowed using an unscheduled visit during the screening period (to reassess 
eligibility). If the subject is receiving a transfusion on the same day as the screening labs, screening 
labs should be collected prior to transfusions. The last result obtained prior to C1D1 (Part 1) or 
Randomization (Part 2) will be used to determine eligibility. 
• For the screening ANC to be considered growth factor independent, a 7-day period after 
stopping the growth factor should be observed, or 7 half-lives of growth factor used, 
whichever is longer. ANC should then be retested, and results must be within specified 
limits per inclusion criteria. 
• For the screening platelets ≥ 75 x 109/L to be considered independent of platelet transfusion 
support; platelet count must be stable for 3-4 days after the transfusion. Platelets should 
then be retested, and results must be within specified limits. 
The screening period may extend beyond 28 days upon approval from the sponsor. In these cases, 
all screening procedures with the exception of the ICF, will still be assessed within the protocol-
specified windows prior to Randomization as described per protocol. 
Prestudy transfusion history data will be collected for 16-week period prior to C1D1 (Part 1) or 
Randomization (Part 2). RBC transfusion requirements in the 16-week period prior to C1D1 
(Part 1) or Randomization (Part 2) will be considered for the eligibility assessment. 
The first QUALMS, FACT-An and EQ-5D-5L assessments will be administered prior to 
administration of study drug on Day 1 of Cycle 1, and before any tests, procedures, dosing or other 
consultations are performed, when possible (see Section 9.6). 
As of Amendment 4, due to the COVID-19 pandemic all subjects in screening who have or develop 
clinical signs and symptoms of COVID-19 infection, if possible, should have COVID-19 testing 
performed according to local recommendations to assess COVID-19 status. Subjects should not 
be randomized under any of the following conditions: 
• 
Subject has confirmed COVID-19 infection based on testing 
• 
Subject has clinical signs and symptoms consistent with COVID-19 infection in the absence 
of testing 
• 
Subject does not have clinical signs and symptoms consistent with COVID-19 infection but 
have been exposed to a person with confirmed COVID-19 infection based on testing 
Enrollment can be considered after the subject has tested negative for COVID-19 infection 
according to local guidelines or, if testing was not performed, is asymptomatic (eg, no fever, no 
cough, no shortness of breath, no breathing difficulties) and it has been at least 14 days since the 
start of symptoms. If a subject tests positive for COVID-19 while on study, treatment may 

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begin/resume after 14 days from positive test and only after symptom free for at least 24 hours 
(smell and taste changes may linger and should not prevent from restarting treatment). 
The guidance included above regarding the screening period also apply to the Ventricular 
Repolarization substudy. 
9.1.4. 
Treatment Phase 
The Treatment Phase will begin on Day 1 of Cycle 1 and will continue until discontinuation of 
study drug.  
Treatment Phase 
A treatment cycle is defined as 28 days. A window of ±3 days is allowed for visits to the clinic. 
Details of the procedures performed during the Treatment Phase for Part 1 and Part 2 are outlined 
in the Time and Events Schedules (Table 1 and Table 3). Subjects will be monitored for adverse 
events, laboratory abnormalities, and clinical response. All Treatment Phase visit procedures are 
to be done predose, unless otherwise specified, and laboratory test results must be reviewed prior 
to administering study drug. Adverse events and changes to concomitant medications will be 
recorded (see Section 11.11). Dose modifications will be made according to criteria described in 
Sections 6.1.1, 6.1.2, and 6.1.3. The investigator will assess subject response to therapy using the 
efficacy measurements and disease response criteria according to the modified IWG 2006 criteria 
(Attachment 5) (see Section 11.13 for adjudication of assessments by independent review). 
All clinical evaluations and laboratory studies may be repeated more frequently, if clinically 
indicated. Note that additional weekly blood counts should be performed to follow-up any 
occurrence of Grade ≥3 thrombocytopenia or neutropenia until there is a return to baseline values. 
Additional coagulation testing should be performed if the subject experiences a hemorrhagic event. 
Disease Evaluations must be performed every 12 weeks from Cycle 1 Day 1 (±7 days) up to 
Week 72, then every 24 weeks (±7 days) until suspected PD, and at the time of suspected PD or 
suspected CR, PR, mCR (only for subjects with baseline bone marrow aspirate blasts >5%). The 
required assessments at these disease evaluations are detailed in the Time and Events Schedule 
(Table 1, Table 3, and Table 14). In the main study of Part 2, follow up samples of bone marrow 
aspirate/biopsy must be submitted for central review at the time of suspected response (CR, PR, 
or mCR) and at the time of suspected PD; however, local assessment will be used for investigator-
assessed response evaluations and treatment decisions. In case of an investigator-assessed CR, PR, 
or mCR per modified IWG 2006 criteria (Attachment 5), all disease assessments including bone 
marrow aspirate should be repeated 4-8 weeks from time of initial assessment of CR, PR, or mCR 
for confirmatory purposes, if clinically feasible. If the confirmatory bone marrow assessment is 
not feasible, stability of improved blood counts for 8 weeks is sufficient to define CR and PR per 
modified IWG 2006 criteria. 
Subjects enrolled in the Ventricular Repolarization substudy after Protocol Amendment 7 will 
haver bone marrow aspirate and biopsy per local standard of care or investigator discretion. 

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If PD is diagnosed, or the subject discontinues study drug for other reasons, then the subject will 
complete the End of Treatment Visit within 30 ±3 days after the last dose of study drug and enter 
the Posttreatment Follow-up Phase. 
End of Treatment/Early Withdrawal 
An End of Treatment Visit will be scheduled within 30 ±3 days after the last dose of study drug 
for all subjects, including those discontinuing study drug for any reason, except for lost to 
follow-up, death, or withdrawal of consent for study participation. Subjects who discontinued from 
study drug due to disease progression, adverse event, lack of response, or other reasons and enter 
the Posttreatment Follow-up Phase should have the End of Treatment Visit completed before 
starting any subsequent MDS treatment. If a subject is unable to return to the site for the End of 
Treatment Visit, then the subject should be contacted to collect adverse events that occur within 
30 days after the last dose of the last study drug. Additional information on reporting adverse 
events may be found in Section 11.11. 
The PGIC, FACT-An, QUALMS, and EQ-5D-5L questionnaires should also be completed at the 
End of Treatment Visit (before any tests, procedures, or other consultations are performed, when 
possible, see Section 9.6). If the questionnaires are conducted over a telephone call with the 
subject, then the subject’s questionnaire responses will be read over the telephone to the site staff 
who will record the data in the questionnaires. If the subject is unable to complete the assessment 
during the End-of-Treatment Visit, then the reason for not completing the questionnaire will be 
documented (eg, too ill, subject refused). Subjects enrolled in the Ventricular Repolarization 
substudy after Protocol Amendment 7 are not required to perform PRO assessments. 
9.1.5. 
Posttreatment Phase (Follow-Up)  
The Posttreatment Follow-up Phase is the time between the End-of-Treatment Visit and the end of 
study participation or end of study. During this phase, contact will be made as detailed in the Time 
and Events Schedules (Table 1 and Table 3) until the subject has died, is lost to follow-up, or has 
withdrawn consent. 
If study drug is discontinued for any reason other than disease progression, a response assessment 
should be performed at the time of suspected disease progression. 
Collection of transfusion data should continue every 4 to 6 weeks until the first transfusion in the 
posttreatment follow-up phase. 
If the information on survival status and subsequent therapy is obtained via telephone contact, then 
written documentation of the communication must be available for review in the source 
documents. If the subject has died, then the date and cause of death will be collected and 
documented on the eCRF. Where allowed by local law, public records may be used to document 
death for the purpose of obtaining survival status. 
As per the Time and Events Schedule for the main study of Part 2 (Table 3), sites should attempt 
to administer the PRO questionnaires before any tests, procedures, or other consultations are 

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performed, when possible, (see Section 9.6). Subjects who visit the site for the follow-up 
assessments should complete the questionnaires at that time. If the assessments are conducted via 
a telephone call with the subject, then the subject’s questionnaire responses will be read over the 
telephone to the site staff who will record the data in the questionnaires. If the subject is unable to 
complete the assessments during the Posttreatment Follow-up Phase, then the reason for not 
completing the questionnaires will be documented (eg, too ill, subject refused). Subjects will be 
required to complete PRO questionnaires in posttreatment follow-up until the start of subsequent 
therapy. 
The sponsor will ensure that subjects benefiting from treatment with imetelstat will be able to 
continue treatment after the End of the Study. Subjects who were assigned to the placebo arm in 
the main study will be instructed that they should return to their primary physician to determine 
standard of care. 
9.1.6. 
Extension Phase 
Subjects benefiting from imetelstat treatment at the end of the main study (ie, 24 months after last 
subject randomized in the main study of Part 2) per investigator assessment may continue to 
receive imetelstat during the Extension Phase. Subjects in the Posttreatment Follow-up Phase of 
the main study will also continue in the Extension Phase for extended follow-up for assessment of 
survival status, subsequent anticancer therapy, and monitoring of disease progression, including 
progression to AML (Table 5). Subjects will be followed in the Extension Phase for at least 5 years 
from the first dose of imetelstat received in Part 2 of the main study (including treatment and 
follow-up), or 3 years of post-treatment follow-up from the last dose of study treatment, whichever 
occurs later, or until death, withdrawal of consent, study termination, or until a subject is lost to 
follow-up. During the Extension Phase, the Independent HEC will be available to review all 
hepatic adverse events and liver function test abnormalities at least on a quarterly basis, or more 
frequently if needed. 
Imetelstat-treated subjects in the QTc substudy may also enter the Extension Phase after the 
clinical cut off for the primary analysis is reached for the substudy. The end of study for the QTc 
substudy subjects will be when the subjects from the main study complete the Extension Phase. 
Prior to entering the Extension Phase, subjects must sign and date an updated ICF. After sponsor 
communication of the completion of the main study, the Extension Phase will begin and subjects 
will follow the Time and Events Schedule for the Extension Phase (Table 5). All requirements for 
administration of imetelstat, including guidelines for dose modification, will continue during the 
Extension Phase (see Section 6). Treatment may continue until there is loss of benefit or 
unacceptable toxicity, as determined by the investigator according to local standard of care, or end 
of the Extension Phase. 
Subjects who discontinue imetelstat during the Extension Phase, or who have already discontinued 
study treatment before entering the Extension Phase, will be contacted to determine survival status 
and disease progression, including progression to AML every 16 weeks ±7 days (from the EOT 

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visit date) until the Extension Phase ends. Procedures for documentation of survival follow-up are 
described in Section 9.1.5. 
9.2. 
Endpoints 
Additional details and definitions are provided in Section 11, Statistical Methods. 
9.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the rate of RBC TI lasting at least 8 weeks. The 
8-week RBC TI rate is defined as the proportion of subjects without any RBC transfusion during 
any consecutive 8 weeks (56 days) starting from Study Day 1. Study Day 1 is defined as the day 
of the first dose for subjects enrolled in Part 1 and the day of randomization for subjects enrolled 
in Part 2. 
9.2.2. 
Secondary Endpoints 
• 
Safety of imetelstat in subjects with MDS (eg, incidence, intensity, and type of adverse events, 
vital signs measurements, clinical laboratory values, ECGs changes, and deaths); 
• 
24-week RBC TI rate, defined as the proportion of subjects without any RBC transfusion 
during any consecutive 24 weeks (168 days) starting from Study Day 1; 
• 
Time to the 8-week (24-week) RBC TI, defined as the interval from Study Day 1 to the first 
day of the first 8-week (24-week) RBC TI period; 
• 
Duration of RBC TI, defined as the first day of the longest RBC TI period to the date of the 
first RBC transfusion after the TI period starts; 
• 
Rate of hematologic improvement, including HI-E, per modified IWG 2006; 
• 
Rates of CR, PR, or mCR per modified IWG 2006; 
• 
OS, defined as the interval from Study Day 1 to death from any cause. Survival time of living 
subjects will be censored on the last date a subject is known to be alive or lost to follow-up; 
• 
Progression free survival, defined as the time interval from Study Day 1 to the first date of 
disease progression or death from any cause, whichever occurs first. For subjects who do not 
have documented disease progression and who are still alive at the end of the study or clinical 
cutoff will be censored at the last disease evaluation date. 
• 
Time to progression to AML, defined as the interval from Study Day 1 to the date of AML 
diagnosis. For subjects who have not progressed to AML and are still alive at the cutoff date 
for the analysis or who withdraw from the study (withdrawal of consent or lost to follow-up), 
data will be censored at the date of the last disease evaluation; 
• 
Amount and relative change in RBC transfusions; 
• 
Rate of myeloid growth factors usage, defined as the proportion of subjects receive any 
myeloid growth factors starting from Study Day 1; duration of myeloid growth factor 
administered starting from Study Day 1; 
• 
Assessment of QUALMS, FACT-An, and EQ-5D-5L; 

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• 
Pharmacokinetic parameters (eg, Cmax, AUC0-t), and immunogenicity of imetelstat (eg, 
antibodies to imetelstat); 
• 
Medical resource utilization data including hospitalization, emergency room visits, and 
hematology specialist visits  ; 
• 
ECG parameters including change in QT interval by Fridericia’s correction method (ΔQTcF) 
in the Ventricular Repolarization substudy (Part 2 only). 
9.2.3. 
Exploratory 
Exploratory endpoints are not applicable for subjects participating in the Ventricular 
Repolarization substudy (after Protocol Amendment 7);  
• 
TA and hTERT at baseline and the change from baseline, TL at baseline only; 
• 
Cytogenetic status at baseline and change over time for cytogenetic response; 
• 
Mutation status at baseline and change over time including at the time of suspected response 
(CR, PR, mCR, HI-E [Hb]) or PD; 
• 
Immune profiles at baseline and change from baseline (Part 1 only). 
9.3. 
Efficacy  
Evaluations of efficacy are based on the modified IWG Response Criteria for MDS, as revised in 
2006 (see Attachment 5).7 
9.3.1. 
Evaluations  
Refer to Table 1 for Part 1 and Table 3 for the main study of Part 2 for a schedule of assessments. 
Subjects participating in the Ventricular Repolarization substudy after Amendment 7 will have 
study evaluations performed as per the Time and Events Schedule in Table 14 of Attachment 11. 
Study evaluations performed in the Extension Phase can be found in Table 5. 
9.3.1.1. 
Transfusions 
Transfusion data will be collected during the treatment and posttreatment periods throughout the 
study as specified in the Time and Event Schedules. Transfusion is monitored at each visit for 
imetelstat infusion (every 4-week cycle), at each disease evaluation visit, and at all unscheduled 
visits during treatment. During the posttreatment phase, transfusion data will be collected every 
4 to 6 weeks until the first transfusion in follow-up. Enhanced operational monitoring will be 
implemented to seek tranfusion information from other documented sources. Enhanced and 
continuous medical review will be implemented to identify any sudden but unsustained increase 
of Hb values and to query whether tranfusion has occurred. 
Data to be collected include the date of transfusion, number of units and type of blood products 
transfused and the pre-transfusion Hb and platelet count. Red blood cell transfusions may be 
administered based on Hb level, investigator’s assessment of the subject’s clinical signs and 
symptoms, and local clinical practice. As the volume of 1 unit of RBC transfusion may vary 
regionally, one unit is defined as the amount that is intended to raise Hb by approximately 1 g/dL 

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in an adult patient (ie, one standard pRBC unit or equivalent). The total number of RBC units 
required over rolling 8-week time periods will be calculated to identify subjects who achieve RBC 
TI or transfusion reduction. 
9.3.1.2. 
Hemoglobin Assessment 
Hemoglobin levels will be measured as detailed in the Time and Event Schedules for Part 1 and 
Part 2 as per Table 1 and Table 3, respectively. For a given subject, the same local laboratory 
should be used for each hematology assessment throughout the study, to the extent possible. In 
Part 2, in addition to the local laboratory, a central laboratory will be used for all planned Hb 
assessments. Subjects enrolled in the Ventricular Repolarization substudy (after Protocol 
Amendment 7) are not required to send samples for central Hb laboratory assessments. Treatment 
decision and investigator-assessed disease response evaluations will be based on the local 
laboratory results (see Section 11.13 for adjudication of assessments by independent review). 
Sponsor assessed HI-E will primarily be based on the central laboratory results. Investigator- and 
sponsor assessments based on local laboratory data will also be presented. 
Hematologic improvement-erythroid (HI-E) response is defined as i) a Hb rise of at least 1.5 g/dL 
above the pretreatment level and lasts at least 8 weeks or ii), reduction of at least 4 units of RBC 
transfusion units/8 weeks compared with the prior RBC transfusion burden (criterion adapted from 
the modified IWG 2006 [Attachment 5]). Pretreatment Hb level is defined as the average of all the 
Hb values in the 8 weeks prior to C1D1, including the value on C1D1 (Part 1 or Part 2) and 
excluding values that were within 14 days after transfusion (thus considered to be influenced by 
transfusion). If there were no Hb values that met this definition of not being influenced by 
transfusions, then the baseline value is used. 
9.3.1.3. 
Bone Marrow Assessment  
Bone marrow aspirate and biopsy must be performed as detailed in the Time and Event Schedules 
for Part 1 and the main study of Part 2 as per Table 1 and Table 3, respectively. Bone marrow 
aspirate and biopsy must be available for submission for central pathology review prior to the 
Randomization in the main study of Part 2 to confirm diagnosis and eligibility for study. Central 
pathology review is not required for subjects participating in the Ventricular Repolarization 
substudy (after Protocol Amendment 7). 
Central Pathology Review (Main Study of Part 2) 
A sample of the baseline bone marrow aspirate and biopsy must be submitted to the Independent 
Central Pathology Reviewer for diagnostic confirmation. These samples will consist of bone 
marrow aspirate smears, peripheral blood smears, and bone marrow biopsy (either in formalin or 
unstained recut sections). (Refer to the manual for further instructions on sample preparation, 
handling and shipping.) 
All subsequent bone marrow samples performed for Disease Evaluations, including those at the 
time of suspected response (CR, PR, or mCR in subjects with >5% baseline bone marrow aspirate 
blasts) and PD must be submitted for central review. These samples will consist of bone marrow 
aspirate smears, peripheral blood smears, and in the case of PD, bone marrow biopsy (either in 

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formalin or unstained recut sections). (Refer to the manual for further instructions on sample 
preparation, handling and shipping.) 
Samples of bone marrow aspirate will be used for central cytogenetic assessment (refer to 
Section 9.5). 
9.4. 
Pharmacokinetics and Immunogenicity 
9.4.1. 
Sample Collection and Handling 
Plasma samples (sparse sampling) will be collected from all subjects as described in the Time and 
Events Schedule for Pharmacokinetic Sampling for Part 1 (Table 2) and for the main study of 
Part 2 (Table 4). A serial sampling schedule was carried out in up to approximately 15 subjects 
before implementation of Amendment 2. In the Ventricular Repolarization substudy after Protocol 
Amendment 7, blood for PK samples will be collected on C1D1 prior to study drug administration 
through 8 hours after start of infusion (see schedule of events in Attachment 11). 
Samples will be used to evaluate the pharmacokinetics as well as the immunogenicity of imetelstat 
(antibodies to imetelstat). Venous blood samples will be collected, and the plasma will be divided 
into 2 to 3 aliquots (1 aliquot for pharmacokinetic analysis, 1 aliquot for immunogenicity 
assessment [when appropriate], and 1 aliquot as a back-up). Samples collected for analyses of 
imetelstat plasma concentration and antibodies to imetelstat may additionally be used to evaluate 
safety or efficacy aspects that address concerns arising during or after the study period, for further 
characterization of immunogenicity or for the evaluation of relevant biomarkers or metabolites of 
imetelstat. Genetic analyses will not be performed on these samples. Subject confidentiality will 
be maintained.  
The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual or 
equivalent document for sample collection requirements. Collected samples must be stored under 
the specified and controlled conditions for the temperatures indicated in the Laboratory Manual. 
9.4.2. 
Analytical Procedures 
Pharmacokinetics 
Plasma samples will be analyzed to determine concentrations of imetelstat using a validated, 
specific, and sensitive hybridization enzyme-linked immunosorbent assay method by or under the 
supervision of the sponsor. Only samples from imetelstat treated subjects will be analyzed for 
imetelstat concentration. 
Immunogenicity 
The detection and characterization of antibodies to imetelstat will be performed using a validated 
assay method by or under the supervision of the sponsor. All plasma samples collected for 
detection of antibodies to imetelstat will also be evaluated for imetelstat plasma concentration to 
enable interpretation of the antibody data. Only samples from imetelstat treated subjects will be 
analyzed for immunogenicity and corresponding imetelstat concentration. 

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9.4.3. 
Pharmacokinetic Parameters 
Intensive Pharmacokinetic Sample Analysis 
Pharmacokinetic parameters (Cmax, AUC0-t) will be derived, for subjects in Part 1 (up to 
approximately 15 subjects), from plasma concentration versus time data for imetelstat, but more 
parameters may be estimated if needed. The pharmacokinetic parameters for imetelstat are defined 
as follows: 
Cmax 
 
Maximum observed plasma concentration 
AUC0-t  
Area under the plasma concentration-time curve from time 0 to t  
More parameters may be estimated if warranted by the data. 
Sparse Pharmacokinetic Sample Analysis 
Descriptive statistics (geometric and arithmetic means, standard deviation, coefficient of variation 
[%]) will be provided to summarize imetelstat plasma concentrations at each sampling time point 
for both Part 1 and the main study of Part 2. Population pharmacokinetic analysis will be performed 
to estimate pharmacokinetic parameters such as clearance and volume of distribution. In addition, 
exposure parameters (eg, Cmax or AUC) may be selected to further explore pharmacokinetic-
pharmacodynamic relationships between exposure and relevant pharmacodynamic, or biomarker 
information. 
9.4.4. 
Immunogenicity Assessments 
Antibodies to imetelstat (anti-drug antibodies) will be evaluated in all subjects in Part 1 and the 
main study of Part 2 according to the Time and Events Schedules (Table 1 and Table 3). 
Samples will be used to evaluate the pharmacokinetics as well as the immunogenicity of imetelstat 
(antibodies to imetelstat) (see Section 9.4.1). If possible, any time an infusion-related reaction is 
observed during the study, an unscheduled blood sample should be drawn as soon as possible after 
the reaction for potential immune response analysis. These samples will be tested by the sponsor 
or sponsor’s designee. Plasma samples will be screened for antibodies binding to imetelstat and 
the titer of confirmed positive samples will be reported. Other analyses may be performed to verify 
the stability of antibodies to imetelstat and/or further characterize the immunogenicity of 
imetelstat. 
9.5. 
Biomarkers  
Subjects enrolled in the Ventricular Repolarization substudy (after Amendment 7) are not 
required to have biomarker assessments performed. 
Telomerase Activity and Telomere Length Analyses:  
Baseline (predose on Day 1 of Cycle 1) peripheral blood samples will be collected from all subjects 
in both Part 1 and Part 2, and on-treatment peripheral blood samples will be collected from all 
subjects, as outlined in the Time and Events Schedules (Table 1 and Table 3), to isolate leukocytes 

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and analyze TA. Baseline (C1D1 predose) samples will be collected to analyze TL in Part 1 and 
Part 2 as outlined in Table 1 and Table 3. 
hTERT RNA Expression Analysis:  
Baseline (C1D1 predose) peripheral blood samples will be collected from all subjects in both Part 
1 and Part 2. Additional on-treatment peripheral blood samples will be collected from all subjects 
as outlined in the Time and Events Schedules (Table 1 and Table 3) to assess hTERT level. 
Mutation Analysis:  
Peripheral blood samples will be collected from all subjects as outlined in the Time and Events 
Schedules (Table 1 and Table 3) for mutation analysis. For Part 1, blood samples at baseline and 
at the time of suspected response (CR, PR, mCR, HI-E [Hb]) or PD will be collected to evaluate 
the change of mutation. For Part 2, blood samples will be collected at baseline, every 12 weeks 
after C1D1, at time of suspected response (CR, PR, mCR, HI-E [Hb]) or PD. Genomic DNA will 
be prepared from blood to characterize mutation status on a panel of MDS related genes by next-
generation sequencing or other methodology to evaluate the association of baseline mutation status 
and the change of mutation with clinical response. 
Immunophenotype Analysis (Part 1 only):  
Blood samples will be collected from all subjects as outlined in the Time and Events Schedules 
(Table 1 and Table 3) and may be used to explore imetelstat effects on myeloid progenitor cells 
differentiated into terminal functional myeloid cells by immunophenotyping and functional 
profiling using flow cytometer or cytometry by time of flight (CyTOF) or similar assays. A portion 
of the previously collected blood samples may be used to evaluate imetelstat effects on key 
cytokine and chemokines that are involved in inflammation, immune response, and repair by 
immuno-multiplexing analysis or other methodology where necessary. 
Cytogenetic Analysis:  
Bone marrow aspirate samples will be collected from all subjects as outlined in the Time and 
Events Schedules (Table 1 and Table 3) for karyotype analysis to characterize cytogenetics at 
screening to correlate with clinical response.  
For subjects with a cytogenetic abnormality at baseline, follow up samples should be collected 
every 24 weeks after C1D1, at the time of suspected CR or PR and every 24 weeks thereafter up 
to and including PD to evaluate eradication or reduction of a pre-existing abnormality for assessing 
cytogenetic response.  For subjects with a normal baseline cytogenetic result, a sample should be 
collected at disease progression to evaluate appearance of a new abnormality for assessing possible 
mechanisms of progression. Peripheral blood may be submitted in place of an aspirate only if a 
bone marrow aspirate cannot be obtained (eg, dry tap). The same sample type collected at 
screening must be collected throughout the subject’s participation in the study when possible. Sites 
will be provided with the baseline result report to determine what follow up samples should be 
collected. 

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Bone marrow sampling for cytogenetics on treatment is not required for subjects participating in 
the Ventricular Repolarization substudy (after Protocol Amendment 7). 
Bone marrow aspirate for RNA Seq or CyTOF: 
If sufficient sample is obtained, bone marrow aspirates may be characterized by technologies such 
as quantitative real-time polymerase chain reaction (qRT-PCR), gene expression profiling, 
microRNA, methylation, mutation, RNA sequencing and CyTOF analyses or other similar 
technologies utilized for analysis of RNA expression or proteins. Bone marrow sampling for RNA 
Seq or CyTOF is not required for subjects participating in the Ventricular Repolarization substudy 
(after Protocol Amendment 7). 
Stopping Analysis 
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Samples will be collected only at sites where local regulations and shipping 
logistics permit. Biomarker analysis may be deferred or not performed, if during or at the End of 
the Study, it becomes clear that the analysis will not have sufficient scientific value for biomarker 
evaluation, or if there are not enough samples or responders to allow for adequate biomarker 
evaluation. In the event the study is terminated early or shows poor clinical efficacy, completion 
of biomarker assessments is based on justification and intended utility of the data. Additionally, if 
sufficient pharmacodynamic information is obtained from TA, TL and hTERT testing of at least 
30 subjects, further on-treatment sample collections may cease, without requiring a protocol 
deviation or waiver. 
9.6. 
Patient Reported Outcomes (Part 2 Only) 
Patient-reported outcomes will be assessed in subjects with MDS at the visits indicated in the Time 
and Events Schedule (Table 3) using the PRO measures described below. The questionnaires and 
instructions will be provided as separate paper documents, and subject responses will be 
transcribed to the eCRF by site staff. The protocol assessment questionnaires need to be done in 
the same order at each visit and for each subject to ensure that the subject is answering these as 
consistently as possible. At all visits, the questionnaires should be completed before any tests, 
procedures, dosing, or other consultations are performed and before the subject is informed of any 
assessment results (eg, Hb values), when possible. Subjects should be provided a private, quiet 
area to complete the questionnaires. During the posttreatment period, if the questionnaires are 
conducted over a telephone call with the subject, then the subject’s questionnaire responses will 
be read over the telephone to the site staff who will record the data in the questionnaires. If the 
subject is unable to complete the assessment during the EOT visit, then the reason for not 
completing the questionnaire will be documented (eg, too ill, subject refused). The study site staff 
should instruct the subject to carefully read the instructions and questions of the PRO instrument(s) 
prior to marking responses, that there are no right or wrong answers, and that their responses to 
the questionnaire will not be used to determine their study eligibility. 
PRO evaluation is not required for subjects participating in the Ventricular Repolarization 
substudy (after Protocol Amendment 7). 

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The EQ-5D-5L is a generic measure of health status (Attachment 7). For purposes of this study, 
the EQ-5D-5L will be used to generate utility scores for use in cost-effectiveness analyses. The 
EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression plus a visual analog scale rating “health today” 
with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health 
state).8,29 The scores for the 5 separate questions are categorical and cannot be analyzed as cardinal 
numbers. However, the scores for the 5 dimensions are used to compute a single utility score 
ranging from zero (0.0) to 1 (1.0) representing the general health status of the individual. 
The FACT-An (version 4) is one of the scales from the Functional Assessment of Chronic Illness 
Therapy Measurement System (Attachment 6). It consists of the FACT-G (General version) and 
20 questions labeled “Additional concerns” which measure anemia/fatigue. 
The FACT-G (version 4) is a 27-item compilation of general questions divided into 4 primary 
quality-of-life domains: 
• Physical well-being 
• Social/family well-being 
• Emotional well-being 
• Functional well-being 
The FACT-G (version 4) is considered appropriate for use with subjects with any form of cancer 
and has also been used and validated in other chronic illness conditions. The additional items of 
the FACT-An allow for constructing a Fatigue subscale. The subject is asked to rate the scale items 
as it applies to the past 7 days, on a 5-point scale (0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite 
a bit, 4=Very much). Negatively stated items will be reversed by subtracting the response from 4. 
After reversing the proper items, items are summed to a total to generate a score on a (sub)scale.6,53 
The QUALMS1 is a 38-item measure that assesses health-related quality of life for subjects with 
MDS (Attachment 8). Thirty-three items are used to calculate the total score, as well as the 14-item 
physical burden (QUALMS-P), 3-item benefit-finding (QUALMS-BF), and 11-item emotional 
burden (QUALMS-E) subscales. There are also 5 single-item questions presented at the end of the 
measure that do not form part of the overall scale, as they are not applicable to all subjects with 
MDS. 
The PGIC is used to capture the patient’s perspective of improvement or decline in MDS over 
time (Attachment 9). The PGIC has a 7–point response scale ranging from 1 (very much improved) 
to 7 (very much worse), with 4 representing no change. It will be used as one of the anchors for 
certain psychometric performance tests and estimating meaningful important difference. 

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9.7. 
Medical Resource Utilization (Part 2 Only) 
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF in Part 2 by the investigator and study-site personnel for all subjects throughout the study 
from the time of first dose until EOT visit or 30 days after the last dose of study drug, whichever 
occurs later. Medical resource utilization data collection is not required for subjects participating 
in the Ventricular Repolarization substudy (after Protocol Amendment 7). 
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be used 
to conduct exploratory economic analyses and will include: 
• Frequency and duration of hospitalization (total days length of stay, including duration by 
wards; eg, intensive care unit) 
• Outpatient medical encounters and treatments (including physician or emergency room visits, 
selected tests and procedures, and medications) 
9.8. 
Safety Evaluations 
All subjects who receive at least 1 dose of study drug will be considered evaluable for toxicity. 
Any clinically relevant changes occurring during the study must be recorded in the eCRF. Any 
clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable endpoint is reached. The 
study will include the following evaluations of safety and tolerability according to the time points 
provided in the Time and Events Schedule for Part 1 and Part 2 (Table 1 and Table 3,  respectively). 
Adverse Events 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or 
the subject’s legally acceptable representative) for the duration of the study. Adverse events will 
be followed by the investigator as specified in Section 12 Adverse Event Reporting. Adverse 
events will be reported and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. 
Adverse Events of Interest (AEI) 
Specific adverse events or groups of adverse events will be followed as part of standard safety 
monitoring activities by the sponsor. These events will be reported to the sponsor within 24 hours 
of awareness irrespective of seriousness (ie, serious and non-serious adverse events) following the 
procedure described in the protocol for serious adverse events and will require enhanced data 
collection. The Imetelstat Questionnaire for Adverse Events Of Interest eCRFs must be completed 
for each AEI. For this study the adverse events of special interest are: 
• ALT Grade ≥3 (>5.0 x ULN) 
• AST Grade ≥3 (>5.0 x ULN) 

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• Bilirubin Grade ≥3 (>3.0 x ULN) 
• ALP Grade ≥ 3 (>5.0 x ULN) 
• All hepatic adverse events 
• ALT or AST Grade ≥ 2 (>3.0 x ULN) WITH Bilirubin Grade ≥ 2 (>2.0 x ULN) 
For these events, laboratory assessments should be repeated once or twice weekly until bilirubin 
with fractionation return to baseline levels. Additionally, subjects with Grade 1 and Grade 2 
treatment-emergent elevations in AST, ALT, ALP and bilirubin at the time of treatment 
discontinuation should continue to have laboratory assessments monthly until resolution to at least 
baseline or until the start of subsequent therapy, whichever comes first. All hepatic adverse events 
and LFT abnormalities will be reviewed by an Independent Hepatic Expert Committee, at least 
quarterly, and as needed. 
9.8.1. 
Clinical Laboratory Tests  
All laboratory tests should be performed at the laboratory facilities associated with the 
investigational site. Laboratory certificates or accreditation and normal ranges of the laboratory 
facility at the site must be submitted to the sponsor before the enrollment of any subject at the site. 
If the subject has the laboratory assessments conducted at a laboratory facility other than the one 
associated with the investigational site, the investigator must submit to the sponsor laboratory 
certificates or accreditation and normal ranges for that facility as well.  The laboratory reports must 
be filed with the source documents. In addition, central laboratory will be utilized for hematology 
panel (hemoglobin, platelet count, white blood cell count, ANC and manual absolute peripheral 
blast count) and will be used for HI-E efficacy assessment. Local hematology panel results may 
be used for investigator-assessed response evaluations and treatment decision. 
Blood samples for serum chemistry and hematology to assess the safety of study drug will be 
collected. Required laboratory tests must be performed within 48 hours of the scheduled visit. For 
C1D1 only, clinical laboratory tests do not need to be repeated if the screening tests were 
performed within 5 days of the start of study drug. For all cycles, if tests are repeated on the day 
of the visit, the most recent results should be reviewed before dosing. 
For a given subject, the same local laboratory should be used for each hematology assessment 
throughout the study, to the extent possible. The investigator must review the laboratory report, 
document this review, and record any clinically relevant changes occurring during the study in the 
adverse event section of the eCRF. For example, laboratory abnormalities leading to an action 
regarding any study drug (dose reduction, temporary stop, delay of the start of a cycle or permanent 
stop) or the start of concomitant therapy should be reported. For each laboratory abnormality 
reported as an adverse event, the following laboratory values should be reported in the laboratory 
section of the eCRF: the value indicative of the onset of each toxicity grade; the most abnormal 
value observed during the AE, and the value supporting recovery to Grade ≤ 1 or to baseline values. 

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The following tests will be performed by the local laboratory at the time points shown in the Time 
and Events Schedule. All clinical evaluations and laboratory studies may be repeated more 
frequently, if clinically indicated. In some cases, if a site’s local laboratory does not assess the 
laboratory tests noted below, other laboratory tests may be performed to calculate the values to be 
assessed (eg, total iron binding capacity and serum iron may be collected to calculate transferrin 
saturation). 
• Hematology Panel: hemoglobin, platelet count, white blood cell count, absolute peripheral 
blast count, ANC  
Additional weekly blood counts should be performed to follow-up any occurrence of Grade ≥3 
thrombocytopenia or neutropenia until there is a return to baseline values. 
• Coagulation: international normalized ratio (INR), (or prothrombin time [PT]), and activated 
partial thromboplastin time (aPTT)  
Additional coagulation testing should be performed if the subject experiences a hemorrhagic 
event.  
• Serum Chemistry Panel (Routine): sodium, potassium, blood urea nitrogen (or urea), 
creatinine, total bilirubin, ALT, AST, ALP, lactate dehydrogenase, and albumin. Assessment 
of total bilirubin with fractionation is required at screening; fractionation post-screening is also 
required if total bilirubin is abnormal. 
Additional labs may be assessed locally to demonstrate eligibility if the subject will be enrolled 
with elevated bilirubin levels due to Gilbert’s syndrome, ineffective erythropoiesis due to 
MDS, or hemolysis due to RBC transfusion. 
• Expanded Chemistry Panel for LFT Investigations: gamma-glutamyl transpeptidase 
(GGT), chloride, bicarbonate, magnesium, and fractionated bilirubin required at screening for 
subject eligibility or as applicable for adverse event of interest. 
• Viral Hepatitis: Screening for hepatitis will include comprehensive hepatitis serology A 
through E. Hepatitis D serology is only required if the subject tests positive for the hepatitis B 
surface antigen (HBsAg). Assessment may be performed by local or central laboratory. 
• Serum Erythropoietin 
• Serum Ferritin, Transferrin Saturation 
Total iron binding capacity and serum iron (Fe) may be performed to calculate transferrin 
saturation if transferrin saturation is not available at the site. 
• Anemia Supplemental Panel: B12, folic acid, reticulocytes  
• Pregnancy Testing: Serum or urine pregnancy test for β-hCG  
In addition, the following hematology tests will be performed at the central laboratory: 
hemoglobin, platelet count, white blood cell count and ANC; and manual absolute peripheral blast 
count. 

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9.8.2. 
Electrocardiogram 
A 12-lead electrocardiogram will be performed in all subjects in Part 1 and in the main study of 
Part 2 during screening as specified in the Time and Events Schedules (Table 1 and Table 3). 
During the collection of ECG, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before ECG 
collection and should refrain from talking or moving arms or legs. ECG abnormalities that are 
considered to be clinically relevant by the investigator (not present prior to or worsening from 
C1D1) are to be documented as adverse events. 
In Part 2, a separate Ventricular Repolarization substudy will be performed with serial ECG and 
PK sampling. See Attachment 11 for additional information. 
9.8.3. 
Vital Signs 
Temperature, pulse/heart rate, and blood pressure will be recorded, preferably while the subject is 
in a seated position, at the time points specified in the Time and Events Schedules (Table 1, 
Table 3, Table 5, and Table 14). Vital signs abnormalities that are considered to be clinically 
relevant by the investigator are to be documented as adverse events. 
9.8.4. 
Physical Examination  
Screening physical examination should include body weight, height, and the evaluation of head, 
eye, ear, nose, and throat, cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems. Only a limited symptom-directed physical examination 
and weight assessment is required on Day 1 of all cycles after baseline. New or worsened 
abnormalities should be recorded as adverse events if appropriate. 
As of Amendment 4, due to the COVID-19 pandemic all subjects should be closely monitored for 
signs and symptoms of COVID-19 infection. Subjects that develop clinical signs and symptoms 
should have COVID-19 tests performed according to local recommendations per local standard of 
care to assess COVID-19 status. Refer to Section 6.1.4 for treatment modification guidelines. 
Cases of suspected or confirmed COVID-19 infection should be reported as an AE or SAE, as 
appropriate. 
9.8.5. 
ECOG Performance Status 
The ECOG performance status scale will be used to grade changes in the subject’s activities of 
daily living. 
9.9. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. Refer to the Time and Events Schedules (Table 1, Table 3, Table 5, and Table 14) 
for the timing and frequency of all sample collections. Instructions for the collection, handling, 
storage, and shipment of samples are found in the Laboratory Manual that will be provided. 

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10. 
SUBJECT COMPLETION/WITHDRAWAL 
10.1. 
Completion 
A subject will be considered to have completed the study if he or she has died, has not been lost to 
follow-up, or has not withdrawn consent for study participation before the end of the study. 
10.2. 
Discontinuation of Study Treatment  
If a subject is experiencing clinical benefit in the study without significant toxicity that puts the 
subject at risk, or routine noncompliance that puts the study outcomes at risk, investigators should 
consider continuing the subject on treatment. If a subject shows evidence of progressive disease, 
but the investigator feels they are still experiencing clinical benefit from imetelstat, the sponsor 
should be contacted to discuss potential continuation of treatment. If a subject’s study treatment 
must be discontinued, the event will not result in automatic withdrawal of the subject from the 
study and investigators should reinforce the need for subjects to stay in the study for survival 
follow-up. 
A subject's study drug should be discontinued if: 
• 
The investigator believes that for safety reasons (eg, adverse event or subject experiences 
unacceptable toxicity) it is in the best interest of the subject to discontinue study treatment  
• 
The subject becomes pregnant 
• 
The subject experiences overt disease progression or relapse 
• 
The subject refuses further treatment  
• 
A serious protocol violation has occurred, as determined by the principal investigator or the 
sponsor 
End-of-Treatment and posttreatment follow-up assessments should be obtained. The reason(s) a 
subject discontinues treatment will be recorded on the eCRF. 
10.3. 
Withdrawal from the Study 
A subject will be withdrawn from the study for any of the following reasons: 
• 
Lost to follow-up 
• 
Withdrawal of consent 
• 
The sponsor discontinues the study 
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn subject 
may not be assigned to another subject. Subjects who withdraw will not be replaced. If a subject 

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withdraws from the study before the end of the Treatment Phase, the End-of-Treatment visit 
procedures and the posttreatment follow-up phase assessments should be obtained. 
 
10.3.1. 
Withdrawal from the Use of Samples in Future Research 
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention for 
research are presented in the main ICF. 
11. 
STATISTICAL METHODS 
A general description of the statistical methods to be used to analyze the efficacy and safety data 
in Part 1 and the main study in Part 2 is outlined below. Specific details will be provided in the 
Statistical Analysis Plan. The cardiac safety analysis in regard to ECG and concentration-QTc 
analysis in the Ventricular Repolarization substudy based on the additional 45 subjects will be 
performed separately from the primary analysis of 170 subjects in the main study of Part 2. These 
data may be available after the primary analysis of the main study has already been completed. 
Statistical methods for the substudy are in Attachment 11 and detailed in the Ventricular 
Repolarization Statistical Analysis Plan. 
With Protocol Amendment 8, the Extension Phase analysis focused on disease progression, 
including progression to AML, OS, PFS, and long-term safety data will be conducted at the end 
of the Extension Phase. 
11.1. 
Analysis Populations 
For Part 1:  Efficacy and safety analyses will be performed using the treated population, which 
will include all subjects who receive at least 1 dose of study drug. 
For Part 2: The primary analysis population will be the intent to treat (ITT) population from the 
main study, which will include all randomized subjects. Safety will be evaluated for the population 
of all treated subjects. Subgroup analyses will be performed as appropriate, and details will be 
specified in the Statistical Analysis Plan. 
The biomarker analysis will consist of all subjects in the main study who received at least 1 dose 
of study drug and had at least 1 sample collected during treatment. The same subjects will be 
included in population pharmacokinetic/pharmacodynamic modeling if it is to be performed. 
11.2. 
Subject Information  
Study Day 1 (ie, Study Entry) is defined as the day of the first dose for subjects enrolled in Part 1 
and the day of randomization for subjects enrolled in Part 2. Continuous variables will be 
summarized using descriptive statistics such as mean, median, standard deviation, 25th/75th 
percentiles, and range. Categorical variables will be summarized using frequency tables. For  
time-to-event variables, the Kaplan-Meier method will be used for descriptive summaries. 

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11.3. 
Sample Size Determination 
Approximately 270 subjects (57 subjects enrolled in Part 1, approximately 170 subjects in the main 
study of Part 2, and approximately 45 subjects in Ventricular Repolarization substudy of Part 2) 
will be enrolled in the study. The initial cohort of 32 subjects enrolled into Part 1 was expanded 
with Amendment 2 to include an additional 25 subjects who meet the revised entrance criteria, for 
a total of 57 subjects in Part 1. 
On the basis of historical data, the RBC TI rate is expected to be approximately 7.5%39,41 in 
subjects with low or intermediate-1 risk MDS without any active treatment. The RBC TI rate with 
imetelstat treatment is expected to be approximately 30% based on preliminary data from Study 
CP14B019. The futility criteria before Amendment 2 were defined as follows: If 4 or fewer 
subjects among 30 subjects in Part 1 achieve RBC TI lasting at least 8 weeks, the study will be 
stopped unless there is compelling clinical evidence of efficacy in one or more other endpoints 
(eg, transfusion reduction, erythroid improvement). The assumption was that if the RBC TI rate of 
30% with imetelstat treatment is true, the probability of passing the futility criterion would be 97%.  
Upon review of the efficacy and safety data observed with the 7.5 mg/kg dose among 32 subjects 
in the initial cohort of Part 1, a subset of 13 subjects was identified with higher hematologic 
response rates. These were subjects with non-del(5q) MDS and without prior exposure to either 
hypomethylating agents or lenalidomide. As of Amendment 2, Part 1 was expanded to include 
only subjects who meet these criteria, with the goal to confirm the safety and efficacy data seen in 
this subset and to re-confirm the dose. Twenty-five additional subjects with non-del(5q) MDS and 
without prior exposure to either hypomethylating agents or lenalidomide were enrolled for a total 
of 38 (from 57 enrolled in Part 1) that met these criteria.  
Since data from Part 1 for this target population show clinical benefit of treatment with imetelstat 
(see Section 1.1.5 for summary of data from the 38 subjects in the target population), Part 2 of the 
study will be initiated.  
In the main study of Part 2, approximately 170 subjects will be randomized in a 2:1 ratio to receive 
either imetelstat or placebo. Using a 2:1 ratio randomization and a 2-group continuity corrected 
Chi-square test with 0.05 (2-sided) significance level, 150 subjects are needed to achieve a power 
of approximately 88% to detect the difference between a RBC TI rate of 30% in the imetelstat 
group and a RBC TI rate of 7.5% in the placebo group. After correction for a 10% drop-out rate, 
a total of approximately 170 subjects (115 in imetelstat group and 55 in placebo group) will be 
needed. The overall study power from Part 1 and the main study of Part 2 is approximately 85%. 
11.4. 
Efficacy Analyses  
The primary efficacy analysis is planned at 12 months after the last subject is randomized in the 
main study of Part 2, and the final analysis for the main study is planned at 24 months after 
randomization of the last subject in the main study of Part 2. Efficacy data in Part 1 will be 
descriptively summarized based on the treated population. Efficacy data in Part 2 will be compared 
between the imetelstat and placebo groups based on the ITT population. Any available efficacy 
data from Ventricular Repolarization substudy will be descriptively summarized in addition to the 

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efficacy data from the main study in Part 2. 
Part 1 
The proportion of subjects with 8-week RBC TI, 24-week RBC TI, CR, PR, and hematologic 
improvement, and other binary endpoints, will be summarized with percentage along with its 95% 
2-sided exact confidence interval. The time to 8-week RBC TI and time to 24-week RBC TI will 
be summarized descriptively based on 8-week and 24-week RBC TI responders, respectively. The 
Kaplan-Meier method will be used to estimate the distribution of duration of RBC TI based on 8-
week and 24-week RBC TI responders, respectively. The distributions of OS, PFS, and time to 
progression to AML will be summarized using similar Kaplan-Meier methods. 
Part 2 Main Study 
The analysis for the primary endpoint, 8-week RBC TI, will be based on the ITT population from 
the main study in Part 2 (approximately 170 subjects). The RBC TI rates will be summarized with 
frequency and percentage along with a 2-sided 95% confidence interval for each treatment group. 
The comparison will be based on the stratified Cochran-Mantel-Haenszel test adjusting for the 
stratification factors at a two-sided significance level of 0.05. Note that in order to be considered 
transfusion independent, a subject must have completed continuous transfusion assessment 
throughout the observation period during which his or her transfusion independence is determined. 
The proportion of subjects with 24-week RBC TI, CR, PR, mCR, and other binary endpoints, will 
be evaluated using the same statistical methods as for the primary endpoint. 
The distributions of OS, PFS, and time to progression to AML will be compared using a stratified 
log rank test for the ITT population. The Kaplan-Meier method will be used to estimate the 
distribution for each treatment. The treatment effect (hazard ratio) and its 2-sided 95% confidence 
intervals are to be estimated using a stratified Cox regression model with treatment as the sole 
explanatory variable. The reasons of censoring in time to progression to AML will be tabulated. 
The time to 8-week and 24-week RBC TI will be summarized descriptively based on ITT 8-week 
and 24-week RBC TI responders, respectively. The Kaplan-Meier method will be used to estimate 
the distribution of duration of RBC TI based on ITT 8-week and 24-week RBC TI responders, 
respectively. 
The amount and relative change in RBC transfusions will be summarized descriptively by 
treatment by time point. 
Change from baseline in scores from QUALMS, FACT-An, and EQ-5D-5L will be summarized 
descriptively by treatment group. The PRO measure of interest and analysis methods (eg, 
responder analysis, longitudinal analysis with repeated measures) will be specified in the Statistical 
Analysis Plan. 
A sequential gate-keeping procedure will be implemented to ensure that the overall type I error 
rate for the secondary endpoints is controlled. Details of selected secondary endpoints to be tested 

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and the testing procedure will be specified in the Statistical Analysis Plan. 
11.5. 
Pharmacokinetic Analyses  
The pharmacokinetic-evaluable population is defined as subjects who have received 1 dose of 
study drug and at least 1 post infusion sample. All plasma concentrations below the lowest 
quantifiable concentration or missing data will be labeled as such in the concentration data 
presentation. Concentrations below the lowest quantifiable concentration will be excluded in the 
calculation of summary statistics. All subjects and samples excluded from the analysis will be 
clearly documented in the study report. Descriptive statistics will be used to summarize imetelstat 
plasma concentrations at each nominal sampling time point for pharmacokinetic-evaluable 
population. Details of planned pharmacokinetic analysis will be provided in a specific PK-
statistical analysis plan (SAP). 
Descriptive statistics will be provided to summarize imetelstat plasma concentrations at each 
sampling time point for subjects undergoing serial pharmacokinetic sampling in Part 1. Non-
compartmental pharmacokinetic analysis will be performed on these subsets of subjects. 
Pharmacokinetic parameters as listed in Section 9.4.3 will be derived and descriptive statistics 
provided. 
11.6. 
Immunogenicity Analyses  
The incidence of antibodies to imetelstat will be summarized for all subjects who receive at least 
1 dose of imetelstat and have appropriate samples for detection of antibodies to imetelstat 
(ie, subjects with at least 1 sample obtained after administration of at least 1 dose of imetelstat). 
The results will be summarized for subjects with appropriate samples for the detection of 
antibodies to imetelstat. 
11.7. 
Pharmacokinetic/Pharmacodynamic Analyses 
If required, a population pharmacokinetic/pharmacodynamic analysis may be performed using 
nonlinear mixed-effects modeling. Data may be combined with relevant Phase 1 and/or Phase 2 
studies for the analyses. If the analysis is conducted, then details will be provided in a separate 
report with the population pharmacokinetics analysis results. 
 
11.8. 
Biomarker Analyses  
Biomarker measures and the change from baseline will be listed, tabulated, and plotted where 
appropriate. Subjects may be grouped by treatment, biomarker subgroups, or clinical response. 
Correlation of baseline or changes of biomarkers with clinical parameters will be analyzed by 
appropriate statistical methods (eg, parametric or non-parametric, univariate or multivariate). 
Results of biomarker analyses may be presented in a separate report. Planned analyses are based 
on the availability of clinically valid assays and may be deferred if emerging study data show no 
likelihood of providing useful scientific information. 

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11.9. 
Medical Resource Utilization Analyses (Part 2 only) 
Frequency and duration of hospitalization, frequency of emergency room visit, and specialty 
physician visit will be listed and summarized where appropriate. Results may be grouped by 
treatment, subgroups, or clinical response. 
11.10. Safety Analyses 
Safety analyses will be performed using the treated population. Safety will be evaluated using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
(Version 4.03). The safety parameters to be evaluated are the incidence, intensity, and type of 
adverse events, clinically significant changes in the subject’s physical examination findings, vital 
signs measurements, clinical laboratory results (hematology and chemistry), and deaths. Exposure 
to study drug and reasons for discontinuation will be tabulated. Safety variables are to be tabulated 
by descriptive statistics (n, mean, median, standard deviation, minimum, and maximum; or n and 
percent). 
Adverse Events 
Treatment-emergent adverse events are adverse events that occur after the start of study drug 
administration, through the Treatment Phase, and for 30 days following the last dose of study drug; 
any adverse event considered treatment-related regardless of the start date of the event; or any 
event that is present at baseline but worsens in severity or is subsequently considered drug-related 
by the investigator. The number and percent of subjects with treatment-emergent adverse events 
will be summarized according to intensity (NCI-CTCAE, Version 4.03) and drug relationship as 
well as categorized by System Organ Class and preferred term by treatment arm. 
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are adverse events with onset during the Treatment Phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
included in the analysis. For each adverse event, the percentage of subjects who experience at least 
1 occurrence of the given event will be summarized by treatment group. In addition, comparisons 
between treatment groups will be provided if appropriate. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event. 
Subjects with adverse events of special interest may be counted or listed. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be included in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline. 

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Parameters with predefined NCI-CTCAE toxicity grades will be summarized. A summary of the 
shifts in selected laboratory hematology and serum chemistry parameters from baseline to the 
worst toxicity grade during the study will be provided. The worst toxicity grade during the study 
will be tabulated. 
Electrocardiogram   
Electrocardiogram data from Part 1 and the main study of Part 2 will be listed. Attachment 11 
includes an analysis plan for ECG data from the additional 45 subjects participating in the 
Ventricular Repolarization substudy. 
Vital Signs 
Descriptive statistics of temperature, heart rate, and blood pressure (systolic and diastolic) values 
and changes from baseline will be summarized. The percentage of subjects with clinically 
important changes from baseline will be summarized. 
11.11. Independent Data Monitoring Committee  
An independent DMC will be established to monitor safety data. The DMC will consist of at least 
2 medical experts in the relevant therapeutic area and at least 1 statistician. For Part 1 of the study, 
the DMC performed ad hoc expedited reviews of any ≥Grade 4 hemorrhagic event occurring on 
the study or any other safety concerns identified by the sponsor. During Part 2, the DMC will meet 
periodically to review overall safety data and will also perform ad hoc expedited review of all 
≥Grade 4 hemorrhagic events as they are reported. After each review during Part 1 or Part 2 of the 
study, the DMC will make recommendations regarding the conduct of the study. The roles, 
responsibilities, and memberships of the DMC, Statistical-Support Group, and study team are 
described a separate DMC charter. 

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11.12. Independent Hepatic Expert Committee  
An Independent HEC consisting of 3 hepatologists will be established to monitor all hepatic 
adverse events and LFT abnormalities will be reviewed at least on a quarterly basis, and more 
frequently if needed. This same committee may also review hepatic safety events from other 
ongoing studies with imetelstat. The Independent HEC responsibilities, authorities, and procedures 
will be documented in a charter. Review of hepatic AEs and LFT abnormalities will continue in 
the Extension Phase. 
11.13. Independent Review Committee  
An IRC will be established to adjudicate investigator-assessed disease response (CR, PR, mCR, 
or cytogenetic response) and response (CR, PR, mCR, or cytogenetic response) for subjects with 
>5% baseline bone marrow aspirate blasts based on the central pathology reviewer’s assessment 
in the main study of Part 2. The IRC will assess response based on the modified IWG Response 
Criteria 2006 for MDS as outlined in Attachment 5. The IRC responsibilities, authorities, and 
procedures will be documented in a charter. 
12. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures. 
12.1. 
Definitions 
12.1.1. 
Adverse Event Definitions and Classifications 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product (Definition per International 
Conference on Harmonisation [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. Note: The sponsor collects adverse events starting from the signing of the ICF (refer 
to Section 12.3.1, All Adverse Events, for time of last adverse event recording). 
Serious Adverse Event 
A serious adverse event based on ICH and European Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose: 

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• 
Results in death 
• 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Female subjects 
who become pregnant during the course of the study up to 30 days after the last dose or a female 
partner of a male subject who becomes pregnant up to 90 days of the last dose for the male subject. 
These should usually be considered serious. 
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must be 
reported as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (eg, all-cause mortality). 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For imetelstat, the expectedness/listedness of an adverse 
event will be determined by the sponsor as to whether or not it is listed in the Investigator’s 
Brochure. 
Adverse Event Associated with the Use of the Drug 
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2. 
12.1.2. 
Attribution Definitions 
Not Related 
An adverse event that is not related to the use of the drug. 
Doubtful 
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. 

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Possible 
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s). 
Very Likely 
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
12.1.3. 
Severity Criteria 
An assessment of severity grade will be made using the NCI-CTCAE (Version 4.03) as follows: 
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities. 
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity. 
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities. 
Grade 4 (Life-threatening): Urgent intervention indicated. 
Grade 5 (Death): Death. 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities). 
12.2. 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting and/or safety 
evaluation include, but are not limited to: 
• 
Overdose of a sponsor study drug 
• 
Suspected abuse/misuse of a sponsor study drug 
• 
Inadvertent or accidental exposure to a sponsor study drug 
• 
Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor study drug, eg, name confusion) 
• 
Exposure to a sponsor study drug from breastfeeding 

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• 
Female subject becomes pregnant during the course of the study and up to 30 days after the 
last dose or the female partner of a male subject becomes pregnant during the course of the 
study up to 90 days after the last dose for the male subject    
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF, as well as on the SAE Form. 
12.3. 
Procedures 
12.3.1. 
All Adverse Events 
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until 30 days after the last dose of study drug. 
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported using the Serious Adverse Event/Adverse Event 
of Interest Form. Any adverse event thought to be potentially related to study drug must be reported 
to the sponsor irrespective of timing from the last dose of study drug. The sponsor will evaluate 
any safety information that is spontaneously reported by an investigator beyond the time frame 
specified in the protocol. 
All AE and pregnancy reporting will continue to be collected in the Extension Phase. 
Progressive disease of MDS should NOT be reported as an adverse event, but instead 
symptoms/clinical signs of disease progression may be reported. Otherwise, all events that meet 
the definition of a serious adverse event will be reported as serious adverse events, regardless of 
whether they are protocol-specific assessments. Anticipated events will be recorded and reported 
as described in Attachment 10. 
Adverse events of interest are listed in Section 12.3.3. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as “upper 
respiratory infection”). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions. 
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events, the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 

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and the sponsor has determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the investigators (and the 
head of the institute, where required). 
The investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
A SUSAR will be reported to regulatory authorities unblinded. Participating investigators and 
IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified. 
For all studies with an outpatient phase, including open-label studies, the subject must be provided 
with a “wallet (study) card” and instructed to carry this card with them for the duration of the study 
indicating the following: 
• 
Study number 
• 
Statement, in the local language(s), that the subject is participating in a clinical study 
• 
Investigator’s name and 24-hour contact telephone number 
• 
Local sponsor’s name and 24-hour contact telephone number (for medical staff only) 
• 
Site number 
• 
Subject number 
• 
Any other information that is required to do an emergency breaking of the blind 
12.3.2. 
Serious Adverse Events 
All serious adverse events occurring during the study must be reported to the sponsor’s delegated 
Safety CRO by study-site personnel within 24 hours of their knowledge of the event. 
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event/Adverse Event of Interest Form, which must be completed and signed by a 
physician from the study site and transmitted to the sponsor within 24 hours. The initial and 
follow-up reports of a serious adverse event should be made by facsimile (fax) or email. 
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the subject’s participation in the study, must be followed until any of the 
following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct 

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• 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a subject’s participation in a study must be reported as a serious adverse event, 
except hospitalizations for the following: 
• 
A standard procedure for study medication administration will not be reported as a serious 
adverse event. Hospitalization or prolonged hospitalization for a complication of study 
medication administration will be reported as a serious adverse event. 
• 
The administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable serious adverse 
event. 
• 
A procedure for protocol/disease-related investigations (eg, surgery, scans, sampling for 
laboratory tests, bone marrow sampling, pharmacokinetic or biomarker blood sampling). 
Hospitalization or prolonged hospitalization for a complication of such procedures remains a 
reportable serious adverse event. 
• 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility). 
• 
Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event. 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to  
Section 12.1.1, Adverse Event Definitions and Classifications). 
12.3.3. 
Adverse Events of Interest 
Specific adverse events or groups of adverse events will be followed as part of standard safety 
monitoring activities by the sponsor. These events must be reported to the sponsor within 24 hours 
of awareness irrespective of seriousness (ie, serious and non-serious adverse events of interest), 

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following the procedure described above for serious adverse events and will require enhanced data 
collection. For this study, the adverse events of special interest are: 
12.3.3.1. 
Elevated Liver Function Tests (LFTs) 
Elevations in the following LFTs will be captured as adverse events of interest: 
• ALT Grade ≥3 (>5.0 x ULN) 
• AST Grade ≥3 (>5.0 x ULN) 
• Bilirubin Grade ≥3 (>3.0 x ULN) 
• ALP Grade ≥ 3 (>5.0 x ULN) 
• ALT or AST Grade ≥ 2 (>3.0 x ULN) WITH Bilirubin Grade ≥ 2 (>2.0 x ULN) 
12.3.3.2. 
Hepatic Adverse Events 
All hepatic adverse events will be captured as adverse events of interest. 
12.3.4. 
Pregnancy  
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to 
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the 
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious 
adverse events and must be reported using the Serious Adverse Event/Adverse Event of Interest 
Form. Any subject who becomes pregnant during the study must discontinue further study 
treatment. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their knowledge 
of the event using the appropriate pregnancy notification form. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
12.4. 
Contacting Sponsor Regarding Safety 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document. 
13. 
PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 

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analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide.  
13.1. 
Procedures 
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event. 
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor or its designee according to the serious adverse event reporting timelines (refer 
to Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor. 
13.2. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the sponsor or its designee who should be 
contacted regarding product quality issues are listed on the Contact Information page(s), which 
will be provided as a separate document. 
14. 
STUDY DRUG INFORMATION 
14.1. 
Physical Description of Study Drug(s) 
The imetelstat supplied for this study is supplied as a sterile lyophilized powder in a sealed, 
stoppered, clear glass vial. Each single-dose 10 mL or 8 mL vial contains 210 mg of imetelstat 
sodium per vial and is designed to deliver 200 mg of reconstituted Imetelstat Sodium for Injection 
at a concentration of 33.33 mg/mL. It will be manufactured and provided under the responsibility 
of the sponsor. Refer to the imetelstat IB25 for a list of excipients. 
The placebo supplied for this study is supplied as a non-active lyophilized product with similar 
appearance as imetelstat and provided in the same primary packaging components (vial, stopper 
and cap) as the active drug product that will be supplied. 
14.2. 
Packaging 
Imetelstat is supplied in glass vials that when reconstituted, contains imetelstat at a concentration 
of 33.33 mg/mL. 
During Part 1, imetelstat will be supplied to the site/pharmacy in bulk supply with unblinded labels. 
During Part 2, imetelstat and placebo will be provided to the site in matching vials with blinded 
labels. Once the study is unblinded, imetelstat will be provided to the site/pharmacy as open label 
bulk supply, except QTc subjects who will continue to receive blinded IP until they are 
crossed-over to open label IP. 
14.3. 
Labeling 
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number. 

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14.4. 
Preparation, Handling, and Storage  
All study drug must be stored in the original carton in a refrigerator ranging from 2°C to 8°C (36°F 
to 46°F, refrigerated) and must not be utilized after the expiry date printed on the label. The product 
must not be frozen. Imetelstat and placebo do not contain preservatives; therefore, any unused 
portion remaining in the vial must be discarded. 
Imetelstat and placebo will be reconstituted with 0.9% Sodium Chloride. Refer to the SIPM for 
details regarding dose preparation, storage, and handling.  
14.5. 
Drug Accountability 
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented in the IWRS. All study drug will be stored and disposed of according to the sponsor’s 
instructions. 
Study drug must be handled in strict accordance with the protocol and the container label and must 
be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor’s 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study drug 
will be documented in the IWRS. When the study site is an authorized destruction unit and study 
drug supplies are destroyed on-site, this must also be documented in the IWRS. 
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member of 
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. Study drug may not be relabeled or reassigned for use by other 
subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site 
other than the study sites agreed upon with the sponsor. 
15. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
• 
Study Protocol 
• 
Subject study tools (appointment card, emergency ID card etc., as applicable per country) 
• 
Investigator study tools and quick reference cards 
• 
Imetelstat IB 
• 
Trial Center File, and corresponding specific documentation 
• 
Site Investigational Product Manual, including the investigational product preparation 
instructions 

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• 
Central Laboratory Manual and supplies 
• 
NCI-CTCAE Version 4.03 
• 
PRO questionnaires and user manuals 
• 
IWRS Manual and supplies 
• 
Electronic Data Capture Manual and eCRF Completion Guidelines 
• 
Sample ICFs for Part 1, Part 2 (includes the Extension Phase) of the main study, and the 
Ventricular Repolarization (QTc) substudy 
16. 
ETHICAL ASPECTS 
16.1. 
Study-Specific Design Considerations 
Part 1 is designed as an open-label, single-arm treatment study to evaluate the efficacy and safety 
of imetelstat; all subjects will receive treatment with imetelstat in Part 1. Part 2 is a double-blind, 
randomized design to compare the efficacy of imetelstat to placebo. Discussion on the study design 
rationale is provided in Section 3.1. 
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled. 
The total blood volume to be collected from each subject will be approximately 594 mL in Part 1 
and 569 mL for the main study of Part 2 (see Table 12) and 361 mL in Ventricular Repolarization 
substudy of Part 2 over the course of the study (see Table 16). In the Extension Phase, the total blood 
volume to be collected from subjects who are on imetelstat treatment will be approximately 325 mL 
(see Table 13). The total volume of blood includes laboratory assessments associated with screening 
and treatment including pharmacokinetic and biomarker samples. Subjects enrolled in Part 1 of the 
study are not eligible to enroll in Part 2. The volume of blood to be drawn is considered to be normal 
and acceptable for subjects participating in a cancer clinical study and is deemed reasonable over the 
time frame of the study.  
All participating subjects will receive full supportive care and will be followed closely for safety 
and efficacy throughout the study. Efficacy assessments will be performed by the investigator 
according to modified IWG response criteria 2006 for MDS. Safety assessments will occur through 
regular clinic visits including laboratory analyses. The sponsor will review the safety data on an 
ongoing basis to ensure the safety of the subjects enrolled in this study. An Independent Hepatic 
Expert Committee will review all hepatic adverse events and LFT abnormalities on an ongoing 
basis. An IRC will be established to adjudicate investigator-assessed disease response (CR, PR, 
mCR, or cytogenetic response) in the main study of Part 2 based on the modified IWG 2006 (see 
Section 11.13). An independent DMC will be used in Parts 1 and 2 of the study. 

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16.2. 
Regulatory Ethics Compliance 
16.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible. 
16.2.2. 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations): 
• 
Final protocol and, if applicable, amendments 
• 
Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
• 
Investigator’s Brochure (or equivalent information) and amendments/addenda 
• 
Sponsor-approved subject recruiting materials 
• 
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
• 
Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB) 
• 
Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects 
• 
Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct), the ICF, applicable recruiting materials, and subject compensation 
programs, and the sponsor has received a copy of this approval. This approval letter must be dated 
and must clearly identify the IEC/IRB and the documents being approved. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate: 
• 
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct) 
• 
Revision(s) to ICF and any other written materials to be provided to subjects 
• 
If applicable, new or revised subject recruiting materials approved by the sponsor 

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• 
Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
• 
New edition(s) of the Investigator’s Brochure and amendments/addenda 
• 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually) 
• 
Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
drug 
• 
New information that may adversely affect the safety of the subjects or the conduct of the 
study 
• 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
• 
Report of deaths of subjects under the investigator’s care 
• 
Notification if a new investigator is responsible for the study at the site 
• 
Development Safety Update Report and Line Listings, where applicable 
• 
Any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s). 
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required. 
The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct). 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion. 
16.2.3. 
Informed Consent 
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and 
understand. The informed consent should be in accordance with principles that originated in the 
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and 
sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects (or their legally acceptable representatives) the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is voluntary 
and that they may withdraw consent to participate at any time. They will be informed that choosing 
not to participate will not affect the care the subject will receive for the treatment of his or her 

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disease. Subjects will be told that alternative treatments are available if they refuse to take part and 
that such refusal will not prejudice future treatment. Finally, they will be told that the investigator 
will maintain or have access to a subject identification register for the purposes of long-term follow 
up if needed and that their records may be accessed by health authorities and authorized sponsor 
personnel without violating the confidentiality of the subject, to the extent permitted by the 
applicable law(s) or regulations. By signing the ICF the subject (or their legally acceptable 
representative) is authorizing such access, including permission to obtain information about his or 
her survival status, and agrees to allow his or her study physician to recontact the subject for the 
purpose of obtaining consent for additional safety evaluations, if needed, and subsequent disease-
related treatments, or to obtain information about his or her survival status. 
The subject (or their legally acceptable representative) will be given sufficient time to read the ICF 
and the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject’s or his or her legally acceptable 
representative’s personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject. 
If the subject (or their legally acceptable representative) is unable to read or write, an impartial 
witness should be present for the entire informed consent process (which includes reading and 
explaining all written information) and should personally date and sign the ICF after the oral 
consent of the subject (or their legally acceptable representative) is obtained. 
16.2.4. 
Privacy of Personal Data 
Personal data collected from subjects enrolled in this study will be limited to those data that are 
necessary to fulfill the objectives of the study and processed in compliance with the Patient 
Information and Informed Consent Form (ICF) and agreement(s) with the sponsor governing the 
conduct of the study at the clinical sites. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be utilized. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of subjects confidential. 
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records for purposes such as study-related 
monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also permits the 
transfer of the data to other entities and to other countries in compliance with applicable data 
privacy protection laws and regulations. 
The subject has the data privacy rights set out in the ICF and the applicable data privacy laws and 
regulations in the country in which the study is being conducted. The ICF directs subjects to submit 

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data privacy requests to the study site. The site will report the request to the CRO and/or the 
sponsor. Reasonable steps will be taken to respond to such a request, taking into consideration the 
nature of the request, the conditions of the study, and the applicable data privacy laws and 
regulations. 
Exploratory pharmacodynamics, biomarker, pharmacokinetic and immunogenicity research is not 
conducted under standards appropriate for the return of data to subjects. In addition, the sponsor 
cannot make decisions as to the significance of any findings resulting from exploratory research. 
Therefore, exploratory research data will not be returned to subjects or investigators, unless 
required by law or local regulations. Privacy and confidentiality of data generated in the future on 
stored samples will be protected by the same standards applicable to all other clinical data. 
16.2.5. 
Long-Term Retention of Samples and Use of Data for 
Additional Future Research  
In addition to the procedures and analyses expressly specified in this protocol, samples or data 
collected from subjects may be further analyzed under this protocol to 1) further understand the 
mechanism of action of imetelstat; 2) to understand MDS and why subjects may respond 
differently to imetelstat; 3) to develop and validate imetelstat-related tests/assays (protocol-related 
research). Any research other than described above (including protocol-related research), is 
considered future research. Subjects are given the option to provide express consent to future 
research in the ICF. 
Provided that express consent is obtained from the subject in the ICF, samples collected in this 
study may be stored for up to 15 years (or according to local regulations) for future research. The 
future research may begin at any time during the study or the post-study storage period.  
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored or used for future research (refer to Section 10.3, Withdrawal from the Study (Withdrawal 
from the Use of Samples in Future Research). 
16.2.6. 
Country Selection 
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations. 
17. 
ADMINISTRATIVE REQUIREMENTS 
17.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 

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promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involves only logistic or administrative aspects of the study, the IRB (and IEC where 
required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
(see Contact Information page(s) provided separately). Except in emergency situations, this 
contact should be made before implementing any departure from the protocol. In all cases, contact 
with the sponsor must be made as soon as possible to discuss the situation and agree on an 
appropriate course of action. The data recorded in the eCRF and source documents will reflect any 
departure from the protocol, and the source documents will describe this departure and the 
circumstances requiring it. 
17.2. 
Regulatory Documentation 
17.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met. 
17.2.2. 
Required Prestudy Documentation 
The following documents must be provided to the sponsor before shipment of study drug to the 
study site: 
• 
Protocol and amendment(s), if any, signed and dated by the principal investigator 
• 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee. 
• 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study. 
• 
Regulatory authority approval or notification, if applicable 
• 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable 
• 
Documentation of investigator qualifications (eg, curriculum vitae) 
• 
Completed investigator financial disclosure form from the principal investigator, where 
required 

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• 
Signed and dated clinical trial agreement, which includes the financial agreement or study 
budget 
• 
Any other documentation required by local regulations 
The following documents must be provided to the sponsor before enrollment of the first subject: 
• 
Completed investigator financial disclosure forms from all subinvestigators 
• 
Documentation of subinvestigator qualifications (eg, curriculum vitae) 
• 
Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable 
• 
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable 
17.3. 
Subject Identification 
The investigator agrees to complete a subject identification log to permit easy identification of 
each subject during and after the study. This document will be reviewed by the sponsor study-site 
contact for completeness. 
The subject identification log will be treated as confidential and will be filed by the investigator in 
the study file. To ensure subject confidentiality, no copy will be made. All reports and 
communications relating to the study will identify subjects by subject identification number. In 
cases where the subject is not randomized into the study, the subject number will be used. 
17.4. 
Source Documentation 
At a minimum, source documentation must be available for the following to confirm data collected 
in the eCRF: subject identification, eligibility, and study identification; study discussion and date 
of signed informed consent; dates of visits; results of safety and efficacy parameters as required 
by the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study drug administration information; subject 
worksheets for PROs and date of study completion and reason for early discontinuation of study 
drug or withdrawal from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable. 
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator before 
the study and will be described in the monitoring guidelines (or other equivalent document). 
17.5. 
Case Report Form Completion 
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture will be used for this study. The study data will be transcribed by study-
site personnel from the source documents onto an eCRF and transmitted in a secure manner to the 

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sponsor within the timeframe agreed upon between the sponsor and the study site. The electronic 
file will be considered to be the eCRF. 
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject’s source documentation. All data relating to the 
study must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in 
English. Study site personnel must complete the eCRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit. 
All subjective measurements (eg, pain scale information or other questionnaires) will be completed 
by the same individual who made the initial baseline determinations whenever possible. The 
investigator must verify that all data entries in the eCRFs are accurate and correct. 
All eCRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eCRF. The investigator or study-
site personnel must adjust the eCRF (if applicable) and complete the query. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways: 
• 
Study site personnel can make corrections in the eCRF at their own initiative or as a response 
to an auto query (generated in the eCRF). 
• 
Study site manager can generate a query for resolution by the study-site personnel. 
• 
Clinical data manager can generate a query for resolution by the study-site personnel. 
17.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. 
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
17.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable laws and regulatory requirement(s). 

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The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents must be retained until 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 until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports. 
17.8. 
Monitoring 
The sponsor or its designee will use a combination of monitoring techniques: On-Site Monitoring 
Visits, Remote Telephone Contacts and Central Data Surveillance to monitor this study. 
The sponsor or its designee will perform on-site monitoring visits as frequently as necessary. The 
monitor will record dates of the visits in a study site visit log that will be kept at the study site. The 
first post-initiation visit will be made as soon as possible after enrollment has begun. At these 
visits, the monitor will compare the data entered into the eCRFs with the hospital or clinic records 
(source documents). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to complete the eCRF are known to the sponsor and study-
site personnel and are accessible for verification by the sponsor study-site contact. If electronic 
records are maintained at the study site, the method of verification must be discussed with the 
study-site personnel. 
Direct access to source documentation (medical records, subject PRO worksheets) must be allowed 
for the purpose of verifying that the data recorded in the eCRF are consistent with the original 
source data. Findings from this review of eCRFs and source documents will be discussed with the 
study-site personnel. The sponsor expects that, during monitoring visits, the relevant study-site 
personnel will be available, the source documentation will be accessible, and a suitable 
environment will be provided for review of study-related documents. The monitor will meet with 
the investigator on a regular basis during the study to provide feedback on the study conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site. During these remote contacts, there may be a requirement to provide source 

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documents outside of the site. Home healthcare visits may also occur if the subject is unable to be 
seen at the study site. The process for these will be described in the monitoring guidelines (or 
another equivalent document). 
Central monitoring will take place for data identified by the sponsor as requiring central review. 
17.9. 
Study Completion/Termination 
17.9.1. 
Study Completion 
The end of the main study is defined as 24 months after randomization of the last subject in the 
main study of Part 2. The end of Extension Phase will occur once all subjects in the main study 
have received at least 5 years of imetelstat from the first dose in Part 2 of the main study (including 
treatment and follow-up), or 3 years post-treatment from last dose of study treatment, whichever 
occurs later, or until death, withdrawal of consent, study termination, or until a subject is lost to 
follow-up. The end of study for the QTc substudy subjects will be when the subjects from the main 
study complete the Extension Phase. The sponsor will ensure that subjects benefiting from 
treatment with imetelstat will be able to continue treatment after the end of the study. The final 
data from the study site will be sent to the sponsor (or designee) after completion of the final 
subject assessment at that study site, in the time frame specified in the clinical trial agreement. 
17.9.2. 
Study Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time permitted under the signed clinical trial 
agreement, provided there is reasonable cause and sufficient notice is given to the sponsor in 
advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study drug development 
17.10. On-Site Audits 
Representatives of the sponsor’s or its designee’s clinical quality assurance department may visit 
the study site at any time during or after completion of the study to conduct an audit of the study 
in compliance with regulatory guidelines and company policy. These audits will require access to 
all study records, including source documents, for inspection and comparison with the eCRFs. The 
investigator and study-site personnel are responsible for being present and available for 

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consultation during routinely scheduled study-site audit visits conducted by the sponsor or its 
designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
17.11. Use of Information and Publication 
All information, including but not limited to information regarding imetelstat or the sponsor’s 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory or biomarker research data, generated 
as a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study and will not use it for other purposes without the sponsor’s prior written 
consent. 
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of imetelstat, and thus may be disclosed as 
required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study. 
The results of the study will be reported in a clinical study report generated by the sponsor 
(“Clinical Study Report”) and will contain eCRF data from all study sites that participated in the 
study, data directly transmitted into the sponsor’s database (eg, bone marrow cytogenetics). Results 
of exploratory or biomarker or pharmacokinetic analyses performed after the Clinical Study Report 
has been issued may be reported in a separate report and will not require a revision of the Clinical 
Study Report. Study subject identifiers will not be used in publication of results. Any work created 
in connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data and 
information without approval from the investigator. The investigator has the right to publish study 
site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews may be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 90 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 

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not mandate modifications to scientific content and does not have the right to suppress information, 
but the confidentiality of sponsor’s information will be respected. For multicenter study designs 
and substudy approaches, secondary results generally should not be published before the primary 
endpoints of a study have been published. Similarly, investigators will recognize the integrity of a 
multicenter study by not submitting for publication data derived from the individual study site until 
the combined results from the completed study have been submitted for publication, within 
18 months of the availability of the final data (tables, listings, graphs), or the sponsor confirms 
there will be no multicenter study publication. Authorship of publications resulting from this study 
will be based on the guidelines on authorship, such as those described in the Uniform Requirements 
for Manuscripts Submitted to Biomedical Journals, which state that the named authors must have 
made a significant contribution to the design of the study or analysis and interpretation of the data, 
provided critical review of the paper, and given final approval of the final version. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and/or disclose the existence and the results of clinical studies as required 
by law. 
 
 

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Attachment 1: World Health Organization (WHO) 2008 Classification (Used in Part 2) 
 
MDS Subtype  
Findings: Peripheral Blood  
Findings: Bone Marrow 
Refractory cytopenia with 
unilineage dysplasia (RCUD): 
(refractory anemia [RA]; 
refractory neutropenia [RN]; 
refractory thrombocytopenia 
[RT]) 
Unicytopenia or bicytopenia 
No or rare blasts (< 1%) 
Unilineage dysplasia: ≥10% of 
the cells in one myeloid lineage 
<5% blasts 
<15% of erythroid precursors 
are ring sideroblast 
Refractory anemia with ring 
sideroblasts (RARS) 
 
Anemia 
No blasts 
 
≥15% of erythroid precursors 
are ring sideroblasts 
Erythroid dysplasia only 
<5% blasts 
Refractory cytopenia with 
multi-lineage dysplasia 
(RCMD) 
 
Cytopenia(s) 
No or rare blasts (<1%) 
No Auer rods 
<1 x 109/L monocytes 
 
Dysplasia in ≥10% of cells in 
≥2 myeloid lineages (neutrophil 
and/or erythroid precursors 
and/or megakaryocytes) 
<5% blasts in marrow 
No Auer rods 
±15% ringed sideroblasts 
Refractory anemia with excess 
blasts-1 (RAEB-1) 
Cytopenias 
<5% blasts 
No Auer rods 
<1 x 109/L monocytes 
Uni-lineage or multi-lineage 
dysplasia 
5% to 9% blasts 
No Auer rods 
Refractory anemia with excess 
blasts-2 (RAEB-2) 
Cytopenia(s) 
5% to 19% blasts 
Auer rods  
± <1 x 109/L monocytes 
Uni-lineage or multi-lineage 
dysplasia 
10% to 19% blasts 
Auer rods ±  
Myelodysplastic syndromes, 
unclassified (MDS-U) 
Cytopenias 
<1% blasts 
 
Unequivocal dysplasia in <10% 
of cells in one or more myeloid 
lineages when accompanied by 
a cytogenetic abnormality 
considered as presumptive 
evidence for a diagnosis of 
MDS <5% blasts 
 
Myelodysplastic syndromes 
associated with isolated del(5q) 
Anemia 
Usually normal or increased 
platelet count 
No or rare blasts (<1%) 
Platelets normal or increased 
Normal to increased 
megakaryocytes with 
hypolobated nuclei 
<5% blasts 
Isolated del(5q) cytogenetic 
abnormality  
No Auer rods 
 
SOURCE: 
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important 
changes. Blood. 2009;114(5):937-951. 
 
 

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Attachment 2: French-American-British (FAB) Cooperative Group Classification 
Once a diagnosis of myelodysplastic syndrome (MDS) is established, 5 subtypes of MDS are recognized 
in the FAB classification that are distinguished by the percentage of myeloblasts, presence or absence 
ringed sideroblasts (ie, erythroid precursors with iron deposits surrounding the nucleus), or a monocytosis 
as summarized in the following table: 
 
FAB Category 
Myeloblasts, % 
% Ringed 
Sideroblasts 
Monocytes 
>1 x 109/L 
Bone Marrow 
Blood 
Refractory anemia 
(RA) 
<5 
<1 
<15 
- 
RA with ringed 
sideroblasts (RARS) 
<5 
<1 
>15 
- 
RA with excess blasts 
(RAEB) 
5−20 
<5 
Variable 
- 
Chronic 
myelomonocytic 
leukemia (CMML) 
≤20 
<5 
Variable  
+ 
RAEB in 
transformation 
(RAEB-t) 
21−30 
≥Auer rods 
Variable  
+ / - 
 
SOURCE: Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of the 
myelodysplastic syndromes. Br J Haematol 1982;51:189-199. 
 
 

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Attachment 3: International Prognostic Scoring System (IPSS) for Myelodysplastic Syndrome 
 
 
 
SOURCE: Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis 
in myelodysplastic syndromes. Blood 1997;89:2079-2088. 
 
 

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Attachment 4: Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
 
Grade 
Score  
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, 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. 
 
SOURCE: Eastern Cooperative Oncology Group (ECOG).  
http://www.npcrc.org/files/news/ECOG_performance_status.pdf  

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Attachment 5: International Working Group (IWG) Response Criteria 2006 
Proposed modified International Working Group response criteria for altering natural history 
of MDS 
 
Category 
Response Criteria (responses must last ≥4 weeks) 
Complete remission (CR) 
Bone marrow: ≤5% myeloblasts with normal maturation of all cell 
lines* 
Persistent dysplasia will be noted*† 
Peripheral blood‡: Hb ≥11 g/dL; platelets ≥100 x 109/L; neutrophils 
≥1.0 x 109/L†; blasts, 0% 
Partial remission (PR) 
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 
weeks 
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 Hb 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: 
<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: 
≥50% decrement from maximum remission/response in granulocytes or 
platelets 
Reduction in Hb by ≥2 g/dL 
Transfusion dependence 
∗ 
Dysplastic changes should consider the normal range of dysplastic changes (modification). 
†  
Modification to IWG response criteria. 
‡  
In some circumstances, protocol therapy may require the initiation of further treatment (eg, 
consolidation, maintenance) before the 4-week period. Such patients can be included in the response 
category into which they fit at the time the therapy is started. 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. 

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Attachment 5: (Continued): 
 
International Working Group (IWG) Response Criteria 2006 
 
Proposed modified International Working Group response criteria for hematologic 
improvement 
 
Hematologic 
Improvement* 
Response criteria (responses must last ≥8 weeks)† 
Erythroid response 
(pretreatment, <11 g/dL) 
Hb increase by ≥1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number 
of at least 4 RBC transfusion units/8 weeks compared with the 
pretreatment transfusion number in the previous 8 weeks. Only RBC 
transfusions given for a Hb of ≤9 g/dL pretreatment will count in the 
RBC transfusion response evaluation† 
Platelet response 
(pretreatment, <100 x 
109/L) 
Absolute increase of ≥30 x 109/L for patients starting with >20 x 109/L 
platelets 
Increase from <20 x 109/L to >20 x 109/L and by at least 100%† 
Neutrophil response 
(pretreatment, <1 x 109/L) 
At least 100% increase and an absolute increase >0.5 x 109/L† 
Progression or relapse after 
HI‡ 
At least 1 of the following: 
At least 50% decrement from maximum response levels in granulocytes 
or platelets 
Reduction in Hb by ≥1.5 g/dL 
Transfusion dependence 
∗ 
Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥1 week 
apart (modification). 
†  
Modification to IWG response criteria. 
‡  
In the absence of another explanation such as acute infection, repeated courses of chemotherapy 
(modification), gastrointestinal bleeding, hemolysis, and so forth. It is recommended that 2 kinds of 
erythroid and platelet responses be reported overall as well as by the individual response pattern. 
 
Notes: Deletions to the IWG response criteria are not shown. To convert hemoglobin levels 
(concentrations) from grams per deciliter to grams per liter, multiply grams per deciliter by 10. 
 
Abbreviations: CR: complete remission; DFS: disease-free survival; FAB: French-American-British; Hb: 
hemoglobin; HI: hematologic improvement; IWG: International Working Group; MDS: myelodysplastic 
syndromes; PFS: progression-free survival; PR: partial remission; RBC: red blood cell 
 
 
SOURCE: Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 
2006;108:419-425. 
 
 

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Attachment 6: Functional Assessment of Cancer Therapy − Anemia-Related Effects (FACT-An©) 
 
 

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Attachment 6 (Continued): 
Functional Assessment of Cancer Therapy − Anemia-Related 
Effects (FACT-An) 

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Attachment 6 (Continued): 
Functional Assessment of Cancer Therapy − Anemia-Related 
Effects (FACT-An) 
 
 
Source: Cella D. Functional Assessment of Cancer Therapy – Anemia (FACT-An). Available at: 
https://eprovide.mapi-trust.org/instruments/functional-assessment-of-cancer-therapy-
anemia#member_access_content. Copyright: FACT-An© David Cella, 1997. All rights reserved. 

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Attachment 7: EuroQol 5-Dimension Questionnaire (EQ-5D-5L) 
 
 
 

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Attachment 7: 
EuroQol 5-Dimension Questionnaire (EQ-5D-5L) (Continued) 
 
 
 

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Attachment 7: 
EuroQol 5-Dimension Questionnaire (EQ-5D-5L) (Continued) 
 
 
 
 

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Attachment 8:   
QUALMS Questionnaire  
 
 
 

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Attachment 8: 
QUALMS Questionnaire (Continued) 
 
 
 
 

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Attachment 9: PGIC Questionnaire  
Patient’s Global Impression of Change 
 
Since the start of the treatment you’ve received in this study, symptoms of your 
Myelodysplastic Syndrome are: 
 
 1. Very much improved  
 2. Somewhat improved 
 3. A little improved  
 4. No change 
 5. A little worse  
 6. Somewhat worse 
 7. Very much worse 
 
 
 

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Attachment 10:   
Anticipated Events 
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen. 
For the purposes of this study the following events will be considered anticipated events: 
Disease-related 
Population-related (Subjects ≥65 years) 
• 
Dyspnea 
• 
Fatigue 
• 
Malaise 
• 
Asthenia 
• 
Pyrexia (fever) 
• 
Infection 
• 
Cytopenia 
− 
Anemia 
− 
Thrombocytopenia 
− 
Neutropenia 
− 
Febrile neutropenia 
− 
Leukopenia 
− 
Lymphopenia 
− 
Pancytopenia 
• 
Arrhythmia 
− 
Atrial fibrillation 
• 
Cardiac failure congestive 
• 
Myocardial infarction 
• 
Cerebrovascular accident 
Reporting of Anticipated Events 
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated events 
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any anticipated 
event that meets serious adverse event criteria will be reported to the sponsor as described in Section 12.3.2, 
Serious Adverse Events.  
For anticipated events reported as individual SAEs, the sponsor will make the determination of relatedness 
in addition to and independent of the investigator’s assessment. If an anticipated event is possibly related 
to study drug and meets criteria for expedited reporting, the sponsor will submit a safety report in an 
expedited manner. 
Statistical Analysis 
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events Safety 
Monitoring Plan (ASMP). 
 
 

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Attachment 11:   
Ventricular Repolarization (QTc) Substudy 
 
Subjects should not be enrolled in the Ventricular Repolarization Substudy until enrollment in the main 
study of Part 2 is complete unless a subject is known to meet criteria that would make the subject 
ineligible for the main study (eg, del 5 q, prior HMA therapy). 
Study Objectives 
To evaluate the effect of imetelstat on ventricular repolarization in approximately 45 subjects: 
The primary objective of this substudy is to determine the relationship between the plasma concentrations 
of imetelstat and QTc interval changes. 
The secondary objectives of this substudy are as follows: 
To investigate the effect of imetelstat on the following ECG parameters: heart rate, PR, QRS, and 
T-Wave morphology by using baseline adjusted ECGs on study drug versus placebo 
To evaluate the pharmacokinetics of imetelstat 
Safety and limited efficacy will be assessed as per the Time and Events Schedule below (Table 14). At the 
time of the primary analysis of this substudy, all safety data from the main study will be provided along 
with data specific to this set of subjects. In particular, any cardiac-related adverse events will be summarized 
in both main study and substudy populations. The DMC will review all substudy events on an ongoing 
basis. 
Study Design 
The effect of imetelstat on ventricular repolarization will be centrally analyzed by a third-party cardiac 
safety laboratory in approximately 45 evaluable subjects (approximately 30 and 15 subjects in the imetelstat 
and placebo groups, respectively) enrolled at sites that are participating in the main study protocol. Subjects 
in both the imetelstat and placebo groups will be enrolled in a blinded manner as per the main protocol 
randomization criteria.  
The subjects will undergo the same screening procedures as the main protocol in order to be randomized 
into the study with the exception of central submission and review of bone marrow exam for confirmation 
of diagnosis and central hematology sampling, which are not required. On study follow up bone marrow 
examinations are also not required for subjects enrolled on the substudy and are to be performed per 
investigator discretion and local standard of care. 
If after a minimum of two cycles of treatment a subject enrolled on the substudy has no significant change 
to pRBC transfusion burden or evidence of clinical benefit per Investigator, after discussion with the 
sponsor, the subject may be unblinded. If the subject was on placebo treatment, he/she may be permitted to 
start treatment with imetelstat provided the subject meets criteria for dosing per Section 6.1 of the main 
study. If after unblinding the subject is on imetelstat, the subject may continue to receive treatment if the 
investigator determines there is a favorable risk-benefit profile. Subjects who are unblinded will follow the 
Time and Events Schedule (Table 14) depending on the study treatment to which they were initially 
randomized:  
• 
Placebo: initiate imetelstat and restart assessments at Cycle 1 Day 1, except for the ECG and PK 
evaluations. 
• 
Imetelstat: continue with the next planned cycle as per the Time and Events Schedule (Table 14).  

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Substudy Eligibility Criteria 
Subject eligibility will be reviewed and approved by the sponsor prior to randomization (as defined in 
Section 3.1). 
Inclusion Criteria: 
1. Man or woman ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is 
taking place); 
2. Diagnosis of MDS or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and 
thrombocytosis (MDS/MPN-RS-T) according to WHO criteria confirmed by bone marrow aspirate 
and biopsy within 12 weeks prior to C1D1. 
3. IPSS low or intermediate-1 risk MDS (Attachment 3); 
4. RBC transfusion dependent, defined as requiring at least 4 RBC units transfused over an 8-week period 
during the 16 weeks prior to Randomization (defined in Section 3.1); pre-transfusion Hb should be 
≤9.0 g/dL to count towards the 4 units total; 
5. Has MDS that is relapsed/refractory to ESA treatment as defined by meeting any one of the criteria 
below: 
5.1. Received at least 8 weeks of treatment with a minimum weekly dose of epoetin alfa 40,000 U, 
epoetin beta 30,000 U or darbepoetin alfa 150 mcg (or equivalent agent/dose), without having 
achieved a Hb rise ≥1.5 g/dL or decreased RBC transfusion requirement by at least 4 units over 
8 weeks 
5.2. Transfusion dependence or reduction in Hb by ≥1.5 g/dL after hematologic improvement from 
at least 8 weeks of treatment with therapies outlined in inclusion criteria 5.1, in the absence of 
another explanation. 
5.3. Endogenous serum EPO level >500 mU/mL 
6. Adequate iron stores, defined as transferrin saturation greater than 20% and serum ferritin greater 
than 400 ng/mL, measured within the screening period, or adequate iron stores as demonstrated by 
recent (within 12 weeks prior Randomization) bone marrow examination with iron stain 
7. ECOG performance status 0, 1 or 2 (Attachment 4) 
8. Hematology lab test values within the following limits: 
8.1. ANC ≥1.5 x 109/L independent of growth factor support (defined in Section 9.1.3) 
8.2. Platelets ≥75 x 109/L independent of platelet transfusion support (defined in Section 9.1.3); 
9. Biochemical laboratory test values must be within the following limits: 
9.1. AST, ALT and ALP ≤2.5 times the upper limit of normal (x ULN) 
9.2. Serum creatinine ≤2.0 x ULN 
9.3. Total bilirubin ≤3 x ULN (unless due to Gilbert’s syndrome, ineffective erythropoiesis due to 
MDS, or hemolysis due to RBC transfusion) AND  
Direct bilirubin ≤2 x ULN (unless due to Gilbert’s syndrome, ineffective erythropoiesis due to 
MDS, or hemolysis due to RBC transfusion, where a direct bilirubin value of ≤3 x ULN or less 
than 1/3 of the total bilirubin value is acceptable); 
10. Women of childbearing potential and practicing a highly effective method of birth control consistent 
with local regulations regarding the use of birth control methods for subjects participating in clinical 
studies: eg, established use of oral, injected or implanted hormonal methods of contraception; 

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placement of an intrauterine device or intrauterine system; barrier methods: condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository; male partner sterilization (the vasectomized partner should be the 
sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle 
of the subject). For females, these restrictions apply for 1 month after the end of dosing. Note: If the 
childbearing potential changes after start of the study (eg, woman who is not heterosexually active 
becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective 
method of birth control, as described above. A woman of childbearing potential must have a negative 
serum (β-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at screening and agree to 
be tested on Day 1 of every cycle and at end of treatment (30 days post last dose); 
11. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy 
must agree to use a barrier method of birth control eg, either condom with spermicidal 
foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the 
study. For males, these restrictions apply for 3 months after the end of dosing. 
12. Each subject (or their legally acceptable representative) must sign an informed consent form (ICF) 
indicating that he or she understands the purpose of the procedures required for the study and are 
willing to participate in the study. 
13. Provide informed consent for participation in this Ventricular Repolarization substudy. 
Exclusion Criteria: 
1. Subject has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients (refer to 
the IB25); 
2. Subject has received an experimental or investigational drug or used an invasive investigational 
medical device within 30 days prior to randomization (defined in Section 3.1) or is currently enrolled 
in an interventional investigational study; 
3. Prior treatment with imetelstat; 
4. Have received corticosteroids >30 mg/day prednisone or equivalent within 4 weeks prior to 
randomization; 
5. Has received an ESA or any anti-MDS therapy, chemotherapy, immunomodulatory, or 
immunosuppressive therapy within 4 weeks prior to Randomization (8 weeks for long-acting ESAs); 
6. Prior history of hematopoietic stem cell transplant; 
7. Anemia attributed to factors other than MDS (including hemolysis, chronic renal failure, hepatitis, 
and gastrointestinal bleeding); 
8. Major surgery within 4 weeks prior to randomization (excluding the placement of vascular access 
and other minor surgical procedures); 
9. Diagnosed or treated for malignancy other than MDS, except: 
9.1. Malignancy treated with curative intent and with no known active disease present for ≥3 years 
before randomization  
9.2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 
9.3. Adequately treated cervical carcinoma in situ without evidence of disease; 
10. Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic 
infection requiring IV antibiotics; 

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11. Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to 
enter the study), or known acute or chronic liver disease including cirrhosis; 
12. Females who are pregnant or are currently breastfeeding or planning to become pregnant while 
enrolled in this study or within 1 month after the end of dosing; 
13. Males who plan to father a child while enrolled in this study or within 3 months after the end of 
dosing; 
14. Any life-threatening illness, medical condition, or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, interfere with the imetelstat 
metabolism, or put the study outcomes at undue risk; Subject has any condition for which, in the 
opinion of the investigator, participation would not be in the best interest of the subject (eg, 
compromise the well-being) or that could prevent, limit, or confound the protocol-specified 
assessments; 
15. Subject was previously assessed as having IPSS intermediate-2 or high risk MDS; 
16. Concurrent therapy with medications known to prolong the QT interval and have been associated with 
Torsade de pointes arrhythmia (TdP) (refer to www.crediblemeds.org for the list of drugs to avoid) 
17. Cardiac function abnormalities on screening ECG as follows: 
• 
Resting heart rate outside of 50 to 100 beats per minute 
• 
QTcF >470 msec (or QTcF >490 msec in the presence of a right bundle branch block or ventricular 
conduction delay [QRS >119 msec]), as determined by central assessment based on the average 
value of a triplicate set of ECGs 
• 
Diagnosed or suspected congenital long QT syndrome 
• 
Family history of sudden unexpected death from cardiac-related causes if indicative of a 
pathogenic mutation of cardiac ion channels 
• 
Family history of congenital long QT syndrome 
• 
History of Mobitz II second degree or third degree heart block 
• 
Implantable pacemaker or automatic implantable cardioverter defibrillator 
• 
Complete left bundle branch block 
• 
Chronic or persistent atrial arrhythmia including atrial fibrillation and atrial flutter 
• 
History or presence of clinically relevant heart rhythm disturbances including atrial, junctional, 
re-entry, and ventricular tachycardia 
• 
Unusual T-wave morphology (ie, bifid T-wave) likely to interfere with QT measurements. 
18. History or evidence for any of the following: severe or unstable angina, myocardial infarction, 
symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary 
embolism, cerebrovascular accident including transient ischemic attacks) within 12 months prior to 
Cycle 1 Day 1, New York Heart Association (NYHA) Class II to IV heart disease 
19. Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or 
diastolic BP ≥100 mmHg). Subjects with a history of hypertension are permitted, provided that BP is 
controlled to within these limits by anti-hypertensive treatment 
20. Any skin condition likely to interfere with electrocardiographic electrode placement or adhesion. 
21. History of thoracic surgery likely to cause abnormality of the electrical conduction through thoracic 
tissues.  

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Schedule of Events 
Subjects on the Ventricular Repolarization substudy will follow the Ventricular Repolarization Time and Events Schedule (Table 14) below. 
Table 14  Time and Events Schedule for Part 2 Ventricular Repolarization Substudya 
 
   
PHASE 
Screening Phase 
Treatment Phase 
(4-week cycles ±3 days)  
Posttreatment Follow-up 
Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomization 
Cycle 1 
Day 1 
(predose
) 
Cycle 1 
Day 8, 15, 
22 
Cycle 2 
Day 1, 
8, 15, 
22 
Cycle 3 
Day 1 until 
EOT 
EOT Visit 
30 ±3 days 
after last dose 
Survival Follow-up 
Every 12-16 weeks 
Screening 
 
 
 
 
 
 
 
 
Informed consent 
Refer to Section 9.1.3for guidance regarding COVID-19 and further 
clarification of screening procedures. 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
X 
 
 
 
 
 
Medical history and 
demographics 
 
X 
 
 
 
 
 
 
Study Medication Administration 
Randomization 
Randomization will occur on C1D1 or up to 72h prior to study drug 
administration 
 
X  
 
 
 
 
 
Dispense/administer study 
drug 
Refers to Imetelstat or placebo (see Section 6). The screening 
weight is considered baseline for dose calculation. Recalculate dose 
if ≥10% weight change from baseline. Dosing should begin within 
72 hours of randomization in IWRS. 
 
X 
 
X (D1 
only) 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
Physical exam (including 
weight)  
Full PE at Screening; limited symptom-directed PE thereafter.   
Refer to Section 9.8.4  for guidance regarding COVID-19. 
X 
X 
 
X (D1 
only) 
X 
X 
 
Vital signs 
Includes temperature, HR, SBP and DBP (preferably in a seated 
position). Measured and recorded prior to infusion. 
X 
X 
 
X (D1 
only) 
X 
X 
 
12-lead ECG 
  
Refer to Table 15 
Efficacy Assessments 
 
 
 
 
 
 
 
 
Transfusion history and 
status; myeloid growth factor 
treatment 
Assessment of RBC transfusion requirement 16 weeks prior to 
Randomization and at each clinic visit until the end of treatment. 
Sites should make every attempt to obtain complete information, 
including both in-patient and out-patient transfusions (see Section 
9.3.1.1 for additional information). Pre-transfusion Hb must be 
documented. 
Note: if DE Visit does not align with a Cycle Day 1 visit, then 
hematology (local) is required at the DE Visit. 
X 
X 
 
X (D1 
only) 
X  
X 
X (every 4-6 weeks) until 
first transfusion in 
Posttreatment follow-up 
Hematology (local 
laboratory) 
Screening tests should be within 14 days prior to Randomization. 
For C1D1, no need to repeat if Screening tests performed within 5 
days. Refer to Inclusion Criteria above for further details. After 
C1D1, tests must be performed within 48h before the scheduled 
visit. For all cycles, if tests are repeated on the day of the visit, the 
most recent results should be reviewed before dosing. Perform 
unscheduled weekly follow-up after any Grade ≥3 
thrombocytopenia or neutropenia until values return to baseline. 
X 
X 
X 
X 
X 
X 
X (first visit if feasible) 

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Table 14  Time and Events Schedule for Part 2 Ventricular Repolarization Substudya 
 
   
PHASE 
Screening Phase 
Treatment Phase 
(4-week cycles ±3 days)  
Posttreatment Follow-up 
Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomization 
Cycle 1 
Day 1 
(predose
) 
Cycle 1 
Day 8, 15, 
22 
Cycle 2 
Day 1, 
8, 15, 
22 
Cycle 3 
Day 1 until 
EOT 
EOT Visit 
30 ±3 days 
after last dose 
Survival Follow-up 
Every 12-16 weeks 
Testing should be conducted pre-transfusion, if feasible. 
Hematology panel includes hemoglobin, platelet count, white blood 
cell count, ANC. Absolute peripheral blast count should be done 
prior to randomization and on D1 of each cycle only. 
Note: if DE Visit does not align with a Cycle Day 1 visit, then 
hematology (local) is required at the DE Visit. 
BM aspirate, biopsy 
A BM aspirate and biopsy with iron stain performed locally within12 
weeks prior to Randomization will be used for determination of 
eligibility.  Local cytogenetics results within 12 months prior to 
randomization are also required to determine eligibility per IPSS.  If 
cytogenetic testing cannot be performed locally, a sample may be 
sent for central review. 
X 
BM aspirate and biopsy per local standard of care or investigator 
discretion.    
 
Response assessment 
Per modified IWG 2006; see Attachment 5. Response assessments 
to be performed per local standard or investigator discretion.  
Note: CR, PR or mCR only to be assessed in subjects with >5% 
baseline bone marrow aspirate blasts 
 
Every 12 weeks from C1D1 (±1 week) up to week 72, then every 24 
weeks until suspected PD  
At suspected PD, if 
feasible 
ECOG performance status 
See Attachment 4 
X 
X 
 
X (D1 
only) 
X 
X 
 
Survival status and 
subsequent therapy 
Survival status and subsequent therapy are planned to be collected 
at the EOT visit and throughout survival follow-up period at least 
every 12 to 16 weeks (data may be collected more frequently, if 
needed). 
 
 
 
 
 
X 
X 
Clinical Laboratory Assessments 
Chemistry (local laboratory) 
Screening tests should be performed within 14 days prior to 
Randomization. For C1D1, no need to repeat if Screening tests 
performed within 5 days. After C1D1, tests must be performed 
within 48h before the scheduled visit. Refer to Inclusion Criteria 
above for further details. Refer to Sections 9.8 and 9.8.1 for 
additional detail on required clinical laboratory testing.   
X 
X 
X 
X (D1 
only) 
X 
X 
 
Chemistry panel for LFT 
investigations (local 
laboratory) 
Includes GGT, chloride, bicarbonate, magnesium, and fractionated 
bilirubin. For subjects with AST, ALT, ALP or bilirubin Grade ≥3, 
repeat chemistry panel and LFT investigations panel weekly until 
bilirubin with fractionation is <3x ULN, and AST, ALT and ALP is 
<5x ULN. Subjects with Grade 1 or Grade 2 elevations in AST, ALT, 
ALP or bilirubin at time of treatment discontinuation should continue 
to have tests monthly until resolution to at least baseline grade or 
until the start of subsequent therapy, whichever comes first. 
 
If an adverse event of interest occurs 
 
INR (or PT) and aPTT (local 
laboratory) 
With additional assessments performed during treatment phase if 
subject has a hemorrhagic event. 
X 
Repeat during study if subject has a Grade ≥3 bleeding event 
 
Serum EPO level (local 
laboratory) 
 
X 
Repeat during study per local standard of care or investigator discretion.    
 

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Table 14  Time and Events Schedule for Part 2 Ventricular Repolarization Substudya 
 
   
PHASE 
Screening Phase 
Treatment Phase 
(4-week cycles ±3 days)  
Posttreatment Follow-up 
Phase 
Study Procedures 
Comments 
Up to 28 days 
before 
Randomization 
Cycle 1 
Day 1 
(predose
) 
Cycle 1 
Day 8, 15, 
22 
Cycle 2 
Day 1, 
8, 15, 
22 
Cycle 3 
Day 1 until 
EOT 
EOT Visit 
30 ±3 days 
after last dose 
Survival Follow-up 
Every 12-16 weeks 
Serum ferritin, transferrin 
saturation (local laboratory) 
Total iron binding capacity and serum iron (Fe) may be performed to 
calculate transferrin saturation if transferrin saturation is not 
available at the site. 
X 
X 
 
X (D1 
only) 
X 
X 
 
B12 / folic acid / reticulocytes 
(local laboratory) 
 
X 
 
 
 
 
 
 
Hepatitis serologies 
Comprehensive hepatitis serology panel A through E. Hepatitis D 
serology is only required if the subject tests positive for the hepatitis 
B surface antigen (HBsAg). If the subject screening window is 
>28 days (Section 9.1.3), hepatitis screening results may still be 
used to determine eligibility outside of the initial 28-day screening 
period provided the subject is asymptomatic and does not meet 
Exclusion Criteria no. 11 above.  
X 
 
 
 
 
 
 
Serum or urine pregnancy 
test 
 
X 
 
 
X (D1 
only) 
X 
X 
 
Pharmacokinetics 
Pharmacokinetic samples 
 
Refer to Table 15 
Ongoing Subject Review 
Concomitant therapy 
 
X 
Continuous 
X 
 
Adverse events 
 
X 
Continuous 
X 
 
Abbreviations: BM=Bone Marrow; C=Cycle; CR=complete remission; CyTOF=cytometry by time of flight ; D=Day; DBP=diastolic blood pressure; EOT=end of treatment; EPO=erythropoietin; EQ-5D-5L=EuroQol-EQ-5D-5L; FACT-
An= Functional Assessment of Cancer Therapy - Anemia-Related Effects; HI-E (Hb)=hematologic improvement-erythroid (hemoglobin); HR=heart rate; GGT= gamma-glutamyl transpeptidase; hTERT= human telomerase reverse 
transcriptase; INR=international normalized ratio; IRR=infusion-related reaction; IWRS= interactive web response system; PD=disease progression; PE=physical exam; PGIC= Patient Global Impression of Change; 
PK=pharmacokinetic; PR=partial remission; PT=prothrombin time; QUALMS= Quality of Life in Myelodysplasia Scale; SBP=systolic blood pressure; TA=telomerase activity; TL=telomerase length; ULN=upper limit of normal 
 
a  Subjects who are unblinded will follow the schedule depending on the study treatment to which they were initially randomized.  If placebo, initiate imetelstat and restart assessments at Cycle 1 Day 1 (except for the ECG and PK 
evaluations). If imetelstat, continue with the next planned cycle. 
 

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Table 15 
ECG and PK Assessments for Part 2 Ventricular Repolarization Substudy  
Study 
Procedure 
Screening 
Cycle 1 Day 1a 
 
- 
-1 hr (1hr 
prior to 
dose) 
-0.5 hr 
(half hour 
prior to 
dose) 
0 hr  
(immediately 
pre-dose) 
0.5 hr 
1 hr 
2 hr (immediately 
before end of 
infusion) 
4 hr 
6 hr 
8 hr 
Triplicate 
12-lead 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK 
samplesb 
 
 
 
 
X 
X 
X 
X 
X 
X 
hr=hours 
a All times on Cycle 1 Day 1 are relative to the start of infusion 
b PK samples are to be collected immediately after the triplicate ECG assessment is completed. Exact time of PK sample collection should be recorded. Subjects 
participating in the Ventricular Repolarization substudy will have a total of 6 mL additional blood collected (3 additional samples) for PK assessment than in the Part 2 
main study. 
 

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Methods specific to the Ventricular Repolarization Assessments: 
Digital 12-lead ECG equipment will be provided to each clinical site participating in this substudy by the 
central laboratory for the duration of the substudy. 
ECGs will be collected via Holter Monitoring using a 12-lead ambulatory device. ECGs should be collected 
after the subject has rested quietly and is awake in a fully supine (or semi-recumbent, if supine is not 
tolerated) position for 10 minutes and prior to any blood collection. For each subject, the same position (eg, 
supine or semi-recumbent) should be used for all ECGs collected. Starting on Cycle 1, Day 1, 0.5 hr time 
point matched blood samples for pharmacokinetic analyses will be collected immediately following the 
collection of ECGs and before the collection of blood for all other clinical evaluations. ECGs will be read 
by independent cardiologists from the central laboratory in a blinded manner and via a single reader 
paradigm. 
Schedule of Events Specific to the Ventricular Repolarization Assessments:  
A detailed list and schedule of the required assessments for Ventricular Repolarization assessment is 
provided below and in Table 14.  
The subject should be maintained in the same supine position for each of the 12-lead ECGs. The total 
volume of blood anticipated for the Ventricular Repolarization substudy due to the intensive PK sampling 
is expected to be 6 mL (3 additional samples) more than the main study population. 
 Screening 
Collect a set of triplicate 12-lead ECGs, 2 minutes apart. 
 Cycle 1, Day 1 
At 1 hour and a half hour prior to administering the first dose of study drug, collect a set of triplicate 
12-lead ECGs, 2 minutes apart for each time point, respectively.   
At time 0, just prior to administering the first dose of study drug, collect a set of triplicate 12-lead 
ECGs, 2 minutes apart.  
Administer blinded study drug. 
At 0.5 hours after start of infusion (SOI), 1 hour after SOI, immediately before the end of 2-hour 
infusion, 4, 6, and 8 hours after SOI, collect a set of triplicate ECGs, 2 minutes apart, and 1 blood 
sample for PK analysis for each time point, respectively.   
 
 

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Blood Volume for the Ventricular Repolarization Substudy 
Table 16: 
Volume of Blood to be Collected from Each Subject in the Ventricular 
Repolarization Substudy 
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Subject a 
Total Volume of 
Blood (mL) b 
Safety (including screening and posttreatment 
assessments) 
 
 
 
 - Hematology 
5 
18 
90 
- Prothrombin time (PT)/ international normalized ratio 
(INR) and activated partial thromboplastin time (aPTT) 
5 
1 
5 
 - Serum EPO level 
2 
1 
4 
 - Serum chemistry c 
10 
17 
170 
 - B12/folic acid/reticulocytes, serum ferritin (screening), 
transferrin saturation d 
5 
1 
5 
- Serum Ferritin (post-screening) 
5 
12 
60 
 - Hepatitis serologies 
13 
1 
13 
 - Serum β-hCG pregnancy tests 
2 
1 
2 
Pharmacokinetic samples  
2 
6 
12 
Approximate Total  
 
 
 
                                                       361 mL 
 
Note: An indwelling intravenous cannula may be used for blood sample collection. 
a Volumes below derived for median 12 cycle duration and includes end of treatment visit. 
b Calculated as number of samples multiplied by amount of blood per sample. 
c Serum chemistry includes basic liver function tests. An expanded panel of liver function tests may also be required 
for safety reasons. See Time and Events Schedule above. 
d Total iron binding capacity and serum iron (Fe) may be performed to calculate transferrin saturation if transferrin 
saturation is not available at the site 
 
Rationale for the Study Design 
In accordance with ICH E14 guideline, QT evaluation is now expected to be routine in oncology drug 
development, and a thorough QT (TQT) study should be conducted, if possible, in healthy subjects.  
Due to the mechanism of action and safety profile of imetelstat (predominantly cytopenia), administration 
of imetelstat to healthy subjects at clinically relevant doses is not advised. The maximum tolerated dose is 
different in various patient populations: 7.5 mg/kg every 4 weeks (q4w) in MDS patients; 9.4 mg/kg every 
3 weeks (q3w) in MF patients, and 11.7 mg/kg q4w in solid tumor subjects. Various Phase 1 and 2 solid-
tumor studies did not show meaningful clinical activity and do not warrant further clinical investigation. 
The current focus of clinical development is on hematologic malignancies, namely MDS and MF. Although 
the clinical dose in MDS subjects (7.5 mg/kg) is lower than that in MF subjects (9.4 mg/kg), the exposure 
in MDS subjects at 7.5 mg/kg is higher than that achieved in MF subjects with 9.4 mg/kg. Therefore, the 
exposure in MDS subjects dosed at 7.5 mg/kg represents the highest clinical exposure among hematologic 
malignancies under active clinical development. A supratherapeutic dose is not feasible since 7.5 mg/kg 
appears to be the maximum tolerated dose for MDS subjects. 
Part 1 of MDS3001 enrolled both males and females, with females on average exhibiting 27% and 20% 
higher Cmax and AUC than males respectively. Enrollment of both males and females is expected in the 
Ventricular Repolarization substudy in Part 2, which should lead to adequate representation of each sex in 
the QT evaluation. 

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Pharmacokinetics data from Study MDS3001 (Part 1) and Study MYF2001 consistently demonstrated a 
plasma half-life of approximately 4 to 5 hours and no plasma accumulation at later cycles (starting from 
Cycle 2 Day 1) when imetelstat is given q3w or q4w. The catabolism of the oligonucleotide is expected to 
produce shorter-length oligonucleotides and thus expected to have similar or shorter half-lives in plasma. 
Time points for ECG and pharmacokinetic measurements have been selected to match the expected 
pharmacokinetic profile of imetelstat so that correlations between ECG changes and drug exposure may be 
appropriately evaluated. In addition, to assess potential delayed QT effects, time-matched PK and ECG 
samples are collected at later time points when the plasma concentration of imetelstat is expected to be very 
low. Given these considerations, triplicate ECGs followed by blood samples for pharmacokinetic 
assessment will be collected at 0.5 and 1 hour post start of infusion, 2 hour (immediately before end of 
infusion; EOI), 4, 6, and 8 hours after SOI on Cycle 1 Day 1.  
To assess the QT interval prior to imetelstat exposure, baseline triplicate ECG assessments will be 
performed prior to the first study drug administration at three separate time points on Cycle 1 Day 1 (1 hour  
pre-dose, half hour pre-dose and immediately pre-dose). Because this is a randomized placebo-controlled 
blinded study design, the inclusion of the placebo data allows for the detection of diurnal variation (Garnett 
et al 2018c), baseline triplicate ECG assessment will be collected on Cycle 1 Day 1 at the time points noted 
previously. Following the hour 0 assessments, time-matched triplicate ECG assessment will be collected at 
hour 0.5, 1, 2 (immediately before EOI), 4, 6, and 8 on Cycle 1 Day 1. PK samples are to be collected 
immediately after ECGs.  
Based on the known and expected pharmacokinetic properties of imetelstat, the proposed pharmacokinetic 
and ECG time points on Cycle 1 Day 1 are deemed adequate to characterize the relationship between 
exposure and effect on QT/QTc. 
Sample Size Determination 
The Innovation and Quality in Pharmaceutical Development — Cardiac Safety Research Consortium 
(IQ-CSRC) prospective studya showed that QT assessments performed in a small single ascending dose 
like clinical pharmacology study, using an intense ECG schedule and exposure-response (ER) analysis, can 
detect, and therefore also exclude, small QT effects with the same level of confidence as would a TQT 
study.  
In the current substudy, approximately 45 evaluable subjects will be required to enroll with the aim to obtain 
ECG and pharmacokinetic data from 30 subjects on active treatment and 15 subjects on placebo. Subjects 
who are not evaluable for QTc substudy primary ECG endpoint may be replaced with new subjects. Garnett 
et alb evaluated the operating characteristics of the ER models via simulation, focusing on the performance 
of concentration-QTc models applied to data obtained in crossover and parallel studies. False negatives 
were 2% to 6% for crossover and 2% to 9% for parallel studies, with 12 to 60 subjects per treatment for a 
 
 
a Darpo B, Benson C, Dota C, et al. Results from the IQ-CSRC prospective study support replacement of the thorough 
QT study by QT assessment in the early clinical phase. Clin Pharmacol Ther. 2015 Apr;97(4):326-335. 
b Garnett C, Needleman K, Liu J, Brundage R, Wang Y. Operational characteristics of linear concentration-QT models 
for assessing QTc interval in the thorough QT and phase I clinical studies. Clin Pharmacol Ther. 2016 
Aug;100(2):170-178. 
cGarnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on concentration-QTc 
modeling. [Published correction appears in J Pharmacokinet Pharmacodyn. 2018;45(3):399]. J Pharmacokinet 
Pharmacodyn. 2018;45(3):383-397. 

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dose with 10-ms mean effect. Therefore, 30 subjects on active treatment and 15 subjects on placebo used 
in the current study should have sufficient power to conduct a proper ER analysis. Subjects in the QTc 
substudy may enter the Extension Phase after the clinical cut off for the primary analysis (the  
exposure-response analysis) for the QTc substudy is reached. After the primary analysis, the investigator 
will unblind remaining subjects and, per investigator decision, have the subject crossover to imetelstat prior 
to entering Extension Phase. The subjects will undergo the same screening procedures as the main protocol 
(see Section 9.1.6). 
Statistical Methods 
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. The 
exposure-response (ER) analysis (primary analysis for the QTc substudy) in the substudy based on 
approximately 45 evaluable subjects and will be performed when all evaluable subjects have completed 
Cycle 2. The analysis will be completed separately from the primary analysis of 170 subjects in the main 
study of Part 2. These data may be available after the primary analysis of the main study has already been 
completed. A general description of the statistical methods to be used to analyze the QTc data is outlined 
below. Additional details for ECG and ER analysis will be provided in the Ventricular Repolarization 
Substudy Cardiac Statistical Analysis Plan (SAP). Other Safety data and available efficacy data from the 
substudy will be summarized as described in the main study SAP. 
Standard ECG parameters will be determined for each ECG recording. Corrected QTc intervals will be 
determined using QTcF and QTcB. Changes in ECG intervals from time-matched baseline will be 
calculated. Baseline will be defined as the mean of the values for the triplicate ECG measurements taken at 
3 time points (-1 hour, -0.5 hour, and 0 hour) prior to treatment administration on Cycle 1 Day 1. In addition, 
QTcFs will be categorized based on ICH E14 guidelines. Tables will present the number and percentage of 
subjects meeting or exceeding the following categories: 
QTc interval prolongation: 
Absolute values >450 to ≤480 msec 
Absolute values >480 to ≤500 msec 
Absolute values >500 msec 
QTc interval change from baseline: 
Increase from baseline >30 to ≤60 msec 
Increase from baseline >60 msec 
The primary analysis for this substudy will be based on an ER analysis of the relationship between time-
matched, baseline-adjusted QTcF (∆QTcF) and imetelstat plasma concentrations by linear mixed-effects 
modeling approach. The ∆∆QTcF value will be calculated as the placebo-corrected ∆QTcF estimated from 
the model. Subjects who received study drug and had at least 1 pair of predose and postdose QTc data for 
at least 1 time point will be included in the ER analysis.  
The exposure-response relationship will be evaluated using linear model of ∆QTcF as the dependent 
variable. The data from the study drug and placebo treatment will be included in the model. The drug 
concentration level will be set to zero for placebo treatment. The independent variables included in the 
model will be imetelstat plasma concentrations as the explanatory variate (0 for placebo), centered baseline 
QTcF (i.e., baseline QTcF for individual subject minus the population mean baseline QTcF for all subjects) 

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as an additional covariate, treatment (active = 1 or placebo = 0), time (i.e., nominal post-dose time point) as 
fixed effects, and random effects on the intercept and slope per subject (Garnett et al 2018c).  
The key assumptions of the linear mixed-effects model will be absence of hysteresis and linearity of the 
concentration-response relationship. The linearity of the concentration-response relationship will be 
evaluated by visual inspection of relevant goodness-of-fit (GOF) plots. If the linear concentration-response 
relationship model appears to be inappropriate, a non-linear model, such as Emax, log-linear or other sigmoid 
relationships, will be explored. To detect hysteresis, mean ∆∆QTcF at each nominal time point will be 
calculated as the difference between the mean ∆QTcF for study drug minus mean ∆QTcF for placebo. Mean 
∆∆QTcF will be plotted against nominal time to evaluate the nominal time point of maximum response. 
Absence of hysteresis will be concluded if the time point of maximal effect does not differ from the time 
of peak plasma concentration (tmax) by more than an hour. If the assumption of absence of hysteresis does 
not appear to hold, pharmacokinetic-pharmacodynamic models, such as an effect compartment model or an 
indirect response model, will be explored. If deemed necessary, the concentration-∆QTc models will be fit 
for QTc calculated using other appropriate methods. 
Criteria for a “QT negative” result 
The criterion for a “QT negative” drug is that the upper bound of the 2-sided 90% confidence interval (CI) 
of the predicted mean ∆∆QTc is <20 ms at the observed geometric mean Cmax at 7.5 mg/kg dose of 
imetelstat.a,b 
 
 
 
a Rock EP, Finkle J, Fingert HJ, et al. Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J. 
2009;5:827-836.  
b Sarapa N, Britto MR Challenges of characterizing proarrhythmic risk due to QTc prolongation induced by nonadjuvant anticancer 
agents. Expert Opin. Drug Safety. 2008;7: 305–318. 

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INVESTIGATOR AGREEMENT 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A Study to Evaluate Imetelstat (GRN163L) in Transfusion-
Dependent Subjects with IPSS Low or Intermediate-1 Risk 
Myelodysplastic Syndrome (MDS) that is Relapsed/Refractory 
to Erythropoiesis-Stimulating Agent (ESA) Treatment    
PROTOCOL: 
63935937MDS3001, Amendment 8/USA-1 
IND: 
N/A 
EUDRACT NUMBER: 
2015‐002874‐19 
STUDY DRUG: 
Imetelstat Sodium for Injection (GRN163L for Injection) 
SPONSOR: 
Geron Corporation 
919 E. Hillsdale Blvd., Suite 250 
Foster City, CA 94404 USA 
 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
Please return a copy to Geron at the address provided below.  Please retain the original for your study files. 
Geron Corporation, Clinical Operations 
919 E. Hillsdale Blvd., Suite 250 
Foster City, CA 94404 USA 
 

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Status: Final, Date: 13 December 2022 
 
 
PROTOCOL FINALIZATION SIGNATURE PAGE 
TITLE: 
A Study to Evaluate Imetelstat (GRN163L) in Transfusion-
Dependent Subjects with IPSS Low or Intermediate-1 Risk 
Myelodysplastic Syndrome (MDS) that is Relapsed/Refractory 
to Erythropoiesis-Stimulating Agent (ESA) Treatment 
PROTOCOL: 
63935937MDS3001, Amendment 8/USA-1 
IND: 
N/A 
EUDRACT NUMBER: 
2015‐002874‐19 
STUDY DRUG: 
Imetelstat Sodium for Injection (GRN163L for Injection) 
SPONSOR: 
Geron Corporation 
919 E. Hillsdale Blvd., Suite 250 
Foster City, CA 94404 USA 
 
 
 
 
 
 
 
 
 
, MD 
 
 
Date