Conditions: Primary Myelofibrosis Secondary Myelofibrosis Myeloid Malignancies
Keywords: Myelofibrosis Myelodysplastic Syndromes Myeloproliferative Neoplasm Imetelstat GRN163L
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
This pilot clinical trial studies how well imetelstat sodium works in treating participants with primary or secondary myelofibrosis and other myeloid malignancies. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate overall response rate.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of imetelstat (imetelstat sodium) in myelofibrosis (MF).

II. To evaluate the efficacy of imetelstat in the reduction of spleen size, as measured by physical examination (palpable distance from the left costal margin).

III. To evaluate the efficacy of imetelstat in improving anemia or inducing red blood cell transfusion-independence in previously transfusion-dependent participants (per International Working Group for Myelofibrosis Research and Treatment \[IWG-MRT\] criteria).

IV. To evaluate onset and durability of response as defined in primary and secondary endpoints

EXPLORATORY OBJECTIVES:

I. To evaluate the effect of imetelstat on bone marrow histology, karyotype and JAK2V617F allele burden II. To evaluate the effect of imetelstat on leukocytosis, circulating blast count, circulating immature myeloid cell count and thrombocytosis.

OUTLINE: Participants receive imetelstat sodium intravenously (IV) over 2 hours on day 1. Participants may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The study end when all participants discontinued study drug, the last participant enrolled has been treated for approximately 5.7 years, or imetelstat is commercially available in the United States, whichever occurs first.

Maximum duration of study was approximately 5.7 years. Arm C was never initiated, and participants allocated to Arm C (Imetelstat 9.4 mg/kg \[with MF\]) were reassigned to Arms A and B.

Arms:
arm 1: Participants with MF regardless of spliceosome mutation status or presence of ring sideroblasts received imetelstat 9.4 milligram per kilogram (mg/kg), intravenously (IV) as 2-hour infusion on Day 1 of each 21-day cycle in Core Phase up to 9 cycles. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). arm 2: Participants with MF regardless of spliceosome mutation status or presence of ring sideroblasts received imetelstat 9.4 mg/kg, IV as 2-hour infusion on Days 1, 8, and 15 of 21-day cycle in Cycle 1 followed by 9.4 mg/kg on Day 1 of each 21-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). arm 3: Participants with blast-phase myelofibrosis/acute myeloid leukemia (MF/AML) received imetelstat 9.4 mg/kg, IV as 2-hour infusion weekly on Days 1, 8, 15, 22 of a 28-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). arm 4: Participants with MF and spliceosome mutations or ring sideroblasts present received 2 cycles (Cycles 1-2) of imetelstat 7.5 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or the possibility of dose escalation to imetelstat 9.4 mg/kg weekly if response to the initial dose was insufficient up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). arm 5: Participants with MF without spliceosome mutations or ring sideroblasts present received 2 cycles (Cycles 1-2) of imetelstat 9.4 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or imetelstat 7.5 mg/kg twice weekly on Days 1, 3 for 2 cycles of 28-day cycle (Cycles 3-4) followed by imetelstat 7.5 mg/kg 3-times-weekly on Days 1, 3, 5 of Cycles 5 and beyond of 28-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). arm 6: Participants with either myelodysplastic syndromes/ myeloproliferative neoplasm (MDS/MPN) or MDS and spliceosome mutations or ring sideroblasts present received 2 cycles of 28-day cycle (Cycles 1-2) of imetelstat 7.5 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or the possibility of dose escalation to imetelstat 9.4 mg/kg weekly if response to the initial dose was insufficient up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years).

Interventions: intervention 1: Imetelstat
Intervention descriptions: intervention 1: Imetelstat sodium administered as IV over 2 hours with treatment as long as participants derive clinical benefit or until end of study.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Pilot Open-Label Study of the Efficacy and Safety of Imetelstat (GRN163L) 
in Myelofibrosis and Other Myeloid Malignancies 
NCT Number: 
NCT01731951 
 
Document Date: 
 
Clinical Study Protocol: 05 October 2015 
 
 
 
 
 
 
 
 


Page 1 of 90
CLINICAL STUDY PROTOCOL
TITLE:
A Pilot Open-Label Study of the Efficacy and Safety of 
Imetelstat (GRN163L) in Myelofibrosis and other Myeloid 
Malignancies
PROTOCOL NUMBER:
CP14B019 (formerly MC1285)
IND:
116129
EUDRACT NUMBER:
N/A
STUDY DRUG:
JNJ-63935937 (Imetelstat Sodium for Injection) (formerly 
GRN163L for Injection)
SPONSOR:
Janssen Research & Development
Document History
(Effective Date)
Activation
October 26, 2012
Mayo Add1
April 12, 2013
Mayo Add2
June 7, 2013
Mayo Add3
August 8, 2013
Mayo Add4
August 29, 2013
Mayo Add5
December 4, 2013
Mayo Add6
Protocol changes not approved
Mayo Add7
December 30, 2013
Mayo Add8
February 18, 2014
Mayo Add 9
March 3, 2014
Mayo Add 10
April 7, 2014
Geron Document History
Amendment 11
(Protocol Finalization Date)
July 31, 2014
Janssen Research & 
Development Document 
History
(Approval Date)
Amendment 12
21 January 2015
Amendment 13
5 October 2015
EDMS number:
EDMS-ERI-98370922, 2.0


Protocol CP14B019, Amendment 13
Page 2 of 90
 
 
 
PROTOCOL FINALIZATION SIGNATURE PAGE
TITLE:
A Pilot Open-Label Study of the Efficacy and Safety of 
Imetelstat (GRN163L) in Myelofibrosis and other Myeloid 
Malignancies
PROTOCOL NUMBER:
CP14B019 (formerly MC1285)
IND:
116129
EUDRACT NUMBER:
N/A
STUDY DRUG:
Imetelstat Sodium for Injection (GRN163L for Injection)
SPONSOR:
Janssen Research & Development
Document History
(Effective Date)
Activation
October 26, 2012
Mayo Add1
April 12, 2013
Mayo Add2
June 7, 2013
Mayo Add3
August 8, 2013
Mayo Add4
August 29, 2013
Mayo Add5
December 4, 2013
Mayo Add6
Protocol changes not approved
Mayo Add7
December 30, 2013
Mayo Add8
February 18, 2014
Mayo Add 9
March 3, 2014
Mayo Add 10
April 7, 2014
Geron Document History
Amendment 11
(Protocol Finalization Date)
July 31, 2014
Janssen Research & 
Development History
(Approval Date)
Amendment 12
21 January 2015
Amendment 13
5 October 2015


Protocol CP14B019, Amendment 13
Page 3 of 90
 
 
TABLE OF CONTENTS
Protocol Finalization Signature Page...............................................................................................2
PROTOCOL AMENDMENTS .....................................................................................................18
1.
BACKGROUND ........................................................................................................22
1.1.
Myelofibrosis..............................................................................................................22
1.2.
Telomeres and Telomerase Inhibition ........................................................................22
1.3.
Imetelstat.....................................................................................................................23
1.3.1.
Nonclinical Pharmacology..........................................................................................23
1.3.1.1.
Efficacy Studies ..........................................................................................................23
1.3.1.2.
Effects on Cancer Stem Cells .....................................................................................23
1.3.2.
Nonclinical Safety Studies..........................................................................................24
1.3.3.
Clinical Experience with Imetelstat............................................................................25
1.3.4.
Safety Experience .......................................................................................................29
1.3.4.1.
Hematologic Events....................................................................................................29
1.3.4.2.
Coagulation Changes..................................................................................................30
1.3.4.3.
Infections ....................................................................................................................30
1.3.4.4.
Hepatobiliary Events...................................................................................................30
1.3.4.5.
Infusion Reactions ......................................................................................................32
1.3.4.6.
Gastrointestinal Events...............................................................................................32
1.3.4.7.
Constitutional Symptoms............................................................................................32
1.4.
Rationale for Conducting this Study...........................................................................33
1.4.1.
Rationale for Dose and Schedule................................................................................34
2.
GOALS.......................................................................................................................39
2.1.
Primary........................................................................................................................39
2.2.
Secondary....................................................................................................................39
2.3.
Exploratory .................................................................................................................39
3.
PATIENT ELIGIBILITY............................................................................................40
3.1.
Inclusion Criteria ........................................................................................................40
3.2.
Exclusion Criteria.......................................................................................................41
4.
TEST SCHEDULE.....................................................................................................43
4.1.
Test Schedule For Hepatic Safety Monitoring And Follow Up After 
Discontinuing Imetelstat.............................................................................................46


Protocol CP14B019, Amendment 13
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5.
GROUPING FACTORS.............................................................................................47
6.
REGISTRATION/RANDOMIZATION PROCEDURES..........................................47
6.1.
Registration Procedures..............................................................................................47
7.
PROTOCOL TREATMENT......................................................................................48
7.1.
Treatment Schedule ....................................................................................................48
7.1.1.
Imetelstat Treatment ...................................................................................................48
7.1.1.1.
Arm A Treatment Schedule........................................................................................49
7.1.1.2.
Arm B Treatment Schedule ........................................................................................49
7.1.1.3.
Arms C and D Treatment Schedule............................................................................50
7.1.1.4.
Arms E and G Treatment Schedule ............................................................................50
7.1.1.5.
Arm F Treatment Schedule.........................................................................................51
7.2.
Pre-Medication ...........................................................................................................52
8.
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS..............................53
8.1.
Retreatment Criteria....................................................................................................53
8.2.
Dose Reduction...........................................................................................................53
8.2.1.
Hepatoxicity................................................................................................................55
8.3.
Infusion Reaction........................................................................................................56
9.
ANCILLARY TREATMENT/SUPPORTIVE CARE ...............................................57
10.
ADVERSE EVENT (AE) REPORTING AND MONITORING ...............................57
10.1.
Safety Parameters and Definitions..............................................................................57
10.1.1.
Adverse Event.............................................................................................................58
10.1.2.
Serious Adverse Event................................................................................................58
10.2.
Methods and Timing for Capturing and Assessing Safety Parameters.......................59
10.2.1.
Adverse Event Reporting Period ................................................................................59
10.2.2.
Eliciting Adverse Events ............................................................................................60
10.2.3.
Assessment of Severity and Causality of Adverse Events..........................................60
10.3.
Procedures for Recording Adverse Events .................................................................61
10.3.1.
Recording Adverse Events on the eCRF ....................................................................61
10.3.1.1.
Diagnosis Versus Signs and Symptoms......................................................................61
10.3.1.2.
Adverse Events Occurring Secondary to Other Events ..............................................61
10.3.1.3.
Persistent or Recurrent Adverse Events......................................................................62
10.3.1.4.
Abnormal Laboratory Values......................................................................................62
10.3.1.5.
Deaths .........................................................................................................................62


Protocol CP14B019, Amendment 13
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10.3.1.6.
Preexisting Medical Conditions..................................................................................62
10.3.1.7.
Worsening of MF........................................................................................................63
10.3.1.8.
Hospitalization, Prolonged Hospitalization, or Surgery.............................................63
10.3.1.9.
Pregnancy....................................................................................................................63
10.3.1.10.
Hepatic Adverse Events and Abnormal Liver Biochemistries ...................................63
10.4.
Expedited Reporting Requirements for Serious Adverse Events...............................64
10.4.1.
Reporting Requirements for Fatal/Life Threatening SAEs Related to 
Investigational Product ...............................................................................................64
10.4.2.
Reporting Requirements for All SAEs .......................................................................64
10.5.
Type and Duration of Follow-Up of Patients after Adverse Events...........................65
10.6.
Post-Study Adverse Events.........................................................................................65
11.
TREATMENT EVALUATION .................................................................................66
11.1.
Myelofibrosis..............................................................................................................66
11.2.
MDS............................................................................................................................68
12.
DESCRIPTIVE FACTORS........................................................................................70
13.
TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF 
PATIENT....................................................................................................................70
14.
BODY FLUID BIOSPECIMENS...............................................................................71
15.
DRUG INFORMATION ............................................................................................71
15.1.
Imetelstat (GRN163L) ................................................................................................71
15.1.1.
Background.................................................................................................................71
71
72
15.1.4.
Administration............................................................................................................72
15.1.5.
Pharmacokinetic information: ....................................................................................72
15.1.6.
Potential Drug Interactions .........................................................................................73
15.1.7.
Safety Experience .......................................................................................................73
15.1.8.
Drug Procurement.......................................................................................................73
15.1.9.
Nursing Guidelines .....................................................................................................73
16.
STATISTICAL CONSIDERATIONS AND METHODOLOGY ..............................74
16.1.
Statistical Design (To Be Evaluated Independently in Each Arm).............................74
16.2.
Analysis Plan ..............................................................................................................76
16.3.
Primary Outcome Analyses(to be evaluated in each arm independently) ..................77


Protocol CP14B019, Amendment 13
Page 6 of 90
16.4.
Secondary Outcome Analyses (to Be Evaluated in Each Arm Independently) ..........77
16.4.1.
Adverse Events ...........................................................................................................77
16.4.2.
Spleen Response.........................................................................................................77
16.4.3.
Transfusion-Independence..........................................................................................77
16.4.4.
Durability of Response ...............................................................................................78
16.5.
Exploratory Outcomes (to Be Evaluated in Each Arm Independently)......................78
16.5.1.
Bone Marrow Histology and JAK2V617F Allele Burden..........................................78
16.5.2.
Leukocytosis, Thrombocytosis, Peripheral Blood Blast and Immature Cell 
Count...........................................................................................................................78
16.6.
Over Accrual...............................................................................................................78
16.7.
Data and Safety Monitoring........................................................................................78
16.8.
Adverse Event Stopping Rules (to Be Evaluated in Each Arm Independently).........79
16.9.
Inclusion of Women and Minorities...........................................................................79
17.
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS ............................81
17.1.
Tissue and Biospecimen Submission..........................................................................81
17.2.
Initial and Response Evaluation Materials .................................................................81
18.
REFERENCES ...........................................................................................................83
APPENDIX A.
DIPSS-PLUS RISK CATEGORIES IN MYELOFIBROSIS............................85
APPENDIX B.
WORLD HEALTH ORGANIZATION (WHO) DIAGNOSTIC 
CRITERIA FOR POLYCYTHEMIA VERA, ESSENTIAL 
THROMBOCYTHEMIA AND PRIMARY MYELOFIBROSIS3 ...................86
APPENDIX C.
INTERNATIONAL WORKING GROUP FOR 
MYELOPROLIFERATIVE NEOPLASMS RESEARCH AND 
TREATMENT (IWG-MRT) RECOMMENDED CRITERIA FOR 
POST-POLYCYTHEMIA VERA AND POST-ESSENTIAL 
THROMBOCYTHEMIA MYELOFIBROSIS..................................................87
APPENDIX D.
PERFORMANCE STATUS SCALE................................................................88
APPENDIX E.
ANAPHYLAXIS PRECAUTIONS...................................................................89
INVESTIGATOR AGREEMENT.................................................................................................90
LAST PAGE ..................................................................................................................................90


Protocol CP14B019, Amendment 13
Page 7 of 90
LIST OF TABLES
Table 1:
Phase I Clinical Trials with Imetelstat........................................................................27
Table 2:
Phase II Trials with Imetelstat ....................................................................................28
Table 3:
Test Schedule:  Core Phase = Cycle 1 – Cycle 9; Extension Phase = Cycle 10 
and Beyond .................................................................................................................43
Table 4:
Test Schedule for Hepatic Safety Monitoring And Follow Up After 
Discontinuing Imetelstat.............................................................................................46
Table 5:
Arms E and G Dosing if Criteria met = Yes...............................................................51
Table 6:
Arm F Dosing if Criteria met = Yes ...........................................................................51
Table 7:
Arm F Dosing if Criteria met = No: Cycles 3 and 4...................................................52
Table 8:
Criteria met = No: Cycles 5 and beyond.....................................................................52
Table 9:
Dose Reductions.........................................................................................................53
Table 10:
Dose Levels (Based on Adverse Events in Table 9)...................................................54
Table 11:
ALERT: Serious Adverse Event (SAE) reporting may be required for some 
adverse events (See Section 10)..................................................................................54
Table 12:
Guidelines for Managing Infusion Reactions .............................................................56
Table 13:
Adverse Event Grade (Severity) Scale........................................................................60
Table 14:
Causal Attribution Guidance ......................................................................................61
Table 15:
Revised International Working Group for Myeloproliferative Neoplasms 
Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) 
response criteria for myelofibrosis..............................................................................66
Table 16:
Definition of Disease Response in MDS:...................................................................68
Table 17:
Proposed Modified International Working Group Response Criteria for 
Hematologic Improvement .........................................................................................69
Table 18:
Expected Sizes of Racial by Gender Subsets..............................................................80
Table 19:
Summary Table of Tissue Biospecimens for this Protocol.........................................81
LIST OF FIGURES
Figure 1:
Schema – Arm A ..........................................................................................................9
Figure 2:
Schema – Arm B.........................................................................................................10
Figure 3:
Schema – Arms C and D ............................................................................................11
Figure 4:
Schema – Arm E.........................................................................................................12
Figure 5:
Schema – Arm F .........................................................................................................14
Figure 6:
Schema – Arm G ........................................................................................................16


Protocol CP14B019, Amendment 13
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Figure 7:
Inhibition of Telomerase Activity by Imetelstat in a DU145 Tumor Flank 
Model and Liver Telomerase Inhibition Model..........................................................35
Figure 8:
Imetelstat (GRN163L) Tissue Distribution in Rats ....................................................36
Figure 9:
Imetelstat Weekly AUCinf in Patients and in Xenograft Mice....................................37


Protocol CP14B019, Amendment 13
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Note: All Study Arms (A, B, C, D, E, F, and G) are now permanently closed to accrual
Figure 1:
Schema – Arm A
(Note: Arm A permanently closed to accrual)
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information.
1 Cycle length = 21 days. For patients who do not achieve a CR or PR by the end of Cycle 6, the frequency of dosing may be 
increased and the cycle length will be 21-28 days. For patients whose response has plateaued for a minimum of 3 months, the 
dose frequency may be reduced, or treatment may be interrupted until relapse then restarted, and the cycle length will be the 
length of the dosing interval.  See Section 7.1. For all patients who did not experience a treatment emergent abnormality in 
liver function tests (LFTs), defined as any grade abnormality in patients with normal value at baseline or any higher grade shift 
from baseline in patients with an abnormal baseline, or value more than 2x baseline if baseline was Grade ≥ 3, or hepatic 
adverse events are present at imetelstat discontinuation, obtain LFT follow-up until 30 days from the last imetelstat dose. The 
length of the last cycle will be until 30 days after the last dose.  For patients who experienced a treatment emergent abnormality 
in LFTs, as defined above, or hepatic adverse events are present at imetelstat discontinuation, obtain follow-up per test 
schedule (see Section 4 for details) until resolution to at least baseline grade or less than 2x baseline value if baseline was 
Grade ≥ 3 for at least 2 consecutive determinations. The length of the last cycle will be until the resolution is confirmed.
2 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The 
study will end when all subjects have discontinued study drug, the last patient enrolled has been treated for 5 years, or 
imetelstat is commercially available in the United States, whichever occurs first.
3 Except relapse that occurs during dose interruption.  These patients may restart treatment at the physician’s discretion per 
Section 7.1.
Registration
Cycles 1-91 (Core Phase):
IV Imetelstat
Repeat every 21 days x 9 cycles2
Event Monitoring/
Hepatic Safety Monitoring
PD at any time3
Unacceptable adverse events
       Event
Patient refusal
                    Monitoring/
     Hepatic Safety Monitoring
Cycles 101 and Beyond (Extension Phase):
IV Imetelstat
Repeat every 21 days2
(see schedule of events for details)


Protocol CP14B019, Amendment 13
Page 10 of 90
Figure 2:
Schema – Arm B
(Note:  Arm B permanently closed to accrual)
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information.
1 Cycle length = 21 days. For patients who do not achieve a CR or PR by the end of Cycle 6, the frequency of dosing may be 
increased and the cycle length will be 21-28 days.  For patients whose response has plateaued for a minimum of 3 months, the 
dose frequency may be reduced, or treatment may be interrupted until relapse then restarted, and the cycle length will be the 
length of the dosing interval.  See Section 7.1.  For all patients who did not experience a treatment emergent abnormality in 
liver function tests (LFTs), defined as any grade abnormality in patients with normal value at baseline or any higher grade shift 
from baseline in patients with an abnormal baseline, or value more than 2x baseline if baseline was Grade ≥3, or hepatic 
adverse events are present at imetelstat discontinuation, obtain LFT follow-up until 30 days from the last imetelstat dose.  The 
length of the last cycle will be until 30 days after the last dose.  For patients who experienced a treatment emergent abnormality 
in LFTs, as defined above, or hepatic adverse events are present at imetelstat discontinuation, obtain follow-up per test 
schedule (see Section 4 for details) until resolution to at least baseline grade or less than 2x baseline value if baseline was 
Grade ≥3 for at least 2 consecutive determinations. The length of the last cycle will be until the resolution is confirmed.
2 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The 
study will end when all subjects have discontinued study drug, the last patient enrolled has been treated for 5 years, or 
imetelstat is commercially available in the United States, whichever occurs first.
3 Except relapse that occurs during dose interruption.  These patients may restart treatment at the physician’s discretion per 
Section 7.1.
Registration
Induction 
Cycle 11 (Core Phase):
IV Imetelstat Days 1, 8, 15
Event Monitoring/
Hepatic Safety Monitoring
PD at any time3
Unacceptable adverse events
             Event
Patient refusal
                          Monitoring/
Hepatic Safety Monitoring
Maintenance
Cycles 2-91 (Core Phase):
IV Imetelstat Day 1
Repeat every 21 days2
Cycles 10 and Beyond (Extension Phase):
IV Imetelstat Day 1
Repeat every 21 days2


Protocol CP14B019, Amendment 13
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Figure 3:
Schema – Arms C and D
(Note: Arms C and D permanently closed to accrual)
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information.
1 Cycle length = 28 days. For all patients who did not experience a treatment emergent abnormality in liver function tests 
(LFTs), defined as any grade abnormality in patients with normal value at baseline or any higher grade shift from baseline in 
patients with an abnormal baseline, or value more than 2x baseline if baseline was Grade ≥ 3, or hepatic adverse events are 
present at imetelstat discontinuation, obtain LFT follow-up until 30 days from the last imetelstat dose.  The length of the last 
cycle will be until 30 days after the last dose.  For patients who experienced a treatment emergent abnormality in LFTs, as 
defined above, or hepatic adverse events are present at imetelstat discontinuation, obtain follow-up per test schedule (see 
Section 4 for details) until resolution to at least baseline grade or less than 2x baseline value if baseline was Grade ≥ 3 for at 
least 2 consecutive determinations. The length of the last cycle will be until the resolution is confirmed.
2 For patients without response after the first two cycles, dosing might be increased to either Days 1, 3, 5 or Days 1, 3 every 2 to 
4 weeks, per physician discretion.  See Section 7.1.
3 For patients whose response has plateaued for a minimum of 3 months, the dose frequency may be reduced, or treatment may 
be interrupted until relapse then restarted, at the physician’s discretion.  See Section 7.1.
4 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The 
study will end when all subjects have discontinued study drug, the last patient enrolled has been treated for 5 years, or 
imetelstat is commercially available in the United States, whichever occurs first.
5 Except relapse that occurs during dose interruption.  These patients may restart treatment at the physician’s discretion per
Section 7.1.
Registration
Cycle 1-91 (Core Phase):
IV Imetelstat Days 1, 8, 15, 22
Repeat every 28 days2,3
Event Monitoring/
Hepatic Safety Monitoring
Cycles 10 and Beyond (Extension Phase):
IV Imetelstat Day 1, 8, 15, 22
Repeat every 28 days4,3
PD at any time5
Unacceptable adverse events
       Event
Patient refusal
                    Monitoring/
          Hepatic Safety Monitoring


Protocol CP14B019, Amendment 13
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Figure 4:
Schema – Arm E
(Note: Arm E permanently closed to accrual) (myelofibrosis patients with spliceosome mutations or ring 
sideroblasts)
1 Cycle length = 28 days. For all patients who did not experience a treatment emergent abnormality in liver function tests 
(LFTs), defined as any grade abnormality in patients with normal value at baseline or any higher grade shift from baseline in 
patients with an abnormal baseline, or value more than 2x baseline if baseline was Grade ≥ 3, or hepatic adverse events are 
present at imetelstat discontinuation, obtain LFT follow-up until 30 days from the last imetelstat dose.  The length of the last 
cycle will be until 30 days after the last dose.  For patients who experienced a treatment emergent abnormality in LFTs, as 
defined above, or hepatic adverse events are present at imetelstat discontinuation, obtain follow-up per test schedule (see 
Section 4 for details) until resolution to at least baseline grade or less than 2x baseline value if baseline was Grade ≥ 3 for at
least 2 consecutive determinations. The length of the last cycle will be until the resolution is confirmed.
Registration
Cycles 1-21 (Core Phase):
IV Imetelstat Day 1
Repeat every 28 days x 2 cycles
Cycles 3-92 (Core Phase)
IV Imetelstat Day 1
Repeat every 28 days 3
Cycles 3 and Beyond (Core Phase)
Treat as Arm F (Cycle 3 will start with 
Cycle 1 of Arm F dosing schedule)
Cycles 103 and Beyond (Extension Phase)
IV Imetelstat Day 1 
Repeat every 28 days4
Event Monitoring/
Hepatic Safety Monitoring
PD at any time 5
Unacceptable adverse events
     Event
Patient refusal
                  Monitoring/
          Hepatic Safety Monitoring
Any one of the following at the end of cycle 2:

Greater than 75% reduction in leukocyte count

Greater than 75% reduction in platelet count

Greater than 50% reduction in spleen size in patients with baseline palpable splenomegaly of >5 cm

Greater than 2 gm/dL increase in hemoglobin level from baseline without transfusions
Yes
No


Protocol CP14B019, Amendment 13
Page 13 of 90
2 In patients who do not achieve CR or PR, by the end of Cycle 4, the frequency of dosing may be increased to every week or 
every 2 weeks, at the physician’s discretion. 
3 For patients whose response has plateaued, without signs of further improvement, for a minimum of 3 months, dosing 
frequency may be reduced to every 2 to 3 months, or treatment may be interrupted until relapse then restarted, at the 
physician’s discretion.  
4 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The 
study will end when all subjects have discontinued study drug, the last patient enrolled has been treated for 5 years, or 
imetelstat is commercially available in the United States, whichever occurs first.
5 Except relapse that occurs during dose interruption.  These patients may restart treatment at the physician’s discretion per 
Section 7.1.


Protocol CP14B019, Amendment 13
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Figure 5:
Schema – Arm F 
(Note: Arm F permanently closed to accrual) (myelofibrosis patients without spliceosome mutations or ring sideroblasts)
1 Cycle length = 28 days. For all patients who did not experience a treatment emergent abnormality in liver function tests 
(LFTs), defined as any grade abnormality in patients with normal value at baseline or any higher grade shift from baseline in 
patients with an abnormal baseline, or value more than 2x baseline if baseline was Grade ≥ 3, or hepatic adverse events are 
present at imetelstat discontinuation, obtain LFT follow-up until 30 days from the last imetelstat dose.  The length of the last 
cycle will be until 30 days after the last dose.  For patients who experienced a treatment emergent abnormality in LFTs, as 
defined above, or hepatic adverse events are present at imetelstat discontinuation, obtain follow-up per test schedule (see 
Section 4 for details) until resolution to at least baseline grade or less than 2x baseline value if baseline was Grade ≥ 3 for at
least 2 consecutive determinations. The length of the last cycle will be until the resolution is confirmed.
2 In patients who do not achieve CR or PR, by the end of Cycle 4, the frequency of dosing may be increased to every two weeks,
at the physician’s discretion. 
Registration
Cycles 1-21 (Core Phase):
IV Imetelstat Day 1
Repeat every 28 days x 2 cycles
Cycles 3-92,3 (Core Phase)
IV Imetelstat Day 1
Repeat every 28 days 
Cycles 3-9 (Core Phase) 2,3,6
IV Imetelstat, Days 1, 3
Repeat every 28 days
Cycles 103 and Beyond (Extension Phase)
IV Imetelstat Day 1 
Repeat every 28 days4
Event Monitoring/
Hepatic Safety Monitoring
PD at any time 5
Unacceptable adverse events
       Event
Patient refusal
                    Monitoring/
        Hepatic Safety Monitoring
Any one of the following at the end of cycle 2:

Greater than 75% reduction in leukocyte count

Greater than 75% reduction in platelet count

Greater than 50% reduction in spleen size in patients with baseline palpable splenomegaly of >5 cm

Greater than 2 gm/dL increase in hemoglobin level from baseline without transfusions
Yes
No
Cycles 103 and Beyond (Extension Phase)
IV Imetelstat Days 1, 3
Repeat every 28 days4
Event Monitoring/
Hepatic Safety Monitoring


Protocol CP14B019, Amendment 13
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3 For patients whose response has plateaued, without signs of further improvement, for a minimum of 3 months, dosing may be 
reduced to Day 1 every 28 days or Days 1 and 3 every 2 to 3 months or treatment may be interrupted until relapse then 
restarted, all at the physician’s discretion.
4 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The 
study will end when all subjects have discontinued study drug, the last patient enrolled has been treated for 5 years, or 
imetelstat is commercially available in the United States, whichever occurs first.
5 Except relapse that occurs during dose interruption.  These patients may restart treatment at the physician’s discretion per 
Section 7.1.
6 If criteria still not met after Cycles 3 and 4, at the physician’s discretion, dosing might be increased to Days 1, 3, and 5 every 
28 days. 


Protocol CP14B019, Amendment 13
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Figure 6:
Schema – Arm G 
(Note: Arm G permanently closed to accrual) (MDS/MPN or MDS patients with spliceosome mutations or ring sideroblasts)
1 Cycle length = 28 days.  For all patients who did not experience a treatment emergent abnormality in liver function tests 
(LFTs), defined as any grade abnormality in patients with normal value at baseline or any higher grade shift from baseline in 
patients with an abnormal baseline, or value more than 2x baseline if baseline was Grade ≥ 3, or hepatic adverse events are 
present at imetelstat discontinuation, obtain LFT follow-up until 30 days from the last imetelstat dose.  The length of the last 
cycle will be until 30 days after the last dose.  For patients who experienced a treatment emergent abnormality in LFTs, as 
defined above, or hepatic adverse events are present at imetelstat discontinuation, obtain follow-up per test schedule (see 
Section 4 for details) until resolution to at least baseline grade or less than 2x baseline value if baseline was Grade ≥3 for at
least 2 consecutive determinations. The length of the last cycle will be until the resolution is confirmed.
2 In patients who do not achieve CR or PR, by the end of Cycle 4, the frequency of dosing may be increased to every week or 
every 2 weeks, at the physician’s discretion.
3 For patients whose response has plateaued, without signs of further improvement, for a minimum of 3 months, dosing 
frequency may be reduced to every 2 to 3 months, or treatment may be interrupted until relapse, at the physician’s discretion.
Registration
Cycles 1-21 (Core Phase):
IV Imetelstat Day 1
Repeat every 28 days x 2 cycles
Cycles 3-92 (Core Phase)
IV Imetelstat Day 1
Repeat every 28 days 3
Cycles 3 and Beyond (Core Phase)
Treat as Arm F (Cycle 3 will start with 
Cycle 1 of Arm F dosing schedule)
Cycles 103 and Beyond (Extension Phase)
IV Imetelstat Day 1 
Repeat every 28 days4
Event Monitoring/
Hepatic Safety Monitoring
PD at any time 5
Unacceptable adverse events
   Event
Patient refusal
               Monitoring/
   Hepatic Safety Monitoring
Any one of the following at the end of cycle 2:

Greater than 75% reduction in leukocyte count

Greater than 75% reduction in platelet count

Greater than 50% reduction in spleen size in patients with baseline palpable splenomegaly of >5 cm

Greater than 2 gm/dL increase in hemoglobin level from baseline without transfusions
Yes
No


Protocol CP14B019, Amendment 13
Page 17 of 90
4 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The 
study will end when all subjects have discontinued study drug, the last patient enrolled has been treated for 5 years, or 
imetelstat is commercially available in the United States, whichever occurs first.
5 Except relapse that occurs during dose interruption.  These patients may restart treatment at the physician’s discretion per 
Section 7.1.


Protocol CP14B019, Amendment 13
Page 18 of 90
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Geron Protocol Amendment 11 
(prior to transfer to Janssen 
Research & Development)
31 Jul 2014
Amendment 12 
21 Jan 2015
Amendment 13
5 Oct 2015
Amendments are listed beginning with the most recent amendment following transfer to Janssen 
Research & Development.
Amendment 13 (5 Oct 2015)
The overall reason for the amendment: To limit collection of follow-up study data to that critical for assessment 
of safety outcomes, and to allow subjects who are benefiting from imetelstat to continue to receive study treatment 
beyond 3 years.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify and emphasize that additional hepatic laboratory surveillance is explicitly required for 
subjects in safety follow-up who had ongoing treatment-emergent abnormalities in LFTs or hepatic adverse events 
when imetelstat was discontinued,
Figures 1-6
Revised “Event Monitoring” to “Event Monitoring/Hepatic Safety Monitoring” in the 
schematic diagrams for each treatment arm.
Rationale: To remove the limitation on duration of study treatment for patients who continue to derive clinical 
benefit beyond 3 years.
Figures 1-6, footnotes
7.1.1.1 Arm A 
Treatment Schedule 
(footnote 1)
7.1.1.2 Arm B 
Treatment Schedule
(footnote 1),
7.1.1.3 Arms C and D 
Treatment Schedule,
(footnote 1)
7.1.1.4 Arms E and G 
Treatment Schedule, 
(footnote 1)
7.1.1.5 Arm F Treatment 
Schedule,
(footnote 1)
8.1 Retreatment Criteria
Changed the possible duration of imetelstat study treatment beyond 3 years. Patients 
may continue to receive imetelstat study treatment for as long as they derive clinical 
benefit or until study end. The study will end when all subjects have discontinued study 
drug, the last patient enrolled has been treated for 5 years, or imetelstat is commercially 
available in the United States, whichever occurs first.
Rationale: The status of other imetelstat studies has changed. 
1.3.3 Clinical 
Experience with 
Imetelstat, Table 2
Database lock dates have been added for 4 Phase II imetelstat studies. The title of 
Study CP14B015 has been corrected to add “or Polycythemia Vera” and the study 
status has been changed from “Completed treatment (in safety follow up)” to 
“Completed”.


Protocol CP14B019, Amendment 13
Page 19 of 90
Rationale: To limit study procedures in the Extension Phase and at study completion to those needed for safety 
follow-up.
4 Test Schedule, Table 3 
Physical examination for hepatomegaly and splenomegaly, and transfusion assessment 
removed as required assessments during the Extension Phase. Peripheral blood smear 
and IWG assessment of response removed as required assessments during the 
Extension Phase and at Study Completion/Early Termination. Urinalysis removed at 
Study Completion/Early termination.
4 Test Schedule, 
Table 3, footnote 9
Revised to delete chloride, bicarbonate, glucose, GGT, uric acid, amylase, and lipase 
from serum chemistry assessment.
4 Test Schedule, 
Table 3, footnote 10
Revised hematology assessment to replace differential count with absolute neutrophil 
count and to remove RBC count, MCV, MCH, MCHC, RDW, and MPV.
4 Test Schedule, 
Table 3, footnote 14
Clarified to allow a ±7-day window for hepatic event follow-up and redefined the end 
of the Event Monitoring Phase of the study from 5 years after registration for each 
subject to the time at which the last patient has completed study treatment. Follow-up 
during the Event Monitoring Phase can be completed via telephone call.
Rationale: To streamline and clarify hepatic monitoring. 
4.1 Test Schedule for 
Hepatic Safety 
Monitoring, Table 4, 
footnote 3
CBC has been limited to WBC count, ANC, hemoglobin, and platelet count. 
4.1 Test Schedule for 
Hepatic Safety 
Monitoring, Table 4
The footnote “Concomitant medications include alternate treatment for MPN/MDS” 
has been deleted; remaining footnotes have been renumbered accordingly.
Rationale: To clarify requirements for study drug dose modification.
8.2 Dose Reduction
Sentence added to the end of the first paragraph clarifying that once an imetelstat dose 
reduction has occurred, the dose should not be subsequently re-escalated.
Rationale: Update description of drug preparation procedures. Reconstitution time is estimated at 15 minutes 
based on an updated product description.
15.1.3 Preparation and 
Storage
Text describing lyophilized imetelstat as reconstituting easily has been deleted. 
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or typographical changes were made.


Protocol CP14B019, Amendment 13
Page 20 of 90
Amendment 12 (21Jan 2015)
The overall reason for the amendment: The overall reason for the amendment is to transfer sponsorship of this 
study from Geron to Janssen Research & Development and to update safety reporting accordingly.
Applicable Section(s)
Description of Change(s)
Rationale: To update the language in the protocol to indicate the transfer of sponsorship from Geron to Janssen 
Research & Development and to establish the safety reporting procedures under the new sponsorship.
10.1. Safety 
Parameters and 
Definitions; 
10.3.1.9. Pregnancy;
10.6. Post-Study 
Adverse Events
Language changed to indicate transfer of sponsorship.
10.4.1. Reporting 
Requirements for 
Fatal/Life Threatening 
SAEs Related to 
Investigational 
Product
Deleted the former medical monitor contact information and replaced with the following: 
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.
10.4.2. Reporting 
Requirements for All 
SAEs
Deleted the former procedures for reporting SAEs and replaced with the new procedures.
16.7. Data and Safety 
Monitoring
Updated the membership of the safety review committee and updated the following text
(bold text indicates additions; strikeout indicates deletions): The Medical Monitor study 
responsible physician or Drug Safety Scientist safety physician may convene a meeting 
sooner should any concerns arise from review of data or from the Investigator safety 
physician.
Added text to indicate that an independent hepatic safety panel will review emergent 
relevant safety data if needed.  
Rationale: To align the current protocol with the administrative amendment memorandum that was issued by 
Geron on 12 Sep 2014.
4. Test Schedule, 
Table 3, footnote 6
Removed the check mark in the table for an abdominal ultrasound at study completion or 
early termination (± 1 week);
Revised the footnote to indicate that a Doppler ultrasound of abdomen will be performed 
post baseline only as clinically indicated at the discretion of the investigator. 
4. Test Schedule, 
Table 3, footnote 9;
4.1. Test Schedule for 
hepatic safety 
monitoring and follow 
up after discontinuing 
imetelstat, Table 4, 
footnote 3
Revised the text to state that serum haptoglobin and reticulocyte count should be performed
only if clinically indicated.
Rationale: Included information regarding the lift of the clinical hold by the U.S. FDA.
1.3.4.4. Hepatobiliary 
Events
Added: Following a complete response submitted by Geron, the clinical hold was lifted by 
the U.S. FDA on 31 October 2014.
Rationale: To update information regarding Phase II trials with imetelstat.


Protocol CP14B019, Amendment 13
Page 21 of 90
1.3.3. Clinical 
Experience with  
Imetelstat, Table 2
The study status of protocol number CP14B013 was marked as completed.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


Protocol CP14B019, Amendment 13
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1.
BACKGROUND
1.1.
Myelofibrosis
The term myelofibrosis (MF) includes both primary myelofibrosis (PMF) and post-polycythemia 
vera/essential thrombocythemia myelofibrosis (post-PV/ET MF) (Tefferi 2011).  MF is currently 
classified as a chronic myeloproliferative neoplasm (MPN) and is characterized by clonal 
proliferation of pluripotent hematopoietic stem cells and abnormal cytokine expression
(Tefferi 2011).  Patients with MF typically present with anemia, marked splenomegaly and 
profound constitutional symptoms (night sweats, pruritus, early satiety, bone pain, cough, fever, 
etc.). In addition, some patients might display thrombocytopenia, leucopenia, thrombocytosis, 
leukocytosis, and non-hepatosplenic extramedullary hematopoiesis (EMH) (Tefferi 2011).  
Current drug therapy for MF, such as erythropoiesis stimulating agents (ESAs), hydroxyurea and 
JAK inhibitors have not been shown to influence survival and are often used for palliative 
purposes only (Tefferi 2011).  Allogeneic stem cell transplantation (ASCT), which is so far the 
only curative option, carries a high treatment-related mortality and morbidity (Tefferi 2011).
The International Prognostic Scoring System (IPSS), used for risk stratification in PMF, uses risk 
factors assessed at time of diagnosis: age >65 years, constitutional symptoms, hemoglobin
< 10 gm/dL, leukocyte count >25 x 109/L and peripheral blood blasts >1% (Tefferi 2011).
Subsequently, the IPSS prognostic variables were used to devise a dynamic IPSS (DIPSS) that 
can be utilized at any point during the disease (Tefferi 2011). Most recently, DIPSS was further 
revised to DIPSS-plus by the incorporation of 3 additional IPSS/DIPSS-independent risk factors, 
including red cell transfusion need, platelet count <100 × 109/L, and unfavorable karyotype
(Tefferi 2011); the latter includes complex karyotype or sole or 2 abnormalities that include +8, 
−7/7q−, i(17q), inv(3), −5/5q−, 12p−, or 11q23 rearrangement. The 8 DIPSS-plus risk factors are 
currently used to define low (no risk factors), intermediate- 1 (1 risk factor), intermediate-2 (2 or 
3 risk factors), and high (≥4 risk factors) risk groups with respective median survivals of 15.4, 
6.5, 2.9, and 1.3 years (Tefferi 2011). Patients with MF can progress into blast phase disease 
(BP-MF), defined by the same criteria used by WHO for acute myeloid leukemia (AML) (i.e. 
20% or more blasts in the peripheral blood or bone marrow). Some patients with MPN share 
certain morphologic features with those with myelodysplastic syndromes (MDS). The WHO 
classifies such cases as MDS/MPN overlap and their clinical features are similar to patients with 
MF (i.e. severe anemia, splenomegaly, leukocytosis and thrombocytosis).
1.2.
Telomeres and Telomerase Inhibition
Telomeres consist of tandem repeats of the 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 (McEachern 2000).  
Telomeres shorten approximately 50–120 nucleotides (nt) at each cell division (Harley 2002;
Harley 1997).  When telomeres get critically short, they can no longer cap the telomere 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 two essential 


Protocol CP14B019, Amendment 13
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components:  the human telomerase 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 (Harley 1997).
Normal somatic cells have relatively long telomeres (~9–12 kilobases) (Rufer 1999) and typically 
do not express detectable levels of telomerase. In contrast, telomerase activity has been detected 
in 80–90% of cancers tested to date, and is key to cell immortalization through maintenance of 
telomere length (TL) (Shay 1997).  Most tumors have shorter telomeres, compared to their 
normal tissue counterparts, in spite of telomerase activation.  These two characteristics make 
telomerase a promising therapeutic target for cancer.
1.3.
Imetelstat
Imetelstat (GRN163L) is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that 
acts as a potent specific inhibitor of telomerase.  Telomerase inhibition leads to the loss of a 
cancer cell’s ability to maintain TL, resulting in cell-cycle arrest, apoptosis, or senescence.  The 
mechanism of action of imetelstat is not an antisense-based approach.  Imetelstat does not cause 
down regulation of mRNA encoding either the hTR or hTERT subunits of telomerase, nor does it 
affect RNAse H activity, which typically causes degradation of mRNA when it is targeted by an 
antisense phosphoramidate oligonucleotide.  Imetelstat binds with high affinity to hTR and is a 
competitive inhibitor of telomerase enzymatic activity (Asai 2003; Herbert 2005).  Studies have 
shown that 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 (Stewart 2010) (Harley 2008).
1.3.1.
Nonclinical Pharmacology
1.3.1.1.
Efficacy Studies
Data from nonclinical efficacy studies have shown that imetelstat inhibits telomerase in tumor 
cells and compromises cancer cell viability in vitro.  Imetelstat has broad tumor growth inhibition 
activity in multiple xenograft models, including non-small cell lung, breast, colorectal, 
pancreatic, glioblastoma multiforme (GBM), myeloma, neuroblastoma, hepatic and ovarian 
cancers.
1.3.1.2.
Effects on Cancer Stem Cells
Numerous studies have identified a relatively rare subpopulation of tumor-initiating cells (TICs), 
also termed cancer stem cells (CSCs), in multiple cancer types.  CSCs are distinct from the bulk 
tumor cell population, yet share the properties of increased telomerase activity (TA) and short 
telomeres, making CSCs of multiple tumor types promising targets for telomerase inhibition.  In 
vitro studies have demonstrated that imetelstat inhibits telomerase, and is effective in targeting 
CSCs from myeloma, melanoma, breast, pancreatic, pediatric glioma, neuroblastoma, prostatic, 
lung and glioblastoma multiforme tumor types (Joseph et al. 2010b; Marian et al. 2010a).  
Treatment of CSCs with imetelstat results in increased apoptosis, induction of senescence, and 
inhibition of proliferation, sphere formation, and clonogenicity.  In vivo studies demonstrated 
that imetelstat is able to significantly inhibit CSC-mediated tumor engraftment and growth in 


Protocol CP14B019, Amendment 13
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breast, pancreatic, glioblastoma, neuroblastoma, and myeloma xenograft models (Joseph et al. 
2010a; Hochreiter 2006; Shammas 2008; Dikmen 2009; Castelo-Branco 2011; Marian 2010b).
1.3.2.
Nonclinical Safety Studies
Imetelstat was evaluated in a broad range of toxicology studies to support its use as a 
systemically-delivered anticancer agent in humans.  The general toxicology of imetelstat was 
assessed in rodents and non-human primates.  Imetelstat nonclinical safety studies were carried 
out in mice, rats, rabbits, and cynomolgus monkeys.  Support for the proposed clinical dose and 
schedule is based primarily on the repeat-dose studies in mice (dosed twice weekly for 26 weeks) 
and cynomolgus monkeys (dosed once weekly for 9 months).
Toxicities generally fit into two main categories:  (1) those related to plasma concentrations of 
imetelstat, reflecting interactions with blood components, and (2) those reflecting tissue 
deposition and associated inflammatory effects, as were evident from histopathology evaluations.
Toxicities observed with imetelstat treatment included cytopenias, complement activation, and 
coagulation abnormalities.  Complement activation and coagulation abnormalities were related to 
plasma concentrations of imetelstat.  The etiology of the cytopenias is not clear; a direct effect on 
hematopoietic progenitor cells cannot be excluded.
Early intravenous (IV) bolus range-finding studies helped define the high-dose toxicity profile 
and repeat-dose studies characterized the full range of potential target organs for imetelstat-
related adverse effects.  At high doses in rodents (i.e., ≥30 mg/kg IV bolus), effects on 
hematology and coagulation parameters were observed, including elevated activated partial 
thromboplastin time (aPTT), hemorrhage, and decreased platelet and red blood cell pools.  The 
occurrence of peripheral cytopenias, most notably thrombocytopenia, was sometimes 
accompanied by decreases in red blood cell (RBC) parameters and mild anemia.  In non-human 
primates, hematological effects (decreases in RBC parameters and platelets at doses ≥15 mg/kg) 
were present but to a lesser extent than those seen in rodents.  In ex vivo colony-forming assays 
using human bone marrow progenitors, imetelstat did not significantly inhibit erythroid or 
myeloid colony number (although colony morphology was compromised at 15 M), but 
megakaryocyte colony growth was inhibited at ≥3.75 μM (50% inhibitory concentration [IC50] ~5 
μM).
Inhibition of coagulation (aPTT prolongation) and activation of complement pathways (increased 
plasma levels of Bb and C5a split products and decreased total hemolytic complement [CH50]) 
were noted.  These effects were reversible and similar to acute blood level-related toxicities seen 
with other polyanionic oligonucleotides.  There was no clinical evidence of clotting 
abnormalities in monkeys at relatively high doses that produced over 3-fold increases in aPTT.
Severe complement-mediated adverse reactions were noted in some of the monkey dose-finding 
studies; however chronic complement activation at doses ≤ 15 mg/kg did not result in any 
adverse constitutional outcomes.  Similar to other oligonucleotides in this class, imetelstat-
mediated activation of the alternative complement pathway is believed to stem from binding to 
an inhibitory complement protein (Factor H), which, if sufficiently depleted, initiates an 
activation cascade with the formation of biologically active split products culminating in 


Protocol CP14B019, Amendment 13
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hemodynamic changes (mainly hypotension).  In monkeys, this may result in significant 
cardiovascular toxicity.  In the case of imetelstat, the threshold blood level for complement 
activation is approximately 200 g/mL.  Toxicokinetic analyses confirmed that these acute 
effects are reversible after 24 hours and can be managed by adjusting the dose and duration of 
infusion of imetelstat.
Administration of imetelstat intravenously to monkeys at doses of up to 15 mg/kg over 2 hours 
once weekly for 9 months was well tolerated.  Data from studies in rats suggested that imetelstat 
was taken up by many tissues, primarily liver, kidneys and, to a lesser extent, the spleen and bone 
marrow; these are the target organs for histopathologic alterations.  Microscopic examination of 
tissues revealed mild to moderate changes in the kidney (mesangial thickening, 
glomerulonephritis/sclerosis, deposition in interstitium, renal tubular hemorrhage, protein casts, 
and regeneration), liver (telangiectasis and deposition in Kupffer cells), uterus (atrophy of the 
endometrium), choroid plexus (minimal lymphoid follicle formation and mononuclear cellular 
infiltration), and general systemic arteritis including at the injection site at doses starting at 
5 mg/kg.  The observations in the kidney did not show signs of reversibility in the recovery group 
animals; however, it is not unusual for such inflammatory lesions to persist for several months in 
monkeys.  The endometrial atrophy was only noted after 9 months of chronic dosing at 15 mg/kg 
and was absent in the recovery animals.  The remaining morphological changes in the liver and 
the inflammatory vasculitis (choroids plexus and systemic arteritis) showed signs of resolution in 
the recovery group animals.
Most of these histological findings are thought to be due to pro-inflammatory activity common to 
many oligonucleotides and derived from a programmed physiological reaction of the body to 
their foreign nucleic acid structure and are heightened when the molecule is chemically modified 
to inhibit degradation by endogenous nucleases.  In general, the changes observed in the groups 
that received imetelstat at doses up to 15 mg/kg were of limited severity and were not associated 
with any tissue degeneration or other alterations that would suggest compromised organ function. 
Most changes showed evidence of recovery after a 14-week drug-free period.
Imetelstat was not teratogenic in mice or rabbits following bolus or 2-hour continuous 
intravenous (IV) infusion of 30 mg/kg.  In rabbits, embryo-lethality was noted as increased post-
implantation loss at 30 mg/kg due to an increase in early resorptions, resulting in higher 
incidence of litter loss at this dose level that correlated to a decrease in litter size and viable 
fetuses.
Additional findings from nonclinical studies that may predict the safety of the clinical dose 
include:  (1) absence of effects on cardiovascular (human ether-à-go-go related gene [hERG] 
inhibition, electrocardiogram [ECG]), respiratory, and neurological function, and (2) absence of 
genetic toxicity in tests for mutagenicity and clastogenicity.
Please refer to the Imetelstat Investigator’s Brochure (IB) for further details.
1.3.3.
Clinical Experience with Imetelstat
Table 1 and Table 2 summarize all clinical trials with imetelstat initiated by Geron to date.


Protocol CP14B019, Amendment 13
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A total of 491 patients have been enrolled in Geron Phase I and II imetelstat clinical trials of 
which 374 received imetelstat either as a single agent or as combination therapy.
Six Phase I studies have been initiated since 2005, of which three were single-agent studies and 
three were combination studies.  The study designs and status are summarized below and 
presented in Table 1.  A total of 183 patients were treated with imetelstat in Phase I; enrollment 
and study treatment has been completed and the databases locked for all six studies.  
In Phase II clinical trials, imetelstat was investigated as a single agent in CP14B015 (ET/PV), as 
single-agent or combination therapy in CP14B013 (multiple myeloma [± lenalidomide]) and 
CP14B012 (NSCLC [± bevacizumab]), and as combination therapy in CP14B014 (MBC 
[paclitaxel ± bevacizumab]).  As of 21 May 2013, a total of 191 patients were treated with 
imetelstat in Phase II (Table 2).


Protocol CP14B019, Amendment 13
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Table 1:
Phase I Clinical Trials with Imetelstat
Protocol 
Number
Protocol Title
Patients 
Enrolled
Patients 
Treated 
(Data Cut-
off Date)
Dose and Schedule of Imetelstat
Key Study Endpoints
Study 
Status
Single Agent Trials
CP14A004 A Phase I Sequential Cohort, Dose Escalation Trial to 
Determine the Safety, Tolerability, and Maximum 
Tolerated Dose of Weekly Administration of 
GRN163L in Patients with Refractory or Relapsed 
Multiple Myeloma
20
20
(Locked 
15Nov2010)
3.2, 4.8, 6.0, 7.2 mg/kg over 2 
hours weekly; 6.0 mg/kg on Days 
1, 8 every 21 days.
Primary:  Safety, tolerability, 
MTD
Secondary: PK, anti-tumor 
activity, pharmacodynamics
Completed
CP04-151
A Phase I/II, Sequential Cohort, Dose Escalation Trial 
to Determine the Safety, Tolerability, and Maximum 
Tolerated Dose of Weekly Administration of 
GRN163L in Patients with Refractory or Relapsed 
Chronic Lymphoproliferative Disease
28
28
(Locked 
15Feb2011)
20, 40, 80, 160, and 240 mg/m2
over 6 hours weekly; 160 and 
200 mg/m2 over 2 hours weekly; 
200 mg/m2 over 2 hours on Days 1 
and 8
Primary:  Safety, tolerability, 
MTD
Secondary: PK, anti-tumor 
activity, pharmacodynamics
Completed
CP05-101
A Phase I, Sequential Cohort, Dose Escalation Trial 
to Determine the Safety, Tolerability, Maximum 
Tolerated Dose, and Optimal Infusion Duration of 
Weekly Administration of GRN163L in Patients with 
Refractory or Relapsed Solid Tumor Malignancies
75
75
(Locked 
21Mar2011)
0.4, 0.8, 1.6, 3.2, 4.8 mg/kg over 2 
hours weekly; 4.8, 6.0, 7.5, 9.4, 
11.7 mg/kg on Days 1, 8 every 21 
days; 9.4, 11.7 mg/kg once every 
28 days
Primary:  Safety, tolerability, 
MTD
Secondary: PK, anti-tumor 
activity, pharmacodynamics
Completed
Combination Trials
CP14A005 A Phase I Sequential Cohort, Dose Escalation Trial to 
Determine the Safety, Tolerability, and Maximum 
Tolerated Dose of Weekly Administration of 
GRN163L in Combination with Paclitaxel and 
Carboplatin in Patients with Advanced or Metastatic 
Non-Small Cell Lung Cancer
27
27
(Locked 
15Oct2010)
3.2 mg/kg over 2 hours weekly; 
3.2 mg/kg over 2 hours once every 
21 days; 3.2, 4.8, 6.0 and 7.5 mg/kg 
on Days 1, 8 every 21 days.
Primary:  Safety, tolerability, 
MTD
Secondary: PK, anti-tumor 
activity 
Completed
CP14A011 A Phase I Study of GRN163L in Combination with 
Bortezomib and Dexamethasone in Patients with 
Relapsed or Refractory Multiple Myeloma
9
9
(Locked 
15Dec2010)
160, 200 mg/m2 over 2 hours Days 
1, 8 every 21 days
Primary:  Safety, tolerability
Secondary: PK, anti-tumor 
activity 
Completed
CP14A010 A Phase I/II Study of GRN163L in Combination with 
Paclitaxel and Bevacizumab in Patients with Locally 
Recurrent or Metastatic Breast Cancer
24
24
(Locked 
28Mar12)
160, 240, 300, 375 mg/m2 Days 1, 
8, 15 every 28 days; 300 and 375 
mg/m2 Days 1, 15 every 28 days; 
300 mg/m2 Day 8 every 28 days.
Primary:  Safety, tolerability
Secondary: PK, anti-tumor 
activity 
Completed


Protocol CP14B019, Amendment 13
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Table 2:
Phase II Trials with Imetelstat
Protocol 
Number
Protocol Title
Patients 
Enrolled
Patients 
Treated 
Dose and Schedule of 
Imetelstat
Key Study Endpoints
Study 
Status
Randomized Trials
CP14B012
A Randomized Phase II Study of Imetelstat as 
Maintenance Therapy after Initial Induction 
Chemotherapy for Advanced Non-Small Cell 
Lung Cancer (NSCLC)
116
114
(Locked 
19Sep2013
9.4 mg/kg over 2 hours 
on Days 1,8 every 21 
days
Primary:  PFS
Secondary: Safety, tolerability, 
ORR 
Completed
CP14B014
A Randomized Phase II Study of Imetelstat 
(GRN163L) in Combination with Paclitaxel 
(With or Without Bevacizumab) in Patients with 
Locally Advanced or Metastatic Breast Cancer
166
161
(Locked 
10Dec2012)
300 mg/m2 on Day 1 
every 21 days
Primary:  PFS
Secondary: Safety, ORR, clinical 
benefit rate
Completed 
(early 
termination)
Single-Arm Trials
CP14B013
A Phase II Trial to Determine the Effect of 
Imetelstat (GRN163L) on Patients with 
Previously Treated Multiple Myeloma
13
13
(Locked 
20Nov2014)
9.4 mg/kg over 2 hours 
on Days 1,8 every 28 
days
Primary:  Improvement in response
Secondary: Safety, tolerability, 
PFS, circulating myeloma CSCs
Completed 
CP14B015
A Phase II Trial to Evaluate the Activity of 
Imetelstat (GRN163L) in Patients with Essential 
Thrombocythemia or Polycythemia Vera who 
Require Cytoreduction and Have Failed or Are 
Intolerant to Previous Therapy, or who Refuse 
Standard Therapy
20
20
(Locked 
06Apr2015)
7.5 -11.7 mg/kg over 2 
hours weekly or as 
needed based on 
hematologic response
Primary:  Hematologic response 
(ET), Hematocrit (PV)
Secondary: Safety, tolerability, 
duration of hematologic, response, 
molecular response, histologic 
response at 2 years, on study, 
phlebotomy rate (PV)
Completed  


Protocol CP14B019, Amendment 13
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1.3.4.
Safety Experience
The overall summary of clinical safety for imetelstat is primarily based on the 374 imetelstat 
treated patients in all 10 Geron sponsored Phase I and II trials to date. Where relevant, additional 
clinical safety information (e.g., from investigator-sponsored trials) is incorporated. For 
additional details, refer to the IB.  A summary of clinical safety is provided below.
1.3.4.1.
Hematologic Events
Cytopenias, in particular thrombocytopenia, were dose-limiting in both single-agent imetelstat 
trials and when combined with other chemotherapies.  The frequency and severity of all 
cytopenias, particularly thrombocytopenia and neutropenia, were 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 patients had 
been exposed, and low marrow reserve. 
Grade 2-4 thrombocytopenia typically occurred after 1 to 4 weeks of dosing, with higher dose 
intensity associated with the earlier onset.  The occurrence of the first episode of Grade 3-4 
thrombocytopenia was observed as late as Cycle 7 with single-agent imetelstat.  Recovery to 
Grade ≤ 1 usually occurred within 12 weeks.
Grades 3 and 4 neutropenia typically occurred after 2 to 3 weeks of dosing, with the first 
observed episode occurring as late as Cycle 29 in single-agent trials.  Resolution to Grade ≤ 1 
typically occurred within 12 weeks.
The etiology of cytopenias is currently unclear, and may possibly be due to the direct inhibition 
of telomerase in hematopoietic progenitor cells or the non-specific toxicity related to the 
molecular class of the compound.  
During the course of the current myelofibrosis trial CP14B019 (formerly MC1285) more 
persistent and profound myelosuppression, particularly thrombocytopenia, was observed. In the 
cohort (B) treated with an initial intensive weekly regimen for four doses, two patients developed 
profound prolonged cytopenias following the last dose in the weekly dosing period.  One patient 
recovered after holding the dose and was retreated at a lower dose and schedule 16 weeks after 
her last imetelstat dose.  The second patient experienced associated clinical outcomes of febrile 
neutropenia and a fatal intracranial hemorrhage (ICH) in the setting of Grade 4 
thrombocytopenia. These data suggests that some patients with myelofibrosis may be more 
susceptible to the myelosuppressive effects of imetelstat.
Bleeding events have been associated with thrombocytopenia in Geron sponsored trials; these 
may be serious and severe enough to be potentially life threatening.  The most frequently 
observed event was epistaxis. There have been two fatal bleeding events of Intracranial 
hemorrhage (ICH) in the setting of Grade 4 thrombocytopenia reported.  The first was the subject 
enrolled in CP14B019 (formerly MC1285), as noted above, who experienced a fatal ICH 
following profound Grade 4 thrombocytopenia for approximately 4 weeks.  The second fatal ICH 
was in a 
 IST involving a  year-old 
 with medulloblastoma of the posterior fossa.  


Protocol CP14B019, Amendment 13
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This event occurred in the setting of Grade 4 thrombocytopenia approximately 3 weeks after the 
first cycle of imetelstat.
Febrile neutropenia has been observed at a low incidence, particularly in combination with 
taxanes.  Since Grade 3 and 4 neutropenia with imetelstat treatment is observed quite frequently, 
patients should be closely monitored for infections and appropriate management instituted per 
institutional standards to mitigate and manage potentially life threatening infections.  
1.3.4.2.
Coagulation Changes
In the Phase I imetelstat trials in which serial aPTT was measured following infusion, transient 
aPTT prolongations were observed in all patients which, at doses ≥ 3.2 mg/kg and 160 mg/m2, 
were as high as Grade 3.  Resolution to Grade 1 or normal limits was within 24 hours.  
Nonclinical studies suggest that aPTT prolongation is correlated with plasma concentrations of 
imetelstat.  PT prolongations occurred infrequently and the majority was Grade 1.  In the Phase II 
trials, aPTT and PT were not routinely measured.  No bleeding events associated with 
coagulation abnormalities were reported in these trials.
1.3.4.3.
Infections
Infections are frequently reported across all imetelstat trials, with an overall incidence of 43.0%.  
The most frequently reported events are urinary tract infection and upper respiratory tract 
infections. 
Most patients had normal neutrophil counts proximal to the infection episodes. 
Febrile neutropenia is infrequent and significant infections attributed to imetelstat associated 
with Grade ≥3 neutropenia have not been reported.  
1.3.4.4.
Hepatobiliary Events
Abnormalities in serum aminotransferases (i.e., alanine aminotransferase [ALT] and aspartate 
aminotransferase [AST]) or alkaline phosphatase (ALP) with, in some cases, accompanying 
bilirubin elevations were observed in patients in the Phase II ET/PV trial (CP14B015).  
Elevations in ALT and AST appear to be early, self-limiting and Grade 1 in severity, although 
AST elevations were more persistent.  Acute Grade 2 and Grade 3 elevations in ALT with 
accompanying elevations in AST have also been observed (4 patients/20%) at the 9.4 mg/kg 
weekly dose level, and these resolved to baseline with imetelstat dose holds and dose reductions. 
Persistent Grade 1 elevations in ALP and AST were also observed and appear to occur with 
longer duration of exposure to imetelstat and may be accompanied by Grade 1 
hyperbilirubinemia, although some intermittent Grade 2 elevations in bilirubin have also been 
reported.  Bilirubin fractionations were primarily unconjugated among these patients. The 
clinical significance of these persistent ALP elevations and reversibility upon stoppage of 
imetelstat is not understood at present and remains under close monitoring.    


Protocol CP14B019, Amendment 13
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In this trial (CP14B015) an 
 year old 
 patient, who had been receiving imetelstat for 
almost 3 years, developed hepatic encephalopathy and subsequently died of bleeding esophageal 
varices.  
 had experienced persistently elevated Grade 1 AST and ALP on trial. This was a 
highly complex case, with the subject having multiple comorbidities and concomitant 
medications making assessment of the role of imetelstat extremely challenging, though it cannot 
be definitely excluded.
The low grade liver biochemistry patterns observed in CP14B015 trial were also observed in 
other imetelstat trials, but with lesser frequency, which may be somewhat attributable to shorter 
treatment and observation time on study in advanced malignancy trials.  The abnormal laboratory 
observations may be dose related and may be more frequent when imetelstat is administered in 
combination with other cytotoxic agents.  The majority of findings attributable to imetelstat are 
biochemical abnormalities without clinical sequelae and do not appear to be clinically significant 
in patients with advanced malignancies.  Severe hepatobiliary events, including fatal outcomes
may, however, occur in these patients.  Refer to IB Section 5.3.5.7 for further details. 
On 11 March 2014, the United States Food and Drug Administration (U.S. FDA) issued Geron a 
full clinical hold citing lack of evidence of reversibility of hepatotoxicity, risk for chronic liver 
injury, and lack of adequate follow up in subjects who experienced hepatotoxicity. All subjects 
enrolled in Geron-sponsored clinical trials permanently discontinued imetelstat treatment and 
enrollment of new subjects to clinical trials was not allowed. Continued safety surveillance was 
implemented as part of an extended hepatic safety follow-up period of all subjects in ongoing 
Geron-sponsored trials who had liver biochemistry abnormalities and/or hepatic adverse events 
that first appeared during imetelstat treatment, or worsened from baseline during treatment, and 
were continuing at the time subjects’ discontinued imetelstat treatment. Reversibility of these 
abnormalities and/or hepatic adverse events back to normal or baseline levels after discontinuing 
imetelstat were assessed. Data were collected from subjects who discontinued imetelstat 
treatment as a result of the clinical hold, as well as those who discontinued for any reason and 
met safety follow-up criteria prior to the clinical hold. Following a complete response submitted 
by Geron, the clinical hold was lifted by the U.S. FDA on 31 October 2014.
On 12 March 2014, the then sponsor-investigator for Study MC1285 was issued a partial clinical 
hold by the FDA. The safety issues cited by the FDA for the partial clinical hold included a 
safety signal of hepatotoxicity identified in clinical trials of imetelstat and whether this 
hepatotoxicity was reversible. Previously enrolled subjects who were deriving clinical benefit 
according to the principal investigator were allowed to continue treatment with imetelstat but no 
new subjects may be registered. Following a complete response submitted by the sponsor-
investigator to the FDA, this partial clinical hold was lifted by the FDA on 11 June 2014. 
Emergent hepatobiliary data continues to be monitored on an ongoing basis and third party 
hepatology experts will be consulted as necessary to continue to refine the understanding of this 
signal as data emerge.


Protocol CP14B019, Amendment 13
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1.3.4.5.
Infusion Reactions
Oligonucleotides have been previously reported to cause complement activation and related 
infusion reactions with the potential to cause non-complement-related hypersensitivity reactions. 
In the Phase II trials where all patients had routine prophylaxis, 19.4% of imetelstat-treated 
patients had an infusion reaction.  The events are sporadic and a patient may not necessarily 
experience a subsequent event with successive infusions. Infusion reactions are generally mild to 
moderate in severity but symptoms and signs may occasionally be Grade 3 or 4 (incidence 3%) in 
severity.  Reactions may be more frequent or severe with imetelstat dose levels exceeding 9.4 
mg/kg.  Reactions may be ameliorated, but are not always prevented, by required premedication 
with corticosteroids, diphenhydramine, and/or acetaminophen.
1.3.4.6.
Gastrointestinal Events
Gastrointestinal events of all grades are some of the most frequently reported events reported 
with imetelstat-treatment.
Nausea is the most frequent event. Diarrhea, vomiting, abdominal pain, and constipation were 
also frequently reported.  These events resolve between infusions, usually within 7 days. The 
majority of these events are Grade 2 or less in severity, but severe episodes of diarrhea, vomiting 
and abdominal pain necessitating hospitalization for adequate management may occur. 
Stomatitis and mucositis, Grade 2 or less in severity, have also been observed with both 
single-agent imetelstat and in combination regimens.  Grade 3 events have been observed in 2 
patients receiving imetelstat in combination with taxane chemotherapy, which may be the main 
contributor to the event. The majority of the episodes reportedly resolve, including all Grade 3 
events.
1.3.4.7.
Constitutional Symptoms
Constitutional symptoms within a few days of imetelstat infusion, including headache, nausea, 
vomiting, diarrhea, fatigue, myalgia, arthralgias, fever, flu-like illness, and chills are frequently 
observed with imetelstat treatment, consistent with what has been reported with other 
oligonucleotides.  These symptoms are also common in oncology patients.  The events are 
usually self-limiting, are mostly Grade 1 to 2 in intensity and resolve within 7 days or less. 
The most frequently reported Grade 3 event was fatigue. Other Grade 3 events were diarrhea, 
musculoskeletal pain, and nausea, all observed in less than 2% of these patients.  No Grade 4 
events were observed. 
Supportive treatment was usually with non-steroidal anti-inflammatory drugs, opiate analgesics, 
and antiemetics.  Corticosteroid use was not frequent, other than as prophylaxis for infusion 
reactions per protocol, in which case dexamethasone was primarily used.


Protocol CP14B019, Amendment 13
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1.4.
Rationale for Conducting this Study
PMF, post-PV/ET MF, BP-MF and MDS/MPN are diseases associated with high morbidity and 
mortality and in whom currently available medications, including the recently developed JAK 
inhibitors, carry minimal impact on the natural history of the disease including overall and 
leukemia-free survival. The currently available drugs have so far failed to favorably affect bone 
marrow pathology, cytogenetic abnormalities, JAK2V617F allele burden and have had limited 
effect in alleviating anemia or controlling leukocytosis or thrombocytosis. JAK inhibitors have 
been shown to provide benefit in reducing spleen size and alleviating symptoms but do not 
appear to offer any additional value.  Furthermore, these medications are often associated with 
side effects, including anemia and thrombocytopenia.
The key obstacle to the value of JAK inhibitor therapy in MF is the fact that the disease is not 
necessarily defined by a JAK-STAT-relevant mutation and that its molecular pathogenesis 
includes many other mutations and aberrant pathways. Imetelstat may be particularly beneficial 
in this regard since it targets abnormal proliferation regardless of its molecular underpinnings. In 
addition, the drug has the following properties that are relevant to patients with MF and 
MDS/MPN:

Ability to target CSCs and TICs

Inhibition of colony-forming unit-megakaryocytes (CFU-Mk) in vitro. 

Ability to target diseases with short TL, such as myeloproliferative neoplasms

Ability to inhibit telomerase, which is highly active in leukocytes of patients with 
myeloproliferative neoplasms.

Longer imetelstat PK residence time in the bone marrow and spleen, compared to 
plasma
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 (Harley 2008).  TA (as measured in 
granulocytes) is notably high in patients with myeloproliferative neoplasms (Ferraris 2005a).  
Additionally, TL (measured in granulocytes) in patients with myeloproliferative neoplasms is 
short, regardless of JAK2 mutational status; therefore, telomerase inhibition could potentially 
benefit both JAK2 V617F and JAK2 wild-type patients (Terasaki 2002; Ferraris 2005b;
Bernard 2009).
Imetelstat is a potent, specific inhibitor of telomerase.  In ex-vivo studies of normal progenitor 
cells, imetelstat did not inhibit erythroid or myeloid colony number or proliferation (CFU-E, 
BFU-E, total erythroid, CFU-GM, CFU-GEMM, or total colony forming cells).  Imetelstat did 
selectively reduce megakaryocyte colonies in culture, but only CFU-Mk large colonies, which 
represent megakaryocyte colonies derived from the most primitive lineage-restricted progenitor 
cells (data on file; see Figure 4).  This suggests a sensitivity of early megakaryocyte progenitors
to imetelstat compared to more mature megakaryocytes.  This sensitivity appears to coincide with 


Protocol CP14B019, Amendment 13
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the period of highest TA during progenitor cell differentiation.  As patients with 
myeloproliferative neoplasms have high TA and shorter TL, imetelstat is expected to have an 
effect on early megakaryocyte progenitors and the CSC clone, which presumably also have high 
TA and short TL.  Due to the low or transient expression of telomerase in normal tissues, 
including normal stem cells, and generally longer telomeres in normal cells vs. tumor cells, a 
degree of tumor specificity may be provided with imetelstat.
1.4.1.
Rationale for Dose and Schedule
Nonclinical studies indicate that imetelstat inhibits TA for 3–7 days after a single IV 
administration, as shown in Figure 7 in a DU145 tumor flank model and liver telomerase
inhibition model. Accordingly, the rationale to test various starting dose schedules that include 
weekly dosing to every three weeks dosing is to find the balance between efficacy (need drug 
present to inhibit telomerase) and toxicity. 






Protocol CP14B019, Amendment 13
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and 11.7 mg/kg Day 1 every 28 days.  Doses of 7.5 mg/kg and above led to exposure in patients 
that was above that associated with tumor growth inhibition in xenograft models (see Figure 9).
Figure 9:
Imetelstat Weekly AUCinf in Patients and in Xenograft Mice
In the Phase I study in patients with solid tumors, imetelstat 4.8 mg/kg weekly was the highest 
weekly dose studied.  At this dose, in this heavily pretreated population, there was no dramatic 
reduction in platelet counts in patients whose baseline platelet counts were > 250 x 103/μL.  In 
the higher dose cohorts (7.5, 9.4, and 11.7 mg/kg) in which imetelstat was given on Days 1 and 8 
of 21-day cycles, there was a greater reduction in platelet count compared to the 4.8 mg/kg 
weekly cohort.  The greatest impact on platelets was observed in the 9.4 mg/kg and 11.7 mg/kg 
cohorts.  A reduction in platelet counts of approximately 30% from baseline usually occurred 
after three to six doses in the lower dose cohorts (weekly schedule) and after two to three doses 
in the higher dose cohorts (Days 1 and 8 every 21 days schedule).  Hematologic toxicity was 
generally mild to moderate in the 7.5 mg/kg dose cohort and occurred less frequently compared 
with the 9.4 and 11.7 mg/kg dose cohorts of heavily pretreated patients with solid tumors.  Grade 
4 thrombocytopenia was reported in one patient in each of the 9.4 mg/kg and 11.7 mg/kg dose 
cohorts and Grade 4 neutropenia was reported in 2 patients in the 9.4 mg/kg dose cohort.  
However, dosing on Days 1 and 8 were not held until these cytopenias occurred in Cycle 2.  


Protocol CP14B019, Amendment 13
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There were no cases of Grade 3 or Grade 4 thrombocytopenia in the 9.4 mg/kg and 11.7 mg/kg 
every 28 days cohorts and one case of Grade 3 neutropenia in the 11.7 mg/kg dose cohort.  
In patients with ET, weekly dosing (7.5 to 11.7 mg/kg) was well tolerated with few Grade 3 or 
Grade 4 hematologic or non-hematologic toxicity (Baerlocher et al. 2012); Grade 3 or 4 adverse 
events regardless of attribution included: Grade 4 non-febrile neutropenia 14.3%, Grade 3
neutropenia 28.6%, no Grade 3 or Grade 4 thrombocytopenia, Grade 3 anemia (probably 
unrelated) 7.1%, Grade 3 increase in transaminases 14.3%, Grade 3 infusion reactions 7.1%, 
Grade 3 infection (cellulitis) 7.1%, Grade 3 fatigue, Grade 3 bleeding events (post-operative) 
7.1% and Grade 3 headaches 7.1%. Based on these data, we want to start with an every 21-day
schedule, to first evaluate safety in our MF patient population and subsequently proceed with 
weekly dosing to maximize efficacy. The particular strategy was chosen because of the fact that 
patients with MF might be even more vulnerable for the myelosuppressive side effects of the 
drug. Accordingly, we plan to start with the first cohort of 11 patients receiving 9.4 mg/kg/every 
21 days, complemented with appropriate dose reduction in case of toxicity to 7.5 mg/kg and 6 
mg/kg every 21 days, if necessary.
After the first 11 patients on Arm A were enrolled and most of them followed for at least 3 
cycles, it has become apparent that the every 21 days schedule was safe and no Grade 3 or Grade 
4 non-hematologic toxicities were observed. The experience was the same for the second 11-
patient cohort in Arm B where patients received weekly treatment x 4 followed by every 3 weeks 
treatment. Based on this experience in 22 patients, an Arm C cohort was recently added where 
patients were to receive weekly treatment until toxicity ensued. However, it recently came to our 
attention that a subset of patients experienced severe Grade 4 myelosuppression and these very 
same patients were also the ones who ultimately responded to treatment. Close scrutiny allowed 
us to discover that some of the imetelstat-sensitive patients displayed bone marrow ring 
sideroblasts, which is a morphological feature that is known to be highly associated with 
spliceosome mutations. We followed up with this discovery and under a separate IRB-approved 
laboratory protocol, we discovered that virtually all of our patients that suffered Grade 4
myelosuppression (and treatment response) were spliceosome-mutated. As such we are making 
the current protocol amendment that includes the following:

Abandon Arm C and assign the 11 patients slotted to be enrolled in Arm C to either 
Arm A (if spliceosome-mutated) or Arm B (spliceosome unmutated)

Consolidate Arms A, B and C (total n = 33) for the purposes of communication of 
results at meeting and publication of results.

Add three additional arms (Arms E, F and G) that build on our aforementioned novel 
observations and allow a more accurate and safer treatment strategy that takes into 
account spliceosome mutational status.
These amendments are done to hopefully maximize response rate without undermining safety 
profile (Baerlocher et al. 2012). To that effect, we plan to include patients with BP-MF and 
spliceosome-mutated MDS/MPN or MDS, considering their poor prognosis and absence of 
effective therapy for such patients.


Protocol CP14B019, Amendment 13
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2.
GOALS 
2.1.
Primary

To evaluate overall response rate in each arm. For the purposes of this protocol, 
response for Arms A, B, C, E, and F will be according to IWG-MRT criteria (see 
Section 11). For arm G response will be according to the International Working 
Group response assessment as reported by Cheson et al. (2006; Section 11.2). 
Response for Arm D is defined by reduction in peripheral blood and bone marrow 
blast count to <5% and lasting for at least 2 months (see Section 16.2).
2.2.
Secondary

To evaluate the safety and tolerability of imetelstat in each arm (per NCI CTCAE, 
v4.0).

To evaluate the efficacy of imetelstat in the reduction of spleen size, as measured by 
physical examination (palpable distance from the left costal margin) in each arm.

To evaluate the efficacy of imetelstat in improving anemia or inducing red blood cell 
transfusion-independence in previously transfusion-dependent patients (per IWG-
MRT criteria; see Section 11) in each arm.

To evaluate onset and durability of response as defined in primary and secondary 
endpoints in each arm.
2.3.
Exploratory

To evaluate the effect of imetelstat on bone marrow histology, karyotype, and 
JAK2V617F allele burden in each arm.

To evaluate the effect of imetelstat on leukocytosis, circulating blast count
(blast % x WBC), circulating immature myeloid cell count (sum of blast, 
promyelocyte, myelocyte and metamyelocyte % x WBC), and thrombocytosis in each 
arm.


Protocol CP14B019, Amendment 13
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3.
PATIENT ELIGIBILITY
3.1.
Inclusion Criteria

Diagnosis of one of the following

Arms A, B, E, and F only: PMF per the revised World Health Organization 
(WHO) criteria (Appendix B), 

Arms A, B, E, and F only: post-ET/PV MF per the IWG-MRT criteria 
(Appendix C).

Arm D only: Blast-phase MF defined as the presence of 20% or more blasts in the 
peripheral blood or bone marrow 

Arm G only:  MDS/MPN or MDS patients with spliceosome mutations including 
SF3B1, SRSF2 and U2AF1 mutations or ring sideroblasts. Diagnosis of 
MDS/MPN and MDS is per WHO criteria (Tefferi and Vardiman 2008).  Direct 
sequencing will be used to confirm the presence or absence of spliceosome 
mutations.

Indication for treatment of one of the following: 

Arms A, B, E and F only: High-risk or Intermediate-2 risk MF (as defined by the 
Dynamic International Prognostic Scoring System [DIPSS-plus]; Appendix A).

Arm G only: presence of severe anemia defined as hemoglobin of <9 g/dL or 
other indications for cytoreductive therapy per physician discretion

Presence of the following: 

Arms E and G only:  spliceosome mutations, including SF3B1, SRSF2 and 
U2AF1 mutations (by direct sequencing) or ring sideroblasts.

Absence of the following:

Arm F only:  spliceosome mutations (by direct sequencing) and ring ring 
sideroblasts

≥ 18 years of age with life expectancy of ≥12 weeks.

Able to provide informed consent and be willing to sign an informed consent form.

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
(Appendix D).


Protocol CP14B019, Amendment 13
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
Evidence for acceptable organ function ≤14 days of study registration as evidenced 
by the following:

SGOT (AST) 2.5 x upper limit of normal (ULN) (or 5 x ULN if in the investigator’s 
opinion the elevation is due to extramedullary hematopoiesis)

SGPT (ALT) ≤2.5 x upper limit of normal (ULN) (or ≤5 x ULN if in the 
investigator’s opinion the elevation is due to extramedullary hematopoiesis)

Total bilirubin ≤3.0 mg/dL (or direct bilirubin <1 mg/dL).

Creatinine ≤3.0 mg/dL.

Absolute neutrophil count ≥1000/µL (this requirement not needed for Arm D).

Platelet count ≥50,000/µL (this requirement not needed for Arm D).

Females of childbearing potential must have a negative pregnancy test ≤ 7 days prior 
to registration, unless they are surgically sterile (i.e., hysterectomy), OR 
postmenopausal (FSH >30 U/mL).

Females of childbearing potential must agree to take appropriate precautions to avoid 
pregnancy (with at least 99% certainty) from screening through end of study. 
Permitted methods for preventing pregnancy must be communicated to study subjects 
and their understanding confirmed.

Males must agree to take appropriate precautions to avoid fathering a child (with at 
least 99% certainty) from screening through follow-up. Permitted methods for 
preventing pregnancy should be communicated to the subjects and their understanding
confirmed.
3.2.
Exclusion Criteria

Females who are pregnant or are currently breastfeeding.

Any chemotherapy (e.g., hydroxyurea), immunomodulatory drug therapy (e.g., 
thalidomide), immunosuppressive therapy, corticosteroids >30 mg/day prednisone or 
equivalent, growth factor treatment (e.g., erythropoietin) or JAK inhibitor therapy ≤
14 days prior to registration.

Subjects with another active malignancy. Note: Patients with early stage squamous 
cell carcinoma of the skin, basal cell carcinoma of the skin or cervical intraepithelial 
neoplasia are eligible for enrollment.

Known positive status for HIV.


Protocol CP14B019, Amendment 13
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
Any unresolved toxicity greater or equal to Grade 2 from previous anticancer therapy, 
except for stable chronic toxicities not expected to resolve.

Incomplete recovery from any prior surgical procedures or had major surgery ≤4 
weeks prior to registration, excluding the placement of vascular access and other 
minor surgical procedures.

Presence of acute active infection requiring antibiotics.

Uncontrolled intercurrent illness or any concurrent condition that, in the Investigator’s 
opinion, would jeopardize the safety of the patient or compliance with the protocol.


Protocol CP14B019, Amendment 13
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4.
TEST SCHEDULE
All routine assessments must be performed within 3 days of the day indicated on the Visit Schedule (except for screening).
Table 3:
Test Schedule: Core Phase = Cycle 1 – Cycle 9; Extension Phase = Cycle 10 and Beyond
Assessment
Screening 
(≤14 days 
Prior to 
registration)
≤24 hours 
before each 
imetelstat 
infusion Cycles 
1-9 or end of 
cycle during 
interruption1
Weekly 
in first 2 
cycles 
End of 
Cycle 3 
End of 
Cycle 9
Every Cycle 
in extension 
phase prior to 
infusion 
(Cycles 10 
and beyond) 1
At study 
completion or 
early 
termination 
(± 1 week) 2
Event Monitoring
Every 3 mo until 
PD or subsequent 
treatment for MF
Every 6mo after 
PD or subsequent 
treatment for 
MF14
Physical examination including 
weight (height at screening)3,4
X
X
X
X
Physical examination for 
hepatomegaly and 
splenomegaly3,4
X
X
X
X
Transfusion Assessment
X
X
Record adverse events4
X
X
X
X
X
Record concomitant medication
X
X
X
ECOG performance status 
(Appendix D) 4
X
X
X
X
12-lead ECG 
X
Chest x-ray
X
Serum pregnancy test4,5
X
X
X
Abdominal Ultrasound6
X
Urinalysis7
X
X
X


Protocol CP14B019, Amendment 13
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Assessment
Screening 
(≤14 days 
Prior to 
registration)
≤24 hours 
before each 
imetelstat 
infusion Cycles 
1-9 or end of 
cycle during 
interruption1
Weekly 
in first 2 
cycles 
End of 
Cycle 3 
End of 
Cycle 9
Every Cycle 
in extension 
phase prior to 
infusion 
(Cycles 10 
and beyond) 1
At study 
completion or 
early 
termination 
(± 1 week) 2
Event Monitoring
Every 3 mo until 
PD or subsequent 
treatment for MF
Every 6mo after 
PD or subsequent 
treatment for 
MF14
Temperature and vital signs 8
X
X
X
X
X
Serum chemistry,4,9
X
X
X
X
X
X
Serum calcium, phosphorus, 
magnesium, total protein
X
X
X
X
CBC,4,10
X
X
X
X
X
X
Peripheral blood smear4
X
X
X
X
Serum Epo level
X
X
X
International Working Group 
(IWG) Assessment of response4
X
X
INR (or PT) and aPTT7 4
X
X
Bone marrow biopsy and aspirate 
with cytogenetic and JAK2 
V617F studies11
X12
X12,13
Follow-up for survival and 
disease status and information of 
subsequent treatment for MF 14
X
R 
Samples may be used by Mayo Clinic or sponsor for research tests that include granulocyte JAK2V617F allele burden measurement, plasma cytokine 
analysis and other tests that are deemed insightful.
CBC = complete blood count
1
In case of interruption, a cycle will be 3 months while treatment is held. 
2 For all patients who did not experience a treatment emergent abnormality in liver function tests (LFTs), defined as any grade abnormality in patients with 
normal value at baseline or any higher grade shift from baseline in patients with an abnormal baseline, or value more than 2x baseline if baseline was Grade ≥ 3,
or hepatic adverse events are present at imetelstat discontinuation, obtain LFT follow-up until 30 days from the last imetelstat dose. The length of the last cycle 
will be until 30 days after the last dose.  For patients who experienced a treatment emergent abnormality in LFTs, as defined above, or hepatic adverse events 


Protocol CP14B019, Amendment 13
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are present at imetelstat discontinuation, obtain follow-up per test schedule (see Section 4 for details) until resolution to at least baseline grade or less than 2x
baseline value if baseline was Grade ≥ 3 for at least 2 consecutive determinations. The length of the last cycle will be until the resolution is confirmed.
3
Screening physical examination should include the evaluation of head, eye, ear, nose, and throat (HEENT), cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems.  Changes from baseline abnormalities should be recorded at each subsequent physical examination.  
New or worsened abnormalities should be recorded as adverse events if appropriate.  As part of tumor assessment, physical examinations should also include 
the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.
4
If screening assessment was performed within 7 days prior to dosing Day 1 Cycle 1 assessment does not need to be repeated, and the screening assessment will 
serve as baseline.
5
All women of childbearing potential (including those who have had a tubal ligation).  For all other women, documentation must be present in the medical 
history.
6
In addition to baseline abdominal ultrasound, a Doppler ultrasound of abdomen will be performed post baseline only as clinically indicated at the discretion of 
the investigator. The ultrasound will assess status of hepatobiliary architecture, which includes detection of any gross liver abnormalities; results will be 
compared to the baseline scan.
7
Urinalysis to include blood, leukocytes, glucose, protein, pH, specific gravity, ketones, and nitrates.
8
Vital signs will include measurements of temperature, heart rate, and systolic and diastolic blood pressure.
9
Serum chemistries include sodium, potassium, BUN, creatinine, total and direct bilirubin, albumin, ALT, AST, alkaline phosphatase, LDH, and serum ferritin.
In the event of new onset treatment emergent total bilirubin of Grade 2 or higher perform a reading of concurrent fasting bile acids and, to assess for 
hemolysis, a concurrent peripheral smear. Serum haptoglobin and reticulocyte count should also be performed if clinically indicated.
10 CBC must be repeated weekly in patients with treatment-emergent ANC ≤1.0 x 109/L or platelet count< 75x 109/L. CBC includes hemoglobin, platelet count, 
WBC count, and absolute neutrophil count (ANC). 
11 If bone marrow biopsy and aspirate with cytogenetics and JAK2 V617F studies were performed as standard of care < 30 days prior to the patient signing 
consent procedure need not be repeated. 
12 Need to be submitted for central review.  See Section 17 for details.
13Only in patients achieving CI, PR or CR per IWG-MRT criteria (See Section 11) for Arms A, B,C, E, F and G, and for patients achieving <5% peripheral blood 
blast percentage, for Arm D. The bone marrow examination can be performed earlier if patients were to achieve responses earlier or per investigator 
discretion.  For the extension phase, only perform as clinically indicated.
14 Follow-up for survival status, disease follow-up status, notice of first relapse or progression in event monitoring phase, notice of first subsequent treatment and 
notice of new primary malignancy.  Patients will be initially followed every 3 months (±7 days) after study completion or early treatment termination until 
progressive disease or subsequent treatment for MF. Patients will then be followed every 6 months (±7 days). Follow-up during the Event Monitoring Phase 
can be completed via telephone call. The Event Monitoring Phase of the study will be considered complete once the last patient has completed study 
treatment.




Protocol CP14B019, Amendment 13
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5.
GROUPING FACTORS
All study arms (A, B, C, D, E, F, and G) are now permanently closed to enrollment.
6.
REGISTRATION/RANDOMIZATION PROCEDURES
6.1.
Registration Procedures
1. To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The   registration/randomization application 
is available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at 
between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday).
The instructions for the registration/randomization application are available on the 
MCCC web page (http://hsrwww.mayo.edu/ccs/training) and detail the process for 
completing and confirming patient registration.  Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent.  Patient registration via the registration/randomization application can be 
confirmed in any of the following ways:

Contact the MCCC Registration Office 
  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration.

Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.”
2. Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
.  If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved.
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary.


Protocol CP14B019, Amendment 13
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3. Prior to accepting the registration, the registration/randomization application will verify 
the following:

IRB approval at the registering institution

Patient eligibility

Existence of a signed consent form

Existence of a signed authorization for use and disclosure of protected health 
information (U.S.A. institutions only) [delete parenthetical expression (only) when 
not applicable, i.e. no non-USA participants]
4. Treatment on this protocol must commence at Mayo Clinic Rochester under the 
supervision of a hematologist.
5. Treatment cannot begin prior to registration and must begin 7 days after registration.
6. Pretreatment tests/procedures (see Section 4) must be completed within the guidelines 
specified on the test schedule.
7. All required baseline symptoms (see Section 10.6) must be documented and graded.
8. Study drug is available on site.
7.
PROTOCOL TREATMENT
7.1.
Treatment Schedule 
7.1.1.
Imetelstat Treatment
This is a single center, open-label study of imetelstat in patients with Intermediate-2 or high risk 
PMF/post-ET/PV MF (Arms A, B, C, E and F) or blast-phase MF (Arm D only) or spliceosome-
mutated (or with ring sideroblasts) MDS/MPN (Arm G only).
Imetelstat will be administered as a 2-hour IV infusion (± 10 minutes).  The current weight will 
be used to calculate the dose of imetelstat.  All patients must be premedicated prior to imetelstat 
administration. 
As of 22 January 2014, all arms are permanently closed to accrual.


Protocol CP14B019, Amendment 13
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7.1.1.1.
Arm A Treatment Schedule
(Arm A permanently closed to accrual)
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 
days1
Imetelstat
9.4 mg/kg
IV as 2 hour 
infusion
12,3
Every 21 days
1 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study 
end. The study will end when all subjects have discontinued study drug, the last patient enrolled has been treated 
for 5 years, or imetelstat is commercially available in the United States, whichever occurs first.
2 If the patient has not achieved a CR or PR, by the end of Cycle 6, the dosing frequency may be increased to up to 
weekly using the current dose level at the discretion of the Investigator. The patient must be tolerating the current 
dose level without significant toxicity.  Increase in dosing frequency is only allowed after Cycle 6.  The cycle 
length will be 21-28 days.  If the dosing frequency is increased to once weekly, the cycle length will remain 21 
days.  If the dosing frequency is increased to once every 2 weeks, the cycle length will be 28 days.
3 For patients whose response has plateaued for a minimum of 3 months, the dosing frequency may be reduced after 
Cycle 6 and the cycle length will be the length of the dosing interval.  For example, if the dosing frequency is 
decreased to once every 3 months, the cycle length will be 84 days. Dosing can also be interrupted until relapse 
and restarted, in such patients, per physician discretion.  In the case of interruption, a cycle will be 3 months while
treatment is held and the patient will restart at the dose level/schedule they were receiving at the time of 
interruption.
7.1.1.2.
Arm B Treatment Schedule
(Arm B permanently closed to accrual)
Induction: Cycle 1
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days
Imetelstat
9.4 mg/kg
IV as 2 hour 
infusion
1, 8, 15
Cycle 1 is 21 days
Maintenance: Cycles 2 and beyond1
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days
Imetelstat
9.4 mg/kg
IV as 2 hour 
infusion
12,3
Every 21 days (Cycles 2
and beyond)
1 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study 
end. The study will end when all subjects have discontinued study drug, the last patient enrolled has been treated 
for 5 years, or imetelstat is commercially available in the United States, whichever occurs first.
2 If the patient has not achieved a CR or PR, by the end of Cycle 6, the dosing frequency may be increased to up to 
weekly using the current dose level at the discretion of the Investigator. The patient must be tolerating the current 
dose level without significant toxicity.  Increase in dosing frequency is only allowed after Cycle 6.  The cycle 
length will be 21-28 days.  If the dosing frequency is increased to once weekly, the cycle length will remain 21 
days.  If the dosing frequency is increased to once every 2 weeks, the cycle length will be 28 days.
3 For patients whose response has plateaued for a minimum of 3 months, the dosing frequency may be reduced after 
Cycle 6 and the cycle length will be the length of the dosing interval.  For example, if the dosing frequency is 
decreased to once every 3 months, the cycle length will be 84 days. Dosing can also be interrupted until relapse 
and restarted, in such patients, per physician discretion.  In the case of interruption, a cycle will be 3 months while 
treatment is held and the patient will restart at the dose level/schedule they were receiving at the time of 
interruption.


Protocol CP14B019, Amendment 13
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7.1.1.3.
Arms C and D Treatment Schedule
(Arms C and D permanently closed to accrual)
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days1
Imetelstat
9.4 mg/kg
IV as 2 hour 
infusion
1, 8, 15, 222
Every 28 days
1 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study 
end. The study will end when all subjects have discontinued study drug, the last patient enrolled has been treated 
for 5 years, or imetelstat is commercially available in the United States, whichever occurs first.
2 For patients without response after the first two cycles, dosing might be increased to either Days 1, 3, 5 or Days 1,
3 every 2 to 4 weeks, per physician discretion. For patients whose response has plateaued for a minimum of 3 
months, the dosing frequency may be reduced after Cycle 6 and the cycle length will be the length of the dosing 
interval.  For example, if the dosing frequency is decreased to once every 3 months, the cycle length will be 84 
days.  Dosing can also be interrupted until relapse and restarted, in such patients, per physician discretion.  In the 
case of interruption, a cycle will be 3 months while treatment is held and the patient will restart at the dose 
level/schedule they were receiving at the time of interruption.
NOTE:  As of Addendum 3, Arms A, B, and C are permanently closed to accrual.  The 11 
patients slotted to be enrolled in Arm C will now be treated with either the Arm A (if 
spliceosome-mutated/with ring sideroblasts) or Arm B (if spliceosome unmutated) treatment 
schedule.
7.1.1.4.
Arms E and G Treatment Schedule
(Arms E and G permanently closed to accrual)
Induction Cycle 1 and 2 Dosing
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days
Imetelstat
7.5 mg/kg
IV as 2 hour infusion
1
Cycle is 28 days
Maintenance:  Cycles 3 and beyond1
1 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study 
end. The study will end when all subjects have discontinued study drug, the last patient enrolled has been treated 
for 5 years, or imetelstat is commercially available in the United States, whichever occurs first.
If any one of the following criteria is met at the end of Cycle 2, then follow the Table 5 dosing
schedule below.  If no criteria are met, follow the instructions below. 

Greater than 75% reduction in leukocyte count

Greater than 75% reduction in platelet count

Greater than 50% reduction in spleen size in patients with baseline palpable 
splenomegaly of >5 cm

Greater than 2 gm/dL increase in hemoglobin level from baseline without transfusions


Protocol CP14B019, Amendment 13
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Table 5:
Arms E and G Dosing if Criteria met = Yes 
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days
Imetelstat
7.5 mg/kg
IV as 2 hour infusion
11,2
Cycle is 28 days
1 In patients who do not achieve CR or PR by the end of Cycle 4, the frequency of dosing may be increased to every 
week or every two weeks, at the physician’s discretion
2 For patients whose response has plateaued, without signs of further improvement, for a minimum of 3 months, 
dosing frequency may be reduced to every 2 to 3 months, or treatment may be interrupted until relapse and 
restarted, at the physician’s discretion.  In the case of interruption, a cycle will be 3 months while treatment is held 
and the patient will restart at the dose level/schedule they were receiving at the time of interruption.
Criteria met = No
Treat as specified in Arm F (Cycle 3 will start with Cycle 1 of Arm F dosing schedule)
7.1.1.5.
Arm F Treatment Schedule
(Arm F permanently closed to accrual)
Induction Cycle 1 and 2 Dosing
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days
Imetelstat
9.4 mg/kg
IV as 2 hour infusion
1 
Cycle is 28 days
Maintenance:  Cycles 3 and beyond1
1 Patients may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study 
end. The study will end when all subjects have discontinued study drug, the last patient enrolled has been treated 
for 5 years, or imetelstat is commercially available in the United States, whichever occurs first.
If any one of the following criteria is met at the end of Cycle 2, then follow the Table 6 dosing 
schedule below.  If no criteria are met, follow the Table 7 and Table 8 dosing schedule below. 

Greater than 75% reduction in leukocyte count

Greater than 75% reduction in platelet count

Greater than 50% reduction in spleen size in patients with baseline palpable 
splenomegaly of >5 cm

Greater than 2 gm/dL increase in hemoglobin level from baseline without transfusions
Table 6:
Arm F Dosing if Criteria met = Yes
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days
Imetelstat
9.4 mg/kg
IV as 2 hour infusion
1
Cycle  is 28 days


Protocol CP14B019, Amendment 13
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Table 7:
Arm F Dosing if Criteria met = No: Cycles 3 and 4
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days
Imetelstat
7.5 mg/kg
IV as 2 hour infusion
1 and 31,2
Cycle is 28 days
1 In patients who do not achieve CR or PR by the end of Cycle 4, the frequency of dosing may be increased to every 
two weeks, at physician’s discretion.
2 For patients whose response has plateaued, without signs of further improvement, for a minimum of 3 months, 
dosing frequency may be reduced to Day 1 every 28 days or Days 1, 3 every 2 to 3 months, or treatment may be 
interrupted until relapse and restarted, all at the physician’s discretion.  In the case of interruption, a cycle will be 3 
months while treatment is held and the patient will restart at the dose level/schedule they were receiving at the time 
of interruption.
Table 8:
Criteria met = No: Cycles 5 and beyond
Agent
Dose
Route
Day
Cycle (ReRx) ± 3 days
Imetelstat
7.5 mg/kg
IV as 2 hour infusion
1, 3, and 51, 2
Cycle is 28 days
7.2.
Pre-Medication
In Phase I studies, some patients experienced infusion-related reactions to imetelstat, including 
but not restricted to allergy/hypersensitivity reaction (e.g., rash, fever, urticaria, dyspnea, 
bronchospasm, chills/rigors, myalgias, headache, fatigue, nausea and/or vomiting) during or 
within 24 hours of an infusion.  Reactions were sporadic in nature and did not occur at a higher 
frequency with the first administration of imetelstat.  These reactions were usually mild to 
moderate and generally resolved with slowing or interruption of the infusion and with supportive 
care (diphenhydramine, corticosteroids, and/or IV saline).  The mechanism is not entirely clear 
but may involve complement activation. (See Section 8 for the Infusion reaction guidelines and
Appendix E.)
All patients will require premedication with diphenhydramine (2550 mg, PO or IV) and 
hydrocortisone (100 mg PO or IV) or equivalent before receiving imetelstat.


Protocol CP14B019, Amendment 13
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8.
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS
8.1.
Retreatment Criteria
Subjects may receive treatment for a maximum of 9 cycles during the “Core Phase” of the study. 
Subjects may be allowed to continue therapy beyond 9 cycles in an “Extension Phase” of the 
study if they do not meet any of the withdrawal criteria, do not have disease progression and are 
receiving some clinical benefit, at the discretion of the principle investigator. Patients may 
continue to receive imetelstat study treatment for as long as they derive clinical benefit or until 
study end. The study will end when all subjects have discontinued study drug, the last patient 
enrolled has been treated for 5 years, or imetelstat is commercially available in the United States, 
whichever occurs first.
Patients will be evaluated for safety and efficacy at the end of each cycle during both the core and 
extension phases of the study. 
8.2.
Dose Reduction
Once the need for dose reduction has been established (as per Table 11), treatment with 
imetelstat may be restarted, after reversal of drug-related toxicity (as per Table 11 ), with one 
level dose reduction, for patients receiving treatment every 21 days (see Table 10), or an increase 
in dosing interval (using the same drug dose) in patients receiving the drug every week; in the 
latter instance, dosing frequency is first increased to every two weeks and then to every 3 weeks, 
in case of recurrent toxicity that requires dose reduction (see Table 9). Once a dose reduction has
been instituted, the dose should not be re-escalated.
Table 9:
Dose Reductions
Dose Frequency
Action
Once weekly
Reduce to once every 2 or once every 4 weeks at same dose level
(dose level might also be decreased per physician discretion per
Table 10)
Once every 2 weeks
Reduce to once every 4 weeks at same dose level (dose level might 
also be decreased per physician discretion per Table 10)
Once every 3 weeks
Reduce one dose level per Table 10
Once every 4 weeks
Reduce one dose level per Table 10


Protocol CP14B019, Amendment 13
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Table 10:
Dose Levels (Based on Adverse Events in Table 9)
Dose Level
All arms
01
9.4 mg/kg D1 
-1
7.5 mg/kg D1 
-2
6 mg/kg D1 
1 Dose level 0 refers to the starting dose (except Arms E and G).
Table 11:
ALERT: Serious Adverse Event (SAE) reporting may be required for some 
adverse events (See Section 10)
ADVERSE EVENT/ 
laboratory test abnormality 
(must be at least possibly related to 
drug to qualify as a dose-modifying 
event)
AGENT
ACTION1
AT TIME OF RETREATMENT (i.e. imetelstat infusion beyond Day 1, Cycle 1)
Absolute neutrophil count (ANC)  <1.0 x 
109/L
Imetelstat
Hold imetelstat.2Restart at the next lower 
dose level (see Section 8.2), once ANC 
recovers to ≥1.0 x 109/L
Platelet count <50 x 109/L
Imetelstat
Hold imetelstat.2  Restart at the next lower 
dose level (see Section 8.2), once platelet 
count recovers to ≥ 50 x 109/L.
Absolute neutrophil count (ANC) <1.5 x 
109/L and also associated with >75% drop 
from ANC recorded at Day 1 of the 
previous cycle
Imetelstat
Hold imetelstat.2  Restart at the next lower 
dose level  (see Section 8.2), once ANC 
recovers to ≥ 1.5 x 109/L
Platelet count <100 x109/L and also 
associated with >75% drop from platelet 
count recorded at Day 1 of the previous 
cycle
Imetelstat
Hold imetelstat.  2Restart at the next lower 
dose level (see Section 8.2), once platelet 
count recovers to > 100 x 109/L.
SGOT (AST) and SGPT (ALT)  ≥ Grade 3 
Imetelstat
Hold imetelstat.  Restart at the next lower 
dose level see Section 8.2), if recovered to 
Grade 1 or less (or to pre-study baseline).
Total Bilirubin >3.0 mg/dL (or direct 
bilirubin 1≥ mg/dL)
Imetelstat
Hold imetelstat.  Restart at the next lower 
dose level (see Section 8.2), if recovered to 
Grade 1 or less (or to pre-study baseline).
Creatinine >3.0 mg/dL
Imetelstat
Hold imetelstat.  Restart at the next lower 
dose level (see Section 8.2), if recovered to 
Grade 1 or less (or to pre-study baseline).


Protocol CP14B019, Amendment 13
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ADVERSE EVENT/ 
laboratory test abnormality 
(must be at least possibly related to 
drug to qualify as a dose-modifying 
event)
AGENT
ACTION1
Allergic Reaction Grade 2
Imetelstat
Hold imetelstat.  Restart at the next lower 
dose level if adverse event reduced to <
Grade 1. Discontinue imetelstat if event 
reoccurs at lower dose.
Allergic Reaction Grade 3
Imetelstat
Discontinue imetelstat and go to event 
monitoring per Section 4
Any Grade 33
Imetelstat
Hold imetelstat.  Restart at the next lower 
dose level (see Section 8.2), if adverse event 
reduces to < Grade 2.
Any Grade 44
Hold imetelstat.  Restart at the next lower 
dose level (see Section 8.2), if adverse event 
reduces to < Grade 2.
1 Use the following to describe actions in the Action column:

Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient does not make 
up the omitted dose(s) at a later time

Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does make up the 
delayed dose(s) when the patient meets the protocol criteria to restart drugs. Hold for maximum of 28 days, 
and then contact principal investigator and medical monitor.

Discontinue = The specified drug(s) are totally stopped.
2 Not required for cohort D.
3 Except fatigue, nausea, vomiting, diarrhea and hyperuricemia that persist despite treatment with optimal anti-
diarrheals or anti-emetics.  Such toxicity will be taken into account, for dose holding only when it persists despite 
appropriate treatment. 
4 Except Grade 4 uric acid toxicity. Such toxicity will be taken into account for dose holding only when refractory 
to appropriate treatment.
In addition to any of the above toxicities, in the event of a drug-related Grade 2 or higher toxicity 
that the patient cannot tolerate or at the discretion of the Investigator, dosing may be reduced.
8.2.1.
Hepatoxicity

Diagnosis of a treatment emergent hepatic adverse event such as hepatitis, jaundice or 
other hepatic AEs or hepatic biochemistry abnormalities of clinical significance 
should lead to additional monitoring and an evaluation of ongoing benefit-risk with 
imetelstat; dose modification and/or study treatment termination should be considered 
in such cases and discussed with the medical monitor.  Consider a hepatic 
consultation if indicated. External experts may also be consulted by the sponsor to 
review each case individually. 

See Table 11 above for dose modifications. All imetelstat dose reductions due to
liver enzyme elevations are permanent.  


Protocol CP14B019, Amendment 13
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
Discontinue imetelstat permanently and enter follow-up if a significant hepatic event, 
including hepatic biochemistry abnormalities, indicating the potential for severe 
hepatic injury is observed without a more likely cause than study treatment.  Baseline 
liver laboratory abnormalities and clinical presentation should be taken into 
consideration.  Bilirubin should be fractionated and be primarily conjugated.
For patients who enter hepatic safety monitoring and follow up after imetelstat discontinuation 
refer to Table 4 for details of clinical parameters and duration of follow-up.  
8.3.
Infusion Reaction
The guidelines described in Table 12 should be followed for managing imetelstat infusion
reactions (See Appendix E).
Table 12:
Guidelines for Managing Infusion Reactions
Infusion Reaction
Management Guideline
Grade 1
Mild and transient (e.g., mild flushing, 
rash, pruritis, fever)
Evaluate and manage symptomatically as needed.
May complete infusion if reaction remains mild, with 
stable vital signs and does not worsen to Grade 2 or 
more.
Grade 2
Moderate (e.g., moderate flushing, rash, 
dyspnea, chest discomfort, hypotension)
Stop infusion
Manage symptomatically:

Administer diphenhydramine 25 mg and 
dexamethasone 10 mg IV, if required (particularly if 
not received within last 4 hours)

Consider IV fluids, acetaminophen, oxygen, 
bronchodilators etc.
After recovery, resume infusion at half the previous rate 
for 15 minutes

If no further symptoms occur, complete the infusion 
at the full dose rate

If symptoms recur, discontinue imetelstat  
Grade 3
Severe (not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion; recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae (e.g., renal impairment, 
pulmonary infiltrates)
Stop infusion 
Administer supportive care as indicated

Consider epinephrine, corticosteroids, 
diphenhydramine, IV fluids, acetaminophen, oxygen, 
bronchodilators, vasopressors, etc.
Discontinue imetelstat


Protocol CP14B019, Amendment 13
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Grade 4
Life-threatening (e.g., anaphylaxis, 
angioedema severe hypotension requiring 
vasopressors, respiratory distress 
requiring ventilator support)
Stop infusion
Administer supportive care as indicated
Discontinue imetelstat 
9.
ANCILLARY TREATMENT/SUPPORTIVE CARE

Antiemetics may be used at the discretion of the attending physician.

Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records.

Diarrhea:  This could be managed conservatively with loperamide.  The 
recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 
hours until diarrhea free (maximum 16 mg/day).

In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.  

If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever 
or severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or 
vomiting should be hospitalized for intravenous hydration and correction of 
electrolyte imbalances.
10.
ADVERSE EVENT (AE) REPORTING AND MONITORING
10.1.
Safety Parameters and Definitions
Safety assessments will consist of recording all adverse events (AEs) and serious adverse events 
(SAEs); protocol-specified hematology and clinical chemistry variables; measurement of 
protocol-specified vital signs; and the results from other protocol-specified tests that are deemed 
critical to the safety evaluation of imetelstat.
Janssen Research & Development or its designee is responsible for reporting relevant SAEs to 
the Competent Authority, other applicable regulatory authorities, and participating Investigators, 
in accordance with ICH guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements.


Protocol CP14B019, Amendment 13
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Janssen Research & Development or its designee is responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory agencies and 
competent authorities by telephone or fax within 7 calendar days after being notified of the event. 
Janssen Research & Development or its designee will report other relevant SAEs associated with 
the use of the study medication to the regulatory agencies and competent authorities by a written 
safety report within 15 calendar days of notification or other agreed upon timelines.
10.1.1.
Adverse Event
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational product or other protocol-imposed intervention, regardless of 
attribution.
During the extended hepatic safety follow-up, once patients have discontinued imetelstat 
treatment, an AE is defined as an unfavorable and unintended sign, symptom, or disease 
occurring during the follow-up period or temporally associated with a protocol-imposed 
intervention, regardless of attribution.
This includes the following:

AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with MF that were not 
present prior to the AE reporting period (see Section 10.2.1)

Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies)

AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
medication washout, or no treatment run-in)

Preexisting medical conditions, judged by the Investigator to have worsened in 
severity or frequency or changed in character during the protocol-specified AE 
reporting period
10.1.2.
Serious Adverse Event
An SAE is any AE that is any of the following:

Fatal (i.e., the AE actually causes or leads to death)

Life threatening (i.e., the AE, in the view of the Investigator, places the patient at 
immediate risk of death)

Requires or prolongs inpatient hospitalization

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions)


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
A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational product(s)

Considered a significant medical event by the Investigator (i.e., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs.
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of an AE 
(as in mild, moderate, or severe pain); the event itself may be of relatively minor medical 
significance (such as severe headache).  “Serious” is a regulatory definition and is based on 
patient or event outcome or action criteria usually associated with events that pose a threat to a 
patient’s life or vital functions.  Seriousness (not severity) serves as the guide for defining 
regulatory reporting obligations.
Severity and seriousness should be independently assessed when recording AEs and SAEs on the 
eCRF.
10.2.
Methods and Timing for Capturing and Assessing Safety Parameters
The Investigator is responsible for ensuring that all AEs and SAEs (as defined in Section 10.1)
are recorded on the eCRF and reported to the Sponsor in accordance with protocol instructions.
10.2.1.
Adverse Event Reporting Period
After initiation of imetelstat, all AEs and SAEs regardless of attribution will be collected until 
30 days following the last administration of study treatment or at study completion/early 
treatment termination. After this period, Investigators should report only SAEs that are felt to be 
related to study treatment, unless the patient is continuing on study for additional hepatic safety 
monitoring as defined in Section 10.3.1.10.
For patients who have discontinued imetelstat and are undergoing extended hepatic safety 
follow-up due to ongoing liver biochemistry abnormalities or hepatic AEs, monitoring and data 
collection, including all AEs and SAEs regardless of attribution, should continue as defined in 
Table 4.
See Section 10.6 for post-study AE reporting.




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To ensure consistency of causality assessments, the Investigator should apply the following 
general guidelines:
Table 14:
Causal Attribution Guidance
Is the AE/SAE suspected to be caused by the investigational product based on facts, evidence, science-
based rationales, and clinical judgment?
YES
The temporal relationship of the AE/SAE to investigational product administration makes a causal 
relationship possible, AND other drugs, therapeutic interventions or underlying conditions do not 
provide sufficient explanation for the AE/SAE.
NO
The temporal relationship of the AE/SAE to investigational product administration makes a causal 
relationship unlikely, OR other drugs, therapeutic interventions or underlying conditions provide a 
sufficient explanation for the AE/SAE.
Note: 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 the 2 kinds of 
erythroid and platelet responses be reported overall as well as by the individual response pattern.
10.3.
Procedures for Recording Adverse Events
10.3.1.
Recording Adverse Events on the eCRF
The Investigator should use correct medical terminology/concepts when recording AEs on the 
eCRF.  Avoid colloquialisms and abbreviations.
A separate Adverse Event eCRF should be used for each medical concept that needs to be 
recorded.
10.3.1.1.
Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE on a separate eCRF.  If a diagnosis is subsequently established, it 
should be reported to Janssen Research & Development per the CRF Completion Guidelines.
10.3.1.2.
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause.  For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE on the eCRF.
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the eCRF.  For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the eCRF.


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10.3.1.3.
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution between patient evaluation 
timepoints.  Such events should only be recorded once in the eCRF unless their severity 
increases.  If a persistent AE becomes more severe, it should be recorded again on the Adverse 
Event eCRF.
A recurrent AE is one that occurs and resolves between patient evaluation timepoints and 
subsequently recurs.  All recurrent AEs should be recorded on Adverse Event eCRF.
10.3.1.4.
Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs on the eCRF (e.g., abnormalities that require study drug dose modification, 
discontinuation of study treatment, more frequent follow-up assessments, further diagnostic 
investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5 ULN associated with cholecystitis), only the diagnosis 
(e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE on the eCRF.  If the laboratory abnormality can 
be characterized by a precise clinical term, the clinical term should be recorded as the AE.  For 
example, an elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, seriousness, or 
etiology changes.
10.3.1.5.
Deaths
All deaths that occur during the protocol-specified AE reporting period (see Section 10.1.2),
regardless of attribution, will be recorded on an eCRF and expeditiously reported to the Sponsor. 
This includes death attributed to progression of MF.
If the death is attributed to progression of MF, record “Mylefibrosis progression” as the SAE 
term on the SAE Report Form.
When recording a death on an eCRF or SAE Report Form, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept.  If the cause of 
death is unknown and cannot be ascertained at the time of reporting, record “Unexplained 
Death.”
10.3.1.6.
Preexisting Medical Conditions
A preexisting medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study.  When recording such events on an Adverse 


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Event eCRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., “more frequent headaches”).
10.3.1.7.
Worsening of MF
Worsening of and/or progression of MF should not routinely be recorded as an AE or SAE if not 
resulting in death. These data will be captured as efficacy assessment data. However worsening 
and/or progression of MF should be recorded an SAE if fatal (see Section 10.1.2 or if the
investigator assesses the disease progression to be related to imetelstat.   
10.3.1.8.
Hospitalization, Prolonged Hospitalization, or Surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE unless specifically instructed otherwise in this protocol.
There are some hospitalization scenarios that do not require reporting as an SAE when there is no 
occurrence of an AE.  These scenarios include a planned hospitalization or prolonged 
hospitalization to:

Perform an efficacy measurement for the study

Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed

Receive scheduled therapy for the target disease of the study
10.3.1.9.
Pregnancy
If a female patient becomes pregnant while receiving investigational therapy or within 90 days 
after the last dose of investigational product, a Pregnancy Notification Form should be 
completed, printed, and faxed to the Sponsor or its designee within 24 hours of learning of the 
pregnancy, using the fax numbers provided by the Sponsor.
Abortion, whether therapeutic or spontaneous, should always be classified as serious (as the 
Sponsor considers these medically significant), recorded on a Serious Adverse Event Form (SAE 
Form) and expeditiously reported to the Sponsor.
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a 
male patient exposed to the investigational product should be recorded and reported as an SAE.
10.3.1.10. Hepatic Adverse Events and Abnormal Liver Biochemistries
Abnormal liver biochemistries and hepatic AEs should be reported per routine protocol reporting 
procedures on the relevant eCRF (e.g., Adverse Event eCRF, chemistry CRF).
In the event a patient has discontinued imetelstat, but qualifies for the extended hepatic safety 
follow-up due to ongoing liver biochemistry abnormalities or hepatic AEs at the study 


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completion/early treatment termination visit, monitoring and data entry into the relevant eCRF 
(i.e., adverse event, laboratory data, and concomitant medications) should continue per the 
guidelines in Table 4.  These assessments should occur regardless of the initiation of alternate
MF treatments.
10.4.
Expedited Reporting Requirements for Serious Adverse Events
10.4.1.
Reporting Requirements for Fatal/Life Threatening SAEs Related to 
Investigational Product
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the Investigator 
to the investigational product will be telephoned to the Medical Monitor immediately, followed 
by submission of written case details on an SAE Form within 24 hours as described in 
Section 10.3.
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. 
10.4.2.
Reporting Requirements for All SAEs
All serious adverse events occurring during the study must be reported to the appropriate Sponsor 
contact person 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 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).
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 may be attributed to agents other than the study treatment or to factors unrelated to 
study conduct

It becomes unlikely that any additional information may 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)


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10.5.
Type and Duration of Follow-Up of Patients after Adverse Events
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
stabilized, are determined to be irreversible by the Investigator, the patient initiates alternate MF 
treatment (unless undergoing extended hepatic safety follow-up), the patient is lost to follow-up, 
or it has been determined that the study treatment is not the cause of the AE/SAE.  Resolution of 
AEs and SAEs (with dates) should be documented on the Adverse Event eCRF and in the 
patient’s medical record to facilitate source data verification (SDV).
The Sponsor or its designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate the 
SAE report (e.g., hospital discharge summary, consultant report, or autopsy report).
10.6.
Post-Study Adverse Events
For patients who discontinue the study and are not in the extended hepatic safety follow-up, the 
Investigator should report any death or other SAE occurring beyond 30 days following the last 
administration of study drug that the Investigator deems related to study drug.  
For patients undergoing extended hepatic safety follow-up, SAEs will continue to be collected 
regardless of attribution, beyond 30 days following the last administration of study drug, per the 
guidelines in Section 10.3.1.10.
The Investigator should also, upon becoming aware of, report the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that participated in this 
study.  
The Investigator should report these events on an SAE Form to the Sponsor as described in 
Section 10.3 above.


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11.
TREATMENT EVALUATION
11.1.
Myelofibrosis
Table 15:
Revised International Working Group for Myeloproliferative Neoplasms 
Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) 
response criteria for myelofibrosis.
Response
categories
Required criteria (for all response categories, benefit must last for ≥12 weeks in order to 
qualify as a response)
Complete
Remission
(CR)
Bone marrow: 1 Age-adjusted normocellularity; <5% blasts; ≤Grade 1 myelofibrosis2, AND
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; Neutrophil count ≥1 x 109/L and <UNL;
Platelet count ≥100 x 109/L and <UNL; <2% immature myeloid cells3, AND
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence of EMH
Partial
Remission
(PR)
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; Neutrophil count ≥1 x 109/L and <UNL;
Platelet count ≥ 100 x 109/L and <UNL; <2% immature myeloid cells3, AND
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence of EMH, 
OR
Bone marrow: 1 Age-adjusted normocellularity; <5% blasts; ≤Grade 1 myelofibrosis2, AND
Peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; Neutrophil count ≥1 x 109/L and 
<UNL;
Platelet count ≥50 but <100 x 109/L and <UNL; <2% immature myeloid cells3, AND
Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence of EMH
Clinical
Improvement
(CI)
The achievement of anemia, spleen or symptoms response without progressive disease or
increase in severity of anemia, thrombocytopenia or neutropenia4
Anemia
response
Transfusion-independent patients: a ≥20 g/L increase in hemoglobin level5
Transfusion-dependent patients: becoming transfusion-independent6
Spleen
response7
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable8, 
OR
A baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by ≥50%8
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for spleen 
response
Confirmation by MRI or CT showing ≥35% spleen volume reduction is recommended (but not 
required)


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Response
categories
Required criteria (for all response categories, benefit must last for ≥12 weeks in order to 
qualify as a response)
Progressive
disease9
Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM, OR
A ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 5 to 10 cm, 
OR
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 cm, OR
Leukemic transformation confirmed by a bone marrow blast count of ≥20%, OR
A peripheral blood blast content of ≥20% associated with an absolute blast count of ≥1 x 109/L 
that lasts for at least 2 weeks
Stable disease
Belonging to none of the above listed response categories
Relapse
No longer meeting criteria for at least CI after achieving CR, PR or CI, OR
Loss of anemia response persisting for at least one month, OR
Loss of spleen response persisting for at least one month
Key: CT = computed tomography; EMH = extramedullary hematopoiesis (no evidence of EMH implies the absence of 
pathology- or imaging study-proven non-hepatosplenic EMH); LCM = left costal margin; MRI = magnetic resonance 
imaging; UNL = upper normal limit
1 Baseline and post-treatment bone marrow slides are to be stained at the same time and interpreted at one sitting by 
a central review process. Cytogenetic and molecular responses are not required for CR assignment.
2 Grading of myelofibrosis is according to the European classification (Thiele et al. Haematologica 2005;90:1128) . 
It is underscored that the consensus definition of “a complete remission bone marrow” is to be used only in those 
patients where all other criteria, including resolution of leukoerythroblastosis, are met. It should also be noted that 
it was a particularly difficult task for the working group to reach a consensus regarding what represents a complete 
histological remission.
3 Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood 
cells. In splenectomized patients, <5% immature myeloid cells is allowed.
4 See table 15 for definitions of anemia response, spleen response and progressive disease. Increase in severity of 
anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in hemoglobin level from 
pre-treatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is 
defined as a 2-grade decline, from pre-treatment baseline, in platelet count or absolute neutrophil count, according 
to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In addition, assignment to clinical 
improvement (CI) requires a minimum platelet count of ≥25,000 x 109/L and absolute neutrophil count of ≥0.5 x 
109/L.
5 Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting the strict criteria for 
transfusion-dependency at the time of study enrollment (see below), but have received transfusions within the 
previous month, the pre-transfusion hemoglobin level should be used as the baseline
6 Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood 
cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in the absence of 
bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 
28 days prior to study enrollment. Response in transfusion dependent patients requires absence of any PRBC 
transfusions during any consecutive “rolling” 12-week interval during the treatment phase, capped by a hemoglobin 
level of ≥85 g/L.
7 In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy
8 Confirmation of spleen or liver responses by imaging studies is recommended (but not required), where a ≥35% 
reduction in spleen or liver volume, assessed by magnetic resonance imaging (MRI) or computed tomography 
(CT), is required for confirmation. Furthermore, a≥35% volume reduction in the spleen or liver, by MRI or CT, 
constitutes a response regardless of what is reported with physical examination.
Symptoms are evaluated by the Myeloproliferative Neoplasm Symptom Assessment Form total symptom score 
(MPN-SAF TSS). The MPN-SAF TSS is assessed by the patients themselves and includes fatigue, concentration, 


Protocol CP14B019, Amendment 13
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early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is 
from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF 
TSS is the summation of all the individual scores (0-to-100 scale). Symptoms response requires ≥50% reduction in 
the MPN-SAF TSS.
9 Confirmation by MRI or CT is recommended (but not required) to confirm progressive disease assignment for 
splenomegaly, where a ≥25% increase in spleen volume from baseline is required for confirmation. Baseline 
values for both physical examination and imaging studies refer to pre-treatment baseline and not to post-treatment 
measurements.
11.2.
MDS
The International Working Group response assessment as reported by Cheson et al. (2006) will 
be utilized.
Table 16:
Definition of Disease Response in MDS:
Category
Response Criteria 
Complete Remission (CR)
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines1
Persistent dysplasia will be noted1,2
Peripheral blood3
Hgb ≥ 11 g/dL
Platelets ≥ 100 x 109/L 
Neutrophils ≥ 1.0 x 109/L2
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
Stable Disease (SD)
Failure to achieve at least PR, but no evidence of progression for > 8 weeks
Failure (FAIL)
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a 
more advanced MDS FAB subtype than pretreatment
Relapse after CR or PR
At least 1 of the following:
Return to pretreatment bone marrow blast percentage
Decrement of ≥ 50% from maximum remission/response levels in 
granulocytes or platelets
Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence


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Category
Response Criteria 
Disease Progression (PD)
For patients with:
Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts
5%-10% blasts: ≥ 50% increase to > 10% blasts
10%-20% blasts: ≥ 50% increase to > 20% blasts
20%-30% blasts: ≥ 50% increase to > 30% blasts
Any of the following:
At least 50% decrement from maximum remission/response in 
granulocytes or platelets
Reduction in Hgb by ≥ 2 g/dL
Transfusion dependence
1 Dysplastic changes should consider the normal range of dysplastic changes (modification).
2 Modification to IWG response criteria.
3 In some circumstances, protocol therapy may require the initiation of further treatment (e.g., 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.
Table 17:
Proposed Modified International Working Group Response Criteria for 
Hematologic Improvement
Hematologic improvement1
Response criteria2
Erythroid response (pretreatment,< 
11 g/dL)
Hgb increase by ≥1.5 g/dL
Relevant reduction of units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 wk compared with the pretreatment transfusion 
number in the previous 8 wk. Only RBC transfusions given for a Hgb of 
≤9.0 g/dL
pretreatment will count in the RBC transfusion response evaluation2
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%2
Neutrophil response (pretreatment,
< 1.0 x 109/L)
At least 100% increase and an absolute increase > 0.5 X_109/L2
Progression or relapse after HI3
At least 1 of the following:
At least 50% decrement from maximum response levels in granulocytes 
or platelets
Reduction in Hgb by ≥1.5 g/dL
Transfusion dependence
Note: To convert hemoglobin levels from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
Hgb indicates hemoglobin; RBC: red blood cell; HI: hematologic improvement.
1 Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥ 1 week apart 
(modification).
2 Modification to IWG response criteria.
3 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 the 2 kinds of erythroid and platelet 
responses be reported overall as well as by the individual response pattern.


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12.
DESCRIPTIVE FACTORS

Category of MF (see Appendix B):  Primary Myelofibrosis vs. Post ET Myelofibrosis 
vs. Post PV Myelofibrosis vs. blast-phase MF vs MDS/MPN or MDS

DIPSS-plus risk (see Appendix A):  High-risk MF vs. Intermediate-2 risk MF
13.
TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF 
PATIENT
Patients who are CR, PR, CI, or SD will continue treatment per protocol.
Patients will be discontinued from treatment and go to event-monitoring phase per Section 4 for
any of the following reasons:

Disease progression (Except relapse that occurs during dose interruption).

Leukemic transformation (as per WHO criteria)

Any clinical adverse event, laboratory abnormality, intercurrent illness or other 
medical condition or situation which occurs such that continued participation in the 
study would not be in the best interest of the participant

Hepatotoxicity criteria for treatment discontinuation (see Section 8.2.1)

Pregnancy

Diagnosis of positive status for HIV or hepatitis B or C

Continued failure to comply with study procedures or use of the drug as specified in 
the study protocol such that continued participation in the study would not be in the 
best interest of the participant

Withdrawal of consent

Initiation of non-protocol therapies

Administrative decision by investigator or sponsor
A patient is deemed ineligible if after registration, it is determined that at the time of registration, 
the patient did not satisfy each and every eligibility criteria for study entry.  The patient may 
continue treatment off-protocol at the discretion of the physician as long as there are no safety 
concerns, and the patient was properly registered. The patient will go directly to the event-
monitoring phase of the study. 






Protocol CP14B019, Amendment 13
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24 hrs post-treatment of 5.54 μg/mL.  This confirmed the presence of imetelstat in the 
target tissue, bone marrow, after IV administration to MM patients.
b. Distribution – Vdss ranged from 41/3 to 71.2 mL/kg at doses of 4.8 to 11.7 mg/kg.
c.
Excretion – T1/2 following a single-dose ranged from 4 to 5 hours.  Similar to other 
oligonucleotides, imetelstat excretion is probably mainly via the urinary tract 
following metabolism of the oligonucleotide sequence into smaller fragments.  Based 
on a preliminary population pharmacokinetic analysis of 59 patients who received 2-
or 6-hour weekly IV infusions of imetelstat 0.4 to 11.7 mg/kg (30−1155 mg) or 
20−240 mg/m2 (37.4−516 mg), the estimated CL of imetelstat varied by body size 
(body weight or BSA) and dose. After correcting for body size, the CL at a BSA of 
1.86 m2 was 0.206 L/hr and total CL was 0.84 L/hr at a dose of 9.4 mg/kg (≈ 380 
mg/m2).
15.1.6.
Potential Drug Interactions
To date, no known drug interactions have been identified with imetelstat treatment.
15.1.7.
Safety Experience
Refer to Section 1.3.4 for safety experience. 
For further details, see the Imetelstat Investigator’s Brochure.
15.1.8.
Drug Procurement
Imetelstat will be provided free of charge to study participants by Janssen Research & 
Development.
15.1.9.
Nursing Guidelines
As drug is early in development, not all side effects can be known at this time. Monitor patients 
carefully and instruct patient to report any side effects to the treating physician and/or study team 
immediately.
In Phase I studies cytopenias (thrombocytopenia and neutropenia) were the primary dose-limiting 
side effects especially when administered with other cytotoxic agents. Monitor CBC 
w/differential closely. Instruct patients in signs and symptoms of infection and to report any 
unusual bruising or bleeding to the study team immediately.
Infusion reactions have been seen and are usually mild-moderate in nature. These usually occur 
shortly after infusion initiation and can occur with subsequent cycles, despite tolerability of 
previous cycles. Have emergency medications on hand and administer at the physician’s 
discretion (See Section 8.3 and Appendix E).
Patients may experience prolonged aPTT times. Instruct patients to report any unusually 
bleeding to study team immediately.


Protocol CP14B019, Amendment 13
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Gastrointestinal side effects (diarrhea, nausea, vomiting, etc.) have been seen (See Section 9).
Treat symptomatically and monitor for effectiveness.
Fatigue is common.  Instruct patient in energy conserving lifestyle.
16.
STATISTICAL CONSIDERATIONS AND METHODOLOGY 
Overview:  This protocol will assess the efficacy of different schedules of imetelstat in six 
cohorts of patients with myelofibrosis (including blast-phase disease in Arm D) and one cohort 
of patients with MDS/MPN or MDS with spliceosome mutations or ring sideroblasts using a 
phase II study design in each arm independently.
Descriptive statistics will be used to summarize baseline patient characteristics, treatment 
administration, efficacy, and safety outcomes.  Descriptive summaries of discrete data will 
present the number of patients and the incidence as a frequency and as a percentage.  Descriptive 
summaries of continuous data will present the group mean, standard deviation, median, 
minimum, maximum, and sample size.  
For regulatory reporting purposes, there are two time points for the analyses:  (1) the primary 
analysis 48 weeks after the last patient has been enrolled, and (2) the final analysis after all 
patients have completed the study.  A separate and detailed statistical analysis plan (SAP) 
developed prior to primary analysis will supersede analyses specified in the protocol.  Deviations 
from the SAP will be noted in the final study report.  
Primary Endpoint: The primary endpoint in each arm of this trial is overall response rate.  
Overall response will be defined as a CI, PR, or CR (for Arms A, B, C, E, and F) according to the 
IWG-MRT consensus criteria for MF, or as a HI, PR or CR (for Arm G) according to the IWG 
consensus criteria for MDS, or the achievement of <5% peripheral blood and bone marrow blast 
% that lasts for at least two months (for Arm D).
16.1.
Statistical Design (To Be Evaluated Independently in Each Arm)
In a phase II study conducted at Mayo Clinic including 27 myelofibrosis patients treated with 
single agent Lenalidomide, 37% of patients responded in terms of anemia or splenomegaly. In a 
similar study conducted at M.D. Anderson Cancer Center, a response rate of 24% in terms of 
anemia or splenomegaly was seen in 41 myelofibrosis patients also treated with single agent 
lenalidomide (Tefferi et al. 2006). A response rate similar to or better than Lenalidomide would 
be of interest for myelofibrosis patients treated with single agent Imetelstat. Although this study 
also includes response in terms of platelets or ANC, we would expect the majority of these 
patients to also have a response in terms of anemia or splenomegaly. In addition, we would 
expect patients with MDS/MPN or MDS with spliceosome mutations or ring sideroblasts to 
show similar outcomes to myelofibrosis.  Therefore, an overall response rate of 30% would be 
considered early evidence of promising activity, for Arms A, B, C, E, F, and G. For Arm D, 20% 
response rate would be considered promising based on our single institutional experience of 91 


Protocol CP14B019, Amendment 13
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patients with blast phase MF (Mesa et al. 2005); in the particular study, induction chemotherapy
resulted in 0% CR and short-lived reversal to chronic phase disease in 41%. 
Arms A, B, C, D, and G:  The largest success proportion where the proposed treatment regimen 
would be considered ineffective in this population is 10%, and the smallest success proportion 
that would warrant subsequent studies with the proposed regimen in this patient population is 
30%. The following two-stage Simon optimum design (Simon 1989) uses 11 or 26 patients to 
test the null hypothesis that the true success proportion in a given patient population is at most 
10%.
16.2111Stage 1: Enter 11 patients into each arm of the study (i.e. 11 patients each in Arms A, B, 
C, D, and G). If 0 or 1 successes are observed in the first 11 evaluable patients for each arm of 
the study, we will consider the regimen ineffective and terminate the particular arm of the study. 
Otherwise, if the number of successes is at least 2, we will proceed to Stage 2.
Stage 2: Enter an additional 15 patients into each arm of the study. If 4 or fewer successes are 
observed in the first 26 evaluable patients, considering each arm of the study separately, we will 
consider this regimen ineffective as it applies to the particular arm of the study. If 5 or more 
successes are observed in the first 26 evaluable patients, we may recommend further testing of 
this regimen in subsequent studies in this population.
Power and Significance Level: Assuming that the number of successes is binomially distributed, 
with a significance level of 9%, the probability of declaring that the regimen warrants further 
studies (i.e., statistical power) under various success proportions and the probability of stopping 
accrual after the first stage can be tabulated as a function of the true success proportion as shown 
in the table below.
If the true success proportion is…
0.10
0.15
0.20
0.25
0.30
Then the probability of declaring that 
the regimen is promising and warrants 
further study is…
0.09
0.28
0.52
0.72
0.85
And the probability of stopping after 
the first stage is…
0.70
0.49
0.32
0.20
0.11
As of Addendum 3, accrual to Arm C will be permanently discontinued due to preliminary 
evidence showing difference in outcome based on presence vs. absence of spliceosome 
mutations. The 11 patients slotted to enroll on Arm C will now be treated per the Arm A or Arm 
B dose schedule and then Arms A and B will permanently close. A total of 34 patients will be 
accrued between Arms A, B, and C. Due to incomplete accrual in these arms, the 33 evaluable 
patients that have been accrued to these arms will be combined and reported together as a pilot 
study. Since this group will not have a formal statistical design, the reporting of results in this 
group will be primarily descriptive in nature.
Arms E and F:  The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 10%, and the smallest success proportion that would 
warrant subsequent studies with the proposed regimen in this patient population is 30%.  The 


Protocol CP14B019, Amendment 13
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following one-stage binomial design uses 25 patients to test the null hypothesis that the true 
success proportion in a given patient population is at most 10%.
Final Decision Rule:  If 4 or fewer successes are observed in the first 25 evaluable patients, we 
will consider this regimen ineffective in this patient population. If 5 or more successes are 
observed in the first 25 evaluable patients, we may recommend further testing of this regimen in 
subsequent studies in this population.
Power and Significance Level: Assuming that the number of successes is binomially distributed, 
with a significance level of 10%, the probability of declaring that the regimen warrants further 
studies (i.e., statistical power) under various success proportions can be tabulated as a function of 
the true success proportion as shown in the table below.
If the true success proportion is…
0.10
0.15
0.20
0.25
0.30
Then the probability of declaring that 
the regimen is promising and warrants 
further study is…
0.10
0.32
0.58
0.79
0.91
Over Accrual: If more than the target number of patients are accrued, the additional patients will 
not be used to evaluate the stopping rule or used in any decision making process. Analyses 
involving over accrued patients are discussed in Section 16.6.
Sample Size:  As of Addendum 3, accrual to Arm C will be permanently discontinued.  The 11 
patients slotted to enroll on Arm C will now be treated per the Arm A or Arm B dose schedule.  
A total of 34 patients will be accrued between Arms A, B, and C.  Accrual will continue per 
protocol in Arm D and three additional arms (Arms E, F, and G) will be added.  A total of 26 
evaluable patients (Arms D and G) or 25 evaluable patients (Arms E and F) will be accrued in 
each of the remaining arms.  An additional 3 patients will be accrued in each arm to account for 
patients who need to be replaced.  Therefore, the maximum overall sample size across all arms of 
the study is now 148 patients.
As of 22Jan2014 study is closed to enrollment with a total of 80 patients enrolled.
Accrual Rate and Study Duration:  As of 22Jan2014, all arms have permanently discontinued 
accrual.  The 11 patients slotted to enroll on Arm C will now be treated per the Arm A or Arm B 
dose schedule.  
Other considerations:  Adverse events, quality/duration of response, and patterns of treatment 
failure observed in this study, as well as scientific discoveries or changes in standard care will be 
taken into account in any decision to terminate the study
16.2.
Analysis Plan
For regulatory reporting purposes, the primary analysis will commerce 48 weeks after the last 
patient has been enrolled, and the final analysis after all patients have completed the study.  
Analysis of patients with blast-phase MF (Arm D) and those with MDS/MPN or MDS (Arm G) 
will be performed and presented separately.


Protocol CP14B019, Amendment 13
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16.3.
Primary Outcome Analyses(to be evaluated in each arm 
independently)
Definition:  The primary endpoint in each arm of this trial is the overall response rate.  For Arms 
A, B, C, E, and F overall response is defined to be a CI, PR, or CR noted as the objective status 
according to the IWG-MRT consensus criteria for MF.  Response in Arm G is defined as HI, PR 
or CR according to the IWG criteria for MDS (Cheson et al. 2006).  Response in Arm D is 
defined by a durable (2 months or more) decrease in peripheral blood and bone marrow blast 
percentage to less than 5%. All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for overall response.
Estimation:  The proportion of successes will be estimated in each arm by the number of 
successes divided by the total number of evaluable patients. Ninety-five percent Clopper-
Pearson exact binomial confidence intervals for the true success proportion will be calculated. 
16.4.
Secondary Outcome Analyses (to Be Evaluated in Each Arm 
Independently)
16.4.1.
Adverse Events
All eligible patients that have initiated treatment will be considered evaluable for assessing 
adverse event rate(s).  The maximum grade for each type of adverse event will be recorded for 
each patient, and frequency tables will be reviewed to determine patterns.  Additionally, the 
relationship of the adverse event(s) to the study treatment will be taken into consideration.  
16.4.2.
Spleen Response
Spleen response is defined as either a minimum 50% reduction in palpable splenomegaly of a 
spleen that is at least 10 cm at baseline or a spleen that is palpable at less than 10 cm but more 
than 5 cm at baseline becomes not palpable. Spleen size will be measured by physical 
examination (palpable distance from the left costal margin) at baseline and as part of each 
response assessment. The proportion of patients achieving spleen response per the IMG-MRT 
criteria (Section 11) will be calculated by the number of patients who achieve spleen response 
divided by the total number of evaluable patients with spleen involvement at baseline (estimated 
to be approximately 80% of patients).  Same method will be applied to splenectomized patients
for assessment of hepatomegaly response. Ninety-five percent Clopper-Pearson exact binomial 
confidence intervals for the true proportion of patients with spleen response will be calculated.
16.4.3.
Transfusion-Independence
Transfusion dependency is defined by a history of at least 2 units of red blood cell transfusions in 
the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically 
overt bleeding (see IWG-MRT criteria; Section 11). The proportion of patients achieving 
transfusion independence during the first 9 cycles of treatment will be estimated by the number
of patients who achieve transfusion independence divided by the total number of evaluable 
patients who were transfusion dependent at baseline.  Ninety-five percent Clopper-Pearson exact 


Protocol CP14B019, Amendment 13
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binomial confidence intervals for the true proportion of patients who become transfusion 
independent will be calculated. The same statistical method will be applied to anemia response 
for Arms A, B, E and F per IWG-MRT for myelofibrosis (Tefferi et al. 2013) and erythroid 
response for Arm G per IWG response criteria for MDS (Cheson et al. 2006).
16.4.4.
Durability of Response
Durability overall response will be estimated using the Kaplan-Meier method. Approximate 95%
confidence intervals for median duration of response will be computed using the formula 
proposed by Brookmeyer and Crowley.  The same method will be applied to hepatosplenic 
response and anemia response for Arms A, B, E, F, and D and erythroid response for Arm G. 
16.5.
Exploratory Outcomes (to Be Evaluated in Each Arm 
Independently)
Due to the small overall sample size, the results of the following analyses will be considered 
exploratory and hypothesis-generating in nature.
16.5.1.
Bone Marrow Histology and JAK2V617F Allele Burden
Bone marrow fibrosis and granulocyte JAK2V617F allele burden will be assessed for all patients 
at baseline and at the time of the response bone marrow examination for patients who achieve a 
CR, PR, or CI for Arms A, B, C, E, and F, CR, PR, and HI for Arm G and for patients achieving 
durable (2 months or more) decrease in peripheral blood and bone marrow blast to less than 5% 
for Arm D.  Bone marrow fibrosis grade will be evaluated by a central review pathologist and the 
fibrosis grade will be confirmed by the PI. The proportion of patients achieving reversal of bone 
marrow fibrosis to a lower grade will be assessed and reported descriptively.  JAK2V617F allele 
burden will be summarized descriptively at each time point and changes over time will be 
evaluated.
16.5.2.
Leukocytosis, Thrombocytosis, Peripheral Blood Blast and Immature Cell Count
The proportion of patients with baseline leukocytosis, thrombocytosis or increased peripheral 
blood blast or immature cell count, who achieve normalization or at least a 50% reduction in 
their counts will be calculated and reported descriptively
16.6.
Over Accrual
If more than the target number of patients are accrued, the additional patients will be included in 
final endpoint estimates and confidence intervals.
16.7.
Data and Safety Monitoring
A safety committee internal to Janssen Research & Development will review the safety data after 
approximately every 3 months until all patients have terminated from the study.  The safety 
review committee will consist of a study responsible physician, safety physician and a 


Protocol CP14B019, Amendment 13
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biostatistician.  The findings of the safety committee will be shared with the study Investigator.  
The study responsible physician or safety physician may convene a meeting sooner should any 
concerns arise from review of data or from the Investigator.
In addition to the safety committee, an independent hepatic safety panel will review emergent 
relevant safety data, if needed.  If there is evidence that imetelstat is responsible for the 
occurrence of a life-threatening, irreversible, or fatal hepatotoxicity a full investigation will be 
conducted on the data available for imetelstat treatment of patients with myelofibrosis.  The 
investigation may include, but is not limited to, a benefit-risk analysis with external adjudication 
by the hepatic safety panel and other specialties as necessary.  Trial modifications, including trial 
closure, will be considered based on the results of this investigation.
16.8.
Adverse Event Stopping Rules (to Be Evaluated in Each Arm 
Independently)
The stopping rules specified below are based on the knowledge available at study development.  
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the 
study re-opening to accrual or (2) at any time during the conduct of the trial and in consideration 
of newly acquired information regarding the adverse event profile of the treatment(s) under 
investigation.  The study team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below.
Accrual will be temporarily suspended to this study if at any time we observe events considered 
at least possibly related to study treatment (i.e. an adverse event with attribute specified as  
“possible”, “probable”, or “definite”) that satisfy either of the following:

If 3 or more out of the first 10 treated patients experience Grade 4 non-hematological 
toxicities

If after the first 10 patients have been treated, 30% of patients experience Grade 4
non-hematologic toxicities
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or “unlikely to be 
related”, to verify their attribution and to monitor the emergence of a previously unrecognized 
treatment-related adverse event.
At study activation, this study will have been registered within the “ClincialTrails.gov” web site. 
The Primary and Secondary Endpoints (i.e., “Outcome Measures”) along with other required 
information for this study will be reported on ClinicalTrials.gov. 
16.9.
Inclusion of Women and Minorities
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin.
There is no information currently available regarding differential effects of this regimen in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences to 


Protocol CP14B019, Amendment 13
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exist. Therefore, although the planned analysis will, as always, look for differences in treatment 
effect based on racial and gender groupings, the sample size is not increased in order to provide 
additional power for subset analyses.
The geographical region served by MCCC has a population which includes approximately 3% 
minorities. Based on prior MCCC studies involving similar disease sites, we expect about 3% of 
patients will be classified as minorities by race and about 50% of patients will be women. 
Expected sizes of racial by gender subsets are shown in Table 18 below.
Table 18:
Expected Sizes of Racial by Gender Subsets
Ethnic Category
Sex/Gender
Females
Males
Unknown
Total
Hispanic or Latino
1
1
0
2
Not Hispanic or Latino
73
73
0
146
Unknown
0
0
0
0
Ethnic Category: Total of all subjects
74
74
0
148
Racial Category
American Indian or Alaskan Native
0
0
0
0
Asian
0
0
0
0
Black or African American
2
2
0
4
Native Hawaiian or other Pacific Islander
0
0
0
0
White
72
72
0
144
More than one race
0
0
0
0
Unknown
0
0
0
0
Racial Category: Total of all subjects
74
74
0
148
Ethnic 
Categories:
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, or other 
Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used in addition to 
“Hispanic or Latino.”
Not Hispanic or Latino
Racial 
Categories:
American Indian or Alaskan Native – a person having origins in any of the original peoples of North, 
Central, or South America, and who maintains tribal affiliations or community attachment.
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, or the 
Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, 
the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have been 
recorded as Pacific Islanders in previous data collection strategies.) 
Black or African American – a person having origins in any of the black racial groups of Africa. Terms 
such as “Haitian” or “Negro” can be used in addition to “Black or African American.”
Native Hawaiian or other Pacific Islander – a person having origins in any of the original peoples of 
Hawaii, Guam, Samoa, or other Pacific Islands.
White – a person having origins in any of the original peoples of Europe, the Middle East, or North 
Africa.


Protocol CP14B019, Amendment 13
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17.
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS
Central review of the bone marrow will be performed by Dr.
at the Mayo Clinic in 
Rochester, MN. Fibrosis grading and other histology changes will be documented.  
17.1.
Tissue and Biospecimen Submission
Table 19:
Summary Table of Tissue Biospecimens for this Protocol
Type of Tissue 
Biospecimen to 
Submit
Mandatory 
or Optional
When to Submit
Reason for Submission
Initial Bone 
Marrow Biopsies
Mandatory
Patients who achieve a CR, PR, or 
CI in the core phase (Cycles 1-9)1:  
Submit with the response bone 
marrow biopsy
Patients who do not achieve a CR, 
PR, or CI in the core phase (Cycles 
1-9):  Submit at the end of Cycle 9 
or at the time of early 
discontinuation if patient receives < 
9 cycles
Central review to evaluate 
extent of marrow 
involvement by 
myelofibrosis, bone marrow 
cellularity and percentage of 
blasts and ring sideroblasts
Response Bone 
Marrow Biopsies
in patients who 
achieve a CR, PR, 
or CI during the 
core phase
Mandatory
≤30 days after response bone 
marrow biopsy
Central review to evaluate 
extent of marrow 
involvement by 
myelofibrosis, bone marrow 
cellularity and percentage of 
blasts and ring sideroblasts
1 During the core phase 9 cycles, PR, or CI by the end of Cycle 9:  Submit at the end of Cycle 9 or at the time of 
early discontinuation.
17.2.
Initial and Response Evaluation Materials
Submit the following materials to Dr. 
:

8-10 unstained and charged slides (or tissue block) from each bone marrow biopsy

Bone Marrow Form for each bone marrow being submitted

Baseline and Response Bone Marrow Biopsy Report
Slides should be placed in appropriate slide container(s) and labeled with the protocol number, 
study patient number, and patient initials.


Protocol CP14B019, Amendment 13
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The pathologist will forward the completed Bone Marrow Form and accompanying reports to the 
study QAS for scanning and data entry purposes to the following:
QAS for CP14B019 (formerly MC1285)
200 First Street SW
NW Clinic 3-24
Rochester, MN 55905
Phone:
Refer to Test Schedule (Section 4). Data will be collected using an electronic data capture
system (EDC) based upon pre-specified electronic case report forms (eCRFs) and completion 
guidelines (CCGs).


Protocol CP14B019, Amendment 13
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IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood 2006;108(5):1497-503.
Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health 
Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22(1):14-22.
Terasaki Y, Okumura H, Ohtake S, Nakao S. Accelerated telomere length shortening in granulocytes: a diagnostic 
marker for myeloproliferative diseases. Exp Hematology 2002;30: 1399–404.
The Commission of the European Communities, Commission Directive 2005/28/EC.
The European Parliament and the Council of the European Union, Directive 2001/20/EC.


Protocol CP14B019, Amendment 13
Page 85 of 90
APPENDIX A. DIPSS-PLUS RISK CATEGORIES IN MYELOFIBROSIS.
The Dynamic International Prognostic Scoring System (DIPSS)-plus prognostic model for primary myelofibrosis 
(PMF). The DIPSS-plus prognostic model for PMF uses 8 risk factors to predict survival: age >65 years, 
hemoglobin level <10 g/dL, leukocyte count >25 × 109/L, circulating blasts ≥ 1%, presence of constitutional 
symptoms, presence of unfavorable karyotype, platelet count <100 × 109/L, and the presence of red cell transfusion 
need. 
*
Transfusion dependency is defined by a history of at least 2 units of red blood cell transfusions in the last month 
for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding.  Please note 
that a transfusion-dependent patient automatically has 2 risk factors because of transfusion need (1 risk point) 
and hemoglobin level <10 g/dL (1 risk point). 
**
Constitutional symptoms constitute weight loss >10% of baseline value in the year preceding diagnosis, 
unexplained fever, or excessive sweats persisting for >1 month.
*** Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include +8, −7/7q−, i(17q), 
inv(3), −5/5q− 12p−, or 11q23 rearrangement.


Protocol CP14B019, Amendment 13
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APPENDIX B. WORLD HEALTH ORGANIZATION (WHO) 
DIAGNOSTIC CRITERIA FOR POLYCYTHEMIA VERA, 
ESSENTIAL THROMBOCYTHEMIA AND PRIMARY 
MYELOFIBROSIS3
2008 WHO Diagnostic Criteria
Polycythemia Vera1
Essential Thrombocythemia1
Primary Myelofibrosis1
Major 
criteria
1
Hgb > 18.5 g/dL (men)
> 16.5 g/dL (women)
Or2
1
Platelet count ≥ 450 x 109/L
1
Megakaryocyte proliferation
and atypia***3 accompanied 
by either reticulin and/or 
collagen fibrosis, or4
2
Presence of JAK2V617F 
or JAK2 exon 12 
mutation
2
Megakaryocyte proliferation 
with large and mature 
morphology.
2
Not meeting WHO criteria 
for CML, PV, MDS, or other 
myeloid neoplasm
3
Not meeting WHO criteria for 
CML, PV, PMF, MDS or 
other myeloid neoplasm
3
Demonstration of 
JAK2V617F or other clonal 
marker
or 
no evidence of reactive 
marrow fibrosis
4
Demonstration of JAK2V617F 
or other clonal marker
or 
no evidence of reactive 
thrombocytosis 
Minor 
criteria
1
BM trilineage 
myeloproliferation
1
Leukoerythroblastosis
2
Subnormal serum Epo 
level
2
Increased serum LDH level
3
EEC growth
3
Anemia
4
Palpable splenomegaly
Key: BM, bone marrow; Hgb, hemoglobin; Hct, hematocrit; Epo, erythropoietin; EEC, endogenous erythroid 
colony; WHO, World Health Organization; CML, chronic myelogenous leukemia; PV, polycythemia vera; PMF, 
primary myelofibrosis; MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase
1 PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and 2 
minor criteria. ET diagnosis requires meeting all 4 major criteria. PMF diagnosis requires meeting all 3 major 
criteria and two minor criteria.
2 Or Hgb or Hct > 99th percentile of reference range for age, sex, or altitude of residence or red cell mass > 25% 
above mean normal predicted  or Hgb > 17 g/dL (men)/ > 15 g/dL (women) if associated with a sustained increase 
of 2 g/dL from baseline that cannot be attributed to correction of iron deficiency
3 Small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded 
nuclei and dense clustering.
4 In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow 
cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e. pre-fibrotic PMF).


Protocol CP14B019, Amendment 13
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APPENDIX C. INTERNATIONAL WORKING GROUP FOR 
MYELOPROLIFERATIVE NEOPLASMS RESEARCH 
AND TREATMENT (IWG-MRT) RECOMMENDED 
CRITERIA FOR POST-POLYCYTHEMIA VERA AND 
POST-ESSENTIAL THROMBOCYTHEMIA 
MYELOFIBROSIS
Criteria for post-polycythemia vera myelofibrosis
Required criteria:
  1
Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria 
  2
Bone marrow fibrosis Grade 2–3 (on 0–3 scale) or Grade 3–4 (on 0–4 scale) (see footnote for details) 
Additional criteria (two are required):
  1
Anemia or sustained loss of requirement for phlebotomy in the absence of cytoreductive therapy
  2
A leukoerythroblastic peripheral blood picture
  3
Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥ 5 cm (distance of the tip 
of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly
  4
Development of  ≥ 1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, 
unexplained fever (>37.5°C)
Criteria for post-essential thrombocythemia myelofibrosis
Required criteria:
  1
Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO 
  2
Bone marrow fibrosis Grade 2–3 (on 0–3 scale) or Grade 3–4 (on 0–4 scale) (see footnote for details)
Additional criteria (two are required):
  1
Anemia and a ≥ 2 g/dL decrease from baseline hemoglobin level
  2
A leukoerythroblastic peripheral blood picture
  3
Increasing splenomegaly defined as either an increase in palpable splenomegaly of  ≥ 5 cm (distance of the 
tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly
  4
Increased lactate dehydrogenase
  5
Development of  ≥ 1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, 
unexplained fever (>37.5°C)
Note: Grade 2–3 according to the European classification:5 diffuse, often coarse fiber network with no evidence of 
collagenization (negative trichrome stain) or diffuse, coarse fiber network with areas of collagenization (positive 
trichrome stain). Grade 3–4 according to the standard classification:6 diffuse and dense increase in reticulin with 
extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and 
dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with 
significant osteosclerosis.


Protocol CP14B019, Amendment 13
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APPENDIX D. PERFORMANCE STATUS SCALE
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about > 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair > 50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair
5
Dead


Protocol CP14B019, Amendment 13
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APPENDIX E. ANAPHYLAXIS PRECAUTIONS
EQUIPMENT NEEDED

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use, as indicated per 
standard institutional practice

Antihistamines

Corticosteroids

Bronchodilators, vasopressors, etc.

Endotracheal tube and other resuscitation equipment

IV infusion solutions, tubing, catheters, etc.
PROCEDURES
In the event of a suspected anaphylactic reaction during infusion, the following procedures 
should be performed:
1. Stop the infusion.
2. Apply a tourniquet proximal to the injection site to slow systemic absorption.  Do not 
obstruct arterial flow in the limb.
3. Maintain an adequate airway and monitor vital signs.
4. Administer antihistamines, epinephrine, or other medications such as bronchodilators, 
vasopressors, corticosteroids, etc. to manage patient symptomatically, as required by 
patient status and directed by the physician in charge.
5. Continue to observe the patient and document observations and manage symptomatically.



SAP_001.pdf: 
 
Official Title: 
A Pilot Open-Label Study of the Efficacy and Safety of Imetelstat (GRN163L) 
in Myelofibrosis and Other Myeloid Malignancies 
NCT Number: 
NCT01731951 
 
Document Date: 
 
Statistical Analysis Plan: 16 July 2018 
 
 
 
 
 
 
 
 


1
Approved, Date: 16 July 2018
Janssen Research & Development *
Statistical Analysis Plan
A Pilot Open-Label Study of the Efficacy and Safety of Imetelstat (GRN163L) in 
Myelofibrosis and other Myeloid Malignancies
Protocol CP14B019; Phase 2
JNJ-63935937  (Imetelstat)
Status:
Approved
Date:
16 July 2018
Prepared by:
Document No.: EDMS-ERI-167553671, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
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.


JNJ-63935937  (Imetelstat)
Statistical Analysis Plan CP14B019
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Approved, Date: 16 July 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 3
ABBREVIATIONS ........................................................................................................................................ 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Trial Objectives ................................................................................................................................ 4
1.2.
Trial Design ...................................................................................................................................... 4
1.2.1.
Arm A Treatment Schedule .......................................................................................................... 5
1.2.2.
Arm B Treatment Schedule .......................................................................................................... 5
1.2.3.
Arm C and D Treatment Schedule ............................................................................................... 6
1.2.4.
Arm E Treatment Schedule .......................................................................................................... 6
1.2.5.
Arm F Treatment Schedule........................................................................................................... 7
1.2.6.
Arm G Treatment Schedule.......................................................................................................... 7
1.3.
Sample Size Justification ................................................................................................................. 9
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 9
2.1.
Baseline ........................................................................................................................................... 9
2.2.
Study Day......................................................................................................................................... 9
2.3.
Missing and Partial Dates ................................................................................................................ 9
2.4.
Analysis Set ................................................................................................................................... 10
3.
SUBJECT INFORMATION................................................................................................................ 11
3.1.
Demographics and Baseline Characteristics ................................................................................. 11
3.2.
Disposition Information................................................................................................................... 11
3.3.
Extent of Exposure ........................................................................................................................... 11
3.4.
Protocol Deviations........................................................................................................................... 11
3.5.
Prior and Concomitant Medications ............................................................................................... 11
4.
EFFICACY ......................................................................................................................................... 11
4.1.
Analysis Specifications................................................................................................................... 11
4.1.1.
Level of Significance................................................................................................................... 11
4.1.2.
Data Handling Rules................................................................................................................... 11
4.2.
Primary Efficacy Endpoint.............................................................................................................. 12
4.2.1.
Definition..................................................................................................................................... 12
4.2.2.
Analysis Methods........................................................................................................................ 12
4.3.
Major Secondary Endpoints........................................................................................................... 12
4.3.1.
Definition..................................................................................................................................... 12
4.3.2.
Analysis Methods........................................................................................................................ 13
4.3.3.
Other Measurements Collected.................................................................................................. 13
5.
SAFETY............................................................................................................................................. 13
5.1.
Adverse Events .............................................................................................................................. 13
5.2.
Death.............................................................................................................................................. 14
5.3.
Clinical Laboratory Tests................................................................................................................ 14
5.4.
Other Safety Tests ......................................................................................................................... 14
REFERENCES............................................................................................................................................ 15


JNJ-63935937  (Imetelstat)
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AMENDMENT HISTORY
Draft: June 30, 2017
ABBREVIATIONS
AE
Adverse Event
CI
Clinical Improvement
CR
Complete Remission
DIPSS
Dynamic International Prognostic Scoring System
DoR
Duration of Response
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ET MF
Essential Thrombocythemia Myelofibrosis
HI
Hematological Improvement
IV
Intravenous
IWG-MRT
International Working Group for Myeloproliferative Neoplasms Research and Treatment
MDS
Myelodysplastic Syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MF
Myelofibrosis
MPN
Myeloproliferative Neoplasm
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OS
Overall Survival
PMF
Primary Myelofibrosis
PR
Partial Remission
PV  
Polycythemia Vera
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMQs
Standardized MedDRA Queries
WBC
White Blood Cell


JNJ-63935937  (Imetelstat)
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1.
INTRODUCTION
This statistical analysis plan (SAP) is to lay out key analysis elements including definitions of analysis 
sets, derived variables, and statistical methods for the planned analyses for imetelstat (JNJ-63935937)
Study CP14B019.
1.1.
Trial Objectives
Primary Objective
To evaluate overall response rate in each of the six study arms (Arm A, B, D, E, F and G). The overall 
response rate for Arm C will be grouped with either A or B for analysis.
Response for Arms A, B, E, and F will be evaluated according to IWG-MRT criteria. For arm G, response 
will be according to the International Working Group response assessment as reported by Cheson et al. 
(2006). Response for Arm D will be defined by reduction in peripheral blood and bone marrow blast 
count to <5% and lasting for at least 2 months.
Secondary Objectives

To evaluate the safety and tolerability of imetelstat in each arm (per NCI CTCAE, v4.0).

To evaluate the efficacy of imetelstat in the reduction of spleen size, as measured by 
physical examination (palpable distance from the left costal margin) in each arm.

To evaluate the efficacy of imetelstat in improving anemia or inducing red blood cell 
transfusion-independence in previously transfusion-dependent subjects (per IWG-MRT 
criteria) in each arm.

To evaluate onset and durability of response as defined in primary and secondary endpoints 
in each arm. 
Exploratory Objectives

To evaluate the effect of imetelstat on bone marrow histology, karyotype, and JAK2V617F allele 
burden in each arm.

To evaluate the effect of imetelstat on leukocytosis, circulating blast count (blast % x WBC), 
circulating immature myeloid cell count (sum of blast, promyelocyte, myelocyte, and metamyelocyte 
% x WBC), and thrombocytosis in each arm.
1.2.
Trial Design
This was a single center, open-label study of imetelstat in subjects with Intermediate-2 or high risk 
PMF/post-ET/PV MF (Arms A, B, C, E and F) or blast-phase MF (Arm D only) or spliceosome-mutated 
(or with ring sideroblasts) MDS/MPN (Arm G only).
As of 22 January 2014, all arms were permanently closed to accrual.


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1.2.1.
Arm A Treatment Schedule
1.2.2.
Arm B Treatment Schedule


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1.2.3.
Arm C and D Treatment Schedule
1.2.4.
Arm E Treatment Schedule
(myelofibrosis subjects with spliceosome mutations or ring sideroblasts)


JNJ-63935937  (Imetelstat)
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1.2.5.
Arm F Treatment Schedule
(myelofibrosis subjects without spliceosome mutations or ring sideroblasts)
1.2.6.
Arm G Treatment Schedule
(MDS/MPN or MDS subjects with spliceosome mutations or ring sideroblasts)


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1.3.
Sample Size Justification
As a pilot study, the trial was not designed as a fixed sample size study. Instead, the probability of success 
or futility was estimated under the assumption of various response rates, and the number of subjects was 
adjusted based on the independent evaluation of each study arm during the trial.
As of protocol Addendum 3, accrual to Arm C was permanently discontinued. The 11 subjects slotted to 
enroll on Arm C were treated per the Arm A or Arm B dose schedule. A total of 34 subjects were to be
accrued between Arms A, B, and C. Accrual was to continue per protocol in Arm D and three additional 
arms (Arms E, F, and G) were added. A total of 26 evaluable subjects (Arms D and G) or 25 evaluable 
subjects (Arms E and F) were to be accrued in each of the remaining arms. An additional 3 subjects were
to be accrued in each arm to account for subjects who needed to be replaced. Therefore, the maximum 
overall sample size across all arms of the study was 148 subjects.
As of 22 January 2014, the study was closed to enrollment with a total of 80 subjects enrolled.
2.
GENERAL ANALYSIS DEFINITIONS
In general, continuous variables will be summarized using descriptive statistics such as mean, standard 
deviation (SD), median, and range. Categorical variables will be summarized using frequency and 
percentage.  For time-to-event variables, the Kaplan-Meier method will be used for descriptive summaries
and for each study arm independently unless otherwise specified.
2.1.
Baseline
Unless specified otherwise, the baseline value for each arm is defined as the last non-missing value 
collected on or before the administration of the first dose of study drug. 
2.2.
Study Day
Study Day 1 is defined as the day of the first dose of study drug that a subject received.
Study Day = assessment date – Study Day 1 + 1.
2.3.
Missing and Partial Dates
In general, imputation of partial missing dates will be made for AE onset date, AE resolution date, date of 
death, start and end dates of concomitant therapy, and date of initial diagnosis.
For AE onset and resolution date, imputation rules listed below will be applied. 

Partial AE onset dates will be imputed as follows:

If the onset date of an adverse event is missing day only, it will be set to:
o
First day of the month that the AE occurred, if month/year of the onset of AE is 
different than the month/year of the first dose date 
o
The day of first dose date, if the month/year of the onset of AE is the same as 
month/year of the first dose date and month/year of the AE resolution date is 
different
o
The day of first dose date or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the first dose date and month/year 
of the AE resolution date are same


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
If the onset date of an adverse event is missing both day and month, it will be set to the 
earliest of:
o
January 1 of the year of onset, as long as this date is after the first dose date
o
Month and day of the first dose date, if this date is the same year that the AE 
occurred
o
The AE resolution date.

Completely missing onset dates will not be imputed.

Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an adverse event is missing day only, it will be set to the earliest 
of the last day of the month of occurrence of resolution or the day of the date of death, if the 
death occurred in that month.

If the resolution date of an adverse event is missing both day and month, it will be set to 
the earliest of December 31 of the year or the day and month of the date of death, if the death 
occurred in that year.

Completely missing resolution dates will not be imputed.
For start and end dates of concomitant therapies, if the start or end date is completely missing, no 
imputation will be performed. If the start or end date is partially missing, the following imputation rules 
will be used. 

If only the day is missing, the 15th day of the month will be used. 

If both the day and month are missing, the 30th of June will be used.
If the medication/therapy was taken prior to study start, and the imputed start date is after first dosing 
date, further adjust the imputed start date as the day prior to first dosing date; if the medication/therapy 
was taken after study start, and the imputed start date is prior to first dosing date, further adjust the 
imputed start date as first dosing date. Also adjust the imputed medication/therapy end date so that it is on 
or after first dosing date.
For date of death and date of initial diagnosis, the following rule will be applied.

If date is completely missing, no imputation will be made. 

If year is missing, no imputation will be made.

If only year is present but month and day are missing, then June 30th will be used.

If only day is missing but year and month are available, then the 15th of the month will be used. 
However, the above imputations will be modified by the following rules:

If such imputed date for initial diagnosis is on or after study consent date, then consent date - 1 
will be used. 

If the imputed date is for a date of death and is before the last date that the subject is known to be 
alive, the latter date + 1 will be used.
2.4.
Analysis Set
All Treated analysis set includes all subjects who received at least 1 dose of study drug and will be used 
for safety analyses unless otherwise specified.


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Eligible analysis set is a subset of the all treated analysis set that excludes ineligible subjects who did not 
satisfy each and every eligibility criteria for study entry. Eligible analysis set will be used for efficacy 
analysis unless otherwise specified.
The 11 subjects slotted to enroll in Arm C but treated per the Arm A or Arm B dose schedule will be 
summarized with Arm A or Arm B subjects based on actual treatment received. 
3.
SUBJECT INFORMATION
3.1.
Demographics and Baseline Characteristics
Demographics and disease characteristics data will be summarized for the all treated analysis set and the
eligible analysis set, including sex, age (years), race, ethnicity, ECOG performance status, weight (kg),
myelofibrosis subtype (primary, post ET, or post PV), DIPSS-Plus risk status, transfusion dependence, 
baseline laboratory values/categories, spleen and liver assessments.
The corresponding listing will also be provided.
3.2.
Disposition Information
Number of subjects treated, discontinued from treatment/study, and reasons for discontinuation will be 
summarized by study arm for the all treated analysis set.
The corresponding listing will also be provided.
3.3.
Extent of Exposure
A listing of subjects’ exposure including study day, dose received, dose adjustment, corresponding 
reason, and other related information will be presented for all subjects in the all treated analysis set.
3.4.
Protocol Deviations
A listing of subjects with major protocol deviations including cycle numbers and the type of deviation 
will be provided.
3.5.
Prior and Concomitant Medications
Prior and concomitant medication information collected on eCRF will be listed separately for all subjects 
in the treated analysis set.
4.
EFFICACY
4.1.
Analysis Specifications
4.1.1.
Level of Significance
All tests and 95% confidence intervals presented will be 2-sided.
4.1.2.
Data Handling Rules
Unless specified otherwise, missing values will not be imputed.


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4.2.
Primary Efficacy Endpoint
4.2.1.
Definition
The primary endpoint in each arm is the overall response rate. For Arms A, B, E, and F overall response 
is defined to be a CI, PR, or CR noted as the objective status according to the IWG-MRT consensus 
criteria for MF. Response in Arm G is defined as HI, PR or CR according to the IWG criteria for MDS 
(Cheson et al. 2006). Response in Arm D is defined by a durable (2 months or more) decrease in 
peripheral blood and bone marrow blast percentage to less than 5%. The primary outcome will be the 
percentage of responses observed in each arm in the eligible analysis set.
4.2.2.
Analysis Methods
The number and percentage of responders in the eligible analysis set will be reported by each treatment 
arm along with 95% Clopper-Pearson exact binomial confidence intervals. Subjects’ response status 
collected at each cycle will be listed.
4.3.
Major Secondary Endpoints
4.3.1.
Definition
Spleen Response
Spleen response is defined as either a minimum 50% reduction in palpable splenomegaly of a spleen that 
is at least 10 cm at baseline or a spleen that is palpable at less than 10 cm but more than 5 cm at baseline 
becomes not palpable.
Transfusion Independence
Transfusion dependency is defined by a history of at least 2 units of red blood cell transfusions in the last 
month or a baseline hemoglobin level of less than 85 g/L that was not associated with clinically overt 
bleeding. For a transfusion dependent subject, transfusion independence is defined as he/she met either of 
the following conditions:

Received no more than 1 unit of red blood cell transfusions in a rolling time interval of 30 days or 
more.

Had a hemoglobin level increase over baseline more than 2g/dl if his/her baseline hemoglobin
level was less than 85 g/L and received no transfusion.
Time to Response (TTR) 
Time to response is defined as the duration from Study Day 1 to the earliest date that a response is first 
documented. For non-responders, it will be censored at the date of progressive disease/relapse or the date 
of the last adequate assessment, whichever comes first.
Duration of Response (DoR)
Duration of response is defined for responders as the interval from date of the initial documentation of a 
response to the date of first documented evidence of disease progression (or relapse for subjects who 
experience CR). For those subjects who are still without progression/relapse, DoR will be censored at the 
last adequate assessment.
Overall Survival (OS) 
OS is defined as the interval from Study Day 1 to the date of 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.


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4.3.2.
Analysis Methods
Subjects’ status of spleen response and transfusion-independence will be listed for all eligible subjects.
Duration of response will be estimated using the Kaplan-Meier method. Approximate 95% confidence 
intervals for median duration of response will be computed using the formula proposed by Brookmeyer 
and Crowley. The same method will be applied for OS.
4.3.3.
Other Measurements Collected
Time to response, transfusion, bone marrow, physical exam, spleen/liver assessment, and ultrasound 
result will be listed separately.
5.
SAFETY
Safety will be analyzed using the incidence and severity of adverse events and laboratory tests based on 
the all treated analysis set.
5.1.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The severity of adverse events is assessed in National 
Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) Version 4.0. 
Treatment-emergent AEs will be defined as those events that 1) occur on or after the first dose of study 
drug, through the treatment phase, and for 30 days following the last dose of study drug or until 
subsequent anti-cancer therapy if earlier; 2) any event that is considered study drug-related regardless of 
the start date of the event; or 3) any event that is present at baseline but worsens in severity or is 
subsequently considered drug-related by the investigator.
An overview summary table of treatment-emergent AEs will be provided, including drug related AEs, 
CTCAE grade ≥3 AEs, serious AEs, and deaths.
Treatment-emergent AEs will be summarized by system organ class and preferred terms. For each 
treatment-emergent adverse event, the percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized. Tables will be sorted by frequency in incidence (the highest to lowest 
incidence) in the total column. The same summary will be provided for the treatment-emergent AEs with 
CTCAE grade ≥3, treatment-emergent AEs considered related to study treatment, and serious treatment-
emergent AEs.
A summary of the number of subjects who discontinued study treatment because of 1 or more AEs by 
system organ class and preferred term will be provided. This table includes AEs leading to 
discontinuation of study treatment for those subjects indicated as having discontinued study treatment due 
to an adverse event on the end of treatment eCRF page.
Treatment-emergent bleeding events will be identified using standardized MedDRA queries (SMQs) by 
matching the event terms in SMQ “HAEMORRHAGES” and
the first SMQ
subcategory 
“HAEMORRHAGE TERM (EXCL LABORATORY TERMS).” The number of subjects with treatment-
emergent bleeding events will be summarized for each treatment arm.
A listing of all adverse events will be provided.


JNJ-63935937  (Imetelstat)
Statistical Analysis Plan CP14B019
14
Approved, Date: 16 July 2018
5.2.
Death
A summary of all deaths and cause of death will be tabulated by treatment arm. Specifically, the number 
of subjects who died during the study will be summarized for the all treated population. The primary 
cause of death collected on eCRF page will be reported. 
A listing of death information will be provided.
5.3.
Clinical Laboratory Tests
The evaluation of clinical laboratory tests will focus on the following selected laboratory analytes or 
events:

Maximum post baseline CTCAE grade of hematological toxicity (anemia, leukemia, neutropenia, 
thrombocytopenia)

Maximum post baseline CTCAE grade related to liver function test (ALT, AST, alkaline 
phosphatase, total bilirubin)

Incidence 
of 
persistent 
(≥4 
weeks) 
and 
severe 
(grade 
≥3 
) 
cytopenia 
(thrombocytopenia/neutropenia) 
The above analyses will be tabulated by treatment arm.
In addition, descriptive statistics (mean, SD, median, range) will be used to summarize observed 
laboratory values and change from baseline in observed value at each scheduled visit for each treatment 
arm.
Shift tables for each cycle will be produced as number of subjects with each baseline CTCAE grade and 
changes to the maximum CTCAE grade by analyte. Shift tables from baseline to worst value on treatment 
will also be provided. 
All the lab data collected (hematology, chemistry, coagulation, urinalysis, and other lab tests) will be 
listed.
5.4.
Other Safety Tests
ECOG performance status, physical exam and infusion reaction will be listed separately by cycle.


JNJ-63935937  (Imetelstat)
Statistical Analysis Plan CP14B019
15
Approved, Date: 16 July 2018
REFERENCES
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de 
Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application 
and proposal for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood 2006;108(2):419-25.