RECITE: A Phase 3 Randomized Placebo-controlled Double-blind Study of Romiplostim for the Treatment of Chemotherapy- Induced Thrombocytopenia in Patients Receiving Oxaliplatin-based Chemotherapy for Treatment of Gastrointestinal, Pancreatic, or Colorectal Cancer
Phase: PHASE3
Conditions: Chemotherapy-induced Thrombocytopenia
Sponsor: Amgen

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  29 July 2021 
Page 1 of 125 
CONFIDENTIAL 
 
 
Title Page 
Protocol Title: 
RECITE:  A Phase 3 Randomized 
Placebo-controlled Double-blind Study of 
Romiplostim for the Treatment of Chemotherapy-
induced Thrombocytopenia in Patients Receiving 
Oxaliplatin-based Chemotherapy for Treatment 
of Gastrointestinal, Pancreatic, or Colorectal 
Cancer 
Short Protocol Title: 
Study of Romiplostim for Chemotherapy-induced 
Thrombocytopenia in Adult Subjects with 
Gastrointestinal, Pancreatic, or Colorectal 
Cancer 
Protocol Number: 
20140346 
Investigational Product: 
Romiplostim 
Trade Name: 
Nplate® 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA  
91320, United States 
Telephone Number: 
1 (805) 447-1000 
Protocol 
Approver 
Name: 
Function: 
Vice President Global Development 
Key 
Sponsor 
Contact 
 
Name: 
 MD 
Address: 
One Amgen Center Drive 
MS 27-3F 
Thousand Oaks, CA 91320 USA 
Telephone Number: 
Email Address: 
EudraCT Number: 
2017‐002992‐25 
NCT Number: 
NCT03362177 
Protocol Date: 
Document Version 
Date 
Original 
28 August 2017 
Amendment 1 
12 March 2018 
Amendment 2 
14 November 2018 
Amendment 3 
27 February 2019 
Amendment 4 
19 August 2019 
Amendment 5 
08 June 2020 
Amendment 6 
Superseding 
Amendment 6 
02 September 2020 
02 November 2020 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  29 July 2021 
Page 2 of 125 
CONFIDENTIAL 
 
 
Amendment 7 
29 July 2021 
Version/Date: 
 
Data Element 
Standards Version 
Date 
5.0 
Not applicable 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000.  For all other 
countries, please call the local toll-free Medical Information number provided by your 
monitor or use Amgen’s general number in the US, 1-805-447-1000. 
 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  29 July 2021 
Page 3 of 125 
CONFIDENTIAL 
 
 
Investigator's Agreement: 
I have read the attached protocol entitled RECITE:  A Phase 3 Randomized 
Placebo-controlled Double-blind Study of Romiplostim for the Treatment of 
Chemotherapy-induced Thrombocytopenia in Patients Receiving Oxaliplatin-based 
Chemotherapy for Treatment of Gastrointestinal, Pancreatic, or Colorectal Cancer, dated 
29 July 2021 agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by:  me 
(including, if applicable, my spouse or legal partner and dependent children) and my sub 
investigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator Date (DD Month YYYY) 
 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  29 July 2021 
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CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Protocol Synopsis ................................................................................................... 9 
2. 
Study Schema and Schedule of Activities ............................................................. 16 
2.1 
Study Schema ........................................................................................... 16 
2.2 
Schedule of Activities ................................................................................ 18 
3. 
Introduction ........................................................................................................... 25 
3.1 
Study Rationale ......................................................................................... 25 
3.1.1 
Rationale for Study Population .................................................. 25 
3.1.2 
Rationale for Study Duration ...................................................... 26 
3.2 
Background ............................................................................................... 26 
3.2.1 
Disease ..................................................................................... 26 
3.2.2 
Amgen Investigational Product Background:  
Romiplostim .............................................................................. 27 
3.2.3 
Amgen-sponsored CIT Studies .................................................. 28 
3.2.4 
Investigator-sponsored CIT Studies ........................................... 29 
3.2.4.1 
Phase 1/2 Study of Romiplostim in Solid 
Tumors .................................................................... 29 
3.2.4.2 
Retrospective Reviews of Romiplostim 
Use for CIT .............................................................. 29 
3.2.4.3 
Ongoing Investigator-sponsored Study.................... 30 
3.3 
Benefit/Risk Assessment ........................................................................... 31 
3.3.1 
Therapeutic Context .................................................................. 31 
3.3.2 
Key Benefits .............................................................................. 32 
3.3.2.1 
Ability to Administer On-time, Full Dose 
Chemotherapy ......................................................... 32 
3.3.2.2 
Reduction in Incidence of 
≥ Grade 2 Bleeding Events ...................................... 32 
3.3.2.3 
Reduction in Incidence of Platelet 
Transfusions ........................................................... 32 
3.3.2.4 
Platelet Nadir........................................................... 33 
3.3.2.5 
Time to First Platelet Response .............................. 33 
3.3.3 
Key Risks .................................................................................. 33 
3.3.3.1 
Medication Errors .................................................... 33 
3.3.3.2 
Thrombotic/Thromboembolic 
Complications.......................................................... 33 
3.3.3.3 
Reoccurrence of Thrombocytopenia After 
Cessation of Romiplostim ........................................ 34 
3.3.3.4 
Increased Bone Marrow Reticulin ............................ 35 
3.3.3.5 
Bone Marrow Fibrosis ............................................. 35 
3.3.3.6 
Progression of Existing Myelodysplastic 
Syndrome ................................................................ 36 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  29 July 2021 
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3.3.4 
Conclusion ................................................................................ 37 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 37 
4.1 
Objectives and Endpoints .......................................................................... 37 
4.2 
Hypotheses ............................................................................................... 38 
5. 
Study Design ........................................................................................................ 39 
5.1 
Overall Design .......................................................................................... 39 
5.2 
Number of Subjects ................................................................................... 40 
5.2.1 
Replacement of Subjects ........................................................... 40 
5.2.2 
Number of Sites ......................................................................... 41 
5.3 
End of Study ............................................................................................. 41 
5.3.1 
End of Study Definition .............................................................. 41 
5.3.2 
Study Duration for Subjects ....................................................... 41 
5.4 
Justification for Investigational Product Dose ............................................ 42 
5.5 
Patient Input on Study Design ................................................................... 42 
6. 
Study Population .................................................................................................. 42 
6.1 
Inclusion Criteria  ...................................................................................... 42 
6.2 
Exclusion Criteria ...................................................................................... 43 
6.3 
Subject Enrollment .................................................................................... 46 
6.4 
Screen Failures ......................................................................................... 46 
7. 
Treatments ........................................................................................................... 47 
7.1 
Treatment Procedures............................................................................... 47 
7.1.1 
Investigational Products: Romiplostim and Placebo................... 47 
7.1.1.1 
Dose formulation ..................................................... 47 
7.1.1.2 
Dosage, Administration, and Schedule .................... 48 
7.1.2 
Non-investigational Products ..................................................... 49 
7.1.3 
Medical Devices ........................................................................ 49 
7.1.4 
Other Protocol-required Therapies ............................................ 49 
7.1.5 
Other Treatment Procedures ..................................................... 50 
7.1.6 
Product Complaints ................................................................... 50 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 50 
7.2 
Method of Treatment Assignment ............................................................. 51 
7.3 
Blinding ..................................................................................................... 51 
7.3.1 
Site Personnel Access to Individual Treatment 
Assignments ............................................................................. 51 
7.3.2 
Access to Individual Subject Treatment Assignments 
by Amgen or Designees ............................................................ 51 
7.4 
Dose Modification ...................................................................................... 52 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 52 

Product:  Romiplostim 
Protocol Number:  20140346 
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7.4.1.1 
Amgen Investigational Product:  
Romiplostim and Placebo ........................................ 52 
7.4.1.2 
Non-Amgen Non-investigational Product:  
Standard-of-care Chemotherapy ............................. 53 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 57 
7.6 
Treatment Compliance .............................................................................. 57 
7.7 
Treatment of Overdose ............................................................................. 57 
7.8 
Prior and Concomitant Treatment ............................................................. 58 
7.8.1 
Prior Treatment ......................................................................... 58 
7.8.2 
Concomitant Treatment ............................................................. 58 
8. 
Discontinuation Criteria ......................................................................................... 58 
8.1 
Discontinuation of Study Treatment........................................................... 58 
8.2 
Discontinuation From the Study ................................................................ 60 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 60 
8.2.2 
Reasons for Removal From Study ............................................. 60 
8.3 
Lost to Follow-up ....................................................................................... 61 
9. 
Study Assessments and Procedures .................................................................... 61 
9.1 
General Study Periods .............................................................................. 61 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 61 
9.1.2 
Treatment Period ....................................................................... 62 
9.1.3 
End of Treatment ....................................................................... 63 
9.1.4 
End of Treatment Period ........................................................... 63 
9.1.5 
Long-term Follow-up .................................................................. 63 
9.1.6 
End of Study Visit ...................................................................... 63 
9.2 
Description of General Study Assessments and Procedures ..................... 64 
9.2.1 
General Assessments ............................................................... 64 
9.2.1.1 
Informed Consent .................................................... 64 
9.2.1.2 
Demographics ......................................................... 64 
9.2.1.3 
Medical History ........................................................ 64 
9.2.1.4 
Physical Examination .............................................. 64 
9.2.1.5 
Physical Measurements .......................................... 64 
9.2.1.6 
Performance Status................................................. 64 
9.2.2 
Efficacy Assessments ................................................................ 64 
9.2.2.1 
Platelet Counts ........................................................ 64 
9.2.2.2 
Bleeding Scale ........................................................ 65 
9.2.2.3 
Chemotherapy Dose ............................................... 65 
9.2.3 
Safety Assessments .................................................................. 66 
9.2.3.1 
Adverse Events ....................................................... 67 
9.2.3.2 
Vital Signs ............................................................... 70 
9.2.3.3 
Electrocardiograms (ECGs) ..................................... 70 
9.2.3.4 
Vital Status .............................................................. 70 

Product:  Romiplostim 
Protocol Number:  20140346 
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9.2.4 
Clinical Laboratory Assessments ............................................... 70 
9.2.4.1 
Pregnancy Testing .................................................. 71 
9.2.5 
Pharmacokinetic Assessments .................................................. 72 
9.2.6 
Antibody Testing Procedures ..................................................... 72 
9.2.8 
Health Economics OR Medical Resource Utilization 
and Health Economics .............................................................. 74 
10. 
Statistical Considerations ...................................................................................... 75 
10.1 
Sample Size Determination ....................................................................... 75 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 77 
10.2.1 
Analysis Sets ............................................................................. 77 
10.2.1.1 
Full Analysis Set ...................................................... 77 
10.2.1.2 
Safety Analysis Set ................................................. 77 
10.2.2 
Covariates ................................................................................. 77 
10.2.3 
Subgroups ................................................................................. 78 
10.2.4 
Handling of Missing and Incomplete Data .................................. 78 
10.3 
Statistical Analyses ................................................................................... 79 
10.3.1 
Planned Analyses ...................................................................... 79 
10.3.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 79 
10.3.1.2 
Primary Analysis ..................................................... 80 
10.3.1.3 
Final Analysis .......................................................... 80 
10.3.2 
Methods of Analyses ................................................................. 80 
10.3.2.1 
General Considerations ........................................... 80 
10.3.2.2 
Efficacy Analyses .................................................... 81 
10.3.2.3 
Safety Analyses ...................................................... 83 
10.3.2.4 
Other Analyses ........................................................ 84 
11. 
References ........................................................................................................... 86 
12. 
Appendices ........................................................................................................... 91 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 92 
12.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 95 
12.3 
Appendix 3.  Study Governance Considerations ....................................... 97 
12.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 105 
Definition of Adverse Event ..................................................................... 105 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 116 
12.6 
Appendix 6.  Sample Storage and Destruction ........................................ 122 

Product:  Romiplostim 
Protocol Number:  20140346 
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12.7 
Appendix 7.  Use of Home Healthcare and Telemedicine During 
the COVID-19 Pandemic ......................................................................... 124 
List of Tables 
Table 2-1.  Schedule of Activities ................................................................................... 18 
Table 7-1.  Investigational Product Dose Adjustment Rules ........................................... 52 
Table 7-2.  Dose Modification Based on Platelet Counts – mFOLFOX6 ........................ 54 
Table 7-3.  Dose Modification Based on Platelet Counts - FOLFIRINOX ....................... 55 
Table 7-4.  Dose Modification Based on Platelet Counts - mFOLFIRINOX .................... 56 
Table 12-1.  Analyte Listing ........................................................................................... 96 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................ 16 
Figure 10-1.  Relationship Between Cycle Correlation and Treatment Effecta ................ 76 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ..................................................................................................... 110 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet .................................... 120 
 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  29 July 2021 
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1. 
Protocol Synopsis 
Protocol Title:  RECITE:  A Phase 3 Randomized Placebo-controlled Double-blind 
Study of Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in 
Patients Receiving Oxaliplatin-based Chemotherapy for Treatment of Gastrointestinal, 
Pancreatic, or Colorectal Cancer 
Short Protocol Title:  Study of Romiplostim for Chemotherapy-induced 
Thrombocytopenia in Adult Subjects with Gastrointestinal, Pancreatic, or Colorectal 
Cancer 
Study Phase:  3 
Indication:  Chemotherapy-induced thrombocytopenia 
Rationale 
This trial is designed to study romiplostim for the treatment of chemotherapy-induced 
thrombocytopenia (CIT) in patients receiving oxaliplatin-based chemotherapy regimens 
for the treatment of gastrointestinal, pancreatic, or colorectal adenocarcinoma, which 
includes cancers of the esophagus, stomach, colon, pancreas, or rectum.  This is a 
randomized, double-blind, placebo-controlled trial to study the safety and efficacy of 
romiplostim in this patient population.  Current management of CIT includes platelet 
transfusions, chemotherapy dose delays and/or dose reductions, and in the United 
States (US), oprelvekin (Neumega) (Neumega Package Insert, 2011).  However, due 
to its side effect profile, oprelvekin is rarely used in the clinical setting and it is no longer 
available from the manufacturer.  Platelet transfusions are often reserved for patients 
with severe thrombocytopenia (platelet counts  10 x 109/L) (Kuter, 2015).  
Chemotherapy dose delays and dose reductions are the most commonly utilized 
measures for managing CIT; however, these measures lead to a reduction in 
chemotherapy relative dose intensity (Denduluri et al, 2015; Lyman et al, 2003).  
Therefore, an unmet need exists for alternative treatment options for CIT.  A recent 
investigator-sponsored study, using a weekly romiplostim dosing schedule, provided 
evidence of efficacy in the treatment of CIT in patients with solid tumors 
(Soff et al, 2017).  The dosage, administration, and schedule selected for study were 
derived from the results of Amgen’s studies, as well as data reviewed from studies using 
romiplostim for the treatment of CIT (Al-Samkari et al, 2018, Soff et al, 2017).  In these 
studies, weekly subcutaneous administration of romiplostim at a dose 2 µg/kg was 
identified as the dose level which not only enables the doubling of platelet count in 
healthy subjects, but could be an efficacious dose for patients with CIT (Wang, 2004).   

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  29 July 2021 
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Objectives/Endpoints 
Objectives 
Endpoints 
Primary 
 
to evaluate the efficacy of romiplostim for 
the treatment of chemotherapy-induced 
thrombocytopenia (CIT) in patients 
receiving chemotherapy for the treatment 
of gastrointestinal, pancreatic, or 
colorectal cancer, measured by the ability 
to administer on-time, full-dose 
chemotherapy 
 
no thrombocytopenia-induced 
modification of any myelosuppressive 
treatment agent in the second and third 
cycles of the planned on-study 
chemotherapy regimen.  
Thrombocytopenia-induced modifications 
include chemotherapy dose 
reduction, delay, omission, or 
chemotherapy treatment discontinuation 
due to platelet counts below 100 x 109/L 
Secondary 
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
depth of platelet nadir 
 
the depth of the platelet count nadir from 
the start of the first on-study 
chemotherapy cycle through the end of 
the treatment period   
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
time to first platelet response 
 
the time to first platelet response, defined 
by platelet count  100 x 109/L in the 
absence of platelet transfusions during 
the preceding 7 days 
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
incidence of  grade 2 bleeding events 
 
the duration-adjusted event rate of 
 grade 2 bleeding events, as assessed 
by Common Terminology Criteria for 
Adverse Events (CTCAE) 
version 5.0 grading scale 
 
to compare the treatment effect of 
romiplostim with that of placebo on overall 
survival 
 
overall survival 
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
incidence of platelet transfusions 
 
platelet transfusion(s) during the 
treatment period  
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
proportion of patients achieving platelet 
response  
 
achieving a platelet count  100 x 109/L at 
any time after study day 1 to week 4 (ie, 
7 days after the planned third dose of 
investigational product) and in the 
absence of platelet transfusions during 
the preceding 7 days   
 
overall safety of romiplostim  
 
adverse events, including 
treatment-emergent adverse events, fatal 
adverse events, serious adverse events, 
and clinically significant changes in 
laboratory values. 
 
anti-romiplostim antibodies and antibodies 
to thrombopoietin (TPO)  
 
myelodysplastic syndromes and 
secondary malignancies 
 

Product:  Romiplostim 
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Hypotheses 
It is anticipated that romiplostim will raise platelet counts faster than placebo, resulting in 
more on-time and full-dose delivery of chemotherapy cycles in subjects with CIT and 
decreasing the incidence of platelet transfusions and bleeding events.   
Overall Design 
This is a phase 3, randomized, placebo-controlled, multicenter, international study for 
the treatment of CIT in adult subjects receiving an oxaliplatin-based chemotherapy 
regimen for the treatment of gastrointestinal, pancreatic, or colorectal cancer.  Subjects 
must have a platelet count ≤ 85 x 109/L on day 1 of the study.  The study will consist of a 
screening period of up to 4 weeks, a treatment period long enough to allow for 
assessment of 3 planned cycles of chemotherapy, a follow-up visit, and long-term 
follow-up (LTFU).  Given that subjects will be assessed for 3 planned cycles of 
chemotherapy, the oxaliplatin-based chemotherapy cycles are 2-3 weeks in duration, 
and the investigational product dose adjustment guidelines allow for up to 12 weeks of 
dosing before a subject is declared a non-responder, the majority of study subjects will 
receive investigational product for a range of between 7-21 weeks. 
Once eligibility is confirmed, subjects will be randomized on day 1 of the study in a  
2 to 1 ratio to receive either romiplostim or placebo, respectively.  Randomization will be 
stratified by tumor type and by baseline platelet count (< 50 x 109/L, ≥ 50 x 109/L).  
Baseline platelet count is defined as platelet count measured most prior to the time of 
the planned investigational product administration.  Gastrointestinal cancers, including 
tumors of the esophagus or stomach, will be included in one stratum, pancreatic cancers 
in a second stratum, and colorectal cancers, including tumors of the colon or rectum, will 
be included in a third stratum.  Subjects will then enter the treatment period, during 
which time they will return to the clinic weekly for local platelet counts, undergo dose 
titrations as needed, and investigational product administration.  If there are multiple 
platelet values performed on a study visit date, the platelet value from the test performed 
most immediately prior to the time of the planned investigational product and/or 
non-investigational product administration will be recorded as the platelet value for that 
study visit date and will be used to determine the subject’s dose of investigational 
product and, when applicable, chemotherapy dose modifications which include dose 
reductions, delays, omissions, and discontinuations.  Subjects will receive weekly 
subcutaneous injections of investigational product throughout the treatment period, 
starting at 2 g/kg and increasing by increments of 1 g/kg to a maximum dose of 

Product:  Romiplostim 
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10 g/kg to reach a target platelet count of  100 x 109/L.  If the subject will be receiving 
concomitant chemotherapy on a study visit date, investigational product will be 
administered immediately after the completion of chemotherapy infusion on 
chemotherapy day 1.  If continuous infusion 5-fluorouracil (5-FU) over 46-48 hours is 
part of the chemotherapy regimen the investigational product may be administered prior 
to beginning or during the continuous infusion 5-FU.   
Subjects will have a follow-up Visit 1 week after the last dose of investigational product.  
Subjects will have their first in-clinic LTFU Visit 30 (+5) days after the last dose of 
investigational product (Safety Follow-up 1).  Subjects will be contacted 30 (+5) days 
after the last dose of the last on-study cycle of chemotherapy (up to 3 cycles) to collect 
adverse event information except for females who are in addition required to come to 
clinic for a highly sensitive urine or serum pregnancy test (Safety Follow-up 2).  Subjects 
will remain in LTFU until the last subject in the trial completes the LTFU Visit 1 year after 
the last dose of investigational product.  During the LTFU period, all subjects will be 
followed by phone or in clinic every 12 weeks (± 2 weeks) from the last dose of 
investigational product until the end of study (EOS) visit.  All subjects should complete 
EOS Visit up to 2 weeks after the last subject in the trial completes their LTFU Visit 
1 year after the last dose of investigational product. 
During LTFU subjects will be followed for the diagnosis of, or progression to, secondary 
malignancies (including myeloid malignancies) or myelodysplastic syndromes, as well as 
vital status and cause(s) of death. 
Number of Subjects 
The study will enroll approximately 162 subjects with CIT and receiving an 
oxaliplatin-based chemotherapy regimen for the treatment of gastrointestinal, pancreatic, 
or colorectal cancer.  Subjects will be stratified based on their tumor type and baseline 
platelet count into 1 of 2 arms (placebo or romiplostim).  
Summary of Subject Eligibility Criteria 
This study will enroll adults ≥ 18 years of age with histologically or cytologically 
confirmed diagnosis of gastrointestinal, pancreatic, or colorectal adenocarcinoma, 
defined as cancer of the esophagus, stomach, pancreas, colon, or rectum, who are 
currently receiving (or plan to receive) a chemotherapy regimen containing 5-FU or 
capecitabine and oxaliplatin (plus irinotecan in FOLFIRINOX or FOLFOXIRI).  Use of an 
oxaliplatin-based combination regimen is permitted with (1) anti-angiogenic agents (such 
as bevacizumab) or (2) targeted therapy (such as anti-epidermal growth factor agents).  

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  29 July 2021 
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Tumor stage will not affect eligibility.  Subjects must have at least 3 remaining planned 
cycles of chemotherapy at enrollment.  Subjects must have a platelet count ≤ 85 x 109/L 
on day 1 of the study. 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
Amgen investigational product (romiplostim or placebo) will be administered in the clinic 
by a qualified healthcare provider as a subcutaneous injection.  The starting dose of 
investigational product will be 2 μg/kg based on the subject’s recorded screening weight.  
Subjects will return to the clinic every 7 days (± 1 day) to provide platelet counts and 
undergo dose titrations under the supervision of the treating physician.  If there are 
multiple platelet values performed on a study visit date, the platelet value from the test 
performed most immediately prior to the time of the planned investigational product 
and/or non-investigational product administration will be recorded as the platelet value 
for that study visit date and will be used to determine the subject’s dose of 
investigational product and, when applicable, chemotherapy dose modifications which 
include dose reductions, delays, omissions, and discontinuations.  Weekly dose 
increases will continue in increments of 1 μg/kg up to a maximum dose of 10 μg/kg in an 
attempt to reach a target platelet count of ≥ 100 x 109/L. 
Non-Amgen, non-investigational chemotherapeutic agents should not be administered 
until platelet counts are ≥ 100 x 109/L, or until at least week 4 (see Section 7.4.1.2), 
whichever occurs first.  Do not start the first cycle of on-study chemotherapy before 
study week 2.  The start of the planned chemotherapy must be no more than 2 days 
after the local laboratory assessments have been taken during the study visit.  
Thereafter, chemotherapy agents will be administered for the treatment of 
gastrointestinal, pancreatic, or colorectal cancer according to chemotherapy dose 
modification guidelines outlined in Section 7.4.1.2.   
Procedures 
Written informed consent must be obtained from all subjects before any study-specific 
screening procedures are performed.  At specified visits, outlined in the Schedule of 
Activities (Table 2-1), subjects will undergo physical exams with measurements of vital 
signs (including respiratory rate, heart rate, blood pressure, and temperature), height 
(screening only) and weight (screening only), Eastern Cooperative Oncology Group 
(ECOG) status, electrocardiogram (ECG), disease status assessment, recording of 
concomitant medications, chemotherapy administered, and incidence of platelet 

Product:  Romiplostim 
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transfusions, as well as review of adverse events and serious adverse events.  Blood will 
be collected for laboratory testing including complete blood counts with differential, blood 
chemistry profiles, anti-TPO and anti-romiplostim antibodies.  Platelet counts, 
prothrombin time (PT), partial thromboplastin time (PTT), and International Normalized 
Ratio (INR) will also be collected.  If there are multiple platelet values performed on a 
study visit date, the platelet value from the test performed most immediately prior to the 
time of the planned investigational product and/or non-investigational product 
administration will be recorded as the platelet value for that study visit date and will be 
used to determine the subject’s dose of investigational product and, when applicable, 
chemotherapy dose modifications which include dose reductions, delays, omissions, and 
discontinuations.  Local laboratory assessments taken during the study visit (± 1 day) 
and recorded in the case report form (CRF) must be the same values as used for 
investigational product dose calculations and chemotherapy dose modifications where 
applicable.  Hemoglobin will be collected locally on day 1 only.  Absolute neutrophil 
counts will be collected locally weekly through safety follow-up (SFU) 1.  Additionally, in 
females of childbearing potential a urine or serum pregnancy test will be performed 
locally.  
 
   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1. 
Statistical Considerations 
General Approach: 
The study will have an overall alpha of 0.05 with 2-sided testing.  To preserve the overall 
significance level, statistical testing of the primary and secondary efficacy endpoints will 
follow a hierarchical structure.  If romiplostim demonstrates superiority to placebo for the 
primary endpoint, then the first secondary endpoint will be tested and so on until an 
endpoint is not significant or the last secondary efficacy endpoint has been tested.   
Sample Size Considerations: 
One-hundred and sixty-two subjects will be randomized in the study with 
2:1 randomization ratio (108 subjects to romiplostim, 54 subjects to placebo).  The study 
has 93% power for the primary endpoint (assuming subject incidence rates of the 
primary endpoint for placebo and romiplostim of 30% and 60%, respectively). 

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One interim analysis will be performed at approximately 81 subjects (50% of the 
planned sample size) completing three cycles of chemotherapy. The non-binding 
futility boundary is constructed using Lan-DeMets spending function with the 
O’Brien-Fleming approach.  Assuming an observed 35%of subjects in the control 
arm with no thrombocytopenia-induced chemotherapy dose modification in one 
cycle, the power is estimated to be 84% at the interim analysis and the probability 
of stopping for futility is 2%.  
Analysis of Primary Endpoint: 
The treatment effect with respect to the incidence of no thrombocytopenia-induced dose 
modification will be tested with a 2-sided Cochran-Mantel-Haenszel test that will adjust 
for the stratification factors at randomization.  In addition, the percentage of subjects in 
each treatment group with no thrombocytopenia-induced chemotherapy dose 
modification will be summarized with an exact binomial 95% CI.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 

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CRC = colorectal cancer; EOS = end of study; GI = gastrointestinal; IP = investigational product; LTFU = long-term follow-up; QW = once weekly; Q12W = every 
12 weeks; SC = subcutaneous, SFU = safety follow-up. 
a Subject randomization will be stratified by tumor type and baseline platelet count (< 50 x 109/L, ≥ 50 x 109/L) measured on study day 1.  GI cancers, including tumors 
of the esophagus and stomach, will be included in one stratum, pancreatic cancers in a second stratum, and CRC, including tumors of the colon or rectum, will be 
included in a third stratum.   
b Subjects will receive weekly IP dosing, starting at 2 µg/kg and increasing by increments of 1 µg/kg to a maximum dose of 10 µg/kg to reach a target platelet count of 
≥ 100 x 109/L.  Non-Amgen, non-investigational chemotherapeutic agents will be administered for the treatment of primary malignancy according to chemotherapy dose 
modification guidelines outlined in Section 7.4.1.2. 
c Treatment period will be long enough to allow for assessment of 3 planned cycles of chemotherapy.  The follow-up visit will occur 1 week after the last scheduled 
dose of investigational product.   
d Subjects will have their first in-clinic LTFU Visit at 30 (+5) days after the last dose of investigational product (SFU 1).  Subjects will be contacted 30 (+5) days after 
the last dose of the last on-study cycle of chemotherapy (up to 3 cycles) to collect adverse event information except for females who are in addition required to come to 
clinic for a highly sensitive urine or serum pregnancy test (SFU 2).  In addition, after the first LTFU Visit, all subjects will be followed by phone or in clinic every  
12 weeks (± 2 weeks) from the last dose of investigational product until the EOS.  During LTFU subjects will be followed for the diagnosis of, or progression to, 
secondary malignancies (including myeloid malignancies) or myelodysplastic syndromes as well as vital status and cause(s) of death.  Note:  30 (+5) days after the last 
dose of IP (Safety Follow-up 1) may not necessarily coincide with 30 days after the last dose of on-study cycle of chemotherapy (Safety Follow-up 2). 
e All subjects should complete EOS Visit up to 2 weeks after the last subject in the trial completes the LTFU Visit 1 year after their last dose of IP.   

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Table 2-1.  Schedule of Activities 
Procedures 
Screening 
Treatment Perioda 
Follo
w upb 
LTFUc 
EOSd 
STUDY WEEK 
Up to 28 days 1e 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
QW
f 
Q4W
g 
1 wee
k after 
last 
dose 
of IP 
SFU 
1 (30 day
s after 
last dose 
of IP) 
SFU 
2 (30 days 
after last 
dose of on-
study cycle of 
chemotherap
y) 
Q12W 
 
Window (days) 
 
 

1 

1 

1 

1 

1 

1 

1 

1 

1 

1 

1 
1 
1 
1 
+5 
+5 
2 wk
s 
+2 wk
s 
ECOG 
performance 
status 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
Electrocardiogra
mh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Assessment/ 
collection/ 
recording/reportin
g of adverse 
events/serious 
adverse events 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Xk 
Xk 
Disease status 
assessmentl 
X 
X 
 
 
 
 
 
 
Xl 
 
 
 
 
 
Xl 
X 
 
 
X 
X 
Page 2 of 5 
Footnotes are defined on the last page of the table 

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Note:  Refer to Appendix 2 for definitions of Chemistry 1, 2, 3, as well as Hematology 1 and 2. 
 a The treatment period will start on the first day of investigational product and will be long enough to allow for assessment of 3 planned cycles of chemotherapy (Please 
refer to Section 5.1).  See Section 8.2 for instructions regarding subjects that choose to discontinue from the study. 
b The follow-up visit will occur 1 week after the last scheduled dose of investigational product.  
c Subjects will enter LTFU at 30 (+5) days after the last dose of IP (SFU 1).  Subjects will be contacted 30 (+5) days after the last dose of the last cycle of 
chemotherapy (up to 3 cycles) to collect adverse event information except for females who are in addition required to come to clinic for a urine or serum pregnancy 
test (SFU 2).  In addition, after the first LTFU Visit, all subjects will be followed by phone or in clinic every 12 weeks (± 2 weeks) from the last dose of 
investigational product until the EOS.  Note:  30 (+5) days after the last dose of IP (SFU 1) may not necessarily coincide with 30 days after the last dose of 
on-study cycle of chemotherapy (SFU 2). 
d All subjects should complete EOS Visit up to 2 weeks after the last subject in the trial completes LTFU at 1 year after the last dose of IP.  EOS Visit can be done by 
phone. 
e The date of the first dose of investigational product is defined as day 1, and will occur on the same day as randomization.  Subsequent study days will occur every 
7 days (± 1 day). 
f After week 12, perform assessments weekly as indicated. 
g After week 12, perform assessments every 4 weeks as indicated. 
h Electrocardiogram will be obtained once during screening period per local institution standard of care. 
i All concomitant therapies will be collected until completion of safety Visits 1 and 2 after which collected concomitant therapies will include the following:  platelet 
related medications: commercial romiplostim, eltrombopag, avatrombopag, lusutrombopag, fostamatinib, and anticoagulants, only. 
j Non-serious adverse events possibly related to any study procedures are reported after signing of the ICF.  All other non-serious adverse events are reported after the 
first dose of protocol-required therapies.  All serious adverse events are reported after signing of the ICF. 
k Both non-serious adverse events and serious adverse events will be collected through 30 (+5) days after the last dose of protocol-required therapies 
(romiplostim/placebo [IP], chemotherapy [non-IP] up to 3 cycles).  Note:  For subjects who discontinue IP prior to completing 3 cycles of chemotherapy, non-serious 
adverse events should be collected through 3 on study chemotherapy cycles.  Serious adverse events will be collected through the EOS.  For the whole duration of 
the LTFU period, non-serious adverse events will be collected through EOS only if mandated by country-specific requirements.  
l Subjects will be followed for the diagnosis of, or progression to, secondary malignancies (including myeloid malignancies) or myelodysplastic syndromes, as well as 
vital status and cause(s) of death.  During the treatment period, disease status assessment will be performed on day 1, week 8 (± 2 weeks), then every 8 (± 2) weeks 
thereafter, and at follow up.  Radiographic assessment is not mandatory during these time intervals. 
m Following enrollment and initiation of IP, the first cycle of chemotherapy during the treatment period should not be administered until platelet counts are ≥ 100 x 109/L 
or until at least week 4, whichever comes first (see Section 7.4.1.2).  Do not start the first cycle of on-study chemotherapy before study week 2.  Thereafter, 
non-Amgen, non-investigational chemotherapeutic agents will be administered for the treatment of primary malignancy according to chemotherapy dose modification 
guidelines outlined in Section 7.4.1.2.  Chemotherapy administration, including information about planned and actual chemotherapy dose and schedule, should be 
recorded throughout 3 on study cycles, at the follow up at one week after the last dose of IP, SFU 1 and SFU 2.  The start of the planned chemotherapy must be no 
more than 2 days after the local laboratory assessments have been taken during the study visit. 
n For subjects who discontinue IP prior to completing 3 cycles of chemotherapy, platelet transfusions should be recorded through 3 on-study chemotherapy cycles. 
o

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p ANC and hemoglobin will be assessed locally.  ANC will be collected through 30 (+5) days after the last dose of IP.  ANC values taken during the study visit (±1 day) 
and recorded in the CRF must be the same values as used for chemotherapy dose modifications where applicable.  For subjects who discontinue IP prior to 
completing 3 cycles of chemotherapy, ANC should be recorded through 3 on-study chemotherapy cycles and the values recorded must be those taken prior to 
scheduled chemotherapy visits and used to inform decisions relating to chemotherapy dose modification.  Any ANCs performed outside of the study visits should 
be recorded if they are used to determine chemotherapy dose in study cycles 1, 2, and 3. 
q If there are multiple platelet values performed on a study visit date, the platelet value from the test performed most immediately prior to the time of the planned 
investigational product and/or non-IP administration will be recorded as the platelet value for that study visit date and will be used to determine the subject’s dose of 
investigational product and, when applicable, chemotherapy dose modifications which include dose reductions, delays, omissions, and discontinuations.  The platelet 
count taken during the study visit (± 1 day) and recorded in the CRF must be the same values as used for IP dose calculations and chemotherapy dose modifications 
where applicable.  For subjects who discontinue IP prior to completing 3 cycles of chemotherapy, platelet counts should be measured through 3 on-study 
chemotherapy cycles to the end of the third on-study cycle and the values recorded must be those taken prior to scheduled chemotherapy visits and used to inform 
decisions relating to chemotherapy dose modification.  Any platelet counts performed in the cycle prior to enrollment should be recorded if they are used to 
determine chemotherapy dose in study cycle 1.  Any platelet counts performed outside of the study visits should be recorded if they are used to 
determine chemotherapy dose in study cycles 1, 2, and 3.   
r Platelet count required prior to receiving the first dose of IP on day 1 – see Section 6.1, inclusion criterion 110.   
s At screening, full chemistry panel to be performed (at screening, both local and central chemistry and hematology labs are to be performed, however, 
local lab values may be used for eligibility).  Thereafter, local lab values for BUN, creatinine, creatinine clearance, GFR, ALT, AST, Alk phos, and total bilirubin 
will be reported at randomization and when a subject is scheduled to receive chemotherapy through 3 on-study chemotherapy cycles.  Local lab chemistries do not 
need to be reported if a subject is not scheduled to receive chemotherapy.  Local lab chemistries taken during the study visit (± 1 day) and recorded in the CRF must 
be the same values as used for chemotherapy dose modifications where applicable.  For subjects who discontinue IP prior to completing 3 cycles of chemotherapy, 
BUN, creatinine, creatinine clearance, GFR, ALT, AST, Alk phos, and total bilirubin should be recorded through 3 on-study chemotherapy cycles for subjects and 
the values recorded must be those taken prior to scheduled chemotherapy visits and used to inform decisions relating to chemotherapy dose modification.  Any of 
these local chemistries performed outside of the study visits should be recorded if they are used to determine chemotherapy dose in study cycles 1, 2, 
and 3. 
t A highly sensitive urine or serum pregnancy test must be performed prior to enrollment within 72 hours prior to the first dose of IP, monthly during the treatment 
period and then at 30 days after the last dose of investigational product and 30 (+5) days after the last dose of protocol-required therapies 30 (+5) days after the last 
dose of on-study cycle of chemotherapy non IP [up to 3 cycles]).  
u Pharmacokinetic samples must be taken prior to administration of IP.  
v Baseline antibody samples must be obtained on day 1 before the first administration of IP.  
w Subjects who test positive for neutralizing antibodies to romiplostim or TPO at the follow up visit will be asked to return for additional follow up testing  
(see Section 9.2.6). 
x Only for subjects without a diagnosis at screening.  Subjects with a known diagnosis of active chronic Hepatitis B or C will require PCR for viral load assessment per 
eligibility criteria.  If medical history confirms HIV infection, no need to repeat test during screening; subject will be ineligible.  Central test required only if cannot be 
performed locally. 
y Investigational product should be administered every 7 days (± 1 day) starting from study day 1.  See Section 5.1 for details on when investigational product 
ends. 
z Collected as part of the local Hematology 1 analysis at screening. 
aa At screening, both local and central chemistry and hematology labs are to be performed, however, local lab values may be used for eligibility. 
 

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3. 
Introduction 
3.1 
Study Rationale 
This trial is designed to study romiplostim for the treatment of chemotherapy-induced 
thrombocytopenia (CIT) in patients receiving oxaliplatin-based chemotherapy regimen 
for the treatment of gastrointestinal, pancreatic, or colorectal cancer, which includes 
cancers of the esophagus, stomach, colon, or rectum.  This is a randomized, 
double-blind, placebo-controlled trial to study the safety and efficacy of romiplostim in 
this patient population.  Current management of CIT includes platelet transfusions, 
chemotherapy dose delays and/or dose reductions, and in the United States (US), 
oprelvekin (Neumega) (Neumega Package Insert, 2011).  However, due to its side 
effect profile, oprelvekin is rarely used in the clinical setting and it is no longer available 
from the manufacturer.  Platelet transfusions are often reserved for patients with severe 
thrombocytopenia (platelet counts  10 x 109/L) due to transfusion-associated costs and 
the potential for transfusion-associated adverse events including, but not limited to, 
infections, allergic reactions, and alloimmunization leading to platelet transfusion 
refractoriness (Kuter, 2015).  Chemotherapy dose delays and dose reductions are the 
most commonly utilized measures for managing CIT.  These measures lead to a 
reduction in chemotherapy relative dose intensity, with literature noting the importance of 
receiving full-dose chemotherapy on schedule in the adjuvant setting 
(Denduluri et al, 2015; Lyman et al, 2003).  Therefore, an unmet need exists for 
alternative treatment options for CIT.  Two prior Amgen-sponsored studies, which used 
fixed doses of romiplostim at the beginning of each chemotherapy cycle, showed no new 
safety signals but did not demonstrate efficacy (Fanale et al, 2009; Natale et al, 2009).  
Several investigator-sponsored studies, which dosed romiplostim pre- and 
post-chemotherapy dose, also showed no new safety signals but did demonstrate 
moderate efficacy (Vadhan-Raj et al, 2010; Vadhan-Raj et al, 2009).  A recent 
investigator-sponsored study, using a weekly romiplostim dosing schedule, provided 
evidence of efficacy in the treatment of CIT in patients with solid tumors 
(Soff et al, 2017).   
3.1.1 
Rationale for Study Population 
The planned phase 3 study will enroll subjects with documented active gastrointestinal, 
pancreatic, or colorectal cancer who have CIT as a consequence of receiving 
an oxaliplatin-based chemotherapy regimen containing 5-fluorouracil 5-FU or 
capecitabine and oxaliplatin (plus irinotecan in FOLFIRINOX or FOLFOXIRI).  In patients 
with metastatic colorectal cancer (CRC), a FOLFOX regimen has been demonstrated in 

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several studies to increase survival rate and decrease disease progression (Andre et al, 
2004; Goldberg et al, 2004).  Thrombocytopenia has been noted in more than 70% of 
patients receiving FOLFOX (Andre et al, 2004).   
In the adjuvant setting, the importance of receiving full-dose chemotherapy on schedule 
(ie, high relative dose intensity) has been well established (Denduluri et al, 2015; 
Lyman et al, 2003).  A retrospective study in patients with metastatic colorectal cancer 
noted that patients with a higher median chemotherapy dose intensity had a positive 
correlation with disease response rate, progression-free survival, and overall survival 
(Nakayama et al, 2014).  Similarly, another retrospective multi-center cohort of patients 
with stage III colon cancer noted improved overall survival and disease-free survival in 
patients receiving a higher relative dose intensity (Aspinall et al, 2015).  Therefore, given 
previous evidence from the literature to suggest the importance of maintaining 
chemotherapy dose intensity in colon and rectal cancers, these tumor types were 
chosen for this study to be able to demonstrate the ability to treat CIT and resume 
chemotherapy treatment.  
3.1.2 
Rationale for Study Duration 
The planned phase 3 studies include a treatment period which will be long enough to 
allow for assessment of 3 planned cycles of chemotherapy.  Subjects entering the study 
will have already received at least one cycle of chemotherapy and noted to have CIT.  
Subjects must have at least 3 remaining planned cycles of chemotherapy.  
Chemotherapy regimen for gastrointestinal, pancreatic, and colorectal cancer uses a 
combination of 5-FU or capecitabine and oxaliplatin (plus irinotecan in FOLFIRINOX or 
FOLFOXIRI). (NCCN Colon Cancer, 2017; NCCN Rectal Cancer, 2017).   
3.2 
Background 
3.2.1 
Disease 
Chemotherapy used to treat cancer can suppress a patient’s bone marrow, which can 
lead to a drop in platelets, neutrophils, and other blood counts.  The occurrence of CIT 
varies with the type and schedule of chemotherapy used.  A retrospective, observational 
cohort study using electronic medical records of over 47 000 adult cancer patients noted 
a prevalence of thrombocytopenia after initiation of chemotherapy ranging between 
21.9 to 64.2 of patients, depending upon the specific chemotherapy regimen 
(Wu et al, 2009).  A separate single-institution retrospective cohort study of 676 adult 
patients receiving chemotherapy noted the frequency of overall thrombocytopenia at 
21.8 (Ten Berg et al, 2011). 

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Chemotherapy-induced thrombocytopenia is a commonly observed effect of 
myelosuppressive chemotherapy.  Clinical symptoms of CIT can occur when platelet 
counts drop below 50 x 109/L and include nosebleeds, bleeding from the gums, 
excessive bleeding from cuts, bruising, petechiae, and increased bleeding during 
surgical and invasive procedures.  In addition, thrombocytopenia increases the risk of 
bleeding among cancer patients who need to be on anticoagulation due to history of 
thromboembolic events.  Chemotherapy-induced thrombocytopenia with platelet counts 
below 100 x 109/L may also lead to a delayed delivery of chemotherapy or a reduction in 
the chemotherapy dose, both of which adversely affects patients (Elting et al, 2001).  It is 
difficult to predict which patients will develop prolonged CIT, and currently the only 
treatments for CIT are observation with chemotherapy dose delay or dose reduction, or 
supportive care with platelet transfusions.  Platelet transfusions are usually reserved for 
patients who experience bleeding while thrombocytopenic or when platelet levels drop 
below 10 x 109/L.  Platelet transfusions often resolve the thrombocytopenia and are 
usually needed for only 3 to 4 days (Kuter, 2015).  Although the benefits from platelet 
transfusions are short-lived, they have the potential to reduce hemorrhagic 
complications; however, repeated transfusions increase the risk of transfusion reactions, 
alloimmunization, and the transmission of infectious agents (Goodnough and DiPersio, 
2002; Schiffer, 2001) and increase health care costs associated with the management of 
these side effects (Heyman and Schiffer, 1990).  In the US, interleukin (IL)-
11 (oprelvekin) has been approved for the prevention of severe thrombocytopenia and 
the reduction of the need for platelet transfusions in patients following myelosuppressive 
chemotherapy.  However, it has been shown to have limited clinical efficacy 
(Gordon et al, 1996; Tepler et al, 1996; Vredenburgh et al, 1998).  Clinical use of 
oprelvekin has been hindered by side effects, including fluid retention, arrhythmias, 
pulmonary edema, and a boxed warning for allergic reactions, including anaphylaxis 
(Neumega United States Prescribing Information).  Moreover, oprevelkin is no longer 
available from the manufacturer.  Because of the lack of availability of safe and 
efficacious therapies, treatment for CIT is considered an unmet clinical need.  This need 
for alternative treatment options for CIT is particularly important for patients receiving 
curative therapy, where dose reductions may lead to poorer disease-free and overall 
survival (Hassan and Waller, 2015; Kuter, 2015). 
3.2.2 
Amgen Investigational Product Background:  Romiplostim 
Romiplostim is a second-generation thrombopoietin (TPO) receptor agonist that 
resemble the function of TPO, but not the peptide structure (Kuter, 2010).  Romiplostim 

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is a “peptibody” formed by the fusion of the Fc portion of an IgG1 monoclonal antibody 
with 4 TPO mimetic peptides.  Romiplostim binds the distal cytokine homology region of 
the TPO receptor and activates the Janus kinase (JAK) and signal transducer and 
activator of transcription (STAT) pathways and the mitogen-activated protein (MAP) 
kinase pathways.  This in turn boosts platelet production similar to endogenous TPO 
(Broudy and Lin, 2004; Kuter, 2010).   
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
romiplostim is provided in the Romiplostim Investigator’s Brochure. 
3.2.3 
Amgen-sponsored CIT Studies 
Two studies have been conducted to evaluate romiplostim in subjects who are 
thrombocytopenic due to the effects of cancer chemotherapy: one study in adult subjects 
with lymphoma and the other study in adult subjects with non-small cell lung cancer 
(NSCLC).  The primary objectives of each study were to evaluate safety and neither 
study demonstrated new safety signals.  
Study 20050154 was a phase 2, randomized, double-blind, placebo-controlled, 
sequential dose-escalation cohort study designed to identify a well-tolerated, effective 
dose and schedule of romiplostim in subjects with NSCLC who had previously 
experienced thrombocytopenia during the chemotherapy cycle immediately preceding 
study entry.  The primary objective was to evaluate safety, and the secondary objective 
was to evaluate efficacy. 
Sixty-three subjects with stage IIIB or stage IV NSCLC who received 21-day cycles of 
gemcitabine/carboplatin or gemcitabine/cisplatin were enrolled in the study.  Subjects 
were sequentially enrolled into 3 dosing cohorts (250, 500, or 750 g) and received 
1 subcutaneous administration of placebo or romiplostim on day 2 of each 
chemotherapy cycle.  Within each cohort, subjects were allocated to romiplostim or 
placebo in a ratio of 4:1, respectively.   
Two subjects (12.5) in the 250 g romiplostim cohort had treatment-related adverse 
events, and 1 subject in the 500 g romiplostim cohort had treatment-related 
grade 2 platelet count increase, which resulted in discontinuation of romiplostim.  
Serious adverse events were reported in 8.3, 43.8, 27.8, and 31.3 of subjects in 
the placebo, 250, 500, and 750 g romiplostim cohorts, respectively; none were 
considered related to investigational product.   

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No statistically significant differences were observed between placebo and romiplostim 
for any of the secondary efficacy endpoints.   
3.2.4 
Investigator-sponsored CIT Studies 
Phase 1/2 studies in solid tumors using pre- and post-chemotherapy dose schemas 
demonstrated the safety and efficacy of romiplostim in these settings.  Current ongoing 
investigator-sponsored study, using a weekly dosing strategy titrated to a target platelet 
count, provided evidence of efficacy in this patient population.  
3.2.4.1 
Phase 1/2 Study of Romiplostim in Solid Tumors  
The safety and efficacy of romiplostim was evaluated in a phase 1/2 study in subjects 
with solid tumors.  Twenty-four subjects who were receiving high-dose chemotherapy 
with carboplatin or doxorubicin and/or ifosfamide were administered romiplostim: 
cohorts 1 and 2 received chemotherapy alone in cycle 1 and with romiplostim in cycle 2.  
Cohort 1 was dosed at 1, 3, or 10 µg/kg subcutaneously for 2 doses, 2 days apart 
starting the day after chemotherapy (post-chemo dosing schedule) 
(Vadhan-Raj et al, 2009).  Cohort 2 was dosed at 10 µg/kg 5 days prior to chemotherapy 
and again following chemotherapy (pre- and post-chemo dosing schedule). 
Twenty-four subjects who received chemotherapy with romiplostim (compared to 
chemotherapy without romiplostim) had a reduction in the duration of thrombocytopenia 
and the platelet nadir counts were either stable or increased.  The number of days with 
platelet counts  100 x 109/L was 7 days in the chemotherapy with romiplostim group 
compared to 10 days in the chemotherapy without romiplostim group (p  0.023), and 
the days with platelet counts  50 x 109/L was 2 days vs 6 days (p  0.001), respectively.  
In the ifosfamide group (n  20), platelet nadir decreased in 7 patients, increased in 
5 patients, and was stable in 8 patients.  The study showed that romiplostim was safe in 
combination with high-dose chemotherapy regimen and reduced severe 
thrombocytopenia and platelet transfusions. 
This study demonstrated efficacy and safety in a combination therapy setting.  However, 
this study enrolled a small number of subjects and did not include efficacy endpoints that 
definitively show clinical benefit of romiplostim in CIT.  
3.2.4.2 
Retrospective Reviews of Romiplostim Use for CIT 
Parameswaran et al (2014), performed a retrospective review of the use of romiplostim 
for dose-limiting CIT in 20 patients at Memorial Sloan-Kettering Cancer Center 
from 2010 to 2012.  Romiplostim was initiated at 1 to 2 g/kg weekly, with dose 

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escalation by 1 g/kg per week until platelet counts responded to  100 x 109/L.  If 
patients resumed chemotherapy, weekly romiplostim was continued.   
Romiplostim improved platelet counts in all 20 patients.  In 19 of 20 patients, platelet 
counts of  100 x 109/L were achieved.  The mean dose of romiplostim to achieve 
adequate platelet response was 2.9 g/kg (range 1.0 to 5.1 g/kg).  Sixteen patients 
achieved platelet response by 2 weeks.  Fifteen patients resumed cytotoxic 
chemotherapy with continued romiplostim support, and 14 tolerated at least 
2 subsequent cycles of chemotherapy, on schedule, without recurrence of dose-limiting 
CIT.   
Review of safety data showed 3 events of deep-vein thrombosis, which would not be 
unexpected in this patient population.  Overall, the immune thrombocytopenia weekly 
dose strategy demonstrated efficacy and safety in this solid tumors retrospective study. 
Al-Samkari et al (2018) performed a retrospective review of the concurrent use of 
romiplostim with cancer chemotherapy in 42 patients at Massachusetts General Hospital 
from 2010 to 2017, of which 22 patients met all inclusion criteria and had an underlying 
solid tumor diagnosis.  The median platelet count nadir prior to romiplostim use was 
74 x 109/L (range 21 – 145 x 109/L).  Romiplostim was administered weekly with a 
median starting dose of 3 µg/kg (range 1 - 10 µg/kg).  Ten of 17 (59%) patients with 
baseline platelet counts < 100 x 109/L achieved platelet counts ≥ 100 x 109/L one week 
after a single dose of romiplostim, with 76% (13 of 17) achieving platelet counts ≥ 100 x 
109/L after 2 to 3 weekly doses.   
All 22 patients were able to receive two or more chemotherapy cycles while on 
romiplostim, with 18 patients receiving chemotherapy at or above the dose intensity of 
the chemotherapy cycle prior to starting romiplostim.   
Review of safety data was notable for no patients having had a thrombotic event while 
receiving romiplostim.  Three (14%) patients had bleeding events but did not require 
platelet transfusions.  Four (18%) patients received platelet transfusions with 2 in 
preparation for a procedure, 1 for anemia and thrombocytopenia, and 1 for treatment of 
CIT.  
3.2.4.3 
Ongoing Investigator-sponsored Study 
In a randomized, controlled study with a cross-over design, subjects with CIT 
(platelets  100 x 109/L) for at least 4 weeks despite chemotherapy delay or dose 

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reduction were randomized 2:1 romiplostim (2 g/kg) to control (observation) 
(Soff et al, 2017).   
The primary endpoint was the proportion of patients achieving a platelet count 
 100 x 109/L by the end of a 3-week treatment period.  Secondary endpoints included 
ability to tolerate resumption of chemotherapy for at least 2 cycles without recurrence of 
CIT. 
An interim analysis was conducted with 23 subjects (n  15 romiplostim arm, 
8 observation arm).  Platelet counts for 14 subjects (93) in the romiplostim arm 
corrected within 3 weeks.  In the observation arm, the platelet levels in 1 subject (12.5) 
spontaneously corrected in 3 weeks, representing a statistically significant difference 
(p  0.001).  The observational arm was discontinued and all subsequent subjects were 
enrolled in the treatment arm. 
Of the 32 subjects who received up front romiplostim, 27 subjects (84%) were able to 
achieve platelet counts ≥ 100 x 109/L by the third week, and 25 subjects (78%) in the 
romiplostim group were able to resume chemotherapy after correction of their CIT. 
There was no evidence of bone marrow side effects from romiplostim treatment.  Four 
(12.5%) of 32 subjects experienced a thromboembolic event (Soff et al, 2017).   
3.3 
Benefit/Risk Assessment 
The following benefit risk assessment supports the conduct of this clinical trial.  
Reference should be made to the Investigator’s Brochure for further data on romiplostim. 
3.3.1 
Therapeutic Context 
Therapeutic options for CIT are limited.  Current management of CIT includes platelet 
transfusions, chemotherapy dose delays and/or dose reductions. 
Platelet transfusions are often reserved for patients with severe thrombocytopenia 
(platelet counts < 10 x 109/L) due to transient benefit and the potential for 
transfusion-associated adverse events including, but not limited to, infections, allergic 
reactions, and alloimmunization leading to platelet transfusion refractoriness (Hod and 
Schwartz, 2008; Kuter, 2015; Slichter et al, 2005).  Chemotherapy dose delays and dose 
reductions are the most commonly utilized measures for managing CIT.  Multiple studies 
across different malignancies have shown that these measures lead to a reduction in 
chemotherapy relative dose intensity (RDI), which may decrease the therapeutic effect 

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of treatment and diminished overall survival of patients (Denduluri et al, 2015; Loibl et al, 
2011; Vadhan-Raj et al, 2009; Lyman et al, 2003).   
Treatment for CIT is considered an unmet medical need because of the lack of safe and 
efficacious therapies in this setting (Kuter, 2015).  This need for alternative treatment 
options for CIT is particularly important for patients receiving curative therapy, where 
dose reductions may lead to poorer disease-free and overall survival 
(Hassan and Waller, 2015; Kuter, 2015). 
3.3.2 
Key Benefits 
3.3.2.1 
Ability to Administer On-time, Full Dose Chemotherapy 
Dose reduction or delays in chemotherapy caused by thrombocytopenia can lead to a 
reduction in relative dose intensity, which can decrease the efficacy of chemotherapy 
and lead to diminished overall survival and health outcomes in patients (Denduluri et al, 
2015; Loibl et al, 2011; Vadhan-Raj et al, 2009; Lyman et al, 2003), therefore the ability 
to administer on-time, full-dose chemotherapy is considered to be a key favorable effect.  
In the retrospective review of romiplostim use for dose-limiting CIT in subjects with a 
wide range of cancer types, 15 of 20 subjects were able to resume cytotoxic 
chemotherapy with continued romiplostim support and 14 tolerated at least 
2 subsequent cycles of chemotherapy, on schedule, without recurrence of dose-limiting 
CIT (Parameswaran et al, 2014).  Analysis of the ongoing, randomized, controlled phase 
2 crossover investigator-initiated studies (IISs) (Soff et al, 2017) of weekly romiplostim 
dosing versus observation for CIT, showed that 84% (27 of 32) of subjects who received 
up front romiplostim were able to achieve platelet counts ≥ 100 x 109/L by the third week, 
and 78% (25 of 32) of subjects in the romiplostim group were able to resume 
chemotherapy after correction of their CIT. 
3.3.2.2 
Reduction in Incidence of ≥ Grade 2 Bleeding Events 
Another key favorable effect is related to the reduction in bleeding events (≥ grade 2) in 
subjects with CIT, which can occur as a consequence of CIT when platelet counts fall 
below 50 x 109/L and can have severe outcome, including death (Elting et al, 2001).   
3.3.2.3 
Reduction in Incidence of Platelet Transfusions 
Platelet transfusions are usually reserved for severe thrombocytopenia following 
chemotherapy due to the potential for transfusion associated side-effects and high 
healthcare costs associated with management of these effects (Kuter, 2015; Heyman 

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and Schiffer, 1990).  It is anticipated that romiplostim will raise platelet counts faster than 
placebo, resulting in the decreased incidence of platelet transfusions.   
3.3.2.4 
Platelet Nadir 
A clinically important effect of nadir platelet counts caused by chemotherapy includes 
bleeding, which can necessitate the need for transfusions and may potentially have a 
severe outcome, including death (Elting et al, 2001).   
3.3.2.5 
Time to First Platelet Response 
A faster platelet response can prevent the need for chemotherapy dose delays, leading 
to improved overall survival in patients.  In the retrospective review of patients with CIT, 
19 of 20 subjects achieved platelet counts ≥100 x 109/L by 3 weeks (Parameswaran et 
al, 2014).  Analysis of the ongoing, randomized, controlled phase 2 crossover 
investigator-initiated studies (Soff et al, 2017) of weekly romiplostim dosing versus 
observation for CIT, showed that 84% (27 of 32) of subjects who received up front 
romiplostim were able to achieve platelet counts ≥ 100 x 109/L by the third week.  In the 
observation group, only 1 of 8 subjects (13%) achieved platelet counts ≥ 100 x 109/L by 
the third week (p < 0.001).  
3.3.3 
Key Risks 
3.3.3.1 
Medication Errors 
Romiplostim is administered in small volumes via subcutaneous injection, and small 
differences in dose may have large effects on platelet counts.  Overdose may result in 
an excessive increase in platelet counts associated with thrombotic/thromboembolic 
complications; underdose may result in low platelet counts that can lead to an increased 
risk of bleeding events.  No medication errors were reported in the Study 20050154, an 
Amgen CIT study.  See Section 7.1.1.2 for information on dosage, administration, and 
schedule of investigational product. 
3.3.3.2 
Thrombotic/Thromboembolic Complications 
Thrombotic complications, which can represent one of the earliest signs of cancer, occur 
at a higher rate in cancer patients than in the general population and have important 
implications for treatment and quality of life (Clagett et al, 1988; Cronin-Fenton et al, 
2010; Prandoni et al, 2002; Shen et al, 1980; White et al, 2005).  Most commonly, these 
events are deep vein thrombosis (DVT) or pulmonary embolism, which are both forms of 
venous thromboembolism (VTE).  Arterial events, such as stroke and myocardial 
infarction occur less commonly (Falanga, 2005).  Venous thromboembolism is also 
associated with increased mortality in cancer patients (Khorana et al, 2006; Lyman, 

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2011).  Chemotherapy agents most strongly correlated with thrombotic complications are 
platinum (8% to 18%), such as cisplatin or carboplatin, asparaginase (4% to 14%), 
fluorouracil (15% to 17%), and antiangiogenic agents, such as thalidomide and 
lenalidomide (Kroger et al, 2006).  Cisplatin, in particular, is correlated with a 12% to 
18% risk of strokes, recurrent peripheral arterial events, and aortic thrombosis (Numico 
et al, 2005).  Research has consistently shown that chemotherapy treatment significantly 
increases the risk of thromboembolic events (Haddad and Greeno, 2006; Kyriazi and 
Theodoulu, 2013; Lyman, 2011). 
In addition to the increased risk of VTE in this patient population, romiplostim treatment 
is expected to increase the number of circulating platelets and platelet counts above the 
normal range and thus carries a theoretical risk for thrombotic/thromboembolic 
complications.  These complications have a high patient impact and any clinical 
sequelae (eg, stroke) may not be reversible.  In this study, subjects with platelet counts 
> 450 x 109/L will have investigational product withheld, with treatment re-initiated when 
platelet counts are ≤ 450 x 109/L (refer to Section 7.4.1.1 for dosage adjustments). 
In the retrospective review of romiplostim for use for dose-limiting CIT 
(Parameswaran et al, 2014), the safety data showed 3 of 20 subjects experienced DVT, 
which would not be unexpected in this patient population.  Three of 51 subjects in the 
phase 1/2 IIS (NCT00147225 Vadhan-Raj et al, 2009), in subjects with solid tumors 
treated with romiplostim, experienced a thromboembolic event (2 subjects with 
pulmonary embolism and 1 subject with DVT). 
In the Amgen-sponsored Study 20050154, none of the subjects in the placebo group 
and 1 subject in each romiplostim-treatment dosage groups experienced a 
thrombotic/thromboembolic event (thrombophlebitis, retinal artery occlusion, and 
pulmonary embolism, respectively). 
3.3.3.3 
Reoccurrence of Thrombocytopenia After Cessation of Romiplostim 
For many patients receiving romiplostim, it is likely that treatment may eventually need to 
be stopped.  There is a clear potential mechanism for increased risk of bleeding if 
treatment is discontinued in the presence of anticoagulants or anti-platelet agents.  
Withdrawal of romiplostim results in decreased TPO receptor stimulation, resulting in a 
decrease in platelet production.  Cases can potentially be very serious and severe 
(including life-threatening cases); however, the risk of recurrence of thrombocytopenia 
can be monitored.  There is currently no subject incidence data available for the adult 
CIT patient population.  In Amgen Study 20050154, although platelet counts were 

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monitored at 1 week after the end of the last chemotherapy cycle (approximately 
4 weeks after the last dose of investigational product), the lack of treatment efficacy 
limited assessment for re-occurrence of thrombocytopenia after cessation of 
romiplostim. 
3.3.3.4 
Increased Bone Marrow Reticulin 
The risk of increased bone marrow reticulin or bone marrow fibrosis is not well 
documented in patients with solid tumors.  Bone marrow changes are more commonly 
studied and frequently occur in patients with hematologic malignancies.  Reticulin 
fibrosis is associated with many benign and malignant conditions (Kuter et al, 2007b).  A 
few studies have sought to elucidate the relationship between increases in bone marrow 
fibrosis and disease pathology (Kuter et al, 2007b).   
Increased bone marrow reticulin may be due to the increased number of 
megakaryocytes in the bone marrow and their subsequent release of cytokines as a 
result of TPO receptor stimulation, consistent with findings associated with other TPOs 
(Kuter, 2007a; Tefferi, 2005).  Increases in bone marrow reticulin have not been 
associated with adverse clinical sequelae, and the reticulin grade are reversible after 
romiplostim is discontinued (Kuter et al, 2009; Study 20080009).   
As with bone marrow fibrosis, romiplostim is not intended to be used chronically in 
subjects with CIT, therefore the risk of increased bone marrow reticulin in subjects with 
CIT is reduced.  Bone marrow evaluations were not part of Study 20050154.  One of 
20 subjects in the retrospective review of romiplostim use in CIT had a repeat bone 
marrow aspirate and biopsy performed after completion of approximately 1 year of 
romiplostim, with no evidence of increased reticulin deposit.   
3.3.3.5 
Bone Marrow Fibrosis 
Bone marrow fibrosis may be potentially very serious and severe, and can cause 
progressive anemia, leukopenia or leukocytosis, thrombocytopenia or thrombocytosis, 
and multi-organ extramedullary hematopoiesis, most commonly causing hepatomegaly 
and symptomatic splenomegaly (Kuter et al, 2007b).  In idiopathic thrombocytopenic 
purpura subjects, increases in bone marrow reticulin have not been associated with 
adverse clinical sequelae, and the reticulin grade are reversible after romiplostim is 
discontinued (Kuter et al, 2009; Study 20080009).  However, in the CIT population the 
risk of bone marrow fibrosis is reduced as romiplostim is not intended to be used 
chronically.   

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3.3.3.6 
Progression of Existing Myelodysplastic Syndrome 
Myelodysplastic syndromes are a group of bone marrow disorders characterized by the 
failure to produce enough healthy blood cells, most commonly in the elderly 
(Bonadies et al, 2017).  Myelodysplastic syndrome is associated with cytopenias and 
increased risk of bleeding and infection (Sekeres and List, 2006).  Cancer patients 
treated with chemotherapy are at elevated risk of developing myelodysplastic syndrome 
(MDS).  Myelodysplastic syndrome that occurs after chemotherapy or radiation 
treatment is known as secondary MDS and can often develop into acute myeloid 
leukemia (AML) (Bonadies et al, 2017).   
Conventional chemotherapy-related leukemia (ie, myelodysplasia and AML) has a 
median time to development of 3 to 5 years, with the risk decreasing markedly after the 
first decade (Bhatia, 2013).  Secondary MDS accounts for about 10% of MDS cases and 
the typical latency period after exposure is 5 to 7 years (Sekeres, 2010).  For TPO 
receptor agonists, there is a theoretical concern that they may stimulate the progression 
of existing myeloid malignancies or MDS.   
In addition, there is concern that romiplostim may change the natural rate of progression 
of MDS to AML.  The evaluation of this risk is confounded by the difficulty of 
distinguishing leukemic blasts from normal early hematopoietic blasts.  In subjects with 
MDS, the natural history of the disease is worsening of the condition, ultimately leading 
to the development of AML.  This is an expected consequence of the disease 
(Germing et al, 2008; Shi et al, 2004). 
In an MDS placebo controlled study (Study 20060198), during the 58-week study period 
in the safety analysis set (168 Nplate and 82 placebo), progression to AML occurred in 
10 (6.0%) subjects in the Nplate arm and 4 (4.9%) subjects in the placebo arm (hazard 
ratio [95% CI] = 1.20 [0.38, 3.84]).  Of the 250 subjects, 210 (84.0%) entered the 
long-term follow-up phase of this study.  With 5-years of follow-up, 29 (11.6%) subjects 
showed progression to AML, including 20/168 (11.9%) subjects in the Nplate arm versus 
9/82 (11.0%) subjects in the placebo arm (hazard ratio [95% CI] = 1.06 [0.48, 2.33]). 
Subjects were excluded from clinical studies (and will also be excluded from this 
study - see exclusion criteria #204) if they had a history of myelodysplastic syndrome.  
No hematological malignancy events were reported in Study 20050154. 

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3.3.4 
Conclusion 
Currently, there is no standard approach to the management of CIT beyond delay or 
reduction of chemotherapy doses and platelet transfusion support.  The benefits and 
risks of romiplostim for the treatment of CIT in the adult population with solid tumors 
have been characterized thus far with 3 IISs, a retrospective review of romiplostim use, 
and the Amgen-sponsored Study 20050154.  These clinical studies investigating the use 
of romiplostim for CIT have demonstrated a favorable benefit-risk balance.  Specifically, 
results provide supportive evidence that the use of romiplostim allows patients with CIT 
to receive chemotherapy treatment cycles as prescribed with no need to delay or reduce 
doses, and reduces severe thrombocytopenia, risk of bleeding, and platelet transfusions.  
These studies also provide evidence that romiplostim also has an acceptable safety 
profile when used in patients receiving high-dose chemotherapy regimens for different 
solid tumor types.  Based upon these studies the benefit-risk balance for romiplostim in 
the phase 3 studies in CIT is also anticipated to be favorable.   
4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
to evaluate the efficacy of romiplostim for 
the treatment of chemotherapy-induced 
thrombocytopenia (CIT) in patients 
receiving chemotherapy for the treatment 
of gastrointestinal, pancreatic, or 
colorectal cancer, measured by the ability 
to administer on-time, full-dose 
chemotherapy 
 
no thrombocytopenia-induced 
modification of any myelosuppressive 
treatment agent in the second and third 
cycles of the planned on-study 
chemotherapy regimen.  
Thrombocytopenia-induced modifications 
include chemotherapy dose 
reduction, delay, omission, or 
chemotherapy treatment discontinuation 
due to platelet counts below 100 x 109/L 
Secondary 
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
depth of platelet nadir 
 
the depth of the platelet count nadir from 
the start of the first on-study 
chemotherapy cycle through the end of 
the treatment period   
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
time to first platelet response 
 
the time to first platelet response, defined 
by platelet count  100 x 109/L in the 
absence of platelet transfusions during 
the preceding 7 days 
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
incidence of  grade 2 bleeding events 
 
the duration-adjusted event rate of 
 grade 2 bleeding events, as assessed 
by Common Terminology Criteria for 
Adverse Events (CTCAE) 
version 5.0 grading scale 

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 
to compare the treatment effect of 
romiplostim with that of placebo on overall 
survival 
 
overall survival 
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
incidence of platelet transfusions 
 
platelet transfusion(s) during the 
treatment period  
 
to compare the treatment effect of 
romiplostim with that of placebo on the 
proportion of patients achieving platelet 
response  
 
achieving a platelet count  100 x 109/L at 
any time after study day 1 to week 4 (ie, 
7 days after the planned third dose of 
investigational product) and in the 
absence of platelet transfusions during 
the preceding 7 days   
 
overall safety of romiplostim  
 
adverse events, including 
treatment-emergent adverse events, fatal 
adverse events, serious adverse events, 
and clinically significant changes in 
laboratory values. 
 
anti-romiplostim antibodies and antibodies 
to thrombopoietin (TPO)  
 
myelodysplastic syndromes and 
secondary malignancies 
 
Exploratory 
4.2 
Hypotheses 
It is anticipated that romiplostim will raise platelet counts faster than placebo, resulting in 
more on-time and full-dose delivery of chemotherapy cycles in subjects with CIT and 
decreasing the incidence of platelet transfusions and bleeding events.   

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5. 
Study Design 
5.1 
Overall Design 
This is a phase 3, randomized, placebo-controlled, multicenter, international study for 
the treatment of CIT in adult subjects receiving oxaliplatin-based chemotherapy for the 
treatment of gastrointestinal, pancreatic, or colorectal cancer.  Subjects must have a 
platelet count ≤ 85 x 109/L on day 1 of the study.  The study will consist of a screening 
period of up to 4 weeks, a treatment period long enough to allow for assessment of 
3 planned cycles of chemotherapy, a follow-up visit, and long-term follow-up (LTFU).  
Given that subjects will be assessed for 3 planned cycles of chemotherapy, the 
oxaliplatin-based chemotherapy cycles are 2-3 weeks in duration, and the investigational 
product dose adjustment guidelines allow for up to 12 weeks of dosing before a subject 
is declared a non-responder, the majority of study subjects will receive investigational 
product for a range of between 7-21 weeks.  
Once eligibility is confirmed, subjects will be randomized on day 1 of the study in a  
2 to 1 ratio to receive either romiplostim or placebo, respectively.  Randomization will be 
stratified by tumor type and baseline platelet count (< 50 x 109/L, ≥ 50 x 109/L).  Baseline 
platelet count is defined as platelet count measured most prior to the time of the planned 
investigational product administration.  Gastrointestinal adenocarcinomas, including 
tumors of the esophagus and stomach, will be included in one stratum, pancreatic 
cancers in a second stratum, and colorectal cancers, including adenocarcinomas of the 
colon or rectum, will be included in a third stratum.  Subjects will then enter the treatment 
period, during which time they will return to the clinic weekly for local platelet counts, 
undergo dose titrations as needed, and investigational product administration.  If there 
are multiple platelet values performed on a study visit date, the platelet value from the 
test performed most immediately prior to the time of the planned investigational product 
and/or non-investigational product administration will be recorded as the platelet value 
for that study visit date and will be used to determine the subject’s dose of 
investigational product and, when applicable, chemotherapy dose modifications, which 
include dose reductions, delays, omissions, and discontinuations.  Subjects will receive 
weekly subcutaneous injections of investigational product throughout the treatment 
period, starting at 2 g/kg and increasing by increments of 1 g/kg to a maximum dose 
of 10 g/kg to reach a target platelet count of  100 x 109/L.  Dose adjustment rules will 
be followed according to Table 7-1.  If the subject will be receiving concomitant 
chemotherapy on a study visit date, investigational product will be administered 
immediately after the completion of chemotherapy infusion on chemotherapy day 1.  If 

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continuous infusion 5-FU over 46-48 hours is part of the chemotherapy regimen the 
investigational product may be administered prior to beginning or during the continuous 
infusion 5-FU.  
Subjects will have a follow-up Visit 1 week after the last dose of investigational product.  
Subjects will have their first in-clinic LTFU Visit 30 (+5) days after the last dose of 
investigational product (Safety Follow-up 1).  Subjects will be contacted 30 (+5) days 
after the last dose of the last on-study cycle of chemotherapy (up to 3 cycles) to collect 
adverse event information except for females who are in addition required to come to 
clinic for a highly sensitive urine or serum pregnancy test (Safety Follow-up 2).  Subjects 
will remain in LTFU until the last subject in the trial completes the LTFU Visit 1 year after 
the last dose of investigational product.  During the LTFU period, all subjects will be 
followed by phone or in clinic every 12 weeks (± 2 weeks) from the last dose of 
investigational product until the end of study (EOS) visit.  All subjects should 
complete EOS Visit up to 2 weeks after the last subject in the trial completes their 
LTFU Visit at 1 year after the last dose of investigational product. 
During LTFU, subjects will be followed for the diagnosis of, or progression to, secondary 
malignancies (including myeloid malignancies) or myelodysplastic syndromes, as well as 
vital status and cause(s) of death. 
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
The study will enroll approximately 162 subjects with CIT and receiving an 
oxaliplatin-based chemotherapy regimen for the treatment of documented active 
gastrointestinal, pancreatic, or colorectal cancer.  Subjects will be stratified based on 
their tumor type and baseline platelet count (< 50 x 109/L, ≥ 50 x 109/L) into 1 of 2 arms 
(placebo or romiplostim). 
Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced.   

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5.2.2 
Number of Sites 
Approximately 100 investigative sites in multiple countries, including United States, 
European Union, and countries in South America, will be included in the study.  Sites 
that do not enroll subjects within 1 year of site initiation may be closed. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s). 
Based on the definition above, the primary completion date is either the date when the 
status (information on whether a given on-study chemotherapy cycle was administered 
as planned, administered at a modified dose, delayed, omitted, or discontinued) of the 
third cycle of the planned on-study chemotherapy regimen is assessed on the last 
subject or the last subject ends the last dose of investigational product plus 30 days, 
whichever occurs later.   
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, LTFU), as applicable. 
Based on the definition above, the EOS date is the date when the last subject in the trial 
has completed his/her EOS Visit. 
5.3.2 
Study Duration for Subjects 
The study will consist of a screening period of up to 4 weeks, a treatment period which 
will be of sufficient duration to allow assessment of 3 planned cycles of chemotherapy, a 
follow-up visit one week following last dose of investigational product, and a LTFU 
period, which will begin 30 (+5) days after the last dose of investigational product.  The 
LTFU period for all subjects will continue until death or until the last subject in the trial 
completes their LTFU Visit 1 year after the last dose of investigational product.  
Therefore, duration of the study for each subject will be from approximately 14 to 
50 months, depending on the length of their LTFU period.   

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5.4 
Justification for Investigational Product Dose 
The doses selected for study were derived from the results of Amgen’s studies in healthy 
subjects and studies in immune thrombocytopenia subjects.   
The initial planned starting dose for this study is consistent with the starting dose from 
Soff et al, 2016.  Notably, the median dose of romiplostim to achieve platelet 
counts  100 x 109/L was similar from two separate retrospective reviews, with 
Parameswaran et al showing 2.9 µg/kg (range 1.0 to 5.1 µg/kg) and Al-Samkari et al 
showing 3 g/kg (range 1 to 10 µg/kg) (Al-Samkari et al, 2018; Parameswaran et al, 
2014).  The starting dose of 2 µg/kg was chosen to limit thrombocytosis which could 
contribute to a pro-thrombotic state in patients with cancer who are potentially more 
prone to thrombotic complications. 
5.5 
Patient Input on Study Design 
Not applicable.   
6. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
System (IVRS)/Interactive Web Response System (IXRS). 
Eligibility criteria will be evaluated during screening and on day 1 of the study for platelet 
count per Section 6.1, inclusion criterion 110.   
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, will not be provided. 
6.1 
Inclusion Criteria  
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures or subject’s legally acceptable representative has provided 
informed consent prior to any study-specific activities/procedures being initiated 
when the subject has any kind of condition that, in the opinion of the investigator, 
may compromise the ability of the subject to give written informed consent.   
102 
Males or females  18 years of age at signing of the informed consent. 
103 
Histologically or cytologically confirmed diagnosis of gastrointestinal, pancreatic, 
or colorectal adenocarcinoma, defined as cancers of the esophagus (including 

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esophagogastric junction [EGJ] cancer), stomach, pancreas, colon, or rectum.  
Tumor stage will not affect eligibility. 
109 
Subjects must be receiving one of the following regimens: 
 
An oxaliplatin-based chemotherapy regimen, containing 5 FU or 
capecitabine plus oxaliplatin (irinotecan may be added for FOLFIRINOX 
or FOLFOXIRI) on a 14- or 21-day schedule, respectively.  
OR 
 
Subjects must have CIT from a non-protocol chemotherapy regimen, 
planning to start treatment with 1 of the above protocol 
chemotherapy regimens which has been delayed ≥ 1 week due to 
CIT. 
Note:  Use of these regimens are permitted with (1) anti angiogenic agents (such 
as bevacizumab) or (2) targeted therapy (such as anti epidermal growth factor 
receptor agents).   
110 
Subjects must have a local platelet count ≤ 85 x 109/L on study day 1. 
106 
Subjects must be at least 14 days removed from the start of the chemotherapy 
cycle immediately prior to study day 1 if they received FOLFOX, FOLFIRINOX or 
FOLFOXIRI, and 21 days removed if they received CAPEOX. 
107 
Subjects must have at least 3 remaining planned cycles of chemotherapy at 
study enrollment. 
108 
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
Previous or Current Medical Conditions 
201 
Acute lymphoblastic leukemia. 
202 
Acute myeloid leukemia. 
203 
Any myeloid malignancy. 
204 
Myelodysplastic syndrome.  Baseline bone marrow biopsy is not required to rule 
out MDS.  However, if a bone marrow biopsy and cytogenetics were performed 
as part of diagnostic or staging work-up, these results will be collected to confirm. 
205 
Myeloproliferative disease. 
206 
Multiple myeloma. 
207 
Within 4 months prior to enrollment, any history of active congestive heart failure 
(New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, 
uncontrolled arrhythmias, clinically significant electrocardiogram (ECG) 
abnormalities, screening ECG with corrected QT (QTc) interval of  470 msec, 
pericardial disease, or myocardial infarction. 
208 
Major surgery ≤ 28 days or minor surgery ≤ 3 days prior to enrollment. 
209 
New or uncontrolled venous thromboembolism or thrombotic events within 
3 months prior to screening.  To be eligible, subjects must have received at least 

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14 days of anticoagulation for a new thrombotic event and considered to be both 
stable and suitable for continued therapeutic anticoagulation during trial 
participation. 
210 
History of arterial thrombosis (eg, stroke or transient ischemic attack) within 
6 months of screening. 
211 
Evidence of active infection within 2 weeks prior to first dose of study treatment.
230 
Known human immunodeficiency virus infection.  Subjects without a documented 
diagnosis in their medical history will require a local laboratory assessment at 
screening.  If local laboratory results are not available, use central 
laboratory results. 
231 
Known active chronic hepatitis B or C infection.  Subjects without a documented 
diagnosis in their medical history will require a local laboratory assessment at 
screening.  If local laboratory results are not available, use central 
laboratory results.  Hepatitis B and C infection is based on the following results: 
 
Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic 
hepatitis B or recent acute hepatitis B). 
 
Negative HBsAg and positive for hepatitis B core antibody: hepatitis B virus 
DNA by polymerase chain reaction (PCR) is necessary.  Detectable hepatitis 
B virus DNA suggests occult hepatitis B. 
214 
Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is 
necessary.  Detectable hepatitis C virus RNA suggests chronic hepatitis C. 
In addition to the conditions listed in exclusion criteria 201 through 206, 
secondary malignancy within the past 5 years except:  
 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
 
Adequately treated cervical carcinoma in situ without evidence of disease. 
 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease. 
 
Prostatic intraepithelial neoplasia without evidence of prostate cancer. 
 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ. 
 
Malignancy treated with curative intent and with no known active disease 
present for  3 years before enrollment and felt to be at low risk for 
recurrence by the treating physician (excluding malignancies listed in 
exclusion criteria 201 – 206). 
215 
Thrombocytopenia due to another etiology other than CIT (eg, chronic liver 
disease, prior history of immune thrombocytopenia purpura). 
Prior/Concomitant Therapy 
216 
Previous use of romiplostim, pegylated recombinant human megakaryocyte 
growth and development factor, eltrombopag, recombinant human TPO, any 
other TPO receptor agonist, or any investigational platelet producing agent. 
Prior/Concurrent Clinical Study Experience 
217 
Currently receiving treatment in another investigational device or drug study, or 
less than 28 days since ending treatment on another investigational device or 

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drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
Diagnostic Assessments 
218 
Anemia (hemoglobin  80 g/L [8 g/dL]) on the day of initiation of investigational 
product as assessed by local labs.  Use of red cell transfusions and 
erythropoietic stimulating agents is permitted throughout the study as per 
institutional guidelines.  
219 
Neutropenia (absolute neutrophil count  1 x 109/L) on the day of initiation of 
investigational product as assessed by local labs.  Use of granulocyte-colony 
stimulating factor is permitted throughout the study as per institutional guidelines. 
232 
Abnormal renal function with creatinine clearance  30 mL/min using the 
Cockcroft-Gault estimated creatinine clearance as assessed by local laboratory 
during screening.  If local laboratory results are not available, use central 
laboratory results. 
233 
Abnormal liver function (total bilirubin  3 X ULN; alanine aminotransferase [ALT] 
or aspartate aminotransferase [AST]  3 X ULN for subjects without liver 
metastases or  5 X ULN for subjects with liver metastases) as assessed by 
local laboratory during screening.  If local laboratory results are not available, 
use central laboratory results. 
Other Exclusions 
222 
Females who are pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 6 months after treatment (and 
chemotherapy) discontinuation (females of childbearing potential should only be 
included after a confirmed menstrual period and a negative highly sensitive urine 
or serum pregnancy test.) 
223 
Females of childbearing potential unwilling to use a highly effective method of 
contraception during treatment and for an additional 6 months after treatment 
(and chemotherapy) discontinuation.  Refer to Appendix 5 for additional 
contraceptive information. 
224 
Males unwilling to use contraception* (male condom or sexual abstinence) or 
their female partner(s) of childbearing potential who are unwilling to use a highly 
effective method of contraception during treatment (and chemotherapy) and for 
an additional 6 months after treatment (and chemotherapy) discontinuation.   
*If the male’s sole partner is of non-childbearing potential, he is not required to 
use additional forms of contraception during the study. 
225 
Subject has known sensitivity to any of the products to be administered during 
dosing. 
226 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg,
 to 
the best of the subject and investigator’s knowledge. 
227 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion.   

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228 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment (and chemotherapy) and for an additional period 
of 6 months after treatment (and chemotherapy) discontinuation. 
229 
Male subjects unwilling to abstain from donating sperm during treatment (and 
chemotherapy) and for an additional 6 months after treatment (and 
chemotherapy) discontinuation. 
6.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 12.3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  Subjects may be randomized into this study only once.  The 
investigator is to document this decision and date, in the subject’s medical record and 
in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as the point 
when the subject signs the informed consent) receives a unique subject identification 
number before any study-related activities/procedures are performed.  The subject 
identification number will be assigned by the IVRS/IXRS.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  Also, in case of re-consent due to expiring window for consent during 
screening, the subject number will remain the same.  This number will not necessarily be 
the same as the randomization number assigned for the study.   
6.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.   

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If a subject is a screen failure, the following electronic case report forms (eCRFs) 
are required:  Demographics, Was Subject Enrolled?, and Investigator Signature 
(electronic signature).  
If a Serious Adverse Event is observed from the time Informed Consent is signed 
up to the point of screen failure, the following eCRFs are also required:  Events, 
Medical History and Concomitant Medications.  The pages only need to be 
updated for information relating to the Serious Adverse Event.  For interventional 
trials, certain events are to be reported/transmitted to Amgen Safety within 
24 hours of awareness.  Individuals who do not meet the criteria for participation in this 
study (screen failure) may be rescreened up to 3 times at the discretion of the 
investigator.  Further rescreening requires approval from Amgen Medical Monitors.  
If a subject is being rescreened, he or she may need to reconsent to the study to ensure 
that the IRB/IEC approved main informed consent form is signed within 28 days of 
enrollment or randomization.  Subjects who are determined not eligible after rescreening 
must be screen-failed in the IVRS/IXRS and the reason for the screen-failure provided.   
7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment described in Section 7.1 below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products: Romiplostim and Placebo 
7.1.1.1 
Dose formulation 
Romiplostim will be manufactured and packaged by Amgen Inc., and distributed using 
Amgen’s clinical study investigational product distribution procedures.   
Romiplostim is supplied in a 5 mL single-use vial as a sterile, white, preservative-free, 
lyophilized powder containing histidine, mannitol, sucrose, and polysorbate 20, and has 
a pH 5.0 when reconstituted with sterile water for injection.   

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Placebo will be provided in identical 5 mL single-use vials as a sterile, white, 
preservative-free, lyophilized powder containing histidine, mannitol, sucrose, and 
polysorbate 20 and has a pH 5.0 when reconstituted with sterile water for injection. 
7.1.1.2 
Dosage, Administration, and Schedule 
Investigational product will be administered in the clinic by a qualified healthcare 
provider as a subcutaneous injection.  The starting dose of investigational product will be 
2 μg/kg based on the subject’s recorded screening weight.  Subjects will return to the 
clinic every 7 days ( 1 day) to provide platelet counts and undergo dose titrations under 
the supervision of the treating physician.  Local laboratory assessments taken during the 
study visit ( 1 day) and recorded in the CRF must be the same values as used for 
investigational product dose calculations and chemotherapy dose modifications where 
applicable. The study visits will start on study day 1 and continue every 7 days 
(1 day) measured relative to study day 1.  If there are multiple platelet values 
performed on a study visit date, the platelet value from the test performed most 
immediately prior to the time of the planned investigational product and/or 
non-investigational product administration will be recorded as the platelet value for that 
study visit date and will be used to determine the subject’s dose of investigational 
product and, when applicable, chemotherapy dose modifications which include dose 
reductions, delays, omissions, and discontinuations.  Any platelet counts performed in 
the cycle prior to enrollment should be recorded if they are used to determine 
chemotherapy dose in study cycle 1.  Any platelet counts performed outside of 
the study visits should be recorded if they are used to determine chemotherapy 
dose in study cycles 1, 2, and 3. 
Investigational product dose adjustments are based on changes in platelet counts 
only.  Weekly dose increases will continue in increments of 1 μg/kg up to a maximum 
dose of 10 μg/kg in an attempt to reach a target platelet count of  100 x 109/L (see 
Section 7.4.1.1 for more detail).  If the subject will be receiving concomitant 
chemotherapy on a study visit date, investigational product will be administered 
immediately after the completion of chemotherapy infusion on chemotherapy day 1.  If 
continuous infusion 5-FU over 46-48 hours is part of the chemotherapy regimen the 
investigational product may be administered prior to beginning or during the continuous 
infusion 5-FU.  The total volume of preparation, planned dose, quantity administered, 
start date/time, and box number of investigational product are to be recorded on each 
subject's CRF(s). 

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If the subject misses the visit window (7 days ± 1 day), the investigational product 
(IP) dose should be considered missed for that week and given at the next weekly 
study visit. 
All study visit procedures, including IP administration, must be completed within 
the study visit window (± 1 day).  
7.1.2 
Non-investigational Products 
In this study, the non-Amgen, non-investigational planned chemotherapeutic agents will 
be administered according to chemotherapy dose modification guidelines outlined in 
Section 7.4.1.2.  These guidelines will only apply to the 3 on-study cycles of this protocol 
and while recommended it will not be necessary for the investigators to follow them 
outside of the 3 study cycles. 
Chemotherapeutic agents are commercially available and will not be provided or 
reimbursed by Amgen (except if required by local regulation).  The investigator will be 
responsible for obtaining supplies.  Guidance on dose modification of chemotherapeutic 
agents can be found in Section 7.4.1.2. 
The dose of non-investigational product used, start date, stop date, and reasons for 
chemotherapy dose reduction are to be recorded on each subject's CRF(s).  The 
chemotherapy doses are to be recorded using the same units for all 3 on-study 
cycles and the cycle prior to enrollment.   
The start of the planned chemotherapy must be no more than 2 days after the 
local laboratory assessments have been taken during the study visit. 
7.1.3 
Medical Devices 
No investigational devices will be used in this study.   
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
7.1.4 
Other Protocol-required Therapies 
No additional therapies are required by the protocol.   

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7.1.5 
Other Treatment Procedures 
Other than Amgen investigational product (romiplostim and placebo) and non-Amgen, 
non-investigational standard of care chemotherapeutic agents, no other treatment 
procedures are required by the protocol. 
7.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for 
distribution to market or clinic by either (1) Amgen or (2) distributors and partners for 
whom Amgen manufactures the material.  This includes all components distributed 
with the drug, such as packaging drug containers, delivery systems, labeling, and 
inserts. 
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Product complaints will be collected for: romiplostim and placebo.  
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following medications are not permitted throughout the 3 on-study cycles: 
 
Commercially available romiplostim (Nplate) 
 
Other thrombopoietic receptor agonists (eg, eltrombopag [Promacta or Revolade], 
avatrombopag [Doptelet]) 
 
Recombinant human TPO 
 
Oprelvekin (Neumega) 
 
Herbal supplements that are associated with bleeding side effects including, but not 
limited to, gingko biloba, garlic, ginseng, fish oil, dong quai, feverfew.  Garlic and 
ginseng taken through a normal diet would not be excluded. 
 
Any other investigational agents that are not approved  
 
Subjects must not schedule any elective surgeries during the treatment period and 
for at least 28 days after the last administration of investigational product.  If a 
subject undergoes any urgent surgery during the course of the study, investigational 
product must be withheld and the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.  A subject may be allowed to resume 
investigational product if both the investigator and sponsor’s medical monitor agree 
to restart study therapy. 

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7.2 
Method of Treatment Assignment 
Subjects will be randomized in 2:1 allocation ratio, to romiplostim or placebo, 
respectively, in double-blind manner.  
The randomization number will be provided by the IVRS/IXRS system. 
The randomization will be stratified by tumor type and baseline platelet count  
(< 50 x 109/L, ≥50 x 109/L).  Gastrointestinal tract cancers, including tumors of the 
esophagus or stomach, will be included in one stratum, pancreatic cancers will be 
included in a second stratum, and colorectal cancers, including tumors of the colon or 
rectum, will be included in a third stratum. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
7.3 
Blinding 
This is a double-blind study.  Treatment assignment will be blinded to all subjects, site 
personnel, and Amgen as described below. 
7.3.1 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment is to only be unblinded when knowledge of the 
treatment is essential for further clinical management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
Unblinding is done via IVRS.  The Amgen Trial Manager must be notified before the 
blind is broken unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the subject’s condition.  In this case, the Amgen Trial 
Manager must be notified within 24 hours after breaking the blind.  The date and reason 
that the blind was broken must be recorded in the source documentation and CRF, as 
applicable. 
7.3.2 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information is not to be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded except as specified (eg, Section 7.3.1). 

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7.4 
Dose Modification 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.1.1 
Amgen Investigational Product:  Romiplostim and Placebo 
Each subject’s dose of investigational product (romiplostim or placebo) will be adjusted 
based on weekly platelet counts (see Table 7-1).  The target platelet count at 
initiation of the first on-study cycle of chemotherapy is  100 x 109/L.  Starting 
from week 4, subjects may start the first cycle of chemotherapy with dose 
adjustments according to the dose modification guidelines listed below.   
If there are multiple platelet values performed on a study visit date, the platelet value 
from the test performed most immediately prior to the time of the planned investigational 
product and/or non-investigational product administration will be recorded as the platelet 
value for that study visit date and will be used to determine the subject’s dose of 
investigational product and, when applicable, chemotherapy dose modifications, which 
include dose reductions, delays, omissions, and discontinuation.  Local laboratory 
assessments taken during the study visit (± 1 day) and recorded in the CRF must be the 
same values as used for investigational product dose calculations and chemotherapy 
dose modifications where applicable.  Any platelet counts performed in the cycle 
prior to enrollment should be recorded if they are used to determine 
chemotherapy dose in study cycle 1.  Any platelet counts performed outside of 
the study visits should be recorded if they are used to determine chemotherapy 
dose in study cycles 1, 2, and 3.   
Table 7-1.  Investigational Product Dose Adjustment Rules 
Platelet count (x 109/L) 
Investigational Product Dose Adjustment Rulea 
< 100 
Increase dose by 1 µg/kg each week (to a maximum of 10 µg/kg) 
100 - 250 
Dose remains constant 
251 - 450 
Dose reduced by 1 ug/kg.  Do not withhold doseb, c 
> 450 
Withhold dosed 
IP = investigational product 
a The starting dose of investigational product will be 2 µg/kg based on the subject’s recorded screening 
weight.  See Section 7.1.1.2 for full details. 
b If the current dose is 1 μg/kg and a dose reduction is required, the dose will be withheld until the platelet 
count falls to < 100 x 109/L.  Once the platelet count is < 100 x 109/L, dosing will resume at a dose of 1 μg/kg 
using the dose adjustment rules above. 
c If platelet count > 250 x 109/L is due to a platelet transfusion in the preceding 7 days, the subject will 
continue to receive investigational product at the previous dose level. 
d For patients who previously had their dose withheld because their platelet count was > 450 x 109/L, restart 
IP based on dose withheld and according to adjustment rules above.  

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Subjects who have a platelet count < 100 x 109/L for 4 consecutive weeks at the 
maximum investigational product dose of 10 μg/kg should be discontinued from 
investigational product, allowing for up to 12 weeks of dosing before a subject is 
declared a non-responder.  To assess if a subject has responded to the 12th dose 
given at the beginning on the 12th week of the study, the platelets would be drawn 
a week later at the week 13 visit when a subject has completed 12 weeks of 
dosing. 
Dosing will be discontinued at any time during the study if neutralizing antibodies to 
romiplostim or to endogenous TPO are detected.  
The reason for dose change of investigational product is to be recorded on each 
subject’s CRF(s). 
7.4.1.2 
Non-Amgen Non-investigational Product:  Standard-of-care 
Chemotherapy 
The following will be specified prior to the first administration of investigational product:  
chemotherapy agents in the planned treatment regimen, planned total dose and unit of 
each agent, number of days per cycle, and planned dosing schedule.  The planned 
chemotherapy regimen reflects what the investigator considers standard dose and 
schedule for that regimen.  The following will be captured during the treatment period:  
the actual chemotherapy dose and unit administered; date of administration; whether the 
subject experienced a dose reduction, delay, or omission due to thrombocytopenia; 
whether the subject experienced chemotherapy treatment discontinuation due to 
thrombocytopenia; and whether there was a reason other than thrombocytopenia for 
dose reduction, delay, omission, or discontinuation.  An independent adjudicator will 
periodically verify the reason for chemotherapy dose modification in the study.  
Chemotherapy dose modifications include dose reductions, dose delays, dose 
omissions, and treatment discontinuations.  During the 3 on study cycles, a 
chemotherapy delay must be increments of 1 week to align with the weekly study visits if 
applicable. 
Following enrollment and initiation of investigational product, the first cycle of 
chemotherapy during the treatment period should not be administered until platelet 
counts are ≥ 100 x 109/L or until at least week 4, whichever occurs first.  If platelet 
counts at the start of chemotherapy cycle 1 are < 100 x 109/L, recheck platelet 
count 1 week later and continue to hold until platelet count ≥ 100 x 109/L.  Starting 
from week 4, subjects may start the first cycle of chemotherapy with dose 

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adjustments according to the dose modification guidelines listed below.  If the 
platelets remain < 100 x 109/L, the investigator has the discretion to continue IP for 
dose escalation up to 12 weeks before beginning the first on-study chemotherapy 
cycle.  After 12 weeks without starting study cycle 1 on IP, the subject is 
considered a non-responder.   
Do not start the first cycle of on-study chemotherapy before study week 2.  The 
start of the planned chemotherapy must be no more than 2 days after the local 
laboratory assessments have been taken during the study visit.  The reason for dose 
change of non-Amgen non-investigational products is to be recorded on each subject’s 
CRF(s).  Any chemotherapy dose modifications made for reasons other than 
thrombocytopenia will be captured in the CRF. 
The investigator should not perform any dose modifications due to CIT if the 
subject’s platelet count is above the levels listed in the dose modification 
guidelines.  Do not dose modify for cycle 1 unless the platelets are < 100 x 109/L 
on or after week 4.  Use dose modification guidelines for cycles 2 and 3. 
Chemotherapy dose modifications for thrombocytopenia for patients with gastric, 
esophageal, pancreatic, colon, or rectal adenocarcinoma receiving an oxaliplatin-based 
regimen should be conducted as follows.  
Table 7-2.  Dose Modification Based on Platelet Counts – mFOLFOX6 
Blood Counts  
Delay Cycle 
Oxaliplatin 
5-FU 
Platelets 
< 75 x 10⁹/L 
day 1 (at the 
beginning of a 
chemotherapy 
cycle) 
Delay by 1 week and 
until platelets have 
recovered ≥ 75 x10⁹/L. 
 
 
1st occurrence of a 
2 week delay or delay 
for 1 week on 2 
separate occasions 
 
Eliminate 5-FU bolus 
If no bolus was given 
reduce cIV 5-FU by 
20% 
2nd Occurrence of a 
2 week delay or delay 
for 1 week on 2 
separate occasions 
Reduce oxaliplatin 
dose from 85 to 
65 mg/m2 
Reduce cIV 5-FU by 
20% 
Platelets 
< 50 x 10⁹/L 
during 
treatment 
Delay next dose until 
platelets recover to 
≥ 75 x10⁹/L. 
Reduce oxaliplatin 
dose to 75 mg/m2 
(adjuvant therapy) or 
to 65 mg/m2 
(metastatic CRC) 
 
5-FU = 5-fluorouracil; cIV = continuous intravenous; CRC = colorectal cancer 
Source:  Oxaliplatin USPI; Cheeseman et al, 2002; Hochster et al, 2008. 

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Delay treatment cycle by one week for platelets < 75 x 10⁹/L on the day 1 of 
treatment.  If treatment is delayed for 2 weeks or delayed for one week on 
2 separate occasions, eliminate 5-FU bolus. If no bolus was given reduce cIV 5-FU 
by 20%.  With the second occurrence, reduce cIV 5-FU by 20% and reduce 
oxaliplatin dose from 85 to 65 mg/m2.  For platelets <50 x 10⁹/L during treatment 
delay next dose until platelets recover to ≥ 75 x10⁹/L then reduce oxaliplatin dose 
to 75 mg/m2 (adjuvant therapy) or to 65 mg/m2 (metastatic CRC). 
Table 7-3.  Dose Modification Based on Platelet Counts - FOLFIRINOX 
Blood Counts  
Delay Cycle 
Oxaliplatin 
5-FU 
Irinotecan 
Platelets 
< 75 x 10⁹/L 
day 1 (at the 
beginning of a 
chemotherapy 
cycle) 
Delay by 1 week 
and until 
platelets have 
recovered ≥ 75 
x10⁹/L. 
Reduce 
oxaliplatin dose 
from 85 to 
60 mg/m2 
Reduce bolus 
and cIV 5-FU to 
75% of original 
dose 
 
 
 
 
2nd Occurrence:  
reduce dose to 
150 mg/m2 
Platelets 
< 50 x 10⁹/L 
during 
treatment 
 
Reduce 
oxaliplatin dose 
from 85 to 
60 mg/m2 
Reduce bolus 
and cIV 5-FU to 
75% of original 
dose 
 
 
 
 
2nd Occurrence:  
reduce cIV 5-FU 
an additional 
25% 
2nd Occurrence:  
reduce dose to 
150 mg/m2 
5-FU = 5-fluorouracil; cIV = continuous intravenous 
Source:  Conroy et al, 2011. 
If day 1 treatment delayed by 1 week for platelet count < 75 x 10⁹/L, reduce 
oxaliplatin dose from 85 to 60 mg/m2 and reduce both the bolus and cIV 5-FU to 
75% of original doses.  For second occurrence, reduce irinotecan dose to 150 
mg/m2.  Beginning in on-study chemotherapy cycle 2 if nonrecovery after 2-week 
delay, or third occurrence of platelets < 75 x 10⁹/L, discontinue treatment.  For 
platelet count < 50 x 10⁹/L during treatment, reduce oxaliplatin dose from 85 to 
60 mg/m2 and the cIV 5-FU dose to 75% of the original dose.  For the second 
occurrence, reduce dose of irinotecan to 150 mg/m2 and the dose of cIV 5-FU an 
additional 25%.  Discontinue treatment for third occurrence. 

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Table 7-4.  Dose Modification Based on Platelet Counts - mFOLFIRINOX 
Blood Counts  
Delay Cycle 
Oxaliplatin 
5-FU 
Irinotecan 
Platelets 
< 75 x 10⁹/L 
day 1 (at the 
beginning of a 
chemotherapy 
cycle) 
Delay by 1 week 
and until 
platelets have 
recovered ≥ 75 
x10⁹/L. 
Reduce 
oxaliplatin dose 
from 85 to 
60 mg/m2 
Reduce cIV 5-
FU to 75% of 
original dose 
 
 
 
 
2nd Occurrence:  
reduce dose to 
120 mg/m2 
Platelets 
< 50 x 10⁹/L 
during 
treatment 
 
Reduce 
oxaliplatin dose 
from 85 to 
60 mg/m2 
Reduce cIV 
5-FU to 75% of 
original dose 
 
 
 
 
2nd Occurrence:  
reduce cIV 5-FU 
an additional 
25% 
2nd Occurrence:  
reduce dose to 
120 mg/m2 
5-FU = 5-fluorouracil; cIV = continuous intravenous 
Source:  Conroy et al, 2018 
If day 1 treatment delayed by 1 week for platelet count <75 x 10⁹/L, reduce 
oxaliplatin dose from 85 to 60 mg/m2 and reduce the cIV 5-FU to 75% of original 
doses.  For second occurrence, reduce irinotecan dose to 120 mg/m2.  Beginning 
in on-study chemotherapy cycle 2 if nonrecovery after a 2-week delay, or if there 
is a third occurrence of platelets <75 x 10⁹/L, discontinue treatment.  For platelets 
< 50 x 10⁹/L during treatment, reduce oxaliplatin dose from 85 to 60 mg/m2 and the 
infusional FU dose to 75% of the original dose.  For the second occurrence, 
reduce dose of irinotecan to 120 mg/m2 and the dose of infusional FU an 
additional 25%.  Discontinue treatment for third occurrence. 
The dose modifications for the FOLFOXIRI regimen in colorectal cancer patients 
were not published in the original phase III trial (Falcone et al, 2007).  Use the dose 
modifications above based on those in a trial using a comparable regimen 
(FOLFIRINOX) for advanced pancreatic cancer (Conroy et al, 2011). 
For CAPEOX (Nehls et al, 2008; Capecitabine USPI), delay the treatment cycle for 
one week if the platelet count is < 100 x 10⁹/L on day 1. If treatment is delayed for 
2 weeks or delayed for 1 week on 2 separate occasions, reduce the doses of 
oxaliplatin and capecitabine by 10% to 20%.  Subsequent treatment cycles should 
be delayed until the platelets are ≥ 75 x 10⁹/L. 

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Renal insufficiency requiring dose modification  
 
For patients with severe renal impairment (creatinine clearance < 30 mL/min), the 
starting dose of oxaliplatin should be reduced to 65 mg/m2 (Oxaliplatin 
prescribing information, 2017).  
 
Decrease the dose of capecitabine by 25% in patients with CrCl 30-50 mL/min 
and hold for more severe kidney disease. (Xeloda USPI 2019) 
 
For irinotecan there is no specific dose reduction recommendation for renal 
insufficiency. (Irinotecan USPI) 
Hepatic insufficiency requiring dose modification  
 
For patients with hepatic impairment with total bilirubin > 5 mg/dL,   
5-fluorouracil should not be administered (Floyd et al, 2006). Decrease the dose 
of capecitabine by 25% in subsequent cycles for bilirubin > 1.5-3 x ULN.  (Blum, 
1999) 
 
The dose of irinotecan should be reduced by 25% in patients with bilirubin > 
1.5-3 x ULN. (Floyd 2006).  
Where there are multiple toxicities including thrombocytopenia, renal, and hepatic 
toxicities dose modification should be made after reviewing all applicable dose 
modification guidelines provided and choosing the lowest recommended dose for the 
most severe grade of toxicity. 
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM. 
7.6 
Treatment Compliance 
Investigational product will be administered in the clinic by a qualified healthcare 
provider as a subcutaneous injection.  Study clinic staff will note the dose and time of 
dosing on the CRF.   
7.7 
Treatment of Overdose 
In high-dose preclinical studies, the noted effects were related to the pharmacological 
action of romiplostim.  Overdose may result in an excessive increase in platelet counts 
associated with thrombotic/thromboembolic complications.  In the event of an 
investigational product overdose, platelet counts should be monitored frequently and 
investigational product dose withheld if platelet counts are > 450 x 109/L.  Reinitiate 
treatment with investigational product when platelet counts are ≤ 450 x 109/L and refer to 
Section 7.4.1.1 for dosage adjustments.   

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7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior anti-cancer therapies that were being taken/used from 3 years prior to enrollment 
through the informed consent will be collected. 
For prior therapies being taken for treatment of gastrointestinal, pancreatic, or colorectal 
cancer, collect therapy name, indication, dose, unit, start date and stop date.  
For all other prior therapies, such as radiotherapy, collect therapy name, indication, site 
(radiotherapy only), dose, unit, frequency route, start date and stop date. 
7.8.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7. 
All concomitant therapies will be collected until completion of safety follow-up (SFU) 1 
and SFU 2 after which collected concomitant therapies will include the following: platelet 
related medications: commercial romiplostim, eltrombopag, avatrombopag, 
lusutrombopag, fostamatinib, and anticoagulants, only. 
For platelet transfusions, collect reason, dose, volume, unit, and start date.  For all other 
concomitant therapies, collect therapy name, indication, dose, unit, frequency, start date 
and stop date.   
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 

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investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 2-1) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
and must document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product and/or other protocol-required therapies or 
procedures should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data.  In particular, the recording of planned chemotherapy 
administration, which is vital in determining the primary endpoint, can be obtained 
through medical records if the subject agrees to remain on study despite choosing to 
discontinue investigational product and other study-related procedures. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 12.3. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance  
 
Adverse event 
 
Subject request 
 
Requirement for alternative therapy 
 
Disease progression or relapse per investigator 
 
Protocol-specified criteria; see Section 7.4: 
o Subjects who have a platelet count < 100 x 109/L for 4 consecutive weeks 
at the maximum investigational product dose of 10 μg/kg should be 
discontinued from investigational product.  
o Administration of investigational product should be discontinued at any 
time during the study if neutralizing antibodies to romiplostim or to 
endogenous TPO are detected.  

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 
Pregnancy 
8.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Appendix 6 for further details).   
All subjects who discontinue taking protocol-required therapies, should be encouraged 
where possible to remain on study to complete the rest of their study visit(s) as would be 
required by the study protocol.  If a subject makes the decision to fully terminate their 
participation whilst in the trial, the subject should continue to complete the following visits 
if not already completed: 
 
the follow-up visit (1 week after the last dose of IP) and  
 
the first safety follow up visit (SFU 1) (30 days after the last dose of IP) 
 
the second SFU 2 (30 days after the last dose of on-study cycle of chemotherapy) 
 
the EOS Visit (if the subject is in LTFU and has completed all the above follow up 
visits, then the EOS Visit can be completed at the time of terminating their 
participation from the study)  
 
If the subject has yet to complete the above follow-up visits, then the EOS Visit 
should be performed at the same time as the final follow up visit eg, SFU 2. 
If the subject does not wish to complete any further visits, then the EOS procedures 
should be completed (if the subject consents to this) and listed as the subjects last visit 
on the date the subject decides to terminate early. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable for this study. 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 

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 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up  
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
is able to continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts are 
to be documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly 
available records (where permitted) to ascertain survival status.  This ensures 
that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible. 
9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 

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signed the informed consent form, the site will register the subject in the IVRS/IXRS and 
screen the subject in order to assess eligibility for participation.  The screening window is 
up to 4 weeks. 
At screening, both local and central chemistry and hematology labs are to be 
performed, however, local lab values may be used for eligibility. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be rescreened up to 
3 times at the discretion of the investigator.  Further rescreening requires approval from 
Amgen Medical Monitors.  
Rescreen subjects must first be registered as screen failures in IVRS/IXRS and 
subsequently registered as rescreens.  Once the subject is registered as rescreen, a 
new 4-week screening window will begin.  Subjects will retain the same subject 
identification number assigned at the original screening.  If the rescreening period begins 
more than 28 days after the original signing of the informed consent form, all screening 
procedures, including informed consent, must be repeated.  If the rescreening and 
randomization occurs within 28 days after the original signing of the informed consent, 
only those criteria that were originally not met would be required to be repeated. 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1).  On-study visits may be 
completed within  1 day.  The date of the first dose of investigational product is defined 
as day 1, and will occur on the same day as randomization.  All subsequent doses and 
study visits will be scheduled based on the day 1 date and will occur weekly throughout 
the treatment period.  Investigational product is to be administered only after all other 
study visit procedures have been completed during each visit that it is required.  If the 
subject will be receiving concomitant chemotherapy on a study visit date, investigational 
product will be administered immediately after the completion of chemotherapy infusion 
on chemotherapy day 1.  If continuous infusion 5-FU over 46-48 hours is part of the 
chemotherapy regimen the investigational product may be administered prior to 
beginning or during the continuous infusion 5-FU.  Given that subjects will be assessed 

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for 3 planned cycles of chemotherapy, the oxaliplatin-based chemotherapy cycles are 
2-3 weeks in duration, and the investigational product dose adjustment guidelines allow 
for up to 12 weeks of dosing before a subject is declared a non-responder, the majority 
of study subjects will receive investigational product for a range of between 7-21 weeks. 
9.1.3 
End of Treatment 
The treatment period will be long enough to allow for assessment of 3 planned cycles of 
chemotherapy (see Section 5.1 for details).   
The follow-up visit will occur 1 week ( 1 day) after the last scheduled dose of 
investigational product. 
9.1.4 
End of Treatment Period 
The follow-up visit is scheduled to be 7 days ( 1 day) after the last dose of 
investigational product.  End of treatment period (EOTP) is defined as the latest 
assessment date of that visit.  If a subject does not complete a follow-up visit, then 
EOTP will be 7 days after the last dose of investigational product or the EOS date, 
whichever is earlier. 
9.1.5 
Long-term Follow-up 
Subjects will have an in-clinic LTFU Visit 30 (+5) days after the last dose of 
investigational product.  (Safety Follow-up 1).  Subjects will be contacted 30 days 
(+1 week) after the last dose of the last on-study cycle of chemotherapy (up to 3 cycles) 
to collect adverse event information except for females who are in addition required to 
come to clinic for a highly sensitive urine or serum pregnancy test (Safety Follow-up 2).  
In addition, after the first LTFU Visit, all subjects will be followed by phone or in clinic 
every 12 weeks (± 2 weeks) from the last dose of investigational product until the 
EOS.  During LTFU subjects will be followed for the diagnosis of, or progression to, 
secondary malignancies (including myeloid malignancies) or myelodysplastic 
syndromes, as well as vital status and cause(s) of death. 
9.1.6 
End of Study Visit 
Excluding early termination of the study, the EOS Visit for individual subjects will be 
defined as up to 2 weeks after the last subject in the trial completes their LTFU 
Visit 1 year after the last dose of investigational product. EOS Visit can be done by 
phone. 

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9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
9.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
9.2.1.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started 3 years prior to screening through the time of signing of informed consent.  
Medical history will include information on the subject’s concurrent medical conditions.  A 
history of prior and/or concurrent use of alcohol and tobacco will be obtained.  Record all 
findings on the medical history CRF.   
9.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
9.2.1.5 
Physical Measurements 
Height in centimeters and weight in kilograms should be measured without shoes.   
9.2.1.6 
Performance Status  
The performance status will be assessed using the ECOG performance status scale. 
9.2.2 
Efficacy Assessments 
9.2.2.1 
Platelet Counts 
Platelet counts will be measured at each visit (on a weekly basis) during the treatment 
period and throughout the 3 on-study cycles to the end of the third study cycle for 
patients receiving investigational product and non-investigational product.  Platelet 
counts will be assessed locally.  If there are multiple platelet values performed on a 
study visit date, the platelet value from the test performed most immediately prior to the 
time of the planned investigational product and/or non-investigational product 
administration will be recorded as the platelet value for that study visit date and will be 

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used to determine the subject’s dose of investigational product and, when applicable, 
chemotherapy dose modifications which include dose reductions, delays, omissions, and 
discontinuations.  Note:  For subjects who discontinue investigational product prior to 
completing 3 cycles of chemotherapy, platelet counts should be measured through 
3 on-study chemotherapy cycles to the end of the third on-study cycle, and the values 
recorded must be those taken prior to scheduled chemotherapy visits and used to inform 
decisions relating to chemotherapy dose modification.   
9.2.2.2 
Bleeding Scale 
Subjects must be assessed for signs and symptoms of bleeding at every weekly visit.  
These findings must be reported as per CTCAE grading criteria (Miller et al, 1981).  
Grading is based on physical examination at the time of the visit by the investigator or on 
patient’s history supplemented by available medical reports.  Bleeding manifestations 
reported by the patient but not visible at the time of data collection are graded 1.  
9.2.2.3 
Chemotherapy Dose  
The planned and delivered chemotherapy dose will be recorded as area under the 
curve, milligram per kilogram, or milligram per square meter. 
Chemotherapy administration, including information about planned and actual 
chemotherapy dose and schedule, should be recorded throughout 3 on study cycles, at 
the follow up at one week after the last dose of IP, SFU1 and SFU2.  For the purposes of 
determining dose reductions, for those subjects continuing protocol-required 
chemotherapy regimens, the on-study chemotherapy doses will be compared to the 
planned chemotherapy dose recorded on study day 1, defined by the dose administered 
in the chemotherapy cycle immediately prior to study entry.  For subjects beginning a 
protocol-required chemotherapy regimen, the planned dose for cycle 1 will be the 
standard dose determined by the Investigator.  Chemotherapy dose modifications 
occurring during on-study cycle 1 will not count toward the primary endpoint even if due 
to CIT.  If a chemotherapy dose modification occurs during on-study cycle 1 the new 
baseline for comparison will reset to the chemotherapy dose modifications that occurred 
in cycle 1, even if not attributable to CIT.  This will also apply to dose modifications 
occurring during on study cycle 2.  For the purposes of determining dose delays, the 
difference between the start date of a given chemotherapy cycle and the start date of the 
chemotherapy cycle immediately prior to the given cycle will be calculated and 
compared to the planned cycle length of the regimen.  During the 3 on study cycles, a 
chemotherapy delay must be increments of 1 week to align with the weekly study visits if 

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applicable.  Delayed, reduced, omitted, and discontinued doses within a cycle will also 
be counted as dose modifications even if they do not cause the start of the next cycle to 
be delayed.  Note:  For subjects who discontinue investigational product prior to 
completing 3 cycles of chemotherapy, chemotherapy dose and schedule should be 
recorded through 3 on-study chemotherapy cycles to the end of the third on-study cycle.  
In this situation the local laboratory assessments recorded must be those taken prior to 
scheduled chemotherapy visits and used to inform decisions relating to chemotherapy 
dose modification.  Any local laboratory tests performed in the cycle prior to 
enrollment should be recorded if they are used to determine chemotherapy dose 
in study cycle 1.  Any local laboratory tests performed outside of the study visits 
should be recorded if they are used to determine chemotherapy dose in study 
cycles 1, 2, and 3 (see Schedule of Activities [Section 2.2] for further information). 
For the primary endpoint, we will capture information at each weekly study visit on the 
actual chemotherapy dose and unit, start/stop dates, whether the subject experienced a 
dose reduction, delay, or omission due to thrombocytopenia with platelet counts below 
100 x 109/L, whether the subject experienced chemotherapy treatment discontinuation 
due to thrombocytopenia with platelet counts below 100 x 109/L or per the guidelines 
provided when there is thrombocytopenia for the specific tumor types and regimens 
(Section 7.4.1.2), and whether there was a reason other than thrombocytopenia for dose 
reduction, delay, omission, or discontinuation.  Chemotherapy dose delays, dose 
reductions, and dose omissions will be permitted according to chemotherapy dose 
modification guidelines outlined in Section 7.4.1.2.  For each planned chemotherapy 
agent, any thrombocytopenia related modifications which include dose reduction, dose 
delays, dose omission, and treatment discontinuation, at any time during on-study cycle 
2 or 3 will be counted as failure in the primary endpoint analysis.  An independent 
adjudicator will periodically verify the reason for chemotherapy dose modifications during 
on-study cycles 1-3. 
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(Table 2-1). 

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9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE 
version 5.0 and is described in Appendix 4. 
Adverse events possibly related to any study procedures are reported after signing of 
the ICF.  All other adverse events are reported after the first dose of protocol-required 
therapies (romiplostim/placebo [investigational product], chemotherapy 
[non-investigational product] up to 3 cycles).  The investigator is responsible for ensuring 
that all adverse events observed by the investigator or reported by the subject that occur 
after signing of the ICF or from the first dose of protocol-required therapies, as specified 
above, through the 30 (+5) days after the last dose of protocol-required therapies (last 
dose of investigational product and last dose of last cycle [up to 3 cycles] of 
chemotherapy non-investigational product) are reported using the Event CRF.  If 
mandated by country-specific requirements, non-serious adverse events will be collected 
through the whole duration of the LTFU period until EOS.  
Note:  For subjects who discontinue investigational product prior to completing 3 cycles 
of chemotherapy, non-serious adverse events should be collected through 3 on-study 
chemotherapy cycles.   
9.2.3.1.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the end of study are reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE version 5.0 grading scale differs from the 
regulatory criteria for serious adverse events.  It is left to the investigator’s judgment to 
report these grade 4 abnormalities as serious adverse events.  For any adverse event 
that applies to this situation, comprehensive documentation of the event’s 
severity must be recorded in the subject medical records. 

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9.2.3.1.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events after the 
protocol-required reporting period (as defined in Section 9.2.3.1.1.2) is complete, 
these serious adverse events will be reported to Amgen (regardless of causality).  The 
investigator will report serious adverse events to Amgen within 24 hours following the 
investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
If further safety related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records after the subject ends the study. 
9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Appendix 4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 

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Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team (SAT) as appropriate.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and until 30 days after 
the last dose of protocol-required therapies. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in Appendix 5.  
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 

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9.2.3.2 
Vital Signs 
Vital signs will be monitored throughout the duration of the study as indicated in the 
Schedule of Assessments (Table 2-1).   
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in the most 
recumbent position possible.  The position selected for a subject should be the same 
throughout the study and documented on the vital signs CRF.  The temperature location 
selected for a subject should be the same throughout the study and documented on the 
vital signs CRF.  If abnormalities are found and they are considered an adverse event, 
record on the Event CRF.   
9.2.3.3 
Electrocardiograms (ECGs) 
Electrocardiograms will be performed at screening per local institution standard of care.  
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position possible.   
The ECG must include the following measurements: heart rate, QRS, QT, QTc, and PR 
interval.   
The investigator will review all ECGs.  Once signed, the original ECG tracing will be 
retained with the subject's source documents.  At the request of the sponsor, a copy of 
the original ECG will be made available to Amgen. 
9.2.3.4 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause(s) of death should be obtained. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 

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clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities.  
Local laboratory assessments taken during the study visit (± 1 day) and recorded in the 
CRF must be the same values as used for investigational product dose calculations and 
chemotherapy dose modifications where applicable.  The start of the planned 
chemotherapy must be no more than 2 days after the local laboratory assessments have 
been taken during the study visit.  Any local laboratory tests performed in the 
cycle prior to enrollment should be recorded if they are used to determine 
chemotherapy dose in study cycle 1.  Any local laboratory tests performed 
outside of the study visits should be recorded if they are used to determine 
chemotherapy dose in study cycles 1, 2, and 3. 
Except at screening, laboratory/analyte results that could unblind the study 
(pharmacokinetic and antibodies samples) will not be reported to investigative sites or 
other blinded personnel until the study has been unblinded.  However, if the value for 
any laboratory analyte is significantly outside of the reference range by a predefined 
value, the local and central laboratory will notify the investigative site of the absolute 
value of the analytes to ensure adequate safety oversight of the enrolled subject.  Also, if 
positive neutralizing antibodies to romiplostim or TPO are detected, the central 
laboratory will notify the investigative site to ensure adequate safety oversight of the 
enrolled subject.   
9.2.4.1 
Pregnancy Testing 
For females of childbearing potential, a highly sensitive urine or serum pregnancy test 
should be completed prior to enrollment within 72 hours prior to the first dose of 
investigational product, monthly during the treatment period, and then at 30 days after 
the last dose of investigational product and 30 (+5) days after the last dose of 
protocol-required therapies 30 (+5) days after the last dose of on-study cycle of 
chemotherapy non-investigational product [up to 3 cycles]).   

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Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Appendix 5 for contraceptive requirements.  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.6 
Antibody Testing Procedures 
Refer to the central laboratory manual for instructions on collection, preparation, storage, 
and shipment of antibody samples.  The week 1 baseline antibody sample must be 
obtained before the first administration of investigational product. 
Antibody samples will assess safety, development of binding and neutralizing antibodies 
to romiplostim and the potential to bind to endogenous TPO.  While the subject is 
receiving investigational product, blood samples will be collected for anti-romiplostim 
antibodies at predose (day 1), week 8, and at the follow-up visit.   
Blood samples will be collected from all subjects for the measurement of 
anti-romiplostim binding antibodies.  Samples testing positive for binding antibodies will 
also be tested for neutralizing antibodies.  Additional blood samples may be obtained to 
rule out anti-romiplostim antibodies during the study. 
Subjects who test positive for neutralizing antibodies to romiplostim at the final 
scheduled study visit will be asked to return for additional follow-up testing.  This testing 
should occur every 3 months starting from when the site has been notified of the positive 
result, until: (1) neutralizing antibodies are no longer detectable or (2) the subject has 
been followed for a period of at least 1 year (± 4 weeks).  More frequent testing 
(eg, every month) or testing for a longer period of time may be requested in the event of 

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safety-related concerns.  Follow-up testing will not be required where it is established 
that the subject did not receive romiplostim. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-romiplostim antibody 
response may also be asked to return for additional follow-up testing. 
Should a subject have a loss of response or fail to maintain a response to investigational 
product, sites should contact the Clinical Research Associate to inform Amgen that an 
unscheduled serum sample will be required to rule out anti-romiplostim antibodies.   

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9.2.8 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Medical resource utilization and health economics data, associated with medical 
encounters, will be collected in the CRF by the investigator and study-site personnel for 
all subjects throughout the study.  Protocol-mandated procedures, tests, and encounters 
are excluded.  
The data collected may be used to conduct exploratory economic analyses and will 
include: 
 
Number and duration of medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient) 
 
Duration of hospitalization (total days or length of stay, including duration by 
wards) 
 
Number and type of diagnostic and therapeutic tests and procedures 

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 
Outpatient medical encounters and treatments (including physician or emergency 
room visits, tests and procedures, and medications) 
 
Quality of life measures 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
A sample size of 162 is chosen with 2:1 randomization ratio (108 romiplostim, 
54 placebo), stratified by tumor type (Gastrointestinal, Pancreatic, and Colorectal) and 
baseline platelet count (< 50 x 109/L, ≥ 50 x 109/L).  In two small studies (Al-Samkari et 
al, 2018; Soff et al, 2017), few patients with CIT spontaneously recovered their platelet 
counts to adequate levels:  5 of 22 (23%) and 1 of 8 (13%), respectively.  A 
phase 2 study showed 75% (24 out 32 subjects) subjects resumed chemotherapy after 
treatment with romiplostim (Soff et al, 2017).  From retrospective reviews, between 65% 
(13 of 20 subjects) and 82% (18 of 22 subjects) subjects did not have any 
thrombocytopenia-induced chemotherapy dose modifications after treatment with 
romiplostim (Parameswaran et al, 2014; Al-Samkari et al, 2018). 
Thrombocytopenia-induced chemotherapy dose modifications in one cycle may be 
correlated with the previous cycle outcome.  Assume that 𝑝 is the probability of receiving 
a planned on-study chemotherapy regimen with no thrombocytopenia-induced 
chemotherapy dose modifications in a cycle, 𝜌 is the cycle correlation and the correlation 
is the same in romiplostim group and control group, the probability of receiving the 
planned chemotherapy regimen with no thrombocytopenia-induced chemotherapy dose 
modifications in two subsequent cycles, 𝑝2,3 for cycle 2 and 3, can be calculated 
as 𝑝2,3 = 𝑝2 +  𝜌𝑝(1 −𝑝). 
A higher cycle correlation is shown to be associated with a lower odds ratio of treatment 
effect for romiplostim vs control (Figure 10-1). 

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Figure 10-1.  Relationship Between Cycle Correlation and 
Treatment Effecta 
 
a Assume 30% and 60% probability of having no dose modifications in one cycle for placebo and 
romiplostim respectively. 
From conservative considerations, probability of receiving the planned on-study 
chemotherapy regimen with no thrombocytopenia-induced chemotherapy dose 
modifications in one cycle for subjects treated in placebo group and romiplostim group is 
assumed to be 30% and 60% respectively, with a strong cycle correlation of 0.7 between 
two subsequent cycles.  The odds ratio of having no thrombocytopenia-induced 
chemotherapy dose modifications in two cycles for romiplostim vs placebo is 3.6  
(Figure 10-1).  
The chosen sample size of 162 (108 romiplostim, 54 placebo) will provide 93% power to 
detect the treatment effect between the romiplostim group and the placebo group as 
defined in the primary endpoint at a two-sided significance level of 0.05 using a 
Cochran-Mantel-Haenszel (CMH) test.  Power calculations were performed in East 
version 6.4 using a 2-sided CMH test at significance level of 0.05 and stratification by 
tumor type and baseline platelet count (< 50 x 109/L, ≥ 50 x 109/L). 
One interim analysis will be performed at approximately 81 subjects (50% of the 
planned sample size) completing three cycles of chemotherapy. The non-binding 
futility boundary is constructed using Lan-DeMets spending function with the 
O’Brien-Fleming approach.  Assuming an observed 35%of subjects in the control 
arm with no thrombocytopenia-induced chemotherapy dose modification in one 
3
3.5
4
4.5
5
5.5
6
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Odds Ratio (romiplostim versus 
placebo)
Cycle Correlation (ρ)
(0.7, 3.6)

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cycle, the power is estimated to be 84% at the interim analysis and the probability 
of stopping for futility is 2%.   
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
10.2.1.1 
Full Analysis Set 
The full analysis set will include all randomized subjects.  All subjects will be analyzed 
according to the treatment to which they are randomized.  Full analysis set will be used 
for all primary analysis for primary and secondary efficacy endpoints. 
10.2.1.2 
Safety Analysis Set 
The safety population will include all randomized subjects who received at least 1 dose 
of investigational product.  Subjects in the analyses based on the safety analysis set will 
be analyzed according to the treatment group corresponding to the actual treatment 
received.  Subjects who receive at least one dose of romiplostim will be included 
in the romiplostim treatment group. 
10.2.2 
Covariates 
The following baseline characteristics are specified as potential confounding covariates:   
 
Stratification factor of tumor type (Gastrointestinal, Pancreatic, Colorectal) 
 
Stratification factor of baseline platelet count (< 50 x 109/L, 50 x 109/L)  
 
Age (continuous and categorized  65 years,  65 years) 
 
Sex (Male, Female) 
 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Other) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
Region (United States, Europe, Rest of World) 
 
Body mass index 
 
ECOG (1,  2)   
 
Stage of disease (Stage 1 to 3, Stage 4 or recurrent disease) 
 
Line of chemotherapy treatment (1,  2)  
 
Type of chemotherapy regimen (FOLFOX, FOLFIRINOX, FOLFOXIRI, CAPEOX) 
 
Number of previous chemotherapy cycles ( 2,  2) 

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 
Prior or Concurrent Bevacizumab use (Yes, No)  
 
Baseline platelet count (continuous) 
 
Prior bleeding events (Yes, No) 
 
Prior platelet transfusions (Yes, No) 
 
Prior use of erythropoiesis-stimulating agent (Yes, No) 
 
Prior use of granulocyte colony-stimulating factor (Yes, No)  
 
Prior use of programmed cell death 1 inhibitors or programmed cell death ligand 
1 inhibitors (Yes, No) 
 
Concurrent use of programmed cell death 1 inhibitors or programmed cell death 
ligand 1 inhibitors (Yes, No) 
Concurrent use of medication at baseline means the medication has been administered 
on or after the start of the current chemotherapy regimen. 
Descriptive analyses will be provided including summary statistics for continuous 
covariates and percentage of subjects by each level of categorical covariates.   
For each above specified covariate, sensitivity analyses will be explored to evaluate any 
potential confounding:  (1) a 2-sided CMH test checking conditional independence 
between treatment groups and primary endpoint outcomes controlling for each individual 
covariate, (2) a logistic regression with primary endpoint outcome as dependent variable 
and explanatory variables from treatment group, the specified covariate, interaction of 
treatment by covariate. 
10.2.3 
Subgroups 
The study is not powered to draw conclusions from subgroup analyses.  However, 
exploratory analyses will be conducted to examine the consistency of the treatment 
effect in the primary endpoint for the below subgroups: 
 
Sex (Male vs Female) 
 
Stage of disease (Stage 1 to 3, Stage 4 or recurrent disease) 
 
Prior or Concurrent Bevacizumab use (Yes, No) 
 
Number of previous chemotherapy cycles  ( 2, > 2) 
 
Type of chemotherapy regimen (FOLFOX, FOLFIRINOX, FOLFOXIRI, CAPEOX) 
 
Baseline platelet count (< 50 x 109/L,  50 x 109/L) (stratification factor) 
 
Tumor type (Gastrointestinal, Pancreatic Colorectal) (stratification factor) 
10.2.4 
Handling of Missing and Incomplete Data 
For primary analysis on the thrombocytopenia-induced dose modification, subjects 
with complete missing visits (missing chemotherapy and none of the protocol specified 

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assessments are performed) or partial visits (missing chemotherapy but some of the 
protocol specified assessments are performed) without platelet count assessment for 
cycle 2 and/or cycle 3 are imputed as having thrombocytopenia-induced dose 
modification in cycle 2 and/or cycle 3.  Subjects with missing chemotherapy but 
having platelet count assessment within 2 days of the planned chemotherapy start 
or chemotherapy discontinuation will be determined by the adjudication 
committee. 
Potential missing visits or missing assessments may result from below reasons: 
 
Death 
 
Early discontinuation of chemotherapy 
 
Consent withdrawal or lost to follow up 
10.3 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 5.3.1. 
10.3.1 
Planned Analyses 
10.3.1.1 
Interim Analysis and Early Stopping Guidelines 
One interim futility analysis will be performed at approximately 81 subjects 
completing three cycles of chemotherapy. The primary endpoint, which is the 
proportion of subjects with no thrombocytopenia-induced chemotherapy dose 
modification in the second and third cycles of the planned on-study 
chemotherapy regimen, will be analyzed at the interim analysis. Dose modification 
assessments will be based on the central review by the independent adjudication 
committee.  The futility boundary for the primary endpoint is p-value of 0.438, 
which corresponds to an OR of 1.086.  The study may be stopped for futility if the 
non-binding futility boundary is crossed. 
Due to slow enrollment, there will be no enrollment pause during the interim 
analysis.  An independent Data Monitoring Committee (DMC) will perform the 
futility analysis.  The DMC will make recommendation to Amgen regarding the 
continuation of the study.  The DMC will be supported by an independent 
biostatistics group which is responsible for preparing reports.  Details regarding 

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the responsibilities of the DMC and the independent biostatistics group will be 
described in the DMC Charter. 
10.3.1.2 
Primary Analysis 
The primary analysis will be performed at the primary completion date.  The primary 
completion date is defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary endpoint.  Based on the 
definition above, the primary completion date is either the date when the status 
(information on whether a given on-study chemotherapy cycle was administered as 
planned, administered at a modified dose, delayed, omitted or discontinued) of the third 
cycle of the planned on-study chemotherapy regimen is assessed on the last subject or 
the last subject ends the last dose of investigational product plus 30 days, whichever 
occurs later.  The data that are collected up to the primary completion date will be 
cleaned and locked for the primary analysis purposes.  The study will be unblinded at 
the primary analysis. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit).  
10.3.1.3 
Final Analysis 
When the last subject in the trial completes LTFU at 1 year after the last dose of 
investigational product, the final database will be locked for the final analysis.   
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
The primary efficacy endpoint will be compared between the romiplostim and placebo 
groups at the significance level of 0.05 using a 2-sided test.  If statistical significance is 
achieved for the primary endpoint in favor of romiplostim, the following secondary 
efficacy endpoints will be tested using a fixed sequence hierarchical testing 
procedure to control the family-wise Type I error rate below 2-sided 0.05 level.  
The family of hypotheses is ordered as follows:   
 
the depth of platelet count nadir from the start of the first on-study chemotherapy 
cycle through the end of the treatment period 
 
the time to first platelet response, defined by platelet count ≥ 100 x 109/L, in the 
absence of platelet transfusions during the preceding 7 days.  Subjects who did not 
achieve a response event during the treatment period are censored at their last 

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platelet count assessment date up to the EOTP or study day 1 if they did not have 
any platelet assessment  
 
the duration-adjusted event rate of ≥ grade 2 bleeding events as assessed per 
CTCAE version 5.0 grading scale 
 
overall survival 
 
platelet transfusion(s) during the treatment period  
 
achieving platelet count  100 x 109/L at any time after study day 1 to week 4 
(ie, 7 days after the planned third dose of investigational product) in the absence of 
platelet transfusions during the preceding 7 days 
Starting with the hypothesis of platelet count nadir, if any null hypothesis in the 
sequence is rejected at a 2-sided significance level of 0.05, then the subsequent 
hypothesis will be tested; if any null hypothesis is accepted, then the subsequent 
hypotheses will not be tested. 
Summary statistics without formal testing will be provided for other endpoints.   
10.3.2.2 
Efficacy Analyses 
10.3.2.2.1 
Primary Endpoint 
Primary endpoint is no thrombocytopenia-induced modification of any myelosuppressive 
treatment agent in the second and third cycles of the planned on-study chemotherapy 
regimen.  Chemotherapy dose modification in the first cycle of the planned on study 
chemotherapy regimen will not be counted toward the primary endpoint.  Chemotherapy 
dose modification includes dose reduction, delay, omission, and discontinuation.  The 
proportion of subjects with no thrombocytopenia-induced modification will be provided 
with a 95% CI for each treatment group.  A 2-sided CMH test will be used to compare 
groups controlling for the stratification factors of tumor type and baseline platelet count.  
The common odds ratio for romiplostim vs placebo will be estimated along with a 95% 
CI.  The difference in proportions between treatment groups will be provided with a 95% 
CI.  Additional sensitivity analysis will be described in the Statistical Analysis Plan. 
10.3.2.2.2 
Secondary Endpoints 
10.3.2.2.2.1 
Depth of Platelet Nadir 
The first secondary endpoint is the depth of platelet nadir from the start of the first 
on-study chemotherapy cycle through the EOTP.  Linear regression models will be used 
to compare the mean nadir between the romiplostim and placebo groups.  Dependent 
variables will include the treatment group, the stratification factor of tumor type and 
baseline platelet count, and the interactions between treatment group and the 
stratification factors.  The normality assumption for linear regression models will be 

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checked using a normal probability plot of the residuals and the Shapiro-Wilk test 
(Shapiro and Wilk, 1965).  If the data fail to meet the normality assumption, data 
transformation or a non-parametric method may be considered.  The detailed analysis 
plan will be described in the Statistical Analysis Plan. 
10.3.2.2.2.2 
Time to Platelet Response 
The time to first platelet response is defined by platelet count ≥ 100 x 109/L in the 
absence of platelet transfusions during the preceding 7 days.  Time to first platelet 
response will be calculated from the study day 1 to the date of achieving first platelet 
count ≥ 100 x 109/L.  Subjects who did not achieve a response event during the 
treatment period are censored at their last platelet count assessment date up to the 
EOTP or study day 1 if they did not have any platelet assessment.   
A 2-sided log-rank test stratified by tumor type and baseline platelet count will be 
performed to determine whether time to first platelet response is significantly different 
between treatment groups.  The hazard ratio of achieving platelet response for 
romiplostim vs placebo and its corresponding 2-sided 95 CI will be provided using a 
stratified Cox regression model.   
Kaplan-Meier curves for the time to achieving first platelet response will be presented 
along with Kaplan-Meier estimates and 2-sided 95% CIs at specified time points (week 
3, week 4, etc) for each treatment group.  In addition, Kaplan-Meier quartiles (median, 
25th, and 75th percentiles) will be estimated with 2-sided 95 CI, if estimable. 
10.3.2.2.2.3 
Duration-adjusted Event Rate of  Grade 2 Bleeding Events 
Duration-adjusted event rate of grade ≥ 2 bleeding events are calculated as total number 
of events divided by the total duration (per 100-subject-years) from study day 1 until the 
date of last dose of investigational product plus 30 days.  The number of 
grade ≥ 2 bleeding events will be summarized for each treatment group.  An Andersen-
Gill model (Andersen and Gill, 1982) with a robust variance estimator (Lin and Wei, 
1989), stratified by tumor type and baseline platelet count, will be used to analyze 
recurrent bleeding events and will provide hazard ratio with 95% CI and p-value 
comparing treatment groups. 
10.3.2.2.2.4 
Overall Survival 
Overall survival time is calculated from study day 1 to death.  Subjects who have not 
died will be censored at their last contact date.  A 2-sided stratified log rank will test 

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differences of survival rates between the two treatment groups.  A hazard ratio with 
95% CI from a stratified Cox regression model will describe the treatment effect.   
10.3.2.2.2.5 
Platelet Transfusion 
The proportion of subjects with at least 1 platelet transfusion during the treatment period 
will be provided with a 95 CI for each treatment group and the difference in proportions 
between treatment groups will be provided with a 95% CI.  A 2-sided CMH test will be 
used to compare groups controlling for the stratification factors of tumor type and 
baseline platelet count.  The common odds ratio for romiplostim vs placebo will be 
estimated along with a 95 CI. 
10.3.2.2.2.6 
Achieving a Platelet Count ≥ 100 x 109/L 
The proportion of patients achieving platelet count  100 x 109/L at any time after 
study day 1 to week 4 (ie, 7 days after the third planned dose of investigational product) 
in the absence of platelet transfusions during the preceding 7 days, will be provided with 
a 95% CI for each treatment group and the difference in proportions between treatment 
groups will be provided with a 95% CI.  A 2-sided CMH test will be used to compare 
groups controlling for the stratification factors of tumor type and baseline platelet count.  
The  common odds ratio for romiplostim vs placebo will be estimated along with a 95 
CI. 
10.3.2.2.3 
Exploratory Endpoints 
Analyses for exploratory endpoints will be described in the statistical analysis plan. 
10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Adverse Events 
The subject incidence of treatment-emergent adverse events will be summarized by 
system organ class, by preferred term according to Medical Dictionary for Regulatory 
Activities (MedDRA) for each treatment group.  This summary for treatment-emergent 
adverse events will include the following categories: 
 
all adverse events  
 
fatal adverse events 
 
serious adverse events  
 
treatment-related adverse events  
 
adverse events of interest, such as hemorrhage and thrombotic/thromboembolic 
events  
 
adverse events leading to investigational product discontinuation 

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10.3.2.3.2 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at selected 
time points by treatment group.  Shifts in grades of safety laboratory parameters from 
baseline to worst post-baseline value for pre-specified laboratory parameters will be 
tabulated by treatment group.   
10.3.2.3.3 
Vital Signs 
The analyses of vital signs will include summary statistics at selected time points by 
treatment group.   
10.3.2.3.4 
Physical Measurements 
The analysis of weight will include summary statistics by treatment group.   
10.3.2.3.5 
Antibody Formation 
The number and percentage of subjects who develop anti- romiplostim and anti-TPO 
antibodies (binding and if positive, neutralizing) at any time will be tabulated by treatment 
group. 
10.3.2.3.6 
Exposure to Investigational Product 
The duration of investigational product exposure, cumulative dose, average weekly 
dose, and most frequently received dose will be summarized using descriptive statistics.   
10.3.2.3.7 
Exposure to Non-investigational Products 
Descriptive statistics of chemotherapy agents and the percentage of dose reduction will 
be summarized by treatment group. 
10.3.2.3.8 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term for each treatment group as coded by the World Health Organization 
Drug (WHODRUG) dictionary. 
10.3.2.4 
Other Analyses 
The number and percentage of subjects who experience an event will be tabulated for 
each of the following endpoints: myelodysplastic syndromes and secondary 
malignancies (including progression from myelodysplastic syndrome to acute myeloid 
leukemia).  In addition, Kaplan-Meier curves and hazard ratios with 95% CIs will be 
calculated for myelodysplastic syndrome free time (censor at death), myelodysplastic 
syndrome free survival time (consider death an event), secondary malignancy free time 
(censor at death), and secondary malignancy free survival time (consider death an 

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event).  These analyses will be summarized by treatment group using the safety analysis 
set.  

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12. 
Appendices 

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12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
5-FU 
5-fluorouracil 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase 
CAPEOX 
capecitabine and oxaliplatin 
CIT 
chemotherapy-induced thrombocytopenia 
CMH 
Cochran-Mantel-Haenszel 
 
 
COVID-19 
Coronavirus disease 2019 
CRC 
colorectal cancer 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
DVT 
deep vein thrombosis 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form(s) 
EDC 
electronic data capture 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Study for Individual 
Subject 
Excluding early termination of the study, the EOS Visit for 
individual subjects will be defined as up to 2 weeks after the last 
subject in the trial completes their LTFU Visit 1 year after the last 
dose of investigational product.  
End of Study (EOS, primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s)  
End of Study (end of trial) 
defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the 
study (eg, long-term follow-up), as applicable 
End of Treatment Period 
(EOTP) 
defined as the latest assessment date of the follow up visit 
(7 days [ 1 day] after the last dose of investigational product).  If 
a subject does not complete a follow up visit, then EOTP will be 
7 days after the last dose of investigational product or the EOS 
date, whichever is earlier 
 
 

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Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Study day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject, which should also be the randomization date 
TBL 
total bilirubin 
TPO 
thrombopoietin 
ULN 
upper limit of normal 
VTE 
venous thromboembolism 
 

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12.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the central and local laboratories.  
Additional analyte test results may be reported by the local or central laboratories 
in accordance with standard laboratory procedures (eg, components of a 
hematology panel).  Protocol-specific requirements for inclusion or exclusion of 
subjects are detailed in Sections 6.1 to 6.2 of the protocol.  Additional tests may be 
performed at any time during the study as determined necessary by the investigator or 
required by local regulations. 

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Table 12-1.  Analyte Listing 
Chemistry 1 
(local) 
Chemistry 
2 (local) 
Chemistry 3 
(central) 
Hematology 1 
(local) 
Hematology 2 
(central) 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Adjusted 
calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or urea 
Creatinine 
Total bilirubin 
Direct 
bilirubin 
Alk phos 
AST (SGOT) 
ALT (SGPT) 
Amylase 
Lipase  
 
ASTb 
ALTb 
Alk phosb 
Total 
bilirubinb 
Creatinineb 
BUNb 
GFRb 
CrClb 
 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Adjusted 
calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or urea 
Creatinine 
Uric acid 
Total 
bilirubin 
Direct 
bilirubin 
Alk phos 
LDH 
AST (SGOT) 
ALT (SGPT) 
Amylase 
Lipase 
RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
WBC 
ANC 
Platelet count 
Differential 
 Bands/stabs 
 Eosinophils 
 Basophils 
 Lymphocytes 
 Monocytes  
 Atypical 
lymphocytes 
 
RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
WBC 
ANC 
Differential 
 Bands/stabs 
 Eosinophils 
 Basophils 
 Lymphocytes 
 Monocytes  
 Atypical 
lymphocytes 
 
Central 
Laboratory:   
Romiplostim 
pharmacokinetic 
samplesa 
 
Antibodiesa: 
 To romiplostim 
 Cross-reacting 
to endogenous 
TPO 
 
TPO 
Local Laboratory:  
Platelet count 
Hemoglobin 
ANC 
Urine or serum 
pregnancyc 
PT/INR 
PTT 
Hepatitis B 
surface antigend 
Hepatitis B core 
antibodyd 
Hepatitis C 
antibodyd 
HIVd 
 
Alk phos  alkaline phosphatase; ALT  alanine aminotransferase; ANC  absolute neutrophil count; 
AST  aspartate aminotransferase; BUN  blood urea nitrogen; CrCl = creatinine clearance; 
GFR = glomerular filtration rate; HIV  human immunodeficiency virus; INR  international normalization 
ratio; LDH  lactase dehydrogenase; MCH  mean corpuscular hemoglobin; MCHC  mean corpuscular 
hemoglobin concentration; MCV  mean corpuscular volume; PTT  partial thromboplastin time; 
PT  prothrombin time; RBC  red blood cell count; RDW  red cell distribution width; SGOT  serum 
glutamic oxaloacetic transaminase; SGPT  serum glutamic-pyruvic transaminase; 
TPO  thrombopoietin; WBC  white blood cells  
a These lab parameters should be blinded. 
b Local lab values for BUN, creatinine, creatinine clearance, GFR, ALT, AST, Alk phos, and total bilirubin will 
be reported when a subject is scheduled to receive chemotherapy through 3 on-study chemotherapy cycles.  
Local lab chemistries do not need to be reported if a subject is not scheduled to receive chemotherapy.  
c A highly sensitive urine or serum pregnancy test must be performed. 
d Only performed using central laboratories if unable to perform using local laboratories. 

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12.3 
Appendix 3.  Study Governance Considerations 
Data Monitoring Committee 
An Independent Biostatistics Group (IBG) will perform periodic safety analyses for 
review by an independent Data Monitoring Committee (DMC), which will include at least 
2 clinicians and at least 1 biostatistician who are external to Amgen.  The IBG and DMC 
will have access to subjects’ individual treatment assignments.  To minimize the 
potential introduction of bias to the conduct of the study, members of the DMC and Data 
Monitoring Group will not have any direct contact with study site personnel or subjects.  
The DMC will communicate major safety concerns and recommendations regarding 
study modification or termination based on the safety parameters to Amgen in 
accordance with the DMC charter.  The DMC will also review the interim futility 
analysis results to assess if the study should stop for futility. 
Records of all meetings will be maintained by the DMC for the duration of the study.  
Records of all meetings will be transferred and stored in the trial master folder at the 
conclusion of the study.  Further details are provided in the DMC charter. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document that Amgen distributes to the site.  
The investigator must send a copy of the approval letter from the IRB/IEC and amended 

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protocol Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 

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obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening and randomization occurs within 28 days from the previous informed 
consent form signature date. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each subject the objectives of the exploratory research.  Subjects will be told 

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that they are free to refuse to participate and may withdraw their specimens at any time 
and for any reason during the storage period.  A separate signature will be required to 
document a subject’s agreement to allow any remaining specimens to be used for 
exploratory research.  Subjects who decline to participate will not provide this separate 
signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the case report form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 

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collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors (ICMJE) Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
Authorship credit is to be based on: (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above. 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
All persons designated as authors must qualify for authorship, and all those who qualify 
are to be listed. 
Each author must have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 

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The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 

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records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
CRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the 
Interactive Voice Response System (IVRS)/Interactive Web Response System (IXRS) 
system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as 
 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 

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Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 

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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
 

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12.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for male and female of childbearing potential 
are outlined in Section 6. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to the fetus if they become pregnant or father a 
child during treatment and for 6 months after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
The investigator must discuss these contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal acceptable contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment 

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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of < 1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject)  
Contraception Methods for Male Subjects 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject)  
 
Use a condom during treatment and for an additional 6 months after the last dose of 
protocol-required therapies 
 
The female partner should consider using a highly effective method contraception. 
Note:  If the male’s sole female partner is of non-childbearing potential he is not required 
to use additional forms of contraception during the study. 
Unacceptable Methods of Birth Control for Male and Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 30 days after treatment 
discontinuation.  

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 
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 12-2).  The worksheet must be submitted to Amgen Global Patient Safety 
within 24 hours of learning of a subject’s pregnancy.  (Note:  Sites are not required 
to provide any information on the Pregnancy Notification Worksheet that violates the 
country or regions local privacy laws.) 
 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female subject 
who becomes pregnant while taking protocol-required therapies through 30 days 
after discontinuation of protocol-required therapies.  This information will be 
forwarded to Amgen Global Patient Safety.  Generally, infant follow-up will be 
conducted up to 12 months after the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 12.4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 8.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
30 days after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet.  The worksheet (see   
Figure 12-2) must be submitted to Amgen Global Patient Safety within 24 hours of 
the site’s awareness of the pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Worksheet that violates the country or 
regions local privacy laws.) 
 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female partner to 
obtain additional pregnancy information. 

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 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 30 days after the last dose of 
protocol-required therapies. 
 
Information will be recorded on the Lactation Notification Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 222. 
 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 30 days after the last dose of 
protocol-required therapies. 

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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 

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12.6 
Appendix 6.  Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Activities can be analyzed for 
any of the tests outlined in the protocol and for any tests necessary to minimize risks to 
study subjects.  This includes testing to ensure analytical methods produce reliable and 
valid data throughout the course of the study.  This can also include, but is not limited to, 
investigation of unexpected results, incurred sample reanalysis, and analyses for 
method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
gastrointestinal, pancreatic, or colorectal cancer, the dose response and/or prediction of 
response to romiplostim, characterize antibody response, and characterize aspects of 
the molecule (eg, mechanism of action/target, metabolites).  Results from this analysis 
are to be documented and maintained, but are not necessarily reported as part of this 
study.  Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
sample types (eg, blood, tumor) samples and any other components from the cells can 
be located and destroyed.  Samples will be destroyed once all protocol-defined 
procedures are completed.  However, information collected from samples prior to the 
request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 

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appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 12.3 for subject confidentiality. 
 

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telemedicine services or an appropriate platform if supplied by the sponsor to conduct 
study procedures as required according to the Schedule Activities (Table 2-1), subject to 
the investigator’s discretion.  
For example, procedures performed using telemedicine may include: 
 
Physical examination (limited to procedures that can be performed visually) 
 
Assessments of adverse events and concomitant medications 
 
ECOG performance status 
 

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Amendment 7 
Protocol Title:  RECITE:  A Phase 3 Randomized Placebo controlled 
Double-blind Study of Romiplostim for the Treatment of Chemotherapy-
induced Thrombocytopenia in Patients Receiving Oxaliplatin-based 
Chemotherapy for Treatment of Gastrointestinal, Pancreatic, or Colorectal 
Cancer 
Amgen Protocol Number Romiplostim 20140346 
 
Amendment Date: 
29 July 2021 
 
Rationale: 
The rationale for this protocol amendment is to include the following updates: 
Changes to inclusion criteria: Due to the low accrual to study 20140346 
and the high number of screen failures the following changes are being 
made to the inclusion criteria: 
 
Change Day 1 platelet count from < 75 x 10⁹/L to ≤ 85 x 10⁹/L  
 
Allow subjects to be registered if a protocol allowed chemotherapy 
regimen is planned and has been delayed due to CIT for at least a 
week. 
Expand chemotherapy dose modification guidelines to minimize variation 
among sites in dosing chemotherapy for CIT.  The current guidelines are 
primarily from the individual drug’s label. Only the FOLFOX regimen is in 
the oxaliplatin label. The other protocol approved regimens are not in the 
oxaliplatin label. The dose modification guidelines that were used in the 
phase 3 clinical trials that demonstrated their efficacy and safety were 
added to the protocol to reduce variation in dosing among sites.  
Allow screening laboratory studies to be done locally to determine patient 
eligibility and minimize the time before registration. 
 
One interim futility analysis will be performed when approximately 81 
subjects complete three cycles of chemotherapy. The primary endpoint, 
which is the proportion of subjects with no thrombocytopenia-induced 
chemotherapy dose modification in the second and third cycles of the 
planned on-study chemotherapy regimen, will be analyzed at the interim 
analysis. 
 
Administration, typographical and formatting changes were made 
throughout the protocol.  Updates have been implemented to align with 
the current template. 

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Amgen Proprietary - Confidential 
Superseding Amendment  6 
Protocol Title:  RECITE:  A Phase 3 Randomized Placebo-controlled Double-blind Study 
of Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in 
Patients Receiving Oxaliplatin-based Chemotherapy for Treatment of Gastrointestinal, 
Pancreatic, or Colorectal Cancer 
 
Amgen Protocol Number Romiplostim 20140346 
 
Amendment Date: 
02 September 2020 
Superseding Amendment Date 
02 November 2020 
Rationale: 
The following changes were made to the protocol dated 02 September 2020. 
 
Clarify the dosing schedule of investigational product when it is given on those weeks 
with concomitant chemotherapy. 
 
Clarifies that investigational product is given on chemotherapy day 1 of each 
chemotherapy cycle during the 3 on study cycles.  
 
Text was added that the relevant laboratory tests are checked one time weekly and that 
the start of the planned chemotherapy must be no more than 2 days after the local 
laboratory assessments have been taken. 
 
An administrative change provides guidance to use the chemotherapy dose modification 
guidelines outlined in Section 7.4.1.2. 
 
Another administrative change provides laboratory guidance to be consistent with the 
Schedule of Activities. 
 
Text was added to Appendix 7, Use of Home Healthcare and Telemedicine During the 
COVID-19 Pandemic, that it is not applicable for participating sites in Bulgaria per local 
regulations. 

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Amgen Proprietary - Confidential 
On 02 November 2020, the protocol amendment 6 was superseded to fix the following: 
 
To fix the formatting/Numbering of the section headings from Inclusion criteria 6.1 
onwards. 
 
To fix the other historical formatting issues or editorial changes (including typographical, 
grammatical, and formatting). 

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Amgen Proprietary - Confidential 
Amendment  6 
Protocol Title:  RECITE:  A Phase 3 Randomized Placebo-controlled Double-blind Study 
of Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in 
Patients Receiving Oxaliplatin-based Chemotherapy for Treatment of Gastrointestinal, 
Pancreatic, or Colorectal Cancer 
 
Amgen Protocol Number Romiplostim 20140346 
 
Amendment Date: 
02 September 2020 
 
Rationale: 
 
Clarify the dosing schedule of investigational product when it is given on those weeks 
with concomitant chemotherapy. 
 
Clarifies that investigational product is given on chemotherapy day 1 of each 
chemotherapy cycle during the 3 on study cycles.  
 
Text was added that the relevant laboratory tests are checked one time weekly and that 
the start of the planned chemotherapy must be no more than 2 days after the local 
laboratory assessments have been taken. 
 
An administrative change provides guidance to use the chemotherapy dose modification 
guidelines outlined in Section 7.4.1.2. 
 
Another administrative change provides laboratory guidance to be consistent with the 
Schedule of Activities. 
 
Text was added to Appendix 7, Use of Home Healthcare and Telemedicine During the 
COVID-19 Pandemic, that it is not applicable for participating sites in Bulgaria per local 
regulations. 

Product:  Romiplastim 
Protocol Number:  20140346 
Date:  08 June 2020 
Amgen Proprietary - Confidential 
Amendment 5 
Protocol Title:  RECITE:  A Phase 3 Randomized Placebo-controlled Double-blind Study 
of Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in 
Patients Receiving Oxaliplatin-based Chemotherapy for Treatment of Gastrointestinal, 
Pancreatic, or Colorectal Cancer 
 
Amgen Protocol Number Romiplostim 20140346 
 
Amendment Date: 
08 June 2020 
 
Rationale: 
This protocol is being amended to: 
 
Update inclusion criteria to: 
o Allow new chemotherapy regimens 
o Add pancreatic cancer 
 
Allow three rescreening attempts 
 
Allow Home Health Care and Telemedicine when on-site study visits are 
impacted by the Coronavirus disease 2019 (COVID-19) pandemic  
 
Provide administrative and editorial updates throughout  
 

Product:  Romiplostim
Protocol Number:  20140346
Date:  19 August 2019
Page 1 of 46
CONFIDENTIAL
Amendment 4
Protocol Title:  RECITE:  A Phase 3 Randomized Placebo-controlled Double-blind 
Study of Romiplostim for the Treatment of Chemotherapy-induced 
Thrombocytopenia in Patients Receiving FOLFOX-based Chemotherapy for 
Treatment of Gastrointestinal or Colorectal Cancer
Amgen Protocol Number (Romiplostim) 20140346
EudraCT Number:  2017-002992-25
NCT Number:  NCT03362177
Amendment Date:
19 August 2019
Rationale:
This protocol is being amended to:

add text to clarify that platelet counts, platelet transfusions, adverse events, 
chemotherapy dose and chemistry analytes should be recorded for 3 on-study 
chemotherapy cycles if the subject discontinues investigational product prior to 
completing 3 cycles of chemotherapy

Change Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 to 
version 5.0

Add thrombotic/thromboembolic events to treatment-emergent adverse events of 
interest

Modify criteria to exclude females who are pregnant or breastfeeding or planning to 
become pregnant or breastfeed during treatment and for an additional 6 months after 
after the last dose of protocol-required therapies

Amend protocol exclusion criteria 223 and 224 to reflect that unwillingness to use a 
highly effective method of contraception by female participants or female partner(s) 
of a male participant will meet the respective exclusion criterion

Specify that contraception methods must be used for an additional 6 months after the 
last dose of protocol-required therapies

Add criteria to exclude male subjects who are unwilling to use contraception or 
unwilling to abstain from donating sperm during treatment (and chemotherapy) and 
for an additional 6 months after treatment 

Change contraception requirements for female subjects from acceptable to highly 
effective contraceptive methods
Approved 
 
 

Product:  Romiplostim
Protocol Number:  20140346
Date:  19 August 2019
Page 2 of 46
CONFIDENTIAL

Update analyte table to include local blood urea nitrogen (BUN) collection

Specify that for urine pregnancy testing a highly sensitive urine pregnancy test must 
be performed.

Add text to perform monthly pregnancy test during the treatment period and one 
further pregnancy test at 30 days after the last dose of protocol-required therapies.
Approved 
 
 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  27 February 2019 
Page 1 of 28 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase 3 Randomized Placebo-controlled Double-blind Study of 
Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in 
Patients Receiving FOLFOX-based Chemotherapy for Treatment of 
Gastrointestinal or Colorectal Cancer 
 
Amgen Protocol Number Nplate 20140346 
EudraCT number 2017‐002992‐25 
NCT number NCT03362177 
 
Amendment Date: 
27 February 2019 
 
Rationale: 
This protocol is being amended to: 
• 
Update the order of secondary endpoints.  This is to address FDA request received 
for 20170770 SPA No Ageement letter that the rank of the duration adjusted event 
rate of ≥ Grade 2 bleeding events and platelet transfusions endpoints should be 
higher than achieving a platelet count of ≥100 x 109/L endpoint in the testing strategy 
for the secondary endpoints.  
• 
Add language to clarify definition of dose modifications, which already included 
chemotherapy dose reductions and delays, to also include dose omissions and 
treatment discontinuations.  Any of the above reasons for dose modifications will be 
counted as failures in the primary endpoint analysis. 
• 
Add a stratification factor of baseline platelet count (< 50 x 109/L, ≥ 50 x 109/L) at 
randomization.  Study schema updated to show additional stratification.  
• 
Add guidance on chemotherapy dose modifications due to renal and hepatic toxicity.   
• 
Add an evaluation of the normality assumption strategy for the first secondary 
endpoint and propose possible alternate methods. 
• 
Add additional potential confounding covariate programmed cell death 1 inhibitor use 
and programmed cell death ligand 1 inhibitor use per FDA request.  
• 
Add missing data assessment with possible reasons. 
• 
Make editorial and administrative changes for grammatical reasons as well as for 
internal consistency within the protocol. 
 
Approved 
 
 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  14 November 2018 
Page 1 of 65 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 3 Randomized Placebo-controlled Double-blind Study of 
Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in Patients 
Receiving FOLFOX-based Chemotherapy for Treatment of Gastrointestinal or Colorectal 
Cancer 
 
Amgen Protocol Number Romiplostim 20140346 
EudraCT number 2017-002992-25 
NCT number NCT03362177 
Amendment Date: 
14 November 2018 
Rationale: 
This protocol is being amended to: 
• 
Clarify local laboratory collection of hemoglobin and absolute neutrophil counts on 
day 1 
• 
Include hepatitis and HIV tests at screening in Schedule of Activities for consistency 
within protocol 
• 
Update End of Study Definitions for clarity and consistency 
• 
Clarify hepatitis and HIV testing requirement for subjects without a documented 
diagnosis in medical history 
• 
Clarify concomitant medication timing when a subject is receiving a concomitant 
chemotherapy on a study visit date 
• 
Update study schema by moving number of subjects (N=162) from screening to 
enrollment phase and in alignment with the rest of the protocol 
• 
Update the schedule of assessment to be consistent with updates to the protocol 
• 
Update primary endpoint definition to include any dose delay or dose reduction in 
second and third cycle.  This is to address FDA request that the primary analyses of 
the efficacy endpoints should be based on intent to treat population 
• 
Update the primary analyses of the efficacy endpoints such that subject will meet the 
criteria of the primary endpoint if they have no thrombocytopenia-induced 
modification of any myelosuppressive agent in the second and third cycles of the 
planned on study chemotherapy regimen 
• 
Change the hierarchical order of secondary endpoints with platelet nadir as first 
secondary endpoint, and bleeding events and overall survival moved higher in the 
order  
• 
Clarify the reference time point for monitoring overall survival as 1 year after the last 
dose of investigational product 
• 
Add vital status as part of assessments during long term follow up 
• 
Add instruction on how to handle discordant platelet values if multiple tests are done 
in the same day or ± 1 day 
Approved 
 
 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  14 November 2018 
Page 2 of 65 
CONFIDENTIAL 
 
 
• 
Add thrombocytopenia-related dose modification guidance per chemotherapy and 
tumor type 
• 
Update the number of investigative sites to 100 instead of 125, and remove Canada 
as a separate site  
• 
Update the study duration for subjects to be consistent with the rest of the protocol  
• 
Revise exclusion criterion 220 to exclude only patients with severe renal impairment 
(creatinine clearance < 30 mL/min) 
• 
Update exclusion criteria by excluding subjects with thrombocytopenia due to 
another etiology other than chemotherapy-induced thrombocytopenia (exclusion 
criterion 215) 
• 
Update the General Study Periods in the protocol by adding language to 
accommodate for rescreening that occurs less than 30 days after the original signing 
of the informed consent 
• 
Add a 15% minimum cap regarding enrollment of subjects for each tumor type 
• 
Update the treatment period considering the chemotherapy cycles and the 
investigational product dose adjustment guidelines 
• 
Update the proposed analysis plan to include sensitivity analyses using different 
cutoff values to evaluate the robustness of analysis results 
• 
Revise the strategy for handling missing data to be consistent between the two 
cycles, and for the patients whose cycle 2 or cycle 3 status is missing, sensitivity 
analyses will be explored by imputing the missing observations in cycle 2 and/or 
cycle 3 using the same rule based on the last platelet count assessment when 
calculating the primary endpoint 
• 
Revise relevant language in Section 10 (Statistical Considerations) and respective 
text in synopsis, since secondary endpoint is no longer considered in sample 
size/power calculation 
• 
Make editorial and administrative changes for grammatical reasons as well as for 
internal consistency within the protocol 
Approved 
 
 

Product:  Romiplostim 
Protocol Number:  20140346 
Date:  12 March 2018 
Page 1 of 74 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase 3 Randomized Placebo-controlled Double-blind Study of 
Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in 
Patients Receiving FOLFOX-based Chemotherapy for Treatment of 
Gastrointestinal or Colorectal Cancer 
 
Amgen Protocol Number Romiplostim 20140346 
EudraCT number 2017-002992-25 
NCT number NCT03362177 
Amendment Date: 
12 March 2018 
Rationale: 
This amendment was revised to: 
• 
Specified the chemotherapy regimen and type of cancer to state that romipostim will 
be studied for the treatment of chemotherapy-induced thrombocytopenia in patients 
receiving a FOLFOX-based chemotherapy regimen for treatment of gastrointestinal 
or colorectal cancer: 
o Limit the chemotherapy regimen to ‘FOLFOX-based regimen’. 
o Removed lung and ovarian cancer. 
o Enrollment stratified by gastrointestinal and colorectal cancer. 
• 
Added a secondary endpoint to measure overall survival. 
• 
Added the benefit/risk Assessment. 
• 
Editorial changes (ie, typographic, grammatical, and formatting errors) and 
abbreviation corrections were made throughout the protocol in accordance with 
Amgen Inc. Style Guide. 
Approved