Conditions: Squamous-Cell Non-Small-Cell Lung Cancer
Keywords: Squamous-Cell Non-Small-Cell Lung Cancer FGFR2b-positive Squamous-Cell Non-Small-Cell Lung Cancer SqNSCLC Bemarituzumab Docetaxel
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 74
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the safety and tolerability of bemarituzumab monotherapy and combination with other anti-cancer therapies, and to determine the recommended phase 3 dose of bemarituzumab in combination with other anti-cancer therapies.

Detailed description:

Arms:
arm 1: Participants with SqNSCLC will receive escalating doses of bemarituzumab in combination with docetaxel. arm 2: Participants with SqNSCLC and FGFR2b overexpression will receive the dose of bemarituzumab in combination with docetaxel identified as safe during Part 1. arm 3: Participants with SqNSCLC and FGFR2b overexpression will receive bemarituzumab monotherapy. arm 4: Participants with FGFR2b overexpression will receive the dose of bemarituzumab identified as safe during Part 1 in combination with pembrolizumab, carboplatin and either paclitaxel or nab-paclitaxel.

Interventions: intervention 1: Bemarituzumab intervention 2: Docetaxel intervention 3: Pembrolizumab intervention 4: Carboplatin intervention 5: Paclitaxel intervention 6: Nab-paclitaxel
Intervention descriptions: intervention 1: Intravenous (IV) infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: IV infusion intervention 5: IV infusion intervention 6: IV infusion

Protocol document:
Prot_000.pdf: 
Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
Date:  27 April 2023 
Page 1 of 177 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Phase 1b Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of 
Bemarituzumab Monotherapy and Combination 
with other Anti-Cancer Therapy in Subjects with 
Squamous-Cell Non-Small-Cell Lung Cancer 
(FORTITUDE-201) 
Short Protocol Title: 
A phase 1b study of bemarituzumab 
monotherapy and combination with other 
anti-cancer therapy in SqNSCLC with FGFR2b 
overexpression (FORTITUDE-201) 
Protocol Number: 
20210102 
Investigational Product: 
Bemarituzumab (AMG 552)  
Trade Name: 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA, 91320 
Telephone Number: 
+1 805-447-1000 
Protocol 
Approver 
Name: 
, PharmD 
Function: 
VP Global Development 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA, 91320 
Telephone Number: 
Email Address: 
EudraCT/EU CT Number: 
2021-004058-47/2023-505456-22 
NCT Number: 
NCT05267470 


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
Date:  27 April 2023 
Page 2 of 177 
CONFIDENTIAL  
 
 
Protocol Version Date: 
Document Version 
Date 
Original 
13 September 2021 
Amendment 1 
2 March 2022 
Amendment 2 
27 September 2022 
Superseding 
Amendment 2 
28 October 2022 
Amendment 3 
27 April 2023 
 
Data Elements Standards 
Version: 
8.0 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (International Council for Harmonisation 
[ICH] E6). 
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. 
 
 


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
Date:  27 April 2023 
Page 3 of 177 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 1b Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of Bemarituzumab Monotherapy and 
Combination with other Anti-Cancer Therapy in Subjects with Squamous-Cell 
Non-Small-Cell Lung Cancer (FORTITUDE-201), dated 27 April 2023, and 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) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
Date:  27 April 2023 
Page 4 of 177 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary ................................................................................................ 10 
1.1 
Synopsis ................................................................................................... 10 
1.2 
Study Schema ........................................................................................... 19 
1.3 
Schedule of Activities (SoA) ...................................................................... 20 
2. 
Introduction ........................................................................................................... 47 
2.1 
Study Rationale ......................................................................................... 47 
2.2 
Background ............................................................................................... 47 
2.2.1 
Disease ..................................................................................... 47 
2.2.2 
Amgen Investigational Product Background:  
Bemarituzumab ......................................................................... 48 
2.2.2.1 
Nonclinical Studies with Bemarituzumab ................. 49 
2.2.2.2 
Clinical Studies with Bemarituzumab ....................... 50 
2.3 
Benefit/Risk Assessment ........................................................................... 54 
2.3.1 
COVID-19 .................................................................................. 58 
3. 
Objectives and Endpoints ..................................................................................... 58 
4. 
Study Design ........................................................................................................ 60 
4.1 
Overall Design .......................................................................................... 60 
4.2 
Patient Input into the Study Design ........................................................... 64 
4.3 
Justification for Dose ................................................................................. 64 
4.3.1 
Justification for Amgen Investigational Product Dose: ............... 64 
4.3.2 
Justification for Non-investigational Product Dose ..................... 66 
4.4 
End of Study ............................................................................................. 67 
5. 
Study Population .................................................................................................. 67 
5.1 
Inclusion Criteria ....................................................................................... 68 
5.2 
Exclusion Criteria ...................................................................................... 70 
5.3 
Subject Enrollment .................................................................................... 73 
5.4 
Screen Failures ......................................................................................... 73 
6. 
Study Intervention ................................................................................................. 74 
6.1 
Study Interventions Administered .............................................................. 74 
6.1.1 
Investigational Products ............................................................ 74 
6.1.2 
Non-investigational Products ..................................................... 77 
6.1.3 
Other Protocol-required Therapies ............................................ 80 
6.1.3.1 
Pre- and Post-infusion Medications for 
Chemotherapies ...................................................... 80 
6.1.3.2 
Biopsies .................................................................. 80 
6.1.4 
Medical Devices ........................................................................ 81 
6.1.4.1 
Investigational In Vitro Diagnostic Devices .............. 81 
6.1.4.2 
Other Non-Investigational Medical Devices ............. 81 


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
Date:  27 April 2023 
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6.1.5 
Product Complaints ................................................................... 81 
6.1.6 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 82 
6.2 
Dose Modification ...................................................................................... 82 
6.2.1 
Dose Cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 82 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 86 
6.2.2.1 
Amgen Investigational Product:  
Bemarituzumab ....................................................... 87 
6.2.2.2 
Non-Amgen Non-Investigational Product ................. 92 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 94 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 94 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 94 
6.4.1 
Method of Treatment Assignment .............................................. 94 
6.4.2 
Blinding ..................................................................................... 95 
6.5 
Treatment Compliance .............................................................................. 95 
6.6 
Treatment of Overdose ............................................................................. 95 
6.7 
Prior and Concomitant Treatment ............................................................. 95 
6.7.1 
Prior Treatment ......................................................................... 95 
6.7.2 
Concomitant Treatment ............................................................. 96 
6.7.2.1 
Supportive Care ...................................................... 96 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal ................................................................................... 96 
7.1 
Discontinuation of Study Treatment........................................................... 97 
7.2 
Subject Discontinuation/Withdrawal From the Study ................................. 97 
7.2.1 
Reasons for Removal From Study ............................................. 98 
7.3 
Lost to Follow-up ....................................................................................... 98 
8. 
Study Assessments and Procedures .................................................................... 98 
8.1 
General Study Periods .............................................................................. 99 
8.1.1 
Screening, Enrollment, and/or Randomization ........................... 99 
8.1.2 
Treatment Period ..................................................................... 100 
8.1.3 
Safety Follow-up ...................................................................... 100 
8.1.4 
Long-term Follow-up ................................................................ 100 
8.1.5 
End of Study ............................................................................ 100 
8.2 
General Assessments ............................................................................. 100 
8.2.1 
Informed Consent .................................................................... 100 
8.2.2 
Demographics ......................................................................... 101 
8.2.3 
Medical History ........................................................................ 101 
8.2.4 
Physical Examination .............................................................. 101 
8.2.5 
Physical Measurements .......................................................... 101 
8.2.6 
Substance Use History ............................................................ 101 


Product:  Bemarituzumab (AMG 552) 
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8.2.7 
Performance Status ................................................................. 101 
8.3 
Efficacy Assessments ............................................................................. 101 
8.4 
Safety Assessments ................................................................................ 103 
8.4.1 
Vital Signs ............................................................................... 103 
8.4.2 
Electrocardiograms (ECGs) ..................................................... 103 
8.4.3 
Clinical Laboratory Assessments ............................................. 104 
8.4.4 
Vital Status .............................................................................. 104 
8.4.5 
Other Safety ............................................................................ 104 
8.4.5.1 
Ophthalmologic Examinations ............................... 104 
8.4.6 
Adverse Events and Serious Adverse Events .......................... 105 
8.4.6.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information ................ 106 
8.4.6.2 
Method of Detecting Adverse Events and 
Serious Adverse Events ........................................ 107 
8.4.6.3 
Follow-up of Adverse Events and Serious 
Adverse Events ..................................................... 107 
8.4.6.4 
Regulatory Reporting Requirements for 
Safety Information ................................................. 108 
8.4.6.5 
Safety Monitoring Plan .......................................... 109 
8.4.6.6 
Adverse Events of Special Interest ........................ 109 
8.4.6.7 
Pregnancy and Lactation ....................................... 109 
8.5 
Pharmacokinetic Assessments ................................................................ 110 
8.6 
Pharmacogenetic Assessments .............................................................. 110 
8.7 
Antibody Testing Procedures .................................................................. 110 
8.8 
Biomarkers .............................................................................................. 111 
8.8.1 
Biomarker Samples at Pre-Screening and Screening .............. 111 
8.8.2 
Biomarker Development .......................................................... 112 
8.8.2.1 
Biomarker Future Research .................................. 113 
9. 
Statistical Considerations .................................................................................... 113 
9.1 
Statistical Hypotheses ............................................................................. 113 
9.2 
Sample Size Determination ..................................................................... 113 
9.3 
Populations for Analysis .......................................................................... 114 
9.3.1 
Covariates ............................................................................... 114 
9.3.2 
Subgroups ............................................................................... 114 
9.4 
Statistical Analyses ................................................................................. 114 
9.4.1 
Planned Analyses .................................................................... 115 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................. 115 
9.4.1.2 
Primary Analysis ................................................... 115 
9.4.1.3 
Final Analysis ........................................................ 115 
9.4.2 
Methods of Analyses ............................................................... 115 
9.4.2.1 
General Considerations ......................................... 115 
9.4.2.2 
Efficacy Analyses .................................................. 116 


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
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CONFIDENTIAL  
 
 
9.4.2.3 
Safety Analyses .................................................... 116 
9.4.2.4 
Other Analyses ...................................................... 118 
10. 
References ......................................................................................................... 119 
11. 
Appendices ......................................................................................................... 122 
11.1 
Appendix 1.  List of Abbreviations ........................................................... 122 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 126 
11.3 
Appendix 3.  Study Governance Considerations ..................................... 129 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 139 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 147 
11.6 
Appendix 6.  Sample Storage and Destruction ........................................ 153 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 155 
11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse 
Events ..................................................................................................... 159 
11.9 
Appendix 9.  Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v 1.1 Eisenhauer et al, 2009) ................................. 160 
11.9.1 
Definitions ............................................................................... 160 
11.9.1.1 
Measurable Disease.............................................. 160 
11.9.1.2 
Measurable Lesions .............................................. 160 
11.9.2 
Methods of Measurement ........................................................ 161 
11.9.2.1 
CT/MRI .................................................................. 161 
11.9.2.2 
PET-CT ................................................................. 162 
11.9.2.3 
Ultrasound ............................................................. 162 
11.9.2.4 
Endoscopy, Laparoscopy ...................................... 162 
11.9.2.5 
Tumor markers ...................................................... 162 
11.9.2.6 
Cytology, Histology ............................................... 162 
11.9.2.7 
FDG-PET .............................................................. 163 
11.9.3 
Lesion Evaluation .................................................................... 163 
11.9.3.1 
Baseline documentation of “Target” and 
“Non-target” lesions ............................................... 163 
11.9.3.1.1 Target Lesions ...................................................... 163 
11.9.4 
Response Criteria .................................................................... 164 
11.9.5 
Evaluation of Best Overall Response ....................................... 165 
11.9.6 
Special Notes on Response Assessment ................................ 167 
11.10 Appendix 10.  ECOG Performance Status and NYHA 
Classification ........................................................................................... 170 
11.11 Appendix 11.  Ocular Toxicity Grading .................................................... 171 
11.12 Appendix 12.  LogMAR Conversion Table for Visual Acuity* ................... 173 
11.13 Appendix 13.  Country-specific Requirements ......................................... 174 
 


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
Date:  27 April 2023 
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CONFIDENTIAL  
 
 
List of Tables 
Table 1-1.  Schedule of Activities (Parts 1 and 2 only) ................................................... 20 
Table 1-2.  Schedule of Activities (Part 3 only) .............................................................. 29 
Table 1-3.  Schedule for Activities (Part 4 only) ............................................................. 38 
Table 6-1.  Investigational Products ............................................................................... 75 
Table 6-2.  Study Groups............................................................................................... 76 
Table 6-3.  Non-Investigational Products ....................................................................... 77 
Table 6-4.  Dose Escalation/De-escalation Rules for the mTPI-2 Design ....................... 84 
Table 6-5.  Bemarituzumab Dose Modification Guidelines for Adverse Events .............. 88 
Table 11-1.  Analyte Listing ......................................................................................... 127 
Table 11-2.  DILI Potential Analyte Listing ................................................................... 128 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 156 
Table 11-4.  Evaluation of Target Lesions ................................................................... 164 
Table 11-5.  Evaluation of Non-target Lesions ............................................................. 165 
Table 11-6.  Time Point Overall Response .................................................................. 166 
Table 11-7.  Best Overall Response When Confirmation of Complete 
Response (CR) and Partial Response (PR) Required .......................... 167 
Table 11-8.  Ocular Toxicity Grading ........................................................................... 171 
Table 11-9.  Poland Summary of Changes .................................................................. 174 
Table 11-10.  France Summary of Changes ................................................................ 174 
 


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
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List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 19 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form (paper-based form) ...................................................................... 144 
Figure 11-3.  Pregnancy and Lactation Notification Forms ........................................... 151 


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102  
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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
and Efficacy of Bemarituzumab Monotherapy and Combination with other Anti-Cancer 
Therapy in Subjects with Squamous-Cell Non-Small-Cell Lung Cancer 
(FORTITUDE-201) 
Short Protocol Title:  A phase 1b study of bemarituzumab monotherapy and 
combination with other anti-cancer therapy in SqNSCLC with FGFR2b overexpression 
(FORTITUDE-201) 
Study Phase:  Phase 1b 
Indication:  FGFR2b-positive squamous non-small-cell lung cancer 
Study Rationale 
Bemarituzumab is a humanized monoclonal antibody that targets the fibroblast growth 
factor (FGF) receptor isoform 2b (FGFR2b) with a dual mechanism of FGF binding 
inhibition and antibody-dependent cellular cytotoxicity.  Bemarituzumab monotherapy 
has been investigated in a phase 1 dose-finding study (FPA144-001) and in combination 
with mFOLFOX6 chemotherapy in FGFR2b-positive gastric cancer in the FIGHT study.  
Bemarituzumab efficacy correlated with the degree of FGFR2b overexpression by 
immunohistochemistry (IHC) in gastric cancer and has demonstrated a manageable 
safety profile in combination with mFOLFOX6.  Genomic and IHC data suggest that 
other carcinomas including squamous-cell non-small-cell lung cancer (SqNSCLC) may 
also have a significant rate of FGFR2b overexpression.  This study will evaluate the 
safety, tolerability, and efficacy of bemarituzumab monotherapy as well as the 
combination with other anti-cancer therapy, across different lines of therapy in the locally 
advanced/metastatic setting.  Once a recommended dose of bemarituzumab in 
combination with docetaxel is determined, this study will explore the efficacy of the 
docetaxel combination in FGFR2b+ selected SqNSCLC, as well as the safety and 
efficacy of the bemarituzumab combination with other anti-cancer therapies in the 
first-line metastatic treatment setting. 


Product:  Bemarituzumab (AMG 552) 
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Objective(s) and Endpoint(s)/Estimand(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of bemarituzumab 
monotherapy and combination 
with other anti-cancer therapies  
 
To determine the recommended 
phase 3 dose of bemarituzumab 
in combination with other 
anti-cancer therapies  
 
Dose limiting toxicities (DLTs), 
treatment-emergent adverse 
events, and clinically significant 
changes in vital signs, physical 
examinations, clinical laboratory 
tests, and visual acuity 
Secondary 
 
To characterize the 
pharmacokinetics (PK) of 
bemarituzumab monotherapy 
and in combination with other 
anti-cancer therapies 
 
PK parameters for bemarituzumab 
including, but not limited to, area 
under the concentration time curve 
(AUC), maximum observed 
concentration (Cmax), and observed 
concentration at the end of a dose 
interval (Ctrough) 
 
To evaluate preliminary anti-
tumor activity of bemarituzumab 
monotherapy and in 
combination with other 
anti-cancer therapies 
 
Objective response [defined as 
complete response (CR) + partial 
response (PR)] (as determined by 
investigator per Response 
Evaluation Criteria in Solid Tumors 
[RECIST v1.1]) 
 
Duration of response defined as 
the time from first response to 
disease progression (as 
determined by investigator per 
RECIST v1.1) or death from any 
cause, whichever comes first 
 
Disease control defined as CR + 
PR + stable disease (SD) 
 
Progression free survival (PFS), 
defined as time from first dose of 
investigational product until 
disease progression or death from 
any cause.  Subjects alive without 
progression will be censored at 
their last evaluable disease 
assessment.  Progression will be 
based on assessment by 
investigator per RECIST v1.1 
 
Overall survival (OS), defined as 
time from first dose of 
investigational product until death 
from any cause.  Subjects still alive 
will be censored at the date last 
known to be alive 


Product:  Bemarituzumab (AMG 552) 
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Primary Estimand(s)/Coprimary Estimand(s) 
Not applicable. 
Secondary Estimand(s) 
Not applicable. 
Overall Design 
This is a phase 1b, open-label, multicenter study to evaluate the safety, tolerability, 
pharmacokinetics (PK), and efficacy of bemarituzumab monotherapy and combination 
across different lines of therapy in locally advanced/metastatic SqNSCLC.  This study 
will explore the addition of bemarituzumab to the established standard of care 
immuno-chemotherapy in the first-line treatment setting and the addition to 
chemotherapy in the second line or later setting. 
The study consists of a pre-screening period to collect tissue for FGFR2b testing 
(Parts 2, 3, and 4 only), a 28-day screening period, a treatment period, a safety follow-up 
(SFU) visit, and a long-term follow-up (LTFU) period.  Subjects who discontinue 
bemarituzumab will undergo SFU approximately 28 (+ 3) days after the last dose of 
study treatment.  In addition, subjects will undergo LTFU for survival approximately 
every 3 months (± 1 month) for up to 2 years from the first dose of bemarituzumab.  
Subjects will receive study treatment with bemarituzumab until disease progression (see 
Part 4 below for a possible exception), unacceptable toxicity, subject request, or death 
(whichever occurs first).  
Radiographic assessments will be performed by the investigator according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 and will be performed every 6 weeks 
(Q6W) (± 7 days) until week 54 and then every 12 weeks (± 14 days).  After 
discontinuation of study treatment for reasons other than radiographic disease 
progression or withdrawal of consent, tumor assessments will continue until radiographic 
progression or initiation of additional anticancer therapy. 
The study consists of 4 Parts: 
 
Part 1:  Combination dose exploration with docetaxel 
 
Part 2:  Combination dose expansion with docetaxel 
 
Part 3:  Monotherapy  


Product:  Bemarituzumab (AMG 552) 
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 
Part 4:  Combination with carboplatin, paclitaxel or nab-paclitaxel, and 
pembrolizumab 
Tumor samples from subjects will be required to demonstrate FGFR2b overexpression 
status prior to subjects entering Parts 2, 3, and 4 (and not Part 1) of this study.  This 
study may be amended at a later date to include additional subjects for further efficacy 
evaluation. 
Part 1 
Part 1 of the study will explore the dosing of bemarituzumab in combination with 
docetaxel.  During dose exploration, subjects will be enrolled in groups of 3 to 6 dose 
limiting toxicity (DLT) evaluable subjects per cohort, and escalation will be guided 
primarily by safety responses to different doses. 
The starting dose of bemarituzumab is based on review of the available safety, PK, and 
efficacy data from bemarituzumab monotherapy and bemarituzumab plus mFOLFOX6 
combination studies (FPA144-001, FPA144-004).  The recommended phase 2 dose of 
bemarituzumab in combination with mFOLFOX6 (evaluated in study FPA144-004) was 
determined to be 15 mg/kg intravenous (IV) every 2 weeks (Q2W) with a single 
7.5 mg/kg dose on day 8 of the first cycle.   
The dosing interval will increase from Q2W to every 3 weeks (Q3W) to align with the 
other anti-cancer therapy Q3W dosing schedule.  At Dose Level 1 the same dose of 
15 mg/kg as in FPA144-004 will be tested, but at Q3W instead of Q2W and replacing the 
additional dose of 7.5 mg/kg day 8 with a 1 time loading dose of 22 mg/kg IV on the first 
dosing day.  Dose Level 2 will proportionally increase the bemarituzumab dose, 
including the loading dose, from the Q2W dose studied in FPA144-004 to account for the 
increased Q3W dosing interval.  One cycle of treatment will consist of 21 days.  For 
Part 1, prospective tumor evaluation for FGFR2b overexpression status will not be 
required for enrollment and will enroll up to approximately 18 subjects. 
The planned dose levels are: 
 
Dose Level 1:  bemarituzumab 22 mg/kg IV cycle 1 day 1 followed by 15 mg/kg IV 
day 22 and Q3W thereafter 
 
Dose Level 2:  bemarituzumab 30 mg/kg IV cycle 1 day 1 followed by 22 mg/kg IV 
day 22 and Q3W thereafter 
An additional Dose Level 1a of bemarituzumab 15 mg/kg IV Q3W plus 1 additional 
7.5 mg/kg dose on cycle 1 day 8 only may be explored if dose de-escalation is required 


Product:  Bemarituzumab (AMG 552) 
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from Dose Level 1.  Any other dose levels besides dose levels 1, 2, or 1a, will require a 
protocol amendment prior to enrollment. 
At each dose level, and on each planned dosing day, docetaxel will be administered at 
75 mg/m2 IV Q3W (or 60 mg/m2 IV Q3W for subjects from sites in Japan). 
Part 1 will begin with Dose Level 1.  The study DLT period is 21 days following the first 
dose.  Once 3 to 6 subjects enrolled at a certain dose level are followed for safety for 
21 days, a Dose Level Review Team (DLRT) meeting will be convened. 
The DLRT will evaluate all available safety, laboratory, and PK data as well as rules 
generated from a modified toxicity probability interval design (mTPI-2) (Guo et al, 2017) 
to guide their dose finding recommendations.  The team may recommend escalation to 
the next planned dose, continuation at the current dose level, de-escalation to a lower 
dose, termination of the study, or initiation of enrollment to Part 2 of the study with the 
evaluated dose level.  The mTPI-2 escalation/de-escalation guideline for each dose 
cohort is derived with a target toxicity probability of 0.30, acceptable toxicity probability 
interval of (0.25, 0.33).  A dose level will be considered unsafe, with no additional 
subjects enrolled at that dose level, if it has an estimated 95% or more probability of 
exceeding the target DLT (ie, the elimination boundary). 
Dose exploration will continue until: 
 
a maximum of 18 subjects in Part 1 is reached; or 
 
9 subjects have been treated at a specific dose level; or 
 
the lowest dose level exceeds the elimination boundary 
Part 2 
Once a dose level has been declared safe by the DLRT for Part 1, a dose level can 
enter Part 2 of the study.  Part 2 enrollment will be limited to subjects with prospectively 
identified FGFR2b overexpression status.  A minimum of 10 subjects and a maximum of 
30 subjects will be treated per dose level in Part 2 to better understand the safety profile 
and preliminary efficacy of the combination, and to enable selection of the recommended 
phase 3 dose (RP3D).  Up to 2 dose levels consisting of 10 to 30 subjects each can be 
expanded in Part 2 of the study.  For Part 2, subjects can receive 1 dose of docetaxel 
during pre-screening or screening if initiation of treatment is deemed urgent by the 
investigator.  This bridging dose is not a requirement of the study and is not considered 
part of the clinical study. 


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Part 3 
Part 3 of the study will explore bemarituzumab monotherapy at the dose evaluated in 
study FPA144-004 of 15 mg/kg IV Q2W plus 1 additional 7.5 mg/kg dose on cycle 1 
day 8.  One cycle of treatment will consist of 14 days.  Part 3 enrollment will be limited to 
subjects with prospectively identified tumor FGFR2b overexpression status.  A minimum 
of 10 subjects and a maximum of 30 subjects will be treated in Part 3 to better 
understand the safety profile, PK, and preliminary efficacy of monotherapy 
bemarituzumab in FGFR2b+ SqNSCLC.  Part 3 may enroll subjects concurrently with 
Parts 1, 2, and 4. 
Part 4 
Once a dose level has been declared safe by the DLRT for Part 1, a dose level can 
enter the Part 4 safety run-in.  During the safety run-in, 6 subjects will be evaluated with 
a 21-day DLT period and once the dose has been declared safe in the first-line setting 
with immuno-chemotherapy combination, then Part 4 enrollment can proceed with dose 
expansion.  Dose de-escalation may occur in Part 4, independently of the 
recommendation in Part 1.  Part 4 enrollment will be limited to subjects with 
prospectively identified FGFR2b overexpression status.  A minimum of 10 subjects and 
a maximum of 30 subjects, including the 6 subjects in the safety run-in, will be treated in 
Part 4 to better understand the safety profile and preliminary efficacy of the combination 
and to enable the selection of the RP3D.  Up to 2 dose levels consisting of 10 to 
30 subjects each can be expanded in Part 4 of the study.  Subjects will receive up to 
4 cycles of bemarituzumab, pembrolizumab, and chemotherapy followed by 
bemarituzumab and pembrolizumab maintenance.  In addition to bemarituzumab 
administered on day 1 of every 21-day treatment cycle, subjects will be administered 
pembrolizumab 200 mg day 1 for up to 35 cycles and, for the first four cycles only, the 
combination of carboplatin 6 mg/mL/min and either paclitaxel 200 mg/m2 on day 1 or 
nab-paclitaxel 100 mg/m2 on days 1, 8, and 15.  For Part 4 expansion (and not in safety 
run-in), subjects can receive 1 dose of carboplatin and paclitaxel or nab-paclitaxel with 
or without pembrolizumab during pre-screening or screening if initiation of treatment is 
deemed urgent by the investigator.  This bridging dose is not a requirement of the study 
and is not considered part of the clinical study.   
For Part 4 only, subjects may continue treatment beyond initial RECIST v1.1 progressive 
disease (PD), as assessed by the investigator, as long as they meet the following 
criteria: 


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 
Investigator assessed clinical benefit 
 
Tolerance of study drug 
 
Stable Eastern Cooperative Oncology Group (ECOG) performance status 
 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (ie, central nervous system [CNS] 
metastases) 
Number of Subjects 
It is anticipated that up to 180 subjects will be enrolled in this study, consisting of a 
maximum of 18 subjects in Part 1 and a maximum of 150 subjects in Parts 2, 3, and 4 
combined.  The 150 subjects includes the possibility of 2 cohorts at 2 dose levels of 
bemarituzumab, consisting of 10 to 30 subjects in each of Parts 2 and 4.  Three to 
6 Japanese subjects per dose level will be enrolled in Part 1, Part 2, and/or Part 4, either 
as part of the initial dose level evaluation, or as backfill once the RP3D has been 
determined.  The planned regions for this study will include North America, Asia, Europe, 
and Australia. 
Summary of Subject Eligibility Criteria 
Subjects ≥ 18 years of age (or legal adult within country, whichever is older) at the time 
of informed consent with histologically documented SqNSCLC either previously 
untreated in the locally advanced/unresectable or metastatic setting (Part 4), or 
experienced disease recurrence on or after receiving at least 1 prior systemic therapy 
(Parts 1 and 2), or at least 2 prior systemic therapies (Part 3).  For Parts 1 and 
2 subjects must be candidates for docetaxel.  For Part 4, subjects must be candidates 
for pembrolizumab, carboplatin, and either nab-paclitaxel or paclitaxel.  Parts 2, 3, and 
4 subjects must have FGFR2b overexpression as determined by centrally performed 
IHC testing.  All subjects must have measurable disease per RECIST v1.1. 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
For Parts 1 and 2, bemarituzumab will be administered IV every 21 days on day (D1) of 
each cycle with docetaxel 75 mg/m2 (or 60 mg/m2 for subjects at sites in Japan).  
Bemarituzumab, at doses indicated in the dose exploration, will be administered as an 
approximately 30 minute (± 10 minutes) IV infusion via peripheral vein or central venous 
catheter.  Docetaxel at a dose of 75 mg/m2 (or 60 mg/m2 for subjects at sites in Japan) 
only will be administered over 60 minutes via peripheral vein or central venous catheter.  
One treatment cycle is 21 days. 


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For Part 3, bemarituzumab will be administered IV every 14 days on day (D1) of each 
cycle.  Bemarituzumab, at the dose of 15 mg/kg IV Q2W with a single 7.5 mg/kg dose on 
day 8 of the first cycle, will be administered as an approximately 30 minute 
(± 10 minutes) IV infusion via peripheral vein or central venous catheter.  One treatment 
cycle is 14 days. 
For Part 4, bemarituzumab, at the recommended dose, will be administered as an 
approximately 30-minute ( 10 minutes) IV infusion via peripheral vein or central venous 
catheter.  Pembrolizumab at the dose of 200 mg will be administered by IV infusion on 
day 1 Q3W.  For the first 4 cycles, bemarituzumab and pembrolizumab will be 
co-administered with carboplatin (day 1, at a dose calculated to provide an area under 
the concentration-time curve of 6 mg/mL/min) and either paclitaxel (day 1, 200 mg/m2 of 
body-surface area) or nab-paclitaxel (days 1, 8, and 15, 100 mg/m2 of body-surface 
area).   
Statistical Considerations 
Sample Size Considerations 
With 3, 6, or 9 subjects in a dose level cohort in Part 1, there is approximately 58%, 
82%, and 93% probability, respectively, of observing at least 1 DLT if the true DLT rate 
is 25%. 
With a minimum of 10 subjects each in Parts 2, 3, and 4, there is an approximate 95% 
probability of observing at least 1 DLT if the true DLT rate is 25%, the lower end of the 
acceptable toxicity interval.  Up to 30 subjects may be enrolled to gain further safety and 
preliminary efficacy data.  
Planned Analyses: 
Interim DLRT reviews: 
In Part 1 and Part 4 safety run-in, the DLRT will convene to review all available safety, 
tolerability, laboratory, PK and efficacy data during dose exploration (when every 
3-6 subjects [Part 1] or safety run-in 6 subjects [Part 4] are enrolled at a given dose 
level) and after dose exploration is completed.  The DLRT will only convene when the 
last of those subjects has reached 21 days on study or treatment. 
In Parts 2, 3, and Part 4 dose expansion, the DLRT will convene to review all available 
safety, tolerability, laboratory, PK, and efficacy data once 10 subjects have had the 
opportunity to be followed for at least 12 weeks and again once enrollment is complete, 
and at the primary and final analysis time point. 


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Part 3 may enroll simultaneously with Parts 1, 2, and 4, therefore the timing of DLRT 
meetings may be adjusted so data from multiple study parts can be reviewed at a single 
meeting. 
Primary analysis: 
The primary analysis will occur 12 months after the last subject has been enrolled in the 
study. 
Final analysis  
A final analysis is planned after all subjects have ended the study.   
Analytic Methods: 
Descriptive statistics will be provided for selected demographics, safety, PK, efficacy 
and biomarker data.  Descriptive statistics on continuous data will include means, 
medians, standard deviations, and ranges, while categorical data will be summarized 
using frequency counts and percentages.  Response rates will be presented with 95% 
exact Cls.  Time-to-event endpoints will be summarized using the Kaplan-Meier (KM) 
method. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
No statistical hypothesis will be tested in this study. 
Sponsor Name:  Amgen Inc. 
 




















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NOTE:  Unless otherwise indicated, all assessments during the treatment period are performed prior to study drug administration. 
Bema = bemarituzumab; -hCG = -human chorionic gonadotropin; C = cycle; CT = computed tomography; ctDNA = circulating tumor DNA; D = day; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EoT = end of treatment; FCBP = female subjects of childbearing 
potential; FFPE = formalin fixed paraffin embedded; FGFR2b = fibroblast growth factor receptor isoform 2b; IHC = immunohistochemistry; LTFU = Long-Term 
Follow-up; MRI = magnetic resonance imaging; PD-L1 = programmed death-ligand 1; PK = pharmacokinetic; Q6W = every 6 weeks; SCR = screening; SFU = safety 
follow-up; Q1C = every cycle; Q1C D1 = day 1 of every cycle; Q2C = every 2 cycles. 
a Procedures are to be completed at scheduled time points, unless otherwise specified (eg, laboratory and safety assessments may be completed up to 72 hours prior 
to scheduled study treatment administration). 
b Final samples will be collected 28 ( 3) days after last dose of bemarituzumab (may be collected at SFU if all treatment is discontinued at same time).   
c Safety follow-up assessments should be performed 28 (+ 3) days following the last study treatment administration.   
d Subjects will complete LTFU for survival approximately every 3 months ± 1 month after the SFU visit up to 2 years from the first dose of bemarituzumab.  
e Contrast enhanced CT scan is required for all subjects at screening.  For subjects with brain metastases or history of brain metastases, contrast enhanced brain MRI 
(contrast enhanced CT scan if unable to have MRI) at screening and at each tumor evaluation is required.  Tumor evaluation is to be performed by 
contrast-enhanced CT of the chest and one of the following:  contrast-enhanced CT abdomen with cuts through the pubic symphysis, contrast-enhanced MRI 
abdomen or pelvis, or contrast-enhanced MRI abdomen with cuts through to the pubic symphysis.  Contrast-enhanced images are strongly preferred.  If contrast-
enhanced CT imaging is contraindicated (allergy, medical, etc) radiological imaging to be performed as indicated. 


















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d Subjects will complete LTFU for survival approximately every 3 months ± 1 month after the SFU visit up to 2 years from the first dose of bemarituzumab.  
e Contrast enhanced CT scan is required for all subjects at screening.  For subjects with brain metastases or history of brain metastases, contrast enhanced brain MRI 
(contrast enhanced CT scan if unable to have MRI) at screening and at each tumor evaluation is required.  Tumor evaluation is to be performed by contrast-enhanced 
CT of the chest and one of the following:  contrast-enhanced CT abdomen with cuts through the pubic symphysis, contrast-enhanced MRI abdomen or pelvis, or 
contrast-enhanced MRI abdomen with cuts through to the pubic symphysis.  Contrast-enhanced images are strongly preferred.  If contrast-enhanced CT imaging is 
contraindicated (allergy, medical, etc) radiological imaging to be performed as indicated. 
 




















Product:  Bemarituzumab (AMG 552) 
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2. 
Introduction 
2.1 
Study Rationale 
Bemarituzumab is a humanized monoclonal antibody that targets the fibroblast growth 
factor (FGF) receptor isoform 2b (FGFR2b) with a dual mechanism of FGF binding 
inhibition and antibody-dependent cellular cytotoxicity.  Bemarituzumab monotherapy 
has been investigated in a phase 1 dose-finding study (FPA144-001) and in combination 
with mFOLFOX6 chemotherapy in FGFR2b-positive gastric cancer in the FIGHT study.  
Bemarituzumab efficacy correlated with the degree of FGFR2b overexpression by 
immunohistochemistry (IHC) in gastric cancer and has demonstrated a manageable 
safety profile in combination with mFOLFOX6.  Genomic and IHC data suggest that 
other carcinomas including squamous-cell non-small-cell lung cancer (SqNSCLC) may 
also have a significant rate of FGFR2b overexpression.  This study will evaluate the 
safety, tolerability, and efficacy of bemarituzumab monotherapy as well as the 
combination with other anti-cancer therapy, across different lines of therapy in the locally 
advanced/metastatic setting.  Once a recommended dose of bemarituzumab in 
combination with docetaxel is determined, this study will explore the efficacy of the 
docetaxel combination in FGFR2b+ selected SqNSCLC, as well as the safety and 
efficacy of the bemarituzumab combination with other anti-cancer therapies in the 
first-line metastatic treatment setting. 
2.2 
Background 
2.2.1 
Disease 
Worldwide, lung cancer (small cell and non-small-cell) is the most common type of 
cancer occurring in both males and females (WHO statistics, 2018).   It was estimated 
that in 2021 there would be approximately 235 760 new cases of lung cancer in the US 
alone (American Cancer Society, 2021).  The 5-year survival rate for Non-small-Cell 
Lung Cancer (NSCLC) is 25% (American Cancer Society, 2021).  Squamous-cell 
NSCLC accounts for 20% to 30% of all NSCLC, and while adenocarcinomas, the most 
common histologic subtype of NSCLC, harbor druggable genetic changes, the 
squamous-cell histologic subtype either has extremely low or no druggable genetic 
changes (Rekhtman et al, 2012; Drilon et al, 2012).  So, while in the first-line advanced 
disease setting, SqNSCLC, like adenocarcinoma, is treated with platinum-based 
chemotherapy in combination with checkpoint inhibitor, in the second-line setting and 
later, there are currently no targeted therapy options for SqNSCLC as there are for most 
adenocarcinomas. 


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From studies of tumor DNA, the fibroblast growth factor receptor (FGFR) family is the 
most commonly altered tyrosine kinase family members in SqNSCLC.  Alterations 
(mutations, amplifications, and translocations) in FGFRs 1 through 3 were observed in 
12% of SqNSCLC specimens by exome sequencing and FGFR1 amplifications were 
observed in 22% of SqNSCLC specimens by fluorescence in situ hybridization (FISH) 
(Hammerman et al, 2012; Weiss et al, 2010).  Tumors with FGFR1 amplification or 
FGFR2/3 mutations (some of which lead to dimerization/constitutive activation) have few 
other dominant oncogenic mutations, suggesting that over-activation of FGFRs could be 
genomic drivers of SqNSCLC (Liao et al, 2013; Heist et al, 2012).  Recent data on 
FGFR2b overexpression by IHC (any 2/3 cut-point) suggests the target of 
bemarituzumab is expressed in approximately 21% (95% CI:  16% to 26%) of procured 
SqNSCLC tissues (Amgen, data on file).   
This study will investigate a novel inhibitor of FGFR2b (described in Section 2.2) in 
combination with other anti-cancer therapies.  The combination of pembrolizumab, 
carboplatin, and either nab-paclitaxel or paclitaxel is indicated for the first-line treatment 
of patients with locally advanced or metastatic squamous NSCLC (Paz-Ares et al, 2018; 
Keytruda Summary of Product Characteristics [SPC] 2015; Keytruda United States 
Prescribing Information [USPI], 2014) and is recommended according to the US National 
Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology 
(ESMO) treatment guidelines (NCCN-Guidelines, 2022; Planchard et al, 2018).  
Docetaxel is indicated as a single agent for the treatment of patients with locally 
advanced or metastatic NSCLC after failure of platinum-based chemotherapy (Taxotere 
SPC 2019; Taxotere® USPI 2019) and recommended according to the NCCN and ESMO 
treatment guidelines (NCCN-Guidelines, 2022; Planchard et al, 2018). 
2.2.2 
Amgen Investigational Product Background:  Bemarituzumab 
Bemarituzumab, also called AMG 552, is a humanized monoclonal antibody 
(immunoglobulin G1 [IgG1] isotype) specific to the human FGFR2b receptor that blocks 
FGF ligand binding to the receptor.  Bemarituzumab is directed against the third Ig 
region of the FGFR2b receptor isoform, the region that is alternatively spliced and 
regulates ligand specificity.  This antibody is glycosylated but is produced in a Chinese 
hamster ovary cell line that lacks the FUT8 gene (1,6 Fucosyltransferase) and 
therefore lacks a core fucose in the polysaccharide portion of the antibody.  The 
absence of the core fucose results in higher affinity for the Fc receptor FcRIIIa 
compared to the fucosylated molecule and potentially enhances immune cell-mediated 


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tumor cell killing (Shinkawa et al, 2003).  The antibody has thus been glycoengineered 
for enhanced antibody dependent cell-mediated cytotoxicity (ADCC) (Gemo et al, 2014).  
Bemarituzumab inhibits FGF ligand-stimulated FGFR2b phosphorylation and cell 
proliferation in cell culture in FGFR2b overexpressing gastric, breast cancer, and 
NSCLC cancer lines.  Bemarituzumab also inhibits tumor growth in FGFR2b 
overexpressing gastric and breast xenograft models.  The 3 potential mechanisms of 
action of bemarituzumab thus include blocking ligand binding and downstream signaling, 
decreasing expression of the FGFR2b driver protein, and enhancing ADCC. 
Additionally, since bemarituzumab is specific for the FGFR2b receptor, it does not 
interfere with signaling of the other FGFs/FGFRs, including FGFR2c.  In contrast to the 
FGFR tyrosine kinase inhibitors (TKIs), bemarituzumab does not inhibit FGF23 
signaling.  FGF23 is a ligand involved in calcium/phosphate metabolism and therefore, 
treatment with bemarituzumab is not associated with the hyperphosphatemia associated 
with the FGFR TKIs (Catenacci et al, 2020; Dienstmann et al, 2014; Sequist et al, 2014; 
Andre et al, 2013; Brown et al, 2005). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
bemarituzumab is provided in the Investigator’s Brochure. 
2.2.2.1 
Nonclinical Studies with Bemarituzumab 
Bemarituzumab blocks FGFR2b phosphorylation, downregulates the receptor, and 
inhibits downstream signaling.  The effect on downstream signaling was measured by 
examining phosphorylation of a protein that is directly phosphorylated by the FGFR2 
protein, FGFR substrate-2 (FRS2).  Each of these mechanisms has been explored in 
vitro and in vivo and appears to contribute to the anti-tumor activity of bemarituzumab.  
In FGFR2b-overexpressing human tumor xenograft models, bemarituzumab shows 
dose-related anti-tumor activity with regression and complete responses at well-tolerated 
doses. 
Bemarituzumab demonstrated consistent pharmacokinetic (PK) behavior following 
intravenous (IV) administration in rats and cynomolgus monkeys, and the PK 
characteristics observed were consistent across all studies.  The half-life was 
dose-dependent, ranging from 0.8 days at the lowest doses (1 to 1.5 mg/kg) to at least 8 
days at the highest doses (100 to 150 mg/kg) tested in cynomolgus monkeys.  
Bemarituzumab demonstrated dose-dependent, nonlinear PK that was marked by a 
faster clearance at the terminal phase of the plasma concentration time profile and a 
greater than dose proportional increase in exposure (area under the concentration time 


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curve [AUC]) with increasing dose.  Target-mediated clearance was saturable, marked 
by dose-proportional increases in exposure at doses exceeding this level when dosed at 
weekly intervals.  The PK studies supporting the toxicokinetic studies showed 
dose-dependent increases in exposure (AUCs) supporting the reliability of these studies 
to assess toxicity. 
Significant reproductive and developmental toxicities were observed at all dose levels 
(5 to 100 mg/kg/doses) in the embryo-fetal development with prenatal and postnatal 
development study. 
2.2.2.2 
Clinical Studies with Bemarituzumab 
Clinical safety data are available from 5 studies with bemarituzumab:  FPA144-001 
(phase 1), FPA144-002 (phase 1), FPA144-004 (phase 1/2), 20201098 (phase 1b safety 
run-in), and the current study from dose level review meeting (DLRM)1 and DLRM2 
interim review.  
A phase 1 first-in-human (FIH) dose escalation study (Study FPA144-001) found 
single-agent bemarituzumab to have a tolerable safety profile and a 17.9 (95 CI:  6.1, 
36.9) confirmed response rate in late-line FGFR2b overexpressing gastric cancer (GC) 
(Catenacci et al, 2020).  This phase 1 study was an open-label, multicenter trial 
consisting of a dose escalation in subjects with recurrent solid tumors and a dose 
expansion in subjects with advanced-stage GC that overexpressed FGFR2b at various 
levels.  Bemarituzumab doses ranged from 0.3 to 15 mg/kg.  Seventy-nine subjects were 
enrolled, and the recommended dose was identified as 15 mg/kg every 2 weeks (Q2W) 
based on safety, tolerability, PK parameters, and clinical activity.  As a single agent in 
this late-line setting, the most frequent treatment-related adverse events in the 79 
subjects were fatigue (17.7), nausea (11.4), and dry eye (10.1).  Grade 3 
treatment-related adverse events included nausea (2 subjects) and anemia, 
neutropenia, increased aspartate aminotransferase (AST), increased alkaline 
phosphatase, vomiting, and an infusion reaction (1 subject each).  Three of 28 subjects 
(10.7%) who received a dose of at least 10 mg/kg Q2W for at least 70 days reported 
reversible grade 2 corneal treatment-related adverse events.  No treatment-related 
adverse events of grade 4 or higher were reported (Catenacci et al, 2020). 
Study FPA144-002 was a phase 1, dose escalation study of bemarituzumab in 
Japanese subjects with advanced GC that evaluated 2 dose levels (10 mg/kg and 
15 mg/kg).  This single arm study explored the safety, tolerability, and PK of 
bemarituzumab in Japanese subjects with GC with or without FGFR2b overexpression.  


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No dose limiting toxicities (DLTs) were identified in subjects enrolled in the dose 
escalation cohorts with FPA144 monotherapy in FPA144-002.  Five of 6 subjects (83%) 
enrolled in FPA144-002 experienced an adverse event.  The reported events included 
worsening anemia (2 subjects), constipation, subconjunctival hemorrhage, upper 
respiratory infection, diarrhea, skin rash, nail change, fever, epistaxis, fatigue, myalgia, 
sore throat, arthralgia, pain, infusion related reaction, dry eyes, malaise, and nausea 
(1 subject).  No serious adverse events were reported in this study.  Pharmacokinetic 
data from all 6 subjects were analyzed and showed that bemarituzumab PK profiles from 
Japanese subjects in this study were similar to subjects in Study FPA144-001.   
Study FPA144-004 is a phase 1/2, multicenter, international, double-blind, randomized, 
controlled study designed to evaluate the safety, tolerability, efficacy, and PK of 
bemarituzumab in combination with mFOLFOX6, compared with placebo in combination 
with mFOLFOX6, in selected subjects with unresectable, locally advanced, or metastatic 
GC including cancer of the gastroesophageal junction (GEJ).  The phase 1 portion of the 
study identified that 15 mg/kg with 1 additional dose of 7.5 mg/kg on cycle 1 day 8 in 
combination with a fixed dose of mFOLFOX6 achieved target trough steady state 
plasma concentration (Ctrough,ss) of 60 µg/mL on day 15. 
In the phase 2 Part of FPA144-004, 910 subjects were prescreened for the trial, and 
275 (30.2) had tumors which overexpressed FGFR2b; 155 subjects were randomized, 
and 76 subjects were treated in the bemarituzumab + mFOLFOX6 group and 
77 subjects were treated in the placebo+mFOLFOX6 group.  Treatment-emergent 
adverse events of any grade reported at  10 higher frequency in the 
bemarituzumab + mFOLFOX6 group compared with the placebo + mFOLFOX6 group 
included AST increased (30.3 versus 19.5), stomatitis (31.6 versus 13.0), alanine 
aminotransferase (ALT) increased (28.9 versus 14.3), dry eye (26.3 versus 6.5), 
epistaxis (22.4 versus 3.9), vision blurred (15.8 versus 1.3), keratitis (14.5 
versus 1.3), and punctate keratitis (13.2 versus 2.6).  Grade 3 and higher 
treatment-emergent adverse events were reported in 82.9 of subjects in the 
bemarituzumab + mFOLFOX6 group compared with 74.0 of subjects in the 
placebo + mFOLFOX6 group.  Grade 3 and higher treatment-emergent adverse events 
reported at  5 higher frequency in the bemarituzumab + mFOLFOX6 group compared 
with the placebo + mFOLFOX6 group were stomatitis (9.2 versus 1.3) and limbal 
stem cell deficiency (6.6 versus 0).  Serious adverse events were reported in 


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31.6 of subjects on the bemarituzumab arm and 36.4 of subjects on the placebo arm 
and were qualitatively similar in both arms. 
Ocular-related adverse events associated with the cornea or retina (defined as events 
with Preferred Terms using the Corneal Disorders Standard Medical Dictionary for 
Regulatory Activities [MedDRA] Queries [SMQ] broad search and Retinal Disorders 
SMQ broad search, MedDRA Version 20.1) are considered adverse events of interest 
with bemarituzumab.  Ocular-related adverse events were considered 
treatment-emergent if they began on or after the study drug start date up to 100 days 
after the last dose of any study drug.  Corneal toxicity is expected based on preclinical 
toxicology results in the rat and cynomolgus monkey and on results from the phase 1 
study FPA144-001 with monotherapy bemarituzumab.  Corneal toxicity is hypothesized 
to be related to the mechanism of action of bemarituzumab due to the expression of 
FGFR2b on corneal epithelial cells.  Retinal pigmented epithelial detachment, which has 
been associated with small molecule pan-FGFR TKIs (Pemazyre [pemigatinib] USPI, 
2021; Balversa [erdafitinib] UPSI, 2020), was not reported on the bemarituzumab arm 
in this study. 
In the safety population, an increase in ocular-related adverse events was reported in 
the bemarituzumab+mFOLFOX6 arm compared with the placebo+mFOLFOX6 arm 
(71.1% versus 16.9%).  No serious ocular adverse events were reported.  The most 
frequent (> 10% of subjects) ocular-related adverse events in the 
bemarituzumab + mFOLFOX6 arm were dry eye (26.3%), keratitis (15.8%), vision 
blurred (15.8%), punctate keratitis (14.5%), and corneal epithelium defect (10.5%).  
Grade 3 ocular-related adverse events were reported in 23.7% of subjects in the 
bemarituzumab arm compared to no subjects in the placebo arm.  No grade 4 
ocular-related adverse events were reported. 
Evidence of efficacy of adding bemarituzumab to chemotherapy in subjects with 
FGFR2b overexpressing gastric cancer is supported by results of the FPA144-004 
phase 2 study.  Compared with placebo+mFOLFOX6 treatment, the addition of 
bemarituzumab to mFOLFOX6 led to improvements in Progression Free Survival (PFS) 
(hazards ratio [HR] = 0.72, 95% CI:  0.494, 1.08), overall survival (OS) (HR = 0.77, 
95% CI:  0.52, 1.14; p = 0.0268), and objective response rate (ORR) (difference of 
14.4, 95% CI:  -1.5%, 30.3%).  Efficacy was more pronounced with higher levels of 
FGFR2b overexpression ( 10 vs intent-to-treat [ITT]) across all three efficacy 
endpoints:  PFS, OS, and ORR.  


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Data on the safety of bemarituzumab in combination with programmed death-ligand 1 
(PD-L1) inhibitor in addition to mFOLFOX6 chemotherapy in gastric cancer is available 
from the Phase 1b portion of Study 20210098.  On 14 July 2022 a DLRM was conducted 
to evaluate the safety of the combination of bemarituzumab, mFOLFOX6, and 
nivolumab.  The bemarituzumab dose of 15 mg/kg IV Q2W with a single 7.5 mg/kg dose 
on day 8 of the first cycle was selected based on the results of the bemarituzumab and 
mFOLFOX6 combination.  Eight subjects were enrolled in phase 1b and evaluated for 
DLTs.  Six subjects were men, and 2 subjects were women.  Four subjects were Asian, 
enrolled in Japan, and 4 subjects were White enrolled in the United States.  Ages ranged 
from 50 to 71 years. 
All 8 subjects had metastatic disease; 4 subjects had a diagnosis of gastric 
adenocarcinoma and 4 subjects had gastroesophageal junction adenocarcinoma.  The 
duration from initial diagnosis to enrollment ranged from  1 to 99 months.   
No DLTs were reported among the 8 subjects who completed the DLT observation 
window of 28 days. 
Based on the absence of DLTs and consistent safety and PK profiles with the FIGHT 
study (FPA144-004), suggesting no interactions with nivolumab, the dose level review 
team (DLRT) unanimously agreed to initiate the phase 3 part of the study. 
Data on the safety of bemarituzumab at 2 dose levels in combination with docetaxel in 
SqNSCLC is available from the current study.  On 9 June 2022, a DLRM was conducted 
to evaluate the safety of bemarituzumab with docetaxel.  The bemarituzumab dose 
level 1 was 15 mg/kg IV every 3 weeks (Q3W) with a single loading dose of 22 mg/kg on 
cycle 1 day 1 (C1D1).  Four subjects were enrolled in cohort 1 and evaluated for DLTs.  
Four subjects were men.  Two subjects were Asian, enrolled in Japan, and 2 subjects 
were White enrolled in Europe.  Ages ranged from 60 to 71 years. 
No DLTs were reported among the 4 subjects who completed the DLT observation 
window of 21 days. 
Based on the absence of DLTs and consistent safety and pharmacokinetic profiles with 
the FIGHT study (FPA144-004), suggesting no interactions with docetaxel, the DLRT 
unanimously agreed to initiate cohort 2, escalating bemarituzumab to dose level 2 
(22 mg/kg IV Q3W with a single loading dose of 30 mg/kg of C1D1) in combination with 
docetaxel.   


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On 31 August 2022, a second DLRM was conducted to evaluate the safety of 
bemarituzumab in combination with docetaxel in part 1, cohort 2.  The bemarituzumab 
dose was 22 mg/kg IV Q3W with a single loading dose of 30 mg/kg on C1D1.  Four 
subjects were enrolled in cohort 2 and evaluated for DLTs.  There were three male 
subjects and one female subject.  One Asian subject was enrolled in Japan, and 3 White 
subjects were enrolled in Europe.  The ages ranged from 53 to 77 years. 
One DLT was reported among the 4 evaluable subjects who completed the DLT 
observation window of 21 days.  The DLT reported was a grade 3 stomatitis that began 
9 days after C1D1 of bemarituzumab plus docetaxel, and resolved with supportive 
therapy to a grade 1 stomatitis within 4 days on onset.  
Based on the data review by the DLRM voting members and the consistent safety and 
pharmacokinetic profiles with the FIGHT study (FPA144-004), suggesting no interactions 
with docetaxel, the DLRM unanimously agreed to expand cohort 2, to enroll 5 more 
patients at the dose level 2 (bemarituzumab 22 mg/kg IV Q3W with a single loading 
dose of 30 mg/kg of C1D1) in combination with docetaxel.  
2.3 
Benefit/Risk Assessment 
NSCLC is a highly lethal disease and the SqNSCLC histologic subtype especially has 
limited treatment options especially after first-line treatment.  The median Progression 
Free Survival (mPFS) and median overall survival (mOS) of SqNSCLC treated with 
immuno-chemotherapy in the first-line is 6.4 months and 15.9 months, respectively 
(Paz-Ares et al, 2018).  The mPFS and mOS of SqNSCLC treated with docetaxel in the 
second-line is 2.7 to 2.8 months and 6.0 to 8.2 months, respectively, in recent phase 3 
studies (Paz-Ares et al, 2017; Brahmer et al, 2015).   
Genomic profiling of SqNSCLC and preclinical and clinical data from other FGFR TKIs 
suggest vulnerability to FGFR inhibition (Hashemi-Sadrai and Hanna, 2017; Brahmer et 
al, 2015).  Data from bemarituzumab in gastric cancer (see Section 2.2.2.2) supports a 
tolerable safety profile and evidence of efficacy as monotherapy and in combination with 
chemotherapy.  Recent data on procured SqNSCLC tissues suggests 21% (95% CI 
16% - 26%) demonstrate FGFR2b overexpression by IHC (any 2/3 cut-point), which is 
comparable to the prevalence in gastric cancer.  In addition, the preliminary safety data 
supporting combination of bemarituzumab with docetaxel from this study, therefore 
provides the basis for further exploring bemarituzumab in this combination and with 
doublet platinum-based chemotherapy and PD-L1 inhibition in first line.  A summary of 
the safety profile of bemarituzumab, risk mitigation for ocular toxicity, risks associated 


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with non-investigational medicinal products, and hypothetical overlapping toxicities are 
discussed below. 
Safety profile of bemarituzumab 
To date, bemarituzumab has demonstrated an acceptable safety profile.  Identified risks 
when used in combination with mFOLFOX6 include corneal toxicity, infusion related 
reactions, gastrointestinal toxicity (stomatitis and mucosal inflammation), palmar-plantar 
erythrodysesthesia syndrome, nail toxicity and increase in AST and ALT.  (See 
Section 2.2.2.2 for details).   
Corneal events are very common with bemarituzumab with the most common adverse 
event being dry eye (Section 2.2.2.2).  Although nearly all of the events have been non-
serious, grade 3 events such ulcerative keratitis and punctate keratitis which can lead to 
decreases in visual acuity have been observed.  Corneal events were a common cause 
of treatment discontinuation.  The majority of the corneal events typically resolve with 
treatment interruption or discontinuation and standard of care interventions for the 
corneal events.   
Risk mitigation for corneal toxicity 
The following criteria and measures have been adopted to mitigate the risk of corneal 
toxicity in this study: 
 Eligibility is restricted to subjects without active eye disorders, subjects who do not 
require treatment for ongoing eye diseases, and subjects who agree to stop 
wearing contact lenses during treatment and for at least 100 days after the end of 
treatment.  
 Eligibility is restricted from subjects who may be at risk for corneal complications 
including those with ongoing or recent corneal defects, corneal ulcerations, 
keratitis, or keratoconus, history of corneal transplant or recent corneal surgery 
or ophthalmic laser treatment. 
 Ophthalmology examinations, including assessment of distance corrected visual 
acuity, ocular surface staining (eg, fluorescein), slit lamp exam of the anterior 
segment, tonometry, and retinal examination (either dilated retinal examination or 
3 field retinal photographs).  
 Prophylactic use of ocular lubricants and eyelid hygiene is recommended. 
 Treatment interruption and/or discontinuation for higher grade corneal events (refer 
to Table 6-5 for details). 
The potential risks of bemarituzumab include retinal toxicity, cataract, hypersensitivity, 
sucrose-related renal toxicity, embryo-fetal toxicity and mammary gland changes; the 
risks mitigation measures have been implemented for these potential risks. 


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In the FPA144-004 study which compared mFOLFOX6 with and without bemarituzumab 
in gastric cancer, there was no notable increase in myelosuppression or nausea or 
vomiting.  Stomatitis was greater in the bemarituzumab arm (31.6% versus 13.0%) and 
grade 3 stomatitis events were greater (9.2% versus 1.3%) with 1 subject discontinuing 
treatment due to stomatitis in the bemarituzumab arm.  Diarrhea was greater in the 
bemarituzumab arm 40.8% versus 31.2%, however it appears to be due to a difference 
in grade 1 (31.6% versus 20.8%), whereas grade ≥ 2 was similar across arms.  Similarly, 
epistaxis was more frequently reported in the bemarituzumab + mFOLFOX6 arm 
(22.4% versus 3.9%) which was almost all due to a difference in grade 1 epistaxis 
(19.7% versus 3.9%).  Onycholysis of any grade was higher in the bemarituzumab arm 
(6.6 versus 1.3) and grade 3 onycholysis events were greater (1.3 versus 0) in 
the bemarituzumab arm; no grade 3 events were reported in the placebo arm.  AST and 
ALT elevations were frequently reported in the bemarituzumab + mFOLFOX6 arm 
however majority increases were grade 1 and 2 in severity and none led to treatment 
discontinuation.   
Risks associated with non-investigational medicinal products 
The combination regimen of pembrolizumab, carboplatin, and paclitaxel/nab-paclitaxel is 
associated with neutropenia (most frequently grade 3 to 4) reported in 38 of patients, 
anemia reported in 53 of patients, diarrhea reported in 30 of patients, and nausea 
reported in 36 of patients (Paz-Ares et al, 2018).  Other adverse reactions for the 
combination of pembrolizumab, carboplatin, and paclitaxel/nab paclitaxel are alopecia, 
thrombocytopenia, anorexia, constipation, fatigue, asthenia, arthralgia, peripheral 
neuropathy, vomiting, cough, dyspnea, hypothyroidism, hyperthyroidism, pneumonitis, 
infusion reaction, colitis, hepatitis, severe skin reaction, hypophysitis, thyroiditis, and 
nephritis. 
Docetaxel chemotherapy is associated with neutropenia (most frequently grade 3 to 4) 
reported in 33% of patients, anemia reported in 22% of patients, diarrhea reported in 
20% of patients, nausea reported in 23% of patients and mucosal inflammation reported 
in 9% of patients (Brahmer et al, 2015).  Other adverse reactions for docetaxel are 
infections, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, 
dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, 
nausea, vomiting, alopecia, skin reactions, and myalgia.  


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The individual non-investigational anti-cancer therapies in this study are associated with 
other risks, in addition to the more common toxicities summarized herein.  Refer to local 
prescribing information for complete details. 
Hypothetical overlapping toxicities of bemarituzumab and non-investigational 
products to be used in combination 
Stomatitis, ocular toxicity, infusion-related reaction, nail disorder, diarrhea, 
immune-mediated adverse reactions, and liver enzymes elevation and embryo-fetal 
toxicity represents possible overlapping toxicities when in combination with 
pembrolizumab and the other chemotherapies in this study.  Significant hepatotoxicity is 
associated with docetaxel, thus also representing possible overlapping toxicity.  These 
risks will be mitigated through dose adjustment and treatment 
interruption/discontinuation according to Table 6-5 and Section 6.2.2.2.  
Summary of study population 
As of July 2021, no drug has been approved specifically for the subset of patients with 
FGFR2b-positive cancer.  Based on the FPA144-004 phase 2 trial data, bemarituzumab 
provides a meaningful clinical benefit with an acceptable tolerability profile in newly 
diagnosed patients with advanced stage GC whose tumors overexpress FGFR2b.  This 
study will explore whether the safety profile of bemarituzumab monotherapy or 
combination with chemotherapy and checkpoint inhibitor is acceptable in SqNSCLC.  At 
this early stage in the investigation of bemarituzumab in SqNSCLC, the level of 
expression of FGFR2b needed for efficacy and the prevalence of subjects with FGFR2b 
overexpression status is unknown.  Therefore, the dose exploration part exploring the 
dose of bemarituzumab in combination with docetaxel will not select subjects for 
FGFR2b overexpression status.  Based on the limited data in FPA144-001, in which 
responses were limited to subjects expressing FGFR2b, it is possible that FGFR2b-
negative subjects in dose exploration may not derive additional benefit from the addition 
of bemarituzumab, however, subjects will still be receiving docetaxel as a standard of 
care after first-line therapy.  FGFR2b-negative subjects may be exposed to the 
additional identified safety risk of corneal toxicity, however that risk is likely considerably 
lower than in FPA144-04 in the setting of absence of benefit from bemarituzumab 
because of the shorter expected duration of treatment.  The mPFS of SqNSCLC treated 
with docetaxel in the second-line is 2.7 to 2.8 months, which is considerably shorter than 
the median onset of grade 2 or 3 ocular events in FPA144-04 of 5.0 months.  Parts 2, 3, 
and 4 will select subjects for FGFR2b overexpression.  Additionally, in Part 3 where 


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bemarituzumab monotherapy will be explored, subjects must have failed second line 
therapy to be eligible, and therefore have exhausted available therapies.  
2.3.1 
COVID-19 
Amgen closely monitors the coronavirus disease 2019 (COVID-19) pandemic around the 
world.  As part of this effort, Amgen performs a rigorous assessment, considering the 
study design, patient safety, public health risk, benefit-risk assessment, as well as the 
burden on country healthcare systems.  Decisions are made on a study-by-study and 
country-by-country basis to minimize risk to patients and avoid undue burden on 
healthcare facilities.   
Subjects enrolled in this study are permitted to receive vaccinations for COVID-19, 
however, vaccination should not be administered within 2 days before or after 
bemarituzumab infusion. 
Amgen considers that it is important to continue the proposed development of 
bemarituzumab in this study in order to advance potential therapy options for patients as 
rapidly as possible, while balancing this with appropriate measures to monitor and 
mitigate the potential impact of COVID-19. 
Based on the medical need in the SqNSCLC population and overall evaluation of risks, 
preliminary activity, and potential efficacy associated with bemarituzumab in gastric 
cancer, the Sponsor believes that bemarituzumab has a favorable benefit-risk profile for 
ongoing clinical evaluation.  The above benefit risk assessment supports the conduct of 
this clinical trial.  Reference should be made to the Investigator’s Brochure for 
bemarituzumab and Regional Prescribing Information for other anti-cancer therapies for 
further data. 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of bemarituzumab 
monotherapy and combination 
with other anti-cancer therapies  
 
To determine the recommended 
phase 3 dose of bemarituzumab 
in combination with other 
anti-cancer therapies  
 
Dose limiting toxicities (DLTs), 
treatment-emergent adverse events, 
and clinically significant changes in 
vital signs, physical examinations, 
clinical laboratory tests, and visual 
acuity 


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Secondary 
 
To characterize the 
pharmacokinetics (PK) of 
bemarituzumab monotherapy 
and in combination with other 
anti-cancer therapies 
 
PK parameters for bemarituzumab 
including, but not limited to, area 
under the concentration time curve 
(AUC), maximum observed 
concentration (Cmax), and observed 
concentration at the end of a dose 
interval (Ctrough) 
 
To evaluate preliminary anti-
tumor activity of bemarituzumab 
monotherapy and in 
combination with other 
anti-cancer therapies 
 
Objective response [defined as 
complete response (CR) + partial 
response (PR)] (as determined by 
investigator per Response 
Evaluation Criteria in Solid Tumors 
[RECIST v1.1]) 
 
Duration of response defined as the 
time from first response to disease 
progression (as determined by 
investigator per RECIST v1.1) or 
death from any cause, whichever 
comes first 
 
Disease control defined as CR + PR 
+ stable disease (SD) 
 
Progression free survival (PFS), 
defined as time from first dose of 
investigational product until disease 
progression or death from any 
cause.  Subjects alive without 
progression will be censored at their 
last evaluable disease assessment.  
Progression will be based on 
assessment by investigator per 
RECIST v1.1 
 
Overall survival (OS), defined as 
time from first dose of investigational 
product until death from any cause.  
Subjects still alive will be censored 
at the date last known to be alive 
 
Estimand(s) for Primary Endpoint(s) 
Not applicable. 
Estimand(s) for Secondary Endpoint(s) 
Not applicable. 
Exploratory 
 
To characterize the immunogenicity 
of bemarituzumab 
 
Anti-bemarituzumab antibody 
formation 


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 
To evaluate the expression of 
biomarkers in tumor samples 
 
Expression of biomarkers, 
including, but not limited to 
FGFR2b and programmed 
death-ligand 1 (PD-L1) 
 
To evaluate the relationship between 
exploratory biomarkers and efficacy 
 
Correlation of biomarkers, including 
PD-L1 and FGFR2b 
overexpression status with efficacy 
endpoints 
 
To explore protein and nucleic acid 
biomarkers in blood and tissue 
 
Changes in protein and nucleic acid 
biomarkers in blood and in tumor 
biopsies pre-treatment, 
on-treatment, and at progression 
 
4. 
Study Design 
4.1 
Overall Design 
This is a phase 1b, open-label, multicenter study to evaluate the safety, tolerability, PK, 
and efficacy of bemarituzumab monotherapy and combination across different lines of 
therapy in locally advanced/metastatic SqNSCLC.  This study will explore the addition of 
bemarituzumab to the established standard of care immuno-chemotherapy in the 
first-line treatment setting and the addition to chemotherapy in the second line or later 
setting. 
The study consists of a pre-screening period to collect tissue for FGFR2b testing 
(Parts 2, 3, and 4 only), a 28-day screening period, a treatment period, a safety follow-up 
(SFU) visit, and a long-term follow-up (LTFU) period.  Subjects who discontinue 
bemarituzumab will undergo SFU approximately 28 (+3) days after the last dose of study 
treatment.  In addition, subjects will undergo LTFU for survival approximately every 3 
months (±1 month) for up to 2 years from the first dose of bemarituzumab.  Subjects will 
receive study treatment with bemarituzumab until disease progression (see Part 4 below 
for a possible exception), unacceptable toxicity, subject request, or death (whichever 
occurs first).  
Radiographic assessments will be performed by the investigator according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 and will be performed every 6 weeks 
(Q6W) (± 7 days) until week 54 and then every 12 weeks (± 14 days).  After 
discontinuation of study treatment for reasons other than radiographic disease 
progression or withdrawal of consent, tumor assessments will continue until radiographic 
progression or initiation of additional anticancer therapy. 
The study consists of 4 Parts: 


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 Part 1:  Combination dose exploration with docetaxel 
 Part 2:  Combination dose expansion with docetaxel 
 Part 3:  Monotherapy 
 Part 4:  Combination with carboplatin, paclitaxel or nab-paclitaxel, and 
pembrolizumab 
Tumor samples from subjects will be required to demonstrate FGFR2b overexpression 
status prior to subjects entering Parts 2, 3, and 4 (and not Part 1) of this study.  This 
study may be amended at a later date to include additional subjects for further efficacy 
evaluation. 
Part 1  
Part 1 of the study will explore the dosing of bemarituzumab in combination with 
docetaxel.  During dose exploration, subjects will be enrolled in groups of 3 to 6 dose 
limiting toxicity (DLT) evaluable subjects per cohort, and escalation will be guided 
primarily by safety responses to different doses.  See Section 6.2.1 for additional details 
on DLTs. 
The starting dose of bemarituzumab is based on review of the available safety, PK and 
efficacy data from bemarituzumab monotherapy and bemarituzumab plus mFOLFOX6 
combination studies (FPA144-001, FPA144-004).  The recommended phase 2 dose of 
bemarituzumab in combination with mFOLFOX6 (evaluated in Study FPA144-004) was 
determined to be 15 mg/kg IV Q2W with a single 7.5 mg/kg dose on day 8 of the first 
cycle.   
The dosing interval will increase from Q2W to Q3W to align with the other anti-cancer 
therapy Q3W dosing schedule.  At Dose Level 1 the same dose of 15 mg/kg as in 
FPA144-004 will be tested, but at Q3W instead of Q2W and replacing the additional 
dose of 7.5 mg/kg day 8 with a one-time loading dose of 22 mg/kg IV on the first dosing 
day.  Dose Level 2 will proportionally increase the bemarituzumab dose, including the 
loading dose, from the Q2W dose studied in FPA144-004 to account for the increased 
Q3W dosing interval.  One cycle of treatment will consist of 21 days.  For Part 1, 
prospective tumor evaluation for FGFR2b overexpression status will not be required for 
enrollment and will enroll up to approximately 18 subjects. 
The planned dose levels are: 
 Dose Level 1:  bemarituzumab 22 mg/kg IV cycle 1 day 1 followed by 15 mg/kg IV 
day 22 and Q3W thereafter 
 Dose Level 2:  bemarituzumab 30 mg/kg IV cycle 1 day 1 followed by 22 mg/kg IV 
day 22 and Q3W thereafter 


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An additional Dose Level 1a of bemarituzumab 15 mg/kg IV Q3W plus one additional 
7.5 mg/kg dose on cycle 1 day 8 only may be explored if dose de-escalation is required 
from Dose Level 1.  Any other dose levels besides dose levels 1, 2, or 1a, will require a 
protocol amendment prior to enrollment. 
At each dose level, and on each planned dosing day, docetaxel will be administered at 
75 mg/m2 IV Q3W (or 60 mg/m2 IV Q3W for subjects from sites in Japan). 
Part 1 will begin with Dose Level 1.  The study DLT period is 21 days following the first 
dose.  Once 3 to 6 subjects enrolled at a certain dose level are followed for safety for 
21 days, a DLRT meeting will be convened.  Refer to Section 6.2.1 for additional details 
on the DLRT and dose escalation/de-escalation. 
Dose exploration will continue until: 
 
a maximum of 18 subjects in Part 1 is reached; or 
 
9 subjects have been treated at a specific dose level; or 
 
the lowest dose level exceeds the elimination boundary 
Part 2 
Once a dose level has been declared safe by the DLRT for Part 1, a dose level can 
enter Part 2 of the study.  Part 2 enrollment will be limited to subjects with prospectively 
identified FGFR2b overexpression status.  A minimum of 10 subjects and a maximum of 
30 subjects will be treated per dose level in Part 2 to better understand the safety profile 
and preliminary efficacy of the combination, and to enable selection of recommended 
phase 3 dose (RP3D).  Up to 2 dose levels consisting of 10-30 subjects each can be 
expanded in Part 2 of the study.  For Part 2, subjects can receive 1 dose of docetaxel 
during pre-screening or screening if initiation of treatment is deemed urgent by the 
investigator.  This bridging dose is not a requirement of the study and is not considered 
part of the clinical study. 
Part 3 
Part 3 of the study will explore bemarituzumab monotherapy at the dose evaluated in 
study FPA144-004 of 15 mg/kg IV Q2W plus one additional 7.5 mg/kg dose on cycle 1 
day 8.  One cycle of treatment will consist of 14 days.  Part 3 enrollment will be limited to 
subjects with prospectively identified tumor FGFR2b overexpression status.  A minimum 
of 10 subjects and a maximum of 30 subjects will be treated in Part 3 to better 
understand the safety profile, PK, and preliminary efficacy of monotherapy 


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bemarituzumab in FGFR2b+ SqNSCLC.  Part 3 may enroll subjects concurrently with 
Parts 1, 2, and 4. 
Participants in this clinical investigation shall be referred to as “subjects”.  For the 
sample size justification, see Section 9.2.   
Part 4 
Once a dose level has been declared safe by the DLRT for Part 1, a dose level can 
enter the Part 4 safety run-in.  During the safety run-in, 6 subjects will be evaluated with 
a 21-day DLT period and once the dose has been declared safe in the first-line setting 
with immuno-chemotherapy combination, then Part 4 enrollment can proceed with dose 
expansion.  Dose de-escalation may occur in Part 4, independently of the 
recommendation in Part 1.  Part 4 enrollment will be limited to subjects with 
prospectively identified FGFR2b overexpression status.  A minimum of 10 subjects and 
a maximum of 30 subjects, including the 6 subjects in the safety run-in, will be treated in 
Part 4 to better understand the safety profile and preliminary efficacy of the combination 
and to enable the selection of the RP3D.  Up to 2 dose levels consisting of 10 to 
30 subjects each can be expanded in Part 4 of the study.  Subjects will receive up to 
4 cycles of bemarituzumab, pembrolizumab, and chemotherapy followed by 
bemarituzumab and pembrolizumab maintenance.  In addition to bemarituzumab 
administered on day 1 of every 21-day treatment cycle, subjects will be administered 
pembrolizumab 200 mg day 1 for up to 35 cycles and, for the first four cycles only, the 
combination of carboplatin 6 mg/mL/min and either paclitaxel 200 mg/m2 on day 1 or 
nab-paclitaxel 100 mg/m2 on days 1, 8, and 15.  For Part 4 expansion (and not in safety 
run-in), subjects can receive 1 dose of carboplatin and paclitaxel or nab-paclitaxel with 
or without pembrolizumab during pre-screening or screening if initiation of treatment is 
deemed urgent by the investigator.  This bridging dose is not a requirement of the study 
and is not considered part of the clinical study.   
For Part 4 only, subjects may continue treatment beyond initial RECIST v1.1 progressive 
disease (PD), as assessed by the investigator, as long as they meet the following 
criteria: 
 
Investigator assessed clinical benefit 
 
Tolerance of study drug 
 
Stable Eastern Cooperative Oncology Group (ECOG) performance status 


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 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (ie, central nervous system [CNS] 
metastases) 
4.2 
Patient Input into the Study Design 
Patient input was not obtained for this study. 
4.3 
Justification for Dose 
4.3.1 
Justification for Amgen Investigational Product Dose: 
Study FPA144-004 had clinically meaningful and statistically significant improvement in 
PFS, OS, and ORR in subjects with FGFR2b-positive, non-human epidermal growth 
factor receptor 2 (HER2) positive frontline advanced GC and GEJ with manageable 
safety using 15 mg/kg IV Q2W with 1 additional dose of 7.5 mg/kg on cycle 1 day 8.  
Therefore, the same dose and regimen will be tested in this trial for the monotherapy 
Part 3 arm.  This dose of 15 mg/kg given Q3W instead of Q2W is the proposed dose 
level 1 of bemarituzumab in combination with docetaxel, to align with the docetaxel 
schedule of Q3W dosing.  Dose level 1 will also explore removing the extra dose on 
cycle 1 day 8 and adding a loading dose of 22 mg/kg given once on the cycle 1 day 1.   
Dose Level 2 will increase the bemarituzumab dose, including the loading dose, 
proportionally from the Q2W dose studied in FPA144-004 to account for the increased 
Q3W dosing interval.  Dose level 2 is projected to match the observed concentration at 
the end of a dose interval at steady state (Ctrough,ss) and area under the serum 
concentration versus time curve during the dosing interval at steady state divided by the 
dosing interval (Cavg,ss) of the target Q2W dose (FPA144-004).  Early PK data from 
20210102 Part 1 supports this dose-exposure relationship.  The loading dose is 
recommended because advanced stage NSCLC is an aggressive disease with standard 
chemotherapy only providing a median of approximately 7 months of disease control.  
Shortening the time to achieve target Ctrough levels may help to maximize the potential 
benefit from bemarituzumab. 
A dose of bemarituzumab selected in Part 1 in combination with docetaxel will enter 
Part 4 safety run-in in combination with pembrolizumab, carboplatin, and 
nab-paclitaxel/paclitaxel.  The same dose of bemarituzumab will be utilized because 
both backbone regimens use a Q3W dosing schedule and while the combination of 
individual agents with bemarituzumab is novel, prior studies have evaluated (or will have 
evaluated) the combination of bemarituzumab with other representative agents from 
these same drug classes: 


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1. Taxane (paclitaxel/nab-paclitaxel):  Part 1 of this study will test combination with 
docetaxel 
2. Platinum chemotherapy (carboplatin):  Safety data with oxaliplatin as part of 
mFOLFOX6 chemotherapy in gastric cancer in Study FPA144-004 and the safety 
run-in of Study 20210098 
3. PD-1 inhibitor (pembrolizumab):  Safety run-in of study 20210098 evaluating 
bemarituzumab in combination with mFOLFOX6 and nivolumab in gastric cancer.  
Refer to Section 2.2.2.2 for a summary of the prior clinical studies with bemarituzumab. 
Bemarituzumab at 15 mg/kg Q2W with 1 additional dose of 7.5 mg/kg on cycle 1 day 8 
was selected for study FPA144-004 based on the following data. 
In the phase 1 FPA144-001 monotherapy dose escalation study, bemarituzumab 
demonstrated linear clearance from 1 mg/kg to 15 mg/kg in subjects with solid tumors 
including gastric cancers.  In the linear dose range, maximum observed serum 
concentration (Cmax) and AUC increased dose proportionally.  The estimated half-life by 
noncompartmental analysis ranged from 6.01 to 11.7 days across 1 mg/kg to 15 mg/kg, 
which supports Q2W or less frequent dosing.  
The target Ctrough for bemarituzumab of ≥ 60 μg/mL was derived from nonclinical studies 
including binding affinity for human FGFR2b-Fc and human FcγRIIIa (V158), receptor 
occupancy in vitro, and an efficacy study in vivo.  
Supporting the hypothesis that ≥ 60 μg/mL should be the target minimum Ctrough, all 
subjects who demonstrated a partial response (PR) in the FIH FPA144-001 trial with 
FGFR2b overexpression achieved the target Ctrough,ss of ≥ 60 μg/mL, regardless of dose 
level.  Among all subjects treated with 15 mg/kg Q2W dosing in Study FPA144-001, 
23 of 51 subjects achieved target Ctrough concentration on day 15.  At the same dose by 
the eighth week (steady state), 14 of 16 subjects achieved target Ctrough of ≥ 60 μg/mL.  
The observed PK data from phase 1 portion of Study FPA144-004 indicated that all 
subjects with PK data treated at 15 mg/kg Q2W with 1 additional dose of 7.5 mg/kg on 
cycle 1 day 8 achieved target Ctrough concentration on day 15 and Cmax was within the 
range observed in Study FPA144-001.  Therefore, the addition of a single dose of 
7.5 mg/kg on cycle 1 day 8 minimized the time to reach target Ctrough without increasing 
Cmax.  


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Post FPA144-004 trial, PK modeling and simulation demonstrated that a higher loading 
dose on C1D1 can replace the need for the additional dose on day 8, while still 
maintaining target Ctrough and dosing interval at Cavg exposures in the defined dosing 
interval. 
4.3.2 
Justification for Non-investigational Product Dose 
Parts 1 and 2 
The dosing of docetaxel for subjects in the US and European Union (EU) is 75 mg/m2 
administered intravenously over 1 hour every 3 weeks, in accordance with the docetaxel 
US and EU prescribing information (EU Summary of Product Characteristics [SPC], 
USPI).  The dose of docetaxel for subjects in Japan is 60 mg/m2 administered 
intravenously over 1 hour every 3 weeks, in accordance with the terms of the docetaxel 
regional prescribing information and approved docetaxel dose in Japan (Abe et al, 2015; 
Kudoh et al, 2006).  Refer to Section 6.2.2.2 and regional prescribing information for 
further guidance on docetaxel dose adjustment in the setting of concomitant medications 
and toxicities.   
Part 4 
The dosing of the combination of pembrolizumab, paclitaxel, and nab-paclitaxel is 
according to the regimen studied as part of the KEYNOTE-407 study 
(Paz-Ares et al, 2018) and recommended according the NCCN and ESMO treatment 
guidelines (NCCN-Guidelines, 2022; Planchard et al, 2018).  The order of administration 
should have bemarituzumab administered first followed by pembrolizumab, then taxane 
(paclitaxel or nab-paclitaxel) and finally carboplatin.  Otherwise, local standards for 
administration can be followed.  Either paclitaxel or nab-paclitaxel may be used, 
according to local availability, and if both are available, then according to investigator’s 
preference.  For all the non-investigational products listed here, refer to Section 6.2.2.2 
and latest version of the local prescribing information for further guidance on dose 
adjustment in the setting of concomitant medications and toxicities.  Subjects should be 
pre-medicated according to local standards to prevent hypersensitivity reactions.   
Pembrolizumab 
The dosing of pembrolizumab is 200 mg Q3W according to regional prescribing 
information (Keytruda SPC 2015; Keytruda USPI, 2014).  Pembrolizumab should be 
administered for up to 35 cycles.  


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Paclitaxel 
The dosing of paclitaxel is 200 mg/m2 on day 1 of every 21-day treatment cycle for up to 
4 cycles. 
Nab-Paclitaxel 
The dosing of nab-paclitaxel is 100 mg/m2 on days 1, 8, and 15 of every 21-day 
treatment cycle for up to 4 cycles. 
Carboplatin 
The dosing of carboplatin is at a dose calculated using the Calvert Formula to produce 
an AUC-time curve of 6 mg/mL/min on day 1 of every 21-day treatment cycle for up to 
4 cycles. 
The carboplatin dose should not exceed 900 mg.  
Calvert Formula 
Total Dose (mg) = (target AUC) x (creatinine clearance [CrCl]  25) 
The estimated glomerular filtration rate (GFR) used in the Calvert formula should not 
exceed 125 mL/min.   
4.4 
End of Study 
An individual subject is considered to have completed the study if they have completed 
the last visit shown in the Schedule of Activities (Section 1.3).   
The end of study date for the entire study 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), including any additional parts in the study (eg, LTFU, antibody testing), 
as applicable. 
5. 
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 Response 
Technology (IRT). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 


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Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
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/assent prior to initiation of any study 
specific activities/procedures  
102 
Age ≥ 18 years old (or legal adult within country, whichever is older) at the time 
that the Informed Consent Form (ICF) is signed 
103 
Pathologically confirmed squamous cell lung carcinoma.  Patients with mixed 
histology (eg, adenosquamous) are allowed if there is a squamous component in 
the specimen.  
104 
Disease that is unresectable, locally advanced or metastatic (not amenable to 
curative therapy) 
105 
Part 2, 3, and 4 only:  FGFR2b overexpression as determined by centrally 
performed IHC testing 
106 
Subjects must have archived tumor tissue sample (formalin fixed, paraffin 
embedded [FFPE] sample [FFPE of excisional, or core needle]) taken within last 
5 years or be willing to undergo pre-treatment tumor biopsy (excisional, or core 
needle) for tissue prior to enrollment.   
107 
Subject may or may not have received prior therapy for locally advanced and 
unresectable or metastatic disease depending on the study Part. 

For Parts 1 and 2, subjects may have progressed on, or recurred after at
least 1 prior systemic therapy.

For Part 3 subjects must have progressed on, or recurred after at least 2 prior
systemic therapies.

For Part 4, subjects may not have received prior systemic therapy for their
locally advanced and unresectable or metastatic disease.  For Part 4,
subjects who received peri-operative systemic therapy are eligible if that
adjuvant/neoadjuvant therapy was completed at least 12 months prior to
diagnosis of locally advanced and unresectable or metastatic disease.
For Parts 1, 2, and 3, prior treatment must include a platinum-based doublet 
chemotherapy and checkpoint inhibitor for advanced or metastatic disease, either 
given as one line of therapy or as individual lines of therapy, unless the subject 
has a medical contraindication to one of the required therapies (which must be 
documented in the eCRF).  Additionally, if the subject’s tumor was previously 
identified as having a driver mutation (according to local standard of care or 
guidelines, eg, KRAS G12C, NTRK), which has an approved therapy for which 
the subject is eligible and available, the subject must have received the approved 
therapy in a prior line of treatment. 
If the subject has a medical contraindication to a required prior therapy, that 
medical contraindication must be documented in the eCRF and the subject may 
be enrolled only after the investigator discusses and obtains approval from the 
Amgen medical monitor.  For Part 1 and 3 subjects may have received prior 


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docetaxel therapy in the unresectable or metastatic setting, provided none of the 
prior therapy exclusion criteria are met.   
For Parts 1, 2, and 3:   
 
Adjuvant therapy will count as a line of therapy if the subject progressed on or 
within 6 months of adjuvant therapy administration 
 
If locally advanced and unresectable NSCLC, disease progression on or 
within 6 months of the end of prior curatively intended multimodal therapy will 
count as a prior line of therapy.  
 
Maintenance therapy following platinum-based doublet chemotherapy is not 
considered as a separate line of therapy. 
108 
Measurable disease per RECIST v1.1 criteria. 
109 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
110 
Adequate organ function as follows: 
 Absolute neutrophil count ≥ 1.5 x 109/L 
 Platelet count ≥ 100 x 109/L 
 Hemoglobin ≥ 9 g/dL 
 Creatinine clearance ≥ 50 mL/min.  Cockcroft-Gault formula will be used for 
creatinine clearance calculation.  Twenty-four hour urine collection is not required 
but is allowed.  
 International Normalized Ratio (INR) or prothrombin time (PT) < 1.5 × upper limit of 
normal (ULN) except for subjects receiving anticoagulation, who must be on a 
stable dose of anticoagulant therapy for 6 weeks prior to enrollment.  
Part 1 and 2 only: 
 AST and ALT ≤ 2.5 times ULN, except if alkaline phosphatase > 2.5 times the ULN, 
then AST and/or ALT must be ≤ 1.5 times the ULN 
 Total bilirubin ≤ 1.0 x ULN  
Part 3 only: 
 AST and ALT < 3 x ULN (or < 5 x ULN if liver involvement).  
 Total bilirubin <1.5 x ULN (or < 2 x ULN in case of liver involvement OR Gilbert’s 
disease) 
Part 4 only:   
 AST and ALT < 2.5 x ULN (or < 5 x ULN if liver involvement). 
 Total bilirubin < 1.5 x ULN (or < 2 x ULN in case of liver involvement OR Gilbert’s 
disease) 
111 
Part 1 and 2 only:  Subject must be a candidate to receive docetaxel.   
112 
Part 4 only:  Subject must be a candidate to receive pembrolizumab, carboplatin, 
and paclitaxel or nab-paclitaxel. 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 


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Disease Related 
201 
Mixed small-cell lung cancer  
202 
Untreated or symptomatic central nervous system (CNS) metastases or 
leptomeningeal disease 
 Subjects with asymptomatic CNS metastases are eligible if clinically stable for at 
least 4 weeks and do not require intervention (including use of corticosteroids) 
 Subjects with treated brain metastases are eligible provided the following criteria 
are met: 
 
Definite therapy was completed at least 2 weeks prior to the first planned 
dose of study treatment (stereotactic radiosurgery at least 7 days prior to first 
planned dose of study treatment) 
 
At least 7 days prior to first dose of study treatment:  any CNS disease is 
clinically stable, subject is off steroids for CNS disease (unless steroids are 
indicated for a reason unrelated to CNS disease), and subject is off or on 
stable doses of anti-epileptic drugs 
203 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures at a frequency greater than monthly.  Subjects with 
PleurXTM catheters in place may be considered for the study with Medical Monitor 
approval.  
Other Medical Conditions 
204 
Impaired cardiac function or clinically significant cardiac disease including:  
unstable angina within 6 months prior to first dose of study treatment, acute 
myocardial infarction < 6 months prior to first dose of study treatment, New York 
Heart Association (NYHA) class II-IV congestive heart failure, uncontrolled 
hypertension (defined as an average systolic blood pressure  160 mmHg or 
diastolic 100 mm Hg despite optimal treatment, uncontrolled cardiac 
arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, 
active coronary artery disease, Fridericia’s correction formula (QTc) ≥ 470. 
205 
Peripheral sensory neuropathy grade 2 or higher 
206 
Active infection requiring systemic treatment or any uncontrolled infection within 
14 days prior to first dose of study treatment 
207 
Known human immunodeficiency virus (HIV) infection with CD4+ T-cell (CD4+) 
counts < 350 cells/L, hepatitis C infection (subjects with hepatitis C that achieve 
a sustained virologic response following antiviral therapy are allowed), or 
hepatitis B infection (subjects with hepatitis B surface antigen or core antibody 
that achieve sustained virologic response with antiviral therapy directed at 
hepatitis B are allowed).   
230 
For Part 4 only:  History of solid organ transplantation  
231 
For Part 4 only:  Active autoimmune disease that has required systemic 
treatment (except replacement therapy) within the past 2 years or any other 
diseases requiring immunosuppressive therapy while on the study 
208 
History of interstitial lung disease  


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233 
For Part 4 only:  Subjects who experienced severe, life-threatening or recurrent 
(grade 2 or higher) immune-mediated adverse events or infusion-related 
reactions including those that lead to permanent discontinuation while on 
treatment with immuno-oncology agents  
209 
History or evidence of systemic disease or ophthalmological disorders requiring 
chronic use of ophthalmic corticosteroids 
210 
Evidence of any ongoing ophthalmologic abnormalities or symptoms that are 
acute (within 4 weeks) or actively progressing 
211 
Unwillingness to avoid use of contact lenses during study treatment and for at 
least 100 days after the end of treatment 
212 
Recent (within 6 months) corneal surgery or ophthalmic laser treatment or recent 
(within 6 months) history of, or evidence of, corneal defects, corneal ulcerations, 
keratitis, or keratoconus, or other known abnormalities of the cornea that may 
pose an increased risk of developing a corneal ulcer.   
Prior/Concomitant Therapy 
213 
Part 1 and Part 2:  Subjects that experienced toxicity or hypersensitivity requiring 
discontinuation of prior docetaxel treatment.  
214 
Part 1 only:  Subjects that had disease progression on prior therapy with 
docetaxel. 
215 
Part 2 only: Subjects have received prior docetaxel in unresectable or metastatic 
setting (including subjects who received prior docetaxel in first-line for metastatic 
disease, but not including subjects who received prior docetaxel neoadjuvantly or 
adjuvantly and did not progress within 6 months of end of therapy) except for a 
maximum of 1 dose of docetaxel 
216 
Prior treatment with any selective inhibitor of the FGF-FGFR pathway. 
217 
Any anticancer therapy or immunotherapy within 4 weeks prior to enrollment; 
 
Palliative radiotherapy is allowed, provided it has been completed more than 
14 days prior to the first dose of study treatment 
 
All treatment-related toxicity needs to be resolved to grade ≤ 1 prior the first 
dose of study treatment, with exception of alopecia or toxicities considered 
irreversible (defined as having been present and stable > 21 days) which are 
not otherwise described in the exclusion criteria 
 
Exception for Part 2 and 4 expansion only:  subjects can receive 1 dose of 
each non-investigational anticancer therap(ies) in the respective study part, if 
initiation of treatment is deemed urgent by the investigator 
232 
Part 4 only:  Immunosuppressive doses of systemic medications of  10 mg/day 
of prednisone or equivalent must be discontinued at least 2 weeks before the first 
dose of study drug.  Short courses of high dose corticosteroids and/or continuous 
low dose of prednisone ( 10 mg/day) are allowed.  In addition, inhaled, 
intranasal, intraocular, and/or joint injections of corticosteroids are allowed 
Prior/Concurrent Clinical Study Experience 
218 
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.  Other investigational procedures while participating in this study are 
excluded. 
Other Exclusions 
219 
Major surgical procedure within 28 days prior to first dose of study treatment 
220 
History of other malignancy within the past 2 years, except: 
 curatively treated non-melanoma skin malignancy 
 cervical cancer in situ 
 curatively treated uterine cancer stage I 
 curatively treated ductal or lobular breast carcinoma in situ and not currently 
receiving any systemic therapy 
 localized prostate cancer that has been treated surgically with curative intent and 
presumed cured 
221 
Female subjects of childbearing potential unwilling to use protocol specified 
method of contraception (see Section 11.5) during treatment and for an additional 
6 months after the last dose of protocol-mandated therapy. 
222 
Female subjects who are breastfeeding or plan to breastfeed while on study 
through 4 months after the last dose of protocol-mandated therapy. 
223 
Female subjects planning to become pregnant while on study through 6 months 
after the last dose of protocol-mandated therapy. 
224 
Female subjects of childbearing potential with a positive pregnancy test assessed 
at screening by a serum pregnancy test. 
225 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use 
contraception during treatment and for an additional 6 months after the last dose 
of protocol-mandated therapy.  Refer to Section 11.5. 
226 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 6 months after the last dose of protocol-mandated therapy. 
227 
Known allergy, hypersensitivity, or contraindication to docetaxel (Part 1 and 2 
only), pembrolizumab, paclitaxel, nab-paclitaxel, and carboplatin (Part 4 only) or 
to components of the drug formulations formulation including polysorbate. 
228 
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, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge. 
229 
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. 
5.3 
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 


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committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject or the subject’s legally authorized representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
Each subject who enters into the screening period for the study (defined as 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 IRT.  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. 
Unless directed by Amgen 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.    
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the Subject Enrollment Case Report Form (CRF). 
Sites that do not enroll subjects within 6 months of site initiation may be closed. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events.  Both adverse events and serious adverse 
events occurring up to 14 days after the pre-screening procedure of tumor biopsy 
collection that the investigator deems to be related to the procedure will be collected.   
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened.  Refer to Section 8.1.1. 
6. 
Study Intervention 
Study intervention is defined as any investigational product(s), non-investigational 
product(s), or combination product(s) intended to be administered to a study subject 
according to the study protocol. 


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Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
A summary of the dosing and administration of each treatment is shown in Table 6-1 
below. 
6.1 
Study Interventions Administered 
6.1.1 
Investigational Products 


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Table 6-1.  Investigational Products 
Amgen Investigational Product:a 
Bemarituzumab 
Dosage Formulation 
Bemarituzumab is supplied as a sterile, aqueous, 
colorless to slightly yellowish, pyrogen-free 
solution supplied in single-use glass vials.  The 
composition of the drug product contains 20 
mg/mL active ingredient (supplied as 20 mL vial 
(in 400 mg/vial configuration [20 mL per vial]), L-
histidine, sucrose, and polysorbate 20 at pH 6.0.  
The final investigational product will be provided 
as a solution which should be stored refrigerated 
(2°C to 8°C), protected from light; and will be 
refrigerated liquid protected from light which is 
diluted for administration according to instructions 
provided to the site in a separate Pharmacy 
Manual. 
Unit Dose Strength(s)/Dosage Level(s) 
Part 1:  Dose level 1:  22 mg/kg IV cycle 1 day 1 
followed by 15 mg/kg IV day 22 and Q3W 
thereafter 
Dose level 2:  30 mg/kg IV cycle 1 day 1 followed 
by 22 mg/kg IV day 22 and Q3W thereafter 
Part 2:  At dose level identified in Part 1 
Part 3:  15 mg/kg Q2W IV on day 1 of each cycle 
with an additional dose of 7.5 mg/kg on cycle 1 
day 8 
Part 4:  At dose level identified in Part 1 
Route of Administration 
IV infusion 
Accountability 
The planned dose, quantity administered, start 
date/time, stop date/time, lot number of 
investigational product, reason total quantity 
changed or administration withheld, reason for 
administration delay, and reason for infusion 
interruption are to be recorded on each subject's 
eCRF(s). 
Dosing Instructions 
Bemarituzumab will be administered under 
medical supervision over approximately 
30-minute (± 10 minutes) IV infusion via a 
peripheral vein or central venous catheter.  The 
IV administration set for bemarituzumab infusion 
must contain a 0.22 µm in-line filter. 
Bemarituzumab dosing should occur  3 days of 
scheduled visit date for cycles 1 through 3, and 
may be delayed up to  7 days for every cycle 
thereafter. 
eCRF = electronic case report form; IV  intravenous; Q2W = every 2 weeks; Q3W = every 3 weeks 
a Amgen investigational product will be manufactured and packaged by Amgen and distributed using Amgen 
clinical study drug distribution procedures. 
 


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Table 6-2.  Study Groups 
IV  intravenous; Q2W  every 2 weeks; Q3W  every 3 weeks
Group Title  
 
Group Type 
Group Description  
Part 1 
Combination Dose 
Exploration 
Dose Level 1:  Participants will receive 
bemarituzumab 22 mg/kg IV cycle 1 day 1 followed 
by 15 mg/kg IV day 22 and Q3W thereafter in 
addition to docetaxel. 
Dose Level 2:  Participants will receive 
bemarituzumab 30 mg/kg IV cycle 1 day 1 followed 
by 22 mg/kg IV day 22 and Q3W thereafter in 
addition to docetaxel. 
Part 2 
Combination Dose 
Expansion 
Bemarituzumab and docetaxel at the dose and 
schedule determined in Part 1. 
Part 3 
Monotherapy 
Bemarituzumab 15 mg/kg IV Q2W with single 
7.5 mg/kg dose on cycle 1 day 8. 
Part 4 
Combination 
immuno-chemotherapy 
Bemarituzumab at the dose determined in Part 1 
combined with pembrolizumab, carboplatin, and 
either paclitaxel or nab-paclitaxel. 


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6.1.2 
Non-investigational Products 
Table 6-3.  Non-Investigational Products 
Study Treatment Name 
Non-Investigational Product: 
Docetaxel 
Dosage Formulation 
Sponsor designee will provide docetaxel where 
required from a commercial supply that is clinically 
labelled in accordance with relevant local 
guidelines.  For further details, refer to the 
manufacturer’s prescribing information for the 
respective chemotherapies and the study 
Pharmacy Manual (if applicable). 
Unit Dose Strength(s)/Dosage Level(s) 
75 mg/m2 every 3 weeks for subjects in all 
countries except Japan; 60 mg/m2 for subjects in 
Japan. 
Route of Administration 
IV infusion 
Accountability 
The planned dose, total volume of preparation, lot 
number (unless unable to be recorded due to local 
prescribing procedure in countries where standard 
of care is deemed non-investigational) 
concentration of preparation, quantity 
administered, start date/time, stop date/time, 
reason total quantity changed, or administration 
withheld, reason for administration delay, and 
reason for infusion interruption are to be recorded 
on each subject’s eCRF(s). 
Dosing Instructions 
Docetaxel will be infused at the clinic by a 
qualified staff member over a time frame of 1 hour 
(additional administration time is allowed as per 
local guidelines). 
 
Study Treatment Name 
Non-Investigational Product: 
Carboplatin 
Dosage Formulation 
Sponsor designee will provide carboplatin where 
required from a commercial supply that is clinically 
labelled in accordance with relevant local 
guidelines.  For further details, refer to the 
manufacturer’s prescribing information for the 
respective chemotherapies and the study 
Pharmacy Manual (if applicable). 
Unit Dose Strength(s)/Dosage Level(s) 
The dosing of carboplatin is at a dose calculated 
using the Calvert Formula to produce an AUC-
time curve of 6 mg/mL/min on day 1 of every 21-
day treatment cycle for up to 4 cycles. 
Route of Administration 
IV infusion 


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Study Treatment Name 
Non-Investigational Product: 
Carboplatin 
Accountability 
The planned dose, total volume of preparation, lot 
number (unless unable to be recorded due to local 
prescribing procedure in countries where standard 
of care is deemed non-investigational) 
concentration of preparation, quantity 
administered, start date/time, stop date/time, 
reason total quantity changed, or administration 
withheld, reason for administration delay, and 
reason for infusion interruption are to be recorded 
on each subject’s eCRF(s). 
Dosing Instructions 
Carboplatin will be infused at the clinic by a 
qualified staff member over a time frame of 15-60 
minutes (additional administration time is allowed 
as per local guidelines). 
 
Study Treatment Name 
Non-Investigational Product: 
Nab-paclitaxel 
Dosage Formulation 
Sponsor designee will provide nab-paclitaxel 
where required from a commercial supply that is 
clinically labelled in accordance with relevant local 
guidelines.  For further details, refer to the 
manufacturer’s prescribing information for the 
respective chemotherapies and the study 
Pharmacy Manual (if applicable). 
Unit Dose Strength(s)/Dosage Level(s) 
100 mg/m2 on days 1, 8, and 15 of each 3 week 
cycle for up to 4 cycles. 
Route of Administration 
IV infusion 
Accountability 
The planned dose, total volume of preparation, lot 
number (unless unable to be recorded due to local 
prescribing procedure in countries where standard 
of care is deemed non-investigational) 
concentration of preparation, quantity 
administered, start date/time, stop date/time, 
reason total quantity changed, or administration 
withheld, reason for administration delay, and 
reason for infusion interruption are to be recorded 
on each subject’s eCRF(s). 
Dosing Instructions 
Nab-paclitaxel will be infused at the clinic by a 
qualified staff member over a time frame of 
30 minutes (additional administration time is 
allowed as per local guidelines). 
 


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Study Treatment Name 
Non-Investigational Product: 
Paclitaxel 
Dosage Formulation 
Sponsor designee will provide paclitaxel where 
required from a commercial supply that is clinically 
labelled in accordance with relevant local 
guidelines.  For further details, refer to the 
manufacturer’s prescribing information for the 
respective chemotherapies and the study 
Pharmacy Manual (if applicable). 
Unit Dose Strength(s)/Dosage Level(s) 
200 mg/m2 every 3 weeks for up to 4 cycles. 
Route of Administration 
IV infusion 
Accountability 
The planned dose, total volume of preparation, lot 
number (unless unable to be recorded due to local 
prescribing procedure in countries where standard 
of care is deemed non-investigational) 
concentration of preparation, quantity administered, 
start date/time, stop date/time, reason total quantity 
changed, or administration withheld, reason for 
administration delay, and reason for infusion 
interruption are to be recorded on each subject’s 
eCRF(s). 
Dosing Instructions 
Paclitaxel will be infused at the clinic by a qualified 
staff member over a time frame of 3 hours 
(additional administration time is allowed as per 
local guidelines). 
 
Study Treatment Name 
Non-Investigational Product: 
Pembrolizumab 
Dosage Formulation 
Sponsor designee will provide pembrolizumab 
where required from a commercial supply that is 
clinically labelled in accordance with relevant local 
guidelines.  For further details, refer to the 
manufacturer’s prescribing information for the 
respective chemotherapies and the study 
Pharmacy Manual (if applicable). 
Unit Dose Strength(s)/Dosage Level(s) 
200 mg every 3 weeks  
Route of Administration 
IV infusion 
Accountability 
The planned dose, total volume of preparation, lot 
number (unless unable to be recorded due to local 
prescribing procedure in countries where standard 
of care is deemed non-investigational) 
concentration of preparation, quantity administered, 
start date/time, stop date/time, reason total quantity 
changed, or administration withheld, reason for 
administration delay, and reason for infusion 
interruption are to be recorded on each subject’s 
eCRF(s). 


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Study Treatment Name 
Non-Investigational Product: 
Pembrolizumab 
Dosing Instructions 
Pembrolizumab will be infused at the clinic by a 
qualified staff member over a time frame of 30 
minutes (additional administration time is allowed 
as per local guidelines). 
AUC  area under the concentration time curve; eCRF = electronic case report form; IV = intravenous  
If local guidelines for non-investigational product dosage differs from study dosage 
guidance, then treatment according to local guidelines may be permissible if approved 
by Amgen Medical Monitor. 
6.1.3 
Other Protocol-required Therapies 
All other protocol-required therapies including, pre- and post-infusion medications to 
prevent hypersensitivity reactions that are commercially available are not provided or 
reimbursed by Amgen (except if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these protocol-required therapies. 
6.1.3.1 
Pre- and Post-infusion Medications for Chemotherapies 
Subjects should receive Pre- and Post-infusion medications for chemotherapies 
including antiemetic medication according to regional prescribing information and 
institutional guidelines.   
Subjects receiving docetaxel should be premedicated with oral corticosteroids prior to 
docetaxel administration according to regional prescribing information and local 
standards to reduce the incidence and severity of fluid retention and severity of 
hypersensitivity reactions.   
Subjects receiving paclitaxel should be pre-medicated with oral or IV corticosteroids, and 
both H1 and H2 receptor antagonist according to regional prescribing information and 
local standards to reduce incidence and severity of hypersensitivity reactions.  
6.1.3.2 
Biopsies 
Tumor Biopsy for Enrollment:  When archival tumor tissue within 5 years is not available, 
collection of new tumor tissue is required, as described in Section 8.8. 
Optional Tumor Biopsy for Biomarkers:  Additional tissue biopsy samples will be 
collected at cycle 2 day 1 ( 7 days) at the end of treatment (EoT) ( 7 days) or at time 
of progression, prior to start of another anti-cancer therapy for exploratory biomarkers 
related to mechanisms of primary and secondary resistance.  


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Biomarker assessment can be done only if the biomarker research is allowed according 
to local regulations and agreed by the local Ethics Committees (EC)/Institutional Review 
Board (IRB). 
6.1.4 
Medical Devices 
6.1.4.1 
Investigational In Vitro Diagnostic Devices 
An investigational in vitro diagnostic device, VENTANA FGFR2b (FPR2-D) Robust 
Prototype Assay, developed and manufactured by Ventana Medical Systems, Inc. 
(Roche Tissue Diagnostics 1910 E. Innovation Park Drive, Tucson, Arizona, 85755, 
USA) will be used to measure FGFR2b protein to prospectively identify subjects eligible 
for enrollment, as further described in Section 8.8.1.  The device is intended for the 
qualitative detection fibroblast growth factor receptor type 2b (FGFR2b) protein in FFPE 
neoplastic tissue stained with the OptiView 3,3′-Diaminobenzidine (DAB) IHC Detection 
Kit on the automated BenchMark ULTRA instrument.  The results should be interpreted 
by a qualified pathologist in conjunction with histological examination, relevant clinical 
information, and proper controls. 
6.1.4.1.1 
IVD Compliance 
The investigational in vitro diagnostic (IVD) device will comply with requirements of local 
and other applicable national health authority regulations. 
6.1.4.2 
Other Non-Investigational Medical Devices 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-Amgen 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). 
6.1.5 
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 or 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 investigational products provisioned and/or repackaged/modified by 
Amgen. 


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Any product complaint(s) associated with investigational products/non-investigational 
products supplied by Amgen are to be reported. 
6.1.6 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments and/or procedures are excluded during the treatment period of 
the study: 
 
Anticancer therapies other than those specified in the protocol are prohibited while 
on study treatment.  Radiation therapy for symptom control (eg, bone metastasis) 
or brain may be allowed after discussion with the medical monitor.  Radiation 
therapy may not be given concurrently with bemarituzumab with or without 
chemotherapy.  If radiation therapy is administered, then the next dose of 
bemarituzumab, and chemotherapy, if applicable, must be delayed until at least 7 
days after radiation therapy is completed. 
 
Methylcellulose-based ocular lubricants 
 
Vaccination with a live or live-attenuated vaccines will not be allowed during 
therapy.  Subjects enrolled in this study are permitted to receive vaccinations for 
COVID-19, however, all side effects of the vaccine must be resolved prior to 
enrollment and vaccination should not be administered within 2 days before or after 
bemarituzumab infusion.  
 
Concomitant use of docetaxel, paclitaxel or nab-paclitaxel and drugs that inhibit 
CYP3A4 may increase exposure to docetaxel, paclitaxel or nab-paclitaxel and 
should be avoided.  In subjects receiving treatment with docetaxel (Parts 1 and 2) 
and paclitaxel or nab-paclitaxel (Part 4), close monitoring for toxicity and dose 
reduction should be considered if systemic administration of a potent CYP3A4 
inhibitor (such as ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) cannot be avoided.  
Refer to the regional prescribing information for additional information. 
 
Subjects must not wear contact lenses during bemarituzumab treatment.  It is 
recommended to avoid contact lenses for 100 days after the end of 
bemarituzumab. 
6.2 
Dose Modification 
6.2.1 
Dose Cohort Study Escalation/De-escalation and Stopping Rules 
Dose Level Determination  
In Part 1, a recommendation to escalate to a higher dose cohort will only occur when the 
previous dose regimen(s) have been found to be reasonably tolerated based on 
available study data through the 21-day DLT period for 3 to 6 subjects and upon 
unanimous agreement of the DLRT members.  Available data from previous subject 
groups will also be considered.  Dose level recommendations will be made on a 
treatment cohort basis (not on an individual basis).  After receiving the DLRT 
recommendation, Amgen will render a final decision and will issue a written notification 


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of the dose change decision to investigators.  Further information on DLRM is provided 
in Appendix 3 (Section 11.3). 
Part 1 will begin with Dose Level 1.  The study DLT period is 21 days following the first 
dose.  Once 3 to 6 subjects enrolled at a certain dose level are followed for safety for 
21 days, a DLRT meeting will be convened. 
The DLRT will evaluate all available safety, laboratory, and PK data as well as rules 
generated from a modified toxicity probability interval method (mTPI-2) (Guo et al, 2017) 
to guide their dose finding recommendations.  The team may recommend escalation to 
the next planned dose, continuation at the current dose level, de-escalation to a lower 
dose, termination of the study, or initiation of enrollment in Part 2 of the study with the 
evaluated dose level.  The mTPI-2 escalation/de-escalation guideline for each dose 
cohort is derived with a target toxicity probability of 0.30, acceptable toxicity probability 
interval of (0.25, 0.33).  A dose level will be considered unsafe, with no additional 
subjects enrolled at that dose level, if it has an estimated 95% or more probability of 
exceeding the target DLT (ie, the elimination boundary). 
In Part 1, the DLRT will use guidelines based on an mTPI-2 design as described below: 
1. Subjects in the first cohort are treated at dose level 1. 
2. To assign a dose to the next cohort of subjects, the guidelines in Table 6-4 will be 
used.  In Table 6-4, note the following: 
 “Eliminate” means that the current and higher doses are eliminated from the trial to 
prevent treating any future subjects at these doses because they are overly toxic 
 When a dose is eliminated, de-escalation to the next lower dose level occurs. 
When the lowest dose is eliminated, the trial is stopped for safety.  
 If none of the actions (ie, escalation, de-escalation, or elimination) is triggered, new 
subjects are treated at the current dose. 
 If the current dose is the lowest dose and the rule indicates dose de-escalation, 
new subjects are treated at the lowest dose unless the number of DLTs reaches 
the elimination boundary, at which point the trial is stopped for safety. 
3. Step 2 is repeated until the maximum sample size of 18 is reached or the number of 
subjects treated at the current dose reaches 9, and the decision according to 
Table 6-4 is to stay at the current dose. 


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Table 6-4.  Dose Escalation/De-escalation Rules for the mTPI-2 Design 
Subjects treated at 
the current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Escalate if # of DLT ≤ 
0 
0 
0 
0 
1 
1 
1 
1 
2 
De-escalate if # of DLT 
≥ 
1 
1 
1 
2 
2 
2 
3 
3 
3 
Eliminate if # of DLT ≥ 
NA 
NA 
3 
3 
4 
4 
5 
5 
5 
DLT = dose limiting toxicity; NA = not applicable; mTPI = modified toxicity probability interval 
# of DLT is the number of subjects with at least 1 DLT.  
When none of the actions (ie, escalate, de-escalate or eliminate) is triggered, stay at the current dose for 
treating the next cohort of subjects. “NA” means that a dose cannot be eliminated before treating 
3 subjects. 
Part 4 will begin with a safety run-in using the highest dose determined to be safe from 
Part 1.  The study DLT period is 21 days.  Once a minimum of 6 subjects are dosed and 
followed for 21 days, a DLRT meeting will be convened.  Depending on the observed 
safety data, the following may occur:  (1) expansion of Part 4 with up to 30 subjects at 
the current dose (including the subjects in safety run-in); (2) additional enrollment of 
approximately 6 subjects at the current dose level for DLRT evaluation; or (3) dose 
de-escalation. 
A minimum of 6 subjects must be treated at a dose level with less than 30 incidence of 
DLTs to trigger expansion to up 30 subjects.  A dose level can be expanded with up to 
12 subjects to better understand the safety profile of the combination.  Dose 
de-escalation will occur when a DLT incidence of 30 or higher is observed, or as 
advised by the DLRT.  Information on DLRM is provided in Appendix 3 (Section 11.3). 
The DLRT will meet in Parts 2, 3, and 4 (For Part 4, in addition to the safety run-in) when 
10 subjects have had the opportunity to be followed for at least 12 weeks of response 
data and again once enrollment is complete, and at the primary and final analysis time 
points.  At any point during the study, basing on evolving PK, safety, and/or efficacy 
data, the DLRT may recommend to de-escalate to bemarituzumab dose level 1 in Parts 
2 and 4. 
Enrollment Stopping Rules 
At any point during the study, throughout Parts 1, 2, 3, and 4, enrollment will be paused 
at the occurrence of 2 or more grade 4 or one or more grade 5 adverse events unless 
the events are clearly attributed to causes other than bemarituzumab.  If limited 
information is available at the time the investigator reports the event to the sponsor, 


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enrollment may continue while the sponsor collects additional information about the 
grade 4 or 5 event to determine the underlying cause.  The DLRT will be reconvened to 
review the safety data and determine appropriate next steps that may include, but not be 
limited to, informing investigators and IRBs/IECs, implementing safety/toxicity 
management, informing health authorities, voluntarily putting the clinical trial on hold, or 
proceeding with enrollment.  
Dose Limiting Toxicities 
Dose limiting toxicities are defined as any of the following adverse events considered by 
the investigator related to study drug excluding toxicities clearly related to disease 
progression or intercurrent illness.  Sites are requested to make sure that toxicities are at 
least possibly related to Bemarituzumab, and not considered to be related to the 
concomitant chemotherapy while evaluating DLTs.  
 
Grade 4 neutropenia of any duration 
 
Grade  3 Febrile neutropenia (absolute neutrophil count [ANC]  1000/mm3 with a 
single temperature of  38.3C [101F] or a sustained temperature of  38C 
[100.4F] for more than 1 hour). 
 
Grade 4 thrombocytopenia 
 
Grade 3 thrombocytopenia with grade > 2 bleeding or lasting > 7 days  
 
Grade 4 anemia  
 
Grade 5 toxicity (eg, death not due to disease progression) 
 
Any grade 3 ophthalmologic adverse event that does not resolve within 7 days 
 
Any grade 4 ophthalmologic adverse event 
 
Any grade 4 laboratory value 
 
Any grade 4 vomiting or diarrhea  
 
Grade 3 vomiting or grade 3 diarrhea lasting more than 3 days despite optimal 
medical support  
 
Grade  3 nausea lasting 3 days or more despite optimal medical support   
 
Grade 3 fatigue lasting 1 week or longer 
 
Any subject meeting the criteria for Hy’s Law case (ie, severe drug-induced liver 
injury [DILI]) will be considered a DLT. A Hy’s Law case is defined as: AST or ALT 
values of ≥ 3 x ULN AND with serum TBIL level of > 2 x ULN or international 
normalized ratio (INR) > 1.5 without signs of cholestasis and with no other clear 
alternative reason to explain the observed liver related laboratory abnormalities 
(see Section 11.7 for further explanation of Hy’s law case and Management of 
Hepatic Function).  
 
Any other grade  3 adverse event with the following exceptions: 
 
DLT Exemption:  Asymptomatic grade 3 amylase and/or lipase lasting 
 72 hours, and without radiological signs of pancreatitis 


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 
DLT Exemption:  Asymptomatic grade 3 electrolyte abnormalities that last 
< 72 hours, are not clinically complicated, and resolve spontaneously or respond 
to medical interventions   
 
DLT Exemption:  Other select lab abnormalities that do not appear to be clinically 
relevant or harmful to the subject (eg, grade 3 lymphopenia, 
grade 3 hypoalbuminemia), and/or can be corrected with replacement or 
modifications  
 
DLT Exemption:  A transient (resolving to grade ≤ 1 within 6 hours of onset) 
grade 3 infusion-related adverse event 
 
DLT Exemption (Part 4 only):  Any grade 3 endocrinopathy that is adequately 
controlled by hormonal replacement 
 
If an adverse event is clearly attributable to non-investigational anti-cancer 
therapy and does not exceed the expected severity, this specific adverse event 
may be considered exempt from being a DLT. 
Subjects enrolled in dose exploration may be replaced if they are not evaluable for a 
DLT (ie, a subject did not receive planned study treatment [100 of planned doses of 
bemarituzumab] or ended the study treatment before completion of DLT evaluation 
period for a reason other than experiencing a DLT).  The replaced subject may continue 
on study at the Investigator’s discretion and after discussion with the Medical Monitor.   
Dosing for an individual will be stopped for any occurrence of a DLT or if criteria are met 
as outlined in Section 6.2.2.   
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
A toxicity may be due to one or more components (ie, bemarituzumab, docetaxel, 
pembrolizumab, carboplatin, paclitaxel, nab-paclitaxel) of the study treatment, depending 
on the study Part.  Each study drug considered to be contributing to the toxicity, in the 
opinion of the investigator, should be delayed or modified in accordance with the 
guidelines below.  The other components of the study treatment may be administered on 
schedule if there is no contraindication.  If clinically appropriate, the treating investigator 
can delay any of the treatment components up to a maximum of 7 days to allow 
synchronized administration of all agents.  Dosing intervals of subsequent doses may be 
adjusted as clinically feasible in order to gradually synchronize the entire study 
treatment.  Intervals between 2 consecutive IV doses cannot be less than 14 days for 
Parts 1, 2, and 4 or less than 7 days for Part 3.  Exception:  If any component of 
anti-cancer regimen is delayed or held in the first 3 cycles, bemarituzumab should be 
administered  3 days of scheduled visit date for cycles 1 through 3.  For Part 3 only, 
there is no window for cycle 1 day 8 dose, ie, the visit must occur 7 days after C1D1. 


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Delay of any component of the anti-cancer regimen longer than 21 days should be 
discussed with the medical monitor prior to re-initiation.  If one component is 
permanently discontinued, the rest of the components of the study treatment may 
continue. 
6.2.2.1 
Amgen Investigational Product:  Bemarituzumab 
Bemarituzumab doses may be held for bemarituzumab-related adverse events following 
the guidelines outlined in Table 6-5.  The reason for dose delay of bemarituzumab is to 
be recorded on each subject’s CRF(s).   
Bemarituzumab is to be administered prior to all other study treatment.  After cycle 1, 
bemarituzumab dose should be recalculated only if the weight changes  10 from 
baseline.  If the dose is recalculated, the weight used for the recalculated dose should 
function as the new baseline.   
If dose reductions or interruptions that do not fall within these guidelines are being 
considered by the investigator, these will require discussion with the Sponsor or 
designee. 
Corneal Events 
Any subject with a corneal event which occurs within 100 days of last receiving a dose of 
bemarituzumab, regardless if deemed related or not related to bemarituzumab, should 
be evaluated by an ophthalmologist.  Any subject who reports pain or irritation of the eye 
or change in vision should be evaluated by an ophthalmologist.  Refer to Table 6-5 for 
additional guidance.










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6.2.2.2 
Non-Amgen Non-Investigational Product 
6.2.2.2.1 
Docetaxel 
Dose adjustments for docetaxel are permitted and should be made in accordance with 
the relevant local guidelines and the latest version of the local prescribing information 
with the consideration of the recommendations provided below, which are based on the 
USPI. 
Subjects who are dosed initially at 75 mg/m2 and who experience either febrile 
neutropenia, neutrophils less than 500 cells/mm3 for more than 1 week, severe or 
cumulative cutaneous reactions, or other grade 3 or 4 non-hematological toxicities 
during docetaxel treatment should have treatment withheld until resolution of the toxicity, 
and then resumed at 55 mg/m2.  Subjects who develop  grade 3 peripheral neuropathy 
should have docetaxel treatment discontinued.  Given adverse events related to nail 
toxicity may be additive in the context of the combined use of bemarituzumab and 
docetaxel, in the event of an occurrence of a grade 3 nail infection, paronychia or 
onycholysis, docetaxel must be held until resolution to grade  1.  Docetaxel should not 
be administered to subjects until ANC recovery to  1500 cells/mm3 prior to each dose of 
docetaxel. 
Concomitant use of docetaxel and drugs that inhibit CYP3A4 may increase exposure to 
docetaxel and should be avoided.  In subjects receiving treatment with docetaxel 
(Parts 1 and 2), close monitoring for toxicity and docetaxel dose reduction should be 
considered if systemic administration of a potent CYP3A4 inhibitor (such as 
ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, and voriconazole) cannot be avoided. Refer to the docetaxel 
regional prescribing information for additional information. 
The reason for dose change of docetaxel is to be recorded on each subject’s CRFs.   
6.2.2.2.2 
Carboplatin, Paclitaxel, Nab-Paclitaxel, and Pembrolizumab 
For carboplatin, paclitaxel, nab-paclitaxel, and pembrolizumab dose modifications might 
be permitted to mitigate the adverse reactions according to institutional standards or 
local package inserts, which the investigator may elect to follow over the guidance 
provided herein.  
Dosing interruptions are permitted for logistical reasons not related to study therapy and 
the reason for the interruption should be documented in the eCRF.  Subjects should 
resume study therapy within 21 days of dose interruption. 


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Neurotoxicity 
Subjects receiving paclitaxel and developing grade 3 or 4 neuropathy for 7 days of 
longer should have paclitaxel dose reduced by 20% for subsequent doses.  
Subjects receiving nab-paclitaxel and developing grade 3 or 4 neuropathy should have 
nab-paclitaxel withheld and should resume nab-paclitaxel and carboplatin at reduced 
doses when neuropathy improves to grade 1 or completely resolves.  On first occurrence 
the dose reduction for nab-paclitaxel and carboplatin AUC should be 25%, an additional 
25% for the second recurrence, and discontinuation of treatment if a third recurrence 
should occur. 
Renal impairment 
Alterations in renal function may require carboplatin dose recalculation. 
Hepatic impairment 
Alterations in hepatic function may require paclitaxel dose recalculation. 
Hematologic toxicity 
In the initial phase of combination therapy treatment with pembrolizumab, paclitaxel or 
nab-paclitaxel, and carboplatin should be delayed until ANC is  1.5 x 109/L and platelet 
count is platelet count  100 x 109/L.  Subjects receiving paclitaxel and developing febrile 
neutropenia during the prior cycle should have paclitaxel and carboplatin dose reduced 
by 20-25% for subsequent courses and/or institution of hematopoietic stimulating 
agents.  The carboplatin dose should be reduced by 25% in subjects with platelet count 
nadir of  50 x 109/L and/or neutrophil nadir of  0.5 x 109/L.  An additional dose 
reduction of 25% may be considered at second occurrence, and consider discontinuing 
nab-paclitaxel and carboplatin therapy if a subject qualifies for a third dose reduction.  
Dose reductions for hematologic toxicity should be maintained for subsequent cycles. 
For subjects receiving nab-paclitaxel and developing febrile neutropenia or ANC 
 0.5 x 109/L for  7 days or delay of next cycle by  7 days for thrombocytopenia 
 50 x 109/L withhold nab-paclitaxel and carboplatin treatment until counts recover to an 
ANC of at least 1.5 x 109/L and platelet count of at least 100 x 109/L on day 1, or to an 
ANC of at least 0.5 x 109/L and platelet count of at least 50 x 109/L of day 8 or 15 of the 
cycle.  If treatment is resumed then reduce nab-paclitaxel and carboplatin by 25% at first 
occurrence, and additional 25% at second occurrence, and consider discontinuing 


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nab-paclitaxel and carboplatin therapy if a subject qualifies for a third dose reduction.  
Dose reductions for hematologic toxicity should be maintained for subsequent cycles. 
Pembrolizumab immune-related toxicity 
No dose reduction for pembrolizumab is recommended.  In general, pembrolizumab 
should be withheld for grade  3 immune-mediated adverse reactions, and permanently 
discontinued for life-threatening (grade 4) immune-mediated adverse events, recurrent 
severe (grade 3) immune-mediated reactions that require systemic immunosuppressive 
treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks of initiating steroids. 
Allergic Reaction 
If a subject experiences grade 1 or 2 allergic reaction to carboplatin, premedication 
should be given according to institutional practice prior to subsequent further study drug 
administration.  If a grade 1 or 2 allergic reaction persists into the next cycle, escalation 
of the appropriate premedication should be done according to institutional practice prior 
to administration of carboplatin.  For subjects experiencing grade 3 or 4 allergic 
reactions, treatment with carboplatin should be discontinued. 
Refer to Section 6.7.2.1 for infusion reaction prophylaxis and other supportive care 
guidance. 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on drug accountability for the investigational product will be 
provided to the site. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects who meet eligibility criteria according to the specific study part and enroll in the 
study will be assigned to treatment with bemarituzumab combination with other 
anti-cancer therapy or bemarituzumab monotherapy. 
The enrollment date is to be documented in the subject’s medical record and on the 
Subject Enrollment CRF. 


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6.4.2 
Blinding 
This is an open-label study; procedures to blind treatment assignment are not 
applicable. 
6.5 
Treatment Compliance 
When subjects are dosed at the site, they will receive bemarituzumab, chemotherapy, 
and pembrolizumab (depending on the study part) directly from the investigator or 
designee, under medical supervision.  The date and time of each dose administered in 
the clinic will be recorded in the source documents and recorded in the CRF. 
6.6 
Treatment of Overdose 
The effects of overdose for bemarituzumab are unknown, and there is no available 
antidote.  For overdose information on pembrolizumab or the chemotherapy agents 
please refer to the Regional Prescribing Information. 
In the event of an overdose, subjects should receive appropriate supportive medical care 
and be followed until resolution/stabilization of any clinical issues. A blood sample 
should be collected to determine bemarituzumab serum concentration as soon as 
possible after overdose. 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it 
involved investigational product in the study) must be communicated to the sponsor (or a 
specified designee) using the eCRF page within 24 hours of its occurrence. 
Any overdose associated with clinical symptoms will be recorded as an adverse event or 
serious adverse event, as appropriate.  Details of any signs or symptoms and their 
management should be recorded, including details of any treatments administered for 
the overdose.  All overdoses with clinical symptoms meeting the serious adverse event 
criteria must be reported as described in Section 8.4.6. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
All prior medications must be recorded in the designated eCRF.  This includes prior 
therapies that were being taken/used from 3 months prior to enrollment through informed 
consent and all prior anticancer therapies for advanced or metastatic squamous-cell 
non-small-cell lung cancer dating back to initial diagnosis. 
For prior therapies for advanced or metastatic squamous-cell non-small-cell lung cancer, 
collect therapy name, setting, dose, unit, frequency, start date, stop date, best response, 
and reason for discontinuation.  For anticancer therapies consisting of multiple individual 


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components, information for each component should be collected.  For all other prior 
therapies, collect therapy name, indication, dose, unit, frequency, route, start date, and 
stop date. 
6.7.2 
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 6.1.6. 
To mitigate the risk of corneal toxicities, prophylactic use of ocular lubricants and eyelid 
hygiene is recommended.  Ocular lubricants (eg, preservative-free artificial tears) should 
be self-administered 3 times daily throughout the treatment period and for 28 ( 3) days 
after the last dose.  They may be polyvinyl alcohol-, or liquid polyol-based.  If 
preservative free is not available, formulations with preservatives are allowed.  Avoid 
viscous lubricants which can cause blurriness. 
Concomitant therapies are to be collected from informed consent through the end of 
LTFU period.  For concomitant therapies, including vaccines, collect therapy name, 
indication, dose, unit, frequency, route, start date, and stop date (for SARS-CoV-2 
vaccines collect indication also). 
For subsequent therapies taken for advanced or metastatic squamous-cell 
non-small-cell lung cancer, collect drug name, start date, and stop date. 
6.7.2.1 
Supportive Care 
Subjects can receive supportive care according to local guidelines for blood product 
support, anti-emetics, antibiotics, antivirals, analgesics for pain control, other 
prophylactic treatments, etc.  Hematopoietic stimulating agents may be used if indicated.  
For subjects on anticoagulant therapy, close monitoring of coagulation parameters is 
recommended. 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal 
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 


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study as a whole at any time prior to study completion for the reasons listed in 
Section 7.1. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally authorized representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies and/or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
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 Section 1.3) 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 
and/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. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
decision by sponsor 
 
lost to follow-up 
 
death 
 
adverse event 
 
subject request 
 
ineligibility determined 
 
protocol deviation 
 
non-compliance 
 
disease progression  
 
requirement for alternative therapy 
 
pregnancy 
7.2 
Subject Discontinuation/Withdrawal 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 


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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.  Subjects who are 
withdrawn or removed from treatment or the study will not be replaced.   
If a subject withdraws from the study, they may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor 
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if they repeatedly fail 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, they 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 should 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. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Section 1.3). 


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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 (Section 1.3), is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment, and/or Randomization 
Consent for Tissue Collection for FGFR2b Overexpression Status 
Subjects must consent to provision of archival tissue (or fresh biopsy if archival tissue 
not available within last 5 years) for IHC-confirmed FGFR2b overexpression.  For a 
subject to be eligible for study participation in Parts 2, 3, and 4, positive FGFR2b 
overexpression status must be demonstrated based on a tumor sample either archival or 
fresh. Archival or fresh biopsy specimen may be re-tested if eligibility is not met with the 
first specimen submitted. 
Screening 
The main study informed consent must be obtained before completing any screening 
procedure (other than the tissue collection for FGFR2b overexpression status) or 
discontinuation of standard therapy for any disallowed therapy.  For Parts 2, 3, and 4 
only, positive FGFR2b overexpression status must be confirmed prior to subjects 
entering screening.  After the subject has signed the informed consent form, the site will 
register the subject in the IRT and screen the subject in order to assess eligibility for 
participation.  The screening window is up to 28 days. 
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, (see Section 5.4) 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 eligible for 
re-screening 2 times.  
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 28-day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening, unless directed by Amgen.  Subjects rescreening 


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within 28 days of the signing of the original informed consent only need to repeat the 
assessment(s) that did not originally meet the eligibility criteria; all other initial screening 
assessments do not need to be repeated.  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. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Section 1.3).  On-study visits may be 
completed within 72 hours prior to dosing.  The date of the first dose of protocol-required 
therapies is defined as day 1.  All subsequent doses and study visits will be scheduled 
based on the day 1 date.  Administration of protocol-required therapies is to be 
administered last during each visit that it is required. 
8.1.3 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, a SFU visit will 
be performed approximately 28 (+3) days after the last dose of study treatment. 
8.1.4 
Long-term Follow-up 
Long-term follow up will be conducted every 3 months ( 1 month) up to 2 years from the 
subject’s first dose of bemarituzumab.   
Vital status, disease status (until radiographic disease progression), and subsequent 
ophthalmological medications and anticancer treatment (ie, subsequent therapies taken 
for lung cancer) will be collected.  Visits may be conducted by telephone.  A 
comprehensive ophthalmologic examination should be completed if symptoms are 
reported by the subject up to 100 days after the last dose of bemarituzumab. 
A complete list of assessments that will be conducted during LTFU are designated in the 
Schedule of Activities (Section 1.3). 
8.1.5 
End of Study 
A subject is considered to have completed the study if they have completed the study 
including the last visit or the last follow up shown in the Schedule of Activities 
(Section 1.3). 
8.2 
General Assessments  
8.2.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC and Amgen approved informed consent before any study-specific procedures 
are performed. 


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8.2.2 
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.  
Additionally, demographic data will be used to study the impact on biomarkers variability 
and PK of the protocol-required therapies. 
8.2.3 
Medical History 
The Investigator or designee will collect a complete medical and surgical history that 
started within 5 years prior to enrollment through first dose of study treatment.  Medical 
history will include information on the subject’s concurrent medical conditions.  The 
current toxicity grade will be collected for each condition that has not resolved.  Record 
all findings on the medical history CRF. 
Ophthalmologic history is to be recorded on the targeted ophthalmologic CRF. 
In addition to the medical history above, squamous non-small-cell lung cancer history 
must date back to the original diagnosis, and is to be recorded on the cancer medical 
history CRF.  Local tumor biomarker testing results (if completed) will be collected in the 
appropriate eCRF.  
8.2.4 
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). 
8.2.5 
Physical Measurements 
Height in centimeters and weight in kilograms should be measured without shoes. 
8.2.6 
Substance Use History  
Obtain a detailed history of prior and/or concurrent use of alcohol and tobacco. 
8.2.7 
Performance Status  
Eastern Cooperative Oncology Group performance status will be collected at the 
timepoints indicated in the Schedule of Activities (Section 1.3).  The ECOG criteria for 
this protocol are further defined in Section 11.10. 
8.3 
Efficacy Assessments 
Radiological Imaging Assessment 
The extent of disease will be evaluated by contrast-enhanced computed tomography 
(CT)/magnetic resonance imaging (MRI) according to RECIST v1.1.  In order to reduce 
radiation exposure for subjects, low dose CT should be utilized whenever possible. 


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Screening scans: 
The screening scans should be performed within 28 ( 3) days prior to cycle 1 day 1 and 
include clinical examination and appropriate imaging techniques (preferably CT scans 
with appropriate slice thickness per RECIST v1.1; MRIs are acceptable).  If there are 
multiple screening scans, the one closest to the enrollment date will be used as 
baseline.  
Radiological assessment must include CT/MRI of the chest, abdomen, and pelvis, as 
well as assessment of all other known sites of disease.  Tumor response assessment 
will be performed by the investigator per RECIST v1.1 guidelines (Section 11.9). 
All subjects with brain metastasis must have MRI of the brain performed.  All brain scans 
for subjects with brain metastasis are required to be MRI unless MRI is contraindicated, 
and then CT with contrast is acceptable.  Brain imaging (MRI or CT) of the brain should 
be performed if signs or symptoms suggestive of CNS metastases are present. 
Subsequent scans: 
All subsequent scans should be performed in the same manner (eg, with the same 
contrast, MRI field strength) as at screening preferably on the same scanner.  If the 
imaging modality must be altered (eg, unscheduled assessment) consultation with the 
Amgen medical monitor is recommended. 
During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, as 
well as all other known sites of disease, will be performed independent of treatment 
cycle as specified in the Schedule of Activities (see Section 1.3).  Imaging may also be 
performed more frequently if clinically necessitated at the discretion of the managing 
physician.  Radiologic imaging and tumor assessment will be performed until start of 
new anticancer therapy, disease progression, death, withdrawal of consent, or end of 
study, whichever occurs first.  
Determination of disease response for clinical management and response evaluation will 
be performed at the clinical sites per RECIST v1.1.  Confirmation of response by a 
repeat scan is required after 4 weeks from the first documentation of response.  Scans 
may be submitted to a central imaging core laboratory for archival, and, if needed, 
response assessment including RECIST v1.1, and/or exploratory analysis (eg, 
volumetric and viable tumor measurements).   


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8.4 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(see Section 1.3). 
8.4.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Allow subject to sit for 3-5 minutes before taking 
blood pressure measurement.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF.  The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 
8.4.2 
Electrocardiograms (ECGs) 
Parts 1, 2, and 4 only: 
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 the most recumbent position possible.  The ECG must 
include the following measurements:  Heart rate, QRS, QT, Q-T corrected (QTc), and 
PR intervals.  The principal investigator (PI) or designated site physician 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. 
Part 3 only: 
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 the most recumbent position possible.  
Electrocardiograms should be performed in a standardized method, in triplicate, and run 
consecutively.  Each triplicate, which consists of three 10-second tracings, should be 
completed within a total of 5 minutes from the start of the first to the completion of the 
third, prior to blood draws or other invasive procedures.  Each ECG must include the 
following measurements:  QRS, QT, QTc, RR, and PR intervals. 
 
Baseline ECGs should be collected at 3 timepoints ≥ 5 minutes apart, with each 
baseline ECG performed in triplicate, and with at least 5 minutes between the end 
of each triplicate and the start of the next (total 9 ECGs) 
 
Each post-dose ECG should be performed in triplicate (total 3 ECGs) 


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Baseline is defined as screening.  The PI or central reader will review all ECGs.  
Electrocardiograms will be transferred electronically to an ECG central vendor eg, for 
storage or for analysis per Amgen instructions.  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 or designee.  Standard ECG 
machines should be used for all study-related ECG requirements.  In certain 
circumstances Amgen or designee may be able to provide a standard ECG machine if a 
site is unable to provide one. 
8.4.3 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) 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 Events CRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a 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 Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Section 1.3). 
8.4.4 
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 of death should be obtained. 
8.4.5 
Other Safety 
8.4.5.1 
Ophthalmologic Examinations 
Ophthalmologic examinations will be performed according to the Schedule of Activities 
(Section 1.3).  Ophthalmologic adverse events of any grade up to 100 days after the last 
dose of bemarituzumab should be reported to Amgen by the investigator and evaluated 
by an ophthalmologist. 


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The ophthalmologic examination should include distance corrected visual acuity of each 
eye separately with acuity recorded as the logMAR equivalent (see Section 11.12), slit 
lamp examination of the anterior segment, tonometry (intraocular pressure 
measurement), and ocular surface staining (eg, fluorescein).  In addition, a dilated retinal 
examination or 3 field retinal photographs should be performed at screening and at 
every other ophthalmic examination.  Additionally, optical coherence tomography (OCT) 
of the macula is required for subjects diagnosed with, or with suspected retinal pigment 
epithelium (RPE) detachment.  All assessments are to be done according to local 
practice.   
Distance corrected visual acuity will be assessed using Snellen or Landolt C Chart and 
acuity must be recorded as logMAR equivalent.  The same method should be used at 
screening and throughout the study.  Other visual acuity charts may be utilized, but must 
be agreed with the Amgen medical monitor.   
Ophthalmologic examinations should be performed regardless of dose delays per the 
schedule of activities (See Section 1.3).  The ophthalmological examination may be 
repeated at any time, as clinically indicated, up to 100 days after the last dose of 
bemarituzumab.  After the SFU visit if the subject has any persistent ophthalmologic 
findings, ophthalmologic assessments should continue until resolution of findings, 
withdrawal of consent, death, or lost to follow up.  Ocular adverse events should be 
monitored by an ophthalmologist until resolution. 
The following measures will be implemented for ophthalmologic adverse events: 
 
Monitoring through ophthalmologist visits at baseline and Q6W (- 5 days) for the 
first 24 weeks, and then every 8 weeks (-5 days) thereafter  
 
Ophthalmologic adverse event management guidance for the investigator (refer to 
Table 6-5) 
If any clinically significant changes are noted compared to the previous examination or, if 
the subject has any grade 2 or higher ocular signs or symptoms, the subject should be 
evaluated by an ophthalmologist. 
8.4.6 
Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of adverse events, and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 11.4. 


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8.4.6.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.4.6.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 and is described in 
Section 11.4, except for ocular adverse events which will be graded according to the 
study-specific ocular toxicity grading (see Appendix 11, Section 11.11). 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product or after study-required activity and/or procedures through the end of SFU visit 
are reported using the Events eCRF (refer to Section 8.4.6.6 for collection of ocular 
adverse events after the SFU visit).  
Adverse events within 28 ( 3) days after the last day of study treatment are expected to 
be recorded.  Adverse events of any grade occurring up to 14 days after the pre-
screening procedure of tumor biopsy acquisition for the FGFR2b assay should be 
reported as adverse events if they are deemed related to the pre-screening procedure 
by the investigator. 
8.4.6.1.2 
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 pre-screening or 
main study informed consent through 28 ( 3) days after the last study treatment or 
through the SFU visit for the protocol required reporting period, whichever occurs late, 
are reported using the Events eCRF.  Serious adverse events of any grade occurring up 
to 14 days after the pre-screening procedure of tumor biopsy acquisition for the FGFR2b 
assay should be reported as serious adverse events if they are deemed related to the 
pre-screening procedure by the investigator. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee immediately and no later than 24 hours of the investigator’s awareness of the 
event, as indicated in Section 11.4.  The investigator will submit any serious adverse 
event data to the sponsor immediately and no later than 24 hours of it being available. 
Since the criteria the CTCAE grading scale differs from the regulatory criteria for serious 
adverse events, if adverse events correspond to grade 4 CTCAE toxicity grading scale 
criteria (eg, laboratory abnormality reported as grade 4 without manifestation of life-
threatening status), it will be left to the investigator’s judgment to also report these 


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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. 
8.4.6.1.3 
Serious Adverse Events After the Protocol Required Reporting 
Period 
During the long-term follow-up period, if the investigator becomes aware of serious 
adverse events suspected to be related to investigational product or any fatal adverse 
event (regardless of causality) after the protocol-required reporting period (as defined in 
Section 8.4.6.1.2) is complete, then these serious adverse events will be reported to 
Amgen immediately and no later than 24 hours following the investigator’s awareness of 
the event on the Events CRF. 
After End of Study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator.  However, if 
the investigator becomes aware of serious adverse events (including any fatal cases) 
suspected to be related to investigational product, then these serious adverse events will 
be reported to Amgen immediately and no later than 24 hours following the investigator’s 
awareness of the event on the Events CRF. 
Serious adverse events reported after the end of the study 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. 
8.4.6.2 
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. 
8.4.6.3 
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 7.3).  
Further information on follow-up procedures is given in Section 11.4. 


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All new information for previously reported serious adverse events must be sent to 
Amgen immediately and no later than 24 hours following awareness 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 Events CRF. 
8.4.6.4 
Regulatory Reporting Requirements for Safety Information  
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
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 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. 
For studies in which the treatment assignment is blinded, 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, as appropriate.  Investigators will receive 
notification of related serious adverse events reports sent to regulatory authorities in 
accordance with local requirements. 
Amgen will prepare a single Development Safety Update Report (DSUR) (also referred 
to as Annual Safety Report [ASR] in the EU) for the Amgen Investigational Product.  In 
order to ensure that consolidated safety information for the trial is provided, this single 


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DSUR will also include appropriate information on any other investigational products 
used in the clinical trial, if applicable.   
8.4.6.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.4.6.6 
Adverse Events of Special Interest 
Selected adverse events known as bemarituzumab Events of Special Interest are ocular 
adverse events of any grade or seriousness occurring up to 100 days after the last dose 
of bemarituzumab and should be collected as adverse events.  Any ophthalmological 
events not resolved at the SFU visit must be followed until resolution or no further 
improvement is expected based on an ophthalmology assessment.  Ocular adverse 
events (including corneal adverse events) should be graded using the Ocular Toxicity 
Grading scale provided in Section 11.11. 
Subjects should be assessed for possible bemarituzumab Events of Special Interest 
prior to each dose. 
8.4.6.7 
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 6 months after 
protocol-required therapies.  During the LTFU period, local laboratory results performed 
in walk-in clinics or health centers are acceptable if the subject does not have a 
scheduled clinic visit. 
If a pregnancy is reported, the investigator is to inform Amgen immediately and no later 
than 24 hours of learning of the pregnancy and/or lactation and is to follow the 
procedures outlined in Section 11.5.  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, and ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
Pregnancy Testing 
A highly sensitive (serum) pregnancy test should be completed at screening and within 
72 hours of initiation of investigational product for females of childbearing potential. 


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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 
Form, see Figure 11-3).  Refer to Section 11.5 for contraceptive requirements.  
Additional pregnancy testing should be performed on day 1 of every cycle (Parts 1 and 
2) or day 1 of every other cycle (Part 3) during treatment, 28 ( 3) days after 
discontinuing protocol-required therapies, and monthly (28 [ 3] days) pregnancy testing 
up to and inclusive of 75 (3) days from the last bemarituzumab dose.  If the patient 
continues on docetaxel upon bemarituzumab discontinuation, a one-time pregnancy test 
will be performed upon the patient’s discontinuation of docetaxel during the SFU period. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.5 
Pharmacokinetic Assessments 
Whole blood samples will be collected for measurement of serum concentrations of 
bemarituzumab as specified in the Schedule of Activities (Section 1.3).  Instructions for 
the collection and handling of biological samples will be provided by the sponsor.  The 
actual date and time (24-hour clock time) of each sample will be recorded. 
8.6 
Pharmacogenetic Assessments  
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  This optional assessment is 
separate from genomic analysis of somatic mutations in the tumor and circulating tumor 
DNA (ctDNA) samples included as part of the main study.  The goals of the optional 
studies include the use of genetic markers to help in the investigation of cancer and/or to 
identify subjects who may have positive or negative response to investigational product.  
No additional samples are collected for this part of the study.  For subjects who consent 
to this/these analysis/analyses, DNA may be extracted.  The final disposition of samples 
will be described in Section 11.6. 
8.7 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities (Section 1.3) for the measurement of 
anti-bemarituzumab antibodies.  Samples testing positive for binding antibodies may be 
further characterized. 


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Subjects who test positive for antibodies at the final scheduled antibody time point and 
have clinical sequelae that are considered potentially related to an anti-bemarituzumab 
antibody response will also be asked to return for additional follow-up testing.  This 
testing is to occur approximately every 3 months from the final scheduled antibody time 
point and continue until:  (1) antibodies are no longer detectable; or (2) the subject has 
been followed for a period of at least 1 year (± 4 weeks) post administration of 
bemarituzumab.  More frequent testing or testing for a longer period of time may be 
requested in the event of safety-related concerns. 
Refer to the Schedule of Activities (Section 1.3), as applicable, for specific time points, 
and the laboratory manual for detailed collection and handling instructions. 
8.8 
Biomarkers 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
8.8.1 
Biomarker Samples at Pre-Screening and Screening 
FGFR2b 
Tumor Tissue 
Provision of archival tumor biopsy/resection (bone biopsies and cytology samples are 
excluded) formalin fixed and embedded in paraffin (within 5 years, or fresh biopsy if 
archival sample is not available) is required for assessment of FGFR2b overexpression 
status by IHC.  Unstained slides or blocks are acceptable.  Block return may not be 
possible in every country.  A positive FGFR2b overexpression status result is required 
for enrollment in study Parts 2, 3, and 4 and subjects must consent to tumor tissue 
collection and testing in pre-screening.  For Part 1, tissue collection will be performed 
during screening and FGFR2b IHC testing will be performed retrospectively.  Primary 
tumor and metastatic sites of specimen collection are allowed.  If fresh tissue samples 
need to be collected, these samples should be obtained following local standard of care 
procedures that are not expected to present any additional significant risk to the health, 
safety, and welfare of the subject.  
Subjects for Parts 2, 3, and 4 will be selected for enrollment based on FGFR2b 
overexpression status, as determined by an IHC clinical trial assay (CTA) at a central 
Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (Roche Tissue 


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Diagnostics, Tucson, Arizona, US) that meets US regulatory requirements.  Timing of 
sample collection is described in the Schedule of Activities (Section 1.3).  
The CTA used to select subjects is the VENTANA FGFR2b (FPR2-D) assay, an IHC test 
to determine the FGFR2b overexpression status (positive or negative) in neoplastic 
tissue.  Samples that are deemed positive for FGFR2b overexpression status exhibit any 
moderate (2) to strong (3) membrane staining in tumor cells.   
Subjects who are deemed negative for FGFR2b overexpression status (absence of 
moderate to strong membrane staining) using IHC will not be eligible for enrollment in 
Parts 2, 3, or 4.  It is the responsibility of each investigator to obtain an adequate tumor 
specimen for analysis of FGFR2b positivity for enrollment.  Blocks are preferred, if 
available, but in lieu of blocks, unstained slides are recommended.  The tumor specimen 
submitted should be of sufficient quantity to allow for IHC analysis; see the Laboratory 
Manual for details.  Tumor slide or tumor block specimen processing, labeling, and 
shipping instructions are detailed in the Laboratory Manual that will be distributed with 
the specimen collection kit. 
Once tumor specimens are received, analysis will be performed as efficiently as 
possible, and FGFR2b overexpression status results will be communicated back to the 
investigator or designee. 
PD-L1 testing will be performed on leftover tissue, if available, as listed in the Schedule 
of Activities (Section 1.3).   
8.8.2 
Biomarker Development 
Samples will be collected to develop or address biomarker hypotheses related to 
bemarituzumab activity (eg, to evaluate potential biomarkers that may correlate with 
treatment response).  These samples may also be used for developing methods that 
enable better understanding of the disease.   
Blood and tissue will be collected for biomarker development at the time points specified 
in the Schedule of Activities (Section 1.3), if allowed according to local regulations and 
agreed by EC/ IRB.  Blood samples will be collected and assessed for ctDNA mutational 
profiles for potential association with clinical endpoints.  Circulating tumor DNA plasma 
analysis will include the mandatory paired analysis of subject blood samples to identify 
and select out germline variants, to help refine and determine tumor-specific mutations.  
The ctDNA assessments are used for profiling of somatic mutations.  Germline 
mutational results will not be reported.  Biomarker assessment can be done only if the 


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biomarker research is allowed according to local regulations and agreed by the local 
EC/IRB. 
When tumor samples or optional biopsy samples are available, including 
screening/pre-screening tissue, they will also be used for DNA, RNA, and protein 
expression analysis including somatic (tumor) mutations in order to correlate expression 
with response.  Exploratory genomic analyses of tumor tissue, or biopsies, will include 
the paired sequencing analysis of subject blood cell pellet samples to identify and select 
out germline variants, to help refine and determine tumor-specific mutations.  Germline 
mutational results will not be reported.  None of these samples will be used for screening 
of hereditary traits. 
8.8.2.1 
Biomarker Future Research  
In oncology, there is particular interest in the molecular changes underlying the 
oncogenic processes that may identify cancer subtypes, stage of disease, assess the 
amount of tumor growth, or predict disease progression, metastasis, and responses to 
investigational product(s) or protocol-required therapies. 
If consent is provided by subjects, any remaining samples collected at the time points 
specified in the Schedule of Activities (Section 1.3), including samples collected for 
biomarkers assessments, may be used for future research as described in Section 11.6.  
No additional samples will be collected for biomarker development/future research. 
Amgen or another third-party manufacturer may attempt to develop test(s) designed to 
identify subjects most likely to respond positively or negatively to investigational 
product(s) to investigate and further understand cancer. 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
No statistical hypothesis will be tested. 
9.2 
Sample Size Determination 
It is anticipated that up to 180 subjects will be enrolled in this study, consisting of a 
maximum of 18 subjects in Part 1 and a maximum of 150 subjects in Parts 2, 3, and 4 
combined.  The 150 subjects includes the possibility of 2 cohorts at 2 dose levels of 
bemarituzumab, consisting of 10 to 30 subjects in each of Parts 2 and 4.  Three to 
6 Japanese subjects per dose level will be enrolled in Part 1, Part 2, and/or Part 4, either 
as part of the initial dose level evaluation, or as backfill once the RP3D has been 


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determined.  The planned regions for this study will include North America, Asia, Europe, 
and Australia. 
With 3, 6, or 9 subjects in a dose level cohort in Part 1, there is approximately 58%, 
82%, and 93% probability, respectively, of observing at least 1 DLT if the true DLT rate 
is 25%. 
With a minimum of 10 subjects each in Parts 2, 3, and 4, there is an approximate 
95% probability of observing at least 1 DLT if the true DLT rate is 25%, the lower end of 
the acceptable toxicity interval.  Up to 30 subjects may be enrolled to gain further safety 
and preliminary efficacy data. 
9.3 
Populations for Analysis 
The following populations are defined: 
Population 
Description 
Enrolled 
All subjects enrolled. 
Safety 
All subjects who received at least 1 dose of 
bemarituzumab.  
DLT 
All subjects that are enrolled in Part 1 who received at least 
one dose of bemarituzumab and Docetaxel; and met either 
of the following:  1) experienced a DLT, or 2) completed the 
21-day DLT period, 3) received 100% of their planned 
dose. 
 
9.3.1 
Covariates 
The relationship between covariates and endpoints may be explored and specified in the 
statistical analysis plan if appropriate. 
9.3.2 
Subgroups 
Subgroups may be explored and specified in the statistical analysis plan if appropriate. 
9.4 
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 8.1.5. 


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9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Part 3 may enroll simultaneously with Parts 1, 2, and 4; and Parts 2 and 4 may enroll 
simultaneously.  Therefore, the timing of the DLRMs described below may be adjusted 
so data from multiple study parts can be reviewed at a single meeting.  Interim analyses 
will be based on as-is database snapshots (ie, data that have gone through routine data 
cleaning). 
9.4.1.1.1 
Part 1 
During DLRMs, Amgen, in consultation with the site investigators, will review all 
available cumulative data (safety, tolerability, laboratory, PK, and efficacy) by cohort 
prior to making dose escalation or dose de-escalation recommendations.  Adverse 
events and DLTs observed in all subjects will be evaluated continually and fully 
integrated into all DLRMs and considered in all enrollment and dosing decisions.  A 
DLRM will occur during dose escalation and after dose escalation is complete (21 days 
following last subject enrolled in dose escalation). 
The guidelines for dose escalation or de-escalation to the next dose level are 
determined by using a mTPI-2 design (see Section 6.2.1). 
9.4.1.1.2 
Parts 2, 3, and 4 
Amgen, in consultation with site investigators, will review the data as detailed above 
4 months after the 10th subject has been enrolled, in each of Parts 2, 3, and 4. 
Additional administrative analyses may be performed for Parts 2, 3, and 4 before the 
primary analysis in order to plan for additional studies.    
9.4.1.2 
Primary Analysis 
The primary analysis will be based on a cleaned database lock and will occur 12 months 
after the last subject has been enrolled. 
9.4.1.3 
Final Analysis 
A final analysis will be based on a cleaned database lock will occur after all subjects 
have ended the study. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Data will be summarized by study part, and by dose level within Part 1.  Descriptive 
statistics on continuous data will include means, medians, standard deviations and 
ranges, while categorical data will be summarized using frequency counts and 


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percentages.  Unless otherwise specified, data will be summarized using the Safety 
Analysis Set.  
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Pearson (Clopper and Pearson, 1934).  Kaplan-Meier (KM) 
methods will be used to estimate the median and percentiles for time to event endpoints 
with CI calculated by using the Brookmeyer and Crowley method (Brookmeyer and 
Crowley, 1982).  Kaplan-Meier methods will be used to estimate landmarks for time to 
event endpoints (eg, 1-year OS) with the Greenwood formula (Kalbfleisch and Prentice, 
1980) used to estimate the standard error used in CI calculation. 
9.4.2.2 
Efficacy Analyses 
 
Endpoint/ 
Estimand 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
Listings of secondary efficacy endpoints will be produced for all 
subjects.  
The proportion of subjects with an objective response will be 
estimated along with a 95% CI.  The same method will be used to 
summarize disease control rate. 
For subjects treated at the RP3D, KM curves, KM quartiles with 95% 
CIs, and KM estimates with 95% CIs at landmark time points will be 
estimated for the following endpoints:  duration of objective response 
(for only responding subjects), PFS, and OS.   
Exploratory 
Will be described in the statistical analysis plan finalized before 
database lock 
 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
Endpoint 
Statistical Analysis Methods 
Primary 
The incidence of DLTs, treatment-emergent adverse events, clinical 
laboratory abnormalities, vital signs, and corneal findings will be 
tabulated.  
 
Subject incidence of DLTs will be tabulated by planned dose level for 
Part 1. 
 


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9.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of grade  3 events, fatal adverse events, 
serious adverse events, adverse events leading to discontinuation from investigational 
product or other protocol-required therapies, and adverse events of special interest will 
also be provided.   
9.4.2.3.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics and shifts in 
grades of safety laboratory values between baseline and the worst on-study value. 
9.4.2.3.4 
Vital Signs 
The analyses of vital signs will include summary statistics and shifts in vital sign values 
between baseline and the worst on-study value. 
9.4.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics. 
9.4.2.3.6 
Electrocardiogram 
In Parts 1, 2, and 4 the ECG measurements will be performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; summaries and 
statistical analyses of ECG measurements are not planned, and these data would not be 
expected to be useful for meta-analysis with data from other trials. 
In Part 3, ECG parameters will be summarized with descriptive statistics.  In addition, the 
maximum post-baseline and maximum change from baseline in QT interval will be 
categorized and the number and percentage of subjects in each group will be 
summarized.  ECG data will be listed and select parameters may be plotted. 
9.4.2.3.7 
Antibody Formation 
The incidence and percentage of subjects who develop anti-bemarituzumab antibodies 
at any time will be tabulated. 
9.4.2.3.8 
Exposure to Investigational Product 
The number of days on investigational product, the total dose of investigational product, 
and dose intensity will be summarized using descriptive statistics.   


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9.4.2.3.9 
Exposure to Non-investigational Product 
The number of days on non-investigational product, the total dose of non-investigational 
product, and dose intensity will be summarized using descriptive statistics.   
9.4.2.3.10 
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 dictionary. 
9.4.2.4 
Other Analyses 
Bemarituzumab serum concentration and pharmacokinetic parameters for 
bemarituzumab including, but not limited to, AUC, Cmax and Ctrough will be determined and 
tabulated.  Pharmacokinetic data collected from this study in combination with PK data 
collected from other bemarituzumab studies will be used for population PK analysis.  
Additional analysis will be performed to evaluate relationships between bemarituzumab 
exposure and selected safety or efficacy or any relevant biomarker endpoints.  Details 
and results of these exploratory analyses will be described in separate reports. 


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Rekhtman N, Paik PK, Arcila ME, et al.  Clarifying the spectrum of driver oncogene 
mutations in biomarker-verified squamous carcinoma of the lung:  lack of EGFR/KRAS 
and presence of PIK3CA/AKT1 mutations.  Clin Canc Res.  2012;18(4):1167-1176. 
Sequist LV, Cassier P, Varga A, et al.  Phase I Study of BGJ398, a Selective Pan-FGFR 
Inhibitor in Genetically Preselected Advanced Solid Tumors.  AACR 2014 Annual 
Meeting, San Diego, CA. 
Shinkawa T, Nakamura K, Yamane N, et al.  The Absence of Fucose but Not the 
Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type 
Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular 
Cytotoxicity.  J Biol Chem.  2003;278(5):3466-3473. 
Taxotere Summary of Product Characteristics 2019:  
https://www.ema.europa.eu/en/documents/product-information/taxotere-epar-product-
information_en.pdf  
Taxotere US Prescribing Information:  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020449s080s082lbl.pdf  
Weiss J, Sos ML, Seidel D, et al.  Frequent and focal FGFR1 amplification associates 
with therapeutically tractable FGFR1 dependency in squamous cell lung cancer.  Sci 
Trans Med.  2010;2(62):62ra93. 
World Health Statistics 2018.  https://www.who.int/docs/default-source/gho-
documents/world-health-statistic-reports/6-june-18108-world-health-statistics-2018.pdf. 
 


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11. 
Appendices 
11.1 
Appendix 1.  List of Abbreviations 
 
Abbreviation 
Explanation 
ADCC 
antibody dependent cell-mediated cytotoxicity 
ANC 
absolute neutrophil count 
ALT 
alanine aminotransferase 
ASR 
Annual Safety Report 
AST 
aspartate aminotransferase 
AUC 
area under the concentration time curve 
BIL 
bilirubin 
BOR 
best overall response 
Cavg,ss 
area under the serum concentration versus time curve during the 
dosing interval at steady state divided by the dosing interval 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CLIA 
Clinical Laboratory Improvement Amendments 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CrCl 
creatinine clearance 
CT 
computed tomography 
CTA 
clinical trial assay 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
Ctrough 
observed concentration at the end of a dose interval 
Ctrough,ss 
target trough steady state plasma concentration 
C1D1 
cycle 1 day 1 
DAB 
3,3′-Diaminobenzidine 
DILI 
drug induced liver injury 
DLT 
dose limiting toxicity 
DLRM 
Dose Level Review Meeting 
DLRT 
Dose Level Review Team 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee  
ECG 
electrocardiogram 


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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
electronic data capture 
EMR 
Electronic Medical Record 
EoT 
end of treatment 
eSAE 
electronic Serious Adverse Event 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFPE 
formalin fixed paraffin embedded 
FGF 
fibroblast growth factor 
FGFR 
fibroblast growth factor receptor 
FGFR2b 
fibroblast growth factor receptor isoform 2b 
FIH 
first-in-human 
FISH 
fluorescence in situ hybridization 
FRS2 
FGFR substrate-2 
FSH 
follicle-stimulating hormone 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEJ 
gastroesophageal junction 
GFR 
glomerular filtration rate 
GSO 
Global Safety Officer 
HER2 
human epidermal growth factor receptor 2 
HIV 
human immunodeficiency virus 
HR 
hazards ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IV 
intravenous 
IVD 
in vitro diagnostic 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
Intent-to-treat 


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KM 
Kaplan-Maier 
LTFU 
long-term follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
mOS 
median overall survival 
mPFS 
median Progression Free Survival  
MRI 
magnetic resonance imaging 
mTPI 
modified toxicity probability interval method 
NA 
not applicable 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
Non-small Cell Lung Cancer 
NYHA 
New York Heart Association 
OCT 
ocular coherence tomography 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetic 
PR 
partial response 
PT 
prothrombin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q6W 
every 6 weeks 
QTL 
quality tolerance limit parameter 
QTc 
corrected QT interval 
QTcF 
Fridericia’s correction formula 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RP3D 
recommended phase 3 dose 
RPT 
retinal pigment epithelium   
rSDR/V 
remote Source Data Review and Verification 
SAP 
Statistical Analysis Plan 
SARS CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 
SFU 
safety follow-up 


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SMQ 
Standard MedDRA Query 
SPC 
Summary of Product Characteristics 
SoA 
Schedule of Activities 
SqNSCLC 
Squamous non-small-cell lung cancer 
TBL 
total bilirubin 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the central laboratory and the local 
laboratory.  Additional analyte test results may be reported by the local or central 
laboratory, 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 5.1 to 5.2 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 11-2.  DILI Potential Analyte Listing 
Chemistry 
Total bilirubin, direct bilirubin, ALP, LDH, AST (SGOT), ALT (SGPT), 
creatine kinase, ferritin, gamma-glutamyl transferase, haptoglobin 
Hematology 
Hemoglobin, Platelets, RBC Morphology, RBC Count, WBC Count, WBC 
Differential 
Coagulation 
PT, INR, APTT 
Immunology 
5 Prime Nucleotidase, Alpha-1 Antitrypsin, Antinuclear Antibodies, 
Anti-Smooth Muscle Antibody, Anti-Soluble Liver Ag/Liver-Pancreas Ag, 
Cytomegalovirus IgG Antibody, Cytomegalovirus IgM Antibody, Endomysial 
IgA Antibody, Epstein-Barr Virus EDA IgG Antibody, Epstein-Barr Virus NA 
IgG Antibody, Epstein-Barr Virus VCA IgG Antibody, Epstein-Barr Virus 
VCA IgM Antibody, Hepatitis A Virus IgG Antibody, Hepatitis A Virus IgM 
Antibody, Hepatitis B Core Antibodies, Hepatitis B Core IgM Antibody, 
Hepatitis B Surface Antigen, Hepatitis B Virus DNA Genotyping, Hepatitis B 
Virus Surface Antibody, Hepatitis C Antibodies, Hepatitis C Virus RNA 
Genotyping, Hepatitis D Virus Antibody, Hepatitis D RNA, Hepatitis E RNA, 
Hepatitis E IgG Antibody, Hepatitis E IgM Antibody, Herpes Simplex Virus 
Type 1_2 IgG AB, Herpes Simplex Virus Type 1_2 IgM AB, Human Herpes 
Virus 6 DNA, Human Herpes Virus 7 DNA, Human Herpes Virus 8 DNA, 
Immunoglobulin G, Liver Kidney AB 1, Parvovirus IgM/IgG Antibody, Serum 
Caeruloplasmin, Tissue Transglutaminase IgA Antibody, Toxoplasma 
IgM/IgG, Varicella Zoster Virus Antibody 
Toxicology 
Acetaminophen 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; DILI = drug-induced liver injury; EDA = early antigen; 
Ig = immunoglobulin; INR = international normalized ratio; LDH = lactate dehydrogenase; NA = nuclear 
antigen; PT = prothrombin time; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic transaminase; 
SGPT = serum glutamic pyruvic transaminase; VCA = viral capsid antigen; WBC = white blood cell 
 


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11.3 
Appendix 3.  Study Governance Considerations 
Dose Level Review Meetings (DLRM)  
A DLRM is conducted to review and interpret safety data for the purposes of making 
recommendations about dose-level escalation, dose level de-escalation, subject 
group/cohort continuation, or cohort expansion; making recommendations about non-
dose escalation subject group/cohorts (eg, expanded, highest dose and/or final subject 
group/cohort); and evaluating safety signals for purposes of applying Dose Group/Cohort 
Stopping Rules.  The required DLRT members are the medical monitor, global safety 
officer (GSO), and site investigators.  The DLRT will include all site investigators or only 
actively screening and enrolling site investigators.  The medical monitor, GSO, and site 
investigators are the only voting DLRT members.  The following non-voting Amgen 
representatives may also be part of the DLRT:  clinical study manager, biostatistician, or 
pharmacokinetic scientist. 
The medical monitor must be in attendance and cannot be represented by a voting 
designee or delegate.  Voting designees can be identified as appropriate by the GSO or 
site investigator(s).  A site investigator may identify a delegate (eg, sub-Investigator) who 
is listed in the Delegation of Authority.  If a site investigator does this, the site 
investigator must provide written agreement with the designee or delegate’s vote. 
For a DLRM to occur, the medical monitor must attend, and the GSO or delegate must 
attend.  In addition, a quorum of site investigators must be present (may occur at more 
than one meeting).  A quorum is defined as greater than or equal to 50% of the 
participating investigators or their qualified designee.  The DLRM will be rescheduled if 
these requirements are not met.  
All available study data, including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, electrocardiogram (ECG), 
vital signs, and laboratory results will be reviewed.  Data to be reviewed will be cleaned, 
queried, unqueried. 
Dose level review meetings voting will occur as follows:  there will be a total of 3 votes, 
1 for the medical monitor, 1 for the GSO or delegate, and 1 for all of the site 
investigators or delegates combined.  Regardless of how many site investigators there 
are, all of the site investigators combined will have a total of 1 vote decided by a majority 
of the investigators (defined as greater than or equal to 50%). 


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Dose Level Review Meetings recommendations to escalate to the next planned subject 
group/cohort must be by unanimous vote.  If the voting members of the DLRT are not 
able to reach a unanimous recommendation on whether to escalate to the next planned 
subject group/cohort then this should be reflected in the DLRM Memo.  Other 
recommendations, such as expanding a subject group/cohort or lowering a dose will be 
made by a majority vote. 
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 International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, subject recruitment advertisements) must be submitted to an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the investigator 
and reviewed and approved by the IRB/IEC.  A copy of the written approval of the 
protocol and ICF 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 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 protocol 
Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
During the course of the study, if new information becomes available that alters the 
benefit-risk of the study or the study drug, Amgen will follow applicable regulations to 
notify investigators, the IRB/IEC, and regulatory authorities, as appropriate. 
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 


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 
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 ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the sample ICF are to be 
communicated formally in writing from the Amgen Trial Manager to the investigator.  The 
written ICF 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 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 
obtained.  The authorized person obtaining the informed consent must also sign the ICF. 
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 


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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 ICF is to be signed and personally dated by the subject or a legally 
authorized 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 7.   
If important new information becomes available that may be relevant to the subject’s 
consent during their participation in the study, subjects will be re-consented to the most 
current version of the ICF(s) during their participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(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 
authorized representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF 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 ICF if the rescreening occurs 
within 28 days from the previous ICF signature date. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional future research.  The investigator or authorized designee will 
explain to each subject the objectives of the future research.  Subjects will be told 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 future 
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. 


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The 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 ICFs) are to be kept in 
confidence by the investigator, except as described below. 
Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, 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. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the Sponsor’s systems.  The 
Sponsor uses access-controlled systems to house, review and analyze subject data.  
These systems are backed-up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The Sponsor 
has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 
required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the Sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline. 


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Publication Policy 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be prepared in accordance with Amgen’s publications policy 
and submitted to Amgen for review.  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 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 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, or the acquisition, analysis, or interpretation of data for the work; (2) drafting the 
work 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. 


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Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
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. 
The sponsor or designee 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. 


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In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance and Audit function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Quality tolerance limit parameters (QTLs) will be predefined in the QTL definitions table 
to identify possible systematic issues that can impact participant safety and/or reliability 
of the study results.  These predefined parameters will be monitored during the study.  
Important deviations from the QTL threshold limits for these parameters and remedial 
actions taken will be summarized in the clinical study report. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case Report Forms 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 they 
have 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 Response Technology (IRT) 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 paper questionnaires 
for a clinical outcome assessment or certain demographic information, such as gender, 
race, and ethnicity). 


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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. 
Elements to include: 
 
Subject files containing completed CRFs, ICFs, 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, 
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. 
Remote Source Data Review and Verification 
If permitted by national and/or local regulations, remote Source Data Review and 
Verification (rSDR/V) can be implemented.  The clinical monitor should be provided with 
a secure, read-only access to the Electronic Medical Record (EMR) system, including all 
modules relevant for review.  This access should be restricted to the records of only 
those patients who participate in the trial and who did not object to remote access to 
their medical records.  A list of the monitors to whom remote access has been granted 
should be maintained.  In order to prevent unauthorized access, access rights should be 
revoked once rSDR/V tasks have been completed for the trial.  The EMR system should 
have an audit trail and be able to log information on who accessed data and when.  
Remote access to the EMR should only be possible using a 2 factor authentication. 


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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 a separate 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 11-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
(paper-based form) 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for males and females of childbearing 
potential are outlined in Section 5.2.  Contraceptive use and methods should be 
consistent with local regulations for subjects participating in clinical studies. 
Male and female subjects of childbearing potential should be advised of the pregnancy 
prevention requirements and the potential 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. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include documented 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  Females with 
documented permanent infertility due to an alternate medical cause (eg, Mullerian 
agenesis, androgen insensitivity, gonadal dysgenesis), can be considered not of 
childbearing potential. 
Note:  Bilateral tubal ligation/occlusion is not considered a permanent sterilization 
method. 
Note:  Documentation from the following sources is acceptable to provide confirmation of 
each sterilization method:  1) review of subject’s medical records; 2) subject’s medical 
examination; or 3) subject’s medical history interview. 
A postmenopausal female is defined as: 
 
A woman of ≥ 55 years with no menses for 12 months without an alternative 
medical cause OR 
 
A woman age < 55 years with no menses for at least 12 months and with a 
follicle-stimulating hormone (FSH) level within the definition of “postmenopausal 
range” for the laboratory involved.  In the absence of 12 months of amenorrhea, 
confirmation with more than 1 FSH measurement is required. 
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
 
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, or implantable) 
 
Intrauterine device  


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 
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 method of contraception for female subjects 
stated above (a female condom should not be used because there is a risk of tearing 
when both partners use a condom). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
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 6 months of 
protocol-required therapies. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-3).  
The form must be submitted to Amgen Global Patient Safety immediately and no 
later than 24 hours of the site’s awareness of a subject’s pregnancy.  (Note:  Sites 
are not required to provide any information on the Pregnancy Notification Form that 
violates the country or regions local privacy laws). 
 
After obtaining the female subject’s signed consent 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 6 months after 
the last dose 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. 


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 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an adverse event or serious adverse event.  
Abnormal pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal death, 
congenital anomalies) 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. 
 
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 11.4.  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 while pregnant (see Section 7.1 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 
6 months after the last dose of protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-3) must be 
submitted to Amgen Global Patient Safety immediately and no later than 24 hours 
of the site’s awareness of the pregnancy.  (Note:  Sites are not required to provide 
any information on the Pregnancy Notification Form that violates the country or 
regions local privacy laws). 
 
Males with pregnant partners or whose partners become pregnant during treatment 
and for an additional 6 months after last dose of protocol-required therapies must 
practice sexual abstinence or use a condom through 6 months after discontinuing 
protocol-required therapies. 
 
The investigator will attempt to obtain a signed consent for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed consent 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 4 months after the last dose of 
protocol-required therapies. 


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 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety immediately and no later than 24 hours 
of the investigator’s awareness of the event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 222. 
 
With the female subjects signed consent 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 4 months after the last dose of protocol-required 
therapies. 


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Figure 11-3.  Pregnancy and Lactation Notification Forms 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
When permitted by local regulations, any blood or tissue sample collected according to 
the Schedule of Activities (Section 1.3) 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.  
When permitted by local regulations and 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 the cancer, the dose response and/or prediction of 
response to bemarituzumab or docetaxel, characterize the 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 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 
blood or 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 11.3 for subject confidentiality. 


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11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin (BIL) glucuronidation (eg, 
indinavir, atazanavir) 
 
Alpha-1 antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix. 


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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 11-3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other Protocol-required 
Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product and 
other protocol-required therapies are to be permanently discontinued.  Subjects who 
clearly meet the criteria for permanent discontinuation (as described in Table 11-3) are 
never to be rechallenged. 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 


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 
The event is to be reported to Amgen as a serious adverse event immediately and 
no later than 24 hours of discovery or notification of the event (ie, before additional 
etiologic investigations have been concluded) 
 
The appropriate case report form (CRF) (eg, Events CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 11.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 11-3 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, BIL (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize, or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune 
hepatitis 
 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of: 
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 


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 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic analysis if this has not already 
been collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  
 


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11.8 
Appendix 8.  Protocol-specific Anticipated Serious Adverse Events 
Anticipated serious adverse events are events that are anticipated to occur in the study 
population at some frequency independent of investigational product exposure and do 
not need to be reported individually as a United States Food and Drug Administration 
(FDA) Investigational New Drug (IND) safety report by the sponsor.  Identification and 
reporting of anticipated serious adverse events is the responsibility of the sponsor; the 
investigator is responsible for reporting adverse events and serious adverse events as 
described in Section 8.4.6 and Section 11.4. 
Anticipated Serious Adverse Events for Study 20210102 
MedDRA Preferred Terma 
Lung cancer 
Disease progression 
a Exact Preferred Term according to Medical Dictionary for Regulatory Activities (MedDRA) Version 24 
 


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11.9 
Appendix 9.  Response Evaluation Criteria in Solid Tumors Version 
1.1 (RECIST v 1.1 Eisenhauer et al, 2009) 
11.9.1 
Definitions 
11.9.1.1 
Measurable Disease 
The presence of at least 1 measurable lesion.  If the measurable disease is restricted to 
a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
11.9.1.2 
Measurable Lesions 
11.9.1.2.1 
Measurable Non-nodal Tumor Lesions 
Non-nodal lesions with clear borders that can be accurately measured in at least 
1 dimension with longest diameter  10 mm in computed tomography (CT)/ magnetic 
resonance imaging (MRI) scan with slice thickness no greater than 5 mm.  When slice 
thickness is greater than 5 mm, the minimum size of measurable lesion should be twice 
the slice thickness. 
11.9.1.2.2 
Nodal Lesions 
Lymph nodes are to be considered measurable if  15 mm in short axis when assessed 
by CT/MRI (scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
11.9.1.2.3 
Cystic Lesions 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above for non-nodal 
lesions. 
11.9.1.2.4 
Bone lesions with identifiable soft tissue components 
Bone lesions with identifiable soft tissue components, that can be evaluated by cross 
sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described 
above for non-nodal lesions. 
11.9.1.2.5 
Clinically Measured Lesions 
Visible or palpable lesions can be considered measurable if  10 mm in longest diameter 
for non-nodal or  15 mm in shortest diameter for lymph nodes.  Lesions should be 
measured radiologically if more accurate, if not then measured by calipers. 


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11.9.1.2.6 
Irradiated Lesions 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not measurable unless there has been demonstrated 
progression that is measurable in the lesion prior to enrollment. 
11.9.1.2.7 
Non-measurable Lesions 
All other lesions, including small lesions (longest diameter  10 mm or pathological lymph 
nodes with  10 mm to  15 mm short axis with CT scan slice thickness no greater than 
5 mm) are considered non-measurable.  (When slice thickness is greater than 5 mm, the 
minimum size of measurable lesion should be twice the slice thickness). 
Other examples of lesions usually considered to be non-measurable include: 
 
Lesions with prior local treatment:  tumor lesions situated in a previously irradiated 
area, or an area subject to other loco-regional therapy, should not be considered 
measurable unless there has been demonstrated progression in the lesion. 
 
Categorically, clusters of small lesions, bone lesions without a soft tissue component, 
inflammatory breast disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis and leptomeningeal disease are non-measurable. 
11.9.2 
Methods of Measurement 
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers.  The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and throughout the trial.  
Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam.  Clinical 
lesions will be assessed using calipers (eg, skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. 
11.9.2.1 
CT/MRI 
Contrast-enhanced CT or MRI should be used to assess all lesions.  Optimal 
visualization and measurement of metastasis in solid tumors requires consistent 
administration (dose and rate) of intravenous (IV) contrast as well as timing of scanning.  
CT and MRI should be performed with 5 mm thick contiguous slices.  The longest 
diameter of selected lesions should be measured in the plane in which the images were 
acquired.  Ideally, the same scanner or at least type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.   


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11.9.2.2 
PET-CT  
At present, the low dose or attenuation correction CT portion of a combined positron 
emission tomography (PET)-CT is not always of optimal diagnostic CT quality for use 
with Response Evaluation Criteria in Solid Tumors (RECIST) measurements.  However, 
if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably 
with conventional CT in accurately measuring cancer lesions over time.  Note, however, 
that the PET portion of the CT introduces additional data which may bias an investigator 
if it is not routinely or serially performed.   
11.9.2.3 
Ultrasound  
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from 1 assessment to the next.  If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT or MRI is advised.  If there is concern about 
radiation exposure at CT, MRI may be used instead of CT in selected instances. 
11.9.2.4 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised.  
However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
11.9.2.5 
Tumor markers  
Tumor markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize in a subject with a radiological CR for a 
subject to be considered a CR. 
11.9.2.6 
Cytology, Histology  
These techniques can be used to differentiate between partial response (PR) and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain).  
When effusions are known to be a potential adverse effect of treatment (eg, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 


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neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in 
order to differentiate between response (or stable disease) and progressive 
disease (PD). 
11.9.2.7 
FDG-PET  
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible 'new' disease).  New 
lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm:  
 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.   
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image. 
11.9.3 
Lesion Evaluation 
11.9.3.1 
Baseline documentation of “Target” and “Non-target” lesions 
11.9.3.1.1 
Target Lesions  
 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. 
 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and suitability for accurate repeated measurements.  All other measurable 
lesions will be followed as non-target lesions. 
 
Lymph nodes are considered 1 organ, thus a maximum of 2 measurable lymph 
nodes may be identified as target lesions.  
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum of 
diameters.  The baseline sum of diameters will be used as reference by which to 
characterize objective tumor response. 


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CONFIDENTIAL  
 
 
11.9.3.1.2 
Non-Target Lesions  
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should be recorded at baseline.  These lesions 
should be followed as “present,” “absent,” “unequivocal progression,” or “not evaluable” 
throughout the study.  In addition, it is possible to record multiple non-target lesions 
involving the same organ as a single item on the case report form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). 
11.9.4 
Response Criteria 
Table 11-4.  Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target non-nodal lesions.  Any target 
lymph node must have reduction in short axis to  10 mm, 
NOT total disappearance. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum of 
diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm.  If a subject is missing lesion data at a disease 
assessment and yet progressive disease criteria is met 
despite the missing data, the subject will be classified as 
PD.  
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD 
Not Evaluable (NE) 
When inadequate or no imaging/measurement is done at a 
particular time point, the subject’s response is not 
evaluable (NE) at that time point.  
 
 


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Table 11-5.  Evaluation of Non-target Lesions 
Complete Response (CR): 
Disappearance of all non-nodal non-target lesions and 
normalization of tumor marker level.  All non-target lymph 
nodes must be non-pathological in size ( 10 mm short 
axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesions(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesionsa.  If 
a subject is missing lesion data at a disease assessment 
and yet unequivocal progression is met despite the missing 
data, the subject will be classified as PD. 
Not Evaluable (NE) 
When inadequate or no imaging is done at a particular time 
point, the subject’s response is not evaluable (NE) at that 
time point.  
SD = Stable Disease; PR = partial response. 
a To achieve “unequivocal progression” on the basis of the non-target disease, there must be an overall level 
of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, 
the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. 
11.9.5 
Evaluation of Best Overall Response 
The subject's best response assignment will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions.  
Best overall response (BOR) will be based on all post-baseline disease assessments 
that occur prior to the initiation of subsequent anticancer treatment.  At least 5 weeks 
from the first dose of investigational product must elapse without radiological disease 
progression to meet the minimum criteria for stable disease (SD) duration in order to 
assign a BOR of SD.  In general, subjects not classifiable under the RECIST v1.1 
response categories due to inadequate data or early death will be classified as non 
evaluable (NE) for BOR but will be counted in the denominator of all response rate 
calculations.  


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Table 11-6.  Time Point Overall Response 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 
Subjects with Target ( Non-target) Disease 
CR 
CR or NA 
No 
CR 
CR 
Non-CR/non-PD or NE 
No 
PR 
 
 
 
 
PR 
CR or Non-CR/Non-PD 
or NE or NA 
No 
PR 
SD 
CR or Non-CR/Non-PD 
or NE or NA 
No 
SD 
 
 
 
 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
NE 
CR or Non-CR/Non-PD 
or NE or NA 
No 
NE 
Subjects with Non-target Disease Only 
NA 
CR 
No 
CR 
NA 
Non-CR/Non-PD 
No 
SD (Non-CR/Non-
PD)a 
NA 
CR or Non-CR/Non-PD 
NE 
SD (Non-CR/Non-
PD)a 
NA 
PD 
Any 
PD 
NA 
Any 
Yes 
PD 
NA 
NE 
No 
NE 
CR = complete response; PD = progressive disease; PR = partial response; NA = not applicable; NE = Not 
evaluable; SD = stable disease. 
a Per RECIST v1.1, “SD (Non-CR/Non-PD)” is preferred over “SD” for Non-Target disease since SD is 
increasingly used as endpoint for assessment of efﬁcacy in some trials so to assign this category when no 
lesions can be measured is not advised. 
 


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Table 11-7.  Best Overall Response When Confirmation of Complete Response 
(CR) and Partial Response (PR) Required 
Overall Response First 
Time Point 
Overall Response 
Second Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
CR = complete response; PD = progressive disease; PR = partial response; NE = Not evaluable; 
SD = stable disease. 
a If a CR is truly met at first time point, then any disease at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared 
after CR).  Best response would depend on whether minimum duration for SD was met.  However, 
sometimes “CR” may be claimed when subsequent scans suggest small lesions were likely still present 
and in fact that subject had PR, not CR at the first time point.  Under these circumstances, the original CR 
should be changed to PR and the best response is PR. 
11.9.6 
Special Notes on Response Assessment 
 
Target lesions that become “too small to measure” - While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their measurements recorded at 
each subsequent evaluation, even when very small (eg, 2 mm).  However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being ‘too small to measure’.  When this 
occurs, it is important that a value be recorded on the case report form.  If it is the 
opinion of the radiologist that the non-lymph node lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such 
as in the retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned in 
this circumstance as well).  This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially non-reproducible, therefore providing this 
default value will prevent false responses or progressions based upon measurement 


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CONFIDENTIAL  
 
 
error.  To reiterate, however, if the radiologist is able to provide an accurate 
measure, that should be recorded, even if it is below 5 mm. 
 
New lesions - The term “new lesion” always refers to the presence of a new finding 
that is definitely tumor.  If a new lesion is identified via a modality other than CT or 
MRI, CT or MRI confirmation is recommended unless the new lesion is deemed 
unequivocally tumor.  New findings that are not definitively tumor but may be benign 
(infection, inflammation, etc.) are not selected as new lesions, until that time when 
the review is certain they represent tumor.   
 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease.  If 
additional imaging confirms there is definitely a new lesion, then progression 
should be declared using the date of the initial scan. 
 
A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease 
progression, regardless of any response that may be seen in target or non-target 
lesions present from baseline. 
 
Any locoregional therapy not allowed per protocol 
 
Any subject receiving locoregional therapy not allowed in the protocol while on 
study that directly affects one or more of the target lesions selected at baseline 
will be considered to be non-evaluable at all disease assessments that occur on 
or after the date of locoregional therapy with the exception of disease 
progression.  However, if a lesion was completely resected where pathology was 
benign the subject will still be evaluable for response with 0 dimension reported.  
 
If locoregional therapy was performed on a non-target lesion, that lesion will 
always be assessed as present unless pathology was benign.  
 
Lesions that split or coalesce on treatment - When non-nodal lesions "fragment," the 
longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum and identified as a fragment of the original lesion.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions 
have truly coalesced such that they are no longer separable, the vector of the 
longest diameter in this instance should be the maximal longest diameter for the 
"coalesced lesion". 
 
 “Symptomatic deterioration” alone does not qualify as objective progression.  If 
objective progression was not previously documented, then every effort should be 
made to document objective progression even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish residual disease from scar or 
normal tissue.  When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be further investigated by fine needle 
aspirate/biopsy or FDG-PET, to confirm the CR status.  
 
If a lesion disappears and reappears at a subsequent timepoint it should continue to 
be measured.  However, the patient’s response at the point in time when the lesion 
reappears will depend upon the status of his/her other lesions.  For example, if the 
patient’s tumor had reached a CR status and the lesion reappeared, then the patient 
would be considered PD at the time of reappearance.  In contrast, if the tumor status 
was a PR or SD and 1 lesion which had disappeared then reappears, its maximal 
diameter should be added to the sum of the remaining lesions for a calculated 
response:  in other words, the reappearance of an apparently ‘disappeared’ single 


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lesion amongst many which remain is not in itself enough to qualify for PD:  that 
requires the sum of all lesions to meet the PD criteria. 








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11.12 
Appendix 12.  LogMAR Conversion Table for Visual Acuity* 
Snellen Notation 
Decimal 
Notation (eg, 
Landolt C or Han 
Chun Suk) 
Visual Angle 
Notation 
(min of arc) 
LogMAR 
20 ft 
6 m 
5 m 
4 m 
20/10 
6/3 
5/2.5 
4/2 
2.00 
0.50 
-0.30 
20/15 
6/4.5 
5/3.75 
4/3 
1.33 
0.75 
-0.12 
20/20 
6/6 
5/5 
4/4 
1.00 
1.00 
0.00 
20/25 
6/7.5 
5/6.25 
4/5 
0.80 
1.25 
+0.10 
20/30 
6/9 
5/7.5 
4/6 
0.67 
1.50 
+0.18 
20/40 
6/12 
5/10 
4/8 
0.50 
2.00 
+0.30 
20/50 
6/15 
5/12.5 
4/10 
0.40 
2.50 
+0.40 
20/70 
6/21 
5/17.5 
4/14 
0.29 
3.50 
+0.54 
20/100 
6/30 
5/25 
4/20 
0.20 
5.00 
+0.70 
20/200 
6/60 
5/50 
4/40 
0.10 
10.00 
+1.00 
20/400 
6/120 
5/100 
4/80 
0.05 
20.00 
+1.30 
20/800 
6/240 
5/200 
4/160 
0.03 
40.00 
+1.60 
*Visual acuity must be tested with the patient’s prescribed lenses, as applicable. If the precise visual acuity 
result is not depicted on this table, please choose the closest value. If the result is equidistant between two 
values on this table, please choose the worse visual acuity line. For example, if the visual acuity using 
Landolt C is 0.90 (decimal notation), this is halfway between Snellen 20/20 (1.00 in decimal notation) and 
20/25 (0.80 in decimal notation), and therefore the examiner would select 20/25, with corresponding 
logMAR of +0.10. 
Source:  https://www.aao.org/bcscsnippetdetail.aspx?id=3550b1ca-1740-4e7f-8712-70905c99eb26 




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uncontrolled hypertension (defined 
as an average systolic blood 
pressure  160 mmHg or diastolic 
 100 mm Hg despite optimal 
treatment, uncontrolled cardiac 
arrythmias requiring 
anti-arrhythmic therapy other than 
beta blockers or digoxin, active 
coronary artery disease, 
Fridericia’s correction formula 
(QTc)  470.  
diastolic 100 mm Hg despite optimal 
treatment, uncontrolled cardiac 
arrythmias requiring anti-arrhythmic 
therapy other than beta blockers or 
digoxin, active coronary artery disease, 
Fridericia’s correction formula for 
men, subjects with corrected QT 
interval (QTc)  450 will be excluded; 
whereas for women, subjects 
with QTc  470 will be excluded.  
Section:  5.2, 
Exclusion 
Criteria, 
Prior/Concomitant 
Therapy, 
Criterion 217 
 
Any anticancer therapy or 
immunotherapy within 4 weeks 
prior to enrollment; 
 
Palliative radiotherapy is 
allowed, provided it has 
been completed more than 
14 days prior to the first 
dose of study treatment 
 
All treatment-related toxicity 
needs to be resolved to 
grade  1 prior the first dose 
of study treatment, with 
exception of alopecia or 
toxicities considered 
irreversible (defined as 
having been present and 
stable  21 days) which are 
not otherwise described in 
the exclusion criteria 
 
Exception for Part 2 and 4 
expansion only:  subjects 
can receive 1 dose of each 
non-investigational 
anticancer therap(ies) in the 
respective study part, if 
initiation of treatment is 
deemed urgent by the 
investigator 
Replaced: 
Any anticancer therapy or 
immunotherapy within 4 weeks prior to 
enrollment; 
 
Palliative radiotherapy is allowed, 
provided it has been completed 
more than 14 days prior to the first 
dose of study treatment 
 
The maximal grade 
for irreversible toxicities to be 
considered for participation is 
grade 3.  All subjects with 
grade 2 or 3 toxicities from prior 
anti-cancer therapy that are 
considered irreversible (defined as 
having been present and stable for 
 5 months) may be allowed if 
not otherwise described in the 
exclusion criteria, and if there is 
an agreement to allow 
participation of those subjects 
by both the investigator and the 
sponsor. 
 
Exception for Part 2 and 4 
expansion only:  subjects can 
receive 1 dose of each 
non-investigational anticancer 
therap(ies) in the respective study 
part, if initiation of treatment is 
deemed urgent by the investigator 
Section:  6.2.1.  
Dose Cohort 
Study 
Escalation/De-
escalation and 
Stopping Rules, 
Enrollment 
Stopping Rules 
 
 
At any point during the 
study, throughout Parts 1, 2, 
3, and 4, enrollment will be 
paused at the occurrence of 
2 or more grade 4 or one or 
more grade 5 adverse 
events unless the events are 
clearly attributed to causes 
other than bemarituzumab.  
If limited information is 
available at the time the 
Replaced: 
At any point during the study, throughout 
Parts 1, 2, 3, and 4, enrollment will be 
paused at the occurrence of 2 or more 
grade 4 or one or more grade5 adverse 
events unless the events are clearly 
attributed to causes other than the 
investigational intervention of 
bemarituzumab alone or 
bemarituzumab in combination with 
other anti-cancer therapies.  If limited 


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investigator reports the 
event to the sponsor, 
enrollment may continue 
while the sponsor collects 
additional information about 
the grade 4 or 5 event to 
determine the underlying 
cause.  The DLRT will be 
reconvened to review the 
safety data and determine 
appropriate next steps that 
may include, but not be 
limited to, informing 
investigators and IRBs/IECs, 
implementing safety/toxicity 
management, informing 
health authorities, voluntarily 
putting the clinical trial on 
hold, or proceeding with 
enrollment. 
information is available at the time the 
investigator reports the event to the 
sponsor, enrollment may continue while 
the sponsor collects additional 
information about the grade 4 or 5 event 
to determine the underlying cause.  The 
DLRT will be reconvened to review the 
safety data and determine appropriate 
next steps that may include, but not be 
limited to, informing investigators and 
IRBs/IECs, implementing safety/toxicity 
management, informing health 
authorities, voluntarily putting the clinical 
trial on hold, or proceeding with 
enrollment. 
Events commonly associated with 
non-investigational therapy (see 
below for examples) or progression 
of underlying disease and 
investigator assessed as not possibly 
related to bemarituzumab will not 
count towards enrolment stopping 
rules. 
Examples of events commonly 
associated with non-investigational 
therapies in this study: 
 
In Parts 1 and 2, events 
commonly associated with 
docetaxel: hematologic toxicity 
(neutropenia, anemia, 
thrombocytopenia), severe fluid 
retention, enterocolitis, 
peripheral neuropathy. 
 
In Part 4, events commonly 
associated with the combination 
of pembrolizumab, carboplatin, 
and nab-paclitaxel/paclitaxel: 
hematologic toxicity 
(neutropenia, anemia, 
thrombocytopenia) and immune 
related adverse events 
(pneumonitis, colitis, nephritis, 
endocrinopathies). 
Section:  6.7.2, 
Concomitant 
Treatment, 
Paragraph 5 
(new) 
 
Not applicable. 
Added: 
Investigators should refer to the local 
prescribing information (in particular 
contraindications, warnings and 
precautions) of any protocol-required 
therapies when considering the use 
of concomitant medication (eg, for 
carboplatin caution should be used 
when considering concomitant 
phenytoin, fosphenytoin, loop 


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diuretics, and other potentially 
nephrotoxic or ototoxic drugs). 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, 
and Efficacy of Bemarituzumab Monotherapy and Combination with other Anti-Cancer 
Therapy in Subjects with Squamous-Cell Non-Small-Cell Lung Cancer (FORTITUDE-201) 
Amgen Protocol Number (Bemarituzumab [AMG 552]) 20210102 
EudraCT/EU CT number:  2021-004058-47/2023-505456-22 
NCT number:  NCT05267470 
 
Amendment Date: 
27 April 2023 
 
Rationale: 
Protocol is being amended to update EU CT number and include the European Economic Area 
(EEA) country specific supplements within the protocol appendices. The country specific 
supplements contain specific changes previously approved and apply only to subjects in the 
specified EEA country. 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Superseding Amendment 2 
Protocol Title:  Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Bemarituzumab Monotherapy and Combination 
with other Anti-Cancer Therapy in Subjects with Squamous-Cell Non-Small-Cell 
Lung Cancer (FORTITUDE-201) 
 
Amgen Protocol Number:  20210102 
EudraCT Number:  2021-004058-47 
NCT Number:  NCT05267470 
Amendment Date: 
28 October 2022 
 
Rationale: 
A superseding version of the protocol amendment 2 (PA2) was created to address 
typographical and orthographical errors that have been identified throughout the PA2 
document: 
 
Updated criterion 232 in exclusion criteria section (Section 5.2) to correct 
immunosuppressive doses of systemic medications to more than (>)10 mg/day, 
rather than less than (<)10 mg/day. 
 
Corrected Q3W definition in schedule of activities (Section 1.3) Table 1-3 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Bemarituzumab Monotherapy and Combination 
with Other Anti-Cancer Therapy in Subjects with Squamous-Cell Non-Small-Cell 
Lung Cancer (FORTITUDE-201) 
 
Amgen Protocol Number:  20210102 
EudraCT Number:  2021-004058-47 
NCT Number:  NCT05267470 
Amendment Date: 
27 September 2022 
 
Rationale: 
The key driver for this amendment is addition of the preliminary safety data from Part 1 
of this study supporting further exploration of the combination of bemarituzumab with 
docetaxel in later lines of therapy and addition of the new part of the study, Part 4, 
exploring bemarituzumab in combination with double platinum-based chemotherapy and 
programmed death-ligand 1(PD-L1) inhibitor in first-line.  Additionally, updates were 
incorporated that originated from a program wide update to align this protocol with other 
bemarituzumab protocols, where applicable.  Based on this, the key revisions 
incorporated in the amendment are listed below, and a complete list of changes can be 
found in later section of this summary of change document:  
 
Updated overall design section of the protocol and other applicable protocol sections 
to reflect the addition of Part 4 of the study evaluating bemarituzumab in combination 
with carboplatin, paclitaxel or nab paclitaxel, and pembrolizumab in subjects with 
previously untreated metastatic or locally advanced squamous non-small-cell lung 
cancer (SqNSCLC), with consequential changes to the study schema.   
 
Updated study rationale and other applicable sections of the protocol to reflect 
information regarding bemarituzumab in combination with anti-cancer therapies.   
 
Updated number of subjects to be enrolled in the study from 108 to 180 with the 
addition of Part 4. 
 
Updated background information about bemarituzumab to provide most recent 
results of Study FPA144-004.  
 
Updated Benefit/Risk Assessment to reflect preliminary safety data from Part 1 
supporting further exploration of bemarituzumab in combination with docetaxel at the 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
dose level 2 and to add a rationale supporting exploration of bemarituzumab 
combination with doublet platinum-based chemotherapy and PD-L1 inhibitor in 
first-line. 
 
Protocol language has been aligned, where applicable, to other ongoing 
bemarituzumab protocol amendments, to ensure consistency regarding applicable 
requirements.  Updates to the protocol template have also been reflected in this 
amendment to ensure compliance with current regulatory requirements. 
 
Administration, typographical, and formatting changes were made throughout the 
protocol.  
 


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Page 1 of 99 
 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
Amendment 1 
Protocol Title:  A Phase 1b Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Bemarituzumab Monotherapy and Combination 
with Docetaxel in Subjects with Squamous-Cell Non-Small-Cell Lung Cancer 
(FORTITUDE-201) 
 
Amgen Protocol Number Bemarituzumab 20210102 
 
Amendment Date: 
02 March 2022 
Rationale: 
This protocol is being amended to implement changes requested by regulatory/health 
authorities; and to include globally applicable changes from the French country-specific 
supplement (CSS), program level, and other Bema study level updates.  Language is 
being included throughout to update/clarify the protocol.  Changes including, but not 
limited to, the following were incorporated into the protocol:   
 
Updated the schedule of assessments (SoA) to specify the time at which 
pharmacokinetic (PK) samples are to be collected for Part 1 and 2 combinational 
therapies; to include inform consent language for screening of Part 1 only; to add 
language on reporting of during long-term follow-up (LTFU); to clarify that total 
cholesterol levels for the chemistry panel are required only at screening; to clarify the 
times pharmacokinetic samples are to be collected for Part 1 and 2 combination 
therapy; Additional updates to the archival tissue/fresh biopsy, vital assessments, 
and computerized tomography (CT)/Magnetic resonance imaging (MRI) sections in 
the SoA were also made.   
 
Updated language regarding tumor biopsy assessments, safety follow-up, and ocular 
toxicity grading scale in respective sections 
 
Updated dose-limiting toxicity (DLT) definition to specify that DLTs should be 
considered possibly related to study drug and not concomitant chemotherapy and 
disease progression or intercurrent illness  
 
Updated the dose modification and enrollment stopping rules 
 
Updated inform consent language regarding the screening process for Part 1  


Product:  Bemarituzumab (AMG 552) 
Protocol Number:  20210102 
Date:  02 March 2022 
Page 2 of 99 
 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
 
Updated serious adverse events language to clarify that all serious adverse events 
related to the investigational product need to be recorded during LTFU and reported 
to Amgen 
 
Updated both inclusion and exclusion eligibility criteria sections  
 
Updated pregnancy testing language to clarify that repeat pregnancy test are 
required 28 (+3) days after discontinuing protocol-required therapies, and monthly 
(28 [ 3] days) pregnancy testing up to and inclusive 75 (+3) days from the last 
bemarituzumab dose 
 
Updated safety assessment sections to modify vital sign and ophthalmologic 
examination language  
 
Updated efficacy assessment section to remove reference to imaging manual 
 
Added new pharmacogenetic assessment section (section 8.6) 
 
Biomarker language was updated throughout various sections   
 
Administrative and editorial changes have been made throughout the protocol for 
clarification

SAP_001.pdf: 
Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 1 of 39 
CONFIDENTIAL  
 
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 1b Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of 
Bemarituzumab Monotherapy and Combination with 
other Anti-Cancer Therapy in Subjects with 
Squamous-Cell Non-Small-Cell Lung Cancer 
(FORTITUDE-201) 
Short Protocol Title: 
A phase 1b study of bemarituzumab monotherapy 
and combination with other anti-cancer therapy in 
SqNSCLC with FGFR2b overexpression 
(FORTITUDE-201) 
Protocol Number: 
20210102 
NCT Number: 
NCT05267470 
Authors: 
 – Study Statistician, Parexel  
 – Study Statistician, Parexel  
 – Biostatistics Senior Manager, GBS, 
Amgen Inc. 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA, 91320 
SAP Date: 
Document Version 
Date 
Amendment 1 (V2.0)  
25 June 2024 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
10MAR2023 
The first version of a document. 
Amendment 1 (V2.0) 
25JUN2024 
1) Removed subgroups as no 
planned subgroup analysis. 
2) Updated the definition of study 
day 1 for not dosed subjects. 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 2 of 39 
CONFIDENTIAL  
 
 
 
3) Updated definitions of duration 
of treatment, actual dose 
intensity, average dose per 
cycle and relative dose intensity  
4) Updated the definition of TEAE 
for events related to lung 
cancer or disease progression. 
5) Updated Demographic and 
Baseline Characteristics. 
6) Changes in requirement of 
various lab shift and summary 
tables. 
7) Added parameters in vital signs 
8) Added language for ECG in part 
4 and updated summary 
language for part 3.  
9) Updated Analytical Windows 
Appendix. 
10) Removed Appendix C. 
 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 3 of 39 
CONFIDENTIAL  
 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 3 
1. 
Introduction ............................................................................................................. 9 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 9 
2.1 
Objectives and Endpoints/Estimands .......................................................... 9 
2.2 
Hypotheses and/or Estimations ................................................................. 10 
3. 
Study Overview .................................................................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.2 
Sample Size .............................................................................................. 14 
3.3 
Adaptive Design ........................................................................................ 14 
4. 
Covariates and Subgroups ................................................................................... 14 
4.1 
Planned Covariates ................................................................................... 14 
4.2 
Subgroups ................................................................................................. 14 
5. 
Definitions ............................................................................................................. 14 
6. 
Analysis Sets ........................................................................................................ 23 
6.1 
Enrolled Analysis Set ................................................................................ 23 
6.2 
Safety Analysis Set ................................................................................... 23 
6.3 
DLT Analysis Set ....................................................................................... 23 
6.4 
Pharmacokinetic Analyses Set .................................................................. 23 
6.5 
Interim Analyses Set(s) ............................................................................. 23 
6.6 
Study-specific Analysis Sets...................................................................... 23 
7. 
Planned Analyses ................................................................................................. 23 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 23 
7.2 
Primary Analysis ....................................................................................... 24 
7.3 
Final Analysis ............................................................................................ 24 
8. 
Data Screening and Acceptance ........................................................................... 24 
8.1 
General Principles ..................................................................................... 24 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 24 
8.3 
Handling of Missing and Incomplete Data ................................................. 24 
8.4 
Detection of Bias ....................................................................................... 25 
8.5 
Outliers ..................................................................................................... 25 
8.6 
Distributional Characteristics ..................................................................... 25 
8.7 
Validation of Statistical Analyses ............................................................... 25 
9. 
Statistical Methods of Analysis.............................................................................. 25 
9.1 
General Considerations ............................................................................. 25 
9.2 
Subject Accountability ............................................................................... 26 
9.3 
Important Protocol Deviations ................................................................... 26 
9.4 
Demographic and Baseline Characteristics ............................................... 26 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 4 of 39 
CONFIDENTIAL  
 
 
 
9.5 
Efficacy Analyses ...................................................................................... 29 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 29 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 29 
9.6 
Safety Analyses ........................................................................................ 29 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 29 
9.6.2 
Adverse Events ......................................................................... 29 
9.6.3 
 Ophthalmologic Exam Results .................................................. 30 
9.6.4 
Laboratory Test Results ............................................................ 30 
9.6.5 
Vital Signs ................................................................................. 31 
9.6.6 
Physical Measurements ............................................................ 31 
9.6.7 
Electrocardiogram ..................................................................... 31 
9.6.8 
Antibody Formation ................................................................... 31 
9.6.9 
Exposure to Investigational Product .......................................... 31 
9.6.10 
Exposure to Non-investigational Product ................................... 32 
9.6.11 
Exposure to Concomitant Medication ........................................ 32 
9.7 
Other Analyses ......................................................................................... 32 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 33 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 33 
9.7.3 
Analyses of Health Economic Endpoints ................................... 33 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 33 
9.7.5 
Analysis of COVID-19 Impact .................................................... 33 
10. 
Changes From Protocol-specified Analyses.......................................................... 34 
11. 
Literature Citations / References ........................................................................... 34 
12. 
Prioritization of Analyses....................................................................................... 35 
13. 
Data Not Covered by This Plan............................................................................. 35 
14. 
Appendices ........................................................................................................... 36 
Appendix A Handling of Date, Incomplete Date and Missing Dates ...................... 36 
Appendix B.  Analytical Windows .......................................................................... 38 
 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 5 of 39 
CONFIDENTIAL  
 
 
 
List of Tables 
No table of figures entries found. 
List of Figures 
No table of figures entries found. 
 
 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 6 of 39 
CONFIDENTIAL  
 
 
 
List of Abbreviations 
 
Abbreviation 
Explanation 
AE 
ALT 
Adverse Event 
Alanine Aminotransferase 
APTT 
Activated Partial Thromboplastin Clotting Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Concentration Time Curve 
BOR 
Best Overall Response 
BSA 
CBD 
Body Surface Area 
Clinical Biomarkers and Diagnostics 
CI 
Confidence Interval 
Cmax 
CPMS 
Maximum Observed Concentration 
Clinical Pharmacology, Modeling and Simulation 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
DC 
DCR 
DCO 
DILI 
Observed Concentration at the End of a Dose Interval 
Disease Control 
Disease Control Rate 
Data Cutoff 
Drug Induced Liver Injury 
DLT 
Dose Limiting Toxicity 
DLRM 
Dose Level Review Meeting 
DLRT 
DOR 
Dose Level Review Team 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
EOI(s) 
EOS 
Electronic Case Report Form 
Event(s) of Interest 
End of Study 
EU 
European Union 
FDA 
Food and Drug Administration 
FGFR2b 
Fibroblast Growth Factor Receptor Isoform 2b 
GFR 
Glomerular filtration rate 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 7 of 39 
CONFIDENTIAL  
 
 
 
GSO-DM 
IHC 
Global Study Operations-Data Management 
Immunohistochemistry 
INR 
IP 
IPD 
International Normalized Ratio 
Investigational Product 
Important Protocol Deviation 
IV 
Intravenous 
KM 
Kaplan-Maier 
LTFU 
Long-Term Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
mTPI 
NCI 
NE 
Non-IP 
Modified Toxicity Probability Interval Method 
National Cancer Institute 
Not Evaluable 
Non-Investigational Product 
NSCLC 
OR 
Non-Small Cell Lung Cancer 
Objective Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Prothrombin time 
Q2W 
Every 2 Weeks 
Q3W 
Every 3 Weeks 
QTc 
Corrected QT Interval 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
ROW 
Rest of World 
RP3D 
Recommended Phase 3 Dose 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SFU 
Safety Follow-Up 
SqNSCLC 
SSAP 
TEAE 
TPS 
Squamous Non-Small Cell Lung Cancer 
Supplemental Statistical Analysis Plan 
Treatment Emergent Adverse Event 
Tumor Proportion Score 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 8 of 39 
CONFIDENTIAL  
 
 
 
 
US 
WHO DRUG 
 
United States 
World Health Organization Drug Dictionary 
 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 9 of 39 
CONFIDENTIAL  
 
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20210102, 
Bemarituzumab (AMG 552) dated 27 April 2023.  The scope of this plan includes the 
interim analysis in the form of Dose Level Review Meeting (DLRMs), the primary 
analysis and the final that are planned and will be executed by the Amgen Global 
Biostatistical Science department unless otherwise specified.  Pharmacokinetic (PK), 
pharmacodynamic, and biomarker analyses will be performed by Clinical Pharmacology, 
Modeling and Simulation (CPMS) or the Clinical Biomarkers & Diagnostics (CBD) group. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and 
tolerability of bemarituzumab 
monotherapy and combination 
with other anti-cancer therapies  
 
To determine the recommended 
phase 3 dose of bemarituzumab in 
combination with other anti-cancer 
therapies 
 
Dose-limiting toxicities (DLTs), 
treatment-emergent adverse 
events, and clinically significant 
changes in vital signs, physical 
examinations, clinical laboratory 
tests, and visual acuity 
Secondary 
 
To characterize the 
pharmacokinetics (PK) of 
bemarituzumab monotherapy and 
in combination with other anti-
cancer therapies  
 
 
PK parameters for bemarituzumab 
including, but not limited to, area 
under the concentration time 
curve (AUC), maximum observed 
concentration (Cmax), and 
observed concentration at the end 
of a dose interval (Ctrough) 
 
To evaluate preliminary anti-tumor 
activity of bemarituzumab 
monotherapy and in combination 
with other anti-cancer therapies 
 
Objective response [defined as 
complete response (CR)  partial 
response (PR)] as determined by 
investigator per Response 
Evaluation Criteria in Solid 
Tumors version 1.1 [RECIST v1.1] 
 
Duration of response, defined as 
the time from first response to 
disease progression (as 
determined by investigator per 
RECIST v1.1) or death from any 
cause, whichever comes first 




Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 11 of 39 
CONFIDENTIAL  
 
 
 
The study consists of a pre-screening period to collect tissue for FGFR2b testing (Parts 
2, 3, and 4 only), a 28-day screening period, a treatment period, a safety follow-up (SFU) 
visit, and a long-term follow-up (LTFU) period.  Subjects who discontinue 
bemarituzumab will undergo SFU approximately 28 (+3) days after the last dose of study 
treatment.  In addition, subjects will undergo LTFU for survival approximately every 3 
months (± 1 month) for up to 2 years from the first dose of bemarituzumab.  Subjects will 
receive study treatment with bemarituzumab until disease progression, unacceptable 
toxicity, subject request, or death (whichever occurs first). 
Radiographic assessments will be performed by the investigator according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 and will be performed every 6 weeks 
(Q6W) (± 7 days) until week 54 and then every 12 weeks (± 14 days).  After 
discontinuation of study treatment for reasons other than radiographic disease 
progression or withdrawal of consent, tumor assessments will continue until radiographic 
progression or initiation of additional anticancer therapy. 
The study consists of 4 Parts: 
 
Part 1:  Combination dose exploration with docetaxel 
 
Part 2:  Combination dose expansion with docetaxel 
 
Part 3:  Monotherapy 
 
Part 4: Combination with carboplatin, paclitaxel or nab-paclitaxel, and 
pembrolizumab 
Part 1 
Part 1 of the study will explore the dosing of bemarituzumab in combination with 
docetaxel.  During dose exploration, subjects will be enrolled in groups of 3 to 6 dose 
limiting toxicity (DLT) evaluable subjects per cohort, and escalation will be guided 
primarily by safety responses to different doses. 
The planned dose levels are: 
 
Dose Level 1:  bemarituzumab 22 mg/kg IV cycle 1 day 1 followed by 15 mg/kg IV 
day 22 and Q3W thereafter 
 
Dose Level 2:  bemarituzumab 30 mg/kg IV cycle 1 day 1 followed by 22 mg/kg IV 
day 22 and Q3W thereafter 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 12 of 39 
CONFIDENTIAL  
 
 
 
An additional Dose Level 1a of bemarituzumab 15 mg/kg IV Q3W plus 1 additional 
7.5 mg/kg dose on cycle 1 day 8 only may be explored if dose de-escalation is required 
from Dose Level 1.   
At each dose level, and on each planned dosing day, docetaxel will be administered at 
75 mg/m2 IV Q3W (or 60 mg/m2 IV Q3W for subjects from sites in Japan). 
Part 1 will begin with Dose Level 1.  The study DLT period is 21 days following the first 
dose.  Once 3 to 6 subjects enrolled at a certain dose level are followed for safety for 
21 days, a Dose Level Review Team (DLRT) meeting will be convened. 
The mTPI-2 escalation/de-escalation guideline for each dose cohort is derived with a 
target toxicity probability of 0.30, acceptable toxicity probability interval of (0.25, 0.33).  A 
dose level will be considered unsafe, with no additional subjects enrolled at that dose 
level, if it has an estimated 95% or more probability of exceeding the target DLT (i.e., the 
elimination boundary). 
Dose exploration will continue until: 
 
a maximum of 18 subjects in Part 1 is reached; or 
 
9 subjects have been treated a specific dose level; or 
 
the lowest dose level exceeds the elimination boundary 
Part 2 
Once a dose level has been declared safe by the DLRT, a dose level can enter Part 2 of 
the study.  Part 2 enrollment will be limited to subjects with prospectively identified 
FGFR2b overexpression status.  A minimum of 10 response-evaluable subjects and a 
maximum of 30 response-evaluable subjects will be treated per dose level in Part 2 to 
better understand the safety profile and preliminary efficacy of the combination and to 
enable selection of recommended phase 3 dose (RP3D).  Up to 2 dose levels consisting 
of 10 to 30 subjects each can be expanded in Part 2 of the study.  For Part 2, subjects 
can receive 1 dose of docetaxel during pre-screening or screening if initiation of 
treatment is deemed urgent by the investigator. 
Part 3 
Part 3 of the study will explore bemarituzumab monotherapy at the dose of 15 mg/kg IV 
Q2W plus 1 additional 7.5 mg/kg dose on cycle 1 day 8.  One cycle of treatment will 
consist of 14 days.  Part 3 enrollment will be limited to subjects with prospectively 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 13 of 39 
CONFIDENTIAL  
 
 
 
identified tumor FGFR2b overexpression status.  A minimum of 10 response-evaluable 
subjects and a maximum of 30 response-evaluable subjects will be treated in Part 3 to 
better understand the safety profile, PK, and preliminary efficacy of monotherapy 
bemarituzumab in FGFR2b+ SqNSCLC.  Part 3 may enroll subjects concurrently with 
Parts 1 and 2 and 4. 
Part 4 
Once a dose level has been declared safe by the DLRT for Part 1, a dose level can 
enter the Part 4 safety run-in.  During the safety run-in, 6 subjects will be evaluated with 
a 21-day DLT period and once the dose has been declared safe in the first-line setting 
with immune-chemotherapy combination, then Part 4 enrollment can proceed with dose 
expansion.  Dose de-escalation may occur in Part 4, independently of the 
recommendation in Part 1.  Part 4 enrollment will be limited to subject with prospectively 
identified FGFR2b overexpression status.  A minimum of 10 subjects and a maximum of 
30 subjects, including the 6 subjects in the safety run-in, will be treated in Part 4 to better 
understand the safety profile and preliminary efficacy of the combination and to enable 
the selection of the RP3D.  Up to 2 dose levels consisting of 10 to 30 subjects can be 
expanded in Part 4 of the study.  Subjects will receive up to 4 cycles of bemarituzumab, 
pembrolizumab, and chemotherapy followed by bemarituzumab and pembrolizumab 
maintenance.  In addition to bemarituzumab administered on day 1 of every 21-day 
treatment cycle, subject will be administered pembrolizumab 200mg day 1 for up to 35 
cycles and, for the first four cycles only, the combination of carboplatin 6mg/mL/min and 
either paclitaxel 200 mg/m2 on day 1 or nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. 
For Part 4 expansion (and not in safety run-in), subjects can receive 1 dose of 
carboplatin and paclitaxel or nab-paclitaxel with or without pembrolizumab during pre-
screening or screening if initiation of treatment is deemed urgent by the investigator. 
This bridging dose is not a requirement of the study and is not considered part of the 
clinical study.  
For Part 4 only, subjects may continue treatment beyond initial RECIST v1.1 progressive 
disease (PD), as assessed by the investigator, as long as they meet the following 
criteria: 
 
Investigator assessed clinical benefit  
 
Tolerance of study drug  
 
Stable Eastern Cooperative Oncology Group (ECOG) performance status 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 14 of 39 
CONFIDENTIAL  
 
 
 
 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (ie, central nervous system [CNS] 
metastases) 
A dose of bemarituzumab selected in Part 1 in combination with docetaxel will enter Part  
4 safety run-in in combination with pembrolizumab, carboplatin, and nab-
paclitaxel/paclitaxel 
3.2 
Sample Size 
It is anticipated that up to 180 subjects will be enrolled in this study, consisting of a 
maximum of 18 subjects in Part 1 and a maximum of 150 subjects in Parts 2, 3 and 4 
combined.  The 150 subjects include the possibility of two cohorts at 2 dose levels of 
bemarituzumab, consisting of 10 to 30 subjects in each of Part 2 and 4.  Three to 6 
Japanese subjects per dose level will be enrolled in Part 1, Part 2, and/or Part 4 either 
as part of the initial dose level evaluation, or as backfill once RP3D has been 
determined.   
With 3, 6, or 9 subjects in a dose level cohort in Part 1, there is a 58%, 82%, and 93% 
probability, respectively, of observing at least 1 DLT if the true DLT rate is 25%. 
With a minimum of 10 subjects each in Parts 2, 3 and 4, there is an approximate 95% 
probability of observing at least 1 DLT if the true DLT rate is 25%, the lower end of the 
acceptable toxicity interval.  Up to 30 subjects may be enrolled to gain further safety and 
preliminary efficacy data. 
3.3 
Adaptive Design 
The mTPI-2 design will be employed to guide the DLRT on dose escalation and de-
escalation decisions. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
This phase 1b study has no prespecified covariate analyses. 
4.2 
Subgroups 
No subgroup analysis is planned for the study. 
5. 
Definitions 
 
Area Under the Curve (AUC) 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 15 of 39 
CONFIDENTIAL  
 
 
 
The area under the plasma drug concentration-time curve (AUC) reflects the actual body 
exposure to drug after administration of a dose of the drug. 
Actual cumulative dose (mg) =  
∑
     𝒕𝒐𝒕𝒂𝒍 𝒅𝒐𝒔𝒆 𝒈𝒊𝒗𝒆𝒏 𝒂𝒕 𝒄𝒚𝒄𝒍𝒆 𝒊 (𝒎𝒈)
# 𝒄𝒚𝒄𝒍𝒆𝒔
𝒊
 
Actual cumulative dose (mg/kg) =  
( ∑
     𝒕𝒐𝒕𝒂𝒍 𝒅𝒐𝒔𝒆 𝒈𝒊𝒗𝒆𝒏 𝒂𝒕 𝒄𝒚𝒄𝒍𝒆 𝒊 (𝒎𝒈)/𝒘𝒆𝒊𝒈𝒉𝒕 (𝒌𝒈)𝒊
# 𝒄𝒚𝒄𝒍𝒆𝒔
𝒊
) 
Actual cumulative dose (mg/m2) =  
( ∑
     𝒕𝒐𝒕𝒂𝒍 𝒅𝒐𝒔𝒆 𝒈𝒊𝒗𝒆𝒏 𝒂𝒕 𝒄𝒚𝒄𝒍𝒆 𝒊 (𝒎𝒈)/ 𝑩𝑺𝑨 
# 𝒄𝒚𝒄𝒍𝒆𝒔
𝒊
(𝒎𝟐)𝒊) 
Actual cumulative dose (min*mg/mL) =  
( ∑
     𝒕𝒐𝒕𝒂𝒍 𝒅𝒐𝒔𝒆 𝒈𝒊𝒗𝒆𝒏 𝒂𝒕 𝒄𝒚𝒄𝒍𝒆 𝒊 (𝒎𝒈)/ 𝑮𝑭𝑹 
# 𝒄𝒚𝒄𝒍𝒆𝒔
𝒊
(𝒎𝑳/𝒎𝒊𝒏)𝒊) 
Average dose per cycle administered 
Bemarituzumab 
(mg/kg) 
Actual cumulative dose (mg/kg) / number of cycles 
administered 
Docetaxel, 
Paclitaxel and 
Nab-Paclitaxel 
(mg/m2) 
Actual cumulative dose (mg/m2) / number of cycles 
administered 
Pembrolizumab 
(mg) 
Actual cumulative dose (mg) / number of cycles 
administered 
Carboplatin 
(min*mg/mL) 
Actual cumulative dose (min*mg/mL) / number of cycles 
administered 
 
Actual dose intensity 
For part 1 and 2 (w=3) 
 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 16 of 39 
CONFIDENTIAL  
 
 
 
 
Actual dose intensity 
Bemarituzumab 
(mg/kg)/week  
Actual cumulative dose (mg/kg) / [(Last dose date – first 
dose date + w*7)/7] 
 
 
Actual dose intensity 
Docetaxel 
(mg/m2)/week 
Actual cumulative dose (mg/m2) / [(Last dose date – first 
dose date + w*7)/7] 
 
 
For Part 3 (w=2) 
 
 
Actual dose intensity 
Condition 
Bemarituzumab 
(mg/kg)/week  
Actual cumulative dose (mg/kg) / 
[(Last dose date – first dose date + 
w*7)/7] 
Subject began at least 2 
cycles 
Actual cumulative dose (mg/kg) / w 
weeks 
Subject took only C1D1 
and C1D8 doses 
Actual cumulative dose (mg/kg) / 1 
week 
Subject took only C1D1 
dose 
 
For Part 4 (w=3) 
 
Baseline 
 
Actual dose intensity 
Bemarituzumab 
(mg/kg)/week  
Actual cumulative dose (mg/kg) / [(Last dose date – 
first dose date + w*7)/7] 
Docetaxel, Paclitaxel 
and Nab-Paclitaxel 
(mg/m2)/week 
Actual cumulative dose (mg/m2) / [(First dose date of 
the last cycle – first dose date + w*7)/7] 
Pembrolizumab 
(mg)/week 
Actual cumulative dose (mg) / [(First dose date of the 
last cycle – first dose date + w*7)/7] 
Carboplatin 
(min*mg/mL)/week 
Actual cumulative dose (min*mg/mL) / [(First dose 
date of the last cycle – first dose date + w*7)/7] 


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For any variable, unless otherwise specified, the baseline value is the last non-missing 
assessment taken prior to the first administration of IP/Non-IP.  The following are eligible 
for baseline consideration: 
- 
Assessments taken on the same date and the same time as the first dose of 
IP/Non-IP 
- 
Assessments taken on the same date as the first dose of IP/Non-IP but with 
unknown time, when no assessments on the same date with known time are 
available. 
If a subject is enrolled but does not receive IP/Non-IP, the baseline value is the last non-
missing assessment taken on or prior to enrollment (e.g., at screening). 
Best Overall Response (BOR) 
Best overall response (BOR) for a subject is the best confirmed response from disease 
assessments recorded from the start of the IP administration until the initiation of 
subsequent anticancer treatment.  Confirmation of response by a repeat scan is required 
after 4 weeks from the first documentation of response.  Overall response assessments 
occurring after the start of the first subsequent anticancer therapy will not be included.  
At least 5 weeks from the first dose of IP must elapse without radiological disease 
progression to meet the minimum criteria for SD duration in order to assign a BOR of 
SD.  In general, subjects not classifiable under the RECIST v1.1 response categories 
due to inadequate data or early death will be classified as non-evaluable (NE) for BOR 
but will be counted in the denominator of all response rate calculations. 
Body Mass Index (BMI) 
Body Mass Index will be calculated using the following formula: 
𝐵𝑀𝐼(𝑘𝑔/𝑚2) =  𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)  /  [ℎ𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚)/100]2 
 
Body Surface Area (BSA) 
BSA measures the total surface area of the body and is used to calculate drug dosages 
and medical indicators or assessments.  In addition to BSA derivation provided by site, 
the internal derivation may be provided using the formula: 
𝐵𝑆𝐴 (𝑚2) = 0.007184  x  𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)0.425  x  ℎ𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚)0.725 
 


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Change from Baseline 
Change from Baseline is the arithmetic difference between post-dose assessments and 
baseline value.  
Change (absolute) from Baseline  (Post-baseline Value – Baseline Value) 
Change (percent) from Baseline  [(Post-baseline Value – Baseline Value) /Baseline 
Value] x 100 
Cmax 
Cmax is defined as the maximum observed drug concentration. 
Cmin 
Cmin is defined as the minimum observed drug concentration. 
Ctrough 
Ctrough is defined as the observed concentration at the end of a dose interval. 
Disease Control 
Disease control is defined as complete response (CR) or partial response (PR) or stable 
disease (SD) per RECIST v1.1.  
Disease Control Rate (DCR) 
DCR is defined as proportion of subjects with CR, PR or SD per RECIST v1.1.  
Dose Limiting Toxicity (DLT) 
Dose limiting toxicities are defined as any of the corresponding adverse events listed in 
the protocol during the DLT evaluation period (21 days) considered by the investigator to 
be at least possibly related to bemarituzumab. 
Duration of Response (DOR) 
Duration of response is defined as the time from the first documentation of objective 
response (as determined by investigator per RECIST v1.1) until the first documentation 
of disease progression or death due to any cause, whichever occurs first. 
DOR = (min(PD date, death date) - response start date + 1) ×12 / 365.25  
Only subjects who have achieved OR will be evaluated for DOR.  DOR will be censored 
at the last evaluable post-baseline tumor assessment prior to subsequent anticancer 


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therapy; otherwise, at date of first documentation of objective response (i.e., assign a 
one-day interval). 
Duration of Treatment 
Duration of treatment (weeks) = (date of last dose – date of first dose + 1)/7  
Enrollment Date  
Date of Enrollment on Subject Enrollment CRF.  
End of Study (EOS) 
An individual subject is considered to have completed the study if they have completed 
the last visit shown in the Schedule of Activities of the protocol. 
End of Study Date 
The end of study date for the entire study is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (i.e., 
last subject last visit), including any additional parts in the study (e.g., long-term follow-
up, antibody testing), as applicable. 
Investigational Product (IP) 
The term ‘investigational product’ is used in reference to bemarituzumab. 
Last Known Alive Date  
In analysis of overall survival, subjects still alive are censored at last known alive date, 
defined as the latest date of the following dates. 
• 
Assessment dates from on-study procedures 
• 
Dosing start and stop dates of IP, non-IP, or concomitant medications  
• 
Event start and stop dates 
• 
Survival status date in LTFU 
• 
Date ending IP, non-IP, or study 
Non-Investigational Product (non-IP) 
The term ‘non-investigational product’ is used to reference docetaxel, carboplatin, 
paclitaxel, nab-paclitaxel and pembrolizumab. 
Objective Response (OR) as per RECIST 1.1  


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Objective response is defined as best overall response of confirmed complete response 
(CR) or confirmed partial response (PR), as defined by RECIST 1.1.  Response will be 
assessed by investigator per RECIST v1.1 and recorded in the ‘Overall Response’ field 
on the Tumor Response (RECIST 1.1) eCRF.   
Objective Response Rate (ORR)  
ORR is defined as the proportion of subjects with a best overall response of OR.  
Overall Survival (OS)  
OS is defined as the time from the date of first dose of IP until event of death due to any 
cause through the analysis cutoff (DCO) date.  
OS = (Date of death– date of first dose of IP + 1) ×12 / 365.25  
Subjects still alive will be censored at the date last known to be alive through the DCO 
date.   
Progressive Disease (PD) Date 
Imaging Date entered on the Tumor Response (RECIST 1.1) eCRF that supports 
progressive disease status for Overall Response. 
Progression-Free Survival (PFS) 
Progression-free survival is defined as the time from date of first dose of IP until the first 
documentation of radiologic disease progression or death due to any cause, whichever 
occurs first, in the absence of subsequent anticancer therapy. 
PFS (months) = (min(PD date, death date) - first dose date + 1) x 12 / 365.25 
PFS will be censored at the last evaluable post-baseline tumor assessment prior to 
subsequent anticancer therapy; otherwise, at first dose of IP.  Progression will be based 
on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (derived 
utilizing investigator tumor assessments). 
Relative dose intensity (%)  
For part 1 and 2  
 
IP 
Q3W Dose Level 1 (Part 1) 


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Bemarituzumab 
{ Actual cumulative dose (mg/kg) / Expected dose (mg/kg)  } * 
100 
If last dose date = C1D1 then Expected dose = 22  
If last dose date > C1D1 then Expected dose = 22 + {(last dose 
date – second dose date +21)*15}/21 
 
IP 
Q3W Dose Level 2 (Part 1 and Part 2) 
Bemarituzumab { Actual cumulative dose (mg/kg) / Expected dose (mg/kg)  } * 
100 
If last dose date = C1D1 then Expected dose = 30  
If last dose date > C1D1 then Expected dose = 30 + {(last dose 
date – second dose date +21)*22}/21 
Non-IP 
Q3W 
Docetaxel 
 𝑨𝒄𝒕𝒖𝒂𝒍 𝒄𝒖𝒎𝒖𝒍𝒂𝒕𝒊𝒗𝒆 𝒅𝒐𝒔𝒆(𝒎𝒈/𝒎𝟐)
[𝑳𝒂𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆−𝒇𝒊𝒓𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆+ 𝟐𝟏] ∗𝟕𝟓 𝒎𝒈/𝒎𝟐
𝟐𝟏
∗𝟏𝟎𝟎 
 
(The expected dose level for docetaxel is 60mg/m2 in case of Japanese subjects.) 
 
For Part 3 
 
Relative dose intensity (%)  
IP 
Q2W  
Bema 
{ Actual cumulative dose (mg/kg) / Expected dose (mg/kg)  } * 100 
If last dose date = C1D1 then Expected dose = 15  
If last dose date = C1D8 then Expected dose = 15 + {(last dose 
date – first dose date) * 7.5}/7 
If last dose date > C1D8 then Expected dose = 7.5 + {(last dose 
date – first dose date +14) * 15}/14 
 
For Part 4 
 
Relative dose intensity (%)  
 
IP 
Q3W  


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Bema 
 𝑨𝒄𝒕𝒖𝒂𝒍 𝒄𝒖𝒎𝒖𝒍𝒂𝒕𝒊𝒗𝒆 𝒅𝒐𝒔𝒆 (𝒎𝒈/𝒌𝒈)
𝑰(𝑳𝒂𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆≥𝑺𝒕𝒖𝒅𝒚 𝑫𝒂𝒚 𝟏)[(𝑳𝒂𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆−𝒇𝒊𝒓𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆+ 𝟐𝟏) ∗
𝟐𝟐𝒎𝒈
𝒌𝒈
𝟐𝟏
+ 𝟖 𝒎𝒈/𝒌𝒈)]}
∗𝟏𝟎𝟎 
Non-IP 
Q3W 
Pembrolizumab 
 𝑨𝒄𝒕𝒖𝒂𝒍 𝒄𝒖𝒎𝒖𝒍𝒂𝒕𝒊𝒗𝒆 𝒅𝒐𝒔𝒆(𝒎𝒈)
[𝑳𝒂𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆−𝒇𝒊𝒓𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆+ 𝟐𝟏] ∗𝟐𝟎𝟎 𝒎𝒈
𝟐𝟏
∗𝟏𝟎𝟎 
Carboplatin 
 𝑨𝒄𝒕𝒖𝒂𝒍 𝒄𝒖𝒎𝒖𝒍𝒂𝒕𝒊𝒗𝒆 𝒅𝒐𝒔𝒆(𝒎𝒊𝒏∗𝒎𝒈/𝒎𝑳)
[𝑳𝒂𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆−𝒇𝒊𝒓𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆+ 𝟐𝟏] ∗ 𝒅𝒐𝒔𝒆 (𝒎𝒊𝒏∗𝒎𝒈/𝒎𝑳)
𝟐𝟏
∗𝟏𝟎𝟎 
Paclitaxel 
 𝑨𝒄𝒕𝒖𝒂𝒍 𝒄𝒖𝒎𝒖𝒍𝒂𝒕𝒊𝒗𝒆 𝒅𝒐𝒔𝒆(𝒎𝒈/𝒎𝟐)
[𝑳𝒂𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆−𝒇𝒊𝒓𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆+ 𝟐𝟏] ∗𝟐𝟎𝟎 𝒎𝒈/𝒎𝟐
𝟐𝟏
∗𝟏𝟎𝟎 
Nab-Paclitaxel 
 𝑨𝒄𝒕𝒖𝒂𝒍 𝒄𝒖𝒎𝒖𝒍𝒂𝒕𝒊𝒗𝒆 𝒅𝒐𝒔𝒆(𝒎𝒈/𝒎𝟐)
[𝑭𝒊𝒓𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆 𝒐𝒇 𝒕𝒉𝒆 𝒍𝒂𝒔𝒕 𝒄𝒚𝒄𝒍𝒆−𝒇𝒊𝒓𝒔𝒕 𝒅𝒐𝒔𝒆 𝒅𝒂𝒕𝒆+ 𝟕] ∗𝟏𝟎𝟎 𝒎𝒈/𝒎𝟐
𝟕
∗𝟏𝟎𝟎 
 
(The expected dose level for docetaxel is 60mg/m2 in case of Japanese subjects.) 
Study Day 
For a given visit, the study day for a subject is defined as: 
Study Day  (Visit Date – Study Day 1 date)  1, if the visit is on or after Study Day 1. 
Study Day  (Visit Date - Study Day 1 date), if the visit is prior to Study Day 1. 
Study Day 1 
A subject’s study day 1 is defined as the date of the first dose of IP/Non-IP 
administration after enrollment.  Enrollment date can be used as study day 1 if a 
subject is not dosed with IP and non-IP. 
Treatment Emergent Adverse Events (TEAE) (General) 
TEAE are adverse events starting on or after first dose of IP as determined by "Did event 
start before first dose of investigational product" equal to "No" or missing on the Events 
eCRF and up to and including the earlier of 28days after the last dose of investigational 
product and EOS date.  Events that are directly related to lung cancer or disease 
progression (including, but not limited to, preferred terms “Non-small cell lung 
cancer”, “Disease progression” etc.) will be excluded from TEAE analysis. 
Treatment Emergent Adverse Events (TEAE) (Ocular) 
Ophthalmological events as indicated by the Event Category = ‘Ocular Event’ or 
pertaining to an eye-related EOI starting on or after first dose of IP as determined by 
"Did event start before first dose of investigational product" equal to "No" or missing on 


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the Events eCRF and up to and including the earlier of 100 days after the last dose of 
bemarituzumab and EOS date. 
Treatment-Related AE  
A treatment-related AE is any TEAE with the relationship flag on the Events eCRF page 
indicating there is a reasonable possibility that the event may have been caused by the 
investigational product. 
6. 
Analysis Sets 
6.1 
Enrolled Analysis Set 
The enrolled analysis set will consist of all enrolled subjects. 
6.2 
Safety Analysis Set 
All subjects who have received at least one dose of bemarituzumab. The safety analysis 
set will also serve as the full analysis set. 
6.3 
DLT Analysis Set 
All subjects that are enrolled in Part 1 who received at least one dose of bemarituzumab 
and Docetaxel; and met either of the following: 1) experienced a DLT; or 2) completed 
the 21-day DLT evaluation period, 3) received 100% of their planned dose 
6.4 
Pharmacokinetic Analyses Set 
The PK Analysis Set includes all subjects who have received at least 1 dose of 
bemarituzumab (AMG 552) and have at least 1 PK sample collected.  These subjects 
will be evaluated for PK analysis unless the number of data points required for analysis 
is not enough, or significant protocol deviations have affected the data, or if key dosing 
or sampling information is missing.  The PK analysis set will be used to conduct the 
analysis of PK data, unless otherwise specified. 
6.5 
Interim Analyses Set(s) 
Not applicable 
6.6 
Study-specific Analysis Sets 
Not applicable 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Part 3 may enroll simultaneously with Parts 1, 2, and 4; and Parts 2 and 4 may enroll 
simultaneously.  Therefore, the timing of the DLRMs described below may be adjusted 
so data from multiple study parts can be reviewed at a single meeting.  Interim analyses 


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will be based on as-is database snapshots (ie, data that have gone through routine data 
cleaning). 
Part 1 
During DLRMs, Amgen, in consultation with the site investigators, will review all 
available cumulative data (safety, tolerability, laboratory, PK and efficacy) by cohort prior 
to making dose escalation or dose de-escalation recommendations.  Adverse events 
and DLTs observed in all subjects will be evaluated continually and fully integrated into 
all DLRM and considered in all enrollment and dosing decisions.  A DLRM will occur 
during dose exploration and 21 days following last subject enrolled in a dose cohort 
(every 3 to 6 subjects enrolled at a given dose level). 
Parts 2, 3, and 4 
Amgen, in consultation with site investigators, will review the data as detailed above 4 
months after the 10th subject has been enrolled, in each of Parts 2, 3 and 4. 
Additional administrative analyses may be performed for Parts 2, 3 and 4 before the 
primary analysis in order to plan for additional studies. 
7.2 
Primary Analysis 
Refer to the final analysis. 
7.3 
Final Analysis 
The final analysis will be based on a cleaned database lock and will occur after all 
subjects have ended the study. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
Missing and incomplete dates will be imputed as outlined in Appendix A.  Partial or 
missing death dates will be imputed prior to derivation of any endpoint that utilizes the 
date of death. 


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8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations (IPD).  The clinical 
study team will identify and document the criteria for IPD.  
If applicable, the methods to detect bias are describe in the analyses of particular 
endpoints. 
8.5 
Outliers 
PK concentration data will be evaluated for outliers by visual inspection, and decisions to 
re-assay individual samples will be made in accordance with standard PK evaluation 
practice. 
For non-PK analyses, any suspected outliers at the time of analyses will be investigated 
by the study team and will be included in analyses unless determined to be an error or 
there is supporting evidence or explanation to justify the exclusion.  Any outliers 
excluded from the analysis will be discussed in the Clinical Study Report (CSR), 
including the reasons for exclusion and the impact of their exclusion on the study. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed which in most of the cases are normal distribution.  If required data 
transformations or alternative non-parametric methods of analyses will be performed. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later.  
Additional statistical software may be used to perform exploratory/ad-hoc analyses. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Data will be summarized by cohort.  Continuous variables will be described with the 
mean, standard deviation, median, quartiles, minimum, and maximum.  Categorical data 


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will be summarized with frequency counts and percentages.  Unless otherwise specified, 
data will be summarized using the Safety Analysis Set.  
Confidence intervals (CI) for proportions will be estimated using an exact method 
proposed by Clopper-Pearson (Clopper and Pearson, 1934).  Kaplan-Meier (KM) 
methods will be used to estimate the median and percentiles for time to event endpoints 
with CI calculated by using the Brookmeyer and Crowley method (Brookmeyer and 
Crowley, 1982).  Kaplan-Meier methods will be used to estimate landmarks for time to 
event endpoints (e.g., 1-year OS) with the Greenwood formula (Kalbfleisch and Prentice, 
1980) used to estimate the standard error used in CI calculation. 
9.2 
Subject Accountability 
The number and percent of subjects who were screened, enrolled, received at least one 
dose of IP, discontinued from IP or non-IP (including reasons for discontinuing), 
discontinued the study (including reasons for discontinuing), and completed study will be 
summarized.  The number and percent of subjects enrolled will be tabulated by study 
site and country.  Key study dates for the first subject enrolled, last subject enrolled, last 
subject ended IP, last subject ended study, and data cut-off date for analysis will be 
presented. 
9.3 
Important Protocol Deviations 
Eligibility deviations are defined in the protocol.  Important Protocol Deviations (IPDs) 
categories are defined by the study team before the first subject’s initial visit and 
updated during the IPD reviews throughout the study prior to database lock.  These 
definitions of IPD categories, subcategory codes, and descriptions will be used during 
the course of the study.  A listing of IPDs will be provided. 
9.4 
Demographic and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized by treatment 
groups using descriptive statistics for the safety analysis set as well as the 
pharmacokinetic analysis set for all the four parts of the study.  
These include, but not limited to the following:  
 
Baseline demographics:  
 
Age at enrollment 
- 
As a continuous variable 
- 
As a categorical variable: (< 65 vs ≥ 65 years) 


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- 
As categorical variable: (18 - 64 years vs 65 - 74 years vs 75 - 84 years 
vs ≥ 85 years) 
 
Sex (Male, Female) 
 
Race  
- 
White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multiple and Other  
- 
Asian (Japanese, Asian Indian, Chinese, Korean and Other)  
 
Region (US/EU, Asia, rest of world [ROW]) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
Baseline characteristics: 
 
Weight (kg)  
 
Height (cm) 
 
Body surface area (m2) 
 
Body mass index (kg/m2) 
 
ECOG performance status (0 vs 1 vs 2) 
 
Time since initial diagnosis to study entry (months) 
 
Prior anti-cancer therapy category setting (as per eCRF data) 
 
Prior lines of anti-cancer therapy (first line, second line, third line, fourth 
line, fifth line, sixth line, seventh line, not reported) 
 
Prior radiotherapy for current malignancy setting (as per eCRF data) 
 
Prior surgical procedures for current malignancy intent (as per eCRF data) 
 
TNM Staging at screening (as per eCRF data) 
 
Disease status at screening (metastatic, locally advanced, locally recurrent) 
 
Disease status at initial diagnosis (metastatic; locally advanced, 
unresectable; locoregional, resectable) 
 
History of CNS involvement (yes vs no)  
 
Tumor FGFR2b IHC staining score of 2+ or 3+ (positive, negative, missing) 


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 
Differentiation at screening (well differentiated vs moderately differentiated 
vs poorly differentiated) 
 
Histopathology type at screening (adenocarcinoma, squamous Cell 
carcinoma, large Cell Carcinoma, adenosquamous carcinoma, 
undifferentiated, sarcomatoid, other) 
 
Liver metastasis (yes, no) 
 
 Smoking history 
 
Alcohol history 
 


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9.5 
Efficacy Analyses 
Analysis of efficacy endpoints will be based on the Safety Analysis Set unless otherwise 
specified.  
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
Not Applicable 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The number and percentage of subjects with objective response and disease control will 
be presented along with 95 CI. 
For subjects treated at the RP3D, KM curves, KM quartiles with 95 CIs, and KM 
estimates with 95 CIs at landmark time points will be estimated for the following 
endpoints: duration of objective response (for only responding subjects), PFS, and OS. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 or later will be 
used to code all events categorized as adverse events, to a system organ class and a 
preferred term. 
The handling of incomplete adverse event start and/or end dates is detailed in Appendix 
A.  
Subject incidence of all treatment-emergent adverse events, grade 3 or higher TEAEs, 
grade 4 or higher TEAEs, fatal adverse events, serious adverse events, adverse events 
leading to investigational product interruption, and adverse events leading to 
investigational product withdrawal will be tabulated by alphabetical order of system 
organ class and then by preferred term in descending order of frequency.  
Subject incidence of treatment-emergent adverse events will be tabulated by preferred 
term in descending order of frequency, and also by system organ class, preferred term, 
and grade. 
Subject incidence of all treatment-emergent treatment-related adverse events, grade 3 
or higher TEAEs, grade 4 or higher TEAEs, fatal adverse events, serious adverse 
events, adverse events leading to investigational product interruption, and adverse 
events leading to investigational product withdrawal will be tabulated by alphabetical 
order of system organ class and then by preferred term in descending order of 
frequency. 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 30 of 39 
CONFIDENTIAL  
 
 
 
Treatment-emergent events of interest (EOIs) (including ocular events) will be 
summarized by EOI category and preferred term.  In addition, the subject incidence of all 
treatment-emergent EOIs, grade 3 or higher treatment-emergent EOIs, grade 4 or higher 
treatment-emergent EOIs, serious EOIs, EOIs leading to investigational product 
interruption, and EOIs leading to investigational product withdrawal will be tabulated. 
Time to onset, duration, number of resolved events will be summarized for select EOIs, 
including ocular events. 
If a subject experiences repeated episodes of the same AE, then the subject will be 
counted once when tabulating subject incidence and, where applicable, the highest 
severity grade and strongest causal relationship to investigational product will be 
selected. 
Serious TEAE and fatal TEAE for the safety population will be listed. 
9.6.3 
 Ophthalmologic Exam Results 
Visual acuity (logMAR equivalent) will be summarized for baseline, worst post-
baseline, maximum increase, and last post-baseline visits in the Safety Analysis 
Set. The same will be summarized for subjects with changes in visual acuity related to 
abnormal corneal findings on study as indicated on the Ophthalmology Examination 
eCRF. The times per day of ocular lubricant usage will be summarized.  Unilateral and 
bilateral intraocular pressure and change from baseline will be summarized by visit.  
Compliance of the performance of slit lamp, dilated retinal exam, 3-field retinal 
photographs, ocular surface staining, and optical coherence tomography results will be 
summarized by visit. 
In addition, shift tables between baseline and the worst on-study value will be provided 
according to visual toxicity grades for unilateral and bilateral cases. 
9.6.4 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics over time. 
The number and percentage of subjects with abnormal changes in select laboratory 
endpoints will be summarized for the Safety Analysis Set. 
Shift tables between baseline and the worst on-study value in select laboratory will be 
performed.  Lab parameters will be evaluated in the increasing and/or decreasing 
direction.  The parameters will be provided according to the NCI CTCAE toxicity 
grades and the unscheduled assessments will be included in the shift tables.  


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 31 of 39 
CONFIDENTIAL  
 
 
 
9.6.5 
Vital Signs 
The number and percentage of subjects with abnormal changes in systolic blood 
pressure, diastolic blood pressure, heart rate, respiration rate, body temperature and 
oxygen saturation will be summarized at baseline for the Safety Analysis Set.  In 
addition, minimum post-baseline and maximum post-baseline values will be summarized 
using descriptive statistics.  
9.6.6 
Physical Measurements 
Physical measurements including height, weight and BSA will be summarized at 
baseline using descriptive statistics.  In addition, minimum post-baseline and maximum 
post-baseline weight will be summarized using descriptive statistics. 
9.6.7 
Electrocardiogram 
In Part 1, 2 and 4, the ECG measurements will be performed as per standard of care for 
routine safety monitoring, rather than for purposes of assessment of potential QTc effect.  
Since these evaluations may not necessarily be performed under the rigorous conditions 
expected to lead to meaningful evaluation of QTc data; summaries and statistical 
analyses of ECG measurements are not planned, and these data would not be expected 
to be useful for meta-analysis with data from other trials. 
In Part 3, summaries over time and/or changes from baseline over time will be 
provided for all ECG parameters with descriptive statistics.  In addition, the 
maximum post-baseline and maximum change from baseline in QT interval, QTcF 
interval, QTcB interval will be categorized and the number and percentage of subjects 
in each group will be summarized.  ECG data may be listed and select parameters may 
be plotted. 
9.6.8 
Antibody Formation 
The incidence and percentage of subjects who develop anti-bemarituzumab antibodies 
at any time will be tabulated by cohort. 
9.6.9 
Exposure to Investigational Product 
The number of days on investigational product, the total dose of investigational product, 
and dose intensity will be summarized using descriptive statistics.   
Descriptive statistics will be produced to describe the exposure to IP by cohort.  The 
number of cycles of protocol-specified therapy administered will be summarized.  In 
addition, the duration of therapy in weeks, the cumulative dose, , actual dose intensity 
and relative dose intensity will be summarized.  The number and percent of subjects with 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 32 of 39 
CONFIDENTIAL  
 
 
 
dose modifications (e.g., dose change/withheld, dose delay or dose interruptions) and 
reason for modification will be summarized. 
List of manufacturing lot number will be provided.  
9.6.10 
Exposure to Non-investigational Product  
The exposure to non-IP will be summarized in a similar way to the summary of the 
exposure to IP.  
List of manufacturing lot number will be provided for Amgen supplied non-IP. 
9.6.11 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications from Study 
Day 1 will be summarized by ATC text and by preferred term or category as coded by 
the World Health Organization Drug (WHO DRUG) dictionary.  The number and 
proportion of subjects receiving concomitant medications of interest will be summarized 
by ATC text and by preferred term for each cohort.   
9.7 
Other Analyses 
Other analyses in the study include analyses for PK and biomarker endpoints, which 
may be specified in separate analysis plans.  


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 33 of 39 
CONFIDENTIAL  
 
 
 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Nominal sampling times will be used for individual concentration-time plots and tables. 
Actual dose administered, and actual sampling times will be used for the calculation of 
PK parameters for each subject.  Bemarituzumab serum concentrations with values 
below the lower limit of quantification will be set to zero for analysis.  The reasons for 
excluding any sample from the analyses will be provided.  
Individual concentration-time data will be tabulated and presented graphically.  Summary 
of PK concentration over time and PK parameters will be provided.  Mean concentration-
time profiles for each dose will be provided. 
PK parameters will include AUC, maximum observed concentration (Cmax), and observed 
concentration at the end of a dose interval (Ctrough) for bemarituzumab. 
For Bema, PK parameters will be determined from the time concentration profile using 
the current version of Phoenix WinNonlin based on the PK Analysis Set.  PK parameters 
will be summarized using descriptive statistics including, but not limited to means, 
standard deviations, medians, minimums, and maximums. 
Based on review of the data, analyses to describe the relationship between 
bemarituzumab exposure and either pharmacodynamic effect and/or clinical outcome 
may also be performed. 
Above analyses will be conducted by Amgen CPMS.  
9.7.2 
Analyses of Clinical Outcome Assessments 
Not applicable 
9.7.3 
Analyses of Health Economic Endpoints 
Not applicable 
9.7.5 
Analysis of COVID-19 Impact 
The following summaries to assess the impact of COVID-19 may be provided:  
 
Listing of all subjects impacted by COVID-19 related study disruptions  


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 34 of 39 
CONFIDENTIAL  
 
 
 
 
Subject incidence of IPD and non-important protocol deviation due to COVID-19 
control measures by protocol deviation category, which may include:  
- 
alternative IP administration process  
- 
alternative lab/imaging data process  
- 
alternative site visits  
- 
alternative procedures or methods not included in original study design and not 
identified  
- 
missed/partial missed visits  
- 
missed IP/non-IP  
- 
early end of study  
- 
early end of treatment with IP and non-IP  
- 
early end of safety follow-up 
 
Subject incidence of COVID-19 related dose change/withheld 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
11. 
Literature Citations / References 
Brookmeyer R and Crowley J.  A Confidence Interval for the Median Survival Time.  
Biometrics.  2984;38:29-41. 
Clopper CJ and Pearson ES.  The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial.  Biometrika.  1934;26:404-413. 
Guo W, Wang S-J, Yang S, et al.  A Bayesian interval dose-finding design addressing 
Ockham’s razor:  mTPI-2.  Contemp Clin Trials.  2017;58:23-33. 
Kalbfleisch, J.D. and Prentice, R.L. (1980) The Statistical Analysis of Failure Time Data, 
New York: John Wiley & Sons. 
 
 
 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 35 of 39 
CONFIDENTIAL  
 
 
 
12. 
Prioritization of Analyses 
Not applicable 
13. 
Data Not Covered by This Plan 
Pharmacokinetic, pharmacodynamic, exposure-response and biomarker analyses will be 
performed by Clinical Pharmacology, Modeling and Simulation (CPMS) or Clinical 
Biomarker & Diagnostics (CBD).  Further analysis of clinical outcome assessments may 
be provided in a separate Supplemental Statistical Analysis Plan (SSAP). 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 36 of 39 
CONFIDENTIAL  
 
 
 
14. 
Appendices 
Appendix A Handling of Date, Incomplete Date and Missing Dates 
A1. Imputation Rules for Partial or Missing Start Dates for Concomitant 
Medications and Adverse Events 
The reference date for the following rules is the date of first dose IP (non-IP if a 
subject never took IP) 
 
 
 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
 
3 
1 
 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1=Impute the date of first dose; 2=Impute the first of the month; 3=Impute January 1 of the year; 4=Impute 
January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month or first day of year if month is also missing. 
A2. Imputation Rules for Partial Diagnosis or Procedure Date (Medical History) 
 
If the month and year are present, impute the first day of that month. 
 
If only the year is present, impute January 1 of that year. 
 
If the date is entirely missing, do not impute. 
A3. Imputation Rules for Partial or Missing Stop Dates (Medical History, 
Concomitant Medications, Adverse Events) 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 37 of 39 
CONFIDENTIAL  
 
 
 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date. 
If the imputed stop date is after the end of study date, impute as the end of study date. 
A4. Imputation Rules for Partial or Missing Death Dates 
If death year and month are available but day is missing: 
 
If yyyymm for the derived date last known to be alive equals yyyymm for death date, 
set death date to the day after the derived date last known to be alive. 
 
If yyyymm for the derived date last known to be alive is less than the yyyymm for 
death date, set death date to the first day of the death month. 
 
If yyyymm for the derived date last known to be alive is greater than yyyymm for 
death date, assume the derived date last known to be alive is in error, set death 
date to the first day of the death month; leave derived date last known to be alive 
as is. 
If month and day are missing and year of death is known: 
 
If yyyy for the derived date last known to be alive equals yyyy for death date, set 
death date to the derived day after last known to be alive date. 
 
If yyyy for the derived date last known to be alive is less than yyyy for death date, 
set death date to the first day of the death year. 
 
If yyyy for the derived date last known to be alive is greater than yyyy for death date, 
assume the derived date last known to be alive is in error, set death date to the first 
day of the death year; leave derived date last known to be alive as is. 
If a death date is totally missing: 
Set death date to the day after the derived date last known to be alive. 
 
 
  


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 38 of 39 
CONFIDENTIAL  
 
 
 
Appendix B.  Analytical Windows 
Analytical Windows for Ophthalmology exams are shown below.  If more than one visit 
falls within the same defined window, the visit closets to the target day will be considered 
for analysis.  If two assessment dates are the same distance from the target day, then 
the latest visit will be considered for analysis. 
Analysis windows for Ophthalmology Exams (except for retinal exams) 
Week 
Target Day 
Study Day 
Window Start 
Study Day 
Window End 
Window 
Length 
(Days) 
Baseline 
1 
-28 
1 
30 
6 
43 
2 
64 
63 
12 
85 
65 
106 
42 
18 
127 
107 
148 
42 
24 
169 
149 
197 
49 
32 
225 
198 
253 
56 
40 
281 
254 
309 
56 
48 
337 
310 
365 
56 
56 
393 
366 
421 
56 
64 
449 
422 
477 
56 
72 
505 
478 
533 
56 
80 
561 
534 
589 
56 
88 
617 
590 
645 
56 
96 
673 
646 
701 
56 
104 
729 
702 
757 
56 
112 
785 
758 
  
. 
. 
 
 
 
 
Week x 
x*71 
Week [x-8] Study 
Day Window End 
 1 
Min(Last dose 
date of IP  42, 
Week [x-8] 
Study Day 
Window End  1 
 55) 
(Study Day 
Window 
End - Study 
Day 
Window 
Start)  1 
Safety 
follow-up  
Last dose 
date of 
IP/non-IP  
28 
Last dose date of 
IP/non-IP  1 
Last dose date 
of IP/non-IP  31 
31 
Analysis windows for Retinal Exams 
 


Product:  Bemarituzumab (AMG 552)  
Protocol Number:  20210102 
Date:  25 June 2024 
Page 39 of 39 
CONFIDENTIAL  
 
 
 
Week 
Target Day 
Study Day 
Window Start 
Study Day 
Window End 
Window 
Length 
(Days) 
Baseline 
1 
-28 
1 
30 
12 
85 
2 
127 
126 
24 
169 
128 
225 
98 
40 
281 
226 
337 
112 
56 
393 
338 
449 
112 
72 
505 
450 
561 
112 
88 
617 
562 
673 
112 
104 
729 
674 
. 
. 
 
 
 
 
Week x 
x*71 
Week [x-16] 
Study Day 
Window End  
1 
Min(Last dose 
date of IP  42, 
Week [x-16] 
Study Day 
Window End  1 
 111) 
(Study Day 
Window 
End - Study 
Day 
Window 
Start)  1 
Safety 
follow-up  
Last dose 
date of 
IP/non-IP  
28 
Last dose date 
of IP/non-IP  1 
Last dose date of 
IP/non-IP  31 
31