Clinical trial NCT05653427
Conditions: Carcinoma, Hepatocellular
Sponsor: Janssen Research & Development, LLC
Start date: 2022-12-08; Completion date: 2023-10-10
Enrollment: 18 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to characterize the preliminary antitumor activity of amivantamab at the recommended dose in participants with previously systemically treated hepatocellular carcinoma (HCC)

Detailed description:

Arms: arm 1: Participants will receive amivantamab monotherapy intravenously once weekly on Days 1 and 2 in Cycle 1 and on Days 1 and 15 from Cycle 2 onwards based on body weight. Each cycle is of 28 days.
Interventions: intervention 1: Amivantamab
Intervention descriptions: intervention 1: Amivantamab will be administered intravenously.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 21 February 2023
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Phase 2, Open-Label Study to Evaluate the Safety, Efficacy and Pharmacokinetics of 
Amivantamab Monotherapy in Participants with Previously Treated Advanced 
Hepatocellular Carcinoma
Protocol 61186372HCC2001; Phase 2
Version: Amendment 2
JNJ-61186372 (amivantamab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. Therefore, the legal entity acting as the sponsor for Janssen Research &
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
Studies conducted at sites in the United States (US) will be conducted under US Food & Drug 
Administration Investigational New Drug (IND) regulations (21 CFR Part 312).
NCT Number: NCT05653427
Status:
Approved
Date:
21 February 2023
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-705165, 4.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT05653427


JNJ-61186372 (amivantamab)
Clinical Protocol 61186372HCC2001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 21 February 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
21-February-2023
Amendment 1
23-September-2022
Original Protocol
6-May-2022
Amendment 2 (21 February 2023)
Overall Rationale for the Amendment: The overall reason for this amendment is to clarify the
Inclusion Criteria 4 based on health authority’s feedback.
The changes made to the clinical protocol 61186372HCC2001 as part of Protocol Amendment 2 are listed 
below, including the rationale of each change and a list of all applicable sections. Changes made in previous 
protocol amendment is listed in Section 10.14 Appendix 14: Protocol Amendment History.
The new text is captured in bold font, and deleted text as strike-through, wherever applicable.
Section Number
and Name
Description of Change
Brief Rationale
1.1 Synopsis
2 Introduction
Add (MET also known as cMET) in 
abbreviation brackets for tyrosine protein kinase 
mesenchymal epithelial transition.
Editions were made in abbreviation 
for accuracy and documents 
consistency. 
10.1 Appendix 1 
Abbreviations
Modify definition of MET in abbreviation list:
MET: tyrosine protein kinase mesenchymal 
epithelial transition
1.3 Schedule of 
Activities (SoA)
Add a suggestion sentence in footnote “d”: 
Biopsy collection at late time of screening is 
suggested whenever possible.
Editions were made for the ethical 
consideration and more clinical 
feasible procedure.
3 Objectives and 
Endpoints
Update to BICR language:
Objective response rate (ORR) as determined by 
investigator, according to the Response Criteria 
in Solid Tumors (RECIST) v1.1. Confirmation 
of investigator-assessed ORR may will be 
performed through Blinded Independent Central 
Review (BICR).
Editions were made due to the 
BICR review changed to collect 
and hold review.
8.1 Efficacy 
Assessments
Update to BICR language:
Response may will also be assessed by blinded 
independent central review (BICR) for central 
confirmation.
4.1.1 Screening Period
Deletion of below sentence:
“Informed consent does not expire if the 
screening evaluations are not performed within 
the 28-day Screening Period, although 
evaluations performed outside the screening 
window will need to be repeated.”
Add sentence:
“Informed consent does not expire if the 
screening related procedures are not 
performed within the 28-day Screening 
Period, although evaluations performed 
outside the screening window will need to be 
Edition was made to align with the 
SoA and other section of the 
protocol.


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Section Number
and Name
Description of Change
Brief Rationale
repeated, the exception to this will be fresh 
biopsy sample as long as there is no systemic 
treatment between the first and any 
subsequent re-screening.”
5.1 Inclusion Criteria
Changes were made in inclusion criteria 4:
Participant must be refractory, intolerant to or 
refused at least 1 prior line of systemic therapy. 
Prior therapies may include multi targeted kinase 
inhibitor (MKI) and/or immunotherapy (eg, PD 
1/L1 containing therapy).
Participants should have progressed on 
standard of care (SoC) therapy with 
immunotherapy (eg, PD-1/L1-containing 
therapy) and a multi-targeted kinase inhibitor 
(MKI). Participation is allowed after 
progression with just one of these therapies, if 
the participant is intolerant of, or declining 
treatment with, the other SoC therapy (PD-
1/L1-containing therapy or MKI).
a. Prior adjuvant or neoadjuvant therapy will be 
considered as 1 prior line of systemic therapy for 
the purpose of meeting the eligibility criteria if 
participant experienced progression within 24 
weeks of such therapy. 
b. The intolerance or declining of further 
therapy should be documented in medical record, 
and discussed with the sponsor medical team. 
Note: A line of therapy is defined as a treatment 
regimen with subsequent disease progression
Editions were made in key
inclusion criteria based on China 
health authority’s recommendation 
on eligible participants.
5.1 Inclusion Criteria
Changes were made in inclusion criteria 8:
“and HBV viral load must be less than 2000 
IU/mL prior to the first dose of study 
drugtreatment”
Editions were made for 
clarification and content 
consistency
5.1 Inclusion Criteria
Changes were made in pregnancy test in 
inclusion criteria 12:
A female participant of childbearing potential 
must have a negative highly sensitive serum 
(-human chorionic gonadotropin [-hCG]) 
pregnancy test at screening and within 72 hours 
of the first dose of study treatment and must 
agree to further serum or urine pregnancy 
tests during the study.
Editions were made for content 
consistency with SoA.
5.1 Inclusion Criteria
Changes were made in inclusion criteria 13:
“Note: If a female participant becomes of 
childbearing potential after start of the study the 
female participantwoman must comply with 
point (b.).”
Keep the language consistent with 
the program template.
5.2 Exclusion Criteria
Change was made in exclusion criteria 3:
and asymptomatic for at least 2 weeks and who 
are off or receiving low dose corticosteroid 
treatment ([≤10 mg prednisone or equivalent])
for at least 2 weeks prior to study treatmentprior 
to the first dose of study treatment)
Editions were made for 
clarification and content 
consistency


JNJ-61186372 (amivantamab)
Clinical Protocol 61186372HCC2001 Amendment 2
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Status: Approved,  Date: 21 February 2023
Section Number
and Name
Description of Change
Brief Rationale
Text in bold was added in exclusion criteria 5:
Evidence of portal hypertension with bleeding 
esophageal or gastric varices within the past 3 
months prior to the first dose of study 
treatment.
8.2.4 Clinical Safety 
Laboratory 
Assessments
Add sentence:
“In the event of additional safety monitoring, 
unscheduled laboratory assessments may be 
performed as required and may be done 
locally when an immediate clinical decision 
needs to be made.”
Editions were made to provide the
option on the local lab test in the 
urgent safety monitoring and 
immediate clinical decision.
9.3 Populations for 
Analysis Sets
Deletion of Safety population and the description 
of Safety population. 
The population set for Safety 
analysis was the same with 
population of All treated analysis 
set. Deletion was made to avoid 
redundancy. 
9.4.5 Safety Analyses
Modification was made on sentence:
All safety analyses will be made on the Safety
All treated Population.
10.2 Appendix 2
Add “urea” in Protocol-Required Safety 
Laboratory Assessments:
“Blood urea nitrogen (BUN) or urea”
Optional collection for urea value
was added.
10.12 Appendix 12
The source “Guidance for Industry” reference 
was added for the calculation of eGFR.
Add new references:
Levey (2006, 2007), Mosteller (1987)
Addition of new references.
10.13 Appendix 13
Child-Pugh Classification scoring table:
Prothrombin time prolongation (sec) with 
observed finding of 1.0-3.0<4.0 scored for 1 
point.
Use “Absent”, “Slight” and “Moderate” to 
describe the observed findings of parameter
“Ascites”.
Corrections in Child-Pugh 
Classification scoring table and 
update the table based on NCCN 
guideline 2022 version 4.
10.13 Appendix 13
11 References
Deletion of 2 references:
Child 1964; Pugh 1973
Add new reference:
NCCN 2022
Throughout the 
protocol
Minor editorial, editions for consistency, 
grammatical, or formatting were made.
Other revisions including minor 
editorial, grammatical, formatting, 
or consistency changes were made 
throughout.


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Status: Approved,  Date: 21 February 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
1.
PROTOCOL SUMMARY ..................................................................................................................... 9
1.1.
Synopsis........................................................................................................................................... 9
1.2.
Schema .......................................................................................................................................... 11
1.3.
Schedule of Activities (SoA)........................................................................................................... 12
2.
INTRODUCTION................................................................................................................................ 17
2.1.
Background .................................................................................................................................... 17
2.1.1.
The Epidemiology of HCC .......................................................................................................... 17
2.1.2.
HCC Current Treatment Options and Outcome ......................................................................... 18
2.1.3.
EGFR and MET Signaling Pathways in HCC............................................................................. 19
2.1.4.
Amivantamab and EGFR / MET Signaling Pathway .................................................................. 20
2.1.5.
Amivantamab in Preclinical HCC PDX models........................................................................... 20
2.2.
Study Rationale.............................................................................................................................. 21
2.3.
Benefit-Risk Assessment ............................................................................................................... 23
2.3.1.
Risks for Study Participation....................................................................................................... 23
2.3.2.
Benefits for Study Participation .................................................................................................. 23
2.3.3.
Benefit-Risk Assessment for Study Participation ....................................................................... 24
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 24
4.
STUDY DESIGN ................................................................................................................................ 25
4.1.
Overall Design................................................................................................................................ 25
4.1.1.
Screening Period ........................................................................................................................ 25
4.1.2.
Treatment Period........................................................................................................................ 26
4.1.3.
Follow-up Period......................................................................................................................... 27
4.2.
Scientific Rationale for Study Design............................................................................................. 27
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 28
4.3.
Justification for Dose...................................................................................................................... 28
4.4.
End of Study Definition................................................................................................................... 29
5.
STUDY POPULATION ...................................................................................................................... 29
5.1.
Inclusion Criteria ............................................................................................................................ 30
5.2.
Exclusion Criteria ........................................................................................................................... 34
5.3.
Lifestyle Considerations................................................................................................................. 37
5.4.
Screen Failures .............................................................................................................................. 37
5.5.
Criteria for Temporarily Delaying Administration of Study Treatment ........................................... 37
6.
STUDY TREATMENT AND CONCOMITANT THERAPY ................................................................ 38
6.1.
Study Treatment(s) Administered .................................................................................................. 38
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 39
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 40
6.4.
Study Treatment Compliance ........................................................................................................ 40
6.5.
Dose Modification........................................................................................................................... 40
6.5.1.
Dose Delay Guidance................................................................................................................. 40
6.5.2.
Amivantamab Dose Modification ................................................................................................ 41
6.5.3.
IRRs............................................................................................................................................ 42
6.5.4.
Rash-related Adverse Events..................................................................................................... 44
6.5.5.
Pruritus........................................................................................................................................ 46
6.5.6.
Paronychia.................................................................................................................................. 46
6.5.7.
Oral Mucositis ............................................................................................................................. 47
6.5.8.
Liver Chemistry Abnormalities.................................................................................................... 48


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Status: Approved,  Date: 21 February 2023
6.5.9.
Suspected Pulmonary Toxicity ................................................................................................... 49
6.6.
Continued Access to Study Treatment After the End of the Study................................................ 50
6.7.
Treatment of Overdose .................................................................................................................. 50
6.8.
Concomitant Therapy..................................................................................................................... 51
6.8.1.
Amivantamab Pre-infusion and Post-infusion Medications ........................................................ 51
6.8.1.1.
Amivantamab Pre-infusion Medications .................................................................................. 51
6.8.1.2.
Amivantamab Post-infusion Medications ................................................................................ 52
6.8.2.
Prohibited or Restricted Medications and Therapies.................................................................. 53
6.8.3.
Permitted Medications and Therapies........................................................................................ 53
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 53
7.1.
Discontinuation of Study Treatment............................................................................................... 53
7.1.1.
Liver Chemistry Stopping Criteria............................................................................................... 54
7.1.2.
Rechallenge Criteria ................................................................................................................... 55
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 55
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 56
7.3.
Lost to Follow-up............................................................................................................................ 56
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 56
8.1.
Efficacy Assessments .................................................................................................................... 58
8.2.
Safety Assessments....................................................................................................................... 59
8.2.1.
Physical Examinations................................................................................................................ 59
8.2.2.
Vital Signs................................................................................................................................... 60
8.2.3.
Electrocardiograms..................................................................................................................... 60
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 60
8.2.5.
Pregnancy Testing...................................................................................................................... 60
8.2.6.
ECOG Performance Status ........................................................................................................ 61
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 61
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 61
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 62
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 62
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 62
8.3.5.
Pregnancy................................................................................................................................... 62
8.3.6.
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events ............................................................................................. 63
8.3.7.
Adverse Events of Special Interest............................................................................................. 63
8.4.
Pharmacokinetics........................................................................................................................... 63
8.4.1.
Evaluations ................................................................................................................................. 64
8.4.2.
Analytical Procedures................................................................................................................. 64
8.4.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 64
8.5.
Pharmacogenomics ....................................................................................................................... 64
8.6.
Biomarkers/Pharmacodynamics .................................................................................................... 65
8.7.
Immunogenicity Assessments ....................................................................................................... 66
8.8.
Medical Resource Utilization and Health Economics .................................................................... 66
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 67
9.1.
Statistical Hypotheses.................................................................................................................... 67
9.2.
Sample Size Determination ........................................................................................................... 67
9.3.
Populations for Analysis Sets ........................................................................................................ 67
9.4.
Statistical Analyses ........................................................................................................................ 68
9.4.1.
General Considerations.............................................................................................................. 68
9.4.2.
Primary Endpoint(s).................................................................................................................... 68
9.4.2.1.
ORR......................................................................................................................................... 68
9.4.3.
Secondary Endpoint(s) ............................................................................................................... 68
9.4.3.1.
DoR.......................................................................................................................................... 68
9.4.3.2.
DCR......................................................................................................................................... 69


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Status: Approved,  Date: 21 February 2023
9.4.3.3.
PFS.......................................................................................................................................... 69
9.4.3.4.
OS............................................................................................................................................ 69
9.4.4.
Exploratory Endpoint(s) .............................................................................................................. 69
9.4.5.
Safety Analyses .......................................................................................................................... 69
9.4.6.
Other Analyses ........................................................................................................................... 70
9.4.6.1.
Pharmacokinetic Analyses ...................................................................................................... 70
9.4.6.2.
Pharmacodynamic/Biomarkers Analyses................................................................................ 71
9.4.6.3.
Immunogenicity Analyses........................................................................................................ 71
9.5.
Interim Analysis.............................................................................................................................. 71
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 72
10.1.
Appendix 1: Abbreviations ............................................................................................................. 72
10.2.
Appendix 2: Clinical Laboratory Tests ........................................................................................... 75
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 76
10.3.1.
Regulatory and Ethical Considerations ...................................................................................... 76
10.3.2.
Financial Disclosure.................................................................................................................... 79
10.3.3.
Informed Consent Process ......................................................................................................... 79
10.3.4.
Data Protection ........................................................................................................................... 80
10.3.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 81
10.3.6.
Committees Structure................................................................................................................. 81
10.3.7.
Publication Policy/Dissemination of Clinical Study Data ............................................................ 82
10.3.8.
Data Quality Assurance.............................................................................................................. 83
10.3.9.
Case Report Form Completion................................................................................................... 84
10.3.10.
Source Documents ..................................................................................................................... 84
10.3.11.
Monitoring ................................................................................................................................... 85
10.3.12.
On-Site Audits............................................................................................................................. 86
10.3.13.
Record Retention........................................................................................................................ 86
10.3.14.
Study and Site Start and Closure ............................................................................................... 86
10.4.
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting................................................................................................................................. 88
10.4.1.
Adverse Event Definitions and Classifications ........................................................................... 88
10.4.2.
Attribution Definitions.................................................................................................................. 89
10.4.3.
Severity Criteria .......................................................................................................................... 89
10.4.4.
Special Reporting Situations ...................................................................................................... 90
10.4.5.
Procedures ................................................................................................................................. 90
10.4.6.
Product Quality Complaint Handling........................................................................................... 92
10.4.7.
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 92
10.5.
Appendix 5: Contraceptive and Barrier Guidance ......................................................................... 93
10.6.
Appendix 6: BCLC Staging System ............................................................................................... 96
10.7.
Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments.................................. 97
10.7.1.
Follow-up assessment Algorithm................................................................................................ 97
10.7.2.
Follow-up Assessments.............................................................................................................. 98
10.8.
Appendix 8: New York Heart Association Criteria ....................................................................... 100
10.9.
Appendix 9: Allowed Recent Second or Prior Malignancies........................................................ 101
10.10.
Appendix 10: RECIST 1.1 and mRECIST Quick Reference........................................................ 102
10.11.
Appendix 11: Eastern Cooperative Oncology Group Performance Status Score ....................... 104
10.12.
Appendix 12: Formulas for Estimating Glomerular Filtration Rate Using Modified Diet in 
Renal Disease Formula (in mL/min) ............................................................................................ 105
10.13.
Appendix 13: Child-Pugh Classification....................................................................................... 106
10.14.
Appendix 14: Protocol Amendment History ................................................................................. 107
11.
REFERENCES................................................................................................................................. 109
INVESTIGATOR AGREEMENT ............................................................................................................... 113




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Status: Approved,  Date: 21 February 2023
1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Phase 2, Open-Label Study to Evaluate the Safety, Efficacy and Pharmacokinetics of 
Amivantamab Monotherapy in Participants with Previously Treated Advanced Hepatocellular 
Carcinoma
Amivantamab (also known as RYBREVANT® or JNJ-61186372) is a low fucose, fully human 
immunoglobulin G1 (IgG1)-based bispecific antibody directed against the epidermal growth factor 
receptor (EGFR) and tyrosine protein kinase mesenchymal epithelial transition (MET, also known
as cMET) receptors. Amivantamab is approved in several countries, including the USA and EU, 
for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) with EGFR exon 20 insertion mutations whose disease has progressed on or after 
platinum-based chemotherapy. Amivantamab shows preclinical activity against NSCLC tumors 
with overexpressed wild type EGFR and activation of the MET pathway. Overexpression of EGFR 
and MET have been found in hepatocellular carcinoma (HCC), and the overexpression often 
associates with poor prognosis. By inhibiting EGFR and MET signaling, either by blocking ligand-
induced activation and/or inducing receptor degradation, amivantamab may disrupt these signaling 
pathways and prevent tumor growth and progression. In addition, the presence of high levels of 
EGFR and MET on the surface of tumor cells allows for targeting of these cells for destruction by 
immune effector cells, through antibody-dependent cellular cytotoxicity (ADCC) and antibody
dependent cellular trogocytosis (ADCT).
Therefore, this open-label, multicenter Phase 2 study will assess the safety and anti-tumor activity 
of amivantamab as a monotherapy in participants with HCC.
OBJECTIVES
The primary objective of this study is to characterize the preliminary antitumor activity, by 
objective response rate (ORR), of amivantamab at the recommended Phase 2 dose (RP2D) in 
participants with previously systemically treated HCC. Key secondary objective is to further 
characterize efficacy as well as safety in this population.
Hypothesis
The hypothesis is that amivantamab monotherapy will lead to ORR higher than 10% (ie, 
: ORR≤10%) in participants with advanced HCC.
OVERALL DESIGN
This is an open-label, single arm, multicenter, Phase 2 interventional study of amivantamab as 
monotherapy in participants with previously treated advanced HCC.
The study will commence with Part 1, comprised of 6 participants and data review after at least 1 
complete cycle of amivantamab therapy, for confirmation of dose and safety. For the main Part 2 
of the study, two analyses are planned: an interim analysis for efficacy after 30 response-evaluable 
participants, and a final analysis after 60 response-evaluable participants. The expansion Part 3 of 


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the study may be opened based on the outcome of Part 2. A retrospective analysis will be 
conducted to understand the correlation of biomarker(s), including the expression level of receptor, 
ligand(s) in the EGFR pathway and/or MET pathway, or other biomarkers, with responsive 
population.
NUMBER OF PARTICIPANTS
A target of approximately 60 participants (at least 30 participants with first line Immuno-Oncology
[IO] combination treatment) will be enrolled in this study in Part 1 and 2; an additional 40 
participants may be included in Part 3. 
TREATMENT GROUPS AND DURATION
Amivantamab as an intravenous (IV) infusion in 28-day cycles: 
Cycle 1: Once weekly (with the first dose split over Day 1 [350 mg] and Day 2 [700 mg if body 
weight is <80 kg or 1,050 mg if body weight is ≥80 kg])
Cycles 2+: Days 1 and 15 of each cycle: 1,050 mg (if body weight is <80 kg) or 1,400 mg (if body 
weight is ≥80 kg)
Dose and administration schedule may be adjusted based on safety evaluation team (SET)
recommendations during the study.
As there are investigations ongoing assessing different amivantamab formulations and schedules, 
participants may receive amivantamab according to a different schedule or route of administration. 
Any such change would only be made after an approved protocol amendment.
EFFICACY EVALUATIONS
Response criteria in solid tumors (RECIST) v1.1 criteria will be used to assess participant response 
to treatment. Disease assessments will occur every 6 weeks (±1 week) for the first 12 months, then 
every 12 weeks (±1 week) until disease progression. If a participant achieves partial response (PR) 
or complete response (CR), confirmation of response may occur at least 4 weeks from the initial 
response.
PHARMACOKINETIC/IMMUNOGENICITY EVALUATIONS
Blood samples will be collected from all participants for the measurement of serum amivantamab 
for PK analyses. Sample collection and testing will comply with local regulations.
Serum samples will be screened for antibodies binding to amivantamab and the number of 
confirmed positive samples will be reported. Other analyses may be performed to further 
characterize the immunogenicity of amivantamab.
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
Tumor tissue samples and blood samples will undergo central analysis to investigate levels of 
MET, EGFR, relevant MET/EGFR ligands, and other biomarkers relevant to target biology or 
HCC. The baseline level of these biomarkers and their changes upon treatment will be correlated 


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with response to amivantamab treatment. The relationship of etiology (eg, Hepatitis B [HepB], 
Hepatitis C [HepC]) with clinical response will also be analyzed. Blood samples will also be 
collected from all participants to analyze pharmacodynamics (PD) markers. Sample collection and 
testing will comply with local regulations.
SAFETY EVALUATIONS
The safety of amivantamab will be assessed by physical examinations, vital signs, safety laboratory 
assessments, monitoring of adverse events (AEs), and concomitant medication usage. Adverse 
events that occur from the date of signing the informed consent form (ICF) through 30 days 
following the last dose of study treatment will be recorded.
STATISTICAL METHODS
Sample Size
The null hypothesis is that the ORR of amivantamab monotherapy in advanced HCC patients is 
less than 10%. Assuming the ORR is 20%, approximately 60 participants will be enrolled to have 
over 85% probability to observe the ORR greater than 15%. With this rule additional participants 
(ie, approximately 40) may be enrolled in an expansion phase to test the ORR of amivantamab 
against the null hypothesis with alpha=0.05 (two-sided) if supported by emerging data. Details 
will be provided in the Statistical Analysis Plan. 
1.2.
Schema
Figure 1:
Schematic Overview of the Study












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2.
INTRODUCTION
Amivantamab, also known as JNJ-61186372, is a low fucose, fully human immunoglobulin G1 
(IgG1)-based bispecific antibody directed against the epidermal growth factor receptor (EGFR) 
and tyrosine protein kinase mesenchymal epithelial transition (MET, also known as cMET) 
receptors. Unlike EGFR tyrosine kinase inhibitors (TKIs), which bind to the intracellular portion 
of the EGFR, amivantamab targets the extracellular domain of both EGFR and MET. By 
inhibiting EGFR and MET signaling, either by blocking ligand-induced activation and/or 
inducing receptor degradation, amivantamab may disrupt these signaling pathways and prevent 
tumor growth and progression. In addition, the presence of high levels of EGFR and MET on 
the surface of tumor cells allows for targeting of these cells for destruction by immune effector 
cells, through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent 
cellular trogocytosis (ADCT). Amivantamab shows pre-clinical activity against NSCLC tumors 
with overexpressed wild type EGFR and activation of the MET pathway (Moores 2016). Both 
EGFR and MET have been found to be overexpressed in hepatocellular carcinoma (HCC), and 
the overexpression often associates with poor prognosis. 
This is an open-label, multicenter Phase 2 study of amivantamab monotherapy in participants with 
previously treated advanced HCC. Given the antitumor activity observed in NSCLC, this study 
will evaluate the safety and confirm the recommended Phase 2 dose (RP2D) of amivantamab and 
investigate the preliminary anti-tumor activity of amivantamab as a monotherapy in HCC.
For the most comprehensive nonclinical and clinical information regarding amivantamab, refer to
the latest version of the Investigator's Brochure (IB) and Addenda for amivantamab.
The term “study treatment” throughout the protocol, refers to study drug as defined in Section 6.1,
Study treatments Administered.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
2.1.
Background
2.1.1.
The Epidemiology of HCC
Liver cancer is the 7th most common malignancy and the 3rd leading cause of cancer-related death 
worldwide, with over 906,000 new primary liver cancer cases resulting in 830,000 deaths globally 
in 2020 (Sung 2021; Globocan 2020). The major etiologies of liver cancer include chronic hepatitis 
B virus (HBV) and hepatitis C virus (HCV) infection, alcohol consumption, steatosis, aflatoxin 
exposure (Sherman 2005; Thomas 2005). Primary liver cancer includes HCC (comprising 75%-
85% of cases) and intrahepatic cholangiocarcinoma (10%-15%), as well as other rare types 
(Sung 2021). 


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2.1.2.
HCC Current Treatment Options and Outcome
Patients with HCC are often diagnosed at an advanced stage with distance metastases or with 
disease that is not amenable to surgery or local treatment. Patients have a poor prognosis, with a
5-year overall survival (OS) rate of 10–18% (Zeng 2018; Siegel 2018). In China, liver cancer is 
the 4th most common cancer and 2nd leading cause of cancer death with over 410,000 new primary 
liver cancer cases resulting in 391,000 deaths in 2020 (Zheng 2019; Globocan 2020). China 
accounts for 45.3% and 47.1% of global new primary liver cancer cases, and liver cancer-related 
deaths, respectively (Globocan 2020). Chronic HBV infection is the most frequent cause (84%) of 
HCC in China (Chinese chronic hepatitis B guideline 2019), while in the Western countries chronic 
HCV, alcoholic cirrhosis and non-alcoholic steatohepatitis (NASH) are the main causes 
(Medavaram 2018). 
Systemic therapies are recommended for HCC patients who have advanced disease (BCLC 
[Barcelona clinic liver cancer] stage C) or intermediate-stage disease (BCLC stage B) and 
progressed despite transarterial therapies (Villanueva 2019). Sorafenib was approved in 2007 as 
first-line targeted therapy for advanced HCC based on the success of SHARP and Asia-Pacific 
trial, ushering in the era of systemic treatment (Huang 2020; Llovet 2008; Cheng 2009). With low 
rates of objective tumor responses (2%), however, the clinical benefit of sorafenib remains modest 
and the investigation of additional novel therapeutics that can target the complex molecular 
pathogenesis of HCC is continued. As first-line treatment, lenvatinib was non-inferior to sorafenib 
in OS (13.6 months vs 12.3 months; hazard ratio [HR] was 0.92) and objective response rate (ORR)
(18.8% vs 6.5%) (Kudo 2018), and has surpassed the use of sorafenib as a front-line therapy in the 
current treatment of HCC in China. Newly approved atezolizumab plus bevacizumab in first-line 
treatment shows better OS (19.2 months), PFS (6.8 months) and ORR (30%) than sorafenib 
(Finn 2020) and has become another frequently utilized front-line option. 
The treatment landscape of HCC in second-line setting has been evolving since 2017, with 
regorafenib, nivolumab, pembrolizumab, cabozantinib, and ramucirumab being approved for
patients progressed on or after sorafenib (Bruix 2017; Zhu 2018; Abou 2018; Zhu 2019;
Meyer 2018). In China, regorafenib, apatinib, and local anti- programmed cell death 1 (PD-1)
antibodies (camrelizumab and tislelizumab) monotherapy are approved for advanced HCC in the 
second-line setting. Collectively, the approved second-line monotherapies show modest objective 
response rates (4-17%) and OS benefits (8.5-15.1 months) (Bruix 2017; Zhu 2018; Abou 2018; 
Zhu 2019; Meyer 2018). Recently United States (US) Food and Drug administration (FDA)
conditionally approved nivolumab plus ipilimumab with its encouraging 32% ORR data in
advanced HCC patients previously treated with sorafenib (Yau 2020; Saung 2021). However, it is 
only approved in US and associated with considerable toxicity, with any grade treatment-related 
adverse events and Grade 3-4 treatment-related adverse events (nivolumab 1 mg/kg plus 
ipilimumab 3 mg/kg every 3 weeks) of 94% and 76%, respectively (Yau 2020; Saung 2021).
Despite the encouraging recent progress with multi-targeted TKIs and immune-based therapies for 
advanced HCC, several challenges remain. The most important one is the limited efficacy of 
current treatment options as described above (Bruix 2017; Zhu 2018; Abou 2018; Zhu 2019;
Meyer 2018). Another is drug-related adverse events, which often lead to dose reduction, 


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interruption or discontinuation (Niu 2021). The third challenge is drug resistance, which remains 
a major cause of the failure of targeted therapy (Niu 2021). The underlying mechanisms include 
the intrinsic HCC heterogeneity and clonal evolution, and the lack of reliable biomarkers to 
identify HCC patients most likely to benefit from targeted and immune therapies (Niu 2021;
Rizzo 2021). Considering the high malignancy and heterogeneity of HCC and scarce effective 
treatment options, there is a great unmet need to develop novel drugs for advanced HCC (Yau 2020;
Qin 2020). 
2.1.3.
EGFR and MET Signaling Pathways in HCC
Overexpression and genetic alterations of EGFR and MET have been closely linked to 
tumorigenesis, aggressive progression, and poor prognosis in multiple cancer types, supporting 
their importance as therapeutic targets for cancer therapy (Birchmeier 2003; Hynes 2005; 
Yano 2003). Indeed, agents targeting EGFR (including anti-EGFR antibodies and EGFR TKIs) 
have revolutionized the treatments for patients with colorectal cancer, non-small cell lung cancer 
(NSCLC), and head and neck cancer (Hsu 2018; Li 2020; Taberna 2019). Similarly, the recent 
approval of MET inhibitors in NSCLC with MET Exon14 skipping alteration further expanded 
the treatment options for biomarker selected patients (Mathieu 2021). Although these 2 pathways 
are not currently targeted in the context of HCC, it is reported that approximately 63.2-66.0% and 
25.4-38.8% of patients with HCC have tumors characterized by overexpression of EGFR and 
MET, respectively (Huang 2019; Buckley 2008). The overexpression of MET often associates 
with poor prognosis in HCC (Lee 2013; Kondo 2013). Unlike in NSCLC, where the genetic 
alterations and gene amplification of EGFR and MET drives pathway activation, the activation of 
EGFR and MET pathways are frequently driven by the canonical ligand-receptor binding in HCC. 
Indeed, aberrantly high levels of MET ligand, hepatocyte growth factor (HGF), have been 
implicated in promoting HCC progression and metastasis (Junbo 1999; Yang 2022). Given the 
importance of EGFR and MET pathways in HCC, many clinical trials have examined the activities 
of EGFR or MET targeting agents, although results have been disappointing so far. For example, 
erlotinib, an EGFR TKI, combined with bevacizumab did not achieve encouraging outcome in 
sorafenib-refractory HCC population (irrespective of EGFR status) (Niu 2017; Philip 2012). 
Similarly, studies evaluating the efficacy of tivantinib (a selective oral MET inhibitor, Daiichi 
Sankyo) failed to show clinical benefit in MET-high advanced HCC in a 2nd line Phase 3 study 
(Rimassa 2018).
One possible reason for prior failures in clinical benefit is the redundant signaling pathways that 
may confer primary or required resistance to the therapeutic intervention against a single receptor 
target (Zhang Y 2018). It is well known that the EGFR and MET pathways have many overlapping 
downstream signaling modules, which collectively are pro-tumorigenic and pro-progression
(Yamaguchi 2014; Zhang YZ 2018). Co-overexpression of EGFR and MET has been reported in 
24.5% of HCC patients (Dong 2019), which has been confirmed by in-house data. Thus, the 
suppression of EGFR or MET pathway alone may not be sufficient to block the oncogenic 
signaling and elicit clinical benefit in HCC. In NSCLC, it is well known that MET pathway 
activation mediates treatment resistance with EGFR inhibitors. Similarly, activation of MET
pathway is also found to mediate resistance to Cetuximab in colorectal cancer (CRC) and head and 
neck squamous cell carcinoma (HNSCC) (Novoplansky 2019). Conversely, EGFR amplification 


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is recently found as a resistance mechanism in NSCLC treated by MET TKI (Recondo 2020). 
Importantly, combination of EGFR and MET inhibitors has demonstrated clinical benefit in 
biomarker selected subpopulation analysis in NSCLC clinical trials (Wu 2020; Scagliotti 2020). 
2.1.4.
Amivantamab and EGFR / MET Signaling Pathway
Amivantamab, also known as RYBREVANT® or JNJ-61186372, is a low fucose, fully human 
IgG1-based bispecific antibody directed against the EGFR and MET receptors, that shows 
preclinical activity against tumors with overexpressed wild type EGFR and activation of the MET
pathway. Unlike EGFR TKIs, which bind to the intracellular portion of the EGFR, amivantamab 
targets the extracellular domain of both EGFR and MET. Preclinical data suggest it has at least 3 
potential mechanisms of action, including 1) inhibition of ligand-dependent signaling, 2) 
downregulation of EGFR and MET expression levels, and 3) initiation of ADCC. It is 
hypothesized that by targeting the extracellular domain of EGFR and MET, amivantamab can 
inhibit receptors that display primary resistance to EGFR TKIs (Exon 20 insertion) or have 
acquired either EGFR resistance mutations (T790M or C797S) or secondary activation of the MET
pathway (MET amplification).
Based on early activity observed within the EGFR exon 20 insertion population, amivantamab was
awarded Breakthrough Therapy Designation by FDA and China Center for Drug Evaluation 
(CDE) for the treatment of patients with EGFR exon 20 insertion NSCLC, after progression on 
prior platinum-based chemotherapy. On 21 May 2021, the US FDA granted amivantamab 
accelerated approval for the treatment of adult patients with locally advanced or metastatic NSCLC 
with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has 
progressed on or after platinum-based chemotherapy. Amivantamab is currently approved in 
multiple countries and marketed under the name RYBREVANT®.
2.1.5.
Amivantamab in Preclinical HCC PDX models
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI




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Fc-independent EGFR and MET signal inhibition, multiple Fc-dependent mechanisms (including 
ADCC, macrophage- and monocyte-mediated ADCT) have been implicated in the robust anti-
tumor effect of amivantamab (Moores 2016; Grugan 2017; Vijayaraghavan 2020). The complex 
immune microenvironment in HCC has provided opportunities for immunotherapies. The 
Fc-driven mechanisms of amivantamab may mobilize immune cells in the microenvironment to 
contribute to clinical benefit.
Amivantamab inhibits EGFR and MET signaling functions by blocking ligand-induced activation 
and inducing receptor degradation; disruption of these signaling pathways prevents tumor growth 
and progression. In addition, due to reduced fucosylation, amivantamab has enhanced capability 
to engage immune effector cells. The presence of EGFR and MET on the surface of tumor cells 
allows amivantamab to bind them and to target these cells for destruction by natural killer (NK) 
cells and macrophages, through ADCC and trogocytosis mechanisms, respectively. Based on 
nonclinical data, amivantamab may employ multiple mechanisms to inhibit tumors with aberrant 
EGFR and MET signaling. 
Furthermore, preliminary biomarker evaluation has suggested amivantamab to be more active in 
patients with tumors that have higher expression of EGFR and MET in osimertinib-relapsed EGFR 
mutated NSCLC disease (Bauml 2021).
This study aims to evaluate the clinical activity of amivantamab as a monotherapy in HCC 
participants with previously treated advanced HCC.
Amivantamab Intravenous Dose Rationale
Amivantamab will be administered at the recommended dose (approved for treatment of NSCLC 
with EGFR Exon 20 ins) of 1,050 mg for participants with a baseline body weight (BW) <80 kg 
and 1,400 mg for participants with a baseline BW ≥80 kg. This dose was based on the totality of 
exposure, safety, and efficacy data from the ongoing Phase 1 Study 61186372EDI1001 (EDI1001 
study). Amivantamab for intravenous administration was generally well tolerated at doses up to 
1,750 mg, with no dose limiting toxicity (DLT) reported during the initial dose escalation and no 
maximum tolerated dose identified in NSCLC participants. The recommended dose achieved a 
complete soluble target saturation throughout dosing for EGFR and MET in the NSCLC 
participants. Amivantamab is administered by intravenous (IV) infusion in 28-day cycles, once 
weekly in Cycle 1 (with a split dose on Days 1 and 2), and then every 2 weeks in subsequent 
cycles. 
Over a thousand patients with NSCLC, characterized by diverse EGFR and MET alterations, have 
received amivantamab at the recommended dose, as either a monotherapy or in combination with 
lazertinib, a third generation EGFR TKI, with a safety profile that is consistent with on-target 
activity against EGFR and MET. Toxicities have been manageable, with the majority of treatment-
emergent adverse events (TEAEs) Grade 1 to 2 in severity. Furthermore, amivantamab at doses up 
to 1,750 mg in a Q2W regimen as a monotherapy, and up to 2,100 mg in combination with 
carboplatin and pemetrexed in lung cancer patients, has been demonstrated to be safe and tolerable, 
achieving similar exposures as the approved Q2W dose (Nagasaka 2021). 


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In currently ongoing studies, amivantamab at the recommended dose has been administered to 
participants with gastric and esophageal cancer, providing preliminary evidence for a manageable 
safety profile in patients with digestive system malignancies.
2.3.
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of amivantamab may 
be found in the IB.
2.3.1.
Risks for Study Participation
The safety and tolerability of amivantamab monotherapy has been demonstrated in the Phase 1
Study 61186372EDI1001 in NSCLC patients. Amivantamab was generally well tolerated with a 
safety profile consistent with on-target anti-EGFR and MET activity, paronychia, rash, dermatitis 
acneiform, fatigue and stomatitis (anti-EGFR effects), as well as hypoalbuminemia and peripheral 
edema (anti-MET effects) were observed. However, given that the available clinical data are 
limited to NSCLC participants, unforeseen safety risks including alanine aminotransferase (ALT)/
aspartate aminotransferase (AST) increased associated with the study treatments are possible 
considering the synergistic effect in HCC participants. This study protocol includes the following 
elements to mitigate risks for study participants:

The SET, in conjunction with the coordinating investigator, will review the safety and conduct 
of study periodically. (The initial review of safety will occur after the first 6 participants have 
enrolled and have completed at least 1 complete cycle of amivantamab therapy).

Eligibility criteria have been established to minimize risk, with regards to known safety profile 
of amivantamab. Participants will also be monitored closely for safety throughout the study 
(refer to Safety Assessments), per the scheduled assessments outlined in the SoA (Table 1).

Dose modification guidance is provided to manage toxicities that occur during the study (refer
to Section 6.5 and Section 5.5, including specific guidance for infusion-related reactions 
[IRRs], rash, interstitial lung disease [ILD], liver test abnormalities, or paronychia).
2.3.2.
Benefits for Study Participation
Although many agents targeting EGFR have been approved and are part of standard of care for
many tumor types, no anti-EGFR or anti-MET therapy has been approved in HCC. Amivantamab 
has demonstrated significant activity as monotherapy for the treatment of NSCLC, receiving 
Breakthrough Therapy Designation by the US FDA and China CDE, based on an objective 
response rate (ORR) of 41% in participants with EGFR Exon 20ins disease, after prior treatment 
with platinum-based chemotherapy. Consistent with the unique mechanism of action of 
amivantamab, activity was observed in participants with diverse EGFR mutations, as well as in 
participants with amplification of MET and overexpressed EGFR.
It is anticipated that using this targeted therapeutic approach with amivantamab as a single agent
in refractory HCC participants may provide benefit to these participants.


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2.3.3.
Benefit-Risk Assessment for Study Participation
Considering the measures taken to minimize risk to participants of this study (refer to
Section 2.3.1), the potential risks of amivantamab are justified by the anticipated benefits that may
be afforded to advanced HCC participants with very limited treatment options (refer to
Section 2.3.2). More detailed information about the known and expected benefits and risks of 
amivantamab may be found in the IB and Addenda for amivantamab.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To characterize the preliminary antitumor 
activity 
of 
amivantamab 
at 
the 
recommended dose in participants with 
previously systemically treated HCC
Objective response rate (ORR) as determined by 
investigator, according to the Response Criteria in 
Solid Tumors (RECIST) v1.1. Confirmation of 
investigator-assessed ORR may be performed 
through Blinded Independent Central Review 
(BICR)
Secondary

To assess additional measures of clinical 
benefit with amivantamab

Duration of response (DoR)

Disease control rate (DCR)

Progression-free survival (PFS)

Overall survival (OS)

To characterize the safety and tolerability of 
amivantamab in participants with advanced 
HCC
Incidence of adverse events defined by the National 
Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Criteria version 5.0, 
lab abnormalities and vital signs in participants 
treated with amivantamab as a monotherapy

To assess the pharmacokinetics (PK) and 
immunogenicity of amivantamab following
single and multiple intravenous dose 
administrations
Serum PK parameters including but not limited to 
maximum serum concentration (Cmax), time to reach 
the maximum serum concentration (Tmax), 
AUC(t1-t2), AUCtau, serum concentration 
immediately prior the next study treatment 
administration (Ctrough), and accumulation ratio (R); 
incidence of antidrug antibodies
Exploratory

To further explore the clinical benefit 
achieved 
with amivantamab 
treatment 
through alternative response criteria 
ORR, as determined by Investigator Review, 
according to modified RECIST

Explore tissue biomarkers (including but not limited to EGFR, MET expression) and blood 
biomarkers predictive of clinical response and resistance to amivantamab 

Explore the relationship between serum PK, pharmacodynamic (PD) markers and clinical outcome

Explore the relationship of etiology (eg, HepB, HepC) and clinical response

Explore primary and acquired resistance to amivantamab treatment
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.


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HYPOTHESIS
The hypothesis is that amivantamab monotherapy will lead to an ORR higher than 10% (ie, 
: ORR≤10%) in participants with advanced HCC.
4.
STUDY DESIGN
4.1.
Overall Design
This is an open-label, single arm, multicenter, Phase 2 interventional study of amivantamab as 
monotherapy in participants with previously treated advanced HCC.
The 61186372HCC2001 study will aim to enroll a participant population that is geographically 
reflective of the overall incidence/prevalence of this disease.
A target of approximately 60 participants (at least 30 participants with first-line Immuno-Oncology
[IO] combination treatment) will be enrolled in this study. The study will commence with Part 1, 
comprised of 6 participants and data review after at least 1 complete cycle of amivantamab therapy, 
for confirmation of dose and safety. For the main Part 2 of the study, two analyses are planned: an
interim analysis for review of efficacy after 30 response-evaluable participants, and a final analysis 
after 60 response-evaluable participants. The expansion Part 3 of the study, with approximately 40 
participants, may be opened based on the outcomes of the Part 2 final analysis. A retrospective 
analysis will be conducted to understand the correlation of biomarker(s), including the expression 
level of receptor, ligand(s) in the EGFR pathway and/or MET pathway, or other biomarkers, with 
responsive population.
The SET will be commissioned for this study. Participants’ safety will be monitored throughout 
the study by the SET established by the Sponsor. Refer to Committees Structure in Appendix 3:
Regulatory, Ethical, and Study Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2 Schema.
4.1.1.
Screening Period
The Screening Period starts at the time of the signing informed consent form (ICF) and ends at the 
start of the first administration of study treatment. The ICF must be signed before the first study-
related activity is conducted. Screening procedures must be completed within 28 days before the 
first dose of study treatment. 
To be eligible for participation, all participants must have been previously diagnosed with 
histologically or cytologically confirmed unresectable or metastatic HCC. All participants must 
have progressed on or after the most recent therapy.
During the screening period, participants will be evaluated for study eligibility, as described in the 
Schedule of Activities (SoA). Informed consent does not expire if the screening related procedures
are not performed within the 28-day Screening Period, although evaluations performed outside the 
screening window will need to be repeated, the exception to this will be fresh biopsy sample as 
long as there is no systemic treatment between the first and any subsequent re-screening. Pre-


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treatment biopsy samples will be collected for all participants. Tumor biopsy acquired at screening 
is preferred. If not available, the most recent tumor sample is acceptable. Wherever possible, non-
target lesions should be biopsied rather than target lesions. Biopsy of a target lesion is allowed for 
the pre-treatment sample, but baseline disease assessment must occur a minimum of 1 week after 
the biopsy procedure. Other types of examinations, eg, bone scintigraphy, may also be conducted 
at Screening, per the Investigator’s clinical judgment and local standard of care. Imaging vendor 
acquisition guidelines regarding imaging techniques should be followed. Brain MRI (or brain CT 
scan with contrast if MRI is contraindicated) will also be performed at Screening. If imaging data 
that satisfy the imaging criteria is available as part of the routine care and performed within 28 
days of C1D1, even if prior to signing the ICF, then screening imaging does not have to be 
repeated.
Participants who fail to meet the inclusion and/or meet the exclusion criteria may be rescreened if 
their condition changes. Rescreening must be discussed with and approved by the sponsor on a 
case-by-case basis. Participants who are determined to be eligible for the study due to changes in 
their condition after initially failing screening must sign a new ICF. The data obtained closest to 
the first study treatment administration will be used to determine eligibility.
4.1.2.
Treatment Period
The Treatment Phase will begin on C1D1 with the administration of the study treatment and 
continue as 28-day cycles until the End of Treatment visit, approximately 30 days after 
discontinuation of study treatment. The frequency of study site visits and details of the procedures 
performed are outlined in the Schedule of Activities (SoA). The latest measurements taken before 
administration of the first study treatment will be defined as baseline values. Study treatment will 
continue until documented clinical or radiographic (RECIST Version 1.1) disease progression or 
until the participant meets another criterion for discontinuation of study treatment (Section 7.1).
At each study visit during the treatment phase, participants will undergo safety evaluations, 
including physical examinations and assessment of AEs, vital signs, concomitant medication 
usage, and clinical laboratory parameters. Participants will also have blood samples drawn for 
assessment of PK, PD and immunogenicity parameters and for biomarker evaluations at selected 
visits. 
Safety will be assessed as described in Section 8.2. Any new concomitant medications or changes 
to concomitant medications will be recorded. Adverse event information will be graded using the 
NCI-CTCAE, Version 5.0.
Throughout the Treatment Period, the investigator will assess participant response to therapy using 
RECIST v1.1. Efficacy evaluations are described in Section 8.1.
For participants who discontinue treatment prior to disease progression (reasons such as an adverse 
event), radiological assessments should be performed according to the Schedule of Activities 
(SoA) until the earlier of disease progression or initiation of new anti-cancer therapy. 


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4.1.3.
Follow-up Period
Participants who discontinue study treatment for any reason will be followed for survival in the 
Follow-up Phase. Survival, subsequent anticancer treatment, and disease status will be assessed 
every 12 weeks (±14 days) after the last dose of study treatment or disease progression (whichever 
occurs first), until the end of study, death, lost to follow-up, or withdrawal of consent, whichever 
comes first. If the information is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. If the participant has died, 
the date and cause of death will be collected and documented on the electronic case report form 
(eCRF). Investigators may recontact the participant to obtain long-term follow-up information 
regarding the participant’s safety or survival status as noted in the ICF.
4.2.
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Intervention Groups
This is an open-label non-randomized study; therefore, no blinding or randomization is applied.
Clinical pharmacology assessment
Due to lack of PK, PD and immunogenicity (antibodies to amivantamab, also termed ADA) data 
in HCC patients and in order to better characterize the PK profiles, PK/PD and ADA for this 
population, serum samples will be collected and analyzed for amivantamab concentrations, and 
estimation of basic PK parameters from this concentration-time data will be performed and 
reported. ADA will be evaluated for impact on PK. Pharmacokinetic profiles and parameters will 
be assessed relative to clinical safety, PD (soluble EGFR and soluble MET), efficacy, as available, 
as well as to the efficacious concentrations observed in preclinical studies. 
Biomarker Collection
Pre-treatment tumor samples will be assessed at central labs for EGFR and MET expression at 
protein levels; for HGF and selected EGFR ligands expression at mRNA levels. Post-treatment 
tumor samples, if collected, will also be assessed for these biomarkers to evaluate the changes
from baseline that may indicate target modulation, and track response to treatment. 
Blood samples will be collected at before and after treatment in the study to evaluate circulating 
factors relevant to target and disease biology (eg, MET and EGFR ligands, AFP) and their 
correlation with treatment response.  
Additional biomarkers (eg, DNA, RNA, and protein) relevant to target biology or HCC may also 
be assessed in blood and tissue samples collected during the study to correlate with response, and 
to better understand the mechanisms of response or resistance to amivantamab treatment.
Tumor tissue and blood sample collection and analysis in China will be performed only after 
Human Genetic Resources Administration Office (HGRAO) approval is obtained.


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4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits, 
and potential AEs of the study, and provide their consent voluntarily will be enrolled. Written 
consent/assent may be obtained through various sources (eg, paper or electronic such as eConsent, 
eSignature, or digital signature) as determined by regulations as well as study and/or patient 
preferences.
Thorough scientific evaluation of any treatment before marketing authorization is an ethical and 
regulatory requirement. As the benefits and risks of amivantamab as a monotherapy in this study 
population are not fully known, this study will evaluate safety and clinical activity. Participants 
will be closely monitored throughout the study, as discussed throughout this protocol, for both 
safety and clinical benefit. The SET will review evolving safety data from this study, as well as 
efficacy data as appropriate. Based on the observed activity of amivantamab in NSCLC 
participants, preclinical data of amivantamab in the HCC PDX model, there is adequate 
justification to initiate this study.
As with all clinical studies, there are risks associated with venipuncture and multiple blood sample 
collection. The blood sample collection scheme was designed to collect the minimum number of 
blood samples that accurately and completely describe the pharmacology of the study treatment. 
This minimizes the number of venipunctures and the total volume of blood collected from each 
participant during the study. The total blood volume to be collected is considered to be an acceptable 
amount of blood to be collected over this time period from the population in this study based upon 
the standard of the
Chinese Red Cross blood donation and American Red Cross 
(Chinese Red Cross Society; American Red Cross).
4.3.
Justification for Dose
Amivantamab will be dosed at the approved dose (for treatment of NSCLC with EGFR Exon 20ins) 
of 1,050 mg for participants with a baseline body weight (BW) <80 kg and 1,400 mg for 
participants with a baseline BW ≥80 kg. This dose was based on the totality of exposure, safety,
and efficacy data from the ongoing Phase 1 Study 61186372EDI1001 (EDI1001 study).
Amivantamab for intravenous administration was generally well tolerated at doses up to 1,750 mg, 
with no DLT reported during the initial dose escalation and no maximum tolerated dose identified 
in NSCLC participants. The recommended dose achieved a complete soluble target saturation 
throughout dosing for EGFR and MET in the NSCLC participants.
Amivantamab is administered by IV infusion in 28-day cycles, once weekly in Cycle 1 (with a 
split dose on Days 1 and 2), and then every 2 weeks in subsequent cycles. Over a thousand patients 
with NSCLC, characterized by diverse EGFR and MET alterations, have received amivantamab 
at the recommended dose either as monotherapy or in combination. Amivantamab was generally 


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well tolerated with a safety profile consistent with on-target anti-EGFR and MET activity:
paronychia, rash, dermatitis acneiform, fatigue and stomatitis (anti-EGFR effects), as well as
hypoalbuminemia and peripheral edema (anti-MET effects) and IRR were observed. Furthermore, 
amivantamab at doses up to 1,750 mg in a Q2W regimen as a monotherapy, and up to 2,100 mg 
in combination with carboplatin and pemetrexed in lung cancer patients, has been demonstrated to 
be safe and tolerable, achieving similar exposures as the approved Q2W dose (Nagasaka 2021). In 
addition to NSCLC, amivantamab at the recommended dose has been administered to participants 
with gastric and esophageal cancer, providing preliminary evidence for a manageable safety profile 
in patients with gastrointestinal malignancies. 
For HCC population, at least comparable antitumor potency in vivo between NSCLC and HCC 
animal models was observed. For above reasons, it is considered appropriate to administer the 
RP2D of amivantamab for HCC indication.
4.4.
End of Study Definition
End of Study Definition
The end of study is considered as the last scheduled study assessment shown in the Schedule of 
Activities for the last participant in the study. The final data from the study site will be sent to the 
sponsor (or designee) after completion of the final participant assessment at that study site, in the 
time frame specified in the Clinical Trial Agreement (approximately 12 months after the last 
participant is enrolled).
For participants who complete treatment and who are eligible for continued access program (post 
study access or other open-label extension study under a different/separate protocol), the end of 
study is defined as the end of treatment visit.
Participant Study Completion Definition
A participant will be considered to have completed the study if he or she has died before the end 
of the study or has not been lost to follow-up or withdrawn consent by the end of the study.
When a participant withdraws consent for follow-up before completing the study, the reason for 
withdrawal is to be documented in the case report form (CRF) and in the source document. Every 
effort should be made to clarify to participants the importance of post-treatment follow-up, and 
that withdrawal of consent to further treatment can still allow for participation in follow-up period 
of study.
5.
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before administration of the 
study treatment. Refer to Section 5.4, Screen Failures for conditions under which the repeat of any 
screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 


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representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed. 
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
Sample Size Determination.
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1.
Participants must be ≥18 years (or the legal age of consent in the jurisdiction in which the 
study is taking place) at the time of informed consent.
Type of Participant and Disease Characteristic
2.
Participant must agree to provide protocol defined clinically feasible tissue samples Refer 
to Section 8.6 for details. 
3.
Participant must have histologically or cytologically confirmed diagnosis of HCC 
(fibrolamellar and mixed hepatocellular / cholangiocarcinoma subtypes are not eligible) 
based on pathology report, who have BCLC Stage C disease or BCLC Stage B disease 
not amenable to locoregional therapy or refractory to locoregional therapy, and not 
amenable to a curative treatment approach.
4.
Criterion modified per Amendment 2.
4.1. Participants should have progressed on standard of care (SoC) therapy with 
immunotherapy (eg, PD-1/L1-containing therapy) and a multi-targeted kinase 
inhibitor (MKI). Participation is allowed after progression with just one of these 
therapies, if the participant is intolerant of, or declining treatment with, the other 
SoC therapy (PD-1/L1-containing therapy or MKI).
a.
Prior adjuvant or neoadjuvant therapy will be considered as 1 prior line of 
systemic therapy for the purpose of meeting the eligibility criteria if 
participant experienced progression within 24 weeks of such therapy. 
b. The intolerance or declining of further therapy should be documented in 
medical record, and discussed with the sponsor medical team. 
Note: A line of therapy is defined as a treatment regimen with subsequent disease 
progression
5.
Child-Pugh A classification for liver function assessed within 7 days of first dose of study 
drug. Refer to Appendix 13 for details of Child-Pugh A classification.


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6.
Participant must have measurable disease according to RECIST Version 1.1. Selected
target lesions must meet 1 of 2 criteria: 1) not previously treated with local therapy or 2) 
within the field of prior local therapy but with documented subsequent progression as per 
RECIST v1.1. If only 1 measurable lesion exists and was used for screening biopsy, 
baseline tumor assessment scans must be performed ≥ 7 days after the biopsy.
7.
Participant must have Eastern Cooperative Oncology Group (ECOG) performance status 
0 or 1 within 7 days of first dose of study treatment.
8.
Criterion modified per Amendment 2.
8.1. Participants are eligible to enroll if they have non-viral-HCC or if they have HBV-, 
or HCV-HCC, defined as follows:
a.
Chronic HBV infection as evidenced by detectable HBV surface antigen or HBV 
DNA. Participants with chronic HBV infection must be on antiviral therapy [per 
local standard of care, eg, entecavir (ETV) or tenofovir disoproxil fumarate 
(TDF)] for a minimum of 14 days prior to study entry and willingness to continue 
treatment for the length of the study, and HBV viral load must be less than 
2000 IU/mL prior to the first dose of study treatment. Those participants who are 
anti-HBc (+), and negative for HBsAg, and negative for anti-HBs, and have an 
HBV viral load under 20 IU/mL do not require HBV anti-viral prophylaxis but
need close monitoring.
b. Active or resolved HCV infection as evidenced by detectable HCV RNA or 
antibody.
9.
Participant must have adequate organ and bone marrow function as follows, without 
history of red blood cell transfusion, platelet transfusion, growth factors or albumin 
infusion within 14 days prior to the date of the laboratory test.
a.
Adequate hematologic function:
o
Hemoglobin ≥9 g/dL
o
Absolute neutrophil count ≥1.5× 103/μL, without use of granulocyte colony 
stimulating factor (G-CSF) within 10 days prior to the date of the test
o
Platelets ≥75 × 103/μL
o
For participants not receiving therapeutic anticoagulation: international 
normalized ratio (INR) or activated partial thromboplastin time (aPTT) 
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b. Adequate hepatic function with serum albumin ≥3.1 g/dL, serum bilirubin 
≤2.5 × ULN, and aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤5 × ULN 
c.
Have an estimated glomerular filtration rate (eGFR), based on the Modified Diet 
in Renal Disease (MDRD) 4-variable formula (see Appendix 12), of >50 mL/min
10.
Human immunodeficiency virus-positive participants are eligible if they meet all of the 
following:
a.
No detectable viral load (ie, <50 copies/mL) at screening
b. CD4+ count >300 cells/mm3 at screening
c.
No acquired immunodeficiency syndrome (AIDS)-defining opportunistic 
infection within 6 months of screening
d. Receiving highly active antiretroviral therapy (HAART). Any changes in HAART 
due to resistance/progression should occur at least 3 months prior to screening. A 
change in HAART due to toxicity is allowed up to 4 weeks prior to screening.
Note: HAART that could interfere with study treatment is excluded (consult the sponsor 
for a review of medications prior to enrollment).
Prior Malignancies
11.
May have a prior or concurrent second malignancy (other than the disease under study) 
which natural history or treatment is unlikely to interfere with any study endpoints of 
safety or the efficacy of the study treatment(s) (see Appendix 9 on Allowed Recent 
Second or Prior Malignancies for details).
Sex and Contraceptive/Barrier Requirements
12.
Criterion modified per Amendment 2.
12.1. Afemale participant of childbearing potential must have a negative serum (-human 
chorionic gonadotropin [-hCG]) pregnancy test at screening and within 72 hours of the 
first dose of study treatment and must agree to further serum or urine pregnancy tests 
during the study.
13.
Criterion modified per Amendment 2.
13.1. A female participant must be either of the following (as defined in Appendix 5: 
Contraceptive and Barrier Guidance)
a.
Not of childbearing potential or


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b.
Of childbearing potential and practicing at least 1 highly effective method of 
contraception (details in Appendix 5: Contraceptive and Barrier Guidance) 
contraception throughout the study and through 6 months after the last dose of 
study treatment.
Note: If a female participant becomes of childbearing potential after start of the study the 
female participant must comply with point (b.).
14.
A female participant must not be pregnant, breastfeeding, or planning to become pregnant 
while enrolled in this study or within 6 months after the last dose of study treatment.
15.
A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use 
for the purposes of assisted reproduction during the study and for a period of 6 months 
after receiving the last dose of study treatment. Female participants should consider 
preservation of eggs prior to study treatment as anti-cancer treatments may impair 
fertility.
16.
A male participant must wear a condom when engaging in any activity that allows for 
passage of ejaculate to another person during the study and for a minimum of 6 months 
after receiving the last dose of study treatment. 
If the male participant’s partner is a female of childbearing potential, the male participant 
must use condoms with spermicide and the female partner of the male participant must 
also be practicing a highly effective method of contraception (see Appendix 5: 
Contraceptive and Barrier Guidance). A male participant who is vasectomized must still 
use a condom (with or without spermicide), but the partner is not required to use 
contraception. His female partner, if of childbearing potential, must also be practicing a 
highly effective method of contraception.
If the male participant is vasectomized, he still must wear a condom, but his female 
partner is not required to use contraception.
17.
A male participant must agree not to donate sperm for the purpose of reproduction during 
the study and for a minimum of 6 months after receiving the last dose of study treatment.
Male participants should consider preservation of sperm prior to study treatment as anti-
cancer treatments may impair fertility.
18.
Participant must agree not to plan to father a child while enrolled in this study or within 
6 months after the last dose of study treatment.
Informed Consent
19.
Participant must sign an ICF indicating that the participant understands the purpose of, 
and procedures required for, the study and is willing to participate in the study.


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20.
Participant must be willing and able to adhere to the lifestyle restrictions specified in this 
protocol.
5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
Medical Conditions
1.
Participant has an uncontrolled illness, including but not limited to the following:
a.
Uncontrolled diabetes
b. Ongoing or active bacterial infection (includes infection requiring treatment 
with antimicrobial therapy [participants will be required to complete antibiotics 
1 week before enrollment]), symptomatic viral infection, or any other clinically 
significant infection 
c.
Active bleeding diathesis
d. Psychiatric illness/social situation that would limit compliance with study 
requirements.
e.
Impaired oxygenation requiring continuous oxygen supplementation.
2.
Participants with any of the below due to the underlying HCC
a.
Prior liver transplant
b. History of hepatic encephalopathy
c.
Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or 
cardiac involvement of HCC based on imaging.
d. Any current moderate or severe ascites as measured by physical examination 
that requires active paracentesis for control.
3.
Criterion modified per Amendment 2.
3.1. Participants have symptomatic brain metastases (exception: the participant with 
definitively, locally-treated metastases that are clinically stable, and asymptomatic for 
at least 2 weeks and who are off or receiving low dose corticosteroid treatment [≤10 mg
prednisone or equivalent] for at least 2 weeks prior to the first dose of study treatment). 
If brain metastases are diagnosed on Screening imaging, the participant may be 
rescreened for eligibility after definitive treatment.
4.
History or known presence of leptomeningeal disease.
5.
Criterion modified per Amendment 2.


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5.1. Evidence of portal hypertension with bleeding esophageal or gastric varices within 
the past 3 months prior to the first dose of study treatment.
6.
Participant has a history of (non-infectious) ILD/pneumonitis/pulmonary fibrosis, or 
has 
current
ILD/pneumonitis/pulmonary 
fibrosis, 
or 
where 
suspected 
ILD/pneumonitis/pulmonary fibrosis cannot be ruled out by imaging at screening.
7.
Participant has a history of clinically significant cardiovascular disease including, but 
not limited to: 
a.
Diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior 
to the first dose of study treatment or any of the following within 6 months prior 
to the first dose of study treatment: myocardial infarction, unstable angina, 
stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any 
acute coronary syndrome. Clinically non-significant thrombosis, such as non-
obstructive catheter-associated clots, are not exclusionary.
b. Prolonged corrected QT interval using Fridericia's formula (QTcF) >480 msec 
or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, 
placement of implantable cardioverter defibrillator or atrial fibrillation with 
uncontrolled rate). Note: Participants with cardiac pacemakers who are 
clinically stable are eligible.
c.
Uncontrolled (persistent) hypertension: systolic blood pressure >160 mm Hg; 
diastolic blood pressure >100 mm Hg, or Congestive heart failure (CHF) 
defined as New York Heart Association (NYHA) class III/IV or Hospitalization 
for CHF (any NYHA class) within 6 months of study enrollment.
d. Pericarditis/clinically significant pericardial effusion.
e.
Myocarditis.
8.
Participant has known allergies, hypersensitivity, or intolerance to excipients of 
amivantamab (refer to the IB).
Prior/Concomitant Therapy
9.
Participant had prior approved therapy which may include MKI and/or PD-1/L1-
containing therapy within 2 weeks or 4 half-lives whichever is longer. For agents with 
long half-lives, the maximum required time since last dose is 28 days. Toxicities from 
previous anticancer therapies should have resolved to baseline levels or to Grade 1 or 
less, (except for alopecia or Grade ≤2 hypothyroidism stable on hormone replacement).
10.
Participant had surgery, radiotherapy, and/or locoregional therapy within 4 weeks 
before the first administration of study treatment. Minor surgery (eg, simple excision, 
tooth extraction) have occurred within 7 days before C1D1.
11.
Participant has received prior EGFR or MET-directed therapies.


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12.
Participants has received a live or live attenuated vaccine within 3 months before study
enrollment. Note: the seasonal influenza vaccine and non-live vaccines against 
coronavirus disease 2019 (COVID-19) are not exclusionary.
13.
Participant has, or will have, any of the following:
a.
An invasive operative procedure (except the treatment for the ascites should be 
discussed with sponsor’s medical monitor) with entry into a body cavity, within 
4 weeks or without complete recovery before C1D1. If needed, abdominal 
biopsy for baseline tumor tissue sample may be done less than 4 weeks prior to 
C1D1, as long as the participant has adequately recovered from the procedure 
prior to the first dose of study treatment in the clinical judgement of the 
investigator. 
b. Significant traumatic injury within 3 weeks before the start of C1D1 (all wounds 
must be fully healed prior to Day 1)
c.
Expected major surgery while the investigational agent is being administered or 
within 6 months after the last dose of study treatment.
Diagnostic Assessments
14.
Active co-infection with
a.
Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV 
DNA and HCV RNA. (Participants with a history of HCV infection but who are 
negative for HCV RNA by polymerase chain reaction [PCR] will be considered 
non-infected with HCV.)
b. Hepatitis D infection as evidenced by hepatitis D virus (HDV) antibody in 
participants with hepatitis B.
Other Exclusions
15.
Any condition for which, in the opinion of the investigator, participation would not be 
in the best interest of the participant (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
NOTE: Investigators must ensure that all study enrollment criteria have been met at screening. If 
a participant's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study treatment is given 
such that the participant no longer meets all eligibility criteria, then the participant must be 
excluded from participation in the study. Section 5.4, Screen Failures, describes options for 
retesting. The required source documentation to support meeting the enrollment criteria are noted
in Appendix 3: Regulatory, Ethical, and Study Oversight Considerations.


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5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the study to be eligible for participation:
1.
Refer to Section 6.8, Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3.
Agree to use sun protective measures (such as a hat, sunglasses, and protective 
clothing), limit prolonged exposure to natural sunlight, and avoid artificial sunlight 
(tanning beds or phototherapy) from baseline until at least 2 months after the last dose 
of study treatment. Avoid unnecessary exposure to sunlight. Use broad-spectrum 
sunscreen (containing titanium dioxide or zinc oxide) with a skin protection factor 
(SPF) ≥30.
5.4.
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not enrolled into 
the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Participants who are determined to be eligible for the study after their condition 
changes must sign a new ICF prior to rescreening.
5.5.
Criteria for Temporarily Delaying Administration of Study Treatment
In instances where temporarily study treatment delay is indicated, study treatment with 
amivantamab may be delayed until recovery of toxicity to a level allowing continuation of therapy. 
A participant for whom study treatment was delayed should be assessed at least weekly to ensure 
adequate supportive care is being administered and to assess for improvement of toxicity. For 
majority of clinically significant toxicities dose delay and dose modifications should occur as per 
the guidelines described below (Section 6.5). If dose delay is continued for more than 28 days, 
consult with the medical monitor before restarting study treatment.


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6.
STUDY TREATMENT AND CONCOMITANT THERAPY
6.1.
Study Treatment(s) Administered
Study treatment administration must be captured in the source documents and the CRF.
Amivantamab will be manufactured and provided under the responsibility of the sponsor. Refer to 
the IB for a list of excipients.
Description of Study treatment
Amivantamab is supplied for this study in a glass vial containing 350 mg/vial with concentration 
of 50 mg/mL in a 7 mL vial. The IV infusion will be prepared at the site in 250 mL of diluent 
(Refer to Investigational Product Preparation Instructions [IPPI]).
Dosage Level(s)
Based on the participant's body weight at screening: 1,050 mg (if body weight is 
<80 kg) or 1,400 mg (if body weight is ≥80 kg)
Dosing Instructions
Amivantamab will be administered intravenously in 28-day cycles as follows:
Cycle 1: Once weekly (with the first dose split over Day 1 [350 mg] and Day 2 
[700 mg if body weight is <80 kg or 1,050 mg if body weight is ≥80 kg])
Cycles 2+: Day 1 and 15 of each cycle
IP Packaging and 
Labeling
Study treatment will be provided in 7 mL glass vials, with 350 mg/vial
Amivantamab will be administered intravenously using the escalating infusion rate regimen as 
specified in the IPPI. The product must be infused via a peripheral vein for all Cycle 1 doses; 
infusion via central line is allowed for subsequent dosing starting with the C2D1 dose.
Infusion durations that exceed the planned length of time due to IV bag overfill, minor equipment
calibration factors, and/or participant factors not under the control of administering personnel will
not be considered protocol deviations. The actual infusion time should be accurately recorded.
Refer to IPPI for information describing the stability and administration of amivantamab.
Amivantamab must be administered according to the procedures described in the IPPI and clinical
protocol, under the supervision of qualified staff. Additional guidance is provided below:

On Day 1 of each cycle, review results of hematology and chemistry laboratory assessments
before administering study treatment.

Amivantamab must be diluted as described in the IPPI prior to infusion.

Do not mix or dilute amivantamab with other drugs.

Amivantamab must not be administered as an IV push or bolus.
Dose and administration schedule may be adjusted based on SET recommendations during the 
study.


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As there are investigations ongoing assessing different amivantamab formulations and schedules, 
participants may receive amivantamab according to a different schedule or route of administration. 
Any such change would only be made after approved protocol amendment.
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study treatment must be stored at controlled temperatures according to the requirements on the 
label and protected from light prior to use.
Refer to the pharmacy manual/study site investigational product and procedures manual (SIPPM)
for additional guidance on study treatment preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study treatment received at the site is 
inventoried and accounted for throughout the study. The study treatment administered to the 
participant must be documented on the intervention accountability form. All study treatment will 
be stored and disposed of according to the sponsor's instructions. Study site personnel must not 
combine contents of the study treatment containers.
Study treatment must be handled in strict accordance with the protocol and as indicated on the 
container label, and must be stored at the study site in a limited-access area or in a locked cabinet 
under appropriate environmental conditions. Unused study treatment, and study treatment returned 
by the participant, must be available for verification by the sponsor's study site monitor during on-
site monitoring visits. The return to the sponsor of unused study treatment, or used returned study 
treatment for destruction, will be documented on the intervention return form. When the study site 
is an authorized destruction unit and study treatment supplies are destroyed on-site, this must also 
be documented on the intervention return form.
Potentially hazardous materials containing hazardous liquids, such as used ampules, needles, 
syringes and vials, must be disposed of immediately in a safe manner and therefore will not be 
retained for intervention accountability purposes.
Study treatment must be dispensed under the supervision of the investigator or a qualified member 
of the study site personnel, or by a hospital/clinic pharmacist. Study treatment will be supplied 
only to participants participating in the study. Returned study treatment must not be dispensed 
again, even to the same participant. Study treatment may not be relabeled or reassigned for use by 
other participants. The investigator agrees neither to dispense the study treatment from, nor store 
it at, any site other than the study sites agreed upon with the sponsor. Further guidance and 
information for the final disposition of unused study treatments are provided in the Study 
Reference Manual.


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6.3.
Measures to Minimize Bias: Randomization and Blinding
Study Treatment Allocation
Procedures for Randomization
Randomization will not be used in this study. Participants will be assigned to treatment in the order 
in which they qualify for this study.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.4.
Study Treatment Compliance
The study personnel at the study site will account for all study treatments dispensed and for 
appropriate return. The certificates of delivery and return should be signed.
Study treatments are to be prescribed only by the principal investigator or a qualified physician 
listed as a sub-investigator on required forms. The study treatments may not be used for any 
purpose other than that outlined in this protocol, including other human studies, animal 
investigations, or in vitro testing. All study treatments will be administered as an IV infusion by 
qualified study site personnel and the details of each administration will be recorded in the eCRF 
(including date, start, and stop times of the IV infusion and volume infused). Dispensing of all 
study treatment must also be recorded in the participant’s source documents. 
Administration of pre- and post-infusion medications will be documented in the source documents 
and eCRF.
6.5.
Dose Modification
Any dose/dosage adjustment must be overseen by medically-qualified study site personnel 
(principal or sub-investigator unless an immediate safety risk appears to be present).
6.5.1.
Dose Delay Guidance
In instances where treatment delay is indicated, treatments may be delayed until recovery of 
toxicity to a level allowing continuation of therapy. A participant for whom treatment was delayed 
should be assessed at least weekly to ensure adequate supportive care is being administered and to 
assess for improvement of toxicity.
Participants must meet retreatment criteria for amivantamab (as per Section 6.5.2) in accordance 
with protocol, prior to redosing with the respective agents. 
o
Amivantamab: If there is a delay due to toxicity resulting in 2 consecutive missed doses of 
amivantamab, then participants will discontinue amivantamab infusion unless there is a clear 
clinical benefit after approval by the sponsor.


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6.5.2.
Amivantamab Dose Modification
The following guidance should be followed for dose delay and modification of amivantamab based 
on the toxicity grade of adverse events other than IRRs (Section 6.5.3), rash (Section 6.5.4),
pruritus (Section 6.5.5), paronychia (Section 6.5.6), oral mucositis (Section 6.5.7), liver chemistry 
abnormalities (Section 6.5.8), and pulmonary toxicity (Section 6.5.9). When possible, the Medical 
Monitor should be notified prior to dose modifications.
Table 4:
Guidance for Amivantamab Dose Delay and Modification for Toxicities (Other Than Rash, 
Infusion-Related Reaction, Liver Toxicity, or Pulmonary Toxicity)
Toxicity 
Gradea
Actionb
Length of 
Interruptiond
Dose Modification of Amivantamab after 
Resolution of Adverse Eventc
1
None
N/A
Continue at current dose level. Consider supportive 
care according to local standards as appropriate.
2
None or 
consider 
interruption
≤7 days
If interrupted, restart at current dose level. 
>7 days 
If interrupted, consider restart at next lower dose 
level.
3
Interrupt 
amivantamab
≤7 days
Restart at current dose level.
>7 days 
Restart at next lower dose level.
4
Interrupt 
amivantamab
≤7 days
Restart at next lower dose level
>7 days 
Consider permanently discontinuing amivantamab. 
Participants considered by the investigator and 
sponsor to be benefiting from treatment may be 
continued at a lower dose upon satisfactory 
resolution of the toxicity.
a. Per National Cancer Institute - CTCAE version 5.0.
b. For all toxicities, consider supportive care according to protocol or local standards (if no protocol guidance 
provided), as appropriate.
c. Resolution defined as: Grade ≤1 non-hematologic toxicity or back to baseline.
d. If interruption occurs for more than 1 cycle, contact the Medical Monitor to discuss retreatment.
In case a dose reduction is necessary, the study treatment will be administered as follows: Guidance 
for stepwise dose modification of amivantamab is outlined below in Table 5.
Table 5:
Dose Reduction for Amivantamab
Dosage Level
Amivantamab
Participant <80 kg
Participant ≥80 kg
1 (initial dosage)
1,050 mg Q2W
1,400 mg Q2W
2
700 mg Q2W 
1,050 mg Q2W 
3
350 mg Q2W
700 mg Q2W
4
Withhold
Withhold
Q2W=every 2 weeks (eg, Day 1 and Day 15 of each 28-day cycle).
Dose re-escalation of amivantamab to planned dose may be considered if the toxicity led to the 
dose reduction of amivantamab resolves to baseline or below/to Grade 1 after consultation with 
the Sponsor.


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The following sections provide additional guidance for the prevention, monitoring, and
management of toxicities that have been reported with amivantamab.
6.5.3.
IRRs
IRRs have been commonly observed during treatment with amivantamab, predominantly with the 
first exposure on C1D1, and typically within the first 90 minutes of the infusion. The majority of 
IRRs are Grade 1 or 2. Refer to Summary of Data and Guidance for Investigators in the current 
version of the IB for amivantamab. The guidelines described here are related to the safe 
administration of amivantamab during initial dosing. 
During the amivantamab infusions, participants should be clinically monitored at regular intervals 
(including an assessment prior to the start of infusion) as specified in the Schedule of Activities 
(SoA) (Table 1). The monitoring should include heart rate, blood pressure, temperature, respiratory 
rate, and oxygen saturation measurements. Particularly with the initial dose (C1D1 and C1D2), 
participants should be educated on 1) the likelihood of experiencing an IRR with the initial dose, 
2) the symptoms to anticipate (which include chills, dyspnea, chest discomfort, fever, flushing, 
among others), 3) that they should alert nursing staff if they experience these symptoms, and 4) 
that the experience of an IRR will not preclude further therapy with amivantamab. Participants 
must be monitored closely for early signs and symptoms indicative of an acute IRR. Even with 
mild symptoms, the study treatment infusion should be interrupted immediately, as described in 
the tables below, to prevent more serious grade IRRs from occurring. Trained clinical personnel 
should be prepared to intervene in the event of IRRs. Resources necessary for resuscitation (ie, 
agents such as epinephrine, aerosolized bronchodilator, IV antihistamines, IV corticosteroids; 
medical equipment such as oxygen, airway management equipment including suction, and a 
defibrillator) must be readily available.
Prevention of IRRs
Required prophylaxis for IRRs is described in Section 6.8.1.
Treatment of IRRs 
Participants who experience early symptoms of IRRs, manifesting as fever, chills, rigors, 
bronchospasm, headache, rash, pruritus, arthralgia, hypo- or hypertension or other symptoms, must 
have their amivantamab infusion interrupted, if indicated, and the symptoms managed according 
to the recommendations provided in Table 6. With the initial dose of amivantamab (C1D1 and 
C1D2), interrupting the infusion should be considered even with mild symptoms to prevent more 
severe manifestations of IRR. All Grade 3 or 4 IRRs should be reported within 24 hours to the 
medical monitor.


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Table 6:
Management of Infusion-related Reactions
Toxicity Grade*
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction
Monitor participant as medically indicated until recovery 
from symptoms. If occurring with initial dose (ie, C1D1 
or C1D2), consider early infusion interruption to prevent 
more severe symptoms.
Antihistamine, antipyretic, 
and glucocorticoid, as per
Table 8.
Grade 2 
Mild to moderate 
reaction; therapy or 
infusion interrupted
but responds promptly 
to symptomatic 
treatment
Interrupt infusion
If clinically indicated, start IV fluids; give 
diphenhydramine 50 mg (or equivalent) IV and/or 
paracetamol (acetaminophen) 650 to 1,000 mg; consider 
corticosteroids and bronchodilator therapy; monitor 
participant closely until recovery from symptoms
First interruption for infusion-related reaction: 
Restart infusion at 50% of the rate at the time of 
interruption: if no further evidence of infusion-related 
reaction after 30 minutes, the rate may be increased to 
100% of the infusion rate at the time of interruption; 
monitor participant closely.
Second interruption for infusion-related reaction:
Stop and consider discontinuation of further study 
treatment at that visit; administer diphenhydramine 50 
mg IV or equivalent and monitor participant until 
resolution of symptoms. The amount of study treatment 
infused must be recorded in the eCRF. If continuing 
administration after the second interruption, restart 
infusion at 50% of the rate at the time of the second 
interruption. If no further evidence of infusion-related 
reaction after 30 minutes, the rate may be increased to 
100% of the infusion rate at the time of interruption; 
monitor participant closely. 
Antihistamine, antipyretic, 
and glucocorticoid, as per 
Table 8.
Consider meperidine if 
participant experiences 
chills and rigors.
Grade 3
Severe reaction
Severe reaction that is
prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Stop infusion 
Start IV saline infusion; recommend bronchodilators, 
supplemental oxygen; epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 
to 0.25 mg of a 1:10000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as 
needed (other drugs as appropriate). 
Participant should be monitored until the investigator is 
comfortable that the symptoms will not recur. 
Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. In the case of late-
occurring hypersensitivity symptoms (eg, appearance of 
a localized or generalized pruritus within 1 week after 
treatment), symptomatic treatment may be given (eg, 
oral antihistamine, or corticosteroids), as appropriate. 
Based on severity of 
symptoms, consider 
permanent discontinuation 
of study treatment. 
Consultation with Medical 
Monitor required before 
continuing with 
subsequent dosing.
Grade 4: 
life-threatening; pressor 
or ventilator support 
indicated
Same as for Grade 3
Amivantamab treatment 
must be permanently 
discontinued.
eCRF=electronic case report form; IRR=infusion-related reaction; IV=intravenous.
*Per National Cancer Institute - CTCAE Version 5.0


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6.5.4.
Rash-related Adverse Events
The prevention and management of EGFR inhibitor-induced rash-related TEAEs can be conducted 
in accordance with local institutional guidelines or according to the recommendations below.
Prophylaxis Recommendations
The prophylactic regimen can be managed according to local practice and guidelines; however, 
these should include the following:

Avoid exposure to sunlight. 

Wear protective clothing (including hat, sunglasses, etc). 

Use broad-spectrum sunscreen with an SPF of ≥30 and reapply as necessary. Ultraviolet A 
light can penetrate glass; therefore, sunscreen should also be worn indoors and in vehicles if 
exposed to direct sunlight. Recommended active sunscreen ingredients are zinc oxide and/or 
titanium dioxide.

Apply alcohol-free emollient cream or ointments (eg, glycerin, cetomacrogol, or 
ceramide-based cream) or skin moisturizer on dry areas of the body. These topical agents can 
be applied on a daily basis starting on Day 1 and more often as needed. Ideal time for 
application is after bathing. Creams and ointments are preferred over gels, lotions and oils.

Alcohol-based (eg, gel formulations) topical agents such as steroids, antibiotics, or hand 
sanitizers can dry the skin and should be avoided.
Reactive Management Recommendations
It is strongly recommended that participants who develop rash/skin toxicities receive evaluations 
for management on the specific AE.

Consider consultation with a dermatologist, especially if the rash is Grade 3, atypical in 
appearance or distribution, or does not improve within 2 weeks (for Grade 2 rash).

Consultation with a dermatologist is required if the rash is Grade 4.

Initiate a topical corticosteroid (cream or ointment) twice daily

Examples to use for face: betamethasone valerate 0.05%, hydrocortisone valerate 0.2%, 
or desonide 0.05% 

Examples to use for body: betamethasone valerate 0.1%, triamcinolone acetonide 0.1%

If not already initiated for prophylaxis, initiate systemic antibiotic (such as doxycycline 
100 mg twice daily, minocycline 100 mg twice daily, or cephalexin 500 mg twice daily), or 
increase the dosing if already administered.

If an associated skin infection is suspected, obtain bacterial and fungal cultures followed by 
adjustment of antibiotic or antifungal therapy, based upon culture and susceptibility 
determination.

For skin fissures, use of Monsel’s solution (ferric subsulfate solution), silver nitrate, or zinc 
oxide cream is recommended.


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
For xerosis, fragrance-free moisturizing creams or sprays are recommended.

For desquamation, emollients and mild soap are recommended.

After the rash is controlled, consider gradually tapering the antibiotic.
A suggested algorithm for stepwise management of rash is provided in Table 7.
Table 7:
Suggested Algorithm for Management of Rash
Gradea
Management
Dose Adjustmentb,c
1

Initiate reactive management as above

Reassess after 2 weeks

Continue current dose of 
study treatment
2

Initiate reactive management as above

Reassess after 2 weeks

Continue current dose of 
study treatment
3

Initiate reactive management as above

Start moderate strength topical corticosteroidsd
and systemic antibiotics as above, plus systemic 
prednisone (0.5 mg/kg) for 7 days

Consider low doses of acitretin or isotretinoin 
(20-30 mg/day)

Reassess after 2 weeks

Consider dermatology consultation and manage 
rash per recommendation

Temporarily dose delay of 
study 
treatment 
until 
rash 
improves to ≤Grade 2

For guidance on dose delay 
of study treatment and dose 
modification, refer to Table 4
4

Initiate reactive management as above

Start moderate strength topical corticosteroidsd
and systemic antibiotics as above, plus systemic 
prednisone (0.5 mg/kg) for 7 days

Consider low doses of acitretin or isotretinoin 
(20-30 mg/day)

Reassess after 2 weeks

Consider dermatology consultation and manage 
rash per recommendation

Permanently 
discontinue 
JNJ-61186372
Severe bullous, 
blistering, or 
exfoliating skin 
conditions including 
toxic epidermal 
necrolysis (TEN)

Consult dermatologist and manage rash per 
recommendation.

Permanently 
discontinue 
JNJ-61186372
a. Grading per CTCAE Version 5.0.
b. If amivantamab must be skipped due to toxicity for 2 consecutive doses, then study treatment cannot be restarted 
without consultation from the Medical Monitor. Participants considered by the investigator and sponsor to be 
benefiting from treatment may be continued, potentially at a lower dose upon satisfactory resolution of the 
toxicity.
c. Resolution defined as: ≤Grade 1 toxicity or back to baseline.
d. For example, hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream.
Scalp Rash
Atypical scalp rash and associated infection may develop over time with the use of EGFR 
inhibitors. Treatment options include:

A topical steroid shampoo (eg, clobetasol 0.05%), or an anti-dandruff shampoo with 
anti-inflammatory, antibacterial, and antifungal properties (eg, ketoconazole, selenium sulfide 
[Selsun®], zinc pyrithione [Head and Shoulders®], or Ciclopirox). These shampoos should be 
used twice/week, massaging into scalp, leaving on for 2 to5 minutes, and then rinsing. 


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
Application of a steroid lotion may also be effective (eg, betamethasone valerate 0.1% lotion, 
mometasone furoate 0.1% lotion, or betamethasone dipropionate 0.05% lotion). 

Initiation of a systemic antibiotic (eg, doxycycline 100 mg twice daily, minocycline 100 mg 
twice daily) may also be used to treat acute scalp infection. 
Of note, while wearing hats to avoid sun damage to the scalp is suggested in a prophylactic setting, 
avoiding any headwear for a participant with established scalp rash is strongly recommended to 
prevent further spread of the rash.
6.5.5.
Pruritus
Reactive Management Recommendations
Grade 1 pruritus: 

Apply topical low to moderate strength steroid cream (eg, hydrocortisone 2.5%, desonide 
0.05%, or betamethasone valerate 0.05%), topical calcineurin inhibitor (eg, tacrolimus or 
pimecrolimus), or topical antipruritic containing numbing agent (eg, pramoxine) and menthol.
Grade 2 pruritus:

Apply topical moderate to high strength steroid cream (eg, betamethasone valerate 0.1%, 
triamcinolone acetate 0.1%) or topical antipruritic containing numbing agent (eg, pramoxine) 
and menthol.

Initiate an oral antipruritic (eg, cetirizine, fexofenadine, rupatadine, bilastine) one dose twice 
daily. If still pruritic after 2-5 days, may increase to double dose twice daily.
Grade 3 pruritus:

Initiate an oral antipruritic (as above for Grade 2 pruritus).

Initiate oral pregabalin or gabapentin.

Initiate an oral corticosteroid (eg, prednisone 0.5-1.0 mg/kg/day or equivalent for 5 days).
6.5.6.
Paronychia
Paronychia is a well-recognized toxicity associated with anti-EGFR therapeutics. As a result, there 
are recommendations that should be followed to prevent or minimize participant discomfort 
associated with this toxicity.
Prophylaxis Recommendations

Avoid skin irritants.

Cushion affected areas.

Wear gloves and comfortable shoes.

Apply moisturizer to nails.
Reactive Management Recommendations
Grade 1 paronychia:


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
Use antimicrobial soaks once or twice daily: warm bowl of water+5 mL of bleach (sodium 
hypochlorite) or vinegar (DO NOT USE BOTH TOGETHER); soak for 5 minutes, rinse, pat 
dry, and then apply either emollient or topical treatments below.

Apply topical antiseptic (povidone-iodine 10% solution) twice daily.

Apply a topical steroid ointment (eg, betamethasone valerate 0.1% or clobetasol) or topical 
calcineurin inhibitor (eg, tacrolimus 0.1%) twice daily. If using topical steroid, once resolved, 
switch to topical calcineurin inhibitor daily or decrease to twice per week to maintain. 
Grade 2 or 3 paronychia:

In addition to the guidance for Grade 1 paronychia above:

Apply topical antibiotic/antifungal agent (eg, mupirocin, fusidic acid, clotrimazole, or 
miconazole) twice daily.

Initiate oral antibiotic for at least 14 days (eg, doxycycline 100 mg twice daily, 
minocycline 100 mg twice daily, or cephalexin 500 mg twice daily).

Consult a dermatologist or podiatrist.
6.5.7.
Oral Mucositis
Mucositis is a well-recognized toxicity associated with anti-EGFR therapeutics, and may be 
mild/moderate and localized (Grades 1-2) or severe and widespread (≥Grade 3). As a result, there 
are recommendations that should be followed to prevent or minimize patient discomfort associated 
with this toxicity. Prophylaxis should occur according to local institutional practice and guidelines, 
and should include the following: 
Prophylaxis Recommendations

Use good oral hygiene, dentition review and referral to an oral hygienist if necessary.

Use a soft toothbrush.

Use mild-flavored toothpastes.

Use saline-peroxide or salt and soda mouthwashes 3 or 4 times per day.

Use water soluble lubrication agents like artificial saliva (for xerostomia or dry mouth).

Avoid spicy, acidic, hard, and hot food and beverages.
Reactive Management Guidelines

Asymptomatic or mild symptoms: topical steroid (dexamethasone 0.5/mL elixir) and 
lidocaine 2-5% jelly or solution (swish and spit) 4 times per day. 

Co-trimoxazole lozenges can be used to prevent secondary candida infection.

In cases of moderate to severe pain: 

Compounded mouthwash (eg, “magic mouthwash”) including an antifungal, steroid, 
antihistamine, anesthetic, and/or antacid/mucosal coating agent as per local practice and 
guidelines.


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
Dexamethasone solution 3.3 mg/5 mL swish and spit 4 times per day, and lidocaine jelly 
2-5% or solution 4 times per day. 
6.5.8.
Liver Chemistry Abnormalities
Liver chemistry should be monitored according to the Schedule of Activities (SoA). In addition, 
if the following modified Hy’s Law criteria are observed, study treatment should be held, and the 
event should be reported as a serious adverse event to the Sponsor within 24 hours: 
a) Treatment-emergent ALT or AST >3 x baseline value in combination with total
bilirubin >2 x ULN (of which >35% is direct bilirubin)
b) Treatment-emergent ALT or AST >3 x baseline value in combination with clinical
jaundice
Treatment with amivantamab should be permanently discontinued and the event should be 
reported as a serious adverse event to the Sponsor within 24 hrs when

AST or ALT >10 x ULN for >2 weeks,

AST or ALT >15 x ULN irrespective of duration,

Total bilirubin >5 x ULN for those with normal total bilirubin at entry or >8 x ULN for
participants with elevated bilirubin at study entry, irrespective of duration.

ALT/ AST elevated ≥3 x baseline value and total bilirubin elevated ≥2 x ULN or with clinical 
jaundice, if no other alternative explanation is identified after completing work-up 

Regardless of laboratory values, symptom of hepatic decompensation including

Encephalopathy

Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or gastric 
varices)

New onset of clinical detectable ascites*
Note: *Regarding discontinuation due to ascites, investigators should discuss with sponsor 
medical monitor.
If isolated ALT or AST increase was observed, liver chemistry should be closely monitored (within 
1-3 days and until abnormal values resolve/return to baseline) when 

ALT/AST ≥10 × ULN (The event should be reported as a serious adverse event to the Sponsor 
within 24 hrs. Initiate workup for competing etiologies)

ALT/AST ≥5 × ULN (if normal at baseline) or ALT/AST ≥3 × baseline (if abnormal at 
baseline)
In the event abnormalities of liver function tests require withholding study treatment, liver 
chemistry should be repeated within 1-3 days and until abnormal values resolve/return to 
baseline. Etiology of the liver chemistry abnormality should be investigated, as described below. 


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Liver Event Follow-up Requirements
The following follow-up assessments should be conducted for any participant meeting liver 
chemistry stopping criteria:

Conduct liver imaging (ultrasound, magnetic resonance imaging [MRI], or CT) to evaluate 
liver disease

Monitor liver chemistries (ALT, AST, alkaline phosphatase, bilirubin [including bilirubin 
fractions], and INR), creatinine phosphokinase, and lactate dehydrogenase, 1 to 2 times per 
week until resolution, stabilization, or return to participant’s baseline values

Monitor clinical condition closely

Draw blood samples for unscheduled PK analysis at timepoints when liver chemistry is 
assessed

Record use of concomitant medications, acetaminophen, herbal remedies, other 
over-the-counter medications, or known hepatotoxins

Record alcohol use in the eCRF

Check the viral hepatitis serology as appropriate and include:
o
Hepatitis A IgM antibody
o
Hepatitis B surface antigen, hepatitis B core antibody (IgM) and hepatitis B viral load
o
Hepatitis C viral load
o
Hepatitis E IgM antibody
o
Cytomegalovirus IgM antibody
o
Epstein-Barr viral capsid antigen IgM antibody (or equivalent test)

Assess anti-nuclear antibody, anti-smooth muscle antibody, and type 1 anti-liver kidney 
microsomal antibodies

Refer to a specialist as appropriate
6.5.9.
Suspected Pulmonary Toxicity
The etiology of any clinically significant change in respiratory status and/or non-oncogenic 
radiological appearance suggestive of lung inflammation (eg, ground glass opacities) should be 
investigated in accordance with local practice/guidelines to rule out early ILD/pneumonitis.
The following evaluations are recommended in order to exclude alternative etiologies such as 
lymphangitic carcinomatosis, pulmonary embolism, infection, allergy, and cardiogenic edema:

Detailed focused history reviewing respiratory status and exercise tolerance.

Focused physical exam including full assessment of vital signs (with pulse oximetry).


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
Unscheduled radiological assessment, including chest X-ray or CT scan (high-resolution CT 
is preferred).

Infectious evaluation, including blood and sputum cultures, atypical pneumonia panels, and 
SARS-CoV-2 testing, if indicated

Hematology and other laboratory tests, including serum albumin levels

Referral to pulmonologist for evaluation, including bronchoscopy with biopsy, cell counts, and 
cultures as feasible

Evaluation of cardiac function, if indicated 
Where other causes of respiratory symptoms have been excluded, a diagnosis of ILD/pneumonitis 
should be considered, and study treatment permanently discontinued. For participants with 
symptomatic pneumonitis (Grade 2 or above), treatment with steroids should be initiated per local 
guidelines, in addition to withholding of study treatment.
Documentation of ILD/pneumonitis of any grade should prompt withholding study treatment and 
contacting the medical monitor. Confirmation of ILD/pneumonitis of any grade should prompt 
discontinuation of study treatment and should be reported as an SAE (see Section 8.3.1). If the 
ILD/pneumonitis is attributed to prior radiation, participant can restart after discussion with the 
sponsor’s medical monitor. Pertinent radiological images and reports should be submitted to the 
sponsor.
6.6.
Continued Access to Study Treatment After the End of the Study
Investigators may recontact the participant to obtain long-term follow-up information regarding 
the participant's safety or survival status as noted in the ICF (refer to Informed Consent in
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations).
Participants will be instructed that study treatment will not be made available to them after they 
have completed/discontinued study treatment and that they should return to their primary physician 
to determine standard of care.
Local regulations on continued access will always take precedence. Plans for continued access 
stated in this protocol may change if new information on the benefit-risk profile of amivantamab
becomes available during the study or program.
No continued access will be proposed for this study. At the end of their participation in the study, 
the participants will be instructed that they should return to their primary physician to determine
standard of care, if applicable.
6.7.
Treatment of Overdose
There are no data on overdose from studies of amivantamab.
In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.


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
Evaluate the participant to determine, in consultation with the Medical Monitor, whether study 
treatment must be interrupted or whether the dose should be reduced.

Closely monitor the participant for AE/SAE and laboratory abnormalities.

Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor based on the clinical evaluation of the participant.
6.8.
Concomitant Therapy
Prestudy therapies administered up to 28 days before first dose of study treatment must be recorded 
at screening.
Concomitant therapies must be recorded throughout the study beginning with start of the first dose 
of study treatment to 30 days after the last dose of study treatment. Concomitant therapies should 
also be recorded beyond 30 days only in conjunction with Grade 3 or Grade 4 AEs considered 
related to study treatment, until resolution of event or start of subsequent therapy.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens, or other specific categories of interest) different from the study treatment
must be recorded in the eCRF. Modification of an effective preexisting therapy should not be made 
for the explicit purpose of entering a participant into the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.8.1.
Amivantamab Pre-infusion and Post-infusion Medications
6.8.1.1.
Amivantamab Pre-infusion Medications
Required and optional amivantamab pre-infusion medications for IRRs are summarized in Table 8.
Table 8:
Amivantamab Pre-infusion Medications
Medication
Dose
Route of
Administration
Recommended 
Dosing Window 
Before Infusion
Cycle/Day
Required Pre-infusion Medicationsa,b
Glucocorticoid
Dexamethasone (10 mg) or 
Methylprednisolone (40 mg)
IV
45 to 60 minutes
C1D1
C1D2
Antihistamined
Diphenhydramine (25 to 50 mg) 
or equivalent
IV
15 to 30 minutes
All
Oral
30 to 60 minutes
Antipyreticd
Paracetamol (acetaminophen 650 
to 1,000 mg) or equivalent
IV
15 to 30 minutes
All
Oral
30 to 60 minutes


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Table 8:
Amivantamab Pre-infusion Medications
Medication
Dose
Route of
Administration
Recommended 
Dosing Window 
Before Infusion
Cycle/Day
Optional Pre-infusion Medicationsa
Glucocorticoidc,d
Dexamethasone (10 mg)
Methylprednisolone (40 mg)
IV
45 to 60 minutes
C1D8
and beyond
Oral
60 to 90 minutes
H2 antagonist
Ranitidine (50 mg) or equivalent
IV
15 to 30 minutes
Any
Antiemeticd
Ondansetron (16 mg) or 
equivalent
IV
15 to 30 minutes
Any
Ondansetron (8 mg) or equivalent
Oral
15 to 30 minutes
C=Cycle; D=Day X; IV=intravenous.
a. If a medication noted in this table is not locally available, a similar medication and dose may be substituted 
and administered per local guidelines.
b. Participants for whom required medications are contraindicated should explore alternative medications with 
their study physician. If alternative medications are not suitable for the intent above, participants are not 
required to take the corresponding medication.
c. Beginning with C1D8, optional predose steroids may be administered if clinically indicated for participants 
who experienced an infusion-related reaction on C1D1 or C1D2.
d. Either IV or oral route is selected for antihistamine, antipyretic, glucocorticoid and antiemetic medications.
6.8.1.2.
Amivantamab Post-infusion Medications
Optional amivantamab post-infusion medications may be prescribed and continued for up to 48 
hours after the infusion if clinically indicated, at the discretion of the investigator as described in
Table 9.
Table 9:
Amivantamab Post-infusion Medications
Medication
Dose
Route of
Administration
Administration 
Instructions
Cycle/Day
Optional Post-infusion Medicationsa
Glucocorticoid
Dexamethasone (10 mg) or 
comparable corticosteroid
IV or Oral
As clinically indicated
Any
Antihistamine
Diphenhydramine (25-50 mg) 
or equivalent
IV or Oral
As clinically indicated
Any
Antipyretic
Paracetamol (acetaminophen) 
(650-1,000 mg)
IV or Oral
As clinically indicated
Any
Opiates
Meperidine (25-100 mg)
IV or Oral
As clinically indicated
Any
Antiemeticb
Ondansetron (8-16 mg) or 
equivalent;
long or short acting agents
IV
As clinically indicated
Any
Ondansetron (8 mg) or 
equivalent;
long or short acting agents
Oral 
IV=intravenous.
a. Optional medications can be used prophylactically as clinically indicated. If a medication noted in this table is 
not locally available, a similar medication and dose may be substituted and administered per local guidelines.
b. Either IV or oral route is selected for antiemetic medications.


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6.8.2.
Prohibited or Restricted Medications and Therapies
Prohibited Medications and Therapies
The following concomitant medications and therapies are prohibited during the study. The sponsor 
must be notified as soon as possible of any instances in which prohibited therapies were 
administered.

Any non-study systemic anticancer therapy approved or experimental therapy (other than 
study treatments) for the treatment of HCC is prohibited. 

Surgery, radiotherapy, and/or locoregional therapy (eg: radiofrequency ablation [RFA], 
percutaneous ethanol [PEI] or acetic acid injection [PAI], cryoablation, high-intensity focused 
ultrasound [HIFU], transarterial chemoembolization [TACE], transarterial embolization 
[TAI], etc.) to target lesions prior to disease progression.

Use of live or live attenuated vaccines is prohibited until at least 90 days after the last dose of 
study treatment. For additional guidance, refer to Guidance on Study Conduct During 
COVID-19.
Restricted Medications and Therapies
The following concomitant medications and therapies are restricted until the End of Treatment 
visit and should be avoided, when possible, or used with caution.

Due to the potential for hypomagnesemia associated with EGFR inhibitors, concomitant 
medications that may decrease serum magnesium should be avoided if possible.
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.8.3.
Permitted Medications and Therapies

Supportive care (eg, antibiotics, analgesics, transfusions, diet, osteoclast inhibitors) and 
concomitant medications may be administered according to the standard of care at the site, 
and at the treating physician’s discretion, as clinically indicated. 

Localized therapy of short duration for palliative purposes may be permitted, but only after 
consultation with the Medical Monitor. Study treatment interruption is not required but is 
allowed as per investigator discretion. 

Women using hormonal contraceptives as a means of birth control must continue to use the 
same hormonal contraceptives throughout the study and through 6 months after the last dose 
of study treatment.
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Treatment
A participant's study treatment must be discontinued if:

The participant withdraws consent to receive study treatment


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
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the 
best interest of the participant to discontinue study treatment

The participant becomes pregnant (refer to Section 10.5, Appendix 5: Contraceptive and 
Barrier Guidance).

Noncompliance with study drug administration or procedure requirements.

Documented radiographic (RECIST, Version 1.1) disease progression, unless treatment 
beyond disease progression has been approved by the Medical Monitor.
Exception: Continuation of study treatment after disease progression may be allowed in 
accordance with local practice, after consultation with the Medical Monitor, if the investigator 
believes the participant is deriving clinical benefit. If the participant is treated beyond 
documented disease progression, disease assessments will continue according to the
Section 1.3 Schedule of Activities (SoA), and the investigator and sponsor medical monitor 
must review clinical benefit after each disease assessment.

General or specific changes in the participant’s condition that render the participant 
unacceptable for further treatment in the judgment of the investigator.
If a participant discontinues study treatment for any reason before the end of the treatment period,
then the end of treatment assessments must be obtained and scheduled assessments off study 
treatment should be continued. Study treatment assigned to the participant who discontinued study 
treatment may not be assigned to another participant. Additional participants will not be entered.
7.1.1.
Liver Chemistry Stopping Criteria
Stopping of study treatment for abnormal liver tests is required by the investigator when a 
participant meets one of the conditions outlined in Appendix 7: Liver Safety: Suggested Actions 
and Follow-up Assessments and Study treatment Rechallenge Guidelines or in the presence of 
abnormal liver chemistries not meeting protocol-specified stopping rules if the investigator 
believes that it is in best interest of the participant.
Study treatment should be withheld for any liver chemistry abnormality of ≥Grade 3 severity based 
on CTCAE 5.0 (refer to Table 4). In addition, if the following modified Hy’s Law criteria are 
observed, study treatment should be held, and the event should be reported as a serious adverse 
event to the Sponsor within 24 hours: 
a)
Treatment-emergent ALT or AST >3 x baseline value in combination with total bilirubin 
>2 x ULN (of which >35% is direct bilirubin)
b)
Treatment-emergent ALT or AST >3 x baseline value in combination with clinical jaundice
Treatment with amivantamab should be permanently discontinued when:

AST or ALT >10 x ULN for >2 weeks.

AST or ALT >15 x ULN irrespective of duration.


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
Total bilirubin >5 x ULN for those with normal total bilirubin at entry or >8 x ULN for 
participants with elevated bilirubin at study entry, irrespective of duration.

ALT/ AST elevated ≥3 x baseline value and total bilirubin elevated ≥2 x ULN or with 
clinical jaundice, if no other alternative explanation is identified after completing work-up.

Regardless of laboratory values, symptom of hepatic decompensation including:
o
Encephalopathy
o
Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or gastric 
varices)
o
New onset of clinical detectable ascites*
Note: *Regarding discontinuation due to ascites, investigators should discuss with sponsor medical 
monitor.
In the event abnormalities of liver function tests require withholding study treatment, liver 
chemistry should be repeated within 1-3 days and until abnormal values resolve/return to baseline. 
Etiology of the liver chemistry abnormality should be investigated.
7.1.2.
Rechallenge Criteria
Resumption of study drug administration may be considered if the following criteria are met unless 
the criteria for permanent discontinuation are reached.

A reversible underlying cause not associated with study treatments (eg, alcohol or 
concomitant medication) is clearly identified and agreed upon in consultation with sponsor’s 
medical monitor.

Liver chemistry abnormalities have resolved, or values have returned to baseline.
Note: Any rechallenge case, a discussion should occur with the Sponsor before restarting 
amivantamab.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent
When a participant withdraws before study completion, the reason for withdrawal is to be 
documented in the CRF and in the source document. If the reason for withdrawal from the study 
is withdrawal of consent (or assent) then no additional assessments are allowed.


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Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of 
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent 
form apply (eg, consult with family members, contacting the participant’s other physicians, 
medical records, database searches, use of locator agencies at study completion) as local 
regulations permit.
7.2.1.
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Appendix 3: Regulatory, Ethical, and 
Study Oversight Considerations). In such a case, samples will be destroyed after they are no longer 
needed for the clinical study. Details of the sample retention for research are presented in the main 
ICF.
7.3.
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to enrollment attempts 
should be made to obtain contact information from each participant, eg, home, work, and mobile 
telephone numbers and email addresses for both the participant as well as appropriate family 
members.
A participant will be considered lost to follow-up if the participant repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study site personnel to contact the 
participant are deemed futile. The following actions must be taken if a participant fails to return to 
the study site for a required study visit:

The study site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 
emails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical records.

Should the participant continue to be unreachable, they will be considered to have withdrawn 
from the study.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of screening, efficacy, PK,
immunogenicity, PD, biomarker, benefit-risk, and safety measurements applicable to this study.


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If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: ECG, vital signs, blood draw. Urine and blood collections 
for PK and PD assessments should be kept as close to the specified time as possible. Other 
measurements may be done earlier than specified timepoints if needed. Actual dates and times of 
assessments will be recorded in the source documentation and/or the CRF.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
The total blood volume to be collected from each participant depends upon the duration of 
participation and the required blood volume for local laboratory assessments. The total blood 
volume collected for each participant at screening, end of treatment and follow-up period will be 
approximately 43.5 mL, 36 mL, and 8.5 mL, respectively. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
Sample collection and testing will comply with local regulations.
Study-Specific Materials
The investigator will be provided with the following supplies:

IB for amivantamab

Clinical Protocol

IPPI and SIPPM

Laboratory manual and kits

eCRF completion guidelines

NCI-CTCAE Version 5.0

RECIST guidelines Version 1.1 & Modified RECIST

eDC Manual

Sample ICF


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
Wallet cards

Study treatment (amivantamab will be supplied centrally)

Ancillary supplies (as needed)
8.1.
Efficacy Assessments
Disease assessments will be performed as described in the SoA regardless of any dose 
modifications. More frequent radiologic assessments are allowed if clinically indicated.
CT scan of the chest (including the supraclavicular region), abdomen, pelvis, and any other disease 
location(s), if clinically indicated, should be performed with an IV contrast agent. Participants not 
able to undergo CT scans with IV contrast (eg, due to allergy or renal insufficiency) may have 
non-contrast CT of the thorax and MRI of the abdomen and pelvis with IV contrast at baseline and 
during the study if approved by the sponsor. Contraindications to the CT scan with IV contrast that 
develop post baseline should be discussed with the medical monitor. Identical methodology should 
be used for disease assessment at baseline and throughout the course of the study to characterize 
each identified and reported lesion to document disease status. Techniques other than CT or MRI 
may be used based upon investigator’s judgment, local standard of care, RECIST Version 1.1 and 
modified RECIST guidelines for the use of these alternative techniques. Response may also be 
assessed by blinded independent central review (BICR) for central confirmation.
The baseline disease assessments should be performed as close as possible to the start of treatment, 
but no more than 28 days prior to the first dose. Subsequent assessments should be performed at 6 
weeks (+1 week) after initiation of study treatment administration, then every 6 weeks (±1 week) 
for the first 12 months and then every 12 weeks (±1 week) until objective radiographic disease 
progression. If a participant achieves partial response (PR) or complete response (CR), 
confirmation of response may occur at 4 weeks from the initial response, per RECIST v.1.1. 
Timing for each disease assessment is relative to the first dose of study treatment administration, 
regardless of dose modifications, and will continue until disease progression. If an assessment is 
performed outside of the scheduled visit and the participant has not progressed, every attempt 
should be made to perform the subsequent assessment at their scheduled visit timepoint. Any other 
site at which new disease is suspected should also be imaged.
If the investigator is in doubt as to whether progression has occurred, particularly with response to 
nontarget lesions or the appearance of a new lesion, treatment should be continued until the next 
scheduled assessment (or sooner if clinically indicated) and reassess the participant’s status. If the 
repeated scans confirm progression, then the date of the initial scan should be declared as the date 
of progression. To achieve “unequivocal progression” on the basis of nontarget lesions, there must 
be an overall substantial worsening in nontarget lesions such that, even in the presence of stable 
disease or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in size of 1 or more nontarget lesions is usually 
not sufficient to qualify for unequivocal progression. If symptomatic deterioration (on the basis of 
global deterioration of health status) is recorded as the basis for determining disease progression, 
then the clinical findings used to make the determination must be specified in the eCRF and 


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documented in the source documents. Every effort should be made to document radiographic 
progression even after discontinuation of treatment for symptomatic deterioration, but prior to 
subsequent therapy, if possible. For participants who discontinue study treatment due to toxicity 
or a reason other than objective progressive disease, tumor assessments should be continued per 
schedule until radiographic progressive disease is documented.
Brain MRI scan of participants (CT scan with contrast may also be used to determine the presence 
of brain lesions if MRI is contraindicated) will also be performed at screening if the participant 
has a history of brain metastasis or suspected brain metastasis at screening. Brain scan is not 
required with every subsequent disease assessment, unless clinically indicated, according to local 
guidelines and practices. Participants with a history of brain metastasis at Screening will be 
monitored every 12 weeks (±1 week).
If a participant is deriving clinical benefit and the treatment beyond documented disease 
progression is approved by the sponsor’s medical monitor, disease assessments will continue as 
scheduled and the investigator and the Medical Monitor will review clinical benefit after each 
disease assessment.
A lesion that will be biopsied during Screening should only be assessed as a target lesion if a post-
biopsy imaging is performed >7 days and confirms that it still meets target lesion criteria per 
RECIST v1.1.
8.2.
Safety Assessments
Details regarding the SET are provided in Committees Structure in Appendix 3: Regulatory, 
Ethical, and Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Appendix 4: Adverse 
Events, Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities.
8.2.1.
Physical Examinations
Screening physical examination will include, at a minimum, height, weight, general appearance, 
and an examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, lymphatic system, and nervous system. On Day 1 of each cycle, directed 


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physical examination of involved organs and other body systems will be performed as indicated, 
with clinically significant abnormalities reported as adverse events.
8.2.2.
Vital Signs
Temperature, pulse/heart rate, respiratory rate, blood pressure and O2 saturation will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed in a seated position with a 
completely automated device. Manual techniques will be used only if an automated device is not 
available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest 
in a quiet setting without distractions (eg, television, cell phones).
8.2.3.
Electrocardiograms
Single electrocardiograms (ECGs), performed locally, will be collected at screening to determine 
the eligibility. During the collection of ECGs, participants should be in a quiet setting without 
distractions (eg, television, cell phones). Participants should rest in a supine position for at least 
5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood 
sampling or vital sign measurement is scheduled for the same time point as ECG recording, the 
procedures are recommended to be performed in the following order: ECG(s), vital signs, blood 
draw.
QTcF is calculated using the Fridericia's formula: QTcF = QT/(RR^0.33).
8.2.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in Section 10.2
Appendix 2: Clinical Laboratory Tests. In the event of additional safety monitoring, unscheduled 
laboratory assessments may be performed as required and may be done locally when an immediate 
clinical decision needs to be made. The investigator must review the laboratory results, document 
this review, and record any clinically relevant changes occurring during the study in the AE section 
of the CRF. The laboratory reports must be filed with the source documents. At the start of each 
new cycle, the investigator must confirm that participants meet treatment criteria. 
More frequent clinical laboratory tests may be performed as indicated by the overall clinical 
condition of the participant or abnormalities that warrant more frequent monitoring.
8.2.5.
Pregnancy Testing
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participation in the study.


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8.2.6.
ECOG Performance Status
ECOG performance status score will be evaluated during the screening phase to determine the 
eligibility. Decline in ECOG PS score (refer to Appendix 11: Eastern Cooperative Oncology 
Group [ECOG] Performance Status) should be reported as an AE.
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs, 
and product quality complaints (PQCs), from clinical studies are crucial for the protection of 
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. 
The sponsor has established Standard Operating Procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies 
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally acceptable representative) for the duration of the study.
Further details on AEs, SAEs, and PQCs can be found in Appendix 4: Adverse Events, Serious 
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the 
time a signed and dated ICF is obtained until completion of the participant's last study-related 
procedure, which may include contact for follow-up of safety. 
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study site personnel immediately, but no later than 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study treatment, must be reported. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form and Safety Report Form of the CRF, which must be completed and reviewed by a physician 
from the study site, and transmitted to the sponsor immediately but no later than within 24 hours. 
The initial and follow-up reports of an SAE should be transmitted electronically or by facsimile 
(fax). Telephone reporting should be the exception and the reporter should be asked to complete 
the appropriate form(s) first.


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8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about AE occurrence. 
Solicited Adverse Events
Solicited AEs are predefined local at the injection site and systemic events for which the participant 
is specifically questioned.
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or 
PQC as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.
Adverse events and the special reporting situation of pregnancy, will be followed by the 
investigator as specified in Appendix 4: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute where 
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or 
sponsor where required) must report SUSARs to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB.
8.3.5.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes 
pregnant during the study must discontinue further study treatment. 
Follow-up information regarding the outcome of the pregnancy for female participants who 
become pregnant, or where the pregnancy was the result of male participant and his partner, and 
any postnatal sequelae in the infant will be required.


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8.3.6.
Disease-Related Events and Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments.
Expected progression of disease should not be considered or reported as an AE (or SAE).
However, if determined by the investigator to be more likely related to the study treatment than 
being expected from the underlying disease, the treatment-invoked progression (ie, the treatment 
involved signs/symptoms of such progression) should be reported per the usual reporting 
requirements (refer to Adverse Event Definitions and Classifications in Appendix 4, 
Section 10.4.1 Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting).
Death that is attributed by the Investigator explicitly to progression of disease should not be 
considered nor reported as an AE (or SAE). 
However, if determined by the investigator to be more likely related to the study treatment than 
being expected from the underlying disease, the treatment-invoked death should be reported per 
the usual reporting requirements (refer to Adverse Event Definitions and Classifications in 
Section 10.4.1).
Progression of disease and death due to disease progression should be documented on the 
appropriate eCRF forms (eg, the Disease Progression form and the Death form). Signs or 
symptoms of disease progression that are of clinical significance, such as, but not limited to, spinal 
cord compression, vena cava superior syndrome, major vessel rupture, efflux obstruction or organ 
failure should be documented on the appropriate eCRF forms (eg, the Clinical Progression form).
8.3.7.
Adverse Events of Special Interest
Adverse events of special interest for this study include pneumonitis/ILD, rash, IRR, liver event
and hypoalbuminemia. Additional information may be collected to more fully describe these 
events. Confirmed cases of pneumonitis/ILD (regardless of grade) and liver events meeting the 
threshold in Section 6.5.8 should be reported as serious adverse events (see Section 8.3.1). All 
Grade 3 or 4 IRRs and hypoalbuminemia should be reported within 24 hours to the Medical 
Monitor. Events of rash should follow standard reporting guidelines.
8.4.
Pharmacokinetics
Blood samples will be used to evaluate the PK of amivantamab. Serum collected for PK may 
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or 
after the study period. Genetic analyses will not be performed on these serum samples. Participant
confidentiality will be maintained. Sample collection and testing will comply with local 
regulations.


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8.4.1.
Evaluations
Blood samples will be collected from all participants for the measurement of serum amivantamab
for PK analyses. Sample collection and testing will comply with local regulations. Population PK 
modeling may be performed to assess the potential effect of intrinsic factors on the PK of 
amivantamab and reported separately. Serum samples will be screened for antibodies binding to 
amivantamab and the number of confirmed positive samples will be reported. Other analyses may 
be performed to further characterize the immunogenicity of amivantamab. Table 2
Serum samples will be collected from all participants for PK and immunogenicity assessments of 
amivantamab at the time points outlined in Table 2 (Intense PK Sampling Schedule, 
12 participants) and Table 3 (Sparse PK Sampling Schedule, rest participants).
The exact dates and times of blood sampling must be recorded on the laboratory requisition form. 
Refer to the Laboratory Manual for sample collection requirements. Collected samples must be 
stored under specified, controlled conditions for the temperatures indicated in the Laboratory 
Manual. Blood collected for PK may additionally be used to evaluate safety or efficacy aspects 
that address concerns arising during or after the study period.
8.4.2.
Analytical Procedures
Pharmacokinetics
Serum samples will be analyzed to determine concentrations of amivantamab using a validated, 
specific, and sensitive enzyme-linked immunosorbent assay (ELISA) method by or under the 
supervision of the sponsor.
8.4.3.
Pharmacokinetic Parameters and Evaluations
Parameters
Pharmacokinetic analysis of serum concentration data for amivantamab will be performed. Serum 
amivantamab concentrations and PK parameters will be listed and summarized by the sampling 
interval. In addition, a population pharmacokinetic-based modeling approach may also be applied 
for PK analysis to assess the potential effect of intrinsic and extrinsic factors on the PK of 
amivantamab.
Pharmacokinetic/Pharmacodynamic Evaluations
Pharmacokinetic serum concentration-time data from this study may be analyzed using a
population PK approach. The data collected from this study may also be combined with similar
data from other studies to perform population PK and assess the relationship between PK or
immunogenicity and selected safety and efficacy endpoints. Details will be provided in a
population PK and exposure-response analysis plan and results of the analysis will be presented in 
a separate report.
8.5.
Pharmacogenomics
Pharmacogenomics are not evaluated in this study.


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8.6.
Biomarkers/Pharmacodynamics
Analyses are planned to explore biomarkers in tumor tissue and blood samples that may predict 
sensitivity or resistance to treatment and may indicate the mechanisms of action or mechanism of 
resistance to amivantamab treatment. Correlation of baseline biomarker levels, or changes in 
biomarker levels upon treatment, with response or time-to-event endpoints could identify 
responsive (or resistant) subgroups. The relationship of etiology (eg, HepB, HepC) with clinical 
response will also be analyzed.
Pre-treatment tumor tissue samples will undergo central analysis to investigate levels of MET, 
EGFR, and relevant MET/EGFR ligands. Tumor biopsy acquired at screening is preferred. If not 
available, the most recent tumor sample is acceptable. Post-treatment tumor samples, if collected,
may also be evaluated for these biomarkers. The changes will be analyzed to indicate target 
modulation, and track response to amivantamab. Samples may be collected from primary 
(preferred) or metastatic tumor sites (acceptable), preferably from non-target lesions that are 
actively growing. Biopsy of a target lesion is allowed for the pre-treatment sample, but baseline 
disease assessment must occur a minimum of 1 week after the biopsy procedure. The sponsor’s 
medical monitor must give approval prior to the biopsy of a target lesion at baseline. During the 
study, biopsy of a target lesion is not allowed unless disease progression has occurred.
Blood samples will be collected at timepoints specified in the Schedule of Activities (SoA) for 
analysis of circulating biomarkers (eg, relevant EGFR and MET ligands, AFP) in samples taken 
prior to and after exposure to study treatment. The baseline level of these biomarkers and their 
changes upon treatment will be correlated with response to amivantamab treatment.
Additional biomarkers (DNA, RNA, and/or protein) relevant to target biology and HCC may also 
be assessed in blood and tissue samples collected during the study to help identify sensitive (or 
resistant) population subgroups, to evaluate the drug and clinical response relationship, to better 
understand the mechanisms of response or resistance to amivantamab.
Blood samples will be collected from all participants at selected time points (Table 2 and Table 3) 
to analyze PD markers (eg, soluble EGFR and MET) to evaluate whether the soluble target 
saturation was achieved throughout the dosing.
Sample collection, testing and analysis will comply with local regulations.
Decision on Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data.


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Additional Collections
If it is determined at any time before study completion that additional material is needed from a 
formalin-fixed, paraffin-embedded tumor sample for the successful completion of the protocol-
specified analyses, the sponsor may request that additional material be retrieved from existing 
samples. Also, based on emerging scientific evidence, the sponsor may request additional material 
from previously collected tumor samples during or after study completion for a retrospective 
analysis. In this case, such analyses would be specific to research related to the study treatment(s) 
or diseases being investigated.
Additional blood and tumor tissue samples collection and analysis in China should be performed 
after the approval of HGRAO.
8.7.
Immunogenicity Assessments
Antibodies to amivantamab will be evaluated in serum samples collected from all participants
according to the Table 2 and Table 3. Additionally, serum samples should also be collected at the 
final visit from participants who discontinued study treatment or were withdrawn from the study. 
These samples will be tested by the sponsor or sponsor's designee.
Serum samples will be screened for antibodies binding to amivantamab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to amivantamab and/or further characterize the immunogenicity of amivantamab.
Immunogenicity assessment may also be performed on any PK sample. Sample collection and 
testing will comply with local regulations.
Samples collected for immunogenicity analyses may additionally be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the study period. Genetic analyses 
will not be performed on these serum samples. Participant confidentiality will be maintained.
Analytical Procedures 
The detection and characterization of antibodies to amivantamab will be performed using a 
validated assay method by or under the supervision of the sponsor. All samples collected for 
detection of antibodies to amivantamab will also be evaluated for amivantamab serum 
concentration to enable interpretation of the antibody data. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study treatment(s). 
Samples may be stored up to 15 years (or according to local regulations) following the last 
participant’s last visit for the study at a facility selected by the sponsor to enable further analysis 
of immune responses to amivantamab.
8.8.
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.


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9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1.
Statistical Hypotheses
The hypothesis is that amivantamab monotherapy will lead to an ORR higher than 10% (ie, 
: ORR≤10%) in participants with advanced HCC.
9.2.
Sample Size Determination
Assuming the ORR is 20% for the entire population, approximately 60 participants with advanced 
HCC will be enrolled to have over 85% probability to observe the ORR greater than 15%. With 
this rule, additional participants (ie, approximately 40) may be enrolled in an expansion phase to 
test the ORR of amivantamab against the null hypothesis with alpha=0.05 (two-sided) if supported 
by emerging data. Details will be provided in the SAP. 
Anti-tumor activity within biomarker defined subpopulations will be investigated to identify the 
most responsive patient population who may benefit from amivantamab. With the prevalence of 
50% of the entire population having 25% ORR, it is expected to have approximately 90% power 
to observe the posterior probability (ORR >15%) ≥50% in this population. On the other hand, if 
the biomarker defined population has undesirable ORR (ie, 10%), there is less than 20% 
probability to observe the posterior probability (ORR >15%) ≥50%. More examples are given in 
the Table 10.
Table 10:
Probability to Detect Signal in Sub-Population Under Different Scenarios
Prevalence of effective 
population
ORR for effective population
Power to observe
posterior probability (ORR > 15%) 
≥50% in effective population
25%
10%
18% (type I error)
20%
60%
25%
76%
30%
87%
50%
10%
18% (type I error)
20%
74%
25%
90%
30%
97%
9.3.
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Description
Safety Evaluation
Participants who are enrolled during the safety evaluation
All treated
All participants who receive at least 1 dose of study treatment
Response 
evaluable
All participants satisfy the following criteria:
Received at least 1 dose of study treatment


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At least 1 post-baseline efficacy disease assessments, or discontinued treatment for 
any reason, or had disease progression/death prior to the first postbaseline disease 
assessment 
Pharmacokinetics
All participants who receive at least 1 dose of study treatment and have at least 1 evaluable 
postbaseline measurement
Immunogenicity 
All participants who receive at least 1 dose of study treatment and have at least 1 evaluable 
postbaseline measurement
Biomarker
All participants who receive at least 1 dose of study treatment and have at least 1 biomarker 
measurement
9.4.
Statistical Analyses
The statistical analysis plan will be finalized prior to database lock (DBL) and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints.
9.4.1.
General Considerations
All continuous variables will be summarized using number of participants (n), mean, standard 
deviation (SD), median, minimum and maximum. Discrete variables will be summarized with 
number and percent. The Kaplan-Meier product limit method will be used to estimate the time-to-
event variables including median survival time.
9.4.2.
Primary Endpoint(s)
9.4.2.1.
ORR
The primary efficacy measure is ORR. ORR is defined as the proportion of participants who 
achieve either PR or CR, determined by investigator assessment using RECIST Version 1.1. 
The primary estimand for ORR is defined by the following components:

Population: Participants with advanced HCC

Variable: overall response 

Study drug: amivantamab monotherapy

Intercurrent event: subsequent anticancer therapy. The while-on-treatment policy will be used: 
response after this intercurrent event will not be included

Summary: ORR
The observed ORR and its 95% CI will be calculated.
9.4.3.
Secondary Endpoint(s) 
9.4.3.1.
DoR
The DoR is defined as the time from the date of first documented response (CR or PR) until the 
date of documented progression or death, whichever comes first. The end of response should 


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coincide with the date of progression or death from any cause used for the PFS endpoint. If a 
participant does not progress following a response, then his/her DoR will be censored at the same 
date with PFS. A Kaplan-Meier plot and the median DoR with its 95% CI will be presented.
9.4.3.2.
DCR
The DCR is defined as the proportion of participants achieving complete or partial response or 
stable disease of at least 11 weeks as defined by RECIST Version 1.1. Observed DCR and its two-
sided exact 95% CI will be presented.
9.4.3.3.
PFS
The PFS is defined as the time from the date the first dose until the date of objective disease 
progression or death by any cause, whichever comes first, based on investigator review according 
to RECIST Version 1.1. Participants who have not progressed or have not died at the time of 
analysis will be censored at the time of the latest disease assessment. PFS will be analyzed using 
the same methodology applied to the analysis for DoR. 
9.4.3.4.
OS
The OS is defined as the time from the date of the first dose until the date of death due to any 
cause. Participants who are not known to have died at the time of analysis will be censored based 
on the last recorded date on which the participant was known to be alive. OS will be analyzed 
using the same methodology applied to the analysis for DoR. In addition, the 6-month and 
12-month OS rate along with their 95% CI will also be calculated from the Kaplan-Meier estimate.
9.4.4.
Exploratory Endpoint(s) 
Objective Response Rate by mRECIST (mORR)
The mORR is defined as the proportion of participants who achieve either PR or CR, determined 
by investigator assessment using mRECIST. The observed mORR and its 95% CI will be 
calculated. 
9.4.5.
Safety Analyses
All safety analyses will be made on the All treated Population. Baseline for all laboratory 
evaluations, and vital signs will be defined as the last evaluation done before the first study 
treatment administration.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study treatment through the day of last dose plus 30 days or until the start of 
subsequent anticancer therapy, if earlier, is considered to be treatment-emergent. All reported 
treatment-emergent AEs will be included in the analysis. For each AE, the percentage of 
participants who experience at least 1 occurrence of the given event will be summarized by 
intervention group.


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Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an AE, or who experience a severe or an 
SAE.
Parameters with predefined National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) toxicity grades will be summarized. Change from baseline to the worst AE
grade experienced by the participant during the study will be provided as shift tables.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. Descriptive 
statistics will be calculated for selected laboratory analyte at baseline and for observed values and 
changes from baseline at each scheduled time point. Frequency tabulations of the changes from 
baseline will be presented in pre- versus post-intervention cross-tabulations (with classes for 
below, within, and above normal ranges). Frequency tabulations of the laboratory abnormalities 
will be made. A listing of participants with any laboratory results outside the reference ranges will 
be provided. A listing of participants with any markedly abnormal laboratory results will also be 
provided.
Vital Signs
Vital signs including weight, temperature, pulse/heart rate, respiratory rate, oxygen saturation and 
blood pressure (systolic and diastolic) will be summarized over time, using descriptive statistics 
and/or graphically. The percentage of participants with values beyond clinically important limits 
will be summarized.
9.4.6.
Other Analyses
9.4.6.1.
Pharmacokinetic Analyses
The PK analyses will use the PK population. Serum amivantamab concentrations will be
summarized in tables of mean, SD, median, and range over time, as appropriate. 
Participants will be excluded from the PK analysis if their data do not allow for accurate
assessment of the PK (eg, incomplete administration of the study treatment; missing information
of dosing and sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration database. All participants and samples excluded from the analysis will
be clearly documented in the study report.
Descriptive statistics will be used to summarize amivantamab serum concentrations at each 
sampling timepoint and PK parameters of amivantamab, including but not limited to Cmax, Tmax, 
AUC(t1-t2) (eg, AUCDay 1-8, AUCDay 29-36), AUCtau, Ctrough, and R. Additional serum PK parameters 
could be determined as appropriate.


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Mean or median serum amivantamab concentration versus time profiles will be plotted, and 
individual serum concentration-time profiles may also be plotted.
Population PK modeling of serum concentration-time data may be performed using nonlinear
mixed-effects modeling if appropriate. The exposure-response relationship between amivantamab 
exposure and key efficacy and safety parameters may be explored if the data allow. Details will be 
provided in an analysis plan and detailed results may be reported separately from the Clinical 
Study Report.
9.4.6.2.
Pharmacodynamic/Biomarkers Analyses
The PD/biomarker analyses will use the PD/biomarker population. Analyses are planned to 
evaluate PD and other biomarkers that may be indicative of the mechanisms of action of the drug 
or predictive of efficacy as well as the potential mechanisms of resistance to amivantamab.
The association of biomarker positivity with clinical response or time-to-event endpoints will be 
assessed using appropriate statistical methods for each endpoint. Correlation of baseline biomarker 
expression levels with clinical response or relevant time-to-event endpoints will be performed to 
identify response (or resistant) subgroups.
Additional biomarkers (DNA, RNA, and/or protein) relevant to target biology and HCC may also 
be assessed in blood and tissue samples collected during the study to help identify sensitive (or 
resistant) population subgroups, to evaluate the drug and clinical response relationship, to better 
understand the mechanisms of response or resistance to amivantamab.
9.4.6.3.
Immunogenicity Analyses
The incidence of anti-amivantamab antibodies will be summarized for immunogenicity 
population.
Serum samples will be screened for antibodies binding to amivantamab and the number of 
confirmed positive samples will be reported. Other analyses may be performed to further 
characterize the immunogenicity of amivantamab.
9.5.
Interim Analysis
Two interim analyses are planned: an early review of safety after the first 6 participants have 
enrolled and have completed at least 1 complete cycle of amivantamab therapy, and a futility 
analysis based on ORR will be conducted after 30 participants have been enrolled and are response 
evaluable. The enrollment may be terminated for futility if less than or equal to 2 responders are 
observed. Specific details will be provided in the SET Charter and interim analysis plan.
Otherwise, additional participants will be enrolled for a total of approximately 60 participants for 
the initial analysis, with the potential for expansion to approximately 100 participants.
The SAP will describe the planned interim analyses in greater detail.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
ADA
anti-drug antibody
ADCC
antibody-dependent cellular cytotoxicity
ADCT
antibody-dependent cellular trogocytosis
AE
adverse event
AFP
alpha-fetoprotein
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
APTT
activated partial thromboplastin time
AST
aspartate transaminase
AUC
area under the curve
BCLC
Barcelona clinic liver cancer
-hCG
-human chorionic gonadotropin
BICR
Blinded Independent Central Review
BP
blood pressure
BW
body weight
C#D#
Cycle # Day #
CDE
Center for Drug Evaluation
CHF
congestive heart failure
Cmax
maximum serum concentration
CI
confidence interval
COVID-19
coronavirus disease 2019
CR
complete response
CRC
colorectal cancer
CRF
case report form(s) (paper or electronic as appropriate for this study)
CRO
Contract Research Organization
CT
computerized tomography
CTCAE
common terminology criteria for adverse events
CTM
Clinical Trial Manager
Ctrough
serum concentration immediately prior the next study treatment administration
DBL
database lock
DCR
disease control rate
DLT
dose limiting toxicity
DoR
duration of response
EASL
European Association for the Study of the Liver
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDC
electronic data capture
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EOT
end of treatment
ETV
entecavir
FDA
Food and Drug administration
FOIA
Freedom of Information Act
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GFR
Glomerular Filtration Rate
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
h/hrs
hour
HA
Health Authority
HAART
highly active antiretroviral therapy
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody


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HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDV
hepatitis D virus
Hep B
Hepatitis B
Hep C
Hepatitis C
HGF
hepatocyte growth factor
HGRAO
Human Genetic Resources Administration Office
HIFU
high-intensity focused ultrasound
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HR
hazard ratio
HRT
hormonal replacement therapy
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDMS
isotope dilution mass spectrometry
IEC
Independent Ethics Committee
IgG1
immunoglobulin G1
IgM
immunoglobulin M
IHC
immunohistochemistry
ILD
interstitial lung disease
IND
Investigational New Drug
INR
international normalized ratio
IO
Immuno-Oncology
IPPI
Investigational Product Preparation Instructions
IRB
Institutional Review Board
IRR
infusion-related reactions
IV
intravenous
LD
longest diameter
LDH
lactic acid dehydrogenase
LFT
liver function test
LTMs
Local Trial Managers
MDRD
Modified Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MET
mesenchymal epithelial transition
min
minutes
MKI
multi-targeted kinase inhibitor
MRI
magnetic resonance imaging
NASH
non-alcoholic steatohepatitis
NK
natural killer
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PAI
acetic acid injection
PEI
percutaneous ethanol
PET
positron emission therapy
PCC
protocol clarification communication
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PD-1
programmed cell death 1
PDX
patient-derived xenograft
PFS
progression-free survival
PI
principal investigator
PK
pharmacokinetic(s)


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PQC
Product Quality Complaint
PR
partial response
PT
prothrombin time
Q12W
every 12 weeks
R
accumulation ratio
RECIST
response criteria in solid tumors
RFA
radiofrequency ablation
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
standard deviation
SET
safety evaluation team
SIPPM
Site Investigational Product and Procedures Manual
SoA
Schedule of Activities
SoC
standard of care
SPF
skin protection factor
TACE
transarterial chemoembolization
TAI
transarterial embolization
TBL
total bilirubin
TDF
tenofovir disoproxil fumarate
TEAE
treatment-emergent adverse events
TEN
toxic epidermal necrolysis
TGI
tumor growth inhibition
TKI
tyrosine kinase inhibitors
Tmax
time to reach the maximum serum concentration
ULN
upper limit of normal
US
United States
Vss
steady state volume of distribution
WBC
white blood cell


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10.2.
Appendix 2: Clinical Laboratory Tests 
The following tests will be performed according to the Schedule of Activities by the local and 
central laboratory (if the local lab is not able to be performed the relevant tests, the tests can be 
performed at the central lab):
The actual date of assessment and, if required, the actual time of the assessment of laboratory 
samples will be recorded in the source documentation and in the eCRF or laboratory requisition 
form.
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology

Hemoglobin

Platelet count

Absolute neutrophil count and white blood 
cell (WBC) count 
Coagulation

Prothrombin time (PT) or International 
normalized ratio (INR)

Activated partial thromboplastin time 
(APTT)
Clinical 
Chemistry

Magnesium

Sodium

Calcium

Potassium

Blood Glucose 

Cholesterol

Triglycerides

Gamma-glutamyl transferase (GGT)

Lactic acid dehydrogenase (LDH)

Uric acid
Liver& 
Kidney 
function

LFTs (ALT, AST, total and indirect 
bilirubin, alkaline phosphatase)

Albumin

Blood urea nitrogen (BUN) or urea

Creatininea

Potassium
Urinalysis
Dipstick

Specific gravity

pH

Glucose

Protein

Blood

Ketones

Bilirubin

Nitrite

Leukocyte esterase 
If dipstick is abnormal and clinically
important then urine microscopy 

Red blood cells

White blood cells

Epithelial cells

Crystals

Casts

Bacteria
Serology

Anti-HIV antibody

Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B 
e-antigen (HBeAg), hepatitis B e-antibody (HbeAb) and hepatitis B core antibody 
(HBcAb) (participants tested positive for HBsAg or HBcAb, or both are also required to 
have HBV DNA quantification and HBsAg quantification)

Anti-hepatitis C virus (HCV) antibody (participants tested positive for HCV antibody are
also required to have HCV RNAquantification.)

Hepatitis D (HDV) antibody
Tumor 
marker
Alpha-fetoprotein (AFP)
a.
estimated Glomerular Filtration Rate (eGFR), calculated using the MDRD formular, will be recorded in the
eCRF.


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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1.
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country- or territory-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or 
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification 
communication (PCC) may be prepared. The PCC Document will be communicated to the 
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers 
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC 
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional 
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the 
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator 
or other physician in attendance will contact the appropriate sponsor representative listed in the 
Contact Information page(s), which will be provided as a separate document. Except in emergency 
situations, this contact must be made before implementing any departure from the protocol. In all 
cases, contact with the sponsor must be made as soon as possible to discuss the situation and agree


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on an appropriate course of action. The data recorded in the CRF and source documents will reflect 
any departure from the protocol, and the source documents will describe this departure and the 
circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country/territory, if applicable. A study may not be initiated until all local 
regulatory requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study treatment to 
the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
participant:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable


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
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)

IB (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study treatment


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
New information that may adversely affect the safety of the participants or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the participants

Report of deaths of participants under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
Country/Territory Selection
This study will only be conducted in those countries/ territories where the intent is to launch or 
otherwise help ensure access to the developed product if the need for the product persists, unless 
explicitly addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical 
Design Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the study and 
for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.3.3.
Informed Consent Process 
Each participant must give consent according to local requirements after the nature of the study 
has been fully explained. The ICF(s) must be signed before performance of any study-related 
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the participant can read and understand. The informed consent


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must be in accordance with principles that originated in the Declaration of Helsinki, current ICH 
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study site personnel 
must explain to potential participants the aims, methods, reasonably anticipated benefits, and 
potential hazards of the study, and any discomfort participation in the study may entail. 
Participants will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the participant will receive for the treatment of his or her disease. Participants will 
be told that alternative treatments are available if they refuse to take part and that such refusal will 
not prejudice future treatment. Finally, they will be told that the investigator will maintain a 
participant identification register for the purposes of long-term follow-up if needed and that their 
records may be accessed by health authorities and authorized sponsor personnel without violating 
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations. 
By signing the ICF the participant is authorizing such access, which includes permission to obtain 
information about his or her survival status. It also denotes that the participant agrees to allow his 
or her study physician to recontact the participant for the purpose of obtaining consent for 
additional safety evaluations, and subsequent disease-related treatments, if needed. 
The participant will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent must be appropriately recorded by 
means of the participant's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the participant.
If the participant is unable to read or write, an impartial witness must be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
must personally date and sign the ICF after the oral consent of the participant is obtained.
Participants who are rescreened are required to sign a new ICF.
When prior consent of the participant is not possible, enrollment procedures must be described in 
the protocol with documented approval/favorable opinion by the IEC/IRB to protect the rights, 
safety, and well-being of the participant and to ensure compliance with applicable regulatory 
requirements. The participant must be informed about the study as soon as possible and give 
consent to continue.
10.3.4.
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures


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or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant includes information about, and where 
required per applicable regulations, explicit consent for the processing of personal data and for the 
investigator/institution to allow direct access to his or her original medical records (source 
data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. 
The informed consent also provides information to address the lawful transfer of the data to other 
entities and to other countries/ territories.
The participant has the right to request through the investigator access to his or her personal data 
and the right to request rectification of any data that are not correct or complete, or make requests 
concerning his or her personal data in accordance with applicable data protection law. Reasonable 
steps will be taken to respond to such a request, taking into consideration the nature of the request, 
the conditions of the study, and the applicable laws and regulations.
In the event of a data security breach, the sponsor will apply measures to adequately manage and 
mitigate possible adverse effects taking into consideration the nature of the data security breach as 
necessary to address other obligations such as notifying appropriate authorities in accordance with 
applicable data protection law.
Exploratory research is not conducted under standards appropriate for the return of data to 
participants. In addition, the sponsor cannot make decisions as to the significance of any findings 
resulting from exploratory research. Therefore, exploratory research data will not be returned to 
participants or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
10.3.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand amivantamab, to understand
disease under investigation, to understand differential intervention responders, and to develop 
tests/assays related to amivantamab and HCC. The research may begin at any time during the study 
or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
10.3.6.
Committees Structure
The safety and conduct of the study will be monitored by the SET in conjunction with the 
coordinating investigators. The SET will consist of participating principal investigators, the 
sponsor’s medical monitor, the Safety Management Team Chair, one of the sponsor’s clinical 


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pharmacologists or their designees, and additional sponsor staff as appropriate. The sponsor’s 
statistician or biomarker scientist will be consulted when the SET determines it is necessary. In 
general, SET will monitor the conduct of the study and review study data on an ongoing basis. The 
SET may recommend and decide on modifications in the study conduct which may include, but 
are not restricted to, changes in (1) study treatment administration dose/schedule, (2) allowing 
further enrollment or terminate enrollment of a specific subpopulation to better characterize the 
specific population (3) opening the expansion cohort (4) PK or biomarker sampling times. 
All decisions made by the SET will be documented in a SET decision document. The Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) will be notified for all SET decisions, if 
required. The recommendations of the SET may be instituted by the study team, pending protocol 
amendment, as long as they are consistent with the benefit-risk and fall within the populations 
already reviewed and approved by HA and local IRBs. All the SET documentation will be 
maintained in the sponsor’s study master file and, as applicable, in the investigator’s study files. 
If unexpected safety findings are identified, ad-hoc SET meetings may be called by any member 
of the SET, for any issue or concern, and the SET will assess the safety data in a prompt manner.
The study will include a screening phase, a treatment phase, and a follow-up phase.
10.3.7.
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding amivantamab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including biomarker research data, generated as a result of this 
study, are considered confidential and remain the sole property of the sponsor. The investigator 
agrees to maintain this information in confidence and use this information only to accomplish this 
study and will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of amivantamab, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of any analyses 
performed after the Clinical Study Report has been issued will be reported in a separate report and 
will not require a revision of the Clinical Study Report. 
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work.


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Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information. 
For multicenter study designs and sub-study approaches, secondary results generally should not 
be published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed 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.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the interim results of clinical studies as required by law. The 
disclosure of the study results will be performed after the end of study in order to ensure the 
statistical analyses are relevant.
10.3.8.
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study site personnel before 
the start of the study. The sponsor may review the CRF for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with


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the investigator or designee, as appropriate. After upload of the data into the study database they 
will be verified for accuracy and consistency with the data sources.
10.3.9.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in the CRF. All CRF entries, corrections, 
and alterations must be made by the investigator or authorized study site personnel. The 
investigator must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered into
the CRF in English. The CRF must be completed as soon as possible after a participant visit and 
the forms must be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways:

Investigator and study site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and study 
site personnel.
10.3.10.
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study treatment administration information; and date of study 
completion and reason for early discontinuation of study treatment or withdrawal from the study, 
if applicable. 
The author of an entry in the source documents must be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).


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The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
CRF.
10.3.11.
Monitoring
The sponsor will use a combination of monitoring techniques central, remote, or on-site monitoring 
to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor may
compare the data entered into the CRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF are known to the sponsor and study site personnel and are accessible for verification by the 
sponsor study site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the 
relevant study site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study 
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study site personnel will be available to provide an update on the progress of the 
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.


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10.3.12.
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study site personnel are responsible for being present and available 
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its 
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator must immediately notify the sponsor if he or she has been 
contacted by a regulatory agency concerning an upcoming inspection.
10.3.13.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14.
Study and Site Start and Closure
First Act of Recruitment
The first participant screened is considered the first act of recruitment and it becomes the study 
start date.


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Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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10.4.
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a 
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have 
a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product. (Definition per International Council on 
Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. Note: The sponsor collects adverse events starting with the signing of the ICF (refer 
to All Adverse Events under Section 8.3.1, Time Period and Frequency for Collecting Adverse 
Events and Serious Adverse Events Information, for time of last adverse event recording).
All adverse events, regardless of seriousness, severity, or presumed relationship to study treatment, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology (eg, 
cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human 
Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*


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Note: Events that do not qualify as an AE cannot be reported as a SAE, even if the conditions for 
seriousness are met. In particular, this is the case for events due to disease progression leading to 
death, hospitalization, etc.
*Medical and scientific judgment must be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship 
between the study treatment and the event (eg, death from anaphylaxis), the event must be reported 
as a serious and unexpected suspected adverse reaction even if it is a component of the study 
endpoint (eg, all-cause mortality). 
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information. For amivantamab, the expectedness of an AE will be determined by 
whether or not it is listed in the IB.
10.4.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study treatment is assessed by the Investigator. The following selection 
must be used to assess all AEs.
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3.
Severity Criteria 
An assessment of severity grade will be made by the investigator according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE Version 5.0). Any 
adverse events or serious adverse events not listed in the NCI-CTCAE Version 5.0 should be 
evaluated for severity/intensity by using the standard grades as follows:
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL.*


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Grade 3
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.**
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to adverse event.
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden.
ADL=activities of daily living
Notes: A semi-colon indicates ‘or’ within the description of the grade. 
The investigator must use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
10.4.4.
Special Reporting Situations
Safety events of interest on a sponsor study treatment in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study treatment

Suspected abuse/misuse of a sponsor study treatment

Accidental or occupational exposure to a sponsor study treatment

Medication error, intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson & 
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted 
prescribing or dispensing errors)

Exposure to a sponsor study treatment from breastfeeding

Reporting of participant pregnancy or participant partner(s) pregnancy

Liver chemistry abnormalities that meet the SAE reporting criteria defined in Section 7.1.1.
Special reporting situations must be recorded in the CRF. Any special reporting situation that 
meets the criteria of an SAE must be recorded on the SAE page of the CRF.
10.4.5.
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study treatment, must be 
recorded using medical terminology in the source document and the CRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the CRF their opinion concerning the relationship of the 


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AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical personnel only)

Site number

Participant number

Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the 
participant's discontinuation from the study, must be followed until any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study treatment or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during 
participation in the study must be reported as an SAE, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending 
placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the participant for the duration of 
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Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms 
of clinical sequelae resulting from disease progression/lack of efficacy will be reported if they 
fulfill the SAE definition (refer to Adverse Event Definitions and Classifications in Appendix 4:
Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other Safety 
Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting).
Information regarding SAEs will be transmitted to the sponsor using the SAE reporting form and 
Safety Report Form of the CRF, which must be completed and reviewed by a physician from the 
study site, and transmitted in a secure manner to the sponsor immediately but no later than within 
24 hours. The initial and follow-up reports of an SAE should be transmitted electronically or by 
facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to 
complete the appropriate form(s) first. 
10.4.6.
Product Quality Complaint Handling
Definition
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, reliability, or performance of a distributed product, including its labeling, drug delivery 
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after 
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
10.4.7.
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who must be contacted 
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.


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10.5.
Appendix 5: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
Definitions
Females of Childbearing Potential (FOCBP)
A female is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Females Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in female participant
not using hormonal contraception or hormonal replacement therapy (HRT), however in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
If there is a question about menopausal status in a female participant on HRT, the female 
participant will be required to use one of the non-estrogen-containing hormonal highly 
effective contraceptive methods if she wishes to continue HRT during the study.

permanently sterile

Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or
bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female 
participant experiences menarche) or the risk of pregnancy changes (eg, a female participant who 
is not heterosexually active becomes active), a female participant must begin a highly effective 
method of contraception, as described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by male or female participants must be consistent with local 
regulations regarding the acceptable methods of contraception for those participating in clinical 
studies.
Typical use failure rates may differ from those when used consistently and correctly. Use must be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.


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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)

Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception must be used. 
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of 1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)


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a) Typical use failure rates may differ from those when used consistently and correctly. Use must be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study treatment.
c) Male condom and female condom must not be used together (due to risk of failure with friction).


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10.6.
Appendix 6: BCLC Staging System
BCLC classification: outcome prediction and treatment allocation.
Source: European Association for Study of Liver, 2012


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10.7.
Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments
10.7.1.
Follow-up assessment Algorithm
Treatment-emergent ALT or 
AST
Treatment-emergent 
TBLa
Liver‐related
symptoms 
Actions
ALT/AST ≥3× BL 
Total bilirubin ≥2 x ULN 
(of which ≥ 35% is direct 
bilirubin)
Interrupt study drug. Repeat LFT tests within 1-3 days and until abnormal values 
resolve/return to baseline. The event should be reported as a serious adverse event 
to the Sponsor within 24. Initiate workup for competing etiologies. Study drug 
can be restarted only if another etiology is identified, and liver enzymes return to 
normal or baseline.
ALT/AST ≥3× BL 
Clinical jaundice
Interrupt study drug. Repeat LFT tests within 1-3 days and until abnormal values 
resolve/return to baseline. The event should be reported as a serious adverse event 
to the Sponsor within 24. Initiate workup for competing etiologies. Study drug 
can be restarted only if another etiology is identified, and liver enzymes return to 
normal or baseline.
ALT/AST ≥5× ULN (if normal 
at baseline) or 
ALT/AST ≥3× BL (if abnormal 
at baseline) 
Normal (or no changes in 
baseline TBL in patients 
with Gilbert’s syndrome 
or hemolysis)
Repeat LFT tests within 1-3 days and until abnormal values resolve/return to 
baseline. Interrupt study drug if abnormal values worsened meeting stopping 
criteria (Section 7.1.1) or follow above or below additional guidance if ALT/AST 
≥10 × ULN, or if total bilirubin ≥2 x ULN or jaundice are observed 
ALT/AST ≥10 × ULN  
Repeat LFT tests within 1-3 days and until abnormal values resolve/return to 
baseline. The event should be reported as a serious adverse event to the Sponsor 
within 24 hrs. Initiate workup for competing etiologies. Interrupt study drug if 
abnormal values meet stopping criteria (Section 7.1.1) or follow above guidance 
if total bilirubin ≥2 x ULN or jaundice are observed.
Note: If baseline value is > 50% higher than the screening value, it should prompt a discussion with the medical monitor
BL = baseline defined as Day 1 predose test; LFT = liver function test; TBL = total bilirubin.
a. Study treatment should be withheld for any liver chemistry abnormality of ≥Grade 3 severity based on CTCAE 5.0 (Table 4). 


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10.7.2.
Follow-up Assessments
Liver Event Follow-up Requirements
The following follow-up assessments should be conducted for any participant meeting liver 
chemistry stopping criteria:

Conduct liver imaging (ultrasound, magnetic resonance [MRI], or CT) to evaluate liver 
disease

Monitor liver chemistries (ALT, AST, alkaline phosphatase, bilirubin [including bilirubin 
fractions], and INR), creatinine phosphokinase, and lactate dehydrogenase, 1 to 2 times per 
week until resolution, stabilization, or return to participant’s baseline values

Monitor clinical condition closely

Draw blood samples for unscheduled PK analysis at timepoints when liver chemistry is 
assessed

Record use of concomitant medications, acetaminophen, herbal remedies, other 
over-the-counter medications, or known hepatotoxins

Record alcohol use in the eCRF

Check the viral hepatitis serology as appropriate and include:
o
Hepatitis A IgM antibody
o
Hepatitis B surface antigen, hepatitis B core antibody (IgM) and hepatitis B viral load
o
Hepatitis C viral load
o
Hepatitis E IgM antibody
o
Cytomegalovirus IgM antibody
o
Epstein-Barr viral capsid antigen IgM antibody (or equivalent test)

Assess anti-nuclear antibody, anti-smooth muscle antibody, and type 1 anti-liver kidney 
microsomal antibodies

Refer to a specialist as appropriate
Note: If the local lab is not able to be performed the relevant tests, the tests can be performed at 
the central lab.


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Rechallenge Criteria
Resumption of study drug administration may be considered if the following criteria are met 
unless the criteria for permanent discontinuation are reached.

A reversible underlying cause not associated with study treatments (eg, alcohol or 
concomitant medication) is clearly identified and agreed upon in consultation with sponsor’s 
medical monitor.

Liver chemistry abnormalities have resolved, or values have returned to baseline.
Note: Any rechallenge case, a discussion should occur with the Sponsor before restarting 
amivantamab.


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10.8.
Appendix 8: New York Heart Association Criteria
The following table presents the NYHA classification of cardiac disease:
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of cardiovascular 
disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure 
or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
* Classification of Functional Capacity and Objective Assessment. 
Available at: https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/classes-of-heart-failure 
Accessed 13 Dec 2021.


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10.9.
Appendix 9: Allowed Recent Second or Prior Malignancies
i.
Any malignancy that was not progressing nor requiring treatment change in the last 
12 months.
ii.
Malignancies treated within the last 12 months and considered at very low risk for 
recurrence:
a) Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS).
b) Skin cancer (non-melanoma or melanoma).
c) Non-invasive cervical cancer.
d) Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, 
localized breast cancer and receiving antihormonal agents.
e) Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only 
(RP/RT/focal treatment).
iii.
Other malignancy that is considered at minimal risk of recurrence.
In the event of any questions, consult with the sponsor’s medical monitor prior to enrolling a 
participant.


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10.10. Appendix 10: RECIST 1.1 and mRECIST Quick Reference
RECIST 1.1
Measurable
Tumor Burden
A maximum of 5 target lesions in total (and up to 2 per organ) can be identified at baseline
and measured through the course of therapy.
Minimum Size of
Measurable
Lesions
≥10 mm in longest diameter (LD) and 2X the slice thickness for extranodal lesions.
≥15 mm in short axis for nodal lesions.
≥10 mm in LD for clinical lesions (must be measured using electronic calipers).
≥20 mm in LD for chest X-ray (if clearly defined and surrounded by aerated lung); CT 
is preferable.
Ultrasound (US) cannot be used to measure lesions.
Lymph Nodes
Lymph nodes are considered pathologically enlarged if >10 mm in short axis. 
To be measurable, nodal lesions must be ≥15 mm in short axis. 
Nodal lesions with short axis >10 mm and <15 mm are non- measurable.
The sum of the diameters (LD for extranodal target lesions, short axis for nodal lesions)
is followed through the course of therapy.
Bone Lesions
A lytic or mixed lytic-blastic bone lesion with a soft tissue component assessed on
CT/MRI can be measurable if the minimum size criteria are met.
Blastic bone lesions and bone lesions assessed on bone scan, positron emission therapy 
(PET) or plain films are non-measurable.
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts are not
malignant.
Cystic lesions thought to be metastases can be measurable if they meet the minimum
size criteria. Non-cystic lesions are preferable.
Lesions with 
Prior Local 
Treatment
Lesions in previously irradiated areas (or areas treated with local therapy) are not
measurable unless the lesion has progressed since therapy.
Too Small To 
Measure
If a target lesion becomes too small to measure, a default value of 5 mm is assigned. If the 
lesion disappears, the measurement is recorded as 0 mm.
Lesions That
Split or Coalesce
If extranodal target lesions fragment, the LDs of the fragmented portions are added to 
calculate the sum.
If target lesions coalesce and cannot be distinguished, the LD of the coalesced lesion is
added to the sum.
Definition of 
Complete 
Response (CR)
CR requires the disappearance of all extranodal lesions, the regression of all nodal lesions 
to <10 mm short axis and the normalization of tumor marker level.
Definition of 
Progressive 
Disease (PD)
PD is assessed if the sum of the diameters has increased by ≥20% and ≥5 mm from nadir 
(including baseline if it is the smallest sum).
Patients with measurable disease: for "unequivocal progression" based on non-target 
disease, there must be an overall level of substantial worsening that merits discontinuation 
of therapy (if target disease is SD/PR).
Patients without measurable disease: for "unequivocal progression" of non-target disease, 
the increase in overall tumor burden must be comparable to the increase required for PD of 
measurable disease.
Assessment of 
New Lesions
New lesions should be unequivocal and not attributable to differences in scanning 
technique or findings which may not be tumor (ie, 'new' bone lesions may be healing or 
flare of pre- existing lesions). If on is equivocal, repeat scans are needed to confirm. If 
confirmed, PD is assessed at the date of the initial scan. Lesions identified in anatomic 
locations not scanned at baseline are considered new. New lesions on US should be 
confirmed on CT/MRI.
FDG-PET
New lesions can be assessed using FDG-PET:(-) PET at baseline and (+) PET at follow-up 
is PD based on a new lesion. No PET at baseline and (+) PET at follow-up is PD if the 
new lesion is confirmed on CT. If a subsequent CT confirms the new lesion, the date of 
the PD is the date of the initial PET scan. No PET at baseline and (+) PET at follow-up 
corresponding to preexisting lesion on CT that is not progressing; not PD.


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Recurrence of 
Lesions
For a patient with SD/PR, a lesion which disappears and then reappears will continue to be 
measured and added to the sum. Response will depend upon the status of the other lesions. 
For a patient with CR, reappearance of a lesion would be considered PD.
Overall 
Response
One overall response table integrates target, non-target and new lesions and another table 
integrates non-target and new lesions for the assessment of subjects without measurable 
disease.
Confirmation of 
Response
Confirmation of PR/CR is ONLY required for non-randomized trials where response is the 
primary endpoint. In these trials, subsequent confirmation of PR with one interim 
timepoint of SD is acceptable.
Source: Eisenhauer 2009.
Assessment of Target Lesion Response: Conventional RECIST and mRECIST Assessment for HCC 
Following the AASLD-JNCI Guideline:
RECIST
mRECIST for HCC
CR = Disappearance of all target lesions
CR = Disappearance of any intratumoral arterial 
enhancement in all target lesions
PR = At least a 30% decrease in the sum of diameters 
of target lesions, taking as reference the baseline sum
of the diameters of target lesions
PR = At least a 30% decrease in the sum of diameters 
of viable (enhancement in the arterial phase) target 
lesions, taking as reference the baseline sum of the 
diameters of target lesions
SD = Any cases that do not qualify for either partial 
response or progressive disease
SD = Any cases that do not qualify for either partial 
response or progressive disease
PD = An increase of at least 20% in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum of the diameters of target lesions 
recorded since treatment started
PD = An increase of at least 20% in the sum of the 
diameters of viable (enhancing) target lesions, taking as 
reference the smallest sum of the diameters of viable 
(enhancing) target lesions recorded since treatment 
started
AASLD, American Association for the Study of Liver Diseases; JNCI, Journal of the National Cancer Institute; HCC, hepatocellular 
carcinoma; mRECIST, modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; SD, stable 
disease; PD, progressive disease.
Overall Response Assessment in mRECIST: Responses for All Possible Combinations of Tumor Responses in 
Target and Nontarget Lesions with or without the Appearance of New Lesions
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
IR/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
mRECIST, modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; 
IR, incomplete response; SD, stable disease; PD, progressive disease.
Source: Lencioni 2010.


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10.11. Appendix 11: Eastern Cooperative Oncology Group Performance Status 
Score
Grade 
Eastern Cooperative Oncology Group (ECOG) Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source: Oken 1982


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10.12. Appendix 12: Formulas for Estimating Glomerular Filtration Rate Using 
Modified Diet in Renal Disease Formula (in mL/min)
For standardized serum creatinine (SCr) in mg/dL, the estimated glomerular filtration rate (eGFR) in 
mL/min is: 
	
 = 175   ( 
⁄
).  !	 ("	!#$).%&  1.212() *+,-.  0.742() )12,+1  34 (%)
1.73
Body surface area (BSA) is estimated based on height and weight (Mosteller, NEJM 1987):
34 (%) = 6ℎ	8ℎ9 (:)  ;	8ℎ9 (<)
3600
If creatinine levels are given in µmol/L, the equation above can be used after converting the creatinine 
level to mg/dL:
:#	!98>8>	 ( 
⁄
) = :#	!98>8>	 (μ@A 
⁄ )
88.4
Alternatively, for standardized serum creatinine (SCr) in µmol/L, the eGFR in mL/min is:
	

= 30849   (μ@A 
⁄ ).  !	 ("	!#$).%&  1.212() *+,-.  0.742() )12,+1  34 (%)
1.73
NOTES:

Renal clearance of a drug is proportional to individual GFR (expressed in mL/min) and not BSA-
standardized GFR (mL/min/1.73m2).

The formulas above for the calculation of eGFR are based on MDRD (Levey, Ann Intern Med 2006) 
but have been adapted to estimate GFR in mL/min. (Guidance for Industry)

Serum creatinine values must be standardized: creatinine assay calibration traceable to an isotope 
dilution mass spectrometry (IDMS) reference measurement procedure (this is the case for most assays)
Sources: Levey (2006, 2007), Mosteller (1987) and Guidance for Industry "Pharmacokinetics in patients 
with Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing" available at: 
https://www.fda.gov/media/78573/download


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10.13. Appendix 13: Child-Pugh Classification
CHILD-PUGH SCORE
Chemical and 
Biochemical Parameters
Scores (Points) Increasing Abnormality
1 Point
2 Points
3 Points
Encephalopathy
(grade)
None
1-2
3-4
Ascites
Absent
Slight
Moderate
Albumin (g/dL)
>3.5
2.8-3.5
<2.8
Prothrombin time
Seconds over control
<4
4-6
>6
International
normalized ratio
<1.7
1.7-2.3
>2.3
Bilirubin (mg/dL)
<2
2-3
>3

For primary biliary 
cirrhosis
<4
4-10
>10
Class A=5-6 points; Class B=7-9 points; Class C=10-15 points
Class A:Good operative risk
Class B: Moderate operative risk
Class C: Poor operative risk
References: NCCN 2022


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10.14. Appendix 14: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Protocol amendment summary for previous amendment is provided below.
Amendment 1 (23 September 2022)
Overall Rationale for the Amendment: The overall reason for this amendment is to add revised rash 
and TEN toxicity guidelines to align with the current compound level guidelines.
The changes made to the clinical protocol 61186372HCC2001 as part of Protocol Amendment 1 are listed 
below, including the rationale of each change and a list of all applicable sections.
Section Number
and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities
Other revisions including minor editorial
changes were made in Table 1 and footnotes.
Editions were made for Local laboratory 
Assessments: “Hematology, 
Chemistrychemistry, coagulation, liver and 
kidney function”
Footnote d: add sentence “Biopsy at EOT is 
optional.”
Footnote e: add sentence “Sample collection 
and testing will comply with local 
regulations.”
Minor editions were made for 
content consistency and 
clarification.
6.5.4 Rash-related Adverse 
Events
Added text for management of severe bullous, 
blistering, or exfoliating skin conditions 
including toxic epidermal necrolysis (TEN).
To provide guidance on 
management of severe bullous, 
blistering, or exfoliating skin 
conditions including TEN.
6.5.4 Rash-related Adverse 
Events
Changed dose adjustment of Grade 4 Rash to 
permanent discontinuation of JNJ-61186372.
To change the dose adjustment 
guidance on Grade 4 Rash.
10.2 Appendix 2 Clinical 
Laboratory Tests
Editions were made to the first sentence: The 
following tests will be performed according to 
the Schedule of Activities by the local and 
central laboratory (if the local lab is not able 
to be performed the relevant tests, the tests 
can be performed at the central lab).
LabCorp has been set up to
perform tests for serology and 
AFP. Text was added to align 
with the SOA table descriptions.
10.2 Appendix 2 Clinical 
Laboratory Tests
Added Hepatitis D (HDV) antibody 
assessment in the Protocol-Required Safety 
Laboratory Assessments table. 
This test was missing in previous 
version.
10.2 Appendix 2 Clinical 
Laboratory Tests
Correction was made to sentence “participants 
tested positive for HBsAgb or HBcAb, or both 
are also required to have HBV DNA 
quantification and HBsAg quantification” in 
the Protocol-Required Safety Laboratory 
Assessments table.
Minor error was noted.
10.4.3 Severity Criteria
Deletion of notes for “outcome fatal” and 
“Grade 5” adverse events.
To ensure all Grade 5 events are 
captured.
10.7.2 Follow-up 
Assessments
Add text: Note: If the local lab is not able to 
be performed the relevant tests, the tests 
can be performed at the central lab.
LabCorp has been set up to
perform follow-up assessments 
for liver safety. Note was added 
to provide this option.


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Section Number
and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
The abbreviation “I/O” was changed to “IO” 
for clarification. The definition of “IO” was 
corrected to “Immuno-Oncology”.
To clarify and correct the 
definition error of an 
abbreviation. 
Section 4.1 Overall Design
Section 10.1 Abbreviations
Throughout the protocol
Minor editorial, grammatical, formatting, or 
spelling changes were made.
Other revisions including minor 
editorial, grammatical, 
formatting, or spelling changes 
were made throughout.


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11.
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SAP_001.pdf: 
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Status: Approved, Date: 8 September 2023
Janssen Research & Development
Statistical Analysis Plan
A Phase 2, Open-Label Study to Evaluate the Safety, Efficacy and Pharmacokinetics of 
Amivantamab Monotherapy in Participants with Previously Treated Advanced 
Hepatocellular Carcinoma
Protocol 61186372HCC2001; Phase 2  
JNJ-61186372HCC2001  (Amivantamab)
Status:
Approved
Date:
8 September 2023
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-RIM-1133716, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT05653427


JNJ-61186372HCC2001  (Amivantamab)
Statistical Analysis Plan 61186372HCC2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 8 September 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints ................................................................................................................ 5
1.2.
Study Design.................................................................................................................................... 6
2.
STATISTICAL HYPOTHESES............................................................................................................ 7
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 7
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 7
5.
STATISTICAL ANALYSES................................................................................................................. 8
5.1.
General Considerations ................................................................................................................... 8
5.1.1.
Visit Windows ............................................................................................................................... 8
5.1.2.
Study Day / Relative Day.............................................................................................................. 9
5.1.3.
Baseline Measurements ............................................................................................................... 9
5.2.
Participant Dispositions.................................................................................................................... 9
5.3.
Primary Endpoints Analysis ........................................................................................................... 10
5.3.1.
Objective Response Rate (ORR) ............................................................................................... 10
5.3.1.1.
Definition.................................................................................................................................. 10
5.3.1.2.
Estimand.................................................................................................................................. 10
5.3.1.3.
Analysis Methods .................................................................................................................... 10
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 10
5.4.1.
Duration of Response (DoR) ...................................................................................................... 10
5.4.1.1.
Definition.................................................................................................................................. 10
5.4.1.2.
Analysis Methods .................................................................................................................... 11
5.4.2.
Disease Control Rate (DCR) ...................................................................................................... 11
5.4.2.1.
Definition.................................................................................................................................. 11
5.4.2.2.
Analysis Methods .................................................................................................................... 11
5.4.3.
Progression Free Survival (PFS)................................................................................................ 11
5.4.3.1.
Definition.................................................................................................................................. 11
5.4.3.2.
Analysis Methods .................................................................................................................... 12
5.4.4.
Overall Survival (OS).................................................................................................................. 12
5.4.4.1.
Definition.................................................................................................................................. 12
5.4.4.2.
Analysis Methods .................................................................................................................... 12
5.5.
Exploratory Endpoint Analysis ....................................................................................................... 12
5.5.1.
Objective Response Rate by mRECIST (mORR) ...................................................................... 12
5.5.1.1.
Definition.................................................................................................................................. 12
5.5.1.2.
Analysis Methods .................................................................................................................... 12
5.6.
Safety Analyses ............................................................................................................................. 12
5.6.1.
Extent of Exposure ..................................................................................................................... 13
5.6.2.
Compliance of Disease Evaluation............................................................................................. 13
5.6.3.
Adverse Events........................................................................................................................... 13
5.6.3.1.
Treatment Emergent Adverse Events ..................................................................................... 14
5.6.3.1.1.
All TEAEs ............................................................................................................................. 14
5.6.3.1.2.
Toxicity Grade 3 or higher TEAEs........................................................................................ 14
5.6.3.1.3.
Study Related TEAEs .......................................................................................................... 14
5.6.3.1.4.
Serious TEAEs..................................................................................................................... 15
5.6.3.1.5.
TEAE leading to Study Drug Interruption/ Dose Reduction ................................................. 15
5.6.3.1.6.
TEAE leading to Study Drug Discontinuation: ..................................................................... 15
5.6.3.2.
Adverse Events of Special Interest ......................................................................................... 15


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5.6.3.3.
Deaths ..................................................................................................................................... 16
5.6.3.3.1.
Death due to TEAEs ............................................................................................................ 16
5.6.3.3.2.
All Deaths............................................................................................................................. 17
5.6.4.
Additional Safety Assessments .................................................................................................. 17
5.6.4.1.
Clinical Laboratory Tests......................................................................................................... 17
5.6.4.2.
Vital Signs and Physical Examination Findings....................................................................... 17
5.6.4.3.
Electrocardiogram ................................................................................................................... 18
5.7.
Other Analyses............................................................................................................................... 18
5.7.1.
Pharmacokinetics ....................................................................................................................... 18
5.7.2.
Immunogenicity........................................................................................................................... 18
5.7.3.
Pharmacodynamics (PD)/Biomarkers ........................................................................................ 19
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 19
5.7.5.
Definition of Subgroups ................................................................Error! Bookmark not defined.
5.8.
Interim Analyses............................................................................................................................. 19
5.8.1.
Safety Evaluation Team (SET) ................................................................................................... 20
6.
SUPPORTING DOCUMENTATION .................................................................................................. 21
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 21
6.2.
Appendix 2 Demographics and Baseline Characteristics.............................................................. 22
6.3.
Appendix 3 Protocol Deviations ..................................................................................................... 24
6.4.
Appendix 4 Prior and Concomitant Medications............................................................................ 25
6.5.
Appendix 5 Medical History ........................................................................................................... 26
6.6.
Appendix 6 Adverse Events of Special Interest............................................................................. 27
6.7.
Appendix 7 Laboratory Toxicity Grading........................................................................................ 28
7.
REFERENCES................................................................................................................................... 35


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VERSION HISTORY
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
Original SAP
Not Applicable
Initial release


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1.
INTRODUCTION
This is an open-label, multicenter Phase 2 study of amivantamab monotherapy in participants with 
previously treated advanced hepatocellular carcinoma (HCC).
The purpose of the statistical analysis plan (SAP) is to lay out key elements including definitions 
and statistical methods for the planned analyses for the primary, secondary, exploratory, safety, 
and other endpoints in HCC2001 as supportive data to evaluate the anti-tumor activity of 
amivantamab as a monotherapy in previously treated advanced HCC participants and further 
characterize the safety, tolerability, and preliminary anti-tumor activity of amivantamab.
1.1.
Objectives and Endpoints
Following Objectives and endpoints are defined as per protocol amendment 1 (23 September, 
2022).
Objectives
Endpoints
Primary

To characterize the preliminary antitumor 
activity 
of 
amivantamab 
at 
the 
recommended dose in participants with 
previously systemically treated HCC
Objective response rate (ORR) as determined by 
investigator, according to the Response Criteria in 
Solid Tumors (RECIST) v1.1. Confirmation of 
investigator-assessed ORR will be performed 
through Blinded Independent Central Review 
(BICR)
Secondary

To assess additional measures of clinical 
benefit with amivantamab

Duration of response (DoR)

Disease control rate (DCR)

Progression-free survival (PFS)

Overall survival (OS)

To characterize the safety and tolerability of 
amivantamab in participants with advanced 
HCC
Incidence of adverse events defined by the National 
Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Criteria version 5.0, 
lab abnormalities and vital signs in participants 
treated with amivantamab as a monotherapy

To assess the pharmacokinetics (PK) and 
immunogenicity of amivantamab following
single and multiple intravenous dose 
administrations
Serum PK parameters including but not limited to 
maximum serum concentration (Cmax), time to reach 
the maximum serum concentration (Tmax), 
AUC(t1-t2), AUCtau, serum concentration 
immediately prior the next study treatment 
administration (Ctrough), and accumulation ratio (R); 
incidence of antidrug antibodies
Exploratory

To further explore the clinical benefit 
achieved 
with amivantamab 
treatment 
through alternative response criteria 
ORR, as determined by Investigator Review, 
according to modified RECIST

Explore tissue biomarkers (including but not limited to EGFR, MET expression) and blood 
biomarkers predictive of clinical response and resistance to amivantamab 


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Objectives
Endpoints

Explore the relationship between serum PK, pharmacodynamic (PD) markers and clinical outcome

Explore the relationship of etiology (eg, HepB, HepC) and clinical response

Explore primary and acquired resistance to amivantamab treatment
1.2.
Study Design
This is an open-label, single arm, multicenter, Phase 2 interventional study of amivantamab as 
monotherapy in participants with previously treated advanced HCC.
The 61186372HCC2001 study will aim to enroll a participant population that is geographically 
reflective of the overall incidence/prevalence of this disease.
A target of approximately 60 participants (at least 30 participants with first-line Immuno-Oncology
[IO] combination treatment) will be enrolled in this study. The study will commence with Part 1, 
comprised of 6 participants and data review after at least 1 complete cycle of amivantamab therapy, 
for confirmation of dose and safety. For the main Part 2 of the study, two analyses are planned: an
interim analysis for review of efficacy after 30 response-evaluable participants, and a final analysis 
after 60 response-evaluable participants. The expansion Part 3 of the study, with approximately 40 
participants, may be opened based on the outcomes of the Part 2 final analysis. A retrospective 
analysis will be conducted to understand the correlation of biomarker(s), including the expression 
level of receptor, ligand(s) in the EGFR pathway and/or MET pathway, or other biomarkers, with 
responsive population.
The SET will be commissioned for this study. Participants’ safety will be monitored throughout 
the study by the SET established by the Sponsor.
Figure 1:
Schematic Overview of the Study


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Status: Approved, Date: 8 September 2023
2.
STATISTICAL HYPOTHESES
The hypothesis is that amivantamab monotherapy will lead to an ORR higher than 10% (ie, 
: ORR≤10%) in participants with advanced HCC.
3.
SAMPLE SIZE DETERMINATION
Assuming the ORR is 20% for the entire population, approximately 60 participants with advanced 
HCC will be enrolled to have over 85% probability to observe the ORR greater than 15%. 
Additional participants (ie, approximately 40) may be enrolled in an expansion phase to test the 
ORR of amivantamab against the null hypothesis with alpha=0.05 (two-sided) if supported by 
emerging data.
Anti-tumor activity within biomarker defined subpopulations will be investigated to identify the 
most responsive patient population who may benefit from amivantamab. With the prevalence of 
50% of the entire population having 25% ORR, it is expected to have approximately 90% power
to observe the posterior probability (ORR >15%) ≥50% in this population. On the other hand, if 
the biomarker defined population has undesirable ORR (ie, 10%), there is less than 20% 
probability to observe the posterior probability (ORR >15%) ≥50%. More examples are given in 
the Table .
Table 1:
Probability to Detect Signal in Sub-Population Under Different Scenarios
Prevalence of effective 
population
ORR for effective population
Power to observe
posterior probability (ORR > 15%) 
≥50% in effective population
25%
10%
18% (type I error)
20%
60%
25%
76%
30%
87%
50%
10%
18% (type I error)
20%
74%
25%
90%
30%
97%
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Population
Description
Safety 
Evaluation
Participants who are enrolled during the safety evaluation
All treated
All participants who receive at least 1 dose of study treatment
Response 
evaluable
All participants satisfy the following criteria:
Received at least 1 dose of study treatment
At least 1 post-baseline efficacy disease assessments, or 
discontinued treatment for any reason, or had disease 
progression/death prior to the first postbaseline disease assessment 
Pharmacokinetics
All participants who receive at least 1 dose of study treatment and have at 
least 1 evaluable postbaseline measurement


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Immunogenicity 
All participants who receive at least 1 dose of study treatment and have at 
least 1 evaluable postbaseline measurement
Biomarker
All participants who receive at least 1 dose of study treatment and have at 
least 1 biomarker measurement
The safety evaluation analysis set will be used to evaluate the safety data for the first SET meeting, 
which will include the first 6 subjects who have completed at least 1 completed cycle of 
amivantamab treatment. The supportive analyses for the first SET meeting are specified in the SET 
Charter. All treated analysis set will be used to summarize the study population and characteristics
and the safety data, unless otherwise specified.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
All continuous variables will be summarized using number of participants (n), mean, standard 
deviation (SD), median, minimum and maximum. Discrete variables will be summarized with
number and percent. The Kaplan-Meier product limit method will be used to estimate the time-to-
event variables including median survival time.
5.1.1.
Visit Windows
The study will consist of 3 phases: a screening phase, a treatment phase, and a follow-up phase. 
The screening phase will start at the time of the signing informed consent form (ICF) and end at 
the start of the first administration of study treatment. The ICF must be signed before the first 
study-related activity is conducted. Screening procedures must be completed within 28 days before 
the first dose of study treatment.
The treatment phase will begin on Cycle 1 Day 1 (C1D1) with the administration of the study 
treatment and continue as 28-day cycles until the End of Treatment visit, approximately 30 days 
after discontinuation of study treatment. The frequency of study site visits and details of the 
procedures performed are outlined in the Error! Reference source not found. in study protocol.
Study treatment will continue until documented clinical or radiographic (RECIST Version 1.1) 
disease progression or until the participant meets another criterion for discontinuation of study 
treatment as defined in protocol.
Visit windowing will be based on cycles. Unless otherwise specified, data to be analyzed or 
presented over time will be presented by cycle, day, and time point (as appropriate) that are 
recorded in CRF. 
Participants who discontinue study treatment for any reason will be followed for survival in the 
follow-up phase. Survival, subsequent anticancer treatment, and disease status will be assessed 
every 12 weeks (±14 days) after the last dose of study treatment or disease progression (whichever 
occurs first), until the end of study, death, lost to follow-up, or withdrawal of consent, whichever 
comes first. If the information is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. If the participant has died, 


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the date and cause of death will be collected and documented on the electronic case report form 
(eCRF). Investigators may recontact the participant to obtain long-term follow-up information 
regarding the participant’s safety or survival status as noted in the ICF.
5.1.2.
Study Day / Relative Day
Study day or relative day is defined as: 

Reference date (Day 1) = First dose date of study drug which is Cycle 1 Day 1 (C1D1).

Study Day = assessment date – reference date + 1 for assessment performed on or after the 
reference date; assessment date – reference date for assessment performed before the 
reference date. 
There is no 'Day 0'. First dose date will be the date of starting the study drug.
5.1.3.
Baseline Measurements
Baseline measurement is defined as the closest non-missing measurement taken on or prior to the 
first study drug administration (including time if time is available). If the first administration date 
is missing or the administration is not done, then the baseline measurement is the closest non-
missing measurement taken on or prior to the corresponding visit date.
5.2.
Participant Dispositions
Screened participants and reason for screen failures will be summarized overall.
The number of participants in the following disposition categories will be summarized throughout 
the study overall:

Participants who received study treatment 

Participants who discontinued study treatment

Reasons for discontinuation of study treatment

Participants who terminated study prematurely

Reasons for termination of study

Participants who completed the study
The number of participants who discontinued treatment by cycle with reported reasons will also 
be provide.
A listing of participants will be provided for the following categories: 

Participants who discontinued study treatment

Participants who terminated study prematurely


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5.3.
Primary Efficacy Endpoints Analysis
5.3.1.
Objective Response Rate (ORR)
5.3.1.1.
Definition
The primary efficacy measure is ORR. ORR is defined as the proportion of participants who 
achieve either partial response (PR) or complete response (CR), as defined by investigator 
assessment using RECIST v1.1. Confirmation of investigator-assessed ORR may be performed 
through BICR.
Data obtained up until progression or last evaluable disease assessment in the absence of 
progression will be included in the assessment of ORR. However, any CR or PR, which occurred 
after a further anticancer therapy was received, will not be included in the numerator for the 
ORR calculation. Participants who do not have a tumor response assessment for any reason will 
be considered as non-responders and will be included in the denominator when calculating the 
response rate.
5.3.1.2.
Estimand
The primary estimand for ORR is defined by the following components:

Population: participants with advanced HCC

Variable: objective response 

Study treatment: amivantamab monotherapy 

Intercurrent event: subsequent anticancer therapy. The while-on-treatment policy will be 
used: response after this intercurrent event will not be included 

Summary: ORR
5.3.1.3.
Analysis Methods
ORR will be calculated for response evaluable as well as for the all treated population separately.
The observed ORR and its exact 95% confidence interval (CI) will be calculated.
5.4.
Secondary Efficacy Endpoint(s) Analysis
5.4.1.
Duration of Response (DoR)
5.4.1.1.
Definition
Duration of response (DoR) is defined as the time from the date of first documented response (CR 
or PR) until the date of documented progression or death, whichever comes first. The end of 
response should coincide with the date of progression or death from any cause used for the PFS 


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endpoint. If a participant does not progress following a response, then his/her DoR will be censored 
at the same date with PFS. Participants who started a subsequent anticancer therapy in the absence 
of progression will be censored at the last disease assessment before the start of subsequent 
therapy.
5.4.1.2.
Analysis Methods
DoR will be analyzed using the response evaluable population.
A Kaplan-Meier plot and median DoR with 95% CI (calculated from the Kaplan-Meier estimate) 
will be presented. Confirmation of investigator-assessed DoR may be performed through BICR.
5.4.2.
Disease Control Rate (DCR)
5.4.2.1.
Definition
Disease control rate (DCR) is defined as the percentage of participants achieving complete or 
partial response, as well as durable stable disease (defined as a duration of at least 11 weeks) as 
defined by RECIST v1.1.
5.4.2.2.
Analysis Methods
The DCR and its exact 95% confidence interval (CI) will be calculated using response evaluable 
and all treated population.
5.4.3.
Progression Free Survival (PFS)
5.4.3.1.
Definition
The PFS is defined as the time from the date the first dose until the date of objective disease 
progression or death by any cause, whichever comes first, based on investigator review according 
to RECIST Version 1.1. Participants who have not progressed or have not died at the time of 
analysis will be censored at the time of the latest disease assessment.
Key censoring rules for PFS are summarized below.
Key Censoring rules for PFS
Situation
Date of Censoring
No evaluable baseline or post-baseline disease 
assessment
Censored at the date of first dose of study 
treatment 
Lost to follow up or withdraw from study
Censored at the date of last evaluable disease 
assessment
No documented disease progression or death
Censored at the date of last evaluable disease 
assessment
Started a subsequent anti-cancer therapy in 
absence of progression
Censored at the date of last evaluable disease 
assessment before the start of the subsequent 
therapy


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PFS is calculated in months as follows:
	
 = (  	, ℎ  −        + 1)
(365.25
12
)
5.4.3.2.
Analysis Methods
PFS will be analyzed using response evaluable and all treated population separately.
A Kaplan-Meier plot and median PFS with 95% CI (calculated from the Kaplan-Meier estimate) 
will be presented. Confirmation of investigator-assessed PFS may be performed through BICR.
PFS rates at landmarks (6 months, 9 months and 12 months) with 95% CI will be estimated by
Kaplan Meier method.
5.4.4.
Overall Survival (OS)
5.4.4.1.
Definition
The overall survival (OS) is defined as the time from the date of the first dose until the date of 
death due to any cause. Participants who are not known to have died at the time of analysis will be 
censored based on the last recorded date on which the participant was known to be alive.
5.4.4.2.
Analysis Methods
OS will be analyzed using response evaluable and all treated population separately.
A Kaplan-Meier plot and median OS with 95% CI (calculated from Kaplan-Meier estimate) will 
be presented. OS rates at landmarks (6 months, 9 months and 12 months) with 95% CI will be 
estimated by Kaplan Meier method.
5.5.
Exploratory Efficacy Endpoint Analysis
5.5.1.
Objective Response Rate by mRECIST (mORR)
5.5.1.1.
Definition
The mORR is defined as the proportion of participants who achieve either partial response (PR) 
or complete response (CR), as defined by investigator assessment using mRECIST. 
5.5.1.2.
Analysis Methods
mORR will be calculated for response evaluable as well as for the all treated population separately.
The observed mORR and its exact 95% confidence interval (CI) will be calculated.
5.6.
Safety Analyses
All safety analyses will be based on the all treated population, unless otherwise specified.


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For all continuous safety variables, descriptive statistics by each cohort will include the N, mean, 
standard deviation, median, minimum, and maximum. Categorical variables will be summarized 
by each cohort using frequency counts and percentages.
5.6.1.
Extent of Exposure
The number and percentage of participants who receive study treatment will be summarized
overall and by visit.
Descriptive statistics for duration of study treatment (N, mean, SD, median, and range (minimum, 
maximum)) will be summarized. Duration of study treatment are calculated as [(date of last dose 
of study treatment – date of first dose of study treatment) +1].
The total number of administration cycles of amivantamab received for each participant will be
summarized by descriptive statistics. Cumulative duration of amivantamab will be provided by
cycle (≥1 cycle, ≥2 cycles, …). Total number of amivantamab infusion and the total dose of
amivantamab for each participant will be summarized by descriptive statistics.
The maximum number of treatment cycles received for each subject will be summarized by 
frequency and descriptive statistics.
Number of amivantamab treatment interruption during the infusion due to AE will also be 
summarized.
The relative dose intensity (%) defined as the ratio of total actually received dose versus total
prescribed dose will be summarized by descriptive statistics.
The number (%) of participants with a dose reduction/dose not administrated will be summarized.
Reasons for dose reduction/dose not administrated will also be summarized.
The number (%) of participants with cycle delay will be summarized. The reason for cycle delay 
will also be summarized.
5.6.2.
Compliance of Disease Evaluation
Tumor assessment will occur at regular intervals, as defined per SoA in study protocol. Descriptive
statistics will be provided for imaging assessments using all treated population for:

Number of participants missed at least 1 scheduled disease evaluation

Number of participants missed 2 or more consecutive scheduled disease evaluation

Number of missed scheduled disease evaluation per participant
5.6.3.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. 
Any AE occurring at or after the initial administration of study treatment through the day of last 
dose plus 30 days or until the start of subsequent anticancer therapy, is considered to be treatment 


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emergent. If the event occurs on the day of the initial administration of study treatment, and either 
event time or time of administration are missing, then the event will be assumed to be treatment 
emergent. If the event date is recorded as partial or completely missing, then the event will be 
considered to be treatment emergent unless it is known to be prior to the first administration of 
study treatment based on partial onset date or resolution date. All reported treatment-emergent
adverse events (TEAEs) will be included in the analysis.  For each adverse event, the number and 
percentage of participants who experience at least 1 occurrence of the given event will be 
summarized.
The incidence (%) of TEAEs will be summarized overall, by MedDRA SOC and PT, by toxicity 
grade, and by relationship to study drug administration.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue treatment due to an AE or who experience a severe or an 
SAE.
Incidence of AE / TEAE
Incidence rate (%) is defined as follows:
)  =
* +  ,   ℎ -
.  +  +/  0  ℎ - ∗100
5.6.3.1.
Treatment Emergent Adverse Events
An overview of TEAEs reported through the study will be provided. The overview will include
summaries of participants with TEAEs, with TEAEs related to study drug, with TEAEs of 
maximum toxicity grade of 1 to 5, Serious TEAEs, TEAEs leading to discontinuation of any study 
drug, and deaths due to TEAE.
5.6.3.1.1.
All TEAEs

Incidence (%) of TEAE by SOC and PT
5.6.3.1.2.
Toxicity Grade 3 or higher TEAEs

Incidence (%) of toxicity grade 3 or higher TEAE by SOC and PT
5.6.3.1.3.
Study Related TEAEs

Incidence (%) of TEAEs related to treatment/study drug, by SOC and PT 

Incidence (%) of TEAEs with toxicity grade 3 or higher related to treatment/study 
drug, by SOC and PT 

Incidence (%) of TEAEs leading to study drug interruption/dose reduction related
to treatment/study drug, by SOC and PT


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Status: Approved, Date: 8 September 2023

Incidence (%) of TEAEs leading to study drug discontinuation related to
treatment/study drug, by SOC and PT
5.6.3.1.4.
Serious TEAEs

Incidence (%) of serious TEAEs by SOC and PT

Incidence (%) of serious TEAEs by toxicity grade, and by SOC and PT 

Incidence (%) of serious TEAEs related to treatment/study drug, by SOC and PT 

Listing of participants with any serious TEAEs
5.6.3.1.5.
TEAE leading to Study Drug Interruption/ Dose Reduction

Incidence (%) of TEAEs leading to study drug/dose reduction will be summarized 
respectively by SOC and PT. The summaries will be presented for all toxicity 
grades and for toxicity grade 3 or higher
5.6.3.1.6.
TEAE leading to Study Drug Discontinuation:

Incidence (%) of TEAEs leading to study drug discontinuation will be summarized 
by SOC and PT. The summaries will be presented by all toxicity grades and 
toxicity grade 3 or higher. The AEs leading to discontinuation of study drug are 
based on AEs recorded in the AE CRF page with an action taken of drug 
withdrawal
5.6.3.2.
Adverse Events of Special Interest
Adverse events of special interest are pneumonitis/interstitial lung disease (ILD), rash, infusion-
related-reaction (IRR), liver event and hypoalbuminemia. The MedDRA preferred terms 
associated with each of these categories are identified in Appendix 6. Additional information will 
be collected to fully describe these events.
Treatment-emergent adverse events of special interest will be included for analysis. Incidence (%)
for the following AEs will be provided for each AE of special interest as appropriate:

TEAEs by PT

TEAEs by toxicity grade

TEAEs of toxicity grade 3 or higher by PT

Serious TEAEs by PT

TEAEs related to study drug

Serious TEAEs by PT

Serious TEAEs related to study drug

TEAEs leading to study drug discontinuation by PT

TEAEs leading to study drug discontinuation related to study drug


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Status: Approved, Date: 8 September 2023

TEAEs leading to death by PT
Additional analyses will be provided based on information collected in CRF.
Pneumonitis/ILD
For participants with pneumonitis/ILD, frequency tabulation will be provided for:

Symptom (fever, dry cough, productive cough, dyspnea, chest pain, other)

Pleural effusion present at the time of the pneumonitis/ILD (yes/no）
Relative onset day of pneumonitis/ILD will be summarized by descriptive statistics (N, mean, 
standard deviation, median, and range).
All information related to pneumonitis/ILD collected in CRF page will be presented in listing.
Rash
Relative onset day, duration, and time between onset and the preceding infusion administration in 
days will be summarized by descriptive statistics (N, mean, standard deviation, median, and 
range).
IRR
Incidence (%) of IRR leading to infusion modification (infusion interrupted, infusion rate
decreased, and infusion aborted) will be presented.
Relative onset day and duration in days will be summarized for IRR by descriptive statistics (N, 
mean, standard deviation, median, and range).
Liver Event
Relative onset day and duration in days of liver event will be summarized by descriptive statistics
(N, mean, standard deviation, median, and range).
Hypoalbuminemia
Relative onset day and duration in days of hypoalbuminemia will be summarized by descriptive 
statistics (N, mean, standard deviation, median, and range).
5.6.3.3.
Deaths
5.6.3.3.1.
Death due to TEAEs
The number of participants who died due to TEAEs will be summarized by preferred term and
relationship to study drug. The TEAEs included in this table are AEs with outcome of death or
toxicity grade of 5 recorded in the AE CRF page within 30 days of the last dose or until the start
of subsequent anticancer therapy (if earlier).
A listing of participants who died due to TEAE will be provided.


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5.6.3.3.2.
All Deaths
A summary of all death and cause of death will be tabulated. Specifically, the number of
participants who died during the study will be summarized. The primary cause of death collected
on the death information CRF page will be reported.
The similar summaries will be presented for participants who died within 30 days of last study
drug dose.
5.6.4.
Additional Safety Assessments
5.6.4.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the all treated population.
Descriptive statistics will be presented for all chemistry and hematology laboratory tests at 
scheduled time points. Change from baseline will be summarized and displayed. Plots for selected 
laboratory tests change over time may be provided.
NCI-CTCAE version 5.0 will be used to derive toxicity grades for clinical laboratory tests when 
applicable. Shift tables from baseline to worst value on study (from treatment start to 30 days after 
last dose or the End of Treatment visit date or until the start of subsequent anti-cancer therapy, 
whichever is later) will be provided. The worst toxicity grade during the study will be tabulated. 
An eDISH plot of peak ALT/ AST versus peak BILI will be provided along with a listing of 
subjects who had ALT/ AST values > 3xULN or BILI values > 2xULN.
Laboratory criteria for potential Hy's Law cases are defined as:

Peak aminotransaminases (AT, either ALT or AST) of >3xULN (Upper Limit of Normal)

Total bilirubin ≥2xULN

Alkaline phosphatase (ALK-P) <2xULN prior to or on the same date of the first occurrence 
of total bilirubin ≥2x ULN
Note: data from all the on-treatment (post-baseline) visits are combined to check the above 
laboratory criteria.

All potential Hy’s Law cases based on the laboratory criteria will be presented. 
5.6.4.2.
Vital Signs and Physical Examination Findings
Continuous vital sign parameters including temperature, respiratory rate, oxygen saturation,
pulse/heart rate, blood pressure (systolic and diastolic), as well as weight, Body Mass Index (BMI)
from physical examination will be summarized at each scheduled timepoint. Body Mass Index will 
be calculated as weight (kg)/(height (m))2, at each time point that body weight is measured. The height 
measurement collected at screening will be used in the calculation.
Change from baseline will be summarized over time. Descriptive statistics (mean, standard 
deviation, median, minimum and maximum) will be presented.
Post baseline physical examination findings were collected as AEs, and therefore will not be
summarized.


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5.6.4.3.
Electrocardiogram
Electrocardiograms (ECG) will be performed at screening, and then to confirm any clinically 
significant finding during the study. 
The ECG variables include heart rate, PR interval, QRS interval, QT interval, and QT corrected 
according to Fridericia's formula (QTcF).
A listing of clinically relevant ECG abnormalities will be provided.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
Serum and Plasma samples will be collected from participants for PK and immunogenicity 
assessment of amivantamab as described in SoA in the study protocol.
PK analyses will be performed on the PK analysis set.
Concentrations below the lowest quantifiable concentration or missing data will be labeled as such 
in the concentration data presentations. Concentrations below the lower quantifiable concentration 
will be treated as zero in the summary statistics.
Descriptive statistics (N, mean, SD, median, range, CV (%) and IQ range) will be used to
summarize amivantamab concentrations at each sampling time point and for each PK parameter
of amivantamab. PK data may be displayed graphically, such as mean +/- SD PK concentrations
over time by study intervention.
Amivantamab concentrations will be presented based on the following baseline body weight
categories at each time point:

<80 kg

≥ 80 kg
All participants and samples excluded from the analysis will be clearly documented.
The pharmacokinetic serum concentration-time data collected from this study may be combined 
with data from other studies to perform population PK and assess the relationship between PK or 
immunogenicity and selected safety and efficacy endpoints. Details will be provided in a 
population PK and exposure-response analysis plan and results of the analysis will be presented in 
a separate report.
5.7.2.
Immunogenicity
The incidence (%) of antibodies to amivantamab will be summarized based on immunogenicity
analysis set.
A listing of participants who are positive for antibodies to amivantamab will be provided. The
maximum titers of antibodies to amivantamab will be summarized for participants who are positive 
for antibodies to amivantamab.


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Other immunogenicity analyses may be performed to further characterize the immune responses
that are generated.
5.7.3.
Pharmacodynamics (PD)/Biomarkers
Analyses are planned to explore PD and other biomarkers that may be indicative of the
mechanisms of action of the study intervention or predictive of efficacy. Correlation of baseline
expression levels or changes in expression levels with response or time-to-event endpoints could
identify responsive (or resistant) subgroups. Any PD or other biomarker measures will be listed,
tabulated, and plotted, as appropriate.
Assessment of biomarkers (DNA, RNA, or protein) relevant to hepatocellular carcinoma or other 
cancers or the mechanism of action of study interventions, may also be performed in blood samples 
collected during study to better understand mechanisms of response or resistance to study 
interventions.
Alterations in blood may be evaluated for correlation with response to study interventions, tumor
burden, and disease progression as data warrant.
Biomarker data derived from IHC, RNAscope analyses on tissue specimens collected from this 
study will be used to assess the relationship of exploratory endpoints to efficacy endpoints. Both 
baseline levels and changes of these tissue biomarkers during the study will be analyzed and 
correlated to treatment response and/or resistance.
Additional exploratory endpoints may be explored from serum samples collected from this study, 
and may be used to understand the relationship of these endpoints to efficacy endpoints. Results
of these analyses will be presented in a separate report.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the
end of the study, it becomes clear that the analysis will not have sufficient scientific value for
biomarker evaluation, or if there are not enough samples or responders to allow for adequate
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy,
completion of biomarker assessments is based on justification and intended utility of the data.
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships
The relationship between PK and PD measures may be evaluated by PK/PD modeling. Results of 
PD and exploratory biomarker analyses will be presented in separate reports.
5.8.
Interim Analyses
Two interim analyses are planned: an early review of safety after the first 6 participants have 
enrolled and have completed at least 1 complete cycle of amivantamab therapy, and a futility 
analysis based on ORR will be conducted after 30 participants have been enrolled and are response 
evaluable. The enrollment may be terminated for futility if less than or equal to 2 responders are 


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observed. Otherwise, additional participants will be enrolled for a total of approximately 60 
participants for the initial analysis, with the potential for expansion to approximately 100 
participants.
5.8.1.
Safety Evaluation Team (SET)
The Safety Evaluation Team (SET) will be chaired by sponsor’s Study Responsible Physician or 
designee. SET membership will consist at least of the following members:

Principal investigators (or their designees)

Clinical leader, Study Responsible Physician, Study Responsible Scientist or 
designee

Clinical pharmacologists or their designees

Medical safety leader or designee

Statistician

Biomarker scientist

Any other sponsor or independent expert that the SET determines to be required
In general, the SET will monitor the safety and the conduct of the study. After review of cumulative 
study data, the SET may decide on modifications in the study conduct which may include but are 
not restricted to: (1) study treatment administration schedule, (2) study treatment dosing regimen
(including dose escalation, dose de-escalation), (3) recommendations for best-supportive-care 
measures and AE management, (4) allowing further enrollment or terminate enrollment of a 
specific subpopulation, (5) opening the expansion cohort 3 or adding a cohort for potential 
combination regimen, and (6) PK or biomarker sampling times. Based on these potential 
modifications to regimens, schedules, and best supportive care measures, the SET may recommend 
re-assessment of a monotherapy dose regimen and the right expansion population.
The timing of SET meeting will be convened based on study design: 
1. In the part 1, after 6 participants have completed at least 1 cycle of amivantamab therapy
2. In the part2, an interim analysis for efficacy after 30 response-evaluable participants
3. In the part2, a final analysis after 60 response-evaluable participants   
4. If unexpected safety findings are identified or other reason, ad-hoc SET meetings may be 
called by any member of the SET.
The SET will monitor data on an ongoing basis to ensure the continuing safety of the subjects 
enrolled in the study. Data and reports to be reviewed for SET meeing are specified in the SET 
Charter.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALT/SGPT
alanine aminotransferase
AST/SGOT
aspartate aminotransferase
BICR
Blinded independent central review
BILI
Bilirubin
BMI
body mass index
BSA
body surface area
DCR
Disease control Rate
CI
confidence interval
CR
Complete response
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DoR
Duration of Response
DPS
Data Presentation Specifications
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
Epidermal growth factor receptor
FDA
Food and Drug Administration
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
ORR
Objective response rate
OS
Overall survival
PD
pharmacodynamic(s)
PFS
Progression free survival
PI
principal investigator
PK
pharmacokinetic(s)
PR
Partial response
QT
Uncorrected QT interval
QTc
Corrected QT
QTcF
Corrected QT interval by Fridericia
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SoA
Schedule of Activities
ULN
Upper limit of normal
TEAE
treatment-emergent adverse event
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized. In addition, the distribution 
of participants by site ID will be presented.
Table below presents a list of the demographic variables that will be summarized for all treated 
population.
Demographic Variables
Continuous Variables
Summary Methods
Age ([years])
Descriptive statistics (N, 
mean, standard deviation 
[SD], median and range 
[minimum and maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (<55, ≥55; <65 years, ≥65 years; <75years, ≥75years)
Frequency distribution with 
the number and percentage of 
participants in each category.
Weight (<80 Kg, ≥80 Kg)
Sex (male, female)
Racea (American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or other Pacific Islander, 
White, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
History of Alcohol use (Yes, No)
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'
The following table presents a list of the baseline disease characteristics variables that will be 
summarized for all treated population.
Baseline Disease Characteristics Variables
Continuous Variables
Summary Methods
Time from initial diagnosis to first dose (months)
Descriptive statistics (N, 
mean, standard deviation 
[SD], median and range 
[minimum and maximum]).
Categorical Variables
Baseline ECOG performance status score (0,1)
Frequency distribution with 
the number and percentage of 
participants in each category.
Baseline BCLC stage
Baseline AFP (<400, ≥400)
Baseline Child-Pugh score (A5, A6)
Baseline HBV and/or HCV
Prior lines of therapy
First line treated with immunology/oncology [I/O] 
combination
Intolerance / PD to prior line of therapy (Yes or No)
History of vascular invasion (Yes or No)
History of metastatic disease (Yes or No)
History of extrahepatic metastasis (Yes or No)


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Type of tumor sample (Fresh or Archival)
6.3.
Definition of Subgroups
The following pre-specified subgroup analyses are to be performed for the efficacy and/or safety 
endpoints. Additional subgroup analyses may be planned if deemed necessary.
Subgroup
Definition
Age Group
<55 years, ≥55 years ; <65 years, ≥65 
years; <75 years, ≥75 years
Sex
Male, Female
Race
Asian, Non-Asian
Weight
<80 Kg, ≥80 Kg
History of Alcohol use
Yes, No
Baseline ECOG performance status score
0, 1
Baseline BCLC Stage
B, C
Baseline AFP
≥400, <400
Baseline Child-Pugh score
A5, A6
Baseline HBV and/or HCV
Yes, No; HBV, HCV
Prior lines of therapy
1, 2, ≥3
Frist line treated with 
immunology/oncology [I/O] combination
Yes, No
Intolerance / PD to prior line of therapy 
Yes, No
History of vascular invasion
Yes, No
History of Extrahepatic Metastasis
Yes, No
Prior cancer-related surgery or procedure
Surgery, nonsurgical local therapy 


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6.4.
Appendix 3 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category in all treated 
population.

Developed withdrawal criteria but not withdrawn 

Entered but did not satisfy criteria

Received a disallowed concomitant treatment 

Received wrong treatment or incorrect dose

Other
A listing of all major protocol deviations including participant ID, type of deviation, and reason 
will be provided.


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6.5.
Appendix 4 Prior and Concomitant Medications
Prior and Concomitant medications collected in the CRF page will be coded using the World 
Health Organization Drug Dictionary (WHO-DD) and summarized for all treated population. Prior 
medications are defined as any therapy used before the day of first dose (partial or complete) of 
study intervention. Concomitant medications are defined as any therapy used on or after the same 
day as the first dose of study intervention, including those that started before and continue on after 
the first dose of study intervention.
Prior medications will be summarized by ATC level/preferred terms. The number and percentage 
of participants who received prior systemic therapy will be summarized.
Summaries of concomitant medications will be presented by ATC level/preferred terms. The
proportion of participants who receive each concomitant medication will be summarized as well 
as the proportion of participants who receive at least 1 concomitant medication. 
The incidence (%) of pre-infusion and post-infusion medication will be presented by ATC
level/preferred terms.


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6.6.
Appendix 5 Medical History
Medical history collected at Baseline or Screening visit will be summarized by body system class
and preferred terms for all treated population.


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6.7.
Appendix 6 Adverse Events of Special Interest
Adverse events of special interest are defined as follows:
AE Clinical Importance 
Category
Preferred Term
Infusion Related Reaction
INFUSION RELATED REACTION
Rash
ACNE
ACNE CONGLOBATA
ACNE CYSTIC
ACNE FULMINANS
ACNE PUSTULAR
ACNE VARIOLIFORMIS
ACUTE GENERALISED EXANTHEMATOUS 
PUSTULOSIS
DERMATITIS
DERMATITIS ACNEIFORM
DERMATITIS EXFOLIATIVE
DERMATITIS INFECTED
DRUG ERUPTION
EPIDERMOLYSIS
ERYTHEMA
ERYTHEMA MULTIFORME
EXFOLIATIVE RASH
FOLLICULITIS
HERPES GESTATIONIS
IMPETIGO HERPETIFORMIS
MACULE
MUCOCUTANEOUS RASH
NODULAR RASH
PALMAR ERYTHEMA
PAPULE
PERINEAL RASH
PRIDE SYNDROME
PUSTULE
RASH
RASH ERYTHEMATOUS
RASH FOLLICULAR
RASH MACULAR
RASH MACULO-PAPULAR
RASH MACULOVESICULAR
RASH MORBILLIFORM
RASH PAPULAR
RASH PRURITIC
RASH PUSTULAR
RASH VESICULAR
SJS-TEN OVERLAP
SKIN EXFOLIATION
SKIN LESION
STEVENS-JOHNSON SYNDROME
TOXIC EPIDERMAL NECROLYSIS
TOXIC SKIN ERUPTION
Interstitial Lung Disease
ACUTE INTERSTITIAL PNEUMONITIS
INTERSTITIAL LUNG DISEASE
PNEUMONITIS


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AE Clinical Importance 
Category
Preferred Term
Liver Event
Hypoalbuminemia
6.8.
Appendix 7 Laboratory Toxicity Grading
The grading scale use for lab assessments is based on ‘Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0’.
If a laboratory value falls within the grading as specified below but also within the local laboratory 
normal limits, the value is considered to be normal and will be reset to grade 0.
Pre-baseline measurements will use the same grading ranges as applied to baseline measurements. 
In case a test has two sets of ranges – one for baseline normal and one for baseline abnormal, the 
one for baseline normal will be applied for all measurements taken pre-baseline and on baseline.
Text in gray italic in the table is present in the grading scale but is not applied by Janssen when 
grading lab data.














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7.
REFERENCES
1) Park, Joong‐Won, et al. "Global patterns of hepatocellular carcinoma management from diagnosis 
to death: the BRIDGE Study." Liver International 35.9 (2015): 2155-2166.