Conditions: Select Advanced Solid Tumors
Keywords: IMCnyeso Immunotherapy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 29
Healthy volunteers: no

Brief summary:
IMCnyeso is a bispecific fusion protein designed for the treatment of cancers that express NY-ESO-1 and/or LAGE-1A. This was a first-in-human trial designed to evaluate the safety and efficacy of IMCnyeso in HLA-A\*02:01-positive adult participants whose cancer is positive for NY-ESO-1 and/or LAGE-A1.

Detailed description:
This was planned to be a multi-center, open label, dose finding Phase 1/2 study of single agent IMCnyeso administered in participants with NY-ESO-1 and/or LAGE-A1 positive tumors. The primary objective of the dose escalation phase (Phase 1) was to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of IMCnyeso in participants with advanced solid tumors. Preliminary efficacy was to be evaluated in Phase 2. The study was terminated early (prior to initiation of Phase 2) by the Sponsor as a strategic decision (not based on any safety signal).

Arms:
arm 1: Four fixed-dose, dose escalation cohorts (Cohorts 1 to 4) and 3 intrapatient dose escalation cohorts (Cohorts 5 to 7) to establish the MTD/RP2D of IMCnyeso. arm 2: Three planned cohorts treated at the RP2D to make a preliminary assessment of the anti-tumor activity of IMCnyeso. Phase 2 was not initiated and data were not collected.

Interventions: intervention 1: IMCnyeso
Intervention descriptions: intervention 1: Weekly IV infusions of IMCnyeso

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol IMCnyeso-101
A Phase I/II Open-label, Multi-center Study of the Safety and Efficacy of 
IMCnyeso, an HLA-A*0201-Restricted, NY-ESO-1- and LAGE-1A-specific 
Soluble T Cell Receptor and Anti-CD3 Bispecific Molecule, as a Single Agent in 
HLA-A*0201 Positive Patients with Advanced NY-ESO-1 and/or LAGE-1A
Positive Cancer 
Sponsor:
Immunocore, Ltd. United Kingdom 
EUDRACT Number:   
2017-002243-15 
IND Number:  
134873 
Health Canada Number: 
223059 
Development Phase:   
I/II
Sponsor Emergency Contact:  
Office: 
Mobile: 
Mobile: 
US Office: 
UK Switchboard: 
Protocol Versions:
Current: 
v.4.0
Date of finalization: 
24 February 2020
Previous:  
v.3.0 (12 June 2019)
v.2.0 UK (07 August 2018)
v.2.0 (15 January 2018)
v.1.0 (22 November 2017)
This document contains confidential and proprietary information which is the property of Immunocore Ltd, United 
Kingdom, and therefore is provided in confidence for your review.  It is understood that this information will not be 
disclosed to others without written approval from Immunocore Ltd.
This study will be conducted in compliance with the Declaration of Helsinki (with amendments), and in accordance 
with local legal and regulatory requirements.
1&7


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PROTOCOL VERSION HISTORY
Version
Title
Date
1.0
Original Protocol
22 Nov 2017
2.0
Amendment 1
15 Jan 2018
2.0UK
Local UK Amendment 1
07 Aug 2018
3.0
Global Amendment 2
12 Jun 2019
4.0
Global Amendment 3
24 Feb 2020


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GLOBAL AMENDMENT 3
Amendment Rationale
This amendment includes changes to improve patient safety and efficiency of dose escalation. 
The amendment also includes changes to simplify study logistics during Phase II while 
maintaining appropriate safeguards for patient safety. A detailed description of changes to the 
protocol and rationale for each change is provided in Section 13.5; key changes are summarized 
as follows:
Key Changes to the Protocol
1. Intra-patient escalation (IPE) regimens have been shown to improve tolerability of other 
CD3 bispecifics, including blinatumomab and the related ImmTAC molecule tebentafusp
(Saber, 2017).  Per Protocol Amendment 2, the Study Safety Team may initiate a 1-step 
or 2-step IPE regimen; a new higher dose level must be tested using a fixed-dose regimen 
before it is assessed in a 1-step IPE regimen and, similarly, a new higher dose level must 
be assessed using a 1-step IPE regimen before that dose can be assessed using a 2-step 
IPE regimen. However, it is anticipated that the risk to patients from acute mechanism-
related toxicities is progressively reduced when moving from a fixed-dose regimen to a 
1-step IPE regimen, and further reduced when moving from 1-step to a 2-step IPE 
regimen. Therefore, the dose-escalation rules have been updated, so that at any escalation
step, a new permitted dose level based on the Bayesian Logistic Regression Model
(BLRM) can be assessed using the same regimen as the prior cohort or using a regimen 
with additional steps. Furthermore, because ImmTAC-associated toxicities are generally 
acute, a 28-day DLT period will be used for all schedules.
2. Based on the observation that all signs/symptoms of cytokine release syndrome (CRS), to 
date, have occurred rapidly (within a few hours) following administration of IMCnyeso, 
once dose-escalation is completed and the Study Safety Team (SST) has reviewed all 
available relevant data for at least 6 patients at the recommended Phase II dose (RP2D), 
the SST may decide to reduce the minimum required post-end of infusion monitoring 
time to no less than 8 hours on Cycle 1 Day 1 (C1D1), C1D8, and/or C1D15 during the 
Phase II portion of the study.  Such a decision will take into account the initial 
assessment of safety at the RP2D including whether treatment is well-tolerated at the 
selected RP2D and if any signs/symptoms of CRS occur within 2-4 hours post-end of 
infusion. Consistent with prior versions of the protocol, hospitalization would be 
extended if clinically indicated for any given patient.
3. Eligibility criteria were updated based on Investigator feedback as follows:


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a.
Patients with a clinically stable, asymptomatic Grade 2 endocrine disorder due to 
prior anticancer therapy (previously restricted to hypothyroidism) are permitted to 
be enrolled in the study
b. The minimum allowed creatinine clearance (calculated using Cockcroft-Gault 
formula or measured) was reduced from 50 mL/min to 40 mL/min
c.
The washout period for oral antibiotics was reduced from 14 days to 7 days prior 
to the first dose of study drug (note: no change was made to the washout period 
for IV antibiotics).
4. Instructions for allowed and prohibited concomitant medications were edited to include 
guidance regarding vaccine use.
5. If dose escalation proceeds to a dose of >150 mcg according to BLRM output and 
treatment at this dose level is well-tolerated, additional BLRM simulations may be 
performed to predict rates of toxicity for higher dose levels.


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GLOBAL AMENDMENT 2
Amendment Rationale
This amendment includes changes to improve study enrollment and efficiency while maintaining 
appropriate safeguards for subject safety. This amendment incorporates formatting changes, 
removes redundant information, and corrects inconsistencies and errors noted by sites working 
on the study. Changes made in Local United Kingdom (UK) Amendment 1 were incorporated
globally in this amendment. A detailed description of changes to the protocol and rationale for 
each change is provided in Section 13.5; key changes are summarized as follows:
Key Changes to the Protocol
1. Description of potential risks was revised to incorporate emerging data from related 
molecules including the immune mobilizing T cell receptor against cancer (ImmTAC)
IMCgp100). The cytokine release syndrome section was updated to include frequencies 
of relevant adverse events (AEs).  Potential risks of hepatic and pulmonary events were 
added, as inflammation of tumors within the liver and lungs has been associated with 
AEs following treatment with other immunotherapies.
2. Added provision to allow enrollment in expansion cohorts to be increased from n=9 to 
n=24 (previously fixed at n=10), based on a Simon two-stage design, to enable a more 
robust assessment of efficacy. Updated the primary objective and endpoint for Phase II 
from additional characterization of safety to preliminary anti-tumor activity (best overall
response [BOR] per Response Evaluation Criteria in Solid Tumors [RECIST v1.1]) and 
incorporated interim analysis.
3. Response will no longer be evaluated per modified immune-related RECIST (irRECIST). 
Treatment discontinuation will be required when unequivocal disease progression is 
confirmed (defined as an additional PP increase in tumor burden (sum of diameters 
of both target and new lesions) and/or identification of additional new lesions, at least 
4 weeks after the initial progressive disease (PD) assessment), aligning with more current 
standards (Seymour, 2017).
4. Standardized infusion duration for all cohorts to require a slower infusion on Cycle 1
Day 1 (C1D1; 2 hours) for all patients, with provisions to reduce the infusion time in 
subsequent infusions, to support patient safety and simplify protocol compliance.
5. Intra-patient dose-escalation approaches have proven beneficial for other CD3 
bispecifics, including blinatumomab and the related ImmTAC molecule IMCgp100 
(Saber, 2017). If the emerging safety profile indicates that treatment-related AEs 


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(eg, cytokine release) are more severe following initial doses and less severe after later 
doses, the Study Safety Team may initiate a 1-step or 2-step intra-patient escalation 
regimen and/or allow pre-medication. A longer dose-limiting toxicity (DLT) evaluation 
period and adjusted Cycle 1 schedule were added for patients receiving intra-patient 
escalation.
6. The first three patients at each dose level will be hospitalized for 2 nights after the first 
dose of IMCnyeso. After reviewing safety, pharmacokinetic (PK), and cytokine data 
from at least 3 patients enrolled at a given dose level, the Study Safety Team (SST) may 
decide that 1 night of hospitalization is adequate after the first dose for subsequent 
patients with longer hospitalization if indicated. ImmTACs have short (<24 hour) serum 
half-life and rapid pharmacodynamic effects; when a treatment-related AE occur, the 
onset is anticipated to be rapid (<24 hours post dose). Studies for the related ImmTAC 
molecule IMCgp100 require 1 night of hospitalization after the first dose.
7. The prior assumptions for the Bayesian Logistical Regression Model (BLRM) were 
updated to emphasize emerging clinical data rather than preclinical assumptions of 
maximum tolerated dose (MTD) in guiding escalation increments.  Higher dose levels 
(up to 200 mcg) were included in the model.  The operating characteristics, example dose 
levels, and potential escalation schemes were updated accordingly. 
8. Eligibility criteria were organized for ease of use and updated based on Investigator 
feedback to allow enrollment of patients with Grade 2 hypophosphatemia due to prior 
cancer treatment (if receiving appropriate replacement therapy), Grade 2 hypothyroidism 
(if on stable replacement doses), Grade 2 lymphopenia, and Gilbert’s syndrome.  
Laboratory criteria for hematology must be met with adequate washout from growth 
factors / transfusions.  Laboratory criteria for electrolytes were removed.  Washout for 
prior antibiotics reduced to 2 weeks prior to first dose (versus before start of Screening).  
Prior treatment requirements for Phase I were clarified.  Washout for prior anti-cancer 
therapy clarified as for disease under study.  Exclusion for patients with prior 
hypersensitivity to other biologic drugs or monoclonal antibodies was removed. 
9. DLT criteria for Grade 3 liver function test elevations were adjusted to apply stricter
criteria for high Grade 3 elevations while allowing more time for low Grade 3 elevations 
to resolve. DLT criteria for concurrent ALT/AST and bilirubin increases were aligned 
with Potential Hy’s Law criteria.  DLT criteria regarding amylase / lipase increase were 
added.  DLT criteria for hypotension was modified to align with CRS treatment 
guidelines (vasopressor use does not automatically trigger DLT).  The Sponsor must be 
notified within 24 hours of any serious adverse event (SAE)'/7 Grade 2 cytokine 


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release syndrome (CRS)RU Grade 3 hepatic function abnormality (rather than notified 
immediately for any unexpected  Grade 3 AE). 
10. Allowed/prohibited concomitant medications was edited to provide more flexibility in 
modifying ongoing hypertensive medications, in cases where withholding 
anti-hypertensive medications is contraindicated, allow the monoclonal antibody 
denosumab (as supportive care for patients with bone metastasis), clarify that prohibition 
of anti-cancer therapies refers to systemic therapies for the cancer under study 
(eg, adjuvant tamoxifen for prior breast cancer would not be prohibited), allow 
corticosteroids for known allergy to contrast reagents, and allow SST to recommend 
pre-medication based on the emerging safety profile. 
11. Toxicity management guidelines were updated to align with protocols for other ImmTAC
molecules.  Dose modification requirements were added for each toxicity and grade if not 
already present.  Requirements for Sponsor notification were added. Cytokine-release 
syndrome (CRS) grading will follow the most recent consensus guidelines (Lee; 2019); 
additional information regarding the definition of CRS and recovery from CRS were 
incorporated in a new Appendix. 
12. The schedule of assessment tables were reformatted for ease of use with a few 
clarifications.  Acceptable time windows were added if not previously included and 
adjusted in some cases to improve operational feasibility.  The frequencies of 
electrocardiogram (ECG), chemistry, hematology, and PK evaluations during later cycles 
and cytokine testing on Cycle 1 Day 22 were reduced; the revised plans are adequate to 
assess study endpoints. 
13. Safety Follow-Up changed to 30 days, based on the <24-hour half-life of ImmTAC.  
Added safety assessments at the 30-day post-last-dose visit to allow evaluation of 
resolution of any abnormal findings or laboratory values at End of Treatment.  Clarified 
that patients who initiate subsequent anti-cancer treatment will proceed directly to 
Survival Follow-Up.  Any treatment-related SAE must be reported even if Safety 
Follow-Up has completed. 
14. Additional 
 assessments 
 were 
incorporated to further characterize the pharmacodynamic effects of IMCnyeso treatment.  
Study objectives and endpoints, schedule, and rationale and description of assessments 
were updated accordingly.  
15. On-VWXG\SDLUHGELRSVLHVDUHUHTXLUHGIRUSDWLHQWVSUHYLRXVO\DOOSDWLHQWVLQ
Phase II, as this provides an adequate number of biopsies to meet study objectives and 
allows enrollment of patients who cannot safely undergo multiple on-study biopsies.  The 


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optimal timing for the on-treatment biopsy sample is between Cycle 1 Day 9 and Cycle 1 
Day 16 (previously during Cycles 1 and/or 3, 1-3 days following dosing).  Archival 
biopsies may be used to determine New York esophageal squamous cell carcinoma-1 
(NY-ESO-1) / L antigen family member-1 isoform A (LAGE-1A) status throughout the 
study (previously new biopsies were required for Pre-Screening in Phase II).  Added 
biopsied lesions may not be followed as target lesions for disease assessments per 
RECIST v1.1 unless the lesion is > 2 cm and, in the opinion of the Investigator, the 
biopsy will not appreciably impact the dimensions of the lesion.
Institutional Review Board/Independent Ethics Committee
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) and Health Authorities.  If the original protocol had been 
previously submitted and approved, the changes described in this amended protocol will require 
IRB or IEC approval.  Changes herein are reflected in the Informed Consent.


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LOCAL UK AMENDMENT 1
Amendment Rationale
This amendment updates the contraception requirement in the protocol to be consistent with 
Clinical Trial Facilitation Group recommendations.
The end of trial definition was updated to take into account assessment of the secondary 
endpoints of objective response rate, overall survival, progression-free survival and duration of 
response.
The criteria for study drug discontinuation was updated.
Changes to the Protocol
1. Update to contraception requirement in Section 6.14.1
2. Update to end of study definition in Section 3.6
3. Update to study drug discontinuation in Section 6.16.
4. Administrative update to the Sponsor emergency contacts on page 1.
Institutional Review Board/Independent Ethics Committee
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) and Health Authorities.  If the original protocol had been 
previously submitted and approved, the changes described in this amended protocol will require 
IRB or IEC approval.  Changes herein are reflected in the Informed Consent.


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AMENDMENT 1
Amendment Rationale
This amendment will implement changes to the dose-limiting toxicity (DLT) definition and 
inclusion criteria.
As this is the first-in-human (FIH) assessment of the safety and tolerability of IMCnyeso and the 
safety profile is currently not known, the DLT definition will be modified to include any Grade 5 
event of uncertain etiology.  The DLT definition will be amended to specify that any death that is 
not clearly due to the underlying disease or extraneous causes will be considered a DLT. 
Patients enrolled in this FIH clinical trial should have exhausted existing approved therapies.  As 
recommended in the National Comprehensive Cancer Network guidelines for non-small cell lung 
cancer (NSCLC), patients with sensitizing epidermal growth factor receptor (EGFR) mutations 
or anaplastic lymphoma kinase (ALK) rearrangements should receive targeted therapy as first-
line treatment.  For the Dose-Escalation Phase (Phase I), inclusion criterion #9 ensures that 
enrolled patients are refractory or intolerant to all existing therapies.  This amendment specifies
for the Dose Expansion Phase (Phase II) that patients with NSCLC and an EGFR or ALK 
genomic tumor aberration must have disease progression after treatment with the approved 
targeted therapy for the specific aberration. 
As this is the first clinical trial with IMCnyeso, any remaining 
samples will be stored 
for additional testing to better understand the cancer, the drug response, or to validate 
diagnostic/
 assays.  Specification of storage duration for these samples has been added.  
Changes to the Protocol
1. Additional DLT criterion added (Section 6.12) 
2. Updated inclusion criteria #10 (Section 5.2) to require that during Phase II patients with 
NSCLC harboring ALK rearrangements or EGFR mutations have had prior treatment 
with Health Authority-approved targeted therapies
3. Duration of sample storage has been added (Sections 7.1, 7.10.2) 
4. Additional emergency contact added on cover page 
5. Corrected typographical errors and inconsistencies and inserted minor clarifications 
throughout to improve the readability and content presentation 


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Institutional Review Board/Independent Ethics Committee
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) and Health Authorities.  If the original protocol had been 
previously submitted and approved, the changes described in this amended protocol will require 
IRB or IEC approval.  Changes herein are reflected in the Informed Consent. 


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TABLE OF CONTENTS
PROTOCOL VERSION HISTORY........................................................................................... 2
GLOBAL AMENDMENT 3 ........................................................................................................ 3
GLOBAL AMENDMENT 2 ........................................................................................................ 5
LOCAL UK AMENDMENT 1 .................................................................................................... 9
AMENDMENT 1 ........................................................................................................................ 10
TABLE OF CONTENTS ........................................................................................................... 12
LIST OF IN-TEXT TABLES .................................................................................................... 18
LIST OF IN-TEXT FIGURES .................................................................................................. 19
PRINCIPAL INVESTIGATOR’S SIGNATURE.................................................................... 21
PROTOCOL SYNOPSIS........................................................................................................... 22
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 26
1
BACKGROUND ................................................................................................................ 30
1.1
Overview of IMCnyeso............................................................................................ 30
1.2
Mechanism of Action of IMCnyeso ........................................................................ 30
1.2.1
New York Esophageal Squamous Cell Carcinoma-1 and L Antigen Family 
Member-1 Isoform A................................................................................... 31
1.3
Non-Clinical Experience with IMCnyeso................................................................ 32
1.3.1
Non-Clinical Pharmacology of IMCnyeso .................................................. 33
1.3.2
IMCnyeso Single-Agent Pharmacokinetics................................................. 33
1.3.3
Non-Clinical Toxicology of IMCnyeso....................................................... 34
1.3.4
Non-Clinical Safety Summary..................................................................... 34
1.4
Clinical Safety and Experience................................................................................ 35
1.5
NY-ESO-1 and LAGE-1A Patient Screening Strategy ........................................... 37
1.6
Overview of Disease Setting.................................................................................... 37
1.6.1
Non-Small Cell Lung Cancer....................................................................... 38
1.6.2
Melanoma .................................................................................................... 38
1.6.3
Urothelial Carcinoma................................................................................... 39
1.6.4
Synovial Sarcoma ........................................................................................ 40
2
STUDY RATIONALE....................................................................................................... 41
2.1
Rationale for Study Design...................................................................................... 41


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2.2
Overall Benefit-Risk Assessment ............................................................................ 41
3
STUDY DESIGN................................................................................................................ 43
3.1
Phase I Dose Escalation........................................................................................... 43
3.2
Phase II Dose Expansion ......................................................................................... 44
3.3
Patient Population.................................................................................................... 44
3.4
Definition of Study Periods ..................................................................................... 44
3.5
End of Treatment ..................................................................................................... 44
3.6
Definition of End of Study....................................................................................... 44
3.7
Early Study Termination.......................................................................................... 45
3.8
Post-Study Access to Treatment.............................................................................. 45
4
STUDY OBJECTIVES AND ENDPOINTS.................................................................... 46
5
POPULATION SELECTION CRITERIA ..................................................................... 48
5.1
Patient Population.................................................................................................... 48
5.2
Inclusion Criteria ..................................................................................................... 48
5.3
Exclusion Criteria .................................................................................................... 49
6
STUDY TREATMENTS AND ADMINISTRATION.................................................... 53
6.1
IMCnyeso Study Treatment..................................................................................... 53
6.2
Treatment Regimen and In-Patient Hospitalization................................................. 53
6.3
IMCnyeso Handling, Storage, and Preparation ....................................................... 54
6.4
Study Drug Administration...................................................................................... 54
6.5
Study Drug Compliance and Accountability........................................................... 55
6.6
Drug Supply, Storage, and Disposal........................................................................ 55
6.7
Patient Numbering and Treatment Assignment....................................................... 55
6.8
Dose-limiting Toxicities Observation Period .......................................................... 56
6.9
Starting Dose Rationale ........................................................................................... 56
6.10
Dose-Escalation Decision Making........................................................................... 57
6.10.1 Intra-Patient Escalation................................................................................ 58
6.10.2 Definition of DLT-Evaluable Patients for the Dose-Determining Set......... 61
6.11
Definition of Maximum Tolerated Dose and Recommended Phase II 
Dose ......................................................................................................................... 62
6.12
Definitions of Dose-Limiting Toxicity.................................................................... 62
6.13
Concomitant Therapy............................................................................................... 64


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6.13.1 Permitted Concomitant Therapy .................................................................. 64
6.13.2 Concomitant Therapy Requiring Caution .................................................... 65
6.13.3 Prohibited Concomitant Therapy ................................................................. 65
6.14
Contraception ........................................................................................................... 66
6.14.1 Contraception in Females ............................................................................ 66
6.14.2 Contraception in Males ................................................................................ 67
6.15
Management of Adverse Reactions ......................................................................... 67
6.15.1 IMCnyeso Dose Reductions ........................................................................ 67
6.15.2 IMCnyeso Dose Interruptions ...................................................................... 68
6.16
Treatment Discontinuation....................................................................................... 77
6.17
Replacement of Patients ........................................................................................... 77
6.18
Treatment Past Disease Progression ........................................................................ 77
6.19
Study Discontinuation .............................................................................................. 78
6.20
Overdose .................................................................................................................. 78
7
STUDY SCHEDULE AND ASSESSMENTS .................................................................. 79
7.1
Pre-Screening and Screening Period Schedule ........................................................ 79
7.2
Treatment Period Schedule ...................................................................................... 81
7.3
Safety, Disease Progression, and Survival Follow-Up Period Schedule ................. 84
7.4
Details of Assessments ............................................................................................ 85
7.4.1
HLA-A*02:01 and NY-ESO-1 / LAGE-1A Testing ................................... 86
7.4.2
Patient Demographics and Other Baseline Characteristics .......................... 86
7.4.3
Efficacy Assessments................................................................................... 86
7.4.4
Safety and Tolerability Assessments ........................................................... 87
7.4.5
Pharmacokinetics and Immunogenicity Assessments ................................. 89
7.4.6
 ........................................................................................ 89
7.4.6.1
 ................................................... 89
7.4.6.2
 ........................................................................ 90
7.4.6.3
Skin Punch Biopsy ........................................................................ 91
7.4.6.4
 ........................................................... 91
8
ADVERSE EVENTS AND SAFETY REPORTING ...................................................... 92
8.1
Assessment of Safety ............................................................................................... 92


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8.2
Definitions................................................................................................................ 92
8.3
Criteria for Expectedness......................................................................................... 93
8.4
Assessment of Causality .......................................................................................... 94
8.5
Adverse Event Reporting......................................................................................... 94
8.5.1
Expedited Reporting .................................................................................... 94
8.5.2
Standards for Expedited Reporting.............................................................. 95
8.5.3
Reporting of Out-of-Range Laboratory Test Results as Adverse Events.... 95
8.5.4
Reporting Events Associated with Disease Progression.............................. 95
8.5.5
Reporting Guidelines for Other Observations ............................................. 96
8.5.6
Pregnancy Reporting.................................................................................... 97
8.6
Investigator’s Responsibilities................................................................................. 97
8.7
Sponsor and Clinical Research Organization’s Responsibilities............................. 98
9
STATISTICAL METHODS AND DATA ANALYSES................................................. 99
9.1
General Principles.................................................................................................... 99
9.2
Analysis Sets.......................................................................................................... 100
9.2.1
Full Analysis Set........................................................................................ 100
9.2.2
Safety Analysis Set .................................................................................... 100
9.2.3
Per-Protocol Analysis Set .......................................................................... 100
9.2.4
Dose-Determining Analysis Set................................................................. 100
9.2.5
Pharmacokinetic Analysis Set.................................................................... 100
9.3
Patient Demographics and Other Baseline Characteristics.................................... 101
9.4
Treatment Data....................................................................................................... 101
9.5
Primary Analysis Variables ................................................................................... 101
9.5.1
Phase I: DLT.............................................................................................. 101
9.5.2
Phase II: Efficacy....................................................................................... 102
9.6
Secondary Analysis Variables ............................................................................... 102
9.6.1
Efficacy...................................................................................................... 102
9.6.2
Safety ......................................................................................................... 102
9.6.2.1
Adverse Events ........................................................................... 102
9.6.2.2
Laboratory Abnormalities........................................................... 103
9.6.2.3
Other Safety Variables................................................................ 103


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9.6.2.4
Tolerability.................................................................................. 104
9.6.3
Pharmacokinetics and Immunogenicity..................................................... 104
9.7
Exploratory Analyses............................................................................................. 105
9.8
Interim Analysis..................................................................................................... 105
9.9
Sample Size Calculation ........................................................................................ 106
9.9.1
Phase I Escalation Cohorts......................................................................... 106
9.9.2
Phase II Expansion Cohorts....................................................................... 106
10
DATA HANDLING AND MANAGEMENT ................................................................ 107
10.1
Data Confidentiality............................................................................................... 107
10.2
Site Monitoring...................................................................................................... 107
10.3
Data Collection ...................................................................................................... 107
10.4
Database Management........................................................................................... 108
11
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES ........ 109
11.1
Regulatory and Ethical Compliance ...................................................................... 109
11.2
Responsibilities of the Investigator and Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board.............................. 109
11.3
Informed Consent Procedures................................................................................ 109
11.4
Discontinuation of the Study ................................................................................. 110
11.5
Publication of Study Protocol and Results............................................................. 110
11.6
Study Documentation, Record Keeping, and Retention of Documents................. 110
11.7
Confidentiality of Study Documents and Patient Records .................................... 110
11.8
Audits and Inspections........................................................................................... 111
11.9
Financial Disclosures............................................................................................. 111
12
REFERENCES................................................................................................................. 112
13
APPENDICES.................................................................................................................. 115
13.1
Cytokine Release Syndrome Definitions and Grading.......................................... 115
13.1.1 Definition of CRS ...................................................................................... 115
13.1.2 CRS Grading Criteria................................................................................. 115
13.1.3 Resolution of CRS ..................................................................................... 116
13.1.4 Immune Effector Cell-Associated Neurotoxicity Syndrome..................... 116
13.2
Guidelines for Implementation of RECIST Criteria.............................................. 117
13.2.1 Efficacy Assessments................................................................................. 117


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13.2.2 Definitions of Measurable and Non-Measurable Disease ......................... 117
13.2.3 Methods of Tumor Measurement............................................................... 118
13.2.3.1 Other Tumor Response Considerations ...................................... 118
13.2.4 Definitions of Target and Non-Target Lesions.......................................... 118
13.2.5 Determination of Target Lesion Response ................................................ 119
13.2.6 Determination of Non-Target Lesion Response ........................................ 120
13.2.7 Evaluation of Overall Lesion Response..................................................... 121
13.3
Bayesian Logistic Regression Model..................................................................... 123
13.3.1 Specification .............................................................................................. 123
13.3.2 Operating Characteristics........................................................................... 126
13.3.3 Sample Paths.............................................................................................. 127
13.4
Schedule of Cycle 1 Assessments, Intra-Patient Escalation Regimen................... 130
13.5
Detailed Description and Rationale for Changes................................................... 132
13.5.1 Amendment 3............................................................................................. 132
13.5.2 Amendment 2............................................................................................. 135


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LIST OF IN-TEXT TABLES
Table 4-1:
Study Objectives and Endpoints............................................................................46
Table 6-1:
Dose and Treatment Schedule ...............................................................................53
Table 6-2:
Example IMCnyeso Dose Levels for Phase I Dose Escalation .............................58
Table 6-3:
Criteria for Defining Dose-Limiting Toxicities.....................................................63
Table 6-4:
Recommended Management and Dose Modifications by Toxicity Grade and Type
................................................................................................................................69
Table 7-1:
Schedule of Pre-Screening and Screening Assessments........................................80
Table 7-2:
Schedule of Treatment Period Assessments ..........................................................82
Table 7-3:
Schedule of Follow-Up Assessments.....................................................................85
Table 7-4:
Disease Assessment Collection Plan .....................................................................87
Table 7-5:
ECOG Performance Status ....................................................................................88
Table 7-6:
Local Clinical Laboratory Parameters Collection Plan .........................................89
Table 9-1:
Pharmacokinetic Parameters to be Analyzed.......................................................104
Table 13-1:
ASTCT CRS Grading Criteria.............................................................................115
Table 13-2:
Response Criteria for Target Lesions ..................................................................119
Table 13-3:
Response Criteria for Non-Target Lesions ..........................................................120
Table 13-4:
Overall Lesion Response at Each Assessment (RECIST v1.1) ...........................121
Table 13-5:
Toxicity Categories..............................................................................................123
Table 13-6:
Initial Values for BLRM Simulation ...................................................................125
Table 13-7:
Pseudo-Patient Information .................................................................................126
Table 13-8:
Prior Probabilities ................................................................................................126
Table 13-9:
Scenario 1, No DLT Reported at Any Dose ........................................................127
Table 13-10:
Scenario 2, One DLT Reported at 30 mcg Dose .................................................128
Table 13-11:
Scenario 3, Two DLTs Reported at 100 mcg Dose .............................................128
Table 13-12:
Scenario 4, One DLT at 30 mcg, 2 DLTs at 145 mcg and 2 DLTs at 
100 mcg Dose ......................................................................................................129
Table 13-13:
Schedule of Cycle 1 Assessments, IPE Regimen ................................................130


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LIST OF IN-TEXT FIGURES
Figure 1-1:
IMCnyeso Structure and Functional Domains.......................................................30
Figure 1-2:
Schematic Representation of IMCnyeso Mechanism of Action............................31
Figure 1-3:
Comparison of NY-ESO-1, LAGE-1A, LAGE-1B Protein, and Peptide 
Expression..............................................................................................................32
Figure 3-1:
IMCnyeso-101 Study Design.................................................................................43
Figure 6-1:
Schematic Illustration of a 1-Step IPE Regimen ...................................................59
Figure 6-2:
Schematic Illustration of a 2-Step IPE Regimen ...................................................60
Figure 6-3:
Representative Escalation Path Incorporating IPE ................................................61




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PRINCIPAL INVESTIGATOR’S SIGNATURE
I, the undersigned, have reviewed the protocol, including the appendices, and I will conduct the 
clinical study as described and will adhere to the tripartite International Conference on 
Harmonisation (ICH) guideline E6 (R1): Guideline for Clinical Practice (GCP) and all the ethical 
and regulatory considerations stated. 
The study will not commence without the prior written approval of an appropriately constituted 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC).  No changes will be 
made to the study without prior written approval of the Sponsor and the IRB/IEC, except where 
necessary to eliminate immediate hazard to the study subjects.
Signed By:
__________________________________________
___________________________
Principal Investigator
Date 
_______________________________________________   
Print Name
_______________________________________________     
Institution Name


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PROTOCOL SYNOPSIS
Study Number
IMCnyeso-101
Title 
A Phase I/II Open-label, Multi-center Study of the Safety and Efficacy of IMCnyeso, an 
HLA-A*0201-Restricted, NY-ESO-1- and LAGE-1A-specific Soluble T Cell Receptor 
and Anti-CD3 Bispecific Molecule as a Single Agent in HLA-A*02:01 Positive Patients 
with Advanced NY-ESO-1 and/or LAGE-1A Positive Cancer 
Brief Title
Phase I/II, FIH/dose expansion study of IMCnyeso as monotherapy in HLA-A*02:01
positive Patients with Advanced NY-ESO-1 and/or LAGE-1A positive Cancer
Sponsor and 
Clinical Phase
Immunocore, Ltd.
Phase I/II
Study Drug
IMCnyeso: HLA-A*02:01-restricted, NY-ESO-1- and LAGE-1A-specific soluble T cell 
receptor and scFv anti-CD3 bispecific molecule
Study Type
Interventional
Study Purpose and 
Rationale 
IMCnyeso-101 is a Phase I/II multi-center, open-label, first-in-human (FIH),
multi-ascending dose study of monotherapy IMCnyeso in human leukocyte antigen
(HLA)-A*02:01 positive patients with advanced New York esophageal squamous cell 
carcinoma-1 (NY-ESO-1) and/or L antigen family member-1 isoform A (LAGE-1A)
positive solid tumors.  Patients with a diagnosis of non-small cell lung cancer (NSCLC), 
melanoma, urothelial carcinoma, or synovial sarcoma with antigen positivity for 
NY-ESO-1 and/or LAGE-1A are eligible for study participation.  
IMCnyeso is an immune mobilizing T cell receptor against cancer (ImmTAC), a 
bispecific protein therapeutic comprising a soluble, affinity-enhanced T cell receptor 
(TCR) fused to an antibody single-chain variable fragment (scFv).  The IMCnyeso TCR 
recognizes a peptide from the tumor-associated antigen NY-ESO-1 and/or LAGE-1A, 
presented by HLA-A*02:01.  Once the soluble TCR is engaged, the scFv effector end can 
bind to CD3 on any T cell, redirecting the T cell to produce effector cytokines and/or kill 
the cell presenting the target peptide.  In addition, IMCnyeso-mediated tumor lysis may 
prime an endogenous anti-tumor immune response.   
NY-ESO-1 is expressed in a variety of human malignancies.  Based on quantitative, 
real-time, reverse transcription polymerase chain reaction (qRT-PCR) testing of tumor 
samples conducted by the Sponsor, the frequency of expression of NY-ESO-1 and/or 
LAGE-1A is approximately 65% in synovial sarcoma, 35% in melanoma, 25% in 
urothelial carcinoma, and 15% in NSCLC.
For patients with the advanced malignancies to be studied in this trial, few treatment 
options are available.  IMCnyeso represents a novel approach for treating these patients.


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Study Design
Phase I Dose Escalation:
Dosing will begin with the minimum anticipated biological effect level (MABEL) dose as 
determined by in vitro toxicology studies.  Cohorts will initially enroll 3 to 6 patients.  If 
necessary and deemed appropriate by the Study Safety Team (SST), additional patients 
may be enrolled in a given cohort to make informed dosing decisions.  Cohorts of 2 
patients may be considered for the first 2 doses.  The initial dosing of patients in Phase I
will be staggered, with at least a 1-week interval between the first 2 patients treated at 
each dose level.  
Patients will be observed for dose-limiting toxicities (DLTs) for a period of 1 cycle (28 
days).  Dose-escalation or de-escalation decisions will be determined following review of 
all available safety, PK, and efficacy data, and the dosing recommendations will be 
primarily guided by the Bayesian Logistic Regression Model (BLRM).  The key 
decisions of dose escalation or de-escalation and identification of the MTD and/or the 
RP2D will be made by the SST and will occur during the dose-escalation teleconferences 
(DETC), which will be held once all patients in a given dosing cohort have completed 
DLT evaluation.  All dosing decisions will be agreed upon and documented in the DETC 
meeting minutes.  The SST will include the Study Investigators, the Sponsor Medical 
Monitor, and a statistician.  
If the emerging safety profile indicates that the severity of cytokine-mediated AEs tends 
to become less severe following repeated dosing, the SST may initiate a 1-step or 2-step 
intra-patient escalation (IPE) regimen and/or allow pre-medication as these approaches 
have been beneficial for related therapeutics.
Approximately 27 patients are predicted to be enrolled in Phase I.
Phase II Expansion:
Following the identification of the MTD and/or RP2D in Phase I, patients may be 
enrolled into the 3 Phase II expansion cohorts (NSCLC, urothelial carcinoma, and 
synovial sarcoma) to make a preliminary assessment of the anti-tumor activity of 
single-agent IMCnyeso at the RP2D in these disease settings.
A Simon two-stage design will be used for each Phase II cohort.  If there are no responses 
among the first 9 patients in a cohort, then accrual in that cohort will stop. If there is at 
least one response, at the discretion of the Sponsor up to an additional 15 patients may be 
accrued for a total of up to 24 patients (with at least 3 responses to support further 
evaluation).
Study Treatment
IMCnyeso will be supplied as a sterile, frozen solution, in individual, single-use glass 
vials at a concentration of 0.5 mg/mL.
IMCnyeso will be administered via weekly (QW) intravenous (IV) infusions.  For each 
patient, the first dose will be infused over 2 hours (±15 minutes)IRUGRVHOHYHOV
mcg; the first dose infusion time may be reduced to 1 hour (±10 minutes).  If the first 
dose is well tolerated without  Grade 2 infusion and/or a hypersensitivity reaction, a 
given patient's subsequent infusion times may be reduced to 1 hour (±10 minutes) starting 


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at C1D8, and further reduced to 30 minutes (±10 minutes) starting at C3D1 provided the 
above conditions continue to be met.
For all study medication administration, a physician must be present at the site, or 
immediately available to respond to emergencies.  Patients will be hospitalized for 2 
nights following administration of the first dose (C1D1) of IMCnyeso and will remain at 
the site for overnight observation following the second dose (C1D8).  After reviewing 
safety, PK, and cytokine data from at least 3 patients enrolled at a given dose level, the 
SST may decide that 1 night of hospitalization is adequate after the first dose for 
subsequent patients (with longer hospitalization if indicated).  During Phase I, patients 
receiving IPE over three doses will be hospitalized overnight after each of the first three
doses (C1D1, C1D8, and C1D15). The SST may decide to reduce the minimum required 
monitoring time during Phase II to no less than 8 hours post-end of infusion for C1D1, 
C1D8, and/or C1D15.  Fully functional resuscitation equipment and medications to 
handle acute infusion-related emergencies (eg, anaphylaxis, cytokine release syndrome
[CRS]) must be available at each study site.
Population Under 
Study
In Phase I, HLA-A*02:01-positive patients with a diagnosis of NY-ESO-1 and/or 
LAGE-1A positive advanced NSCLC, melanoma, urothelial carcinoma, or synovial
sarcoma will be enrolled.  In Phase II, patients with HLA-A*02:01 positive and 
NY-ESO-1 and/or LAGE-1A positive advanced NSCLC, urothelial carcinoma, or 
synovial sarcoma will be enrolled and treated at the RP2D.  Patients must meet all 
eligibility criteria to commence dosing.
Efficacy 
Assessments
Tumor response will be determined locally according to RECIST v.1.1.  During the 
study, Immunocore may decide to have a central review of the radiological assessments
performed. 
Safety Assessments
Safety assessments will include physical examination, electrocardiogram (ECG), vital 
signs, weight, performance status, hematology, chemistry, coagulation, urinalysis, thyroid 
function, cytokine testing and the collection of AEs.  
Events of CRS should be assessed in accordance with the American Society of 
Transplantation and Cellular Therapy (ASTCT) Consensus Guidelines (Lee, 2019); all 
other AEs should be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. 
The Investigator must notify the Sponsor within 24 hours of any SAE, DLT Grade 2 
&56RU*UDGHKHSDWLFIXQFWLRQDEQRUPDOLW\.
Based on the available IMCnyeso preclinical data and clinical safety information from 
the related ImmTAC molecule tebentafusp (IMCgp100), IMCnyeso may induce rash, 
tumor flare/pain, lymphopenia (associated with lymphocyte trafficking), and CRS.  
Conservative monitoring and management guidelines as well as definitions of DLT have 
been implemented.  
Statistical 
Considerations
Categorical data will be presented as frequencies and percentages.  For continuous data, 
mean, standard deviation, median, minimum, and maximum will be presented.


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In Phase I, the primary variable is the incidence of DLTs.  An adaptive BLRM guided by 
the escalation with overdose control (EWOC) principle, which mandates the dose for the 
next cohort to have less than 25% chance of excessive toxicity, will be used to make dose 
recommendations and to estimate the MTD/RP2D. 
In Phase II, the primary variable is the best overall response (BOR) based on local 
Investigator assessment per RECIST v.1.1.  A formal interim analysis will be performed 
for each Phase II cohort; ORR will be evaluated for the first 9 patients to determine 
whether enrollment may continue.
Keywords
ImmTAC, NY-ESO-1, LAGE-1A, melanoma, NSCLC, urothelial carcinoma, synovial 
sarcoma


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition of Term
ADA
Anti-drug antibody 
AE
Adverse event 
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
ASTCT
American Society for Transplantation and Cellular Therapy 
AUC
Area under the curve
BLRM
Bayesian Logistic Regression Model
BOR
Best overall response 
BP
Blood pressure 
C#D#
Cycle # Day # 
CD#
Cluster of differentiation #
CL
The total body clearance of drug from the plasma 
Cmax
Maximum observed concentration
CNS
Central nervous system
CR
Complete response 
CRO
Contract research organization
CRS
Cytokine release syndrome 
CT
Computed tomography 
CTA
Cancer Testis Antigen
CTL
Cytotoxic T lymphocyte 
CTLA-4 
Cytotoxic T lymphocyte associated protein-4 
DCR
Disease control rate
DDS
Dose-determining set
DETC
Dose-escalation teleconference
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid


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Abbreviation
Definition of Term
DoR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EGFR
Epidermal growth factor receptor
EOT
End of treatment
EWOC
Escalation with overdose control
FAS
Full analysis set
FDA
Food and Drug Administration
FIH
First-in-human
FSH
Follicle-stimulating hormone
GCP
Good clinical practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HLA-A*02:01
Human leukocyte antigen-A*02:01
HLA-DR
Human leukocyte antigen-DR
HSA
Human serum albumin
ICANS
Immune effector cell-associated neurotoxicity syndrome
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN-Ȗ
Interferon-gamma
IHC
Immunohistochemistry
IL-#
Interleukin-# (eg, IL-6, IL-10)
ImmTAC
Immune mobilizing monoclonal T cell receptor against cancer
IPE
Intra-patient escalation
IRB
Institutional Review Board
IRS
Integrated response system


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Abbreviation
Definition of Term
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous 
kDa
Kilodalton
LAGE-1A 
L antigen family member-1 isoform A
LAGE-1B 
L antigen family member-1 isoform B 
LFT
Liver function test
MABEL
Minimum anticipated biological effect level
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC
Non-small cell lung cancer
NY-ESO-1 
New York esophageal squamous cell carcinoma-1 
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell 
PD
Progressive disease
PD-1 
Programmed death-1 
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
PK
Pharmacokinetics
pM 
Pico molar
PPS
Per-protocol set
PR
Partial response
QD
Every day 
qRT-PCR
Quantitative, real-time, reverse transcription polymerase chain reaction
QTcF
QT interval corrected by Fredericia’s method
QW
Every week 
REB
Research ethics board


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Abbreviation
Definition of Term
RECIST
Response Evaluation Criteria in Solid Tumors 
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
scFv
Single-chain variable fragment
SD
Stable disease
SST
Study safety team
SUSAR
Serious unexpected adverse drug reaction 
t1/2
Terminal elimination half-life
TCR
T cell receptor
TIL
Tumor-infiltrating lymphocyte
Tmax
Time of maximum concentration
TMTB
Total measured tumor burden 
TNF-Į
Tumor necrosis factor-alpha
UK
United Kingdom 
ULN
Upper limit of normal 
US
United States
WHO
World Health Organization 


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1
BACKGROUND 
1.1 Overview of IMCnyeso
Immunocore is developing a new biological entity, IMCnyeso, for the treatment of advanced 
cancers that are positive for the cancer-testis antigens New York esophageal squamous cell 
carcinoma-1 (NY-ESO-1) and/or L antigen family member-1 isoform A (LAGE-1A).  IMCnyeso 
is an immune mobilizing T cell receptor against cancer (ImmTAC), a bispecific protein 
therapeutic comprising a soluble, affinity-enhanced T cell receptor (TCR) fused to an antibody 
single-chain variable fragment (scFv).  One other investigational ImmTAC drug, tebentafusp 
(IMCgp100), is currently in development and being tested in patients with metastatic melanoma 
(Middleton, 2016). 
1.2 Mechanism of Action of IMCnyeso 
IMCnyeso is a 77 kilodalton (kDa) protein which is manufactured in Escherichia coli.  Affinity 
and binding half-life data were generated using soluble proteins and surface plasmon resonance 
(BIAcore) methods, as shown in Figure 1-1.
Figure 1-1:
IMCnyeso Structure and Functional Domains
Anti-CD3 = anti-cluster of differentiation 3; KD = dissociation constant; LAGE-1A = L antigen family member-1
isoform A; NY-ESO-1 = New York esophageal squamous cell cancer-1; T½ = half-life; TCR = T cell receptor.


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The targeting portion of IMCnyeso (the soluble TCR) binds to a peptide fragment of the 
NY-ESO-1 or LAGE-1A tumor antigen presented by human leukocyte antigen (HLA)-A*02:01
on the surface of cancer cells (Liddy, 2012).  HLA molecules are polymorphic; the 
HLA-A*02:01 allele is expressed by approximately 40% to 50% of the Caucasian population in 
the Western World (http://www.allelefrequencies.net/).  The scFv effector end can bind to CD3 
on any T cell, redirecting the T cell to produce effector cytokines and/or kill the cell presenting 
the target (see Figure 1-2).  In addition, IMCnyeso-mediated tumor lysis may prime an 
endogenous anti-tumor immune response.
Figure 1-2:
Schematic Representation of IMCnyeso Mechanism of Action 
CD3 = cluster of differentiation 3; HLA = human leukocyte antigen; LAGE-1A = L antigen family member-1 
isoform A; NY-ESO-1 = New York esophageal squamous cell carcinoma-1.
1.2.1
New York Esophageal Squamous Cell Carcinoma-1 and L Antigen Family Member-
1 Isoform A
The peptide recognized by IMCnyeso is found in NY-ESO-1 and LAGE-1A (Figure 1-3).  In 
contrast, a related tumor antigen, L antigen family member-1 isoform B (LAGE-1B) does not 
contain the specific peptide recognized by IMCnyeso molecule.  


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Figure 1-3:
Comparison of NY-ESO-1, LAGE-1A, LAGE-1B Protein, and Peptide 
Expression
LAGE-1A = L antigen family member-1 isoform A; LAGE-1B = L antigen family member-1 isoform B; 
NY-ESO-1 = New York esophageal squamous cell carcinoma-1.
Expression of NY-ESO-1 and LAGE-1A is restricted to cell types related to human testis and 
human cancers.  The testis is not susceptible to systemic T cell responses and is considered 
immune-privileged (Zhao, 2014).  NY-ESO-1 and LAGE-1A are aberrantly expressed in a wide 
range of cancer indications at varying frequencies (Nicholaou, 2006; National Cancer Institute, 
2017).  For these reasons, NY-ESO-1 / LAGE-1A is an attractive target in cancer 
immunotherapy.
1.3 Non-Clinical Experience with IMCnyeso
The hypothesis of the IMCnyeso preclinical and clinical development programs is that tumors 
with high expression of the NY-ESO and/or LAGE-1A antigen would be most sensitive to the 
mechanism of action of IMCnyeso: T cell redirection against cells presenting the 
HLA-A*02:01-restricted NY-ESO-1 / LAGE-1A peptide.   
The soluble TCR targeting end of IMCnyeso is highly specific for human NY-ESO-1 / 
LAGE-1A peptide presented by human HLA-A*02:01 and does not bind to peptide/HLA 
complexes from non-human species.  The anti-CD3 effector end of IMCnyeso is specific for
human CD3 and does not bind to or activate T cells from other species.  Therefore, there is no 
relevant species in which IMCnyeso pharmacology or toxicology can be tested, and the 
relevance of non-human pharmacokinetic (PK) studies are considered limited.


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1.3.1
Non-Clinical Pharmacology of IMCnyeso
IMCnyeso was evaluated in a series of in vitro investigations to assess potential anti-tumor
activity in patients with tumors that express NY-ESO-1 and/or LAGE-1A.  These data can be 
summarized as follows:
x
IMCnyeso could redirect T cell activity to tumor cells that express NY-ESO-1 and/or 
LAGE-1A.
x
In vitro, IMCnyeso potently recruits and activates healthy donor and cancer patient 
peripheral blood mononuclear cells (PBMCs), leading to the release of pro-inflammatory 
cytokines, chemokines, and killing of cancer cell targets.  The fullest extent of redirected 
T cell killing can take up to 72 hours.
x
In vitro, IMCnyeso potently recruits and activates CD3-positive T cells including 
CD8-positive and CD4-positive T cells resulting in cancer-cell killing, polyfunctional 
T cell activation, and proliferation and expansion of T cells.
x
T cell activation occurs from 5 picomolar (pM) IMCnyeso and the induction of target-cell 
killing from 10 pM.  Above this concentration, tumor cell killing increases in a 
dose-dependent fashion, reaching a plateau at 1 nanomolar (nM).  These assays were 
used to determine the minimum anticipated biological effect level (MABEL) and the 
starting dose for this study (see Section 6.9).
These data demonstrate that IMCnyeso is a potent tumor-killing agent.  Therefore, an 
investigation into the effects of the drug in patients with tumors expressing NY-ESO-1 and/or 
LAGE-1A is warranted.
1.3.2
IMCnyeso Single-Agent Pharmacokinetics
Preclinical PK studies allow determination of parameters including the maximum observed 
concentration (Cmax), the time of maximum concentration (Tmax) to Cmax, the mean residence 
time, half-life in the plasma, and clearance.  Together, these PK data can be modelled to form a 
basis for predictions of how the drug may be dealt with by the human body.  When examined 
alongside distribution and excretion studies these models may provide insight into the fate of 
IMCnyeso following administration.
A single-dose, intravenous (IV) PK study was conducted in C57BL/6 mice.  Nine mice were flat 
dosed (0.1 mg/kg) followed by micro-sampling over 24 hours (Report GSK01-IMC076).  Data 
indicate a Cmax 1.33 mcg/mL, and a t1/2 of approximately 2 hours. 


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1.3.3
Non-Clinical Toxicology of IMCnyeso
In the absence of a relevant toxicology species, IMCnyeso was investigated for potential 
reactivity to normal tissues in vitro.  Given the testis-restricted expression profile of NY-ESO-1 
and LAGE-1A, these assays were a measure of the specificity of IMCnyeso to antigen-negative 
tissues. 
ImmTAC tissue cross-reactivity studies with IMCnyeso give no evidence of cross-reactivity of 
IMCnyeso with a standard panel of normal human tissues.  Normal tissue immunohistochemistry 
(IHC) studies using a commercially available antibody that recognizes NY-ESO-1 were
performed to better understand the protein expression of NY-ESO-1 in normal tissues and thus 
the potential for tissue cross-reactivity.  These studies provide evidence for strong NY-ESO-1 
protein expression in human testis, as expected with the expression profile of a cancer-testis 
antigen gene.  Weak staining was observed with infrequent cells of the spinal cord and cerebral 
cortex indicating there may be rare but low expression of the NY-ESO-1 protein found in the
central nervous system (CNS).
The tissue type to exhibit activity with the lowest concentration of IMCnyeso was normal 
melanocytes (500 pM); however, higher concentrations of IMCnyeso (approximately 100-fold 
greater than the minimal anticipated biological effect level, MABEL) were required to elicit an 
effect in these normal tissue cells (as compared with tumor cell assays).  These data indicate that 
there is a therapeutic window between a dose of drug required to effect NY-ESO-1 and/or 
LAGE-1A positive cancer cells and the doses that may cause potential organ-specific toxicity.  
Additionally, with some healthy donors tested, low levels of cytokines (ie, tumor necrosis 
factor-alpha [TNF-Į] and interferon-gamma [IFN-Ȗ@) were detected when IMCnyeso was 
incubated with fresh whole blood at concentrations 50–100 fold above the MABEL.  However, 
this activity was not broad and was low level indicating that even at these higher levels of drug, 
IMCnyeso is unlikely to cause general broad cytokine release syndrome (CRS).  Collectively, 
these data suggest that monitoring blood cytokines and skin toxicity will be important when 
making dose-escalation decisions regarding IMCnyeso. 
1.3.4
Non-Clinical Safety Summary
In the absence of a relevant toxicology species, IMCnyeso was investigated for potential 
reactivity to tissues other than NY-ESO-1/LAGE-1A positive tissue (ie, testes) in vitro.  Findings 
can be summarized as follows:
x
The use of IHC with 37 human tissue samples did not reveal any cross-reactivity against 
any of the tissue sections for the TCR portion of IMCnyeso.  Binding via the anti-CD3 
portion of IMCnyeso to lymphatic cells was observed as expected.


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x
NY-ESO-1 protein expression was determined by IHC with 37 human tissue samples 
using a commercially available antibody where strong expression was detected in the 
immune-privileged testis.  Low and infrequent expression was detected in cells within the 
spinal cord and cerebral cortex, in more than 1 donor.  Expression of LAGE-1A protein 
could not be determined due to the lack of specific reagents, however ribonucleic acid 
(RNA) analysis in publicly available datasets and literature studies have indicated that the 
expression profile of LAGE-1A is very similar to NY-ESO-1 in normal tissues.
x
IMCnyeso did not cause significant reactivity within the anticipated clinical dose range 
against a panel of HLA-A*02:01 positive, NY-ESO-1/LAGE-1A negative normal cells 
derived from various normal tissue types.
x
The tissue type to exhibit activity with the lowest concentration of IMCnyeso was normal 
melanocytes (500 pM, approximately 100-fold greater than the minimal anticipated 
biological effect level, MABEL).  
x
Within the anticipated clinical dose range, IMCnyeso did not cause broad cytokine 
release against whole blood.
x
Within the anticipated clinical dose range, IMCnyeso did not cause reactivity against 
platelets or cells displaying most other known HLA types (allo-reactivity).
1.4 Clinical Safety and Experience
This is the first-in-human (FIH) study of IMCnyeso.  As of 22Jan2020, 15 patients have been 
enrolled and treated (n=4 at 3 mcg; n=3 at 10 mcg; n=5 at 30 mcg, and n=3 at 100 mcg). No 
dose-limiting toxicity (DLT), treatment-related  Grade 3 adverse event (AE), AE leading to 
discontinuation, or fatal AE has been reported. Treatment-related serious AEs (SAEs) were 
reported in 2 patients; a Grade 1 overdose (attributed to dose-preparation error) was reported in 
Cohort 1 (3 mcg) and an event of Grade 2 CRS was reported in Cohort 4 (100 mcg).  The most 
commonly reported AEs (including reported signs and/or symptoms of CRS) were headache 
(n=10, 67%) and fatigue and pyrexia (each n=9, 60%).  These data are from an ongoing study, 
are not fully validated, and potentially subject to change prior to final database lock. 
Characterization of safety, tolerability, PK, pharmacodynamics, and efficacy are ongoing.
Based on the available IMCnyeso preclinical data, the IMCnyeso mechanism of action, and 
clinical safety information from the tebentafusp clinical trials, IMCnyeso may elicit the 
following adverse drug reactions:
Cytokine Release Syndrome:  Release of pro-inflammatory cytokines (eg, IL-6, IFN-Ȗ, TNF-Į) 
is a predicted pharmacodynamic effect of IMCnyeso.  Based on experience with tebentafusp, 


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symptoms such as pyrexia, chills, nausea, hypotension, and edema were observed in most 
patients, typically 4-24 hours after the first 2-3 doses.  As of August 2018, 2% of patients in the 
IMCgp100-102 study experienced severe (Grade 3) CRS with tebentafusp.  Based on a shared 
mechanism of action with tebentafusp and non-clinical assessments of both molecules in whole 
blood assays, the risk of CRS with IMCnyeso is anticipated to be similar to tebentafusp.  Fully 
functional resuscitation equipment and medications to handle acute infusion-related emergencies 
(eg, anaphylaxis, CRS) must be available at each study site.  Patients will be hospitalized after 
the initial doses of IMCnyeso for monitoring (see Section 6.2).  Scheduled samples will be taken 
for cytokine monitoring and additional samples should be taken in the event of suspected CRS. 
The protocol provides instructions on the recognition and conservative management of 
associated symptoms.
Rash/Pruritus and Skin Toxicity: Effects in human melanocytes were noted in the non-clinical 
toxicology studies at IMCnyeso concentrations of 500 pM (100-fold above MABEL).  In this 
FIH study, special attention is placed on the monitoring of adverse effects of IMCnyeso in the 
skin and conservative management guidance and DLT criteria are implemented for the effects of 
IMCnyeso in the skin.    
Local tumor inflammation: Based on the mechanism of action of IMCnyeso, it may cause 
inflammation within the tumor microenvironment.  Depending on the location of the tumors, 
various AE may occur, including:
x
Hepatic Events: Increased transaminase levels may be observed, especially in patients 
with liver metastasis.  Increased bilirubin may also be observed.
x
Pulmonary Events: Patients with lung metastasis may experience events such as 
dyspnea, pulmonary edema, pulmonary infiltrates, or pleural effusion.
x
Tumor Flare/Pain:  Severe pain at the site of known tumors is predicted with 
IMCnyeso, especially following the first 1–4 weekly (QW) doses.  Patients receiving 
tebentafusp have required admission for IV pain medication.  
Lymphopenia:  Monitoring of patients’ white cell counts will be conducted during the study of 
IMCnyeso.  It is important to note that the trafficking of lymphocytes is a desired effect of 
IMCnyeso.  The lymphopenia observed with tebentafusp has been shown to be transient and 
self-resolving, with lymphocyte counts returning to baseline levels by Day 8. 
Full details can be found in the single reference safety document, which is the current IMCnyeso
Investigator’s Brochure.


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1.5 NY-ESO-1 and LAGE-1A Patient Screening Strategy
IMCnyeso targets the same peptide derived from both the NY-ESO-1 and LAGE-1A proteins.  
Based on in-house and publicly available gene expression datasets (The Cancer Genome Atlas, 
http://cancergenome.nih.gov/), it is known that tumors may express NY-ESO-1, but not 
LAGE-1A.  They may express LAGE-1A, but not NY-ESO-1, and they may express both 
antigens, or neither one.  While the frequencies of these expression patterns vary between 
indications, a significant fraction of tumors in each relevant indication do not express either 
target protein.  In addition, there is substantial intra-tumor heterogeneity of expression of 
positive tumor cells ranging from 0%–100%.  Both factors necessitate selecting patients for trial 
inclusion based on the level of NY-ESO-1 and LAGE-1A expression.
While specific antibodies are available for NY-ESO-1, they are not available for LAGE-1A.  
Thus, a protein-based (immunohistochemistry [IHC]) patient selection assay is not appropriate 
for the detection of expression of both target antigens.  As a result, the Sponsor has developed a 
quantitative, real-time, reverse transcription polymerase chain reaction (qRT-PCR) assay to 
detect gene expression of both NY-ESO-1 and LAGE-1A. 
The cut-point for each antigen was determined from a constellation of data including expression 
in human metastatic tumors and normal human tissues, in vitro efficacy assays, and quantitative, 
real-time, reverse transcription polymerase chain reaction (qRT-PCR) validation studies with 
human tumor samples.    
Based on both IHC and qRT-PCR (NY-ESO-1) and qRT-PCR (LAGE-1A) testing of tumor 
samples conducted by the Sponsor, the frequency of expression of NY-ESO- 1 and/or LAGE-1A 
is approximately 65% in synovial sarcoma, 35% in melanoma, 25% in urothelial carcinoma, and 
15% in non-small lung cell lung cancer (NSCLC); note that expression frequencies are
significantly lower in uveal melanoma and NSCLC adenocarcinoma (Immunocore internal data).
The assay used for patient selection for NY-ESO-1 and/or LAGE-1A positive tumor samples is 
an investigational device and is only to be used to determine inclusion in this study protocol.    
1.6 Overview of Disease Setting
The targeted indications will include patients with advanced NSCLC, melanoma, urothelial 
cancer, or synovial sarcoma that are refractory or resistant to standard treatment regimens, or for 
which no standard treatment exists.  The unmet therapeutic need for these patients remains high 
and access to novel targeted therapies, such as IMCnyeso, may provide clinical benefit.


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1.6.1
Non-Small Cell Lung Cancer
NSCLC accounts for approximately 85% of all lung cancers.  Histologically, NSCLC is divided 
into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.  NSCLC is often 
insidious, producing no symptoms until the disease is well advanced.  At initial diagnosis, 20% 
of patients have localized disease, 25% of patients have regional metastasis, and 55% of patients 
have distant spread of disease. Over 200,000 new cases and over 150,000 deaths are expected 
from lung cancers in the United States (US) in 2017 (American Cancer Society, 2017).
Surgery, chemotherapy, and radiation are the main treatment options for localized NSCLC 
(Pallis, 2012).  Only 30%–35% of patients with NSCLC present with sufficiently localized 
disease at diagnosis that curative, surgical resection may be attempted, and approximately 50% 
of patients who undergo surgical resection experience local or systemic relapse.  Thus, 
approximately 80% of all patients with lung cancer are considered for systemic therapy at some 
point in their illness.  
The first-line treatment for NSCLC can include a platinum combination in all patients or 
immunotherapy with immune checkpoint inhibition, with pembrolizumab (Keytruda® [Merck]; a 
programmed death 1 [PD-1] inhibitor) in patients with programmed death-ligand 1 (PD-L1)
positive disease.  Patients with NSCLC that overexpress the epidermal growth factor receptor 
(EGFR) have been shown to have increased resistance to therapy and are suitable for treatment 
with EGFR tyrosine kinase inhibitors such as Gefitinib (Iressa®) and erlotinib (Tarceva®)
(Derman, 2015).  These drugs have improved survival rates compared with placebo in the 
second- and third-line setting.  The presence of an anaplastic lymphoma kinase (ALK) gene 
rearrangement in NSCLC is associated with responsiveness to ALK tyrosine kinase inhibitors, 
with recent studies demonstrating improved efficacy of alectinib (Alecensa® [Genentech]) over 
crizotinib (Xalkori® [Pfizer]) in the first-line setting (Peters, 2017).
In addition to the first-line setting, immune checkpoint inhibitors have gained increasing 
importance in NSCLC therapy across treatment lines.  Nivolumab (Opdivo® [Bristol-Myers 
Squibb]) is a monoclonal antibody inhibitor of PD-1/PD-L1 approved for use in NSCLC with 
squamous pathology in October 2015 (Zappa, 2016). Pembrolizumab was approved for 
metastatic NSCLC in October 2015, and in 2017, in combination with pemetrexed.  In addition, 
atezolizumab (Tecentriq® [Roche], a PD-L1 inhibitor) was approved in October 2016, for 
patients with metastatic NSCLC who have disease progression during or following 
platinum-containing chemotherapy.
1.6.2
Melanoma
Malignant melanoma continues to represent a major public health problem globally.  
Approximately 87,110 new diagnoses of melanoma and almost 10,000 deaths are expected in the 
US in 2017 (American Cancer Society, 2017).  The rising incidence of melanoma combined with 


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poor outcomes with standard chemotherapy (10%–15% response rate) has led to intense 
investigation of novel approaches using immunotherapy and various combinations in an attempt 
to enhance the anti-tumor immune response.
Until 2011, the alkylating agent, dacarbazine, was the standard of care for patients, despite the 
lack of survival benefit.  However, due to an improved understanding of the biology of 
melanoma and the discovery of oncogenic mutations contributing to disease progression (eg,
BRAF mutations), the BRAF kinase inhibitor, vemurafenib (Zelboraf® [Genetech]), was 
approved by the Food and Drug Administration (FDA) in 2011, and a second BRAF inhibitor,
dabrafenib (Tafinlar® [Novartis]), was approved in 2013.  Both drugs demonstrated an overall 
survival (OS) improvement and a response rate of nearly 50% in clinical trials (Shih, 2015; 
Johnson, 2015).  However, responses to treatment with BRAF inhibitors alone or in combination 
with MEK pathway inhibitors are generally of a shorter duration than those responses noted with 
checkpoint immunotherapy.  During tumorigenesis, cancer cells from a wide range of tumor 
types exploit the immune checkpoint pathways (eg, PD-1, PD-L1 and cytotoxic T lymphocyte 
associated protein 4 [CTLA-4]) to avoid detection by the adaptive immune system (Murphy, 
2016; Chen, 2013).  Blockade of immune checkpoint inhibitors such as CTLA-4, PD-1, and 
PD-L1 have recently been shown to have significant clinical activity in melanoma, leading to the 
approval of a new treatments, which include the PD-1 inhibitors, pembrolizumab and nivolumab,
as well as ipilimumab, a CTLA-4 inhibitor.
1.6.3
Urothelial Carcinoma
Urothelial cancers encompass carcinomas of the bladder, ureters, and renal pelvis, which occur at 
a ratio of 50:3:1, respectively.  Patients with cancer of the upper urinary tract have a 30%–50% 
chance of developing cancer of the bladder at some point in their lives.  However, patients with 
bladder cancer have only a 2%–3% chance of developing cancers of the upper urinary tract.  In 
the US in 2017, it is estimated that there will be 146,650 new diagnoses of urinary system 
cancers, with an estimated 79,030 of these being bladder cancer, and approximately 
32,190 deaths, making urothelial cancer the fourth most common malignancy in American men,
and the ninth most common in women (American Cancer Society, 2017).  
Approximately 25% of patients with urothelial carcinoma will have muscle-invasive disease and 
either present with or later develop metastases.  Systemic chemotherapy is the standard approach 
for the initial treatment of patients with inoperable, locally advanced or metastatic urothelial 
malignancies.  Although initial response rates are high, the median survival with multi-agent 
chemotherapy (cisplatin and gemcitabine or carboplatin and gemcitabine or M-VAC 
[methotrexate, vinblastine, doxorubicin and cisplatin]) shows an increase in long-term survival 
compared to treatment with cisplatin alone (Yafi, 2011).  


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Checkpoint inhibitor immunotherapy has offered an additional option for patients progressing 
after their initial systemic cytotoxic therapy (Wu, 2015).  In February 2017, the FDA granted 
accelerated approval to nivolumab (Opdivo®) for the treatment of patients with locally advanced 
or metastatic urothelial carcinoma who have disease progression during or following 
platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant 
or adjuvant treatment with a platinum-containing chemotherapy.  In addition, multiple PD-1 and 
PD-L1 inhibitors have been approved in this setting.
1.6.4
Synovial Sarcoma
Synovial sarcoma is the fourth most common type of soft tissue sarcoma (STS) and the synovial 
subset represents approximately 5%–10% of all soft tissue sarcomas.  Approximately 700 to 
1200 new cases of synovial sarcoma are expected in the US in 2017 (American Cancer Society, 
2017).  It generally arises in the extremities (approximately 70% of cases) from undifferentiated 
mesenchymal stem cells (Thway, 2014; Kimura, 2016). 
Standard treatment for localized synovial sarcoma is tumor resection, frequently accompanied by 
radiotherapy and/or chemotherapy.  There is a high incidence of late metastasis, occurring in up 
to 50% of patients (Krieg, 2011).  Common sites of metastasis include lung (80%), bone (9.9%),
and liver (4.5%) (Vlenterie, 2016).  There are currently no approved systemic therapies for 
synovial sarcoma and no consensus treatment guidelines.  An anthracycline / ifosfamide 
combination is commonly used for first-line treatment (Riedel, 2018). 
Beyond the first-line chemotherapy treatment, the options are more limited and include multiple 
single-agent and combination chemotherapy, although this setting represents an area of high,
unmet medical need.  Some sarcomas express highly immunogenic antigens and although 
previous immunotherapy attempts in sarcomas have largely been disappointing, more recently 
immunotherapy has regained significant attention and novel targets and immunotherapeutic 
strategies are being investigated.  Recent data with NY-ESO-1 specific TCR transduced 
autologous T cells (NY-ESO SPEAR® TCR) suggest that immune activation against the 
NY-ESO-1 antigen may provide therapeutic benefit to patients with prior therapy and expression 
of the antigen (Mackall, 2017).  Other immunotherapy options include checkpoint inhibitors 
(PD-1/PD-L1), vaccine therapies and adoptive immunotherapy approaches (Mitsis, 2016).


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2
STUDY RATIONALE
2.1 Rationale for Study Design
This study is an open-label, Phase I/II FIH, dose escalation/expansion study of single-agent 
IMCnyeso in HLA-A*02:01 positive patients with advanced NY-ESO-1 and/or LAGE-1A 
positive NSCLC, melanoma, urothelial cancer, or synovial sarcoma.  
In the Phase I portion of the study, the Bayesian Logistic Regression Model (BLRM) guided by 
the escalation with overdose control (EWOC) principle will be used to guide dose-escalation 
decision making and to determine the maximum tolerated dose (MTD) of IMCnyeso as 
monotherapy in NSCLC, melanoma, urothelial cancer, and synovial sarcoma patients.  The 
adaptive BLRM EWOC method controls the risk of DLTs in future patients on study. This 
approach is likely to provide a more accurate estimate of the MTD than a 3 + 3 design.
The decisions regarding dose escalation of IMCnyeso will be made by the Study Safety Team
(SST), which will consist of the Study Investigators, the Sponsor Medical Monitor, and a
statistician.  The SST will be guided by the adaptive Bayesian methodology.  Dosing decisions 
will be made following review of all available data, including safety, PK, and efficacy data (see 
Section 6.10).  
The Phase II expansion cohorts are designed to make a preliminary assessment of the anti-tumor 
activity of single-agent IMCnyeso at the recommended Phase 2 dose (RP2D) in NSCLC, 
urothelial carcinoma, and synovial sarcoma.
2.2 Overall Benefit-Risk Assessment
The study is being conducted with several parameters identified to maximize the benefit of and 
minimize the risks to patients enrolled in the study. There is significant unmet need for therapies 
that provide durable clinical benefit to patients with advanced NSCLC, urothelial carcinoma, or 
melanoma who have progressed following treatment with PD-1 / PD-L1-targeted therapy, and 
for patients with metastatic synovial sarcoma. T cell-based therapy and immunotherapies in 
general have produced profound clinical effects in patients with advanced cancers across a range 
of diagnoses.  
Measures taken to minimize the risks to patients participating in the study include eligibility 
criteria designed to exclude patients at potentially high risk for experiencing treatment-related 
toxicity (Section 5), staggered dosing of the first 2 patients in each cohort (Section 3.2), 
conservative dose-escalation guidelines with implementation of a Bayesian dose-selection 
parameter and overdose control (Section 6.10), as well as management guidance and stopping 
rules for potential IMCnyeso-related AEs (Section 6.15). 


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Based on these measures, the Sponsor believes that the benefit-risk ratio for patients enrolled in 
this study is positive (IMCnyeso-101 FIH Study, “A Phase I/II Open-label, Multi-center Study of 
the Safety and Efficacy of IMCnyeso, an HLA- A*0201-Restricted, NY-ESO-1- and 
LAGE-1A-specific Soluble T Cell Receptor and Anti-CD3 Bispecific Molecule, as a Single 
Agent in HLA-A*0201 Positive Patients with Advanced NY-ESO-1 and/or LAGE-1A Positive 
Cancer”).


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3
STUDY DESIGN
IMCnyeso-101 is a Phase I/II, multi-center, open-label, FIH, multi-ascending dose study of 
monotherapy IMCnyeso in HLA-A*02:01 positive patients with advanced NY-ESO-1 and/or 
LAGE-1A positive solid tumors.
The study will be conducted in 2 phases (see Figure 3-1).
Figure 3-1:
IMCnyeso-101 Study Design
HLA = human leukocyte antigen; NSCLC = non-small cell lung cancer; OR = objective response; 
RP2D = recommended Phase II dose.
3.1 Phase I Dose Escalation 
Phase I dose escalation will enroll patients with advanced NSCLC, melanoma, urothelial 
carcinoma, or synovial sarcoma.  The primary objective is to determine the MTD and/or RP2D 
of IMCnyeso as a monotherapy in these patients.
Cohorts will initially enroll 3–6 patients.  If necessary and deemed appropriate by the SST, 
additional patients may be enrolled in a given cohort to make informed dosing decisions.  
Cohorts of 2 patients may be considered for the first 2 doses.  If any Grade 2 toxicities 
suspected related to IMCnyeso are observed during the first 2 cohorts, the cohorts should then be 
expanded following a discussion among the SST. Dosing will start with 3 mcg, which is the 
MABEL, as determined by in vitro toxicology studies (see Section 6.9).  Phase I is estimated to 
enroll approximately 27 patients (see Section 9.9.1).
The initial dosing of patients in dose-escalation will be staggered, with at least a 1-week interval 
between the first 2 patients treated at each dose level.  The integrated response system (IRS) will 
be used to control patient allocation to treatment and ensure the dosing intervals and cohort 
recruitment complies with the protocol.
Phase I Dose Escalation of IMCnyeso 
• HLA-A*02:01 positive by central assay
• NY-ESO-1 and/or LAGE-1A positive by 
central tumor assay
• Advanced NSCLC, melanoma, urothelial 
carcinoma, and synovial sarcoma 
• n ~ 27
RP2D 
IMCnyeso
Phase II: NSCLC 
IMCnyeso at RP2D
n=9 (if ш 1 OR, may expand to ш24)
Phase II: Urothelial Carcinoma 
IMCnyeso at RP2D
n=9 (if ш 1 OR, may expand to ш24)
Phase II: Synovial Sarcoma
IMCnyeso at RP2D
n=9 (if ш 1 OR, may expand to ш24)


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The key decisions of dose escalation or de-escalation and identification of the MTD and/or the 
RP2D will be made by the SST and guided by the BLRM, as discussed in Section 6.10.  
3.2 Phase II Dose Expansion
Following the identification of the MTD and/or RP2D in Phase I, patients may be enrolled into 
the 3 Phase II expansion cohorts (NSCLC, urothelial carcinoma, and synovial sarcoma) to make 
a preliminary assessment of the anti-tumor activity of IMCnyeso as a single agent in these 
disease settings.  Initially, up to 9 patients may be enrolled in each Phase II cohort.  If there is at 
least one response, at the discretion of the Sponsor up to an additional 15 patients may be 
accrued for a total of up to 24 patients, as discussed in Section 9.9.2.
3.3 Patient Population
In Phase I, HLA-A*02:01-positive patients with a diagnosis of NY-ESO-1 and/or LAGE-1A 
positive advanced NSCLC, melanoma, urothelial carcinoma, or synovial sarcoma will be 
enrolled.  In Phase II, HLA-A*02:01 positive patients with NY-ESO-1 and/or LAGE-1A positive 
advanced NSCLC, urothelial carcinoma, or synovial sarcoma will be enrolled and treated at the 
RP2D.  All patients meet all eligibility criteria (see Section 5).  
3.4 Definition of Study Periods
The study is made up of 6 study periods: (1) Pre-screening, (2) Screening, (3) Treatment, 
(4) Safety Follow-Up, (5) Disease Progression Follow-Up, and (6) Survival Follow-Up.  The 
individual study periods are described in Section 7.
3.5 End of Treatment
IMCnyeso will be administered according to the protocol-defined regimen until the patient meets 
criteria for treatment discontinuation described in Section 6.16.
3.6 Definition of End of Study
An individual patient may end participation in the study for reasons listed in Section 6.19.
The planned end of the study occurs when:
x
A minimum of 80% of patients have completed the follow-up for disease progression or 
have discontinued the study for any reason,
x
All patients have completed treatment and the Safety Follow-Up Period, and
x
The endpoints of best overall response (BOR), OS, progression-free survival (PFS), and 
duration of response (DoR) have been adequately assessed in all subjects.


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Please refer to Section 9 for details of timing of the primary analysis and final reporting of data.
3.7 Early Study Termination
The study can be terminated at any time, for any reason by the Sponsor.  Should this be 
necessary, any ongoing patient should be seen as soon as possible for an End of Treatment 
(EOT) visit (see Section 7.3).
The Investigator may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests.  Under guidance of the 
Sponsor, the Investigator will be responsible for informing the Institutional Review Board (IRB) 
and Independent Ethics Committee (IEC) of the termination of the study.
3.8 Post-Study Access to Treatment
As IMCnyeso is an investigational medication and not currently licensed for sale in any region,
the drug is not available to patients outside of the study protocol.


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4
STUDY OBJECTIVES AND ENDPOINTS
Study objectives and corresponding endpoints are shown in Table 4-1. 
Table 4-1: 
Study Objectives and Endpoints
Objectives 
Endpoints 
Primary - Phase I 
To identify the MTD and/or the RP2D of 
IMCnyeso, as a monotherapy, when administered 
weekly to patients with advanced NSCLC, 
melanoma, urothelial cancer, and synovial 
sarcoma
Incidence of dose-limiting toxicities
Incidence and severity of AE and SAE  
Changes in laboratory parameters, vital signs, and 
ECGs
Dose interruptions, reductions, and 
discontinuations 
Primary – Phase II
To assess the preliminary anti-tumor activity of 
IMCnyeso as monotherapy in advanced NSCLC, 
urothelial cancer, and synovial sarcoma  
BOR as determined by RECIST v1.1 
Secondary- Phase II
To characterize the safety and tolerability of 
IMCnyeso
Incidence and severity of AE and SAE  
Changes in laboratory parameters, vital signs, and 
ECGs
Dose interruptions, reductions, and 
discontinuations 
Secondary- Phase I and Phase II
To assess the preliminary anti-tumor activity of 
IMCnyeso as monotherapy  
Phase I: BOR, PFS, and DoR by RECIST v1.1; 
OS
Phase II: PFS, and DoR by RECIST v1.1; OS 
To characterize the PK profile of IMCnyeso as 
monotherapy  
Serum PK parameters (eg, AUC, Cmax, Tmax, t1/2) 
after single and multiple doses
To evaluate the preliminary incidence of anti-
IMCnyeso antibody formation following multiple 
infusions of IMCnyeso 
Incidence of anti- IMCnyeso antibody formation 
and its impact on PK 
Exploratory 


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Objectives 
Endpoints 
  
  
AE = adverse event; AUC = area under the curve; BOR = best overall response; CD# = cluster of differentiation #; 
Cmax = maximum observed concentration; 
; 
 DoR = duration of response; ECG =electrocardiogram; 
; 
; 
; 
MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; 
; 
 PFS = progression-
free survival; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; 
; RP2D = recommended Phase II dose; SAE = serious adverse event; t1/  = terminal elimination half-life; 
 
; Tmax = time of maximum concentration; 
. 


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5
POPULATION SELECTION CRITERIA
5.1 Patient Population
To fulfill the study objectives, it is essential that appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  Patient eligibility should be reviewed and documented by an appropriate member of 
the site study team.  
5.2 Inclusion Criteria
Patients must meet all the following inclusion criteria to be eligible for inclusion in the study:
General
1.
Male or fHPDOHSDWLHQWVDJH\HDUVRIDJHat the time of informed consent
2.
Ability to understand and provide written informed consent prior to undergoing any study 
procedures
3.
Life expectancy of > 3 months as estimated by the Investigator
4.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at Screening
5.
In the opinion of the Investigator, all other relevant medical conditions must be 
well-managed and stable for at least 28 days prior to first administration of study drug
HLA and Tumor Antigen Testing
6.
HLA-A*02:01 positive as confirmed by the central laboratory
7.
NY-ESO-1 and/or LAGE-1A positive tumor confirmed by the central laboratory
Phase I: Disease Under Study and Prior Anti-Cancer Treatment
8.
Histologically confirmed diagnosis of advanced NSCLC, melanoma, urothelial carcinoma, 
or synovial sarcoma 
9.
Patients must be relapsed from, refractory to, or intolerant to all approved and available 
classes of therapy known to provide clinical benefit for their condition


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Phase II: Disease Under Study and Prior Anti-Cancer Treatment
10.
Histologically confirmed diagnosis of advanced NSCLC, urothelial carcinoma, or synovial 
sarcoma 
11.
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 
criteria (Section 13.1)
12.
A minimum of 10 patients enrolled in Phase II must have disease that is amenable to 
biopsy, and consent to provide biopsies during Screening and on treatment
13.
Patients will have received the following previous therapies. These therapies must have 
been given for unresectable / metastatic disease or given in the adjuvant setting if disease 
progression occurred during or within 6 months of completing adjuvant therapy
x
NSCLC — PD-1/PD-L1 inhibitor.  Patients with a genomic tumor aberration (eg, EGFR, 
ALK) that is targeted by Health Authority-approved agent(s) must be relapsed from, 
refractory to, or intolerant of relevant targeted agent(s)
x
Urothelial cancer — PD-1/PD-L1 inhibitor
x
Synovial sarcoma — at least 1 prior systemic chemotherapy regimen
Contraception
14.
Female patients should either be of non-childbearing potential or must agree to use highly 
effective methods of contraception from Screening until 6 months following administration 
of the last dose of study drug (see Section 6.14)
15.
Male patients must be surgically sterile or use double barrier contraception from enrollment 
through treatment and for 6 months following administration of the last dose of study drug
5.3 Exclusion Criteria
Patients with any of the following will not be included in the study:
Disease Under Study and Prior Anti-Cancer Treatment
1.
Presence of symptomatic or untreated central nervous system (CNS) metastases,
leptomeningeal disease, cord compression, or CNS metastases that require doses of 
corticosteroids within 3 weeks prior to the planned first administration of study drug.  
NOTE: Asymptomatic and adequately treated CNS metastases are not exclusionary
provided the patient is neurologically stable


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2.
Systemic anti-cancer therapy for the disease under study within 2 weeks of the planned first 
administration of study treatment.  For cytotoxic or immunotherapy agents that can present 
with major delayed toxicity (eg, anti-CTLA-4), a 4-week washout period is required
3.
Radiotherapy within 2 weeks of the planned first administration of study drug. NOTE:
palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally 
painful tumor mass, is not exclusionary
4.
Presence of National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Grade 2 toxicity due to prior cancer therapy (except Grade 2 alopecia, 
stable Grade 2 peripheral neuropathy, Grade 2 endocrine disorder [on stable replacement 
doses and without symptoms], Grade 2 hypophosphatemia [on appropriate replacement 
therapy] and Grade 2 ototoxicity) 
Laboratory Parameters
5.
Patient with any out-of-range laboratory values defined as shown below.  Hematology 
evaluations must be performed  7 days after any blood or blood product transfusion and 
 14 days after any dose of hematologic growth factor.
x
Creatinine clearance (calculated using Cockcroft-Gault formula or measured) 
< 40 mL/min
x
Total bilirubin > 1.5 × upper limit of normal (ULN); NOTE: for patients with Gilbert’s 
syndrome; exclude if total bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN)
x
Alanine aminotransferase (ALT) > 3 × ULN
x
Aspartate aminotransferase (AST) > 3 × ULN
x
Absolute neutrophil count (ANC) < 1.0 × 109/L
x
Absolute lymphocyte count < 0.5 × 109/L
x
Platelet count < 75 × 109/L
x
Hemoglobin < 8 g/dL
Medical History and Concomitant Medications
6.
Any active manifestations of autoimmune disease of the skin, including psoriasis and
scleroderma, or history of severe skin manifestation of graft versus host disease


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7.
Clinically significant cardiac disease or impaired cardiac function including any of the 
following:
x
Clinically significant and/or uncontrolled heart disease such as diagnosed congestive 
heart failure (New York Heart Association Class 2), uncontrolled hypertension, or 
clinically significant arrhythmia currently requiring medical treatment
x
Confirmed manually over-read QT interval corrected by Fredericia’s method (QTcF)
> 470 msec on Screening ECG or known history of congenital long QT syndrome
x
History of acute myocardial infarction or unstable angina pectoris < 6 months prior to 
planned first administration of study drug
8.
Active infection requiring systemic antibiotic therapy.  NOTE: Patients requiring systemic 
antibiotics for infection must have completed treatment with any IV antibiotics at least 
14 days before the planned first administration of study drug and any oral antibiotics at 
least 7 days before the planned first administration of study drug
9.
Known history of human immunodeficiency virus (HIV) infection.  Testing for HIV status 
is not necessary unless clinically indicated
10.
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as defined per 
institutional protocol.  Testing for HBV or HCV status is not necessary unless clinically 
indicated or the patient has a history of HBV or HCV infection
11.
Patients receiving systemic treatment with steroid therapy (ie, prednisone > 10 mg daily 
[QD] or the equivalent) or any other immunosuppressive medication at any dose level that 
could interfere with the action of the study drugs, in the opinion of the Principal 
Investigator
x
Treatment for well controlled and asymptomatic adrenal insufficiency is permitted
provided the patient has no history of adrenal crisis and replacement dosing is limited to 
SUHGQLVRQHPJ4'RUWKHHTXLYDOHQW
x
Local steroid therapies (eg, otic, ophthalmic, intra-articular, or inhaled medications) are 
acceptable
12.
Malignant disease other than that being treated in this study, with the following exceptions:
x
Malignancies that were treated curatively and have not recurred within 2 years prior to 
study treatment


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x
Completely resected basal cell and squamous cell skin cancers
x
Any malignancy considered to be indolent and that has never required therapy
x
Completely resected carcinoma in situ of any type
13.
Any medical condition that would, in the Investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures, or interpretation of study results
14.
Any major surgical procedure (as judged by the Principal Investigator) within 2 weeks of 
the planned first administration of study drug. NOTE: Minimally invasive procedures such 
as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion 
of a feeding tube are not considered major surgery and are not exclusionary
15.
Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as 
the state of a female after conception and until the termination of gestation)


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6
STUDY TREATMENTS AND ADMINISTRATION
6.1 IMCnyeso Study Treatment
IMCnyeso will be supplied by the Sponsor, Immunocore.
Dose and treatment schedules are described in Table 6-1 below.
Table 6-1:
Dose and Treatment Schedule
IMCnyeso will be supplied as a sterile, frozen solution, in individual, single-use glass vials at a 
concentration of 0.5 mg/mL.  Each vial is to be used for 1 dose / 1 patient.
The drug solution contains citrate (5.2 mM), phosphate (14.8 mM), trehalose 5% 
(weight/volume), mannitol 1% (weight/volume), and Tween-20 0.05% (weight/volume).  The 
frozen solution appears clear, colorless, or pale yellow when thawed and has a pH 6.0.
6.2 Treatment Regimen and In-Patient Hospitalization
Patients enrolled in this study will receive treatment with single-agent IMCnyeso dosed weekly
on Days 1, 8, 15, and 22 of each 4-week cycle.  All dosages prescribed and dispensed to patients 
and all dose changes during the study must be recorded on the Dosage Administration Record 
and electronic case report form (eCRF).
For each administration of study medication, a physician must be present at the site or 
immediately available to respond to emergencies.  Study sites will be instructed on the 
conservative management of symptoms associated with CRS (eg, hypotension), as described in 
Section 6.15.  Fully functional resuscitation equipment and medications to handle acute 
infusion-related emergencies (eg, anaphylaxis, CRS) must be available at each study site.
Patients will be hospitalized for 2 nights following the administration of the first dose (C1D1) of 
IMCnyeso and will remain at the site for overnight observation following administration of the 
second dose (C1D8). In addition, patients receiving intra-patient escalation (IPE) will be 
hospitalized overnight following the first three doses (C1D1, C1D8, and C1D15).  After 
reviewing safety, PK, and cytokine data from at least 3 patients enrolled at a given dose level, the 
SST may decide that 1 night of hospitalization is adequate after the first dose for subsequent 
Study
Treatments
Pharmaceutical Form and Route of 
Administration
Dose
Frequency and/or 
Regimen
IMCnyeso
Liquid in vial for intravenous infusion 
(single-use vials)
Dose determined by 
cohort level 
Every week 


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patients (with longer hospitalization if indicated). After Phase I is completed and the SST has 
reviewed all available relevant data for at least 6 patients at the RP2D, the SST may decide to
reduce the minimum required monitoring time during the Phase II portion of the study to no less 
than 8 hours post-end of infusion on C1D1, C1D8, and/or C1D15 (with longer hospitalization if 
clinically indicated). Patients who experience certain AEs may require additional in-patient 
monitoring as described in Section 6.15.
6.3 IMCnyeso Handling, Storage, and Preparation
IMCnyeso vials must be stored frozen below -60°C until ready for use.
When required, 1 vial per dose / 1 vial per patient should be thawed at room temperature or at 
2°C–8°C.  The pharmacy preparation involves the dilution of IMCnyeso using 50 mL or 100 mL 
0.9% (weight/volume) sodium chloride infusion bags to which human serum albumin (HSA) has 
been added at a specified concentration.  Due to the low IMCnyeso doses administered in this 
study, the dilution for administration may require the use of more than 1 infusion bag.  Detailed 
instructions for preparation of doses and provision of dilution bags and HSA will be provided in 
the Pharmacy Handling Instruction document.
The start time for the expiry calculation is the time the container closure integrity is breached.  
The prepared IV bag containing IMCnyeso may be stored at room temperature for up to 4 hours 
or at 2°C–8°C for up to 24 hours.  If refrigerated, 30 minutes should be allowed for equilibration 
to room temperature and total room temperature exposure, including equilibration and infusion 
must not exceed 4 hours.  
6.4 Study Drug Administration
For each patient, the first dose will be infused over 2 hours (±15 minutes); for dose levels 
 30 mcg; the first dose may be infused over 1 hour (±10 minutes).  If the first dose is well 
tolerated without *UDGH infusion and/or a hypersensitivity reaction, a given patient's 
subsequent infusion times may be reduced to 1 hour (±10 minutes) starting at C1D8, and further 
reduced to 30 minutes (±10 minutes) starting at C3D1 provided the above conditions continue to 
be met.  Investigators may prolong the infusion time for individual patients if medically 
indicated at any time.
The entire contents of the IV bag will be administered using an infusion pump.  A further 30 mL 
of 0.9% sodium chloride should be used to flush the line after the IMCnyeso solution has been 
infused.  The infusion rate should not be changed, unless necessary to manage acute reactions.  If 
the line is not flushed, this must be documented.  
The initial dosing of patients in the dose-escalation cohorts will be staggered, with at least a 
1-week interval between the first 2 patients at each dose level.  The IRS will be used to control 


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patient allocation to treatment and ensure the dosing intervals and cohort recruitment complies 
with the protocol.
Please refer to Section 6.12 for guidance regarding pre-medication and interruption of 
anti-hypertensive medications around the time of each dose.
6.5 Study Drug Compliance and Accountability
Study treatment will be administered to the patient at the study site by trained study staff.
Patient compliance with the prescribed regimen will be assured as all administrations will be 
performed by site staff under the supervision of the Study Investigator or his/her designee.
The Investigator or his/her designee must maintain accurate records of the receipt and dispensing 
of all study treatment according to local institutional drug accountability processes.  Drug 
accountability documentation will be reviewed by the Study Medical Monitor during site visits 
and at the completion of the study.
6.6 Drug Supply, Storage, and Disposal
Study supplies must be received by designated personnel at the study site, handled and stored 
safely and kept in a secured location where only the Investigator and designated Site personnel 
have access. 
Upon receipt, IMCnyeso vials should be recorded on the Drug Accountability documents and 
placed in a freezer below -60°C, as specified on the drug label.  The freezer used for storage 
should be monitored, alarmed and the Sponsor informed of any temperature excursions.  In the 
event of a temperature excursion any affected supplies should be quarantined, and the Sponsor 
contacted immediately.
All IMCnyeso supplies remaining at the end of the study (following appropriate drug 
accountability procedures) will be destroyed following approval from the Sponsor. This 
destruction will be performed per local institutional practice at the study site or at a third-party 
vendor, as appropriate.  All destruction of study medications must be documented appropriately.
6.7 Patient Numbering and Treatment Assignment
Patients are identified in the study by a 5-digit number that is assigned by the IRS at the time the 
patient is first consented for the study.  The 5-digits are made up of a 2-digit site identifier 
followed by a 3-digit sequential patient number suffix.  This number is retained throughout the 
patient’s participation in the study and ensures that each patient is numbered uniquely across the 
entire study database.


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6.8 Dose-limiting Toxicities Observation Period
The DLT observation period is defined in Section 6.10.2
6.9 Starting Dose Rationale
The rationale for the QW dosing regimen in this study are based on the proof-of-concept clinical 
study of tebentafusp where manageable toxicity was observed with QW dosing of tebentafusp, as 
well as single-agent anti-tumor activity in both uveal and cutaneous melanoma.  
IMCnyeso is a highly human-specific fusion protein.  Neither the anti-CD3 nor the TCR portions 
cross react with any of the standard toxicology species, as discussed in Section 1.3. Therefore, 
there is no relevant toxicology species to enable the setting of a starting dose using the 
conventional no adverse effect level (NOAEL) method.  In the absence of a relevant toxicology 
species, MABEL, with receptor occupancy calculations, was used to set a safe starting dose.  
Derivation of the first clinical dose using the MABEL is shown below. 
In vitro pharmacology assays measuring the efficacy of IMCnyeso against cancer cell lines were 
used to define the MABEL.  In these assays, human T cells were added to target cells with 
different concentrations of IMCnyeso to determine the effects of cytokine release and killing 
induced at the given concentrations of IMCnyeso.  The target cells used were HLA-A*02:01
positive and NY-ESO-1 positive cancer cells, which in the presence of IMCnyeso, induce the 
CD3 positive effector T cells in the PBMC population to both release IFN-Ȗ and kill the tumor 
cells.  In general, IFN-Ȗ release is observed at IMCnyeso concentrations that are lower than the 
concentrations required for the observation of target-cell killing.  Based on the killing assays and 
IFN-Ȗ release assays, the MABEL observed in the in vitro assays for IMCnyeso is 5 pM.  
The acceptable starting dose in the Phase I dose-escalation study is defined as the IV dose of
IMCnyeso with a predicted Cmax of serum at the MABEL (5 pM) and a receptor occupancy
between 10%–30% at Cmax.  The use of Cmax as the PK determinant of the starting dose 
prediction is based on the observed toxicity profile of the first ImmTAC in the clinic, 
tebentafusp, where it was observed that the related and more severe toxicities are observed in the 
immediate hours following dosing, when the concentration of tebentafusp was maximal.  These 
data suggest that toxicity is related to the maximal plasma concentration more than the overall 
exposure or the area under the curve (AUC).  
Thus, the determination of the starting dose is as follows: 
x
Given the observation of immediate rash and hypotension following administration of 
tebentafusp in patients, the appropriate volume of distribution (VD) of an ImmTAC 
would incorporate both the blood and tissue compartments.  A total VD of 8 L was 


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assumed for IMCnyeso based on the observed volume of distribution of tebentafusp in 
patients
x
The molecular weight of the IMCnyeso is 77 kDa; therefore, the expected concentration 
of IMCnyeso in the serum where a minimal biological effect (ie, < 5 pM) would occur is 
approximately 400 pg/mL
x
The PK data in C57BL/6 mice indicates that IMCnyeso displays linear kinetics upon IV 
bolus injection with a t1/2 of 2–3 hours, in accordance with that observed for tebentafusp
x
Assuming a VD of 8 L and an 80-kg patient, the absolute dose to achieve a Cmax of 
400 pg/mL is 3 mcg
x
With the KD (equilibrium dissociation constant) of 41 pM, the receptor occupancy (Saber, 
2016) is anticipated to be approximately 10%
6.10 Dose-Escalation Decision Making
Dosing will begin with the first cohort at the starting dose of 3 mcg QW (Table 6-2).  All doses 
administered to subsequent cohorts of patients will be determined by the SST and will be guided 
by the BLRM and will be subject to both the EWOC principle and the escalation rule.  
Dose-escalation decisions will be made by the SST, which will consist of the Study
Investigators, the Sponsor Medical Monitor, and a statistician.  For each cohort, dose escalation 
or de-escalation decisions will be based on the SST’s review of all relevant data available, from 
all dose levels evaluated in the ongoing study, including safety information, DLTs, all Grade 2 
toxicity data, PK, and pharmacodynamic data from evaluable patients (as defined in 
Section 6.10.2).  The data and BLRM dose recommendations will be discussed and agreed upon 
during the dose-escalation teleconference (DETC), and all decisions will be documented in the 
meeting minutes and shared with all participating Principal Investigators.  
If toxicity resolves following appropriate management and provided treatment discontinuation 
criteria are not met (see Section 6.16), patients experiencing DLTs may continue treatment with 
IMCnyeso only after agreement with the Sponsor Medical Monitor.  With each dose cohort in 
Phase I, determination of the next dose to be tested in the dose escalation will be guided by the 
BLRM.  Decision making will be based on all evaluable patients in the dose-determining set 
(DDS) at each cohort level (see Section 6.10.1).  At each decision point, the BLRM provides an 
estimate of all dose levels of IMCnyeso that do not exceed the MTD and incorporates all DLT 
information at all dose levels for this estimation (see Section 9).  In general, the next dose will 
have the highest chance that the true DLT rate will fall in the target interval (16%–33%) and will 
always satisfy the EWOC principle.  In all cases, the dose for the next cohort will not exceed a 
3.34-fold increase from the previous dose.  Smaller dose increases may be recommended by the 


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Investigators and Sponsor upon consideration of all available clinical data.  Further details of the 
BLRM including additional simulated escalation pathways are provided in Section 13.3.
The estimated dose levels to be tested in this study (in the scenario that no DLT are reported) are 
shown in Table 6-2.  Actual doses will be determined using the BLRM and must be agreed upon 
by the SST.
Table 6-2:
Example IMCnyeso Dose Levels for Phase I Dose Escalation
Dose Level
Estimated IMCnyeso Dose Level
Planned Enrollment
1 (starting dose)
3 mcg
2–6
2
10 mcg
2–6
3
30 mcg
3–6
4
100 mcg
3–6
5
190 mcg
3–6
To better understand the safety, tolerability, and PK profile of single-agent IMCnyeso, additional 
cohorts of patients may be enrolled at preceding dose levels or intermediate dose levels, before 
or in parallel, while proceeding with further dose escalation.  The outcome from these cohorts 
will be included in the BLRM.
If the first 2 patients in a previously untested dose level experience a DLT, additional enrollment 
in that cohort will stop, the BLRM will be updated with this new information, and the SST will 
evaluate the available safety, PK, and pharmacodynamic data.  By incorporating information 
gained at the preceding dose levels and provided the BLRM predicts that the risk of excessive 
toxicity remains below 25% (EWOC), additional patients may be enrolled at this dose level or a 
lower dose level as agreed upon by the SST.
6.10.1 Intra-Patient Escalation
A recent FDA review concluded that incorporation of a step dose / IPE can result in better 
patient tolerance of higher doses of CD3 bispecific molecules (Saber, 2017) due to a 
phenomenon of induced tolerance or tachyphylaxis.  IPE regimens are used for the related 
ImmTAC molecule tebentafusp as well as the approved CD3 bispecific blinatumomab.  
If the severity of cytokine-mediated AEs tend to become less severe following the initial doses of 
study drug using a fixed-dose regimen, the SST may initiate a 1-step IPE regimen, in which a 
lower dose is given on Cycle 1 Day 1 and a higher (target) dose is given on Cycle 1 Day 8 and 
beyond, as shown in Figure 6-1.  


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Figure 6-1:
Schematic Illustration of a 1-Step IPE Regimen
Rules for the 1-step IPE regimen are as follows:
x
The initial target dose level must be a permitted escalation step based on BLRM output
and the consensus of the SST
x
The initial target dose level must not exceed the fixed-dose MTD (if established)
x
The C1D1 dose level must be at least one dose level below the initial target dose, and 
must EHDGRVHOHYHOWKDWKDVEHHQHYDOXDWHGLQSDWLHQWVXVLQJDIL[HG-dose regimen, 
with a decision to escalate based on the BLRM output and SST review of all available 
relevant data.
x
Escalation of the target dose in subsequent cohorts may proceed as in the main dose
escalation: 
o
Separate MTD/RP2D may be identified using fixed-dose and 1-step IPE regimens
o
DLT will be attributed to the dose level of the most recently administered dose prior 
to onset of the DLT (eg, a DLT with onset on C1D4 would be attributed to the C1D1 
dose level, while a DLT with onset on C1D10 would be associated to the C1D8 dose 
level)
x
The dose level for C1D1 remains fixed for all subsequent cohorts
x
Patients receiving IPE must receive the C1D1 dose prior to receiving the target dose 
x
If a 1-step IPE regimen is evaluated in Phase I, it may be selected for further evaluation
in Phase II
Experience with other CD3 bispecific molecules (including tebentafusp and blinatumomab) 
indicates that multi-step IPE may mitigate the risk of a cytokine-mediated AE more effectively 
than a 1-step IPE or fixed-dose regimen.  If further mitigation of cytokine-mediated events is 
desired, the SST may decide to evaluate a two-step IPE regimen, in which an intermediate dose 
is given on Cycle 1 Day 8, as shown in Figure 6-2.
Cycle 1 Day 1:
C1D1 Dose Level
Cycle 1 Day 8:
Target Dose Level
Cycle n Day #:
Target Dose Level
Cycle 1 Day 15:
Target Dose Level


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Figure 6-2:
Schematic Illustration of a 2-Step IPE Regimen
Rules for the 2-step IPE regimen are as follows:
x
The initial target dose level must be a permitted escalation step based on BLRM output
and the consensus of the SST
x
The initial target dose level must not exceed the 1-step dose-escalation MTD (if 
established)
x
The C1D8 dose level must be at least one dose level below the initial target dose, and 
PXVWEHDGRVHOHYHOWKDWKDVEHHQHYDOXDWHGLQSDWLHQWVXVLQJDIL[HG-dose or 1-step 
IPE regimen, with a decision to escalate based on the BLRM output and SST review of 
all available relevant data
x
Escalation of the target dose in subsequent cohorts may proceed as in the main and 1-step
dose escalation: 
o
Separate MTD/RP2D may be identified using fixed-dose, 1-step IPE, and 2-step IPE
regimens
o
DLT will be attributed to the dose level of the most recently administered dose prior 
to onset of the DLT (eg, a DLT with onset on C1D4 would be attributed to the C1D1 
dose level, while a DLT with onset on C1D10 would be associated to the C1D8 dose 
level)
x
The dose levels for C1D1 and C1D8 remain fixed for all subsequent cohorts
x
Patients receiving 2-step IPE must receive the C1D1 and C1D8 doses prior to receiving
the target dose
x
If a 2-step IPE regimen is evaluated in Phase I, it may be selected for further evaluation
in Phase II
An example of how IPE might be implemented is shown in Figure 6-3.
Cycle 1 Day 1:
C1D1 Dose Level
Cycle 1 Day 8:
C1D8 Dose Level
Cycle n Day #:
Target Dose Level
Cycle 1 Day 15:
Target Dose Level


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Figure 6-3:
Representative Escalation Path Incorporating IPE
IPE = intra-patient escalation.  
Actual dose levels will be determined using BLRM and must be approved by SST.  In this scenario, after 3 patients 
were enrolled in Cohort 4 and completed DLT evaluation, the recommended next dose per BLRM was 195 mcg. 
The SST determined that the 195 mcg dose would be better tolerated using a 2-step escalation regimen, and so 
Cohort 5 was opened with a dose of 30 mcg on C1D1, 100 mcg on C1D8, and 195 mcg as the target dose (weekly 
starting on C1D15).
In addition, a patient who is enrolled in a lower dose cohort may move to a higher dose cohort 
once all the following criteria are met:
x
The patient has completed at least 3 cycles of treatment 
x
The patient did not experience any DLT or any  Grade 3 treatment-related toxicity
x
The patient does not have any ongoing  Grade 2 treatment-related toxicity
x
The higher dose cohort has completed SST review with a decision to escalate or was 
determined to be the MTD/RP2D
6.10.2 Definition of DLT-Evaluable Patients for the Dose-Determining Set
Patients are considered as DLT-evaluable if they meet one of the following criteria:
x
Experienced a DLT during the 28-day DLT evaluation period, OR
x
Did not experience a DLT during the 28-day DLT evaluation period, received at least 3
of the 4 planned doses of IMCnyeso (including at least 2 doses at the target dose level), 
and were REVHUYHGIRUGD\VIROORZLQJWKHILUVWGRVH
Cohort 1:
Fixed Dose
3 mcg
Cohort 2:
Fixed Dose
10 mcg
Cohort 3:
Fixed Dose
30 mcg
Cohort 5:
2-Step IPE
30 / 100 / 195 mcg
Cohort 4:
Fixed Dose
100 mcg


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6.11 Definition of Maximum Tolerated Dose and Recommended Phase II Dose
The MTD will be determined if the following conditions are met:
1.
At least 6 patients have been treated at this dose and associated treatment regimen (ie, 
fixed-dose, 1-step IPE, or 2-step IPE).
2.
The dose has the highest posterior probability that the true DLT rate is in the target interval 
for toxicity (16%–33%), as predicted by the BLRM.  The interval boundaries of 16% and 
33% are chosen to be consistent with the traditional 3+3 design toxicity boundary (ie, 1/6 
and 1/3).
3.
The dose satisfies the EWOC principle (the probability that the DLT rate lies within the 
excessive toxicity or the unacceptable toxicity window is less than 25%).
The RP2D will be defined as the dose and associated treatment regimen selected for further 
evaluation in Phase II by the SST. The RP2D will be determined from a synthesis of all data 
available, including safety, tolerability, PK, pharmacodynamics, and preliminary anti-tumor 
activity observations from Phase I.  The RP2D must not exceed the MTD as determined by the 
BLRM. A minimum of 6 patients will be treated at the RP2D in Phase I and monitored through 
the DLT evaluation period before enrollment in Phase II may begin.
During Phase II, following enrollment of at least 12 subjects, if the observed rate of Grade 3 
and/or Grade 4 toxicity considered related to IMCnyeso and meeting the definition of DLT is 
> 30%, a safety teleconference will be convened with the SST to determine if the cohorts should 
continue enrollment.
6.12 Definitions of Dose-Limiting Toxicity
A DLT is defined as an AE or abnormal laboratory value assessed as having a suspected 
relationship to study drug that occurs within the DLT evaluation period (Section 6.10.2), is 
unrelated to disease, disease progression, inter-current illness, or concomitant medications, and 
meets any of the criteria included in Table 6-3.  Any death not clearly due to the underlying 
disease or extraneous causes will be considered a DLT.  Other clinically significant toxicities, 
including a single event or multiple occurrences of the same event that lead to a dosing delay or
interruption lasting > 7 days in Cycle 1, may be considered a DLT by the SST, even if not 
 Grade 3.  Events meeting DLT criteria but occurring outside the DLT evaluation period may 
also be considered DLT by the SST. In the absence of clinically significant signs or symptoms, 
abnormal laboratory values that potentially meet DLT criteria must be confirmed by re-testing at 
least 24 hours after the initial observation.


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Cytokine release syndrome will be graded based on the ASTCT 2019 criteria in Section 13.1.  
NCI CTCAE version 4.03 will be used for all other grading.  The Investigator must notify the 
Sponsor within 24 hours of any DLT (additional events requiring reporting within 24 hours are 
listed in Section 8.5).
Guidance for toxicity management is in Section 6.15.
Table 6-3:
Criteria for Defining Dose-Limiting Toxicities
DLTs include Grade 3 AE occurring during the DLT evaluation period, with a suspected 
relationship to study drug, with the following modifications:
Hematology
Grade 4 neutropenia persisting > 5 days after onset or associated with infection 
is a DLT 
*UDGHfebrile neutropenia is a DLT 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with 
 Grade 3 bleeding is a DLT
Grade 4 anemia is a DLT 
*UDGHlymphopenia in the presence of an infection indicating clinical
significance is a DLT
Hepatic and 
pancreatic 
Grade elevated total bilirubin (> 2 × ULN) with concurrent GUDGH
elevated ALT and/or AST (> 3 × ULN), with no clear alternate etiology 
(eg, biliary obstruction with elevated alkaline phosphatase), is a DLT
Grade 3 isolated ALT and/or AST (> 5-8 × ULN) elevation or Grade 3 isolated 
bilirubin elevation (> 3-5 × ULN) that does not resolve to  Grade 1 within 
14 days of onset is a DLT
 Grade 3 isolated ALT and/or AST (> 8 × ULN) elevation or *UDGH
isolated bilirubin (> 5 × ULN) elevation is a DLT
Grade 3 amylase and/or lipase elevation, with associated clinical signs, 
symptoms, or radiographic evidence of pancreatitis, is a DLT
Gastrointestinal
Grade 3 nausea, vomiting or diarrhea persisting for > 3 days after onset, despite 
optimal therapy, is a DLT
Hypotension
Grade 3 hypotension that does not resolve to  Grade 1 within 6 hours of onset,
despite optimal therapy, is a DLT
Grade 4 hypotension of any duration and with any management is a DLT 
Hypertension
Grade 3 hypertension (s\VWROLF%3PP+JRUGLDVWROLF%3PP+J)
persisting > 2 days after onset, despite treatment, is a DLT
Grade 4 hypertension of any duration is a DLT
Infection
Grade 3 infection or fever in the absence of neutropenia that persists > 7 days 
after onset is a DLT
Grade 4 infection of any duration is a DLT


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DLTs include Grade 3 AE occurring during the DLT evaluation period, with a suspected 
relationship to study drug, with the following modifications:
Tumor Flare
Grade 3 inflammatory reaction at a tumor site associated with local anti-tumor 
immune response that does not resolve to Grade 2 within 7 days after onset is 
a DLT
Electrolyte 
Abnormalities
Grade 3 electrolyte abnormalities that do not resolve to Grade 1 within 3 days
after onset, despite optimal medical management, are DLTs
Grade 4 electrolyte abnormality of any duration is a DLT
Skin toxicity
Grade 3 rash and/or pruritis that persists > 7 days after onset, despite optimal 
medical management, is a DLT
Grade 4 cutaneous toxicity of any duration is a DLT
Fatigue
*UDGHfatigue that persists > 4 days after onset is a DLT
Infusion-related 
reaction / 
hypersensitivity / 
anaphylaxis
Grade 3 infusion-related reaction that does not resolve to  Grade 1 within
6 hours of onset, despite appropriate medical management, is a DLT
Grade 4 infusion reaction is a DLT
Cytokine release 
syndrome 
Grade 3 cytokine release syndrome that does not resolves to Grade 2 within
6 hours after onset, despite optimal medical management (eg, corticosteroid 
dosing), is a DLT
Grade 4 cytokine release syndrome of any duration is a DLT
ALT = alanine aminotransferase; AST = aspartate aminotransferase; DLT = dose-limiting toxicity; SST = Study 
Safety Team; ULN = upper limit of normal.
6.13 Concomitant Therapy
6.13.1 Permitted Concomitant Therapy
In general, concomitant medications and therapies deemed necessary for the supportive care and 
safety of the patient are allowed.  Examples include anti-diarrheal medications, anti-emetics,
electrolyte supplementation, intravenous fluids, hematologic growth factors, or blood 
transfusions. However, hematologic growth factors and blood transfusions should only be 
administered starting with Cycle 2 to avoid confounding interpretation of potential drug-related 
toxicities during the DLT evaluation period.
Patients are required to notify the investigational site staff about any new medications, herbal 
remedies, or dietary supplements taken after the start of the study treatment, regardless of 
treatment duration.  All concomitant medications and significant non-drug therapies (including 
physical therapy, herbal or natural medications and blood transfusions) administered during the 
study must be listed on the Concomitant Medications Log or the Surgical and Medical 
Procedures log in the eCRF.


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IV hydration required to manage toxicity associated with the study medications (eg,
hypotension) should be recorded in the Concomitant Medications Log in the eCRF.  
Palliative radiation therapy to non-target lesions is permitted during the study after consultation 
with the Sponsor Medical Monitor and should be recorded in the eCRF as concomitant therapy.  
6.13.2 Concomitant Therapy Requiring Caution
Anti-coagulant therapy is permitted. International normalized ratio should be monitored as 
clinically indicated per the Investigator’s discretion. Ongoing anti-coagulant therapy should be 
temporarily discontinued to allow tumor biopsy according to institutional guidelines. Recent 
hospitalizations that required low dose heparin for deep vein thrombosis prophylaxis are not a 
contraindication.
Anti-hypertensive drugs are allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, anti-hypertensives should 
not be administered 24 hours before and 24 hours after IMCnyeso administration in the first 
6 weeks of treatment.  Thereafter, anti-hypertensives can be reintroduced at the discretion of the 
Principal Investigator.  Appropriate management of patients with more severe hypertension, 
receiving medications that may cause rebound hypertension when abruptly discontinued, or on 
multiple blood pressure medications, should be discussed with the Sponsor Medical Monitor
prior to making any adjustments during the first 6 weeks of treatment.
Non-live vaccines are allowed but are not to be administered within 14 days before, and 28 days
after, the first dose of IMCnyeso. Following completion of the first treatment cycle, non-live 
vaccines should not be given within 24 hours before or after IMCnyeso administration.
6.13.3 Prohibited Concomitant Therapy
During study treatment, patients may not receive other investigational drugs, agents, devices, 
chemotherapy, or any other systemic therapies that may be active against the cancer under study.  
Additionally, no other therapeutic monoclonal antibodies (excepting denosumab) and no 
immunosuppressive medication may be administered to patients in this study (except as noted in
Exclusion Criterion 11 and Section 6.15).  
While systemic corticosteroid therapy may interfere with the mechanism of action of the study 
medications, its use is permitted/recommended in the following settings: 
x
Pre-medication for known allergy to contrast reagents
x
To manage toxicities (eg, infusion reactions, hypotension not resolving with fluid 
support) as noted in Section 6.15


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x
Replacement-dose steroids LHSUHGQLVRQHPJ4'RUHTXLYDOHQW in the setting of 
adrenal insufficiency (patients with a pre-existing history of adrenal crisis are excluded 
from study participation; see Exclusion Criterion 11)
x
Based on the emerging safety profile of IMCnyeso, the SST may decide to recommend a 
standard pre-treatment regimen (which may include antihistamine, acetaminophen, and/or 
corticosteroid) 
Any additional uses of systemic corticosteroid therapy during the study should be discussed with 
the Sponsor Medical Monitor.
Live or attenuated vaccines are prohibited from 28 days prior to the first dose of IMCnyeso until 
30 days after the last dose of IMCnyeso.
6.14 Contraception
6.14.1 Contraception in Females
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, may be included in the study provided they are using highly effective methods of 
contraception during dosing and for 6 months after the last dose of IMCnyeso.
Highly effective contraception methods include the following:
x
Total abstinence from sexual relations for the duration of the treatment when applicable 
to the lifestyle of the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal
and post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.
x
Female sterilization (surgical bilateral oophorectomy with or without hysterectomy) or 
tubal ligation at least 6 weeks before taking study treatment.  In case of oophorectomy 
alone, this applies only when the reproductive status of the woman has been confirmed 
by follow-up hormone level assessment.
x
Male sterilization (at least 6 months prior to Screening).  For female patients on the study 
the vasectomized male partner should be the sole partner for that patient.
x
Use of oral, injected, implanted, intravaginal, or transdermal hormonal methods of 
contraception (either estrogen and progestogen containing or progestogen-only) 
associated with inhibition of ovulation that have comparable efficacy (failure rate < 1%), 
for example hormone vaginal ring or transdermal hormone contraception.


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x
Placement of an intrauterine device (IUD) or intrauterine system (IUS).
When using oral contraception, women should have been stable and on the same oral 
contraceptive pill for a minimum of 3 months before the start of study treatment.
Women are considered post-menopausal and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age 
appropriate and history of vasomotor symptoms), or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or have had tubal ligation at least 6 weeks prior to study 
treatment.  In the case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow-up hormone level assessment is she considered not of childbearing 
potential.
6.14.2 Contraception in Males
Male patients must be surgically sterile or agree to use double barrier contraception from 
Screening to 6 months after the last dose of IMCnyeso.
6.15 Management of Adverse Reactions
Guidelines for management of AEs and dose modifications are presented in Table 6-4.
Grading of CRS is based on the American Society for Transplantation and Cellular Therapy 
(ASTCT) 2019 consensus grading system shown in Section 13.1.  All other AE are graded per 
NCI CTCAE v4.03.
Appropriate clinical experts should be consulted as deemed necessary in the judgement of the 
Principal Investigator for any AEs observed during the trial.  
6.15.1 IMCnyeso Dose Reductions
Recommended dose reductions of IMCnyeso for observed toxicity should be as follows:  
x
All dose modifications should be based on the worst preceding toxicity  
x
The dose will be reduced  1 dose level from the initial prescribed dose for any toxicity 
requiring dose reduction, as per toxicity management guidelines. NOTE: Following a 
single dose-reduction, if there is no recurrence of toxicity with subsequent doses of 
IMCnyeso, return to the initial prescribed dose is permitted following discussion with the 
Sponsor Medical Monitor
x
If toxicity recurs, the dose may be reduced again, by an additional  1 dose level


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x
Patients who require more than 2 dose reductions of IMCnyeso should permanently 
discontinue treatment  
6.15.2 IMCnyeso Dose Interruptions
One to two doses of IMCnyeso may be omitted to permit resolution of treatment-related toxicity. 
If a patient who misses more than 2 consecutive doses due to a treatment-related toxicity is 
experiencing clinical benefit, and in the opinion of the Investigator, the benefit/risk profile favors 
continued treatment, then treatment may be restarted after discussion with the Sponsor Medical 
Monitor. If more than 3 consecutive doses of IMCnyeso are not administered due to 
treatment-related toxicity or if a > 21-day treatment interruption occurs, the default position is 
that the patient must then permanently discontinue study treatment. 
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value must be followed up at least once a week (or more frequently if 
clinically indicated) for 4 weeks, and at approximately 4-week intervals thereafter, until 
resolution or stabilization of the event, whichever occurs first.  


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Table 6-4:
Recommended Management and Dose Modifications by Toxicity Grade and Type
Grade
Recommended Toxicity Management
Dose Modifications
Cytokine Release Syndrome (occurring at least 1 hour after the start of infusion) - refer to modified grading system in Table 13-1
Grade 1
If not already hospitalized, admit for close observation (eg,
monitor vital signs hourly); implement supportive care per 
institutional standards.  Provide anti-pyretics and analgesics as 
needed; monitor fluid balance (IV fluid support as indicated).  
Consider prophylactic electrolyte supplementation for patients 
receiving IV fluids with low-normal serum phosphorus or 
magnesium. 
Serum should be collected for central lab cytokine assessments 
(see Section 7.4.6.4).
May continue dosing.
Grade 2
Notify the Sponsor within 24 hours of onset.
As above for Grade 1; additionally, monitor with continuous 
cardiac telemetry and pulse oximetry and follow organ function 
closely.  
If the patient experiences dyspnea, consider supportive 
measures such as supplemental oxygen.  
If the patient experiences hypotension, consider bolus IV fluids 
at a rate of approximately 1 L crystalloid per hour.  If the 
patient is asymptomatic and non-orthostatic after infusion of 
2 to 3 L administered over 2 to 3 hours, consider transition to 
maintenance IV fluids until resolved. If hypotension does not 
respond to fluids, consider systemic corticosteroids (eg, 
methylprednisolone 1 mg/kg IV twice daily).  
Do not administer next scheduled dose of IMCnyeso until 
CRS has resolved.
x
Overnight hospitalization is required for the scheduled
next dose of IMCnyeso 


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Grade
Recommended Toxicity Management
Dose Modifications
Grade 3 
As above for Grade 2; additionally, systemic treatment with 
immunosuppressive agents (eg, methylprednisolone 
2 mg/kg/day or equivalent and/or tocilizumab 8 mg/kg IV, not 
to exceed 800 mg/infusion) per institutional guidelines must be 
administered.  Escalate level of care (eg, intensive care unit) as 
indicated.  
For persistent hypotension, treat with a single vasopressor (with 
or without vasopressin).
For hypoxia, provide oxygen with a high-flow device.
Do not administer next scheduled dose of IMCnyeso until 
CRS has resolved.
x
Treatment may continue provided all the following 
conditions are met:
o
Overnight hospitalization is required for the next 
scheduled dose of IMCnyeso 
o
Reduce the IMCnyeso dose by 1 dose level
o
Consider pre-medication (eg, methylprednisolone 
1 mg/kg IV) < 60 min prior to the start of the next 
scheduled infusion
o
,IWKHSDWLHQWH[SHULHQFHV*UDGH&56IROORZLQJ
the first reduced dose, then the next dose of 
IMCnyeso should be administered at the reduced 
dose without pre-medication, but must be 
hospitalized overnight for observation 
x
Any patient that experiences recurrence of Grade 3 CRS 
following re-treatment should permanently discontinue 
study treatment unless the Investigator believes the 
overall benefit-risk favors continued treatment and 
following discussion and agreement with the Sponsor 
Medical Monitor
Grade 4
As above for Grade 3; additionally, consider treating 
hypotension with multiple vasopressors, for hypoxia provide 
oxygen using a positive-pressure device, and consider other 
immunosuppressive agents for persistent or recurrent signs 
and/or symptoms as indicated (eg, infliximab or mycophenolate 
mofetil).
Study medication must be permanently discontinued.


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Grade
Recommended Toxicity Management
Dose Modifications
Rash and/or Pruritus
Grade 1
If symptomatic, consider the systemic antihistamine regimen 
(see Grade 2 guidance below). 
May continue dosing.
Grade 2
Treat according to institutional practice and/or implement 
guidance below.  Use systemic management and/or local skin 
management as indicated by symptoms. With bullous formation 
or blistering rashes, consider dermatology consultation to rule 
out other causes (eg, bullous pemphigoid).  Oral or topical 
corticosteroids can be used.  If bullous formation or blistering 
recur, consult Sponsor Medical Monitor for guidance.
Systemic antihistamine (anti-pruritic) regimens:
Recommended as first-line management of pruritus.  Use 
non-sedating, long-acting antihistamines (cetirizine, 10 mg oral 
or equivalent). If a sedating antihistamine is preferred (eg, 
evening dosing) consider diphenhydramine 25 mg oral or IV.  
The use of sedating antihistamines should be minimized in 
patients with co-morbid pulmonary pathology including 
pulmonary metastases or underlying inflammatory airway 
disease such as COPD or asthma.
Topical corticosteroid regimens;
When involved areas include face and/or intertriginous areas 
(including genitalia) recommend a low potency corticosteroid 
or antihistamine creams.  For other body areas (ie, trunk and 
extremities), recommend a low to medium potency 
corticosteroid cream. Consider spray preparation for ease of 
application on trunk.
May continue dosing.


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Grade
Recommended Toxicity Management
Dose Modifications
Grade 3
As above for Grade 2; additionally, oral corticosteroids can be 
considered in cases of symptomatic rash that do not respond to 
systemic antihistamine and topical corticosteroids.  
Prednisolone 20-40 mg/day (or equivalent) should be given for 
as short a duration as clinically feasible to facilitate symptom 
resolution while minimizing any potential detrimental effect on 
efficacy.  
In addition, montelukast 10 mg by mouth can be given to 
patients with pruritus refractory to antihistamine and local 
corticosteroid treatments.  Patients with persistent, severe 
symptoms who fail to respond to the addition of montelukast 
can be treated with a single hydrocortisone 50 mg IV or 
prednisone 20 mg by mouth after discussion with the Sponsor 
Medical Monitor.
Consider performing a skin punch biopsy (see Section 7.4.6.3).
Do not administer IMCnyeso until rash / pruritus has 
improved WR Grade 1.
x
If Grade 3 rash / pruritus resolves WR*UDGHLQ
< 7 days, treatment may continue at same dose level.
x
If Grade 3 rash / pruritus resolves WR*UDGHLQ–21 
days, restart with 1 dose-level reduction in IMCnyeso. 
x
If the Grade 3 rash / pruritus does not resolve within 
21 days, study medication must be permanently 
discontinued.
Grade 4
As above for Grade 3; additionally, consultation with a 
dermatologist is recommended.
Study medication must be permanently discontinued. 
Infusion-related Reactions (occurring within 1 hour of starting the infusion) / Anaphylaxis 
All grades
Acute allergic reactions should be treated as needed using 
institutional guidelines. In the event of anaphylactic / 
anaphylactoid reactions, any therapy needed to restore normal 
cardiopulmonary status should be implemented immediately. 
Grade 1
Monitor vital signs at least approximately every 15 minutes 
through EOI. 
May continue the infusion


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Grade
Recommended Toxicity Management
Dose Modifications
Grade 2
Treat according to institutional practice.  Provide all supportive 
measures as indicated.  Provide supplemental oxygen and 
fluids, as needed. 
Monitor vital signs (eg, blood pressure, pulse, and temperature), 
pulse oximetry, and continuous cardiac telemetry (if clinically 
indicated) until resolution.  Administer medications, 
supplemental oxygen, and/or IV fluids for symptomatic relief as 
needed.  Antihistamines, acetaminophen (paracetamol), 
bronchodilator therapy, or corticosteroids (eg, 
methylprednisolone 1 mg/kg IV or equivalent) may be 
administered as needed, at the discretion of the Investigator.
Stop infusion and keep IV line open. 
x
If a Grade 2 IRR resolves within 4 hours of onset with 
medical management, may restart the infusion provided 
all the following conditions are met:
o
Oral pre-medications (eg, 1000 mg of 
acetaminophen [paracetamol], 50–100 mg 
diphenhydramine hydrochloride or alternative 
antihistamine) are administered within 60 minutes 
prior to re-starting the infusion, and prior to the next 
scheduled dose of IMCnyeso
o
The restarted infusion rate does not exceed 50% of 
previous rate 
o
Vital signs are monitored at least approximately 
every 15 minutes until the infusion is completed
x
If Grade 2 IRR resolves > 4 hours after onset, or if 
Grade 2 IRR recurs after re-starting the infusion at a 
reduced rate and despite oral pre-medication, do not 
resume infusion. Treatment may continue at the next 
scheduled dose. Consider oral pre-medications for 
subsequent IMCnyeso doses (eg, 1000 mg of 
acetaminophen [paracetamol] and 50–100 mg 
diphenhydramine hydrochloride or alternative 
antihistamine within 60 minutes prior to the start of 
infusion).


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Grade
Recommended Toxicity Management
Dose Modifications
Grade 3
As above for Grade 2; additionally, consider systemic 
immunosuppressive agents (eg, methylprednisolone 1 mg/kg IV 
twice daily) and high-dose or multiple vasopressors as clinically 
indicated per institutional standards.
Discontinue infusion immediately. 
x
If a Grade 3 IRR LPSURYHVWR Grade 1 within 6 hours 
of onset with medical management, treatment may 
continue with the next scheduled dose of IMCnyeso; if 
resolution requires > 6 hours, treatment may continue 
ZLWKDGRVH-level reduction
x
The next scheduled dose is to be delivered using a rate 
of infusion not to exceed 50% of rate used when the IRR 
occurred 
x
Oral pre-medications (eg, 1000 mg of acetaminophen 
[paracetamol], 50–100 mg diphenhydramine 
hydrochloride or alternative antihistamine) are to be 
given within 60 minutes prior to the next scheduled dose 
of IMCnyeso
x
If Grade 3 IRR recurs after re-starting IMCnyeso 
treatment, dosing should be permanently discontinued 
unless the Investigator believes the overall benefit-risk 
favors continued treatment and following discussion and 
agreement with the Sponsor Medical Monitor
Grade 4
Treat as above for Grade 3 infusion-related reaction.
Permanently discontinue study treatment
Hepatic Function Abnormalities
Grade 2
Regular monitoring of liver function tests until improving or 
resolved. Evaluate concurrent medications for agents that may 
prolong or exacerbate laboratory abnormalities.  Consider IV 
corticosteroid therapy (eg, hydrocortisone 100 mg or the 
equivalent) if not improving within 72 hours.
May continue dosing.  


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Grade
Recommended Toxicity Management
Dose Modifications
Grade 3
Notify the Sponsor within 24 hours.
As above for Grade 2; additionally, consider further testing to 
assess liver synthetic function and consider hepatology consult 
to advise on management and additional workup. Consider IV 
corticosteroid therapy (eg, hydrocortisone 100 mg or 
equivalent) per institutional guidelines if not resolving within 
48 to 72 hours.
Do not administer IMCnyeso until LFTs have improved 
WR*UDGHDQGfollowing discussion and agreement
with the Sponsor Medical Monitor.
x
For isolated ALT and/or AST elevation (>5-8 × ULN) or 
isolated total bilirubin elevation (>3-5 × ULN) that 
UHVROYHVWR*UDGH within 7 days, dosing at the current 
dose level may resume
x
For isolated ALT and/or AST elevation (>5-8 × ULN) or 
isolated total bilirubin elevation (>3-5 × ULN) that 
requires > 7 days to resolve, dosing may resume with 
 1 dose-level reduction in IMCnyeso
x
For isolated ALT and/or AST elevation (>8 × ULN) or 
isolated total bilirubin elevation (>5 × ULN) that 
UHVROYHVWR*UDGHGRVLQJVKRXOGEHSHUPDQHQWO\
discontinued unless the Investigator believes the overall 
benefit-risk favors continued treatment, in which case 
dosing may resume with 1 dose-level reduction in 
IMCnyeso
Grade 4
As above for Grade 3; additionally, promptly consider IV 
corticosteroid therapy (eg, hydrocortisone 100 mg or 
equivalent) per institutional guidelines if not resolving within 
24 hours. Perform supplementary testing to assess liver 
synthetic function and obtain hepatology consult to advise on 
management and additional workup.
Study medication must be permanently discontinued. 


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Grade
Recommended Toxicity Management
Dose Modifications
Vomiting
Grade 2
Anti-emetic therapy as per institutional standard.  IV fluids, 
electrolyte supplementation, and other supportive measures for 
additional adverse events as needed.  
May continue dosing.  
Grade 3
Anti-emetic therapy as per institutional standard.  IV fluid 
support and other supportive measures for additional adverse 
events.  
If Grade 3 vomiting persists > 3 days, do not administer 
IMCnyeso until vomiting has LPSURYHGWR*UDGH
x
,I*UDGHYRPLWLQJUHVROYHVWR*UDGHZLWKLQGD\V
of onset, dosing at the current dose level may continue at 
the next scheduled dose
x
If Grade 3 vomiting requires > 3 days to resolve to 
 Grade 1, a 1 dose-level reduction is required for the 
next scheduled dose of IMCnyeso
Grade 4
As above for Grade 3.
Do not administer IMCnyeso until vomiting has 
LPSURYHGWR*UDGH
A 1 dose-level reduction is required for the next scheduled 
dose of IMCnyeso
Other Adverse Events
Grade 1 or 2
Manage according to institutional practice. Monitor as clinically 
indicated for potential worsening and assess whether more 
intense medical intervention is indicated.
May continue dosing.
Grade 3 or 4
Treat according to institutional practice. For immune-related 
AE, consider treatment with corticosteroids.  Consult Sponsor 
Medical Monitor for further guidance as needed.
Consider not administering IMCnyeso until toxicity has
LPSURYHGWR*UDGH
COPD = chronic obstructive pulmonary disease; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; IRR = 
infusion-related reaction; IV = intravenous; LFT = liver function test; NCI = National Cancer Institute.


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6.16 Treatment Discontinuation
Reasons for discontinuation of study treatment will include:
x
Disease progression (Note: Patients may receive treatment after initial disease 
progression per RECIST v1.1 based on criteria in Section 6.18)
x
Initiation of alternative anti-cancer therapy including another investigational agent
x
Unacceptable toxicity as defined in Table 6-3 or any AE that, in the opinion of the 
Investigator or the Sponsor, contraindicates further dosing
x
Withdrawal of consent for further treatment 
x
Lost to follow-up
x
Patient is determined to have met 1 or more of the exclusion criteria or failed to meet all 
inclusion criteria AND continuing to receive IMCnyeso might constitute a safety risk.  
Patients who fall into this category and for whom continuation of treatment is not thought 
by the Investigator to pose a safety risk may, after discussion with the Sponsor Medical 
Monitor, continue to receive study treatment
x
Pregnancy or intent to become pregnant
Information about the EOT visit and follow-up periods is provided in Section 7.3.
6.17 Replacement of Patients
During Phase I, any patient deemed not DLT-evaluable (see Section 6.10.2) may be replaced 
according to the guidelines for Phase I dose escalation, to achieve the minimum number of 
DLT-evaluable patients.
6.18 Treatment Past Disease Progression
Clinical evidence suggests that a minority of patients treated with immunotherapies will derive 
clinical benefit after an initial assessment of PD.  For patients in this study, if initial PD based on 
RECIST v.1.1 occurs, treatment may continue according to the protocol-specified regimen
provided all of the following criteria are met:
x
Absence of signs or symptoms indicating clinically significant disease progression
x
No decline in ECOG performance status


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x
No associated impending threat to vital organ function (eg, cord compression, liver 
function) or indication for immediate palliative therapy (eg, radiation for cord 
compression)
Patients continuing treatment beyond the initial protocol-specified RECIST v.1.1 progression 
must provide separate consent to continue IMCnyeso treatment. Disease assessments will 
continue to be performed according to the schedule in Table 7-2. The size of any new, 
measurable lesions is to be reported in the eCRF.
Patients treated beyond initial disease progression who experience further progression, defined as 
an additional PP increase in tumor burden (sum of diameters of both target and new lesions)
and/or identification of additional new lesions, at least 4 weeks after the initial PD assessment
(Seymour, 2017), must permanently discontinue study treatment. 
6.19 Study Discontinuation
The reasons for discontinuing individual patients from further participation the study include:
x
Patient death
x
Patient lost to follow-up
x
Patient withdraws consent for any further participation in the study including further 
participation in Survival Follow-Up
x
End of the study is reached (see Section 3.6)
6.20 Overdose
No antidote is known for IMCnyeso nor has it been defined what constitutes an overdose.  
However, inadvertent incorrect dosing, such as administration of a higher dose than stated in the 
protocol, should be rigorously monitored for potential (serious) adverse reactions.  Patients 
experiencing toxicity upon incorrect dosing or overdosing must receive adequate, supportive care 
as indicated by the symptoms observed, which will generally include IV corticosteroid therapy, 
at the discretion of the treating physician.  Patients must be followed until full recovery or 
confirmed stabilization of the event.


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7
STUDY SCHEDULE AND ASSESSMENTS
7.1 Pre-Screening and Screening Period Schedule
All patients will be given both a written and verbal description of the study and allowed adequate 
time to ask questions and decide whether they want to participate.  The Investigator (or an 
appropriate delegate at the Investigator Site) will obtain written consent from each patient prior 
to commencing any study-related activities or assessments.  
Pre-Screening activities may begin once a patient has signed the study IRB/IEC-approved 
Pre-Screening ICF.  During Pre-Screening the patient’s HLA-A*02:01, NY-ESO-1, and 
LAGE-1A status will be determined to establish patient eligibility.  Once confirmed 
HLA-A*02:01-positive and NY-ESO-1- and/or LAGE-1A-positive, the patient will be invited to 
take part in the full study and provided with the main study information sheet.  
There is no window for completion of the Pre-Screening activities. Pre-Screening may be 
performed while the patient is still on another anti-cancer treatment, prior to experiencing disease 
progression.
Screening must be completed within 21 days of C1D1; baseline radiological evaluations must be 
performed within 28 days prior to C1D1.  Laboratory and radiological assessments performed as 
part of standard of care prior to signing the ICF may be used if performed within the Screening 
window.  Screening assessments must be repeated if performed outside of the specified 
Screening window.  Patients may re-screen after abnormal labs or symptoms are corrected or 
treated, but these should first be discussed and agreed with the Sponsor.
The schedule of assessments for Pre-Screening and Screening is shown in Table 7-1.


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Table 7-1: 
Schedule of Pre-Screening and Screening Assessments
Procedure
Pre-Screening
Screening
Days (relative to first dose)
-21 to -1 
Informed consent
X 
X 
HLA-A*02:01 testing
X 
NY-ESO-1 / LAGE-1A testing (archival or new biopsy)
X 
Demography
X 
Inclusion/exclusion criteria
X 
Medical history and cancer history
X 
Prior anti-cancer therapy
X 
Prior/concomitant medications
X 
Adverse events
X 
Safety Assessments
Complete physical examination  
X 
Height and weight
ECOG performance status
X 
Vital signs (body temperature, pulse, respiratory rate, blood pressure, 
and oxygen saturation)
X 
12-lead ECG (triplicate)
X 
Hematology panel
X 
Chemistry panel
X 
Coagulation
X 
Urinalysis
X 
Thyroid function
X 
Serum pregnancy test (women of childbearing potential)
X 
Serum FSH test (if required to confirm non-childbearing potential) 
X 
CT/MRI scans for tumor evaluation
X 
Tumor biopsy UHTXLUHGIRUSDWLHQWVLQ3KDVH,,RSWLRQDOIRUDOO
other patients)
X 
X 
CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group;
FSH = follicle-stimulating hormone; HLA = human leukocyte antigen; LAGE-1A = L antigen family member-1 
isoform A; MRI = magnetic resonance imaging; NY-ESO-1 = New York esophageal squamous cell carcinoma-1.


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Pre-Screen Failures: Any patient who signed the Pre-Screen ICF but failed to sign the Main
Study ICF and proceeded with Screening for any reason, will be considered a Pre-Screen failure.  
The histologic diagnosis, HLA-A*02:01 result and tumor antigen screening (NY-ESO-1 and 
LAGE-1A) results will be collected for all Pre-Screen failure patients.  No other data will be 
entered in the eCRF.
Screen Failures: Any patient who signed the Main Study ICF, but failed to start treatment for 
any reason, will be considered a screen failure. The demographic information and reason for 
screen fail must be completed for screen failure patients.  No other data will be entered into the 
eCRF unless the patient experienced any AEs during Screening, which would be reported in the 
usual manner via eCRF AE page (see Section 8).
7.2 Treatment Period Schedule
The treatment period starts with Day 1 of Cycle 1 (C1D1).  A treatment cycle is defined as 
28 days for the purposes of scheduling procedures and evaluations.  
Any assessments required on C1D1 that are also performed as part of Screening do not need to 
be repeated on C1D1 if the data were obtained 72 hours prior to the first dose of study treatment.  
For subsequent visits, pregnancy testing may be performed up to 72 hours prior to dosing and 
other safety assessments may be performed up to 24 hours prior to dosing.
During the study visits, all tests and/or procedures should occur on schedule whenever possible.  
A visit window of ±7 days (with a minimum of 7 days between doses of IMCnyeso) is allowed 
unless otherwise indicated in the protocol.  If study drug infusions are delayed, the assessments 
associated with those infusions should be rescheduled accordingly. However, the timing of 
protocol-specified radiological assessments should be calculated in weeks using C1D1 as 
reference and should not be adjusted because of delays in treatment.
Assessments required during the treatment period are presented by visit inTable 7-2. For 
patients receiving IPE, follow the alternate Cycle 1 schedule provided in Section 13.4.  
Assessments marked “X” should be performed prior to dosing. Assessments that are to be 
performed at multiple timepoints are marked with the number of timepoints (including optional 
timepoints, if applicable) for the visit (eg, 2× is twice) and details of the timepoints are provided 
in the footnote.  Additional details regarding the assessments are provided in Section 7.4. Please 
refer to Section 6 for dosing details. Patients will continue treatment until they meet criteria for 
discontinuation, as described in Section 6.16.


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Table 7-2: 
Schedule of Treatment Period Assessments 
Procedure
Cycle 1
Cycle 2
Cycle 3
Later Cycles
Day of Cycle
1
2
8
9
15
22
1
8
15
22
1
8
15
22
Visits on Days 1, 8, 15, and 22
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
Complete physical examination
X
Abbreviated physical examination
X
X
X
X
X
X
X
X
X
X
X
D1 of each cycle
Weight
X
X
X
D1 of each cycle
Vital signs
~14×
~14×
3×
3×
3×
3×
3×
3×
3×
3×
3×
3×
3× each dosing day
12-lead ECG (single)
2×
2×
2×
2× on C4D1, C5D1, and C6D1
ECOG performance status
X
X
D1 of each cycle
Hematology panel
X
X
X
X
X
X
X
X
X
X
X
X
D1 of each cycle
Chemistry panel
X
X
X
X
X
X
X
X
X
X
D1 of each cycle
Thyroid function
X
X
X
Urine pregnancy test (women of 
childbearing potential)
X 
X 
X 
D1 of each cycle
PK and Immunogenicity
Pharmacokinetic sampling
8×
3×
8×
X
4×
4×
2×
2×
2×
2×
2× on D1 of odd-numbered cycles
Immunogenicity sampling
X
X
X
X
X
D1 of odd-numbered cycles
Disease Assessment
CT/MRI scans and disease 
assessment
X 
Q8W to W40 (C3, C5, C7, C9, C11), 
then Q12W (C14, C17, etc)
Tumor biopsy  
Between C1D9 and C1D16 UHTXLUHGIRUSDWLHQWVLQ3KDVH,,RSWLRQDOIRUDOORWKHUSDWLHQWV
Optional for all patients at time of progression


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IMCnyeso administration
X
X
X
X
X
X
X
X
X
X
X
X
D1, D8, D15, and D22 of each cycle
AE = adverse event; C#D# = Cycle # Day #; 
; CT = computerized tomography; ECG = electrocardiogram;
ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; hr = hour(s); min = minutes; MRI = magnetic resonance imaging; 
; PK = pharmacokinetics; Q#W = every # weeks; 
; W = week. 
ECG assessments are to be done pre-dose and within 1 hour of EOI on indicated days. 
Vital signs (body temperature, pulse, respiratory rate, and blood pressure; in addition, oxygen saturation should be collected for  first 3 cycles of treatment)
are to be assessed at the following timepoints:
x
C1D1/C1D2 and C1D8/C1D9: pre-dose (within 2 hours), EOI (within 15 min), every 2 hours (± 15 min) through 12-hour post-EOI, every 4 hours
(± 30 min) until discharge
x
All other doses: pre-dose (within 2 hours), EOI (within 15 min), and 1-hour post-EOI (± 15 min)
Pharmacokinetics samples are to be collected at the following timepoints:
x
C1D1 and C1D8: pre-dose (within 2 hours), EOI (within 15 min), 1-hour post-EOI (± 15 min), 2-hour post-EOI (± 15 min), 4-hour post-EOI
(± 15 min), 6-hour post-EOI (± 30 min), 8-hour post-EOI (± 1 hr), and 12-hour post-EOI (± 3 hr)
x
C1D2: 24-hour post-EOI (± 4 hr), 36-hour post-EOI (optional, ± 4 hr), and 48-hour post-EOI (optional, ± 4 hr) 
x
C1D9: 24-hour post-EOI (± 4 hr) 
x
C1D15 and C1D22: pre-dose (within 2 hours), EOI (within 15 min), 8-hour post dose (± 1 hr), and 12-hour post-EOI (optional, ± 3 hr) 
x
C2D1, C2D15, C3D1, C3D15, and D1 of subsequent odd-numbered cycles: pre-dose (within 2 hours), EOI (within 15 min) 
x
An unscheduled PK sample should be collected just after an ECG performed due to any unexpected cardiac signal
Central lab cytokine testing samples are to be collected at the following timepoints:
x
C1D1 and C1D8: pre-dose (within 2 hours), 4-hour post-EOI (± 15 min), 8-hour post-EOI (± 1 hr), and 12-hour post-EOI (± 3 hr)
x
C1D2 and C1D9: 24-hour post-EOI (± 4 hr) 
x
C1D15, C1D22, C2D1, and C3D1: pre-dose (within 2 hours) and 4-hour post-EOI (± 15 min)
x
Additional samples may be collected if a patient has suspected CRS.  Recommended timepoints are < 5 hours and 1 week after occurrence of the AE


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7.3 Safety, Disease Progression, and Survival Follow-Up Period Schedule
Patients may voluntarily discontinue study treatment for any reason at any time.  If a patient
decides to discontinue study treatment, the Investigator should make every effort to determine 
the primary reason for this decision and record this information in the patient’s chart and on the 
appropriate eCRF pages.  Reasons for discontinuation of study treatment are outlined in 
Section 6.16.
At the time a patient discontinues study treatment, a visit should be scheduled as soon as 
possible, within 14 days of the last dose of study drug or within 14 days of the decision to 
permanently discontinue study treatment. If the decision to withdraw the patient occurs at a 
regularly scheduled visit, that visit may become the EOT visit. 
Safety Follow-Up Period: Information related to all AEs (including concomitant medication 
taken for ongoing AEs) and SAEs will be collected for 30 days after the last dose of study drug. 
All AEs suspected to be related to study treatment and all SAEs should be followed up QW or as 
clinically indicated until resolution or stabilization. If a patient initiates subsequent systemic 
anti-cancer therapy, the patient will transition from Safety Follow-Up to Survival Follow-Up.  
Treatment-related SAEs should be reported, even if Safety Follow-Up has been completed.
Disease Progression Follow-Up Period: Patients who discontinue study treatment for any 
reason other than death, unequivocal disease progression, lost to follow-up, withdrawal of 
consent, start of new cancer therapy or study termination, should continue tumor evaluation 
assessments until progression of disease per RECIST v.1.1. If patients refuse to return for these 
visits or are unable to do so, every effort should be made to contact them, or a knowledgeable 
informant, by telephone to determine if the patient had disease progression. If a patient starts a 
new anti-cancer therapy during this period, Disease Progression Follow-Up will cease.
Survival Follow-Up Period: Patients will be followed for survival every 3 months (may be done 
by telephone call) until death or until the end of the study is reached, unless they withdraw 
consent or are lost to follow-up. For patients whose status is unclear because they fail to appear 
for study visits without stating an intention to withdraw consent, the Investigator should show 
"due diligence" by contacting the patient, family, or family physician as agreed in the informed 
consent. The Investigator should record in the source documents the steps taken to contact the 
patient, eg, dates of telephone calls, registered letters, etc. A patient should not be considered 
lost to follow-up until due diligence has been completed. Patients lost to follow-up should be 
recorded as such on the appropriate Patient Disposition eCRF.
Assessments required as part of the study are presented by visit in Table 7-3.  A visit window of 
±14 days is allowed during follow-up.


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Table 7-3: 
Schedule of Follow-Up Assessments
Procedure
EOT
30 days post last dose
90 days post last 
dose then Q3M
All Patients
Survival contact 
X 
X 
Subsequent anti-cancer treatment  
X 
X 
X 
Patients in Safety Follow-Up 
Adverse events 
X 
X 
Concomitant medications
X 
X 
Abbreviated physical examination
X 
X 
Weight
X 
X 
Vital signs
X 
X 
12-lead ECG (single) 
X 
Only if abnormal at EOT
ECOG performance status
X 
X 
Hematology panel
X 
X 
Chemistry panel
X 
X 
Coagulation
X 
Only if abnormal at EOT
Urinalysis
X 
Only if abnormal at EOT
Thyroid function
X 
Only if abnormal at EOT
Pregnancy test (serum or urine, women of 
childbearing potential) 
X 
X 
Immunogenicity
X 
Patients in Disease Progression Follow-Up 
CT/MRI scans and disease assessment
Q8W to Week 40 (post C1D1) then Q12W
Tumor biopsy (optional)
Recommended at time of progression
CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = 
End of Treatment; MRI = magnetic resonance imaging; PK = pharmacokinetics; Q3M = every 3 months.
7.4 Details of Assessments
Details for the collection, processing, storage and shipment of all samples are provided in the 
laboratory manual along with the order of prioritization for sampling, where sampling time 
points are scheduled to occur at the same time.  Blood samples scheduled at the same time point 
should be taken after the ECGs have been completed.  Any remaining 
 samples may be 
kept for up to 15 years after the end of the study for additional testing to understand the cancer, 
the drug response, or to validate diagnostic/
assays. 


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7.4.1
HLA-A*02:01 and NY-ESO-1 / LAGE-1A Testing
A 2 mL blood sample will be taken and sent to the central laboratory for DNA extraction and 
determination of HLA-A*02:01 status using a sequence-based assay for HLA-A*02:01.  Any 
remaining DNA sample will be kept up to 15 years in case additional testing is required.
If the patient is already known to be HLA-A*02:01 positive, the HLA sample and tumor sample 
can be submitted in parallel, otherwise patients must have HLA-A*02:01 tested centrally and be 
confirmed as positive prior to tumor samples being sent for NY-ESO-1 and LAGE-1A 
expression testing.    
Patients confirmed as HLA-A*02:01 positive will submit a tumor sample for NY-ESO-1 and 
LAGE-1A expression testing.  This can be an archival or fresh sample.  NY-ESO-1 and 
LAGE-1A antigen positivity will be confirmed using a quantitative, real-time, reverse 
transcription polymerase chain reaction (qRT-PCR) assay that tests in parallel for NY-ESO-1 
and LAGE-1A expression levels.  
Further background regarding the NY-ESO-1 / LAGE-1A screening strategy is provided in 
Section 1.5.
7.4.2
Patient Demographics and Other Baseline Characteristics
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of cancer, details of prior anti-cancer treatments
(including systemic therapy, radiotherapy, and surgery), prior/concomitant medications, prior 
procedures, significant non-drug therapies and any other assessments done for determining 
eligibility for inclusion in the study.  
7.4.3
Efficacy Assessments
Tumor response will be determined locally according to (RECIST) v.1.1.  Further details about 
RECIST v1.1 are in Section 13.1.  Patients may receive treatment after disease progression per 
RECIST v1.1 based on criteria in Section 6.18.
During the study, Immunocore may decide to have a central review of the radiological 
assessments performed.  In such case, the Investigator’s staff will be instructed on how to send 
data from these radiological assessments to the Contract Research Organization (CRO) for 
central review when needed.
The Sponsor reserves the right to request additional scans obtained within 6 months of the 
screening assessment to evaluate tumor growth kinetics prior to and following treatment with 
IMCnyeso.


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See Table 7-4 for details regarding disease assessments.  If a patient is intolerant of iodine-based 
contrast agents, CT may be performed without contrast.  Visible skin lesions and easily palpable 
subcutaneous tumors may be measured by physical examination using a ruler or calipers.  
Ultrasound should not be used to measure sites of disease. 
Table 7-4:
Disease Assessment Collection Plan
Procedure
Screening/Baseline
During Treatment / 
Follow-up
CT or MRI with contrast enhancement
(chest and abdomen; also, pelvis as 
appropriate based on indication and 
extent of disease)
Mandatory
Mandatory
The same imaging modality 
should be used throughout the 
study (CT or MRI)
Brain MRI with contrast
Required only if clinical 
suspicion of brain 
metastasis at Screening
If disease was detected at 
Baseline or if clinically 
indicated
CT = computed tomography scan; MRI = magnetic resonance imaging.
7.4.4
Safety and Tolerability Assessments
Safety will be monitored by performing physical examination, and evaluating vital signs, ECG, 
weight, performance status, hematology, chemistry, coagulation, urinalysis, thyroid function, 
cytokine testing, and collection of AEs. Significant findings present at Screening must be 
included in the Medical History eCRF page.  Significant new findings that begin or worsen after 
the start of Screening must be recorded as AEs in eCRF.
A complete physical examination will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, and neurological system.  If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.  An abbreviated physical 
examination will include the examination of general appearance and body sites as directed by 
signs and symptoms.
Vital signs include body temperature, pulse, respiratory rate, and blood pressure. Additionally, 
blood oxygen saturation should be included in vital sign assessments at Screening and for at least 
the first 3 treatment cycles. Vital signs should be assessed on the scheduled day, even if study 
treatment is being withheld.  More frequent examinations may be performed, at the discretion of
the Investigator, if medically indicated and should be recorded as unscheduled assessments in the 
eCRF.
Height will be measured in cm and body weight to the nearest 0.1 kg in indoor clothing.


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A standard 12-lead ECG will be performed (in triplicate at Screening and once at other 
timepoints). To ensure the safety of the patients, a qualified individual at the Investigator Site 
will review the ECG measurements.  New or worsening clinically significant ECG findings 
occurring after informed consent should be confirmed by performing at least 2 additional ECG 
reads within approximately 30 minutes and taking the average of at least 3 manually over-read 
measurements. Confirmed new or worsening clinically significant ECG abnormalities must be 
reported as AEs in the eCRF.
Eastern Cooperative Oncology Group (ECOG) performance status is determined as indicated in
Table 7-5.
Table 7-5:
ECOG Performance Status
Grade
Eastern Cooperative Oncology Group 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
Death
Laboratory parameters assessed for safety purposes, shown in Table 7-6 will be evaluated 
locally. Normal ranges and accreditation documentation must be provided for all local 
laboratories. More frequent evaluations may be performed if medically indicated; results should 
be recorded as unscheduled laboratory assessments in the eCRF. 


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Table 7-6: 
Local Clinical Laboratory Parameters Collection Plan 
Test Category 
Test Name
Hematology
Hemoglobin, platelets, white blood cells, lymphocytes, and neutrophils
Chemistry
Albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, 
bicarbonate, calcium, chloride, creatinine, glucose 
magnesium, inorganic phosphate, potassium, sodium, total bilirubin (also measure 
direct and/or indirect bilirubin if total bilirubin is > 1.5 × ULN), blood urea 
nitrogen or urea, amylase, and lipase 
Coagulation 
Prothrombin time or international normalized ratio and activated partial 
thromboplastin time
Urinalysis
Bilirubin, blood, glucose, ketones, pH, protein, specific gravity and white blood 
cells (in the event of macroscopic findings, microscopy may be performed at the 
Investigator’s discretion) 
Thyroid 
Free T4 and thyroid stimulating hormone (also measure free T3 if TSH is 
suppressed but free T4 is normal) 
Pregnancy / 
menopausal 
status
hCG (women of childbearing potential)  
FSH (if required to confirm non-childbearing potential) 
hCG = human chorionic gonadotropin; FSH = follicle-stimulating hormone; T3 = triiodothyroxine; T4 = thyroxine; 
TSH = thyroid stimulating hormone.
Pregnancy tests will be performed for all women of childbearing potential.  Any pregnancy must 
be reported as described in Section 8.5.6, and the patient should be withdrawn from treatment.  
For post-menopausal patients, FSH at Screening must be within the laboratory’s 
post-menopausal reference range.
7.4.5
Pharmacokinetics and Immunogenicity Assessments
Blood samples (2 mL) will be taken for IMCnyeso PK analysis.  At C1D1 and C1D8, a full PK 
profile sampling schedule is specified, assuming hospitalization of the patient for these doses and 
“out-patient” sampling at doses 3 and 4 (C1D15 and C1D22).  To generate Cmin data only, 
subsequent sampling is limited to pre-dose and EOT.  It is essential that the actual time and date 
of sample collection is recorded on the patient’s eCRF.   
A 2-mL blood sample will also be taken to measure IMCnyeso anti-drug antibody (ADA) levels.   


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7.4.6.3
Skin Punch Biopsy 
An OPTIONAL skin punch biopsy (3 mm or 5 mm, depending on the size of the area affected) is 
WREHWDNHQLQSDWLHQWVH[SHULHQFLQJ*UDGHUDVK, to characterize immune activation status in 
the skin and potentially identify the mechanisms of skin toxicity.  
  
  


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8
ADVERSE EVENTS AND SAFETY REPORTING
8.1 Assessment of Safety
Timely, accurate and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of patients and is mandated by regulatory agencies worldwide. The 
Sponsor and CRO have established standard operating procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of all safety information. All clinical 
studies conducted by the Sponsor or its affiliates will be conducted in accordance with those 
procedures.
Individual AEs should be evaluated by the Investigator and should be reported to the 
CRO/Sponsor for evaluation. This includes the evaluation of the event’s seriousness and the 
causality between the study drug and/or concomitant therapy and the AE. The CRO/Sponsor is 
required to maintain detailed records of all AEs reported by the Investigator(s) and to perform an 
evaluation with respect to seriousness, causality, and expectedness. On request of a competent 
authority in whose territory the clinical trial is being conducted, the Sponsor should submit 
detailed records of all AEs that are reported by the relevant Investigators. Case report processing 
includes evaluation of data in individual cases, identification of individual cases requiring 
specific handling, recognition and processing of alerts, and any other data processing of 
aggregated cases.
8.2 Definitions
Definitions of AEs, adverse drug reactions, SAEs, serious, unexpected adverse drug reactions
(SUSARs), and AEs of special interest (AESI) are presented below.
AE:  An AE is defined as the appearance of (or worsening of pre-existing) an undesirable sign, 
symptom, or medical condition that occurs after patient’s signed ICF has been obtained.  
Abnormal laboratory values or test results occurring after informed consent constitute AEs only 
if they induce clinical signs or symptoms, are considered clinically significant, require therapy 
(eg, hematologic abnormality that requires transfusion or hematological stem cell support), or 
require changes in study medication.
Adverse drug reaction: An adverse drug reaction is an unwanted or harmful reaction that 
occurs after administration of a drug or drugs and is suspected or known to be due to the drug.  
Adverse drug reactions have traditionally been categorized as pharmacologic (predicted based on 
the pharmacology of the drug) or idiosyncratic (not predicted based on pharmacology).


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SAE:  A SAE is any AE that meets any of the following criteria:
x
Is fatal or life-threatening 
x
Results in persistent or significant disability or incapacity
x
Constitutes a congenital anomaly/birth defect
x
Is medically significant, ie, defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent the outcomes listed above
x
Requires in-patient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for the following:
o
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition 
o
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
o
Treatment on an emergency out-patient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
o
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
Unexpected adverse drug reaction: An adverse drug reaction that is not consistent with 
applicable product information or characteristics of the study drug.
Suspected, unexpected, serious adverse reaction (SUSAR):  A SUSAR is an adverse reaction 
meeting serious criteria (above), the nature or severity of which is not consistent with the 
reference safety information for the investigational drug(s).
Adverse events of special interest (AESI): An AESI (serious or non-serious) is an AE with 
scientific and/or medical concern specific to the Sponsor’s program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor can be appropriate.  CRS 
is considered as an AESI for IMCnyeso. Refer to the IMCnyeso Investigator’s Brochure for 
details on the AESI for IMCnyeso.
8.3 Criteria for Expectedness
The concept of expectedness refers to events that may or may not have previously been observed 
and documented and not necessarily the known pharmacological properties of the medicine.  An 
AE will be unexpected for purposes of regulatory reporting unless it is mentioned in the 


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appropriate reference safety information within the current Investigator’s Brochure for the 
investigational drug, even if it is a medical occurrence expected for the disease being treated.
8.4 Assessment of Causality 
The Investigator decides whether he or she interprets the observed AE as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terms are defined:   
x
Related:  A direct cause and effect relationship between the study treatment and the AE 
is likely  
x
Possibly related:  A cause and effect relationship between the study treatment and the 
AE has not been demonstrated at this time and is not probable, but is also not impossible    
x
Not related:  Without question, the AE is definitely not associated with the study 
treatment
All “related” and “possibly related” AEs and SAEs will be defined as related to study drug.
8.5 Adverse Event Reporting
The Investigator must notify the Sponsor ZLWKLQKRXUVRIDQ\6$('/7 Grade 2 CRS, or 
*UDGHKHSDWLFIXQFWLon abnormality.
8.5.1
Expedited Reporting
Cases of adverse drug reactions from all sources that are assessed as serious are subject to 
expedited reporting. Expedited reporting of cases will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC and Investigators.  
Additionally, any safety information from other observations that could change the benefit-risk 
evaluation of the product will be communicated in an expedited manner to the regulatory 
authorities and all Investigators by the Sponsor. 
The CRO will be responsible for the processing and reporting of SAEs. AEs will be coded by 
using International Conference on Harmonisation (ICH) Medical Dictionary for Regulatory 
Activities.
Minimum criteria for a valid adverse drug reaction case have been established by ICH and 
individual regulatory agencies and are listed as the following:
x
An identifiable reporter


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x
An identifiable patient
x
A reaction/event
x
A suspected medicinal product
x
Other safety issues that also qualify for expedited reporting by the Sponsor are those that 
would materially alter the current benefit-risk assessment of the investigational product 
(sufficient to consider changes in the administration or in the overall conduct of the trial).  
Although these events will not be reported as SUSARs, they might require other action, 
such as putting in place urgent safety measures, the generation of substantial 
amendments, or early termination of the trial. The Sponsor will inform the regulatory 
authorities and all IEC of safety issues that might materially alter the benefit-risk 
assessment of the investigational agents.
8.5.2
Standards for Expedited Reporting
Cases of adverse drug reactions from all sources that are assessed as suspected, unexpected and 
serious (SUSAR) are subject to expedited reporting. Additionally, any safety information from 
other observations that could change the benefit-risk evaluation of the product should be 
promptly communicated to the regulatory authorities. Any other SUSARs associated with the 
investigational product should be reported as soon as the Sponsor becomes aware of them. This 
includes SUSARs that occur in another trial conducted by the same Sponsor, are identified by 
spontaneous reports or a publication, or are transmitted to the Sponsor by another regulatory 
authority.
8.5.3
Reporting of Out-of-Range Laboratory Test Results as Adverse Events
Out-of-range laboratory test results should be reported as AEs if, in the opinion of the Principal 
Investigator, they are clinically significant.  Abnormal laboratory results that are not considered 
to be clinically significant will not be reported as AEs.  Significance of abnormal laboratory 
results should be documented in the study records.  
When an abnormal laboratory value is recorded as an AE, the diagnosis (eg, anemia) should be 
recorded as the event term, not the abnormality (eg, low hemoglobin or hemoglobin decreased).
8.5.4
Reporting Events Associated with Disease Progression
Clinically significant signs or symptoms that occur due to disease progression should be reported 
as AE/SAE. However, to avoid inconsistencies in the clinical database, neither the term “disease 
progression” nor identification of a new lesion should be reported as an AE/SAE. Instead, 
information about disease progression, including any new lesions, is to be reported on the disease 
assessment pages. Similarly, death due to progression of the malignancy under study should not 


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be reported as a fatal SAE, and information about the cause of death is to be reported on the 
death eCRF page.
8.5.5
Reporting Guidelines for Other Observations
Other safety issues that qualify for expedited reporting where they might materially alter the 
current benefit-risk assessment of the investigational product (sufficient to consider changes in 
the administration or in the overall conduct of the trial) include:
x
An increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important
x
A post-study SUSAR that occurs after the patient has completed a clinical trial and is 
reported by the Investigator to the Sponsor
Events that occur during the trial and are relevant in terms of patient safety, but do not fall within 
the definition of SUSAR (therefore are not subject to the reporting requirements for SUSARs) 
are: 
x
A SAE that could be associated with the trial procedures and could modify the conduct of 
the trial
x
A significant hazard to the patient population (eg, lack of efficacy of an investigational 
medicinal product)
x
A major safety finding from a newly completed animal study (eg, carcinogenicity)
x
A temporary halt of a trial for safety reasons if the trial is conducted with the same 
investigational medicinal product in another country by the same Sponsor
x
Safety recommendations of the SST
Although these events/observations will not be reported as SUSARs, they might require other 
action, such as putting in place urgent safety measures, the generation of substantial 
amendments, or early termination of the trial. The Sponsor will inform the regulatory authorities 
and the IEC of safety issues that might materially alter the benefit-risk assessment of the 
investigational medicinal product.
Expedited reporting is not usually required for reactions that are serious but expected or for 
non-serious adverse reactions whether expected or not. It is also usually inappropriate to report 
events that are considered unrelated to the investigational medicinal product.


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8.5.6
Pregnancy Reporting
Pregnancy will be reported through the Pregnancy Reporting Form (paper) and in the eCRF.  The 
Pregnancy Reporting Form (paper) should be completed and reported as indicated to the CRO 
pharmacovigilance team within 24 hours of being made aware of the event.  Women who 
become pregnant during the study will be withdrawn from treatment at the earliest opportunity.  
The CRO will then notify the Sponsor within 1-business day of being informed of the event.  
Following permanent discontinuation of study treatment, every attempt will be made to follow 
the patient and any resulting offspring for up to 6-weeks postpartum, unless otherwise medically 
indicated.  Abortion, stillbirth, or any malformation/disease in the offspring must be reported as a 
SAE. 
For men participating in the study who report the pregnancy of a partner, the Investigator will 
ask to collect information about the results of the pregnancy/birth using the Pregnant Partner 
Form.  The partner may be asked to sign a consent form giving permission for information to be 
collected.  This health information will become part of the research study records.  It will be 
shared with the Sponsor. 
8.6 Investigator’s Responsibilities
The Investigator is responsible for the collection of AE data.  All AEs must be recorded in the 
eCRF.  
The Investigator must report all SAEs within 24 hours of being made aware of the event to 
pharmacovigilance via the clinical database by completing as much information about the AE as 
possible in the eCRF and checking “Yes” on the “Serious?” checkbox.  The initial reporting can 
be supplemented by written reports using the SAE report form provided.   
If the eCRF is unavailable, or paper reports are to be submitted, forms should be faxed to the 
CRO pharmacovigilance team using the safety hotline number: 
x
Safety Hotline (Fax):
(US and Canada), 
(UK)
The following minimum information is required for the SAE report:
x
Patient identification (patient number and age)
x
Trial number
x
Study therapy (dose, route, form, regime, start date, and end date)
x
Concomitant medication (including dose, route, form, regimen, and start date where 
available)


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x
Nature of SAE (overall diagnosis where available or signs and symptoms)
x
Date and time of occurrence
x
Any associated factors (concomitant disease or medication)
x
Proposed relationship to study therapy
x
Outcome
x
Identification of the reporter
x
Action in relation to study (withdrawn from treatment, suspended, or none)
Investigators may be asked for additional information for any reported SAE, such as laboratory 
or diagnostic reports or the outcome of the event.  A SAE follow-up report with attached 
documents (if necessary) should be forwarded to CRO pharmacovigilance as soon as the 
additional information is available by email. The study number IMCnyeso-101 must be in the 
title of any email for study identification purposes and the unique patient identification number
must be referenced.  
8.7 Sponsor and Clinical Research Organization’s Responsibilities
The Sponsor is responsible for the ongoing safety evaluation of the investigational drugs being 
studied. The Sponsor and CRO are responsible for ensuring that expedited reports are made to 
all concerned Investigators, to the IEC where required, and to all regulatory authorities of all 
adverse drug reactions that are both serious and unexpected, findings that could adversely affect 
the health of patients, impact the conduct of the trial, or alter the competent authority’s 
authorization to continue the trial in accordance with local applicable regulations.


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9
STATISTICAL METHODS AND DATA ANALYSES 
9.1 General Principles
Categorical data will be presented as frequencies and percentages.  For continuous data, the 
mean, standard deviation, median, minimum and the maximum will be presented.
The Phase I study data will be analyzed and reported based on all patient data from the dose 
escalation up to the time when all Phase I patients have completed at least 6 cycles of treatment 
or have discontinued study treatment.  Data will be listed, summarized, and analyzed by 
treatment group.  Data for the Phase II expansion cohorts will be reported separately, with a data 
cut off at the point where at least 80% of patients have completed the follow up for disease 
progression or discontinued the study for any reason.  Additional details of data reporting will be 
outlined in the statistical analysis plan (SAP).
The following rules will be followed for reporting results unless stated otherwise:
x
Screen failure patients are those who signed the ICF, but never started the study treatment 
for any reason.  For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the clinical study report as separate listings
x
Baseline is defined as the last assessment prior to the first dose of treatment received 
(ie, C1D1 pre-dose)
x
For Phase I, all summaries, listings, figures and analyses will be performed by treatment 
group
x
For Phase II, all summaries, listings and figures for primary efficacy analyses and safety 
analyses will be presented by disease group (NSCLC, urothelial carcinoma, or synovial 
sarcoma)
Patients from the dose escalation and dose expansion may be pooled for the RP2D.  Additional 
analyses not described here will also be detailed in the SAP.
Unless otherwise stated, missing data will simply be noted as missing on appropriate 
tables/listings.
Compliance with the protocol will be assessed by the number and proportion of patients with 
protocol deviations.  Protocol deviations will be identified prior to database lock and will be 
listed and summarized.


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9.2 Analysis Sets
9.2.1
Full Analysis Set
The full analysis set (FAS) comprises all patients who received at least 1 full dose or partial dose 
of IMCnyeso.  Patients will be analyzed according to the planned treatment. The FAS will be 
used for all listings of raw data, demography and baseline characteristics.  Unless otherwise 
specified, the FAS will be the default analysis set used for analyses.
9.2.2
Safety Analysis Set
The safety analysis set comprises all patients who received at least 1 full dose or partial dose of 
IMCnyeso. Patients will be classified in this set according to initial treatment received.  The 
safety analysis set will be used for the safety summary of the study. If the safety analysis set and 
the FAS are identical, then analyses described by the safety analysis set will not be performed.
9.2.3
Per-Protocol Analysis Set
The per-protocol set (PPS) consists of a subset of FAS patients who meet these 4 criteria:  
x
Presence of measurable disease according to RECIST v1.1
x
At least 1 post-baseline tumor assessment or discontinued prior to the first tumor
assessment  
x
Received at least 1 dose of planned treatment at the RP2D
x
No violation of key inclusion or exclusion criteria (to be defined in the SAP) 
Patients in the PPS will be classified according to planned treatment.  If the PPS and the FAS are 
identical, then analyses described by the PPS will not be performed.
9.2.4
Dose-Determining Analysis Set
The DDS consists of all patients from the safety analysis set in Phase I who meet the criteria 
described in Section 6.10.2.
9.2.5
Pharmacokinetic Analysis Set
The PK analysis set consists of all patients who have at least 1 blood sample providing evaluable 
PK data.  The PK analysis set will be used for all PK analyses. 
Note: Patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples.  These patients will be identified at 
the time of analysis.


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9.3 Patient Demographics and Other Baseline Characteristics
Demographic data, baseline disease characteristics, and other baseline data will be listed in 
detail.  Qualitative data (eg, performance status) and quantitative data (eg, weight) will be 
summarized by descriptive statistics.
9.4 Treatment Data
Actual dose and duration in days of treatment for IMCnyeso, as well as the dose intensity (actual 
dose received/actual duration) and relative dose intensity (the ratio of dose intensity to planned 
dose/planned duration) will be summarized by descriptive statistics by treatment group. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by patient and summarized by anatomical therapeutic chemical 
term and treatment group.
The reason for discontinuation from treatment will be summarized and listed, along with dates of 
first and last doses, duration of exposure to each study drug, and date of discontinuation for each 
patient.
9.5 Primary Analysis Variables
9.5.1
Phase I: DLT
In Phase I, the primary variable is the occurrence of 1 or more DLTs.  An adaptive BLRM 
guided by the EWOC principle will be used to guide dose recommendations and estimate the 
MTD, as described in Section 6.10 and Section 13.3.
Patients in Phase I who are ineligible for the DDS will be excluded from the primary analysis, 
although their data will be used for all remaining analyses. 
As a supportive analysis in the Phase I dose escalation part of the study, a dose-exposure 
relationship may be estimated for IMCnyeso via a BLRM to further guide the dose 
recommendation to targeted exposure of IMCnyeso.  From the estimation of the dose-exposure 
model, the following posterior summaries will be derived for each dose:
x
Mean, median, standard deviation, and 95%-credible interval for the exposure
x
The probability that the true AUC after first dose of treatment achieves the target 
exposure


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9.5.2
Phase II: Efficacy
In Phase II, the primary endpoint is the best overall response (BOR). The primary summary 
measure is ORR, defined as the proportion of patients with a BOR of complete response (CR) or 
partial response (PR) based on local Investigator assessment, as defined in RECIST v.1.1.  ORR 
will be analyzed separately for the Phase II cohorts.  Confirmation of response is required for 
declaring a PR or CR as the BOR.  A confirmed response is defined as a CR or PR followed by a 
CR or PR at least 4 weeks later.  ORR will be summarized with accompanying 95% confidence 
interval.  
9.6 Secondary Analysis Variables
9.6.1
Efficacy
Analysis of efficacy endpoints will be performed using the FAS unless otherwise noted.  For all 
efficacy parameters, data will be listed, summarized, or analyzed by treatment group for the 
Phase I dose escalation and separately for the Phase II expansion cohorts.
Individual lesion measurements and overall response assessments will be listed by patient and 
assessment date.  Best overall response per RECIST v.1.1 will be listed and tabulated.  Best 
overall change in tumor size for individual patients will be shown in waterfall plots.
PFS and OS will be listed by patient.  PFS will be presented graphically using Kaplan-Meier 
plots including all patients treated at the MTD or RP2D and by disease group.  Median PFS time 
and the proportion of patients who are progression-free at 3, 6, 9, and 12 months will be 
estimated for each group.  Similarly, OS will be presented graphically using Kaplan-Meier plots 
including all patients treated at the MTD or RP2D and by disease group.  Median OS time and 
the proportion of patients who are alive at 3, 6, 9, and 12 months will be estimated.
DoR and time-to-response for patients who experience a CR or PR at any time on study will be 
listed by patient.  If a large proportion of patients achieve a response (eg, 5/10), Kaplan-Meier 
plots for DoR will also be produced, and the median DoR will be estimated.  
9.6.2
Safety 
For all safety analyses, the safety analysis set will be used.  All listings and tables will be 
presented by treatment group.
9.6.2.1
Adverse Events
The AE summary tables include only AEs that are new or worsened during the on-treatment 
period (treatment-emergent AEs).  However, all safety data (including those from the pre- and 
post-treatment periods) will be listed and those collected during the pre-treatment and
post-treatment period are to be flagged.


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The incidence of treatment-emergent AEs will be summarized by system organ class and/or 
preferred term, severity (based on NCI CTCAE v.4.03 grades), type of AE, and relation to study 
treatment by treatment group.  Deaths reportable as SAEs and non-fatal SAEs will be listed by 
patient and tabulated by type of AE and treatment group.
Definitions of notably abnormal vital signs results (eg, hypotension) will be specified in the SAP 
and a shift table of Baseline to worst on-treatment result will be produced by the Phase I dose 
escalation and the Phase II expansion groups.
9.6.2.2
Laboratory Abnormalities
For laboratory tests covered by the NCI CTCAE version 4.03, the study team will grade 
laboratory data accordingly.  A grade of 0 will be assigned for all non-missing values not graded 
as 1 or higher.  For laboratory tests where grades are not defined by CTCAE, results will be 
graded by the low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry, and other laboratory data:
x
Frequency table for newly occurring on-treatment Grade 3 or 4 and all grades
x
Shift tables of laboratory and ECG data using CTCAE grades to compare Baseline to the 
worst on-treatment value
x
Listing of all clinically relevant laboratory data and relevant ECG data with values 
flagged to show the corresponding CTCAE grades and the classifications relative to the 
laboratory normal ranges
Other exploratory analyses, eg, figures plotting time course of raw or change in laboratory tests 
over time or box plots, may be specified in the SAP.
9.6.2.3
Other Safety Variables
x
Vital signs, absolute values and changes from Baseline will be summarized.  Normal 
ranges will be specified in the SAP and shift tables of Baseline to worst on-treatment 
results will be produced
x
ECG data:  QTcF interval absolute values and changes from Baseline will be 
summarized.  Abnormalities will be classified according to NCI CTCAE grades and shift 
tables of Baseline to worst on-treatment results will be presented 


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9.6.2.4
Tolerability
Tolerability of study treatment will be assessed by summarizing the number of treatment dose 
interruptions and dose reductions.  Reasons for dose interruptions and dose reductions will be 
listed by patient and summarized.
9.6.3
Pharmacokinetics and Immunogenicity
The PK parameters that will be assessed are presented in Table 9-1.
Table 9-1:
Pharmacokinetic Parameters to be Analyzed
Parameter
Definition
AUClast
The area under the curve (AUC) from time 0 to the last measurable concentration 
sampling time (tlast) (mass × time × volume-1)
AUCinf
The AUC from time 0 to infinity (mass × time × volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single-dose administration (mass × volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single-dose administration (time)
t1/2
The elimination half-life associated with the terminal slope (Oz) of a semi logarithmic 
concentration-time curve (time).  Use qualifier for other half-lives
CL
The total body clearance of drug from the plasma (volume × time-1)
Vz
The apparent volume of distribution during terminal phase (associated with Oz) 
(volume)
AR
Accumulation ratio = maximum observed concentration (Cmax [multiple dose]/Cmax
[single dose])
The safety analysis set will be used in all PK data analysis and PK summary statistics.
Descriptive statistics of all PK parameters for IMCnyeso will include arithmetic and geometric 
mean, median, standard deviation and coefficient of variation, geometric coefficient of variation
and minimum and maximum.  Zero concentrations will not be included in the geometric mean 
calculation. Since Tmax is generally evaluated by a non-parametric method, median values and 
ranges will be given for this parameter.  Missing concentration values will be reported as is in 
data listings.  Concentration values below lower limit of quantitation will be handled as 0 in 
summary statistics and reported as is in data listings.  Any missing PK parameter data will not be 
imputed.


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The PK data will be displayed graphically.  Displays will include individual patient plasma 
concentration profiles (on the linear and log-scale) versus time and geometric mean plasma 
concentration (± standard deviation) versus time, stratified by dose. 
Scatter plots of PK parameters versus dose, or log-dose will also be considered to assess dose 
proportionality.  In a preliminary assessment of dose proportionality, log-transformed AUC and 
Cmax parameter estimates will be examined using the Power Model:
parameter = ea (dose)b
ie, log(parameter) = a + (b * log(dose)) 
where a is the intercept, depending on patients, and b is the slope, measuring the extent of dose 
proportionality.  Dose proportionality implies that the slope of the regression line b = 1 and will 
be assessed by estimating b along with its confidence interval. 
Further analyses may be conducted using population PK approaches.  In addition, a model-based 
approach may be used to explore the potential relationship between efficacy, safety, and/or 
endpoints and IMCnyeso concentration and/or exposure metrics.  All analyses will be 
reported either in the clinical study report or a stand-alone report. 
The safety analysis set will be used in all immunogenicity analyses. The frequency of ADA at 
baseline and following treatment will be summarized. All analyses will be reported either in the 
clinical study report or a stand-alone report.  
9.7 Exploratory Analyses
  
9.8 Interim Analysis
No formal interim analysis is planned during Phase I.  The BLRM will be updated after each 
dose-escalation cohort and the MTD / RP2D will be determined at the end of Phase I
(Section 6.10). 
A formal interim analysis will be conducted during Phase II.  ORR will be evaluated for the first 
9 patients in each Phase II cohort to determine whether enrollment may continue (Section 9.9.2).  


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9.9 Sample Size Calculation
9.9.1
Phase I Escalation Cohorts
Dose decisions will be guided by the BLRM.  Among the simulations that were conducted (see
Section 13.3), the mean sample size was 27 patients, and the sample size was less than 
33 patients in over 80% of simulations.
9.9.2
Phase II Expansion Cohorts
A Simon two-stage design will be used for each Phase II cohort using a 10% probability of a 
Type 1 error, a 20% probability of a Type 2 error, and assuming a target response rate of 20% 
versus 5% response rate for available treatment options. If there are no responses among the first 
9 patients in a cohort, then accrual in that cohort will stop. If there is at least one response, at the 
discretion of the Sponsor up to an additional 15 patients may be accrued for a total of up to 
24 patients (with at least 3 responses to support further evaluation).


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10 DATA HANDLING AND MANAGEMENT
All data collected during this study, including clinical and 
 data, may be pooled with 
data from other studies using the same study drug or a different study drug with a similar 
mechanism (eg, ImmTAC) in order to advance our understanding about study drug safety, 
correlation with a variety of outcomes, or other study endpoints in order inform future 
development provided the patient provides consent to permit such pooling of data. 
10.1 Data Confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations.  Those regulations require a signed patient authorization informing the 
patient of the protected health information that will be collected and the use or disclosure of that 
information.  If the patient revokes authorization to collect or use this information, the 
Investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of patient authorization.  To protect the health information of study patients, access to 
the data collection system will be controlled by a sequence of individual user identification codes 
and passwords that are made available only to authorized trained personnel. 
10.2 Site Monitoring
Before study initiation at trial sites, Sponsor and/or CRO study team members will review the 
protocol and eCRFs with the Investigators and the site study staff.  During the study, the field 
monitor will visit the site regularly to check the completeness of patient records, the accuracy of 
entries on the eCRFs, the adherence of the protocol to Good Clinical Practice, the progress of 
enrollment, and to ensure that study treatments are being stored, dispensed, and accounted for 
according to specifications.  Key study personnel must be available to assist the field monitor 
during these visits.  The Investigator must assure that the site monitor is allowed access to all 
study files, including all site medical records, case and visit notes and laboratory reports. 
10.3 Data Collection
The Investigator is required to maintain source documents for each study patient, consisting of 
case and visit notes (site medical records), containing demographic and medical information, 
laboratory data, ECGs, and the results of any other tests or assessments.  All information 
recorded in the eCRF must be traceable to source documents in the patient's file.  The 
Investigator must also keep an original signed ICF and provide an original signed copy to the 
patient.
This study will use an electronic data capture (EDC) system and the Principal Investigator and 
site study staff will enter the data required by the protocol into the eCRF.  The eCRF will use 
fully validated, secure web-enabled software that conforms to 21 CFR Part 11 requirements.  The 


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Principal Investigator and all identified site staff will not be given access to the EDC system until 
they have been trained.  The Principal Investigator is responsible for assuring that the data 
entered into the eCRF are complete, accurate, and that entry and updates are performed in a 
timely manner.  Field monitors will review the eCRF data entries and assist site personnel with 
any required corrections or additions.
Tissue samples obtained during the study (eg, tumor, blood for PK, or other analyses) will be 
collected from the Investigator Sites and analyzed in laboratories contracted by the Sponsor 
and/or companies employed by the Sponsor (eg, CROs).  Radiological scans will be reviewed 
locally but may be sent for independent central review if deemed necessary.  Field monitors will 
review the eCRF and laboratory paper requisition forms for accuracy and completeness and 
instruct site personnel to make any required corrections or additions.  One copy of the requisition 
form will be forwarded to each analytical laboratory with the respective sample by the site staff 
and 1 copy will be retained at the investigational site.
10.4 Database Management
Sponsor clinical study personnel and trial field monitors will review the eCRF data entries and 
assist site personnel with any required corrections or additions. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system.
Concomitant treatment and prior medication data in the database will be coded using the World 
Health Organization (WHO) Drug Reference List, based on the Anatomical Therapeutic 
Chemical classification.  Medical history, current medical conditions and AEs in the database 
will be coded using the Medical Dictionary for Regulatory Activities terminology.  After 
database lock, the Investigator will receive a CD-ROM of the patient data for archiving at the 
investigational site.


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11 ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES
11.1 Regulatory and Ethical Compliance
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local regulations 
(including European Directive 2001/20/EC and Unites States Code of Federal Regulations, CFR 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki (2013).
11.2 Responsibilities of the Investigator and Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board
Before the start of the study the study protocol and/or other relevant documents (eg, ICFs) will
be reviewed and approved by the competent authority and an appropriately constituted IRB or 
IEC, in accordance with local legal requirements.  The Sponsor must ensure that all ethical and 
legal requirements have been met before the first patient is enrolled in the study.
Prior to study start, the Investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study according to the protocol and to give access to all relevant 
data and records to the Sponsor and/or designated agents of Sponsor (eg, monitors and auditors), 
the IRB or IEC, the research ethics board (REB) and regulatory authorities as required.
11.3 Informed Consent Procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient.  In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he or she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures.  The only
exception is where laboratory and radiologic assessments are performed as part of standard care 
and have been conducted within the screening window (28 days for radiological assessments, 
21 days for all other assessments). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a patient’s informed consent was 
actually obtained will be captured in the eCRF.


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11.4 Discontinuation of the Study
The Sponsor reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 3.7.
11.5 Publication of Study Protocol and Results
The Sponsor will publish the key design elements of this protocol in a publicly accessible 
database (clinicaltrials.gov).  At the time of study and clinical study report completion, the 
results of this study will be either submitted for publication and/or posted in a publicly accessible 
database.
11.6 Study Documentation, Record Keeping, and Retention of Documents
Each participating site will maintain appropriate medical and research records for this study, in 
compliance with Section 4.9 of the ICH E6 Good Clinical Practice, and regulatory and 
institutional requirements for the protection of confidentiality of patients. Each site will permit 
authorized representatives of the Sponsor and regulatory agencies to examine any clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study safety 
and progress.  Source data are all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the Site Principal Investigator. The study eCRF is the primary data collection instrument for the 
study. The Investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the eCRFs and all other required reports. Data reported on the eCRF, that
are derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained.  All data requested on the eCRF must be recorded.
The Investigator should maintain the trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations and 
guidelines. The Investigator should take measures to prevent accidental or premature destruction 
of these documents. Essential documents should be retained for a period of not less than 
15 years from the completion of the clinical trial unless the Sponsor provides written permission 
to dispose of them or requires their retention for an additional period of time because of 
applicable laws, regulations and guidelines.
11.7 Confidentiality of Study Documents and Patient Records
The Investigator must ensure anonymity of the patients; patients must not be identified by name
in any documents submitted to the Sponsor and/or designated agents of Sponsor.  Signed ICFs 


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and a patient enrollment log must be maintained in confidence by the Investigator.  Patients will 
be identified on eCRFs and other documents submitted to the Sponsor by study number.
11.8 Audits and Inspections
Source data and all trial documents must be available to inspections by the Sponsor or designee, 
the CRO and/or Health Authorities.
11.9 Financial Disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site, prior to study start.


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principles-for-medical-research-involving-human-subjects.
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guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 
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13 APPENDICES
13.1 Cytokine Release Syndrome Definitions and Grading
Events of CRS should be assessed in accordance with the ASTCT Consensus Guidelines (Lee, 
2019). 
13.1.1 Definition of CRS
For this study, CRS is defined as a supra-physiological response following IMCnyeso treatment 
that results in the activation or engagement of endogenous T cells. Symptoms can be progressive, 
must include fever at the onset, and may include hypotension, capillary leak (hypoxia), and end 
organ dysfunction. A reasonable temporal relationship to IMCnyeso treatment must be present. 
Investigators should exclude other causes of fever, hypotension, hemodynamic instability, and/or 
respiratory distress such as an overwhelming infection. 
13.1.2 CRS Grading Criteria
Events of CRS are to be graded based on presence of fever and treatment provided for 
hypotension and/or hypoxia, as shown in Table 13-1. Associated constitutional symptoms and/or 
organ toxicities do not influence CRS grading (and are to be graded individually per CTCAE 
v4.03, consistent with AE grading for this study). In patients who have CRS and then receive 
treatment with anti-pyretics or anti-cytokine therapy (eg, tocilizumab or steroids), fever is no 
longer required to grade subsequent CRS severity. In patients experiencing hypotension and 
hypoxia, grading is to be assigned based on the more severe event.
Table 13-1:
ASTCT CRS Grading Criteria
Grade
Fever
with Hypotension
and/or Hypoxia
1
 38.0 °C
None
None
2
 38.0 °C
Not requiring vasopressors
Requiring oxygen delivered by low-flow nasal 
cannula ( 6 L/min) or blow-by
3
 38.0 °C
Requiring a vasopressor with 
or without vasopressin
Requiring oxygen delivered by high-flow nasal 
cannula (>6L/min), facemask, nonrebreather 
mask, or Venturi mask
4
 38.0 °C
Requiring multiple 
vasopressors (excluding 
vasopressin)
Requiring oxygen delivered by positive pressure 
(eg, CPAP, BiPAP, intubation and mechanical 
ventilation)
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; min = minute.


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Grade 5 CRS is defined as death due to CRS in which another cause is not the principle factor 
leading to this outcome.
13.1.3 Resolution of CRS
For purposes of this study, CRS is considered as resolved when fever, hypotension, and hypoxia 
have all resolved (unless there are alternative causes for the fever, hypoxia, and/or hypotension). 
The duration of associated constitutional symptoms and/or organ toxicity should be reported 
independently.
13.1.4 Immune Effector Cell-Associated Neurotoxicity Syndrome
Neurotoxicity (eg, delirium, encephalopathy, aphasia, lethargy, difficulty concentrating, 
agitation, tremors, seizures, and, rarely, cerebral edema) has been observed with autologous T 
cell therapies. Under the ASTCT 2019 guidelines, these events are treated as distinct entity from 
CRS, called immune effector cell-associated neurotoxicity syndrome (ICANS) due to its distinct 
timing and response to intervention. 
Neurologic symptoms may occur during or more commonly after CRS symptoms. The earliest 
manifestations of ICANS are tremor, dysphagia, mild difficulty with expressive speech 
(especially in naming objects), impaired attention, apraxia, and mild lethargy. Expressive aphasia 
appears to be the most characteristic feature of ICANS.
No events of ICANS have been reported following ImmTAC treatment. However, the ASTCT 
2019 guidelines notes that bispecific antibodies that engage immune effector cells may have 
similar neurological side effects. Patients experiencing CRS should be carefully monitored for 
evidence of neurological toxicity.


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13.2 Guidelines for Implementation of RECIST Criteria 
These guidelines are based on the original RECIST for tumor responses (Therasse, 2000), and 
the revised RECIST v1.1 guidelines (Eisenhauer, 2009).  The efficacy assessments and 
definitions of best response and PD for the purposes of the primary endpoint of BOR described 
in this study are based on the RECIST v1.1 criteria (Table 13-2). 
13.2.1 Efficacy Assessments
Tumor evaluations for the purposes of the primary endpoint are made based on RECIST criteria 
(Therasse, 2000), New Guidelines to Evaluate the Response to Treatment in Solid Tumors, 
Journal of National Cancer Institute, Volume 92; pages 205–216 and revised RECIST 
guidelines (version 1.1) (Eisenhauer, 2009).
13.2.2 Definitions of Measurable and Non-Measurable Disease
Measurable disease represents the presence of at least 1 measurable nodal or non-nodal lesion.  
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
Measurable lesions (both nodal and non-nodal): The minimum size of a measurable, non-nodal 
target lesion at Baseline should be no less than double the slice thickness or 10 mm, whichever is 
greater, eg, the minimum non-nodal lesion size for CT/MRI with 5 mm cuts will be 10 mm).
Lytic bone lesions or mixed lesions with identifiable soft tissue components that can be 
evaluated by CT/MRI can be considered as measurable lesions, if the soft tissue component 
meets the definition of measurability.  Measurable nodal lesions (ie, lymph nodes), lymph nodes 
t 15 mm in short axis can be considered for selection as target lesions.  Lymph nodes measuring 
t 10 mm and < 15 mm are considered non-measurable.  Lymph nodes smaller than 10 mm in 
short axis at Baseline, regardless of the slice thickness, are normal and not considered indicative 
of disease.
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above.  Simple cysts with non-enhancing 
walls and low CT density are not considered malignant lesions unless proven by biopsy.
Non-measurable lesions:  All other lesions are considered non-measurable, including small 
lesions (eg, longest diameter < 10 mm with CT/MRI or pathological lymph nodes with t 10 to 
< 15 mm short axis), as well as truly non-measurable lesions eg, blastic bone lesions, ascites, 
pleural/pericardial effusion and inflammatory breast disease.


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13.2.3 Methods of Tumor Measurement 
All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.  Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been used 
to assess the anti-tumor effect of a treatment.  For optimal evaluation of patients, the same 
methods of assessment and technique should be used to assess each reported lesion at Baseline 
and during Follow-up.  Contrast-enhanced CT of chest, abdomen, and pelvis should preferably 
be performed using a 5-mm slice thickness.  If a patient is known to have a medical 
contraindication to CT contrast or develops a contraindication during the trial, the following 
change in imaging modality will be accepted for follow-up: a non-contrast CT of chest (MRI not 
recommended due to respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.
13.2.3.1
Other Tumor Response Considerations
Fluorodeoxyglucose-positron emission tomography, endoscopy, and laparoscopy: The 
utilization of positron emission tomography imaging, endoscopy, and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated.  The utilization of such techniques 
for objective tumor response should be restricted to validation purposes in specialized centers; 
however, such techniques can be useful in confirming complete pathological response when 
biopsies are obtained.
Cytology and histology: Cytology and histology can be used to differentiate between partial 
response (PR) and complete response (CR) in rare cases (ie, after treatment to differentiate 
between residual benign lesions and residual malignant lesions in tumor types such as germ cell 
tumors).  
Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (ie, skin nodules and palpable lymph nodes).  Documentation by color photography is 
recommended for the case of skin lesions, including a ruler to estimate the size of the lesion.  
Clinical disease progression is acceptable and wherever possible, should be confirmed by 
imaging studies.  
13.2.4 Definitions of Target and Non-Target Lesions
For the evaluation of lesions at Baseline and throughout the study, the lesions are classified at 
Baseline as either target or non-target lesions.
Target Lesions:  All measurable lesions (nodal and non-nodal) up to a maximum of 5 lesions in 
total (and a maximum of 2 lesions per organ), representative of all involved organs, should be 
identified as target lesions and recorded and measured at Baseline.  Target lesions should be 


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selected based on their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). 
Each target lesion must be uniquely and sequentially numbered on the eCRF (even if it resides in 
the same organ).  A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for 
all target lesions will be calculated and reported as the baseline sum of diameters.  The baseline 
sum of diameters will be used as reference by which to characterize the objective tumor
response.  Each target lesion identified at Baseline must be followed at each subsequent 
evaluation and documented on eCRF. 
Non-Target Lesions: All other lesions are considered non-target lesions, ie, lesions not fulfilling 
the criteria for target lesions at Baseline.  Presence or absence or worsening of non-target lesions 
should be assessed throughout the study; measurements of these lesions are not required.  
Multiple non-target lesions involved in the same organ can be assessed as a group and recorded 
as a single item (ie, multiple liver metastases).  Each non-target lesion identified at Baseline must 
be followed at each subsequent evaluation and documented on eCRF.
13.2.5 Determination of Target Lesion Response
Table 13-2:
Response Criteria for Target Lesions
Response Criteria
Evaluation of Target Lesions
Complete response
Disappearance of all non-nodal target lesions.  In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis to 
< 10 mma
Partial response
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters
Progressive disease
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded 
at or after Baseline.  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mmb
Stable disease
Neither sufficient shrinkage to qualify for partial response or complete 
response nor an increase in lesions which would qualify for progressive 
disease
a.
Sum of diameters for complete response may not be 0 when nodal lesions are part of target lesions.
b. Following an initial complete response, progressive disease cannot be assigned if all non-nodal target lesions 
are still not present and all nodal lesions are < 10 mm in size.  In this case, the target lesion response is complete 
response.


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Notes on Target Lesion Response
Lesions split: In some circumstances, disease that is measurable as a target lesion at Baseline and 
appears to be 1 mass can split to become 2 or more smaller sub-lesions.  When this occurs, the 
diameters (long axis — non-nodal lesion, short axis - nodal lesions) of the 2 split lesions should 
be added together and the sum recorded in the diameter field on the electronic case report form 
under the original lesion number.  This value will be included in the sum of diameters when 
deriving target lesion response.  The individual split lesions will not be considered as new 
lesions, and will not automatically trigger a PD designation
Lesions coalesced: Conversely, it is also possible that 2 or more lesions, which were distinctly 
separate at Baseline, become confluent at subsequent visits.  When this occurs, a plane between 
the original lesions may be maintained that would aid in obtaining diameter measurements of 
each individual lesion.  If the lesions have truly coalesced such that they are no longer separable, 
the maximal diameters (long axis — non-nodal lesion, short axis - nodal lesions) of the “merged 
lesion” should be used when calculating the sum of diameters for target lesions.  On the 
electronic case report form, the diameter of the “merged lesion” should be recorded for the size 
of 1 of the original lesions while a size of “0” mm should be entered for the remaining lesion 
numbers which have coalesced.
13.2.6 Determination of Non-Target Lesion Response
Table 13-3:
Response Criteria for Non-Target Lesions
Response Criteria
Evaluation of Non-Target Lesions
Complete Response
Disappearance of all non-target lesions.  In addition, all lymph nodes 
assigned a non-target lesion must be non-pathological in size (< 10 mm 
short axis)
Progressive Disease
Unequivocal progression of existing non-target lesionsa
Non-complete response / 
Non-progressive disease
Neither complete response nor progressive disease
a. 
Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of 
the treating physician does prevail, and the progression status should be confirmed later on by the central 
review.
Non-Target Lesion Response
The response for non-target lesions is CR only if all non-target, non-nodal lesions that were
evaluated at Baseline are now all absent and all non-target nodal lesions returned to normal size 


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(ie, < 10 mm).  If any of the non-target lesions are still present, or there are any abnormal nodal 
lesions (ie, t 10 mm), the response can only be “Non-CR/Non-PD.” 
Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such that, 
even in presence of CR, PR, or SD in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  In order for a PD to be assigned on the basis of 
non-target lesions, the increase in the extent of the disease must be substantial even in cases 
where there is no measurable disease at Baseline 
New Lesions
The appearance of a new lesion is always associated with PD and has to be recorded as a new 
lesion in the eCRF.
x
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the first observation of the lesion
x
If new disease is observed in a region which was not scanned at Baseline or where the 
particular baseline scan is not available for some reason, then this should be considered 
PD 
x
A lymph node is considered as a “new lesion” and therefore, indicative of PD if the short 
axis increases in size to t 10 mm for the first time in the study plus 5 mm absolute 
increase
13.2.7 Evaluation of Overall Lesion Response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response, and presence of new lesions as shown below in Table 13-4.
Table 13-4:
Overall Lesion Response at Each Assessment (RECIST v1.1)
Target Lesions
Non-target Lesions
New Lesions
Overall Lesion Response
CR
CR
No
CRa
CR
Non-CR/Non-PD
No
PR
PR
Non-PD
No
PRa
SD
Non-PD
No
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Target Lesions
Non-target Lesions
New Lesions
Overall Lesion Response
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; PD = progressive disease; PR = partial response; RECIST = Response Evaluation 
Criteria in Solid Tumors; SD = stable disease.
a.
This overall lesion response also applies when there are no non-target lesions identified at Baseline.
b. Once confirmed PR was achieved, all these assessments are considered PR.


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13.3 Bayesian Logistic Regression Model
This section (along with Section 6.10) describes the Bayesian Logistic Regression Model 
(BLRM) used to make dose recommendations during Phase I.
13.3.1 Specification
See Section 6.12 for DLT definitions and Section 6.10.2 for definitions of DLT-evaluable 
patients for inclusion in the DDS.
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels will be obtained.  Dose recommendation will be based on the probability 
that the true DLT rate for each dose lies in 1 of the following categories in Table 13-5.
Table 13-5:
Toxicity Categories
Name
Lower Limit
Upper Limit
Under dosing
0%
< 16%
Target toxicity
16%
< 33%
Excessive toxicity
33%
100%
The N-CRM model will predict rates of toxicity for doses between 1 mcg and 200 mcg.  This is 
the limit that has been identified for the purposes of the simulations.  For ease of presentation, 
summaries of the state of the N-CRM model will collapse these 1 mcg dose increments into 
bands as follows:
x
Between 1 mcg and 9 mcg:  no collapsing
x
Between 10 mcg and 18 mcg:  in increments of 2 mcg
x
Between 20 mcg and 200 mcg:  in increments of 5 mcg
Note: If IPE proceeds to a target dose of >150 mcg according to BLRM output and treatment at 
this dose level is well-tolerated, then an additional BLRM that allows for a maximum target dose 
of up to 350 mcg will be constructed. This model will be specific to the dose-toxicity 
relationship of target doses following IPE. The prior distribution for this new model and 
pseudo-patient information will consider posterior distributions from the existing 
BLRM(s). Operating characteristics will be assessed from a series of simulations to be 
summarized in a simulation report. 


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In case of changes in dosing schedule during dose escalation, a BLRM of the same functional 
form will be used to estimate the dose-DLT relationship for each schedule based on a newly 
derived “Bayesian prior” incorporating the historical trial data and the on-study data from 
previous schedule.  Each time the model is updated, all available information on the dose-DLT 
relationship from all explored dosing schedules will be used.  To account for between schedule 
variability in the assessment of a given dosing schedule, the DLT data obtained from other 
explored dosing schedules will be down-weighted.
Escalation Rule
Let d* be the highest dose at which the DLT status of at least 3 patients is known.  A dose is 
cleared if the ratio between it and d* is less than or equal to 3.34.  A dose is eligible if it is both 
cleared and the current posterior estimate of the probability that it lies in the excessive toxicity 
band is less than 0.25 [the EWOC rule].  The dose recommended by the N-CRM will be the 
eligible dose currently with the highest posterior probability of being in the target toxicity band.
Futility Rule
There will be no futility rule.  Phase I cohorts will continue to enroll until either the MTD (or 
RP2D) is identified or the Sponsor terminates the study for other reasons.
Success Rule
The N-CRM model will recommend that enrollment to Phase I cohorts should stop once either 
(a) at least 6 evaluable patients have been treated in the dose range in which the MTD is 
currently thought to lie or (b) no dose is eligible for dosing because of the EWOC rule.  The 
Sponsor reserves the right to continue enrollment in the Phase I cohorts beyond this time if it is 
considered clinically useful so to do.
Enrollment Limit
There will be no enrollment limit.  Enrollment will be open.
Dose-toxicity Model
X-hats: 
Let di = i mcg, i=1, …, 200.  Let ݔො௜denote the nominal dose used in the dose-toxicity model that 
corresponds to di.  Let dref = 0 mcg.  Then ݔො௜= ݀௜െ݀௥௘௙= ݀௜.


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Functional Form: 
Let Yj be a Bernoulli random variable indicating whether the jth patient experiences a DLT 
(Yj=1) or not (Yj=0).  Let ݔො௜௝denote the nominal dose received by the jth patient.  The BLRM 
will model the probability that the jth patient experiences a DLT as
݌൫ܻ௝= 1 หݔො௜௝, ߙ, ߚ, {(ݔො௜௞, ݕ௞); ݇= 1, … , ݆െ1}൯=
݁ఈାఉ௫ො೔ೕ
1 + ݁ఈାఉ௫ො೔ೕ
The Prior: 
The dose-toxicity model is a logistic model and takes the form:
݈݋݃݅ݐ(݌) = Ƚ + ߚݔො
It is assumed that toxicity increases with increasing dose and thus the slope, ȕmust be greater 
than 0.  This assumption is implemented in the model by estimating Ȗwhere ߛ= ln ( ߚ).  The 
prior for Įand Ȗtakes the form
[ߙ]~ܯܸܰ൬ቂ
ߤఈ
ߤఊቃ, ൤
ߪఈ× ߪఈ
ߩ× ߪఈ× ߪఊ
ߩ× ߪఈ× ߪఊ
ߪఊ× ߪఊ
൨൰
Initial valueVIRUȝĮȝȕıĮıȕ DQGȡZHUHEDVHGRQWKHUHVXOWVRIVLPXODWLRQVWXG\RQILOHDW
PPD) and are given in Table 13-6.
Table 13-6:
Initial Values for BLRM Simulation
Parameter
Initial Value
ȝĮ
-2.95
ȝȕ
-5
ıĮ
2.75
ıȕ
2.75
ȡ
0
BLRM = Bayesian Logistic Regression Model.
Bayes’ Theorem will be used to update the values of ȝĮȝȕıĮıȕ DQGȡDQGKHQFHWKH
probabilities of toxicity and toxicity band membership for each dose) after the results of each 
cohort of patients are known.
The pseudo-patient information in Table 13-7 was also included as prior information.


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Table 13-7:
Pseudo-Patient Information
Dose
Number of Patients
Number of DLTs
3
1
0.1
10
1
0.125
30
1
0.15
100
1
0.3
135
1
0.4
200
1
0.5
DLT = dose-limiting toxicity.
This prior gives rise to the probabilities of toxicity and band membership for selected doses as 
shown in Table 13-8.
Table 13-8:
Prior Probabilities
Dose
p(Toxicity)
Probability that Dose is in Toxicity Band:
Under Dosing
Target Toxicity
Excess Toxicity
3 mcg
0.109
0.765
0.156
0.079
10 mcg 
0.118
0.742
0.169
0.089
20 mcg 
0.136
0.697
0.184
0.119
40 mcg 
0.186
0.620
0.187
0.193
80 mcg 
0.268
0.539
0.170
0.290
100 mcg
0.297
0.512
0.165
0.323
140 mcg
0.343
0.471
0.157
0.372
180 mcg
0.378
0.441
0.148
0.412
The dose recommended by the N-CRM model will be subject to clinical review.  The SST may 
select the recommended dose or a lower dose.
13.3.2 Operating Characteristics
Information in this section is based on a simulation study, the results of which are on file at PPD.
When 3 mcg and all higher doses are unsafe, the model described above has an average sample 
of 9.2 patients.  


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When all doses are safe, the model will recommend stopping after an average of 24.5 patients 
(80th centile 33 patients).  
The simulation study also investigated a range of dose-toxicity scenarios with the true MTD 
located at the low end of the dose range, at the high end of the dose range and in the middle of 
the dose range.  Relatively steep and relatively gentle slopes were considered.  The average 
sample size was only slightly affected by the gradient of the dose-toxicity curve and ranged from 
26.9 (80th centile 27) when the true MTD was at the lower end of the dose-toxicity curve to 27.8
(80th centile 33) when the true MTD was at the upper end.  
The chance that the model identified as the MTD a dose which truly was in the target toxicity 
band ranged from 64% to 42% depending on whether the true MTD was at the lower or upper 
end of the dose range.
13.3.3 Sample Paths
The tables in this section (Table 13-9, Table 13-10, Table 13-11, and Table 13-12) illustrate 
various possible paths of dose recommendation and state of the N-CRM model given various 
response patterns that might be observed in the study.  
Table 13-9:
Scenario 1, No DLT Reported at Any Dose
Dose 
(mcg)
Number of DLTs / Number of 
Patients Treated
Estimated MTD
Recommended Next 
Dose
3
0 / 3
38
10
10
0 / 3
67
30
30
0 / 3
185
100
100
0 / 3
198
195
195
0 / 3
>200
200
DLT = dose-limiting toxicity; MTD = maximum tolerated dose.


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Table 13-10: Scenario 2, One DLT Reported at 30 mcg Dose
Dose 
(mcg)
Number of DLTs / Number of 
Patients Treated
Estimated MTD
Recommended Next 
Dose
3
0 / 3
38
10
10
0 / 3
67
30
30
1 / 3
185
100
25
0 / 3
35
35
35
0 / 3
77
75
75
0 / 3
148
145
145
0 / 3
>200
200
200
0 / 3
>200
200
200
0 / 3
>200
Stop
DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
Table 13-11: Scenario 3, Two DLTs Reported at 100 mcg Dose
Dose
Number of DLTs / Number of 
Patients Treated
Estimated MTD
Recommended Next 
Dose
3
0 / 3
38
10
10
0 / 3
67
30
30
0 / 3
185
100
100
2 / 3
61
60
60
0 / 3
70
70
70
0 / 3
78
75
75
0 / 3
87
85
85
0 / 3
100
100
100
2 / 3
83
80
80
0 / 3
87
85
85
0 / 3
91
90
90
0 / 3
97
Stop
DLT = dose-limiting toxicity; MTD = maximum tolerated dose.


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Table 13-12: Scenario 4, One DLT at 30 mcg, 2 DLTs at 145 mcg and 2 DLTs at 
100 mcg Dose
Dose
Number of DLTs / Number of 
Patients Treated
Estimated MTD
Recommended Next 
Dose
3
0 / 3
38
10
10
0 / 3
67
30
30
0 / 3
28
25
25
1 / 3
35
35
35
0 / 3
77
75
75
0/ 3
148
145
145
2 / 3
87
85
85
0 / 3
99
95
95
0 / 3
109
105
105
2 / 3
93
90
90
0 / 3
99
Stop
DLT = dose-limiting toxicity; MTD = maximum tolerated dose.


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13.4 Schedule of Cycle 1 Assessments, Intra-Patient Escalation Regimen
Patients who receive IPE should follow the schedule below during Cycle 1, and the main 
schedule at all other times, including Pre-Screening, Screening, Cycle 2 and subsequent 
treatment cycles, and Follow-up.  
The Cycle 1 schedule is provided in Table 13-13.  Assessments marked “X” should be performed 
prior to dosing.  Assessments that are to be performed at multiple timepoints are marked with the 
number of timepoints (including optional timepoints, if applicable) for the visit (eg, 2× is twice) 
and details of the timepoints are provided in the footnote.  Additional details regarding the 
assessments are provided in Section 7.4. 
Table 13-13: Schedule of Cycle 1 Assessments, IPE Regimen 
Procedure
Cycle 1
Day of Cycle
1 
2 
8 
9 
15
16
22
Adverse events
X 
X 
X 
X 
X 
X 
X 
Concomitant medications
X 
X 
X 
X 
X 
X 
X 
Safety Assessments
Complete physical examination
X 
Abbreviated physical examination
X 
X 
X 
Weight
X 
Vital signs
~14× 
~14× 
~14× 
3×
12-lead ECG (single) 
2×
ECOG performance status
X 
Hematology panel
X 
X 
X 
X 
X 
X 
Chemistry panel
X 
X 
X 
X 
Thyroid function
X 
Urine pregnancy test (women of 
childbearing potential)
X 
PK and Immunogenicity Assessments
Pharmacokinetic sampling
3×
X 
8× 
X 
8×
X 
3× 
Immunogenicity sampling
X 
X 
X 
Tumor biopsy 
Between C1D9 and &'UHTXLUHGIRUSDWLHQWVLQPhase II, 
optional for all other patients)


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Procedure
Cycle 1
IMCnyeso Administration
One-step IPE
C1D1 
dose 
level
Target 
dose 
level
Target 
dose 
level
Target 
dose 
level
Two-step IPE
C1D1 
dose 
level
C1D8
level
Target 
dose 
level
Target 
dose 
level
AE = adverse event; C#D# = Cycle # Day #; CRS = cytokine release syndrome; 
; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of 
infusion; hr = hour(s); min = minutes; 
 PK = pharmacokinetics; 
 
ECG assessments are to be done pre-dose and within 1 hour of EOI on indicated days. 
Vitals (body temperature, pulse, respiratory rate, blood pressure; oxygen saturation should also be assessed for 
 first 3 cycles of treatment), are to be assessed at the following timepoints:
x
C1D1/C1D2, C1D8/C1D9, and C1D15/C1D16: pre-dose (within 2 hours), EOI (within 15 min), every 
2 hours (± 15 min) through 8-hour post-EOI, then every 4 hours (± 30 min) until discharge
x
C1D22: pre-dose (within 2 hours), EOI (within 15 min), and 1-hour post-EOI (± 15 min)  
Pharmacokinetics samples are to be collected at the following timepoints:
x
C1D1: pre-dose (within 2 hours), EOI (within 15 min), 8-hour post-EOI (± 1 hr) 
x
C1D8 and C1D15: pre-dose (within 2 hours), EOI (within 15 min), 1-hour post-EOI (± 15 min), 2-hour 
post-EOI (± 15 min), 4-hour post-EOI (± 15 min), 6-hour post-EOI (± 30 min), 8-hour post-EOI (± 1 hr), 
and 12-hour post-EOI (optional, ± 3 hr)
x
C1D2, C1D9, and C1D16: 24-hour post-EOI (± 4 hr) 
x
C1D22: pre-dose (within 2 hours), EOI (within 15 min), 8-hour post dose (± 1 hr) 
Central lab cytokine testing samples are to be collected at the following timepoints:
x
C1D1: pre-dose (within 2 hours) and 4-hour post-EOI (± 15 min) 
x
C1D8 and C1D15: pre-dose (within 2 hours), 4-hour post-EOI (± 15 min), 8-hour post-EOI (± 1 hr), and 
12-hour post-EOI (optional, ± 3 hr) 
x
C1D2, C1D9, and C1D16: 24-hour post-EOI (± 4 hr) 
x
C1D22: pre-dose (within 2 hours) and 4-hour post-EOI (± 15 min) 
x
Additional samples may be collected if a patient has suspected CRS.  Recommended timepoints are 
within 5 hours and 1 week after onset of CRS. 


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13.5 Detailed Description and Rationale for Changes
13.5.1 Amendment 3
Section 
Change
Rationale
Multiple
The generic name “tebentafusp” is used throughout for IMCgp100
To use current nomenclature
Synopsis
The synopsis was updated as needed to reflect the changes below
To ensure consistency
Section 1.4
Added clinical experience in ongoing study as of 22Jan2020
To provide current enrollment and safety 
information for the study
Section 5.3
The exclusion criterion for minimum creatinine clearance was 
decreased from 50 mL/min to 40 mL/min
Especially in urothelial carcinoma, patients with 
advanced cancers may have decreased renal 
function but are not anticipated to be at elevated 
risk for treatment-related toxicities
Section 5.3
The exclusion criterion for congestive heart failure was updated to 
add the word “diagnosed”: Clinically significant and/or uncontrolled 
heart disease such as diagnosed congestive heart failure (New York 
+HDUW$VVRFLDWLRQ&ODVV
To clarify that the exclusion is for diagnosed 
congestive heart failure rather than signs and 
symptoms that could be confused with Class 2 
congestive heart failure (mild symptoms [mild 
shortness of breath and/or angina] and slight 
limitation during ordinary activity) but are due to 
other causes 
Section 5.3
The exclusion criterion for ongoing  Grade 2 toxicity due to prior 
cancer therapy was updated so that any Grade 2 endocrine disorder 
[on stable replacement doses and without symptoms] is an
exception; previously this exception was limited to hypothyroidism
Other Grade 2 endocrine disorders may occur due 
to prior cancer therapy and are not anticipated to 
be associated with an elevated risk for treatment-
related toxicities if asymptomatic and clinical 
stable on replacement therapy


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Section 
Change
Rationale
Section 5.3
In the exclusion criterion for antibiotic use, the washout period for 
oral antibiotics was reduced from 14 days to 7 days prior to the first 
dose of study drug (note: there was no change to the washout period 
for IV antibiotics).
Patients who responded to oral antibiotics, 
completed treatment at least 7 days before the first 
dose of study drug, and meet all other eligibility 
criteria are not anticipated to be at an elevated risk 
for treatment-related toxicities  
Section 6.2
Added that after Phase I is completed and the SST has reviewed all 
available relevant data for at least 6 patients at the RP2D, the SST 
may decide to reduce the minimum required monitoring time to no 
less than 8 hours post-end of infusion on C1D1, C1D8, and/or 
C1D15 (with longer hospitalization if indicated) during the Phase II 
portion of the study.
Based on the observation that all signs/symptoms 
of CRS, to date, have occurred rapidly (within a 
few hours) following administration of IMCnyeso,
and provided the initial assessment of safety at the 
RP2D supports the dose as being well-tolerated 
and any signs/symptoms suggestive of CRS occur 
within 2-4 hours post-end of infusion, then 
monitoring for 8 hours post-end of infusion
provides an adequate safety margin
Section 6.4
If the Cycle 1 Day 1 dose is  30 mcg, the infusion may be given 
over 1 hour rather than 2 hours
Based on emerging safety data, an initial dose of 
 30 mcg infused over 1hour is anticipated to be 
tolerable and would simplify study conduct 
Section 6.10.1
For any allowed dose escalation step, an option was added to switch 
from a fixed-dose regimen to a 1-step or 2-step IPE regimen (or 
from a 1-step to a 2-step IPE regimen as applicable). Figure 6-3, 
which shows representative escalation paths with IPE options, was 
updated accordingly.
Initial assessment of a new higher dose level is 
anticipated to present less risk when IPE regimen 
is used instead of a fixed-dose regimen
Section 6.10.1 and 
6.10.2
The DLT observation period is 28 days for all regimens (previously 
the DLT observation period was extended for intrapatient escalation 
regimens)
The DLT observation period is designed to allow 
detection of acute treatment-related toxicities, 
which are anticipated to occur within the first 28 
days of treatment, regardless of regimen


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Section 
Change
Rationale
Section 6.10.1
Added an option for patients who were enrolled in a lower dose 
cohort to move to a higher dose level after the higher dose level has 
successfully completed SST review, if the patient has completed at 
least 3 cycles of treatment, and has tolerated treatment well 
To allow patients to receive a dose level that may 
provide more therapeutic benefit, with appropriate 
safeguards for safety
Section 6.13
Added that non-live vaccines are not to be administered within 14 
days before and 28 days after the first dose of IMCnyeso treatment, 
and thereafter not within 24 hours before or after IMCnyeso 
treatment, and live or attenuated vaccines are prohibited from 28 
days prior to the first dose of IMCnyeso until 30 days after the last 
dose of IMCnyeso
Vaccine-related adverse events may be 
exacerbated by immune activation associated with 
IMCnyeso treatment
Section 7
Schedule of Assessments Tables 7-1 and 7-2 were updated to reflect 
changes in Section 7.4.4 shown below
To ensure consistency between the Schedule of 
Assessments tables and the body of the protocol
Section 7
In the Schedule of Treatment Period Assessments table (Table 7-2), 
inconsistencies between the main table and footnote were resolved
Correction of typographical errors
Section 7
The sample collection for pharmacokinetics at the Cycle 1 Day 2 
36-hour post-EOI timepoint is optional rather than mandatory
To aid in protocol compliance
Section 7.4.4
Follicle-stimulating hormone is to be done only if required to 
confirm non-childbearing potential, rather than required for all post-
menopausal women
It is not necessary to test FSH in all 
post-menopausal women
Section 7.4.4
Added that blood oxygen saturation should be assessed at Screening 
and for at least the first 3 treatment cycles
Monitoring oxygen saturation may aid in 
detection and management of cytokine release 
syndrome 


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Section 
Change
Rationale
Section 13.1.1
Added that if dose escalation proceeds to a dose of >150 mcg
according to the BLRM and treatment at this dose level is 
well-tolerated, additional BLRM simulations may be performed to 
predict rates of toxicity for higher dose levels
To enable consideration of higher doses if 
supported by emerging safety data
Section 13.4
The sample collection for pharmacokinetic and central lab cytokine 
assessments at 12 hours post end of infusion are optional rather than 
mandatory
To aid in protocol compliance
13.5.2 Amendment 2
Section in
Amendment 1
Change
Rationale
Cover page
Updated sponsor contact information
The study has a new Medical Monitor
Synopsis
The synopsis was updated as needed to reflect the changes below
To ensure consistency
Synopsis
Inclusion / exclusion criteria, study objectives, and rationale for 
selection of the starting dose were removed from the synopsis
To simplify the synopsis and prevent potential 
inconsistencies
Synopsis
Updated to “Based on the available IMCnyeso preclinical data and 
clinical safety information from the related ImmTAC molecule 
IMCgp100, IMCnyeso may induce rash, tumor flare/pain, 
lymphopenia (associated with lymphocyte trafficking), and cytokine 
release syndrome.  Conservative monitoring and management 
guidelines as well as definitions of DLT have been implemented”
To provide more current and comprehensive 
summary of risk information rather than focusing 
primarily on potential for skin toxicity
Section 1.1
IMCnyeso is a “bispecific protein therapeutic” rather than “bispecific 
biologics”
To clarify that IMCnyeso is a protein 


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Section 1.2
Simplified language describing mechanism of action
To clarify the mechanism of action of IMCnyeso 
Section 1.2
Updated mechanism of action statement to add sentence: "In addition, 
IMCnyeso-mediated tumor lysis may prime an endogenous anti-tumor 
immune response"
To add a description of a second potential 
mechanism of action based on emerging data from 
other ImmTAC clinical trials
Section 1.2
Information about NY-ESO-1 / LAGE-1A testing removed from this 
section and consolidated in Section 1.5 (screening strategy) and 
Section 7.4.1 (description of assessments)
Removed redundant information
Section 1.3
Consolidated description of species specificity of IMCnyeso at the 
start of Section 1.3 and removed this information from the following 
sub-sections
Removed redundant information
Section 1.4
Added clinical experience in ongoing study as of 26Apr2019
To provide current enrollment and safety 
information for the study
Section 1.4
Cytokine release syndrome (CRS) section updated to add: Release of 
pro-inflammatory cytokines (eg, IL-6, IFN-Ȗ, TNF-Į) is a predicted 
pharmacodynamic effect of IMCnyeso.  Based on experience with 
IMCgp100, symptoms such as pyrexia, chills, nausea, hypotension, 
and edema were observed in most patients, typically 4-24 hours after 
the first 2-3 doses.  As of August 2018, 2% of patients in the 
IMCgp100-102 study experienced severe (Grade 3) CRS with 
IMCgp100
To provide more current and comprehensive risk 
information 
Section 1.4
Added that IMCnyeso may cause inflammation within the tumor 
microenvironment.  Depending on the location of the tumors, various 
AEs may occur, including hepatic events and pulmonary events 
To provide more current and comprehensive risk 
information


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Section 1.5
Added that target expression frequencies are significantly lower in 
uveal melanoma and NSCLC adenocarcinoma
To provide additional information regarding target 
antigen expression
Section 1.6.4
A reference was added regarding treatment options for patients with 
synovial sarcoma
To provide a more current reference
Section 2.1,
Section 6.4
The Study Safety Team will include Study Investigators, Sponsor 
Medical Monitor, and a statistician (role of independent medical 
oncologist removed)
For operational simplicity and to align with standard 
practice for FIH studies
Section 2.2
Description of measures taken to minimize risks for patients in the 
study updated to include “eligibility criteria designed to exclude 
patients at potentially high risk for experiencing treatment-related 
toxicity”
To correct an omission
Section 3, 
Section 9
A substantial amount of redundant information was removed; 
hyperlinks were added to the relevant sections where information is 
located
To remove redundant information
Section 3, 
Section 9.9.1
The estimated number of patients in Phase I is 27. In 80% of 
simulations conducted, the sample size was < 33 patients
Estimated patient numbers were updated to reflect 
results of the new BLRM simulations
Section 3, 
Section 9.9.2
Simon 2-stage design incorporated for Phase II with initial enrollment 
of 9 patients and option to enroll 15 additional patients if there is at 
least one response.  A formal interim analysis was added to Phase II
To enable more robust assessment of efficacy and 
provide justification for the Phase II sample size
Section 3.4
Redundant information regarding study periods was deleted from 
Section 3.4 and assessment details moved to Section 7
To remove redundant information and improve 
organization
Section 3.4, 
Section 7.3, 
and others
Safety follow-up changed to 30 days (from 90 days)
30-day safety follow-up is appropriate based on the 
<24-hour half-life of ImmTAC


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Rationale 
Section 3.5 
Substantially shortened.  Criteria for treatment discontinuation 
consolidated in Section 6.16
To remove redundant information and improve 
organization 
Section 3.6 
Clarified requirements for planned End of Study, including requiring 
that secondary endpoints of objective response, overall survival, 
progression-free survival, and duration of response have been 
adequately assessed in all subjects
To ensure that study objectives and endpoints are 
adequately assessed before End of Study 
Section 4 
Redundant body text was removed; objectives and corresponding 
endpoints are shown in table format only 
Removed redundant information and improve 
organization 
Section 2.1, 
Section 3.1, 
Section 4 
The primary objective for Phase II was changed from “to further 
explore the safety and tolerability of the identified RP2D” to 
preliminary efficacy (BOR per RECIST v.1.1).  Safety and tolerability 
is a secondary objective for Phase II.
To align with the goals of the Phase II portion of the 
study 
Section 4 
A secondary efficacy objective (based on RECIST v1.1) was added for 
Phase I
Efficacy is evaluated in Phase I but previously was 
not associated with a study objective 
Section 4, 
Section 7 
Response will no longer be evaluated per modified irRECIST
To simplify study conduct and align with current 
standards in the field
Section 4 
The secondary PK endpoint was clarified to indicate that serum PK 
parameters would be determined after single and multiple doses  
To clarify scope of planned analysis 
Section 4 
The secondary ADA endpoint was updated to include the impact of 
ADA on PK
To clarify scope of planned analysis 
Section 4 


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Change
Rationale 
Section 4 
Section 4 
Section 5.1 
Shortened description of patient population 
To remove redundant information 
Section 5.2, 
Section 5.3
Organized eligibility criteria by topic and simplified 
To aid in protocol compliance
Section 5.2 
Clarified prior treatment requirements for Phase I to “Patients must be 
relapsed from, refractory to, or intolerant to all approved and available 
classes of therapy known to provide clinical benefit for their 
condition” 
To clarify study inclusion criteria
Section 5.2 
Clarified prior treatment requirements for Phase II to note that 
required therapies may have been given in the adjuvant setting if 
disease progression occurred during or within 6 months of completing 
adjuvant therapy, and patients with NSCLC with a genomic tumor 
aberration (eg, EGFR, ALK) that is targeted by Health Authority-
approved agent(s) must be relapsed from, refractory to, or intolerant of 
relevant targeted agent(s).
To align with standard of care 
Section 5.3 
Allow patients with Grade 2 hypophosphatemia [if receiving 
appropriate replacement therapy] or hypothyroidism [if on stable 
replacement doses] due to prior cancer therapy to enroll
Hypophosphatemia due to prior ifosfamide and 
hypothyroidism due to prior checkpoint inhibitors 
are relatively common in the eligible patient 
population and are not expected to be exacerbated 
by IMCnyeso treatment


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Section 5.3
Patients with leptomeningeal disease or cord compression are not 
eligible for study participation
To ensure adequate baseline health status of 
enrolled patients
Section 5.3
Clarify that hematology evaluations used to determine study eligibility 
PXVWEHSHUIRUPHGGD\VIURPDQ\EORRGRUEORRGSURGXFW
WUDQVIXVLRQDQGGD\VIURPDQ\GRVHRIKHPDWRORJLFJURZWKIDFWRU
removed exclusion criteria regarding use of hematopoietic growth 
factors and erythroid stimulating agents
To ensure that enrolled patients have adequate 
hematologic function and simplify the protocol
Section 5.3
Eligibility criteria for renal function will be based only on creatinine 
clearance, rather than creatinine concentration and/or creatinine 
clearance
To reduce ambiguity in eligibility criteria
Section 5.3 
Added for patients with Gilbert’s syndrome exclude if total bilirubin 
> 3.0 × ULN or direct bilirubin > 1.5 × ULN
Slightly elevated bilirubin in patients with Gilbert’s 
syndrome is not a safety concern for IMCnyeso
Section 5.3
Reduced minimum absolute lymphocyte count needed for eligibility to 
<0.5 × 109/L (previously 1.0 × 109/L)
Grade 2 lymphopenia is a relatively common 
finding in patients with advanced cancers and is not 
expected to impact the safety or efficacy of 
IMCnyeso 
Section 5.3
Removed electrolyte lab abnormalities from exclusion criteria
Electrolyte abnormalities can be appropriately 
managed and should not be exclusionary
Section 5.3
Removed exclusion criterion for prior hypersensitivity to other 
biologic drugs or monoclonal antibodies
Prior hypersensitivity to another biologic drug does 
not necessarily indicate elevated risk of 
hypersensitivity to IMCnyeso
Section 5.3
Systemic antibiotics must be completed at least 14 days prior to the 
first dose of study drug (rather than prior to screening)
To improve operational feasibility while 
maintaining appropriate safeguards


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Section 6.1
Deleted “The term investigational drug (study medication) in this FIH 
Phase I/II study refers to IMCnyeso”
To simplify protocol language
Section 6.1
Clarified “Fully functional resuscitation equipment and medications to 
handle acute infusion-related emergencies (eg, anaphylaxis, cytokine 
release syndrome) must be available at each study site”; Previously 
“Fully functional resuscitation facilities must be available at each 
study site”
To clarify facility requirements for investigational 
sites
Section 6.1.1
Clarified that each vial is used for “1 dose /1 patient” (previously 
“1 patient”)
To reinforce that drug product vials are for single 
use
Section 6.2
The first three patients at each dose level will be hospitalized for 
2 nights after the first dose of IMCnyeso.  After reviewing safety, PK, 
and cytokine data from at least 3 patients enrolled at a given dose 
level, the SST may decide that 1 night of hospitalization is adequate 
after the first dose for subsequent patients with longer hospitalization 
if indicated
ImmTACs have short (<24 hour) serum half-life 
and rapid pharmacodynamic effects; based on 
studies for the related ImmTAC molecule, 
IMCgp100, when treatment-related AE occur, the 
onset is anticipated to be rapid (<24 hours post 
dose) and no instances of rapid re-admission due to 
treatment-related AE occurred after discharge 
following one night of hospitalization after dosing. 
Per-protocol patients in the current study will be 
PRQLWRUHGIRU hours (±4 hours) following the 
C1D1 dose.
Section 6.3
Clarified that storage times for prepared doses is determined starting at 
time of vial breach rather than time when dose preparation is complete
To correct an inconsistency 
Section 6.3
Updated drug product storage and infusion windows 
To incorporate new refrigerator stability data 
(2°C-8°C for up to 24 hours)


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Section 6.4
Updated duration of infusion to “the first dose will be infused over 
2 hours (±15 minutes).  If the first dose is well tolerated without 
 Grade 2 infusion and/or a hypersensitivity reaction, a given patient's 
subsequent infusion times may be reduced to 1 hour (±10 minutes) 
starting at C1D8, and further reduced to 30 minutes (±10 minutes) 
starting at C3D1”
To support patient safety and simplify protocol 
compliance (by giving the first infusion over 2 
hours for all patients and by having the same 
reduction in duration of infusion for all cohorts at 
subsequent doses)
Section 6.4
Redundant information regarding concomitant medications was 
removed and hyperlinks added to relevant sections
To remove redundant information and improve 
overall organization
Section 6.10, 
Section 13.3
The prior assumptions for the Bayesian Logistical Regression Model 
(BLRM) were updated.  Higher dose levels were included in the 
model.  The operating characteristics, example dose levels, and 
potential escalation schemes were updated accordingly
To emphasize emerging clinical data rather than 
preclinical assumptions of MTD in guiding 
dose-escalation increments
Section 6.10
If the emerging safety profile indicates that treatment-related AEs (eg, 
cytokine release) are more severe following initial doses and less 
severe after later doses, the Study Safety Team may initiate a 1-step or 
2-step intra-patient escalation regimen.  A longer DLT evaluation 
period and adjusted Cycle 1 schedule were added for patients 
receiving intra-patient escalation
Intra-patient dose-escalation approaches have 
proven beneficial in mitigating acute safety events
for other CD3 bispecifics, including blinatumomab 
and the related ImmTAC molecule IMCgp100
(Saber, 2017)
Section 6.11
Separated criteria for MTD and RP2D
For clarity in study execution
Section 6.12
Added “In the absence of clinically significant signs or symptoms, 
abnormal laboratory values that potentially meet DLT criteria must be 
confirmed by re-testing at least 24 hours after the initial observation.”
To ensure that isolated abnormal laboratory values 
are not considered as DLT unless clinically 
significant and/or confirmed by re-testing
Section 6.12
Redundant information in the DLT criteria table removed
To remove redundant information and provide 
clarity for study execution


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Section 6.12
Grade 4 neutropenia persisting > 5 days after onset or associated with 
infection is a DLT
Transient laboratory findings of Grade 4 
neutropenia in the absence of fever or infection do 
not indicate DLT
Section 6.12
*UDGHO\PSKRSHQLDLQWKHSUHVHQFHRIDQLQIHFWLRQLQGLFDWLQJ
clinical significance is a DLT
Laboratory findings of lymphopenia, in absence of 
infection, do not indicate DLT
Section 6.12
Grade 3 thrombocytopenia associated with bleeding is a DLT if 
bleeding is  Grade 3
Low-grade bleeding does not indicate DLT
Section 6.12
DLT criterion for concurrent elevations in ALT/AST and bilirubin 
were updated to align with Potential Hy’s Law criteria
To align with standards in the field including FDA 
guidance regarding the case definition of Hy’s Law
Section 6.12
Grade 3 ALT/AST were adjusted to apply stricter criteria for 
elevations > 8 × ULN (DLT) than for more modest Grade 3 elevations 
(DLT if not resolved to *UDGHZLWKLQGD\V); previously any 
Grade 3 ALT/AST elevation was not a DLT if resolved to *UDGH
within 72 hours); similar adjustments were also made for bilirubin 
(> 5 × ULN is a DLT regardless of duration; more modest Grade 3 
elevations are DLT if not resolved to *UDGHZLWKLQGD\V
To provide more stringent DLT criteria for more 
severe Grade 3 isolated transaminase or isolated
total bilirubin increase and to align with FDA 
guidance regarding when to discontinue study 
medication in the setting of potential drug-induced 
liver injury
Section 6.12
DLT criterion regarding amylase / lipase increase were added
To ensure only clinically significant findings meet 
DLT criteria
Section 6.12
DLT criterion for hypotension updated to remove “Any event of 
hypotension requiring pharmacologic blood pressure support … of any 
duration is a DLT”
To align with grading and DLT criteria for cytokine 
release syndrome
Section 6.12
Hypertension DLT criteria based on Grade 3 numeric criteria from 
CTCAE 
To clarify which portions of the CTCAE definition 
are applicable


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Section 6.12
Clarified “The Investigator must notify the Sponsor within 24 hours of 
DQ\6$('/7 *UDGH&56RU*UDGHKHSDWLFIXQFWLRQ
abnormality.” rather than “The Investigator must notify the Sponsor 
immediately of any unexpected NCI CTCAE GUDGH$(VRU
laboratory abnormalities.”
To ensure rapid communication of the most 
important safety events and to aid in protocol 
compliance
Section 6.12
Grade 3 skin toxicity is not a DLT if resolved within 7 days 
(previously 4 days)
Based on experience with IMCgp100, a single event 
of Grade 3 skin toxicity is not dose-limiting, but 
may require slightly longer resolution time
Section 6.13
Updated guidance on anti-coagulant therapy to state: Anti-coagulant 
therapy is permitted. International normalized ratio should be 
monitored as clinically indicated per the Investigator’s discretion. 
Ongoing anti-coagulant therapy should be temporarily discontinued to 
allow tumor biopsy according to institutional guidelines. Recent 
hospitalizations that required low dose heparin for deep vein 
thrombosis prophylaxis are not a contraindication
To provide a broader guidance regarding anti-
coagulant therapy that covers newer anticoagulants 
as well as warfarin and heparin
Section 6.13
Added: Appropriate management of patients with more severe 
hypertension, receiving medications that may cause rebound 
hypertension when abruptly discontinued, or on multiple blood 
pressure medications, should be discussed with the Sponsor Medical 
Monitor
To ensure patient safety, in cases where withholding 
anti-hypertensive medications may be 
contraindicated
Section 6.13
Allow treatment with denosumab (previously no monoclonal 
antibodies were allowed)
To allow a standard supportive care agent for 
patients with bone metastasis
Section 6.13
Clarify that prohibition of anti-cancer therapies refers to systemic 
therapies for the cancer under study
To allow anti-cancer therapies for secondary 
malignancies that would not provide therapeutic 
benefit for the disease under study (eg, adjuvant 


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tamoxifen for prior breast cancer would not be 
prohibited) 
Section 6.13
Added: Based on the emerging safety profile of IMCnyeso, the SST 
may decide to recommend a standard pre-treatment regimen (which 
may include antihistamine, acetaminophen, and/or corticosteroid)
Pre-medications are commonly used for other 
anti-CD3 bispecific molecules and may improve 
benefit/risk based on emerging safety profile from 
other ImmTAC programs
Section 6.13
Allow corticosteroids for known allergy to contrast reagents
To allow exception to prohibition of steroid therapy 
for standard management of patients with contrast
reagent allergy
Section 6.15
CRS is to be graded based on the ASTCT 2019 guidelines (Lee; 2019). 
The definition of CRS, grading criteria, and definition of resolution of 
CRS were added in Appendix 1
To align with the most current standards and 
provide further clarification regarding standards for 
reporting, resolution, and data collection of CRS 
events
Section 6.15
In addition to recommended toxicity management, a new column was 
added for dose-modification requirements, and guidance was added for 
each toxicity and grade if not already present
To provide clear guidance regarding when study 
treatment should be interrupted, dose-reduced, or 
permanently discontinued
Section 6.15
AE grading criteria for specific toxicities was removed from toxicity 
management guideline table
To remove redundant information
Section 6.15
Information provided both in table and text removed from table
To remove redundant information
Section 6.15
Information regarding management and dose modifications for 
hypotension were incorporated into the CRS guidance rather than a 
stand-alone category
Based on experience with related molecules, 
potential events of hypotension may occur in the 
context of CRS rather than as an isolated event
Section 6.15
CRS defined as occurring at least 1 hour after the start of infusion; 
IRR defined as occurring within 1 hour of starting the infusion
To clarify when CRS guidance vs. IRR guidance 
should be followed and how to systematically 


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classify events for the purposes of AE data 
collection
Section 6.15
Guideline for Grade 1 CRS updated to remove “assess for potential 
infection”, “treat … neutropenia” and “strongly consider early, high-
dose corticosteroid therapy with changes in vital signs”. Added 
reminder to collect serum for central lab cytokine assessments
To incorporate the most up-to-date management 
approaches, align with other ImmTAC protocols, 
and aid in protocol compliance
Section 6.15
Guideline for Grade 2 CRS updated to add “If patient experiences 
dyspnea, consider supportive measures such as supplemental oxygen”. 
Require overnight hospitalization following the next scheduled dose
To align with ASTCT 2019 guidelines
Section 6.15
Guideline for Grade 3 CRS updated to provide recommended dosing 
for corticosteroids and tocilizumab. Added “for persistent hypotension 
treat with a single vasopressor (with or without vasopressin)” and “for 
hypoxia provide oxygen with a high-flow device”
Added requirements for dose reduction, pre-medication, and overnight 
hospitalization if re-treatment is given.  Added discontinuation criteria 
for recurrent Grade 3 CRS
To incorporate the most up-to-date management 
approaches, align with ASTCT 2019 guidelines, and 
align with other ImmTAC protocols
Section 6.15
Guideline for Grade 4 CRS updated to provide and add “treat 
hypotension with multiple vasopressors, for hypoxia provide oxygen 
using a positive-pressure device, and consider other 
immunosuppressive agents as indicated (eg, infliximab and 
mycophenolate mofetil)”
To incorporate the most up-to-date management 
approaches, align with ASTCT 2019 guidelines, and 
align with other ImmTAC protocols
Section 6.15
Management and dose-modification guidelines for rash and pruritus 
were consolidated into a single section
To remove redundant information and to aid in 
protocol compliance
Section 6.15
Guidance for Grade 2 rash and Grade 2 pruritis updated to allow 
dosing to continue (previously required return to  Grade 1)
To incorporate the most up-to-date management 
approaches and align with other ImmTAC protocols


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Section 6.15
Guidance for Grade 3 rash updated to require treatment 
discontinuation if Grade 3 rash does to not resolve to Grade 1 or better 
within 21 days
To provide guidance for a scenario not discussed in 
the prior version
Section 6.15
Guidance for Grade 3 pruritis updated to consider montelukast 10 mg 
by mouth for patients who are refractory to antihistamine and local 
corticosteroid treatments
To incorporate the most up-to-date management 
approaches and align with other ImmTAC protocols
Section 6.15
Guidance for Grade 1 IRR updated to add a requirement for more 
frequent monitoring of vital signs while removing treatment and 
infusion interruption
To align with CTCAE v4.03 definition of Grade 1 
infusion-related reaction (infusion interruption not 
indicated; intervention not indicated)
Section 6.15
Guidance for Grade 2 IRR updated to monitor pulse oximetry and 
continuous cardiac telemetry (if clinically indicated). If IRR resolves 
in < 4 hours, the infusion may continue upon resolution without the 
previous requirement for an additional 1-hour monitoring period 
before resuming infusion. Added guidance for the scenario of IRR that 
requires > 4 hours to resolve
To ensure patient safety and provide guidance for 
scenarios not included in the prior version
Section 6.15
Guidance for Grade 3 IRR updated to allow treatment to continue only  
at the next scheduled dose (rather than re-starting the interrupted 
infusion on the same day), with mandatory pre-medication and a 
reduced rate of infusion
To provide more extensive mitigation for 
re-treatment following Grade 3 IRR and guidance 
for scenarios not included in the prior version
Section 6.15
Guidance for Grade 4 infusion-related reaction updated to require 
permanent discontinuation of study drug
To provide clear discontinuation criteria
Section 6.15
Guidance for Grade 3 hepatic function abnormality updated to include 
dose-modification guidelines including threshold for treatment 
discontinuation
To provide more extensive risk mitigation in the 
setting of re-treatment and clear guidelines for when 
treatment should be permanently discontinued


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Rationale
Section 6.15
Require permanent treatment discontinuation for Grade 4 hepatic 
function abnormalities
To provide clear discontinuation criteria
Section 6.15
Require treatment interruption for Grade 3 or Grade 4 vomiting and 
require dose reduction for prolonged (>3 days) Grade 3 or any 
duration Grade 4 vomiting
To provide more stringent dose modification for 
severe vomiting
Section 6.16
Reasons for treatment discontinuation were consolidated into a single 
section, with hyperlinks from other protocol sections
To aid in protocol compliance, remove 
inconsistencies and redundancies, and improve 
overall organization
Section 6.16
Updated reason for discontinuation of study treatment to “Disease 
progression (Note: Patients may receive treatment after initial disease 
progression per RECIST v1.1 based on criteria in Section 6.18)”, 
previously unequivocal, confirmed disease progression based on the 
modified irRECIST criteria and/or RECIST v1.1 criteria
To ensure reason treatment is discontinued is 
reported accurately for all patients who discontinue 
treatment due to PD (including initial PD based on 
single assessment per RECIST v1.1, confirmed PD 
based on at least 2 assessments, or symptomatic / 
clinical deterioration consistent with disease 
progression)
Section 6.16
Information about the EOT visit consolidated in Section 7.3
To aid in protocol compliance
Section 6.18
Treatment discontinuation will be required when unequivocal disease 
SURJUHVVLRQLVFRQILUPHGGHILQHGDVDQDGGLWLRQDO 5 mm increase in 
tumor burden [sum of diameters of both target and new lesions] and/or 
identification of additional new lesions, at least 4 weeks after the 
initial PD assessment)
To align with more current iRECIST standards 
(Seymour 2017)
Section 7
Schedule tables were reformatted to have all schedule information for 
each study period within a single table.  Schedule information was 
removed from other protocol sections including the Synopsis
To aid in compliance and reduce inconsistency and 
redundancy


.
Protocol Number:  IMCnyeso-101 
Investigational Product:  IMCnyeso
Version: 4.0, 24Feb2020 
CONFIDENTIAL AND PROPRIETARY
149 of 153
Section in
Amendment 1
Change
Rationale 
Section 7 
Section 7.1, 
Section 7.2.2 
Moved HLA-A*02:01 testing, NY-ESO-1 / LAGE-1A testing, and 
patient demographics and other baseline characteristics to Section 7.4 
To improve protocol organization
Section 7.1 
If the patient is already known to be HLA-A*02:01 positive, the HLA 
sample and tumor sample can be submitted in parallel
To improve operational logistics 
Section 7.2 
Acceptable time windows were added if not previously included and 
adjusted in some cases 
To improve operational feasibility and minimize 
protocol deviations 
Section 7.2 
Added that after C1D1 pregnancy testing may be performed up to 
72 hours prior to dosing and other safety assessments may be 
performed up to 24 hours prior to dosing 
To improve operational feasibility and improve 
protocol compliance 
Section 7.2
Scheduled chemistry and hematology evaluations reduced to Q2W in 
Cycle 3 and Q4W for Cycle 4 and beyond 
To reduce testing during later cycles, when risk of 
new treatment-related AE is lower
Section 7.2 
The visit window during the treatment period is ±7 days; added that 
there must be a minimum of 7 days between doses of IMCnyeso
To ensure an adequate interval between doses of 
study drug, for patient safety
Section 7.3 
Added safety assessments at the 30-day post last-dose visit
To allow evaluation of resolution of any abnormal 
findings or laboratory values at End of Treatment 
Section 7.4 
Clarified that patients who initiate subsequent anti-cancer treatment 
will proceed directly to Survival Follow-up.  Any treatment-related 
SAE must be reported even if safety follow-up has completed 
To minimize confounding effects of subsequent 
anti-cancer therapies when evaluating safety of 
IMCnyeso
Section 5.1, 
Section 7 
All patients may use archival tumor for Pre-Screening  
NY-ESO-1 / LAGE-1A expression is not expected 
to decrease following other treatments. Given the 


.
Protocol Number: IMCnyeso-101
Investigational Product: IMCnyeso
Version: 4.0, 24Feb2020
CONFIDENTIAL AND PROPRIETARY
150 of 153
Section in
Amendment 1
Change
Rationale
rates of antigen positivity, it is not appropriate to 
require biopsy procedures during Pre-Screening
Section 5.1, 
Section 7
On-study paired biopsies for exploratory biomarker evaluations are 
UHTXLUHGIRUSDWLHQWVSUHYLRXVO\DOOSDWLHQWVLQ3KDVH,,
To ensure an adequate number of biopsies to meet 
study objectives while allowing enrollment of 
patients who cannot safely undergo multiple 
on-study biopsies
Section 7.4
Clarified that additional CT/MRI scans (beyond the main schedule) are 
not required at EOT or to confirm response
To correct an inconsistency
Section 7.4
Added: The Sponsor reserves the right to request additional scans 
obtained within 6 months of the screening assessment
To evaluate tumor growth kinetics prior to and 
following treatment with IMCnyeso
Section 7.4
Removed requirement for hepatic MRI at each disease assessment
To align with standard of care for the indications 
under study
Section 7.4
Clarified that pelvis scans are to be done as appropriate based on 
indication and extent of disease
To align with standard of care for the indications 
under study
Section 7.9
Hematocrit removed from required hematology panel
Hemoglobin testing is sufficient for safety 
monitoring given hematocrit is derived value
Section 7.9
Monocytes, eosinophils, and basophils removed from required 
hematology panel
These tests are not required for safety monitoring
Section 7.9
Thyroid function test panel adjusted to include free T3 as a reflex 
assay.  Total T3 testing was removed
Total T3 is less informative and harder to interpret; 
Free T3 may help to interpret thyroid function test 
abnormalities
Section 7.9
Removed specification that urinalysis be performed using dipstick
Non-dipstick urinalysis methods are also acceptable


.
Protocol Number:  IMCnyeso-101 
Investigational Product:  IMCnyeso
Version: 4.0, 24Feb2020 
CONFIDENTIAL AND PROPRIETARY
151 of 153
Section in
Amendment 1
Change
Rationale 
Section 7.9 
Clarified that “blood and glucose” will be evaluated in urine rather 
than “blood glucose”
To clarify the scope of urinalysis assessments
Section 7.9 
Clarified that any patient who becomes pregnant should be withdrawn 
from treatment rather than withdrawn from study
To ensure that the outcome of any pregnancy that 
occurs during the study is assessed
Section 7.9 
Serum collected during potential events of CRS will be evaluated by a 
central laboratory rather than local laboratories
To improve operational feasibility (many local 
laboratories do not perform cytokine testing) and 
consistency of measured values
Section 7.9 
Added that new or worsening clinically significant ECG findings 
should be confirmed by performing at least 2 additional ECG reads 
within approximately 30 minutes 
To ensure accuracy of ECG findings
Section 7.9 
Frequency of ECG adjusted to add assessment on Cycle 4 Day 1.  Last 
planned start-of-cycle ECG assessment is on Cycle 6 (previously 
Cycle 12 in Phase I and Cycle 5 in Phase II)
To reduce testing during later cycles, when risk of 
new treatment-related AE is lower
Section 7.9 
ECG assessments marked to indicate whether single read or triplicate 
is needed
To clarify the required assessment
Section 7.9 
PK timepoint added at 36 hours after the first dose.  An optional 
timepoint was added at 48 hours after first dose 
Sampling schedule adjusted based on emerging PK 
data 
Section 7.9 
PK timepoints in Cycle 3 and beyond simplified to assess pre-dose and 
EOI on Day 1 of odd cycles only (previously Day 1 and Day 15 of odd 
cycles)
To limit PK testing to what is required to assess 
study endpoints
Section 7.9 
Moved skin punch biopsy to 
section 
To align with described purpose and clarify that 
sample retention is aligned with other 
 
specimens


.
Protocol Number:  IMCnyeso-101 
Investigational Product:  IMCnyeso
Version: 4.0, 24Feb2020 
CONFIDENTIAL AND PROPRIETARY
152 of 153
Section in
Amendment 1
Change
Rationale 
Section 7.10 
Section 7.10 
Reduced Cycle 1 Day 22 timepoints for the multiplex cytokine and 
chemokine panel 
To improve operational feasibility
Section 7.10 
The optimal timing for the on-treatment biopsy sample is between 
Cycle 1 Day 9 and Cycle 1 Day 16 (previously during Cycles 1 and/or 
3, 1-3 days following dosing) 
To provide more consistent biopsy timing that is 
aligned with emerging experience from other 
ImmTAC programs 
Section 7.10 
Added biopsied lesions may not be followed as target lesions for 
disease assessments per RECIST v1.1 unless the lesion is > 2 cm and, 
in the opinion of the Investigator, the biopsy will not appreciably 
impact the dimensions of the lesion
To ensure that biopsy does not compromise ability 
to assess response per RECIST v1.1
Section 8.2 
Clarified that disease progression, including identification of new 
lesions (or worsening of existing lesions) or death due to progression 
of the disease under study should not be reported as AE / SAE.  
Information regarding new lesions (or worsening of existing lesions) 
should be reported in the eCRF New Lesion and disease assessment 
pages, information regarding cause of death on Death page, and any 
signs or symptoms that occur as a result of PD and meet the definition 
of AE should be reported on the AE page 
To ensure consistent reporting of patient disposition, 
adverse events, and disease progression
Section 8.2 
CRS is considered as an AESI for IMCnyeso
To facilitate additional data collection and reporting 
to the Sponsor 
Section 8.6 
Age rather than date of birth is to be included on any SAE report 
To protect patient information
Section 8.6 
Updated technical details of the SAE reporting process
For accuracy


.
Protocol Number:  IMCnyeso-101 
Investigational Product:  IMCnyeso
Version: 4.0, 24Feb2020 
CONFIDENTIAL AND PROPRIETARY
153 of 153
Section in
Amendment 1
Change
Rationale 
Section 9 
Statistical analysis plans were revised to report 95% confidence 
interval for ORR (rather than 90%) 
To align with standard practice 
Section 9.5 
Phase II BOR included in primary analysis section
For consistency with updates in objectives / 
endpoints 
Section 9.6.2 
Safety periods updated  
To align with changes in safety follow-up 
Section 9.6.2 
Statistical analysis plans were revised to remove listings for physical 
examination data 
Findings from physical exams are reported as AE 
and will be included in AE listings
Section 9.6.3 
Added immunogenicity analyses in secondary analysis section
To correct an omission 
Section 10 
Added: All data collected during this study, including clinical and 
 data, may be pooled with data from other studies using the 
same study drug or a different study drug with a similar mechanism 
(eg, ImmTAC) in order to advance our understanding about study drug 
safety, 
 correlation with a variety of outcomes, or other 
study endpoints in order inform future development provided the 
patient provides consent to permit such pooling of data 
To provide transparency regarding potential uses of 
study data
Section 13.1 
Appendix regarding modified irRECIST was removed 
irRECIST is no longer being used in this study
Section 13.3 
BLRM dose range was updated to increase the maximum dose from 
120 mcg to 200 mcg 
To ensure that the maximum dose used in BLRM 
simulations exceeds the expected maximum dose in 
dose-escalation
Section 13.4 
Appendix with detailed description of changes and rationale added 
To provide transparency regarding changes in 
Amendment 2

SAP_001.pdf: 
Immunocore
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
CONFIDENTIAL
Date Issued: 08FEB2021
Confidential 
Statistical Analysis Plan
Protocol IMCnyeso-101 
A Phase I/II Open-label, Multi-center Study of the Safety and Efficacy of 
IMCnyeso, an HLA- A*0201-Restricted, NY-ESO-1- and LAGE-1A-specific 
Soluble T Cell Receptor and Anti-CD3 Bispecific Molecule, as a Single 
Agent in HLA-A*0201 Positive Patients with Advanced NY-ESO-1 and/or 
LAGE-1A Positive Cancer
Revision History
Version
Date
Status
2.0
08FEB2021
Final
1.0
30SEP2019
Final
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Immunocore
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
   CONFIDENTIAL
Date Issued: 08FEB2021
- 2 -
Statistical Analysis Plan (SAP) Approval Page
Protocol Title:
A Phase I/II Open-label, Multi-center Study of the Safety and Efficacy of 
IMCnyeso, an HLA- A*0201-Restricted, NY-ESO-1- and LAGE-1A-
specific Soluble T Cell Receptor and Anti-CD3 Bispecific Molecule, as a 
Single Agent in HLA-A*0201 Positive Patients with Advanced NY-ESO-1 
and/or LAGE-1A Positive Cancer
Protocol Number/
Version (Date):
IMCnyeso-101/ V 4.0 (24FEB2020)
SAP Version No.: 
2.0 
Date:   
08FEB2021 
Prepared By:
Author
           ___See Attached ___ 
____________________ 
Immunocore, Ltd 
Signature 
Date: _______________ 
Approved By: 
   
___See Attached ___ 
____________________ 
Immunocore, Ltd 
Signature 
Date: _______________ 
  
 
 
 
 
 
___ See Attached ___ 
 ____________________ 
Immunocore, Ltd 
Signature 
Date: _______________ 
     


Immunocore 
 
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
                                                       CONFIDENTIAL  
Date Issued: 08FEB2021
  
- 3 -
TABLE OF CONTENTS
LIST OF TABLES .................................................................................................................... - 5 -
LIST OF ABBREVIATIONS .................................................................................................. - 6 -
1
INTRODUCTION............................................................................................................. 9
1.1
RATIONALE .................................................................................................................... 9
2
OBJECTIVES ................................................................................................................. 10
2.1
PRIMARY OBJECTIVES ...................................................................................................... 10
2.2
SECONDARY OBJECTIVES ................................................................................................. 10
2.3
EXPLORATORY OBJECTIVES ............................................................................................. 10
3
INVESTIGATIONAL PLAN ........................................................................................ 10
3.1
OVERALL STUDY DESIGN AND PLAN ................................................................................ 10
3.2
STUDY ENDPOINTS ........................................................................................................... 11
3.2.1
Primary Endpoint...................................................................................................... 11
3.2.2
Secondary Endpoints ................................................................................................ 12
3.2.3
Exploratory Endpoints .............................................................................................. 12
3.3
TREATMENTS .................................................................................................................... 12
3.4
DOSE ADJUSTMENT/MODIFICATIONS ............................................................................... 13
4
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 14
4.1
SAMPLE SIZE .................................................................................................................... 15
4.2
RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 16
4.2.1
Treatment and Disease Groups for Reporting .......................................................... 16
4.3
ANALYSIS SETS ................................................................................................................ 16
4.3.1
All Patients Set .......................................................................................................... 17
4.3.2
Full Analysis Set (FAS) ............................................................................................. 17
4.3.3
Safety Analysis Set (SAF) .......................................................................................... 17
4.3.4
Safety RP2D Analysis Set.......................................................................................... 17
4.3.5
Per-Protocol Set (PPS) ............................................................................................. 17
4.3.6
Dose-Determining Analysis Set (DDS) ..................................................................... 17
4.3.7
Pharmacokinetic (PK) Analysis Set .......................................................................... 18
5
PATIENTS DISPOSITION ........................................................................................... 18
5.1
DISPOSITION ..................................................................................................................... 18
5.2
PROTOCOL DEVIATIONS ................................................................................................... 18
6
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 18
6.1
DEMOGRAPHICS ................................................................................................................ 18
6.2
BASELINE DISEASE CHARACTERISTICS ............................................................................. 19
6.3
SMOKING STATUS ............................................................................................................. 19
6.4
MEDICAL HISTORY ........................................................................................................... 19
6.4.1
General Medical History .......................................................................................... 19
6.4.2
Cancer History .......................................................................................................... 19
6.5
PRIOR ANTI-CANCER HISTORY ......................................................................................... 19
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Immunocore 
 
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
                                                       CONFIDENTIAL  
Date Issued: 08FEB2021
  
- 4 -
6.6
INCLUSION AND EXCLUSION CRITERIA ............................................................................. 20
7
TREATMENTS AND MEDICATIONS ....................................................................... 20
7.1
PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 20
7.2
STUDY TREATMENTS ........................................................................................................ 21
7.2.1
Extent of Exposure .................................................................................................... 21
7.2.2
Treatment Compliance and Modifications................................................................ 22
8
SAFETY ANALYSIS...................................................................................................... 22
8.1
DOSE-LIMITING TOXICITY ................................................................................................ 22
8.2
ADVERSE EVENTS ............................................................................................................. 22
8.2.1
Incidence of Adverse Events ..................................................................................... 23
8.2.2
Relationship of Adverse Events to Study Drug ......................................................... 23
8.2.3
Severity of Adverse Event.......................................................................................... 24
8.2.4
Serious Adverse Events ............................................................................................. 24
8.2.5
Adverse Events Leading to Treatment Discontinuation, Dose Interruption and Dose 
Reduction ................................................................................................................................ 24
8.2.6
Deaths ....................................................................................................................... 24
8.3
CLINICAL LABORATORY EVALUATIONS ........................................................................... 25
8.4
VITAL SIGNS ..................................................................................................................... 28
8.5
ELECTROCARDIOGRAM ..................................................................................................... 28
8.6
DOSE INTERRUPTIONS AND REDUCTIONS ......................................................................... 29
9
EFFICACY ANALYSIS ................................................................................................. 29
9.1
PRIMARY EFFICACY ENDPOINT ......................................................................................... 29
9.1.1
Objective Response Rate ........................................................................................... 29
9.2
SECONDARY EFFICACY ENDPOINTS .................................................................................. 30
9.2.1
Progression-free Survival ......................................................................................... 30
9.2.2
Overall Survival ........................................................................................................ 31
10
PHARMACOKINETICS, IMMUNOGENICITY AND PHARMACODYNAMICS
........................................................................................................................................... 31
10.1 PHARMACOKINETICS ........................................................................................................... 31
10.2 IMMUNOGENICITY ............................................................................................................... 33
10.3 PHARMACODYNAMICS ........................................................................................................ 36
11
INTERIM ANALYSIS ................................................................................................... 36
12
CHANGES IN THE PLANNED ANALYSIS .............................................................. 36
13
REFERENCES ................................................................................................................ 36
14
APPENDICES ................................................................................................................. 37
14.1  N-CONTINUAL REASSESSMENT METHOD (N-CRM) .......................................................... 37
14.2   TABLES AND FIGURES (PLANNED) ..................................................................................... 38
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Immunocore 
 
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
                                                       CONFIDENTIAL  
Date Issued: 08FEB2021
  
- 5 -
List of Tables
Table 1 - IMCnyeso Dose Levels for Phase I Dose Escalation ................................................ 14
Table 2 – Potential Phase I Dose Groups .................................................................................. 16
Table 3 - Phase II Disease Cohorts at RP2D ............................................................................ 16
Table 4 - Clinical Laboratory Parameters Collection ............................................................. 26
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Immunocore 
 
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
                                                       CONFIDENTIAL  
Date Issued: 08FEB2021
  
- 6 -
List of Abbreviations
ADA
Anti-drug antibody       
AE
Adverse event       
ALT
Alanine aminotransferase       
AST
AUC
Aspartate aminotransferase
Area under curve
AUClast
Area under the plasma concentration-time curve from time zero to 
time of last measurable concentration
AUCtau
Area under the concentration time profile over the dosing interval
BLRM
BLQ
Bayesian Logistic Regression Model
Below the limit of quantification 
BOR
Best Overall Response
C#D#
Cycle # Day #     
CD#
Cluster of differentiation #     
CL
The total body clearance of drug from the plasma
Cmax
Maximum observed concentration      
CR
Complete response       
CRS
CSR
Cytokine release syndrome      
Clinical Study Report 
CTCAE
Common Terminology Criteria for Adverse Events
DDS
Dose-determining Set
DETC
Dose-escalation teleconference
DLT
Dose-limiting Toxicity
DoR
ECG
ECOG
eCRF
Duration of response
Electrocardiogram  
Eastern Cooperative Oncology Group 
Electronic Case Report Form
EWOC
Escalation with overdose control     
FAS
Full analysis set      
FIH
First in human      
FSH
Follicle stimulating hormone      
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al Study Report 
l Study Report 
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min


Immunocore 
 
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
                                                       CONFIDENTIAL  
Date Issued: 08FEB2021
  
- 7 -
hCG 
Human chorionic gonadotropin 
HLA
Human leukocyte antigen      
HLA-A*0201
Human leukocyte antigen-A*0201      
HLA-DR
Human leukocyte antigen-DR      
ICF
Informed consent form      
ICH
International Conference on Harmonization
IL-#
Interleukin-# (e.g. IL-6, IL-10)     
IPE
Intra-patient escalation
IRS
Integrated response system
IV
Intravenous
LAGE-1A
L antigen family member-1 isoform A
LAGE-1B
L antigen family member-1 isoform B
MedDRA
Medical Dictionary for Regulatory Activities
MTD
N-CRM
Maximum tolerated dose
N-Continual Reassessment Method 
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
NY-ESO-1
New York esophageal squamous cell carcinoma-1
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed death-1
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
PK
Pharmacokinetic
PPS
Per protocol set
PR
Partial response
PT
Preferred Term
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Immunocore 
 
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
                                                       CONFIDENTIAL  
Date Issued: 08FEB2021
  
- 8 -
QTcF
QT interval corrected by Fredericia’s method
QW
Every week
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 dose
SAE
SAF
Serious adverse event
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Stable disease
SOC
System Organ Class
SST
Study Safety Team
t1/2
T3
T4
Terminal elimination half-life
Triiodo thyroxine 
Thyroxine 
TEAE
Treatment-emergent adverse events
TIL
Tumor infiltrating lymphocyte
Tmax
Time of maximum concentration
TSH
Thyroid stimulating hormone 
ULN
Upper limit of normal
US
United States
Vss
Steady state volume of distribution
WBC
White Blood Cell
WHO 
World Health Organization
erse events
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Immunocore 
 
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
                                                       CONFIDENTIAL  
Date Issued: 08FEB2021
  
9
1
Introduction
This statistical analysis plan (SAP) describes the analyses and data presentations for the clinical 
study protocol IMCnyeso-101 version 4.0, dated 24 Feb 2020. This study is a Phase I/II, open-
label, multi-center trial.  Phase I of the study is a dose escalation to determine the maximum 
tolerated dose (MTD) or recommended Phase II dose (RP2D) of IMCnyeso administered weekly 
as monotherapy in patients with advanced non-small cell lung cancer (NSCLC), melanoma, 
urothelial cancer and synovial sarcoma; Phase II of the study is expansion in three disease cohorts 
(NSCLC, urothelial cancer and synovial sarcoma patients). 
Any differences between this SAP and protocol version 3.0 are documented in Section 12. 
This SAP describes statistical analyses that will be produced in three deliveries:
1. Phase I Summary Report 
Based on a cut-off of Phase I patients once MTD/RP2D has been determined and all 
patients having completed DLT evaluation. 
2. Full Clinical Study Report (CSR) of Phase I and Phase II
Based on a cut-off at the time where at least 80% of phase II patients in each cohort have 
completed the follow up for disease progression or discontinued the study for any reason
(once each cohort has reached this point, separate reporting will be considered for each 
cohort).  
x
There will be an interim analysis for each Phase II cohort (s). It will only involve 
BOR endpoint. 
3. Follow-up Abbreviated CSR  
Based on the locked database after 100% follow up of all patients from both phases.  
1.1 Rationale 
Immunocore is developing a new biological entity, IMCnyeso, for the treatment of multiple 
indications where tumors are positive for the cancer-testis antigens New York esophageal 
squamous cell carcinoma-1 (NY-ESO-1) and/or L antigen family member-1 isoform A (LAGE-
1A). The effector function of IMCnyeso (anti-CD3) works by binding and activating T cells via 
cluster of differentiation 3 (CD3). The effector T cells that bind to IMCnyeso and the tumor can 
be tumor-specific cells (tumor-infiltrating lymphocytes [TIL]) but circulating polyclonal T cells 
may also be activated as they traffic through the tumor through normal blood supply. IMCnyeso-
mediated activation of these T cells stimulates the immune system to attack the target tissue.
IMCnyeso was evaluated in a series of in vitro investigations to assess potential anti-tumor activity 
in patients with tumors that express NY-ESO-1 and/or LAGE-1A. These data can be summarized 
as follows: 
x
In vitro, IMCnyeso potently recruits and activates healthy donor and cancer patient 
peripheral blood mononuclear cells (PBMCs), leading to the release of pro-inflammatory 
cytokines, chemokines, and killing of cancer cell targets. The fullest extent of redirected T 
cell killing can take up to 72 hours. 
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x
In vitro, IMCnyeso potently recruits and activates CD3 positive T cells including CD8 
positive and CD4 positive T cells resulting in cancer-cell killing, polyfunctional T cell 
activation, proliferation, and expansion of T cells. 
These data demonstrate that IMCnyeso is a potent tumor-killing agent. Therefore, an investigation 
into the effects of the drug in patients with tumors expressing NY-ESO-1 and/or LAGE-1A is 
warranted.
For additional clinical information regarding IMCnyeso, refer to the latest version of the 
Investigator’s Brochure.  
2
Objectives
2.1 Primary Objectives
The primary objective in Phase I is to identify the MTD and/or the RP2D of IMCnyeso, as a 
monotherapy, when administered weekly to patients with advanced NSCLC, melanoma, urothelial 
cancer, and synovial sarcoma. The primary objective in Phase II is to assess the preliminary anti-
tumor activity of IMCnyeso as monotherapy in advanced NSCLC, urothelial cancer, and synovial 
sarcoma.  
2.2 Secondary Objectives
The following secondary objectives apply to both Phases I and II (reported separately) unless 
otherwise noted: 
x
To characterize the safety and tolerability of IMCnyeso (Phase II only) 
x
To assess the preliminary anti-tumor activity of IMCnyeso as monotherapy 
x
To characterize the PK profile of IMCnyeso as monotherapy
x
To evaluate the preliminary incidence of anti-IMCnyeso antibody formation following 
multiple infusions of IMCnyeso 
2.3 Exploratory Objectives
  
  
  
3
Investigational Plan 
3.1 Overall Study Design and Plan
IMCnyeso-101 is a Phase I/II, multi-center, open-label, first in human (FIH), multi-ascending dose 
study of monotherapy IMCnyeso in HLA-A*0201 positive patients with advanced NY-ESO-1 
and/or LAGE-1A positive solid tumors.  
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The study will be conducted in 2 phases: 
x
Phase I – dose escalation in 4 diseases (advanced NSCLC, melanoma, urothelial 
carcinoma, and synovial sarcoma) to determine the MTD and/or RP2D of IMCnyeso as a 
monotherapy.  The decisions regarding dose escalation of IMCnyeso will be made by the 
Study Safety Team (SST), which will consist of the Study Investigators, the Sponsor 
Medical Monitor, and a Statistician. Dosing decisions will be made following a review of 
all relevant data available, from all dose levels evaluated in the ongoing study, including 
safety information, DLTs, all ı Grade 2 toxicity data, PK, and pharmacodynamic data 
from evaluable patients in the dose-determining set (DDS) (see Section 4.3.6).  The SST
will be guided by the recommendation from the Bayesian Logistic Regression Model 
(BLRM) (see reference 1) since the Phase I design uses N-Continual Reassessment Method 
(N-CRM) of dose escalation with overdose control (EWOC) (see Section 15.2).
x
Phase II – following the identification of the MTD and/or RP2D in Phase I, patients may 
be enrolled into the 3 Phase II expansion cohorts (NSCLC, urothelial carcinoma, and 
synovial sarcoma) to make a preliminary assessment of the anti-tumor activity of 
IMCnyeso as a single agent in these disease settings. Initially, up to 9 patients may be 
enrolled in each Phase II cohort. If there is at least one response, at the discretion of the 
sponsor up to an additional 15 patients may be accrued for a total of up to 24 patients. 
The design is summarized in Figure 1 below: 
Figure 1 - IMCnyeso-101 Study Design 
HLA = human leukocyte antigen; NSCLC = non-small cell lung cancer; RP2D = recommended Phase II dose.
The number of patients in the Phase I escalation part of the study is estimated to be 27 patients. There is no upper limit 
to the sample size in Phase I. However, in 80% of the simulations conducted, the sample size was < 33 patients (see 
Section 4.1).
3.2 Study Endpoints
3.2.1 Primary Endpoint
The primary endpoints in Phase I are:
x
The incidence of dose limiting toxicities 
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x
The incidence and severity of AE and SAE 
x
The changes in laboratory parameters, vital signs, and ECGs 
x
The dose interruptions, reductions, and discontinuations 
The primary endpoint in Phase II is the best overall response (BOR) as determined by RECIST 
v1.1. 
3.2.2 Secondary Endpoints
For both phases, the following will be analyzed: 
x
Progression-free Survival (PFS)
x
Duration of Response (DoR) by RECIST v1.1
x
Overall Survival (OS) 
x
Serum PK parameters (e.g. AUC, Cmax, Tmax, t1/2) after single and multiple doses 
x
The incidence of anti-IMCnyeso antibody formation 
For Phase I only, the following secondary endpoint will also be analyzed: 
x
Best Overall Response (BOR)
For Phase II only, the following secondary endpoints will also be analyzed: 
x
Incidence and severity of AE and SAE 
x
Changes in laboratory parameters, vital signs, and ECGs 
x
Dose interruptions, reductions, and discontinuations 
3.2.3 Exploratory Endpoints 
3.3 Treatments  
For this study, the terms investigational drug and study medication refer to IMCnyeso.  
Patients enrolled in this study will receive treatment with single agent IMCnyeso, dosed weekly 
on Days 1, 8, 15 and 22 until disease progression or other reason to discontinue. Patients will be 
hospitalized for 2 nights following the administration of the first dose (C1D1) of IMCnyeso and 
2) 
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will remain at the site for overnight observation following administration of the second dose 
(C1D8). In addition, patients receiving intra-patient escalation (IPE) will be hospitalized overnight 
following the first three doses (C1D1, C1D8, and C1D15). After reviewing safety, PK, and 
cytokine data from at least 3 patients enrolled at a given dose level, the SST may decide that one 
night of hospitalization is adequate after the first dose for subsequent patients (with longer 
hospitalization if indicated). After Phase I is completed and the SST would review all available 
relevant data for at least 6 patients at the RP2D, the SST may decide to reduce the minimum 
required monitoring time during the Phase II portion of the study to no less than 8 hours post-end 
of infusion on C1D1, C1D8, and/or C1D15 (with longer hospitalization if clinically indicated). 
Patients who experience certain AEs may require additional in-patient monitoring as described in 
Section 6.15 of Protocol V4.0. 
For each patient, the first dose will be infused over 2 hours (±15 minutes); for dose levels İ 30 
mcg; the first dose may be infused over 1 hour (±10 minutes). If the first dose is well tolerated 
without ı Grade 2 infusion and/or a hypersensitivity reaction, a given patient's subsequent 
infusion times may be reduced to 1 hour (±10 minutes) starting at C1D8, and further reduced to 
30 minutes (±10 minutes) starting at C3D1 provided the above conditions continue to be met. 
Investigators may prolong the infusion time for individual patients if medically indicated at any 
time. 
Cohorts 1- 4 would be fixed dose and cohorts 5 - 7 will introduce an intra-patient escalation (IPE). 
If the severity of cytokine-mediated AEs tend to become less severe following the initial doses of 
study drug using a fixed-dose regimen, the SST may initiate a step 1 IPE regimen, in which a lower 
dose is given on Cycle 1 Day 1 and a higher (target) dose is given on Cycle 1 Day 8 and beyond 
(for details: Section 6.10.1 of the Protocol V4.0).   
3.4 Dose Adjustment/Modifications
All doses administered to subsequent cohorts of patients will be determined by the SST and will 
be guided by the BLRM and will be subject to both the EWOC principle and the escalation rule.  
Dose-escalation decisions will be made by the SST, which will consist of the Study Investigators, 
the Sponsor Medical Monitor, and a Statistician.  For each cohort, dose escalation or de-escalation 
decisions will be based on the SST’s review of all relevant data available, from all dose levels 
evaluated in the ongoing study, including safety information, DLTs, all ı Grade 2 toxicity data, 
PK, and pharmacodynamic data from evaluable patients (as defined in Section 6.10.2 of protocol 
version 4.0). The data and BLRM dose recommendations will be discussed and agreed upon during 
the dose-escalation teleconference (DETC), and all decisions will be documented in the meeting 
minutes and shared with all participating Principal Investigators.  
The actual dose levels that have been tested in this study are shown in Table 1 below.  Actual 
doses will be determined using the BLRM and must be agreed upon by the SST. 
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Table 1 - IMCnyeso Dose Levels for Phase I Dose Escalation 
Cohort 
number
Cohort description
IMCnyeso 
Dose(s) Tested
Enrollment
(n)
1
3 mcg fixed dose
3 mcg
4
2
10 mcg fixed dose
10 mcg
3
3
30 mcg fixed dose
30 mcg
5
4
100 mcg fixed dose
100 mcg
3
5
30-100 mcg intra-patient dose escalation
30-100 mcg
5
6
30-100-180 mcg intra-patient dose escalation
30-100-180 mcg
4
7
30-100-300 mcg intra-patient dose escalation
30-100-300 mcg
6 (planned)
To better understand the safety, tolerability, and PK profile of single agent IMCnyeso, additional 
cohorts of patients may be enrolled at preceding dose levels or intermediate dose levels, before or 
in parallel, while proceeding with further dose escalation.  The outcome from these cohorts will 
be included in the BLRM.
If the first 2 patients in a previously untested dose level experience a DLT, additional enrollment 
in that cohort will stop, the BLRM will be updated with this new information, and the SST will 
evaluate the available safety, PK, and pharmacodynamic data.  By incorporating information 
gained at the preceding dose levels and provided the BLRM predicts that the risk of excessive 
toxicity remains below 25% (EWOC), additional patients may be enrolled at this dose level or a 
lower dose level as agreed upon by the SST. 
If the severity of cytokine-mediated AEs tend to become less severe following the initial doses of 
study drug using a fixed-dose regimen, the SST may initiate step 1 intra-patient escalation regimen, 
in which a lower dose is given on Cycle 1 Day 1 and a higher (target) dose is given on Cycle 1 
Day 8 and beyond. Further details can be found in Section 6.10.1 of the protocol. 
A subsection on dose escalation decisions will be included in the CSR, and the BLRM outputs 
produced for the dose escalation meetings will be included in the CSR appendices. 
4
General Statistical Considerations
Categorical data will be summarized using frequencies and percentages. The denominator for all 
percentages will be the number of patients belonging to the analysis set of interest by dose group 
or disease cohort according to the particular summary. Percentages will be presented as integer 
numbers with no decimal part given the small number of patients enrolled. Percentages will not be 
displayed for 0 frequencies. A row denoted “Missing” will be included in count tabulations where 
necessary to account for missing values. 
For continuous data, the mean, standard deviation (SD), median, minimum (Min) and the 
maximum (Max) will be presented. For PK, if concentration results below a lower limit of 
detection (LLOD) and LLOD for a parameter is clinically relevant then it will be included in the 
calculation of standard statistics with that concentration result set at 0; but for cytokines it will be 
set at the midpoint between 0 and the LLOD.  Minimum and maximum will be presented to the 
same number of decimal places as the raw data, mean and median will be presented to 1 more 
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decimal place than the raw data, and standard deviation will be presented to 2 more decimal places 
than the raw data. 
No formal statistical hypotheses will be tested. Where appropriate, two-sided 95% confidence 
intervals will be presented. 
All data summaries and statistical analyses will be performed using the SAS software 
Version 9.4 or higher (SAS Institute, Cary, NC). 
The study day of an event that occurred after or on the first dose date will be calculated as: 
Event Date – C1D1 Date + 1
whereas the study day of an event that occurred before the first dose date will be calculated as: 
Event Date – C1D1 Date
All listings will be sorted for presentation in order of center and patient identification number. Key 
variables to be displayed on each listing will be: Study phase, center, patient identification number, 
age, sex, and race.  
The following rules will be followed for reporting results unless stated otherwise: 
x
Screen failure patients are those who signed the ICF, but never started the study treatment 
for any reason. For these patients, the eCRF data collected will not be included in analyses 
but will be reported in the clinical study report as separate listing. 
x
Baseline is defined as the last assessment prior to the first dose of treatment received (e.g. 
C1D1 pre-dose). 
x
Tables, listings, and figures will be presented for Phase I and II separately or combined 
Phase I/II together as appropriate. 
x
Tables for DLTs will be produced for Phase I and Phase II. 
x
Visit time points will be presented in the form Cycle x Day y. 
Unless otherwise stated in below sections, missing data will not be imputed, but they will simply 
be noted as missing on appropriate tables/listings.  
4.1 Sample Size
Dose decisions will be guided by the BLRM. Among the simulations that were conducted, the 
mean sample size was 27 patients, and the sample size was less than 33 patients in over 80% of 
simulations. 
A Simon two-stage design will be used for each Phase II cohort using a 10% probability of a Type 
1 error, a 20% probability of a Type 2 error, and assuming a target response rate of 20% versus 5% 
response rate for available treatment options. If there are no responses among the first 9 patients 
in a cohort, then accrual in that cohort will stop. If there is at least one response, at the discretion 
of the sponsor up to an additional 15 patients may be accrued for a total of up to 24 patients (with 
at least 3 responses to support further evaluation). 
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4.2 Randomization, Stratification, and Blinding 
The Integrated Response System (IRS) will be used to control patient allocation to treatment and 
ensure the dosing intervals and cohort recruitment comply with the protocol. 
4.2.1 Treatment and Disease Groups for Reporting
The Phase I safety data will be listed, summarized, and analyzed overall and by dose group where
dose groups may incorporate pooling of dose levels; the exact extent of pooling will be defined 
after Phase I actual doses administered are known, and is expected to use the Recommended Phase 
2 dose (RP2D) as threshold (see Table 2).  
Patients who enroll in multiple cohorts will be represented once for each cohort and once in the 
total/overall study columns for summaries that are based on baseline data (e.g. demographics, 
medical history). Listing will be presented for patients who are escalated to a higher dose.  
Table 2 – Potential Phase I Dose Groups
Treatment Group
Dose Group (Label 
for TLF Reporting)* 
Patients included
IMCnyeso < x mcg QW 
< RP2D
All Phase I dose escalation cohorts 
receiving a dose less than RP2D
IMCnyeso = x mcg QW
= RP2D
All Phase I dose escalation cohorts 
receiving the same dose as RP2D
IMCnyeso > x mcg QW
> RP2D
All Phase I dose escalation cohorts 
receiving a dose greater than RP2D 
* x mcg is the Recommended Phase 2 Dose (RP2D) where x is determined during Phase I and administered IV 
over 1-2 hours. 
In Phase II, patients will be analyzed according to the disease cohorts laid out in Table 3.  
Table 3 - Phase II Disease Cohorts at RP2D
Cohort
Disease Cohort
Cohort 1
Advanced NSCLC
Cohort 2
Urothelial Cancer
Cohort 3
Synovial Sarcoma
4.3 Analysis Sets 
The following analysis sets will be defined separately for the Phase I and Phase II parts of the 
study (except for Safety RP2D Analysis Set which is defined across Phase I and Phase II and the 
Per-Protocol Set which is defined just for Phase II). 
In the Phase I part of the study, HLA-A*0201-positive patients with a diagnosis of NY-ESO-1 
and/or LAGE-1A positive advanced NSCLC, melanoma, urothelial carcinoma, or synovial 
sarcoma will be enrolled. In Phase II, HLA-A*0201 positive patients with NY-ESO-1 and/or 
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LAGE-1A positive advanced NSCLC, urothelial carcinoma, or synovial sarcoma will be enrolled 
and treated at the RP2D. 
4.3.1 All Patients Set
The All Patients set includes every patient who provided their main informed consent with 
recorded data in the eCRF. Note that this set includes screening failures.
4.3.2 Full Analysis Set (FAS)
The FAS is a subset of the All Patients Set and it comprises all patients who received at least 1 full 
dose or partial dose of IMCnyeso. In Phase I, patients will be analyzed according to the planned 
treatment or as per the dose groups laid out in  Table 2.  
In Phase II, patients will be analyzed according to the disease cohorts laid out in Table 3. The FAS 
will be used for all listings of raw data, demography and baseline characteristics, and all analyses
unless specified otherwise.
4.3.3 Safety Analysis Set (SAF)
The SAF is a subset of All Patients Set and it comprises all patients who received at least 1 full 
dose or partial dose of IMCnyeso. Patients will be classified in this set according to initial treatment
received (see Table 2) or disease cohort in Phase II (Table 3). The SAF will be used for the safety 
summary of the study.  In Phase I, the SAF will be equivalent to FAS if received doses are equal 
to planned doses (or sufficiently close to be in the same dose grouping). 
4.3.4 Safety RP2D Analysis Set 
The safety RP2D analysis set is a subset of the All Patients Set and it comprises all patients who 
received at least 1 full dose at the RP2D level. This will include patients from both phases 
combined and will be summarized according to disease as per Table 3 but also including 
melanoma from Phase I. 
4.3.5 Per-Protocol Set (PPS)
The Per-Protocol Set consists of a subset of FAS patients in Phase II who meet below 4 criteria
1. Presence of measurable disease according to RECIST v1.1
2. At least 1 post-baseline tumor assessment or discontinued prior to the first tumor 
assessment
3. Received at least 1 dose of planned treatment at the RP2D 
4. No violation of key inclusion or exclusion criteria. 
Patients in the PPS will be classified according to disease cohort as per Table 3. 
4.3.6 Dose-Determining Analysis Set (DDS)
The DDS consists of all patients from the SAF in Phase I who meet the criteria in Section 3.4.  
This set will be used to guide the dose escalation using actual dose received and will not be an 
analysis set used in final reporting. 
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4.3.7 Pharmacokinetic (PK) Analysis Set
The PK analysis set consists of all patients in the SAF with at least 1 post-dose blood sample 
providing evaluable PK data. The PK analysis set will be used for all PK analyses.
Patients may be removed from the estimation of certain PK parameters on an individual basis 
depending on the number of available blood samples. These patients will be identified at the time 
of analysis. 
5
Patients Disposition
5.1 Disposition
The number and percentage of patients ongoing treatment, ongoing in the study, patients who died  
with the corresponding reason for death and whether the death was within 30 days of last dose or 
not, patients who discontinued treatment with the corresponding reason for drop out and patients 
who discontinued the study with the corresponding reason for drop out will be tabulated  by dose 
group.   
In addition, the number and percentage of patients in each analysis set will be shown (as defined 
in Section 4.2.1).   
Percentages will be based on the number of patients assigned to treatment in the FAS.  
Patient disposition data will be presented in a listing for the FAS. 
5.2 Protocol Deviations 
Compliance with the protocol will be assessed by the number and percentage of patients with 
important protocol deviations. Important protocol deviations will be identified prior to database 
lock and will be listed and summarized by category for FAS. The impact of important protocol 
deviations on the study procedures or the analyses will be classified according to the following 
rules: 
x
The important protocol deviation resulted in exclusion from one or more analysis sets (as 
defined in Section 4.3) 
x
The important protocol deviation resulted in permanent discontinuation of study treatment
x
The important protocol deviation resulted in exclusion from one or more analyses  
6
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be presented for FAS. 
Qualitative data (e.g. sex) will be tabulated by category while quantitative data (e.g. weight) will 
be summarized by descriptive statistics. 
Demographic data, baseline disease characteristics, and other baseline data will be listed in detail.
6.1 Demographics
Demographic data will be summarized and include age group (18-<50, 50-<65, ı65), sex, race, 
ethnicity, weight at baseline and height at baseline
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6.2 Baseline Disease Characteristics
ECOG performance status at baseline will be summarized by grade (0 or 1) and a shift table of 
baseline to worst on-treatment result will be presented. 
The latest set of results/values will be used on demographics (e.g. ECOG, height, weight) summary 
if a subject has different values for different cohorts.  
Listing of ECOG performance status at each visit will be presented for the FAS.  
6.3 Smoking Status
Smoking status (smoker, ex-smoker, or non-smoker) at baseline will be summarized together with 
demographics characteristics (see Section 6.1). 
6.4 Medical History
6.4.1 General Medical History
Relevant prior medical history and current medical conditions will be summarized separately, but 
they will be listed together. Medical history and current medical conditions will be coded by using
the International Conference on Harmonization (ICH) Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.0. 
6.4.2 Cancer History
Cancer history will be described by original cancer disease (melanoma, synovial sarcoma, 
urothelial carcinoma, NSCLC) and stage (0, I, II, III, IV) at trial entry.  The type/location on body 
will be listed only, where collected for melanoma and sarcoma. Also, the histology will be listed 
only for NSCLC. 
The duration in months of diagnosis [(Date of Screening - Date of Initial Cancer Diagnosis + 
1)/30.4375] and duration in months of metastatic disease [(Date of Screening - Date of detection 
of metastatic disease + 1)/30.4375] will be summarized by descriptive statistics. 
For calculating the duration of diagnosis and metastatic disease, incomplete dates of initial cancer 
diagnosis and dates of detection of metastatic disease will be imputed as follows (where UK and
UKN indicate unknown or missing day and month respectively):  
x UK-MMM-YYYY: Assume 15-MMM-YYYY. If the month and year are the same as the 
first dose of study drug month and year, then assume the date of first dose of study drug. 
x UK-UKN-YYYY: If the year is prior to the year of first dose of study drug, assume 01-JUL-
YYYY of the collected year. If the year is the same as the first dose of study drug year, then 
assume the date of first dose of study drug. 
6.5 Prior Anti-Cancer History
Prior anti-cancer
therapies classified
as systemic therapy (including chemotherapy, 
immunotherapy, and targeted therapy), radiotherapy, surgery, or “Other” are to be recorded on the 
Prior Anti-neoplastic Therapy eCRF page during screening. The number of lines of prior anti-
cancer therapies and therapy class will be tabulated. The number of lines of prior anti-cancer 
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therapies will also be summarized by descriptive statistics. The number of lines will be calculated 
based on the following: 
A regimen (i.e. unique regimen number) would count as a line of therapy if 
-
(therapy class = systemic therapy) AND (treatment setting = [metastatic disease / palliative 
OR unresectable locally advanced disease / palliative])
or 
-
(therapy class = systemic therapy) AND (treatment setting = primary / neoadjuvant / 
adjuvant / curative) AND (date of detection of metastatic disease <= 6 months after [cancer 
therapy end date in this regimen])
Prior anti-cancer therapies will also be listed for FAS patients.
6.6 Inclusion and Exclusion Criteria
Treated and non-treated patients who did not meet inclusion or exclusion criteria will be listed 
separately for the All Patients Set. 
7
Treatments and Medications
7.1 Prior and Concomitant Medications 
Prior and concomitant medications will be documented at screening and updated during the study.  
Prior and concomitant medications will be coded using the WHO Drug Dictionary Enhanced 
Version WHODDRUG Dec16 WHO-DDE B2.
A prior medication is defined as a medication where both the start and end dates are before the 
date of the initial C1D1 IMCnyeso dose received. 
A concomitant medication is defined as one where the end date is either on or after C1D1 date or 
is missing. The start date of a concomitant medication can be before or after C1D1 date. For a 
medication with partial or completely missing onset date, unless it can be determined to be “prior 
to the first infusion” from the incomplete start date or end date (e.g., month, year is before C1D 
date, or end date is before C1D1 date), the medication will always be assumed to be concomitant. 
Medications initiated prior to the start of study treatment and continued after the start of study 
treatment will be counted as both prior and concomitant medications.
For the purpose of categorizing medications as prior or concomitant, incomplete medication start 
and stop dates will be imputed as follows: 
Missing start dates (where UK and UKN indicate unknown or missing day and month 
respectively): 
x UK-MMM-YYYY: Assume 01-MMM-YYYY. If the month and year are the same as the 
first dose of study drug month and year, then assume the date of first dose of study drug. 
x UK-UKN-YYYY: If the year is prior to the year of first dose of study drug, assume 01-JAN-
YYYY of the collected year. If the year is the same as the first dose of study drug year, then 
assume the date of first dose of study drug. 
$SSURYHG
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Missing stop dates for concomitant medications data will be handled as follows (where UK, UKN 
and UNKN indicate unknown or missing day, month, and year respectively). 
x UK-MMM-YYYY: Assume the last day of the month. 
x UK-UKN-YYYY: Assume 31-DEC-YYYY. 
x UK-UKN- UNKN: Assume ongoing and leave it missing. 
A listing for both prior and concomitant medications will be created for all FAS patients. 
7.2 Study Treatments
7.2.1 Extent of Exposure 
Total number of cycles, expected dose, actual dose and duration in months of treatment for 
IMCnyeso, as well as the dose intensity (total actual dose received/actual duration), the relative 
dose intensity (the dose intensity as percentage of planned dose/planned duration), number of 
doses beyond progression, number of doses beyond progression and the actual dose beyond 
progression will be summarized by descriptive statistics for the SAF. 
x
The treatment period will begin with the first treatment on Day 1 in the first cycle (C1D1). 
For the purpose of treatment scheduling, a cycle consists of 4 weeks (28 days). The total 
number of cycles of study drug received will include also partial cycles and reduced dose
cycles. 
x
The duration is defined as the number of months from the date of the initial C1D1 
IMCnyeso dose received to the last date of IMCnyeso dose received as recorded on EX 
dataset plus the protocol defined post-dose rest (i.e. 1 day). 
Duration of Treatment (months) = (date of last dose - the date of first dose + 1) / 30.4375. 
x
Because study drug reduction may occur during the study, the exposure to study drug will 
also be characterized by total actual dose received, which is defined as the sum of the actual
dose levels during the study.  
x
Dose intensity is the total actual dose received divided by duration of treatment in weeks.  
Dose Intensity (mcg/wk) =  
ௌ௨௠௢௙஺௖௧௨௔௟஽௢௦௘௦
஽௨௥௔௧௜௢௡௢௙்௥௘௔௧௠௘௡௧
x
The relative dose intensity (%) is 100 x (total actual drug given until treatment 
discontinuation) / (expected amount of drug given until treatment discontinuation). If there 
is a difference between the last dose date and the treatment discontinuation date (i.e. the 
date the *decision* was made to stop treatment), then date of last dose would be used.  
x
The actual dose beyond progression is defined as the total actual dose taken by the patient 
after the progression according to RECIST v1.1. Patients who did not progress, will not be 
included in this calculation. The summary of number of doses taken beyond progression 
and corresponding time duration (months) will be provided. 
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7.2.2 Treatment Compliance and Modifications
Study treatment will be administered to the patient at the study site by trained study staff. Patients
compliance with the prescribed regimen will be assured as all administrations will be performed 
by site staff under the supervision of the study investigator or his/her designee. Therefore, no 
analysis of compliance is planned. However, dose interruptions and reductions may occur (see 
Section 8.6). 
8
Safety Analysis 
Safety analysis will be conducted on the SAF for the Phase I dose escalation and separately for the 
Phase II expansion cohorts. Combined outputs for safety may be produced based on the Safety 
RP2D Analysis Set. 
8.1 Dose-Limiting Toxicity 
The incidence of DLTs is the primary endpoint in Phase I. The specific type and grades of AEs 
classified as a DLT can be found in the protocol in Section 6.12. The DLT observation period for 
the Phase I dose escalation cohorts is explained in Section 3.4. 
The number and percentage of patients with at least one DLT will be presented by dose group (as 
defined in Section 4.2.1).  
A listing of key information for DLTs will be presented including patient identification number, 
Preferred Term (PT) of corresponding AE and CTCAE grade. DLT information will be reported 
and summarized for Phase II whenever appropriate
8.2
Adverse Events
All AEs regardless of study drug relationship will either be collected from the signing of consent 
up to the end of the 30 day follow-up based on current protocol versions 3.0 and 4.0 or 90 day
follow up based on the previous protocol versions. Those AEs with onset 31-90 days after the last 
dose will be flagged in the separate adverse events listing.  
1) Treatment-emergent adverse events (TEAEs) are defined as any adverse event after the 
first dose of study drug within 30 days of the last dose of study drug or prior to subsequent 
anti-cancer therapy, whichever is sooner. For adverse events on C1D1, the event onset time 
relative to the first dose time will be considered (if relative or actual times are available), 
otherwise AE starting on C1D1 will be assumed treatment-emergent.
The AE summary tables include only AEs that are new or worsened during the on-treatment period
(TEAEs). However, all safety data (including those from the pre- and post-treatment periods) will 
be listed and those collected during the pre-treatment and post-treatment period are to be flagged.
The incidence of TEAEs will be summarized by system organ class (SOC) and/or PT, severity 
(based on NCI CTCAE v.4.03 grades), and relation to study treatment by treatment group (as 
defined in Section 4.2.1). Serious TEAEs resulting in death and non-fatal serious TEAEs will be 
listed by patient and tabulated by treatment group. There will be a separate listing for TEAE 
leading to treatment discontinuation.  
AEs will be coded by MedDRA version 20.0. 
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For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be imputed 
as follows: 
x
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively):  

UK-MMM-YYYY: If the month and year are different from the month and year of 
the first dose of study drug, assume 01-MMM-YYYY. If the month and year are 
the same as the first dose of study drug month and year, and the end date (after any 
imputation) is on or after the first dose of study drug, then assume the date of the 
first dose of study drug. If the month and year are the same as the first dose of study 
drug month, and year and the end date (after any imputation) is prior to the first 
dose of study drug, then assume the end date for the onset date.  
x
Missing end dates are generally not imputed. However, in the cases of partial missing end 
dates, the following rules will be applied (where UK and UKN indicate unknown or 
missing day and month respectively):  

UK-MMM-YYYY: Assume the last day of the month. 

DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
8.2.1 Incidence of Adverse Events
An overall summary of the number and percentage of patients with at least one TEAE in different 
categories (described here and below) will be provided by treatment group (as defined in Section 
4.2.1). Treatment-emergent AEs will also be presented by SOC and PT. At each level of patient 
summarization, a patient is counted once if the patient reported one or more events. Percentages 
will be calculated out of the number of patients in the SAF. The table is sorted alphabetically for 
SOC and by descending frequency overall for PT. 
Additionally, a summary of TEAEs will be presented by PT alone sorted in descending order of 
frequency overall. In addition, AEs of special interest including CRS (i.e. cytokine release 
syndrome [CRS]) symptoms will be presented in separate tables as needed. 
All AEs will be presented in a listing.  
8.2.2 Relationship of Adverse Events to Study Drug
A summary of TEAEs related to study drug will be presented in a table by incidence of occurrence. 
The investigator will provide an assessment of the relationship of the event to the study drug. The 
possible relationships are “related”, “possibly related” and “unrelated”. All “related” and “possibly 
related” AEs and SAEs will be defined as related to study drug. 
In the TEAE relationship table, if a patient reports multiple occurrences of the same TEAE, the 
highest grade of the related or possibly related will be presented (e.g. if a patient experiences for 
example Grade 3 dyspnea that is ‘potentially related’ and Grade 1 dyspnea that is ‘related’, it 
would give that patient a maximum severity of Grade 3 rather than Grade 1 in the TEAE 
relationship table). Treatment-emergent AEs that are missing a relationship will be presented in 
the summary table as “related” but will be presented in the data listing with a missing relationship. 
Percentages will be calculated based on the number of patients in the SAF. 
$SSURYHG
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The TEAE related to study drug data will be presented by SOC, PT and maximum severity (see 
below), and PT alone in a manner similar to that described in Section 8.2.1. 
8.2.3 Severity of Adverse Event
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the eCRF page. The possible severities are
measured on the CTCAE scale which goes from 1 to 5 where 1=“mild”, 2=“moderate”, 
3=“severe”, 4=“life-threatening” and 5=“fatal”. In the TEAE severity tables, if a patient reported 
multiple occurrences of the same TEAE, only the most severe will be presented. Treatment-
emergent AEs that are missing severity will be presented in tables and listings as “missing”. 
Percentages will be calculated out of the number of patients in the SAF. 
The TEAE data will be presented by SOC, PT and maximum severity in a manner similar to that 
described in Section 8.2.1. Extra columns will be added to show TEAEs having CTCAE grade 3-
4 and 5 separately. Additionally, the grade 3 and 4 TEAEs and related TEAEs will be presented 
by PT alone. 
8.2.4 Serious Adverse Events
Treatment-emergent serious adverse events (SAEs) will be presented in a table. Treatment-
emergent SAEs related to study drug will be presented in a table. A treatment-related treatment-
emergent SAE is a treatment-emergent SAE with any relation to study drug other than “unrelated”. 
Treatment-emergent SAEs that are missing a relationship will be presented in the table as “related” 
but will be presented in the data listing with a missing relationship. At each level of patient 
summarization, a patient is counted once if the patient reported one or more events. Percentages 
will be calculated out of the number of patients in the SAF.  
The treatment-emergent SAE data will be categorized and presented by SOC and PT, and PT alone
in a manner similar to that described in Section 8.2.1. 
8.2.5 Adverse Events Leading to Treatment Discontinuation, Dose Interruption and Dose 
Reduction
A summary of TEAEs with a study drug action taken of “drug discontinued”, “dose interrupted” 
and “dose reduced” will be presented in separate tables. At each level of patient summarization, a 
patient is counted once if the patient reported one or more events. Percentages will be calculated 
out of the number of patients in the SAF. 
The tables will be presented by PT in descending order of frequency from the PT with the highest 
total incidence (that is, summed across all treatment groups, as defined in Section 4.2.1) to the PT
with the lowest total incidence.
8.2.6 Deaths
TEAEs with an outcome of “fatal” will be presented in the overall summary table. A patient is 
counted once if the patient reported one or more events. Percentages will be calculated out of the 
number of patients in the SAF. 
All patients who have a TEAE with an outcome of “fatal” will be presented in a listing.  A listing 
of all deaths recorded during the study will also be produced. This listing will include the cause of 
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death and the period that the event occurred (i.e. the treatment period plus 30 days from last dose 
administered or the follow-up period). 
8.3 Clinical Laboratory Evaluations 
Laboratory parameters assessed for safety purposes will be evaluated locally. Refer to Table 4 for 
a summary of the parameters to be evaluated. Local laboratories must provide normal ranges for 
the parameters being analyzed and accreditation documentation for all local laboratories that 
perform protocol-required assessment. 
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Table 4 - Clinical Laboratory Parameters Collection
Test Category
Test Name
Hematology 
Hemoglobin, platelets, white blood cells, lymphocytes, and neutrophils 
Chemistry
Albumin, alkaline phosphatase, alanine transaminase, aspartate 
transaminase, bicarbonate, calcium, chloride, creatinine, glucose 
magnesium, inorganic phosphate, potassium, sodium, total bilirubin (also 
measure direct and/or indirect bilirubin if total bilirubin is > 1.5 × ULN), 
blood urea nitrogen or urea, amylase, and lipase 
Coagulation
Prothrombin time or international normalized ratio and activated partial 
thromboplastin time
Urinalysis
Bilirubin, blood, glucose, ketones, pH, protein, specific gravity, and white 
blood cells (in the event of macroscopic findings, microscopy may be 
performed at the Investigator’s discretion) 
Thyroid 
Free T4 and thyroid stimulating hormone (also measure free T3 if TSH is 
suppressed but free T4 is normal) 
Pregnancy / 
menopausal 
status
hCG (women of childbearing potential)  
FSH (if required to confirm non-childbearing potential) 
hCG = human chorionic gonadotropin; FSH = follicle-stimulating hormone; T3 = triiodo thyroxine; T4 = thyroxine; 
TSH = thyroid stimulating hormone.
Pregnancy tests will be performed for all women of childbearing potential.  Any pregnancy must 
be reported as described in Section 8.5.6 of the protocol V4.0, and the patient should be withdrawn 
from treatment.  For post-menopausal patients, FSH at screening must be within the laboratory’s 
post-menopausal reference range.
In addition to laboratory parameters obtained by local laboratories, the following parameters will 
be derived (age and weight will be the values at Cycle 1 Day 1): 
x
For patients with Albumin<40 g/L, Corrected calcium (mmol/L) = Total calcium (mmol/L) 
+ ([40 – Albumin (g/L)] × 0.02). Otherwise, Corrected calcium (mmol/L) = Total calcium 
(mmol/L) 
x
Creatinine clearance (mL/min) 
o
For males = [140–age(years)] × weight(kg)/[72 × serum creatinine (mg/dL)]
o
For females = 0.85×[140–age(years)] × weight(kg)/[72 × serum creatinine 
(mg/dL)]
x
If only % lymphocytes reported then: 
Absolute lymphocytes = white blood cell count × % lymphocytes  
x
If only % neutrophils reported then: 
Absolute neutrophils = white blood cell count × % neutrophils  
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On dosing days laboratory safety samples will be collected prior to the IMCnyeso infusion. More 
frequent evaluations may be performed, at the investigator’s discretion, if medically indicated;
results should be recorded as unscheduled laboratory assessments in the eCRF. 
Laboratory parameters obtained by local laboratories and derived parameters will be summarized. 
Any result below the limit of quantification (BLQ) where BLQ for a parameter is clinically 
relevant (Hemoglobin, WBC, Lymphocyte count, Neutrophil count, Platelet count, Albumin, 
Bicarbonate, Calcium, Chloride, Magnesium, Phosphorus, Potassium, Sodium, Glucose, TSH, 
Free T4, Free T3) will be included in the calculation of standard statistics listed in Section 4 with 
the result set as 0.  
Some results might be expressed as a range rather than a single value (e.g. ‘<x’). For such results, 
the value to be considered for summaries is the upper limit of the range if ‘x’ is greater than the 
BLQ (e.g. for ‘<x’ results, the value will be ‘x’). If ‘x’ is the BLQ, the result cannot be included 
in the statistics calculations as explained above.
For laboratory tests covered by the NCI CTCAE version 4.03, the study team will grade laboratory 
data accordingly and grading programming will be performed at SDTM database. For laboratory 
tests covered by NCI CTCAE, a grade of 0 will be assigned for all non-missing values not graded 
as 1 or higher. For laboratory tests where grades are not defined by CTCAE, results will be graded 
by the low/normal/high classifications based on laboratory normal ranges.  
For NCI CTCAE tests, the worst on-treatment result is the maximum grade recorded after baseline. 
For non-NCI CTCAE tests, the worst on-treatment result will be:
1.
“Low”, if any result recorded after baseline is lower than the normal range and no post-
baseline result is higher. 
2.
“High”, if any result recorded after baseline is higher than the normal range and no post-
baseline result is higher. 
3.
“Both”, If both low and high are clinically meaningful, report worst low and worst high 
separately.
Summaries will be generated separately for hematology and biochemistry. These will include: 
x
Absolute values and change from baseline summaries, a graph of the results will be plotted. 
x
Shift tables of laboratory data using CTCAE grades to compare baseline to the worst on-
treatment value, a graph of the results will be plotted. 
x
Listing of all relevant laboratory data with values flagged to show the corresponding 
CTCAE grades and the classifications relative to the laboratory normal ranges.
Shift tables of baseline to worst on-treatment laboratory grade (low/normal/high) will be presented 
for the following parameters with their relative worsening direction: 
x
Low: Hemoglobin, Albumin, Platelets, Neutrophils, and Phosphate. 
x
High: ALP, ALT, APTT, AST, Total bilirubin, Creatinine, Amylase, Lipase, and INR. 
x
Both: WBC Count, Lymphocytes, Calcium, Magnesium, Sodium, Potassium, Corrected 
calcium, and Glucose. 
Central laboratory cytokine data (Interferon Gamma, Interleukin 6, Interleukin 8, Tumor Necrosis 
Factor alpha, Interleukin 10, Interleukin 2) will be summarized and statistics produced as per 
Section 4. A graph of the results will be plotted by all timepoints. It will also be listed.
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8.4 Vital Signs
Vital signs (body temperature, pulse, respiratory rate, and blood pressure) will be performed as 
scheduled (details see Table 7-2 of the protocol V4.0). 
Vital signs pre-dose values and worst absolute values and changes from pre-dose as well as time 
from start of infusion to worst will be summarized for each dose. See Section 9 of the protocol 
V4.0 for definition of observation periods. 
The relevant vital sign values at each visit will be classified into the categories of low, normal, and 
high based on the following reference ranges.  
x
Systolic blood pressure, low is <75 mm Hg or decrease of >=30 mm Hg that results in 
<=90 mm Hg. High is >=160 mm Hg. (CTCAE V4.03, Grade 1: Prehypertension (systolic 
BP 120 - 139 mm Hg), Garde 2: Stage 1 hypertension (systolic BP 140 - 159 mm Hg), 
Grade 3: Stage 2 hypertension (systolic BP >=160 mm Hg))  
x
Diastolic blood pressure, low is <40 mm Hg or decrease of >=20 mm Hg that results in 
<=50 mm Hg. High is >=100 mm Hg. (CTCAE V4.03, Grade 1: Prehypertension (diastolic 
BP 80 - 89 mm Hg), Garde 2: Stage 1 hypertension (diastolic BP 90 - 99 mm Hg), Grade 
3: Stage 2 hypertension (diastolic BP >=100 mm Hg)) 
x
Pulse, low is <60 bpm. High is >100 bpm. 
x
Temperature, low is <=32 ć. High is >=38 ć for any fever and >40 ć for CTCAE grade 
3 fever. (CTCAE V4.03, 1. Fever- Grade 1: 38.0 - 39.0 degrees C, Garde 2: >39.0 - 40.0 
degrees C, Grade 3: >40.0 degrees C for <= 24 hours, Grade 4: >40.0 degrees C for > 24 
hours; 2. Hypothermia- Grade 2: 35 - >32 degrees C; Grade 3: 32 - >28 degrees C; Grade 
4: <=28 degrees C)
x
Weight gain: grade 1 = 5 - <10% from baseline, grade 2 = 10 - <20% from baseline, grade 
3= >=20% from baseline. 
x
Weight loss: grade 1 = 5 - <10% from baseline, grade 2 = 10 - <20% from baseline, grade 
3= >=20% from baseline.   
x
Oxygen saturation, low is < 94% and <88% is Grade 3. 
For those parameters where the values might go in multiple directions (low/high), the results will 
be presented for worst low post-baseline and worst high post-baseline results separately.  Figures 
for vitals during cycle 1, with all timepoints from pre-dose through ~24 hours post-dose will be 
plotted. 
8.5 Electrocardiogram 
A standard 12-lead ECG will be performed as per the assessment schedule in Table 7-2: Schedule 
of Treatment Period Assessments of the protocol V4.0.   
PR Interval (msec), RR Interval (msec), QRS Duration (msec), QT Interval (msec), QTcF interval
(msec), QTcF derivations (formula QTcF = QT interval/Cube Root of RR interval (seconds), when 
required), absolute values and change from baseline will be summarized.  
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QTcF interval absolute values will also be tabulated by the following groups:  
x
<=450  
x
>450 - <=480 msec (Grade 1) 
x
>480 - <=500 msec (Grade 2) 
x
>500 msec (Grade 3). 
Change from Baseline in QTcF interval will be classified as:
x
<=30 msec increase from baseline
x
>30 - <=60 msec increase from baseline
x
>60 msec increase from baseline
A shift table of baseline QTcF to worst on-treatment results will be presented. For rating the worst 
on-treatment value, the following categories will be used based on the varying degrees of 
abnormality above, in the order of least to most severe (top to bottom): 
x
Missing result
x
<=450 msec (i.e. ‘Normal’)
x
>450 - <=480 msec (Grade 1) 
x
>480 - <=500 msec (Grade 2) 
x
>500 msec (Grade 3)
8.6 Dose Interruptions and Reductions
The number of IMCnyeso dose interruptions, dose reductions, escalations and re-escalations will 
be summarized. A dose is considered interrupted when it is not administered for any reason during 
a visit (i.e. investigator answers the question in eCRF: “If No, reason for dose interruption”), when 
a visit is delayed by ı 7 days or omitted, or if an infusion is started and then stopped part-way 
through. If the dose is administered, but the investigator states it is reduced compared to last visit
or if there is a reduction compared to the planned dose (for example, if a patient is assigned to 
30/100/300 and receives 30 mcg on C1D8 that is a reduction from the planned dose of 100 mcg.), 
then the dose is considered as reduced (i.e. the investigator' answers the question in eCRF: “If Yes, 
reason for dose reduction”). 
Reasons for dose interruptions and dose reductions will be listed by patient and summarized. 
9
Efficacy Analysis 
Analysis of efficacy endpoints will be performed using the FAS and PPS for Phase II and only on 
FAS for Phase I.   
No sensitivity or exploratory analysis are planned. 
9.1 Primary Efficacy Endpoint 
The primary efficacy endpoint in Phase II is the BOR as determined by RECIST v1.1. 
9.1.1 Objective Response Rate
The primary summary measure of Best Overall Response (BOR) is the ORR, defined as the 
proportion of patients with a best overall response of CR or PR based on local investigator 
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assessment, as defined in RECIST v.1.1. The denominator in the calculation of the ORR will be 
the number of patients with measurable disease at baseline in the FAS / PPS as appropriate. All 
these patients included in the denominator will be categorized by their BOR (CR, PR, SD, PD, 
NE).
Confirmation of response is required for declaring PR or CR in the ORR. A confirmed response is 
defined as a CR or PR followed by a CR or PR at least 4 weeks later (allowing a window, this will 
need to be at least 3.5 weeks after the original assessment). Patients who have a PD event 
(progression or death) immediately after 2 or more consecutive missed/non-evaluable tumor 
assessment visits, will have a BOR of NE. Specifically for patients who die with no evaluable 
follow-up tumor assessments or no evaluable baseline assessment, if the death occurs immediately 
after the first 2 scheduled scans, then the BOR will also be NE. An exception to this rule is if the 
patient (with no evaluable follow-up tumor assessments or no evaluable baseline assessment) dies 
within 2 visits of first dose of study drug, then the BOR will be PD (for death in the absence of 
progression). 
Tumor response will be determined per local investigator’s assessment, according to RECIST v.1.1 
Individual lesion measurements and overall response assessments will be listed by patient and 
assessment date. Best overall response per RECIST v.1.1 will be listed and tabulated. Change in 
tumor size for individual patients will be shown in spider plots. Duration of Treatment, Tumor 
Response and Response Duration will be shown in swimmer plots. Best overall change in tumor 
size for individual patients will be shown in waterfall plots and may be repeated at 13 and 26 weeks 
(Cycle 3 and Cycle 6).  
Best overall response analysis per RECIST v.1.1 will be repeated for PPS. BOR will be 
summarized for overall and by Synovial cohort.
ORR and DCR (CR + PR + stable disease [SD]) will be summarized with accompanying 95% 
Clopper-Pearson’s confidence interval. A patient is eligible for an assessment of stable disease 
only after 16 weeks from day of first dose. Any SD assessed before 16 weeks will not be counted 
as SD in the DCR. 
DoR and time-to-response for patients who experience a CR or PR at any time on study will be 
listed by patient. Duration of response is the time in months from the date of first documented 
objective response until the date of progression or death (whichever occurs first). If a large 
proportion of patients achieves a response (e.g. 5/10), Kaplan-Meier plots for DoR will also be 
produced, and the median DoR will be estimated. The time-to-response is defined as the time from 
first dose to their first CR or PR.
9.2 Secondary Efficacy Endpoints
9.2.1 Progression-free Survival
PFS is defined as the time from first dose until the date of objective progression, or death from any 
cause, whichever occurs first. Patients who progressed or died immediately after two or more 
missed scheduled tumor assessments will be censored at date of last adequate assessment with 
evidence of no progression. Patients who have not progressed or died at the time of analysis will 
be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 
assessment. These censoring rules apply regardless of what concomitant medications may have 
been taken or if the patient discontinued treatment prior to their last assessment. A sensitivity 
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analysis may be performed if subjects without objective disease progression receive a new anti-
cancer therapy potentially affecting their results. In this analysis such patients will then be censored 
at the date of the last adequate response assessment prior to the new anti-cancer therapy.  
PFS (months) = (Event date – date of first dose + 1) / 30.4375 
The PFS will be presented graphically using Kaplan-Meier plots including all patients treated at 
the MTD or RP2D and by overall and Synovial cohort. Median PFS time and the proportion of 
patients who are progression-free at 3, 6, 9 and 12 months will be estimated for each group. To 
note, the 95% confidence interval will be calculated using “conftype = loglog” option within the 
Proc Lifetest procedure in SAS software. 
PFS per RECIST v.1.1 will be listed by patient and tabulated. 
PFS per RECIST v.1.1 will be repeated for the PPS for Phase II. 
9.2.2 Overall Survival 
OS is defined as the time from the date of first dose until death due to any cause. 
OS (months) = (Death date or censor date – date of first dose + 1) / 30.4375. 
Any patient not known to have died at the time of analysis will be right-censored based on the last 
recorded date on which the patient was known to be alive, i.e. the latest of (i) the “Date of study 
completion” (for those patients still alive) on the End of Study eCRF page and (ii) the “Date patient 
last known to be alive” on the Survival Follow Up eCRF page.”   
The OS will be treated similarly to PFS. Median OS time and the proportion of patients who are 
alive at 3, 6, 9 and 12 months will be estimated. OS will be presented graphically using Kaplan-
Meier plots by overall and Synovial cohort for the FAS and PPS in Phase II. To note, the 95% 
confidence interval will be calculated using “conftype = loglog” option within the Proc Lifetest 
procedure in SAS software. 
OS will be listed by patient.
10 Pharmacokinetics, Immunogenicity and Pharmacodynamics 
10.1 Pharmacokinetics
The PK analysis set will be used for all PK summaries and listings. All analyses will be reported 
in the clinical study report (CSR) and/or a stand-alone report. The following summaries/analyses 
will be provided for PK concentration data:  
x
Listings of IMCnyeso concentrations by cohort, visits and nominal timepoint.  
x
Plot of average pre-dose concentrations versus End of infusion at Day 1 of each Cycle. 
x
Summary of descriptive statistics of IMCnyeso PK concentrations by nominal time point 
in pg/mL. 
o
The statistics to be presented include the n, arithmetic and geometric mean, median, 
standard deviation (Std), coefficient of variation (%CV), minimum, and maximum. 
x
Concentration profile plots for individual patients by Phase and cohort.  
x
Arithmetic mean concentration profile plots by Phase and cohort (colored line for each 
cohort/expansion) with errors bars (SD).  
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For calculating summary statistics, the following considerations will be taken into account:  
x
Concentration values below lower limit of quantitation (LLOQ) will be handled as zero in 
summary statistics. Values <LLOQ will be reported as is in the data listing of collected PK 
concentrations. The LLOQ for IMCnyeso is 25 pg/mL.  
x
If the arithmetic mean is below the LLOQ value (i.e. < 25 pg/mL) then the arithmetic mean 
will be displayed as ‘<LLOQ’ in the summary table. The same holds for the following 
statistics: min, max, and median. The standard deviation and %CV will be reported as Not 
Calculable (NC). 
x
Concentration values and arithmetic means that are below the LLOQ value will be set to 
12.5 pg/mL (half the LLOQ value) for display purposes in the both the individual 
concentration profiles and arithmetic mean profile plots. 
x
The geometric mean will be calculated as the exponential of the arithmetic mean calculated 
from data on a natural log scale. The geometric mean will only be calculated at timepoints 
where all patients have concentration values above the LLOQ (i.e. the min is >LLOQ).  
x
The %CV is calculated as (arithmetic standard deviation / arithmetic mean) × 100. 
Pharmacokinetic parameters will be calculated by non-compartmental methods utilizing Phoenix 
WinNonlin (Certera version 8.2 or higher, Princeton, NJ, US) utilizing the linear/log trapezoidal 
methods. For parameter calculations, concentration values reported as LLOQ at pre-dose will be 
treated as zero (0), all other timepoints reported as LLOQ will be treated as missing. The following 
PK parameters will be calculated for individual patients where possible: 
Cycle 1 Day 1
x
Tmax – time to maximum concentration observed 
x
Cmax – maximum concentration observed 
x
AUClast – area under the concentration time profile from pre-dose to last measurable 
concentration
Cycle 1 Day 8
x
Tmax – time to maximum concentration observed 
x
Cmax – maximum concentration observed 
x
AUCtau – area under the concentration time profile over the dosing interval 
Cycle 1 Day 15 
x
Tmax – time to maximum concentration observed 
x
Cmax – maximum concentration observed 
x
AUCtau – area under the concentration time profile over the dosing interval 
Additional PK parameters may be calculated as the analysts determines meaningful at the time of 
the analysis (e.g. clearance [CL], terminal elimination half-life [t1/2], steady state volume of 
distribution [Vss], etc.) 
The following summaries/analyses will be provided for PK parameters:  
x
Listings of pharmacokinetic parameters by cohort and dose (Cycle and Day).  
x
Summary of descriptive statistics of IMCnyeso PK parameters by cohort and dose           
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o
The statistics to be presented include the n, arithmetic and geometric mean, median, 
standard deviation (Std), coefficient of variation (%CV), minimum, and maximum. 
Any missing PK parameter data will not be imputed.
10.2 Immunogenicity 
Anti-drug Antibody (ADA) analysis will be used to evaluate immunogenicity responses. The 
frequency of ADA at baseline and following treatment will be summarized. All analyses will be 
reported in the CSR and/or a stand-alone report.
Sample ADA values at each visit and time-point will be collected in the following formats, from 
a third-party vendor: 
x
Binding ADA result 
o
Positive: Final result in sample results spreadsheet (SRS) is Positive
o
Negative: Final result in SRS is Negative and PK value is < drug tolerance limit 
of assay (200 ng/mL, which is equivalent to 200,000 pg/mL) 
o
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o
Unevaluable: Sample was unable to be analyzed (insufficient volume, wrong 
matrix, etc.)
x
Binding ADA Titer value 
Missing ADA values will be reported as is in data listings, as ‘No Result’ or ‘No Sample’. 
For each patient, the final ADA status (derived from the cumulative ADA sample results for that 
patient) will be summarized. This will include:
x
ADA status (Unevaluable, Positive, Negative) 
x
ADA Characterization (Treatment-induced, Treatment-boosted, or Pre-existing 
ADA)
x
Time to ADA Onset for treatment-induced ADA patients 
x
ADA Duration category (Transient ADA response or Persistent ADA response) 
x
Max titer for treatment-induced ADA patients 
x
Peak fold increase in titer for treatment-boosted ADA patients 
At a study level, the ADA data summaries will include: 
x
The number (%) of patients who are ADA-positive at baseline – see ADA prevalence
at Baseline definition below. 
x
The number (%) of evaluable patients – see ADA Evaluable Subset definition below. 
x
The number (%) of patients who are ADA-positive at follow-up – see Overall ADA 
incidence definition below. 
x
The number (%) of patients who are ADA-negative at follow-up - see ADA Negative 
Subjects definition below.  
x
The number (%) patients with a treatment-induced ADA (from baseline negative) – 
see Treatment-induced ADA incidence definition below. 
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x
The number (%) patients with a treatment-ERRVWHG-fold) (from baseline positive) 
- see Treatment-ERRVWHG-fold) ADA incidence definition below. 
x
The max titer from patients with treatment-induced ADA. Descriptive statistics 
including the median, IQR of the max titer will also be shown. 
x
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Descriptive statistics including the median, IQR of peak titer fold increases will also 
be shown. 
x
A graphical representation of time to ADA onset and ADA duration for patients with 
treatment-induced ADA. Descriptive statistics (median, minimum and maximum) 
may also be summarized for time to ADA onset and ADA duration. 
The following table gives the variables that will be derived for the binding ADA results and 
titers. 
Variable 
Definition
Baseline ADA result & 
Baseline ADA titer
See Section 9.6.3 of the protocol V4.0  
Pre-existing ADA 
Subject with Positive baseline ADA result (without a boost 
in titer in response to study drug administration). See 
below for definition of Treatment-ERRVWHG-fold) ADA.
ADA prevalence at 
Baseline
The number of subjects with a Positive ADA result at 
baseline as a percentage of the total number of subjects 
tested at baseline for ADA.
ADA Evaluable Subset 
All subjects who received at least one dose of study drug 
and have at least one ADA assessment post-baseline. This 
subset of the SAF will be used for determining ADA 
incidence.
Max titer
Highest titer value post-baseline.
Peak (or max) fold 
increase in titer
Ratio of max post-baseline titer to baseline titer (calculated 
only for subjects with a Positive ADA result at baseline).
Treatment-induced ADA 
Subject in the ADA Evaluable Subset who has a positive 
ADA sample post-baseline with a Negative ADA result at 
baseline.
Treatment-induced 
ADA 
Incidence
Number of treatment-induced ADA subjects / Number of 
subjects in ADA Evaluable Subset with a Negative ADA 
result at baseline.
Treatment-ERRVWHG-
Subject in the ADA Evaluable Subset who has a Positive 
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fold) ADA
ADA sample at baseline and a Positive ADA sample post-
baseline with a titer that has a peak (or max) fold increase 
in titer  compared to baseline.
Treatment-ERRVWHG-
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Number of treatment-boosted -fold) ADA subjects / 
Number of subjects in ADA Evaluable Subset with a 
Positive ADA result at baseline.
Overall ADA Incidence 
(ADA Positive Subjects)
All subjects with a treatment-induced or treatment-boosted 
ADA response (see definitions above) or subjects with 
positive post-baseline ADA sample but do not have a 
baseline ADA sample in the ADA Evaluable Subset.
ADA Negative Subjects
All subjects without a treatment-induced nor treatment-
boosted ADA response in the ADA Evaluable Subset (can 
include subjects classified as Pre-existing ADA). 
ADA Status
Three categories: 
a.
Unevaluable: Patient has no post-baseline ADA 
samples.
b. Positive: See “ADA Incidence (ADA Positive 
Subjects)” definition above. 
c.
Negative: See “ADA Negative Subjects” definition 
above (can include subjects classified as Pre-
existing ADA).
ADA Onset (as applicable)
For subjects with a treatment-induced ADA response: 
number of days from first dose of study drug to the first 
instance of Positive ADA. 
Therefore, ADA Onset = (date of first instance of Positive 
ADA – date of first dose of study drug + 1). 
ADA Duration (as 
applicable)
For subjects with a treatment-induced ADA response: 
number of days from the first instance of Positive ADA to 
last instance of Positive ADA for a subject, such that a 
subsequent Negative ADA follows the last instance of 
Positive ADA.
Therefore, ADA Duration = (date of last Positive ADA* – 
date of first instance of Positive ADA + 1). 
*The last Positive has to exist such that a Negative ADA 
follows the last instance of Positive ADA. If the date of last 
Positive ADA result is the final ADA assessment, then 
ADA duration will be calculated above, but in this case, 
the duration will be concatenated with '+' to imply that the 
ADA duration is at least the calculated number of days. 
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Transient ADA response  
ADA Positive subject (post-baseline) with at least one 
subsequent Negative result, after the last Positive result 
and the ADA Duration is < 20 weeks (i.e. < 140 days). 
Persistent ADA response 
Subject with either (i) an ADA DurDWLRQZHHNVLH
140 days), regardless of whether intervening sample results 
are Positive or Negative; or (ii) if last sample is ADA 
Positive (i.e. where ADA Duration is concatenated with 
‘+’as described above).
10.3 Pharmacodynamics 
Cytokines and lymphocytes are analyzed and are covered by this SAP. No other 
pharmacodynamics analysis would be performed. 
11 Interim Analysis 
No formal interim analysis is planned during Phase I. The BLRM will be updated after each dose-
escalation cohort and the MTD / RP2D will be determined at the end of Phase I (see Section 3.1).
A formal interim analysis will be conducted during Phase II. ORR will be evaluated for the first 9 
patients in each Phase II cohort to determine whether enrollment may continue (see Section 4.1).
12 Changes in the Planned Analysis  
There were no substantial changes from the planned analyses described in the protocol version 4.0, 
dated 24 Feb 2020 to those presented in this SAP.  The following minor detail has changed from 
the protocol: 
x
All Patients Set has been added to allow for additional disposition summaries to be 
conducted 
x
Safety RP2D Analysis Set has been added to allow for some analyses to be conducted on 
patients pooled across phases if they receive RP2D.
13 References
1.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase 
I cancer trials. Stat Med. 2008;27:2420–2439.
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14 Appendices 
14.1  N-Continual Reassessment Method (N-CRM) 
The N-CRM design updates a Bayesian Logistic Regression Model (BLRM) after each 
cohort of patients. At each decision point, the BLRM provides an estimate of all dose levels 
of IMCnyeso that do not exceed the MTD and incorporates all DLT information at all dose 
levels for this estimation (see Section 3.4). In general, the next dose will have the highest 
chance that the true DLT rate will fall in the target interval (16%–33%) and will always 
satisfy the EWOC principle (the next recommended dose or MTD should have less than 25% 
chance that the probability of DLT lies within the excessive toxicity band.). In all cases, the 
dose for the next cohort will not exceed a 3.34-fold increase from the previous dose. Smaller 
dose increases may be recommended by the Investigators and Sponsor upon consideration 
of all available clinical data.
For more information on the BLRM used to make dose recommendations for the Phase I 
dose escalation cohorts in this study, see appendix 13.3 in the protocol V4.0, the simulation 
plan, the simulation report and the simulation report addendums 1, 2 and 3.  
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14.2  Tables and Figures (planned)
Table 14.1.1.1 Patient Disposition – Phase I Full Analysis Set
Table 14.1.2.1.1 Analysis Sets – Phase I All Patients Set
Table 14.1.2.2.1 Important Protocol Deviations – Phase I Full Analysis Set
Table 14.1.3.1 Demographics and Baseline Characteristics – Phase I Full Analysis Set
Table 14.1.4.1.1 Medical History – Phase I Full Analysis Set
Table 14.1.4.1.2 Current Medical Medications – Phase I Full Analysis Set
Table 14.1.5.1 Cancer History – Phase I Full Analysis Set
Table 14.1.6.1 Prior Anti-cancer Therapy – Phase I Full Analysis Set
Table 14.1.6.2 Concomitant Medications – Phase I Full Analysis Set
Table 14.1.6.2.1 Concomitant Medications for Treatment Related Adverse Event – Phase I 
Full Analysis Set
Table 14.1.6.2.2 Concomitant Medications taken by at least 10% of patients – Phase I Full 
Analysis Set
Table 14.1.6.2.3 Concomitant Medications that Started within 1 day of the First Study Dose 
– Phase I Full Analysis Set
Table 14.1.6.2.4 Concomitant Medications that Started within 1 day of the Second Study 
Dose – Phase I Full Analysis Set
Table 14.1.6.2.5 Concomitant Medications that Started within 1 day of the Third Study Dose 
– Phase I Full Analysis Set
Table 14.1.6.3 Concomitant Medications by Preferred Term by more than 5% of patients – 
Phase I Full Analysis Set
Table 14.1.7.1 Drug Exposure – Phase I Safety Analysis Set
Table 14.1.8.1 Dose Interruptions and Reductions – Phase I Safety Analysis Set
Table 14.2.1.1.1 Best Overall Response – Summary of Status Phase I and Phase II Full 
Analysis Set
Table 14.2.1.1.2 Best Overall Response – Summary of Status Phase I & II Full Analysis Set
Table 14.2.2.1.1.1 Progression Free Survival – Summary of Status – Phase I and Phase II 
Full Analysis Set
Table 14.2.2.1.1.2 Progression Free Survival – Summary of Status – Phase I and Phase II 
Full Analysis Set
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Table 14.2.2.2.1.1 Progression Free Survival – Kaplan-Meier Estimates – Phase I and Phase 
II Full Analysis Set
Table 14.2.2.2.1.2 Progression Free Survival – Kaplan-Meier Estimates – Phase I and II Full 
Analysis Set
Figure 14.2.2.3.1.1 Progression Free Survival – Kaplan-Meier Plot – Phase I Full Analysis 
Set
Table 14.2.3.1.1.1 Overall Survival – Kaplan-Meier Estimates – Phase I and Phase II Full 
Analysis Set
Table 14.2.3.1.1.2 Overall Survival – Kaplan-Meier Estimates – Phase I and Phase II Full 
Analysis Set
Figure 14.2.3.2.1.1 Overall Survival – Kaplan-Meier Plot – Phase I Full Analysis Set
Figure 14.2.4.1 Duration of Response – Kaplan-Meier Plot – Phase I Full Analysis Set
Figure 14.2.5.1 Tumor size – Best Percent Change from Baseline Waterfall Plot – Phase I 
Full Analysis Set
Figure 14.2.5.2 Swimmer Plot for Duration of Treatment, Tumor Response and Response 
Duration - Phase I Full Analysis Set
Figure 14.2.5.3 Tumor size – Spider Plot for Change from Baseline – Phase I Full Analysis 
Set
Table 14.2.6.1 Summary of IMCnyeso concentrations (pg/ml) – Phase I PK Analysis Set
Table 14.3.1.3.1 Overall Summary of Treatment-Emergent Adverse Events – Phase I Safety 
Analysis Set
Table 14.3.1.4.1.1 Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term – Phase I Safety Analysis Set
Table 14.3.1.4.2.1 Treatment-Emergent Adverse Events by Preferred Term – Phase I Safety 
Analysis Set
Table 14.3.1.5.1.1 Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Maximum Reported CTCAE Grade – Phase I Safety Analysis Set
Table 14.3.1.5.2.1 Treatment-Emergent Adverse Events by Preferred Term (Grade 3 and 4) 
– Phase I Safety Analysis Set  
Table 14.3.1.5.3.1 Treatment-Emergent Adverse Events Related to Study Drug by System 
Organ Class, Preferred Term and Maximum Reported CTCAE Grade – Phase I Safety 
Analysis Set
Table 14.3.1.5.4.1 Treatment-Emergent Adverse Events Related to Study Drug by Preferred 
Term – Phase I Safety Analysis Set
Table 14.3.1.5.5.1 Treatment-Emergent Adverse Events Related to Study Drug by Preferred 
Term (Grade 3 and 4) – Phase I Safety Analysis Set
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Table 14.3.1.6.1 Treatment-Emergent Adverse Events of Interest by System Organ Class 
and Preferred Term – Phase I Safety Analysis Set
Table 14.3.1.7.1.1 Treatment-Emergent Adverse Events Leading to Treatment 
Discontinuation by Preferred Term – Phase I Safety Analysis Set
Table 14.3.1.7.2.1 Treatment-Emergent Adverse Events Leading to Dose Interruption by 
Preferred Term – Phase I Safety Analysis Set
Table 14.3.1.7.3.1 Treatment-Emergent Adverse Events Leading to Dose Reduction by 
Preferred Term – Phase I Safety Analysis Set
Table 14.3.2.1.1.1 Serious Treatment-Emergent Adverse Events Regardless of Causality 
Overall by System Organ Class and Preferred Term - Phase I Safety Analysis Set
Table 14.3.2.1.2.1 Serious Treatment-Emergent Adverse Events Regardless of Causality 
Overall by Preferred Term - Phase I Safety Analysis Set
Table 14.3.2.1.3.1 Serious Treatment-Emergent Adverse Events Related to Study Drug by 
System Organ Class and Preferred Term - Phase I Safety Analysis Set
Table 14.3.2.1.4.1 Serious Treatment-Emergent Adverse Events Related to Study Drug by 
Preferred Term - Phase I Safety Analysis Set 
Table 14.3.2.1.5.1 Adverse Event of Special Interest of Cytokine Release Syndrome - Phase 
I Safety Analysis Set
Table 14.3.2.2.1 Listing of Deaths – Phase I Safety Analysis Set
Table 14.3.4.1.1 Hematology Laboratory Data Overall - Observed Values and Change from 
Baseline - Phase I Safety Analysis Set
Figure 14.3.4.2.1.1 Hematology Laboratory Data Overall – Line plot of Absolute Values at 
Each Scheduled Time Point - Phase I Safety Analysis Set
Figure 14.3.4.2.2.1 Hematology Laboratory Data Overall – Line plot of Change from 
Baseline at Each Scheduled Time Point - Phase I Safety Analysis Set
Table 14.3.4.3.1.1 Hematology Laboratory Data – Shift Table for CTCAE Grades (Worst 
On-treatment vs. Baseline) - Phase I Safety Analysis Set
Table 14.3.4.3.2.1 Hematology Laboratory Data – Shift Table for Low/Normal/High 
Parameters (Worst On-treatment vs. Baseline) - Phase I Safety Analysis Set
Figure 14.3.4.4.1.1 Hematology Laboratory Data – Worst On-treatment vs Baseline Plot - 
Phase I Safety Analysis Set
Table 14.3.4.5.1 Biochemistry Laboratory Data Overall- Observed Values and Change from 
Baseline - Phase I Safety Analysis Set
Figure 14.3.4.6.1.1 Biochemistry Laboratory Data Overall – Line plot of Absolute Values at 
Each Scheduled Time Point - Phase I Safety Analysis Set
$SSURYHG
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ase I Safe
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y Laborato
ety Analysis Set
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Hematology Labo
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Time Point -
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le


Immunocore 
 
Statistical Analysis Plan, Version 2.0
IMCnyeso-101
                                                  CONFIDENTIAL  
Date Issued: 08FEB2021
  
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Figure 14.3.4.6.2.1 Biochemistry Laboratory Data Overall – Line plot of Change from 
Baseline at Each Scheduled Time Point - Phase I Safety Analysis Set
Table 14.3.4.7.1.1 Biochemistry Laboratory Data – Shift Table for CTCAE Grades (Worst 
On-treatment vs. Baseline)- Phase I Safety Analysis Set
Table 14.3.4.7.2.1 Biochemistry Laboratory Data – Shift Table for Low/Normal/High 
Parameters (Worst On-treatment vs. Baseline) - Phase I Safety Analysis Set
Figure 14.3.4.8.1.1 Biochemistry Laboratory Data – Worst On-treatment vs Baseline Plot - 
Phase I Safety Analysis Set
Table 14.3.5.1.1 Vital Signs Overall - Observed Values and Change from Baseline - Phase 
I Safety Analysis Set
Table 14.3.6.1.1 ECGs Overall - Observed Values and Change from Baseline - Phase I 
Safety Analysis Set
Table 14.3.6.2.1 ECGs – Shift Table for QTcF Abnormalities (Worst On-treatment vs. 
Baseline) - Phase I Safety Analysis Set
Table 14.3.7.1.1 ECOG Performance Status – Observed Values – Phase I Safety Analysis 
Set
Table 14.3.7.2.1 ECOG Performance Status – Shift Table - Phase I Safety Analysis Set
Table 14.3.8.1.1.1 Central Cytokine - Phase I Safety Analysis Set
Figure 14.3.8.2.1 Central Cytokine – Line plot of Absolute Values over Time - Phase I Safety 
Analysis Set
Figure 14.3.8.3.1 Pharmacokinetic concentration – individual patient profile plots on the log 
scale at C1D1 and C1D15 - Phase I PK Analysis Set
Table 14.3.9.1 Summary of 
 Parameters - Phase I PK Analysis Set
Table 14.3.10.1 Immunogenicity anti-drug antibody patient summary – Phase I   Safety 
Analysis Set
Table 14.3.10.2 Immunogenicity anti-drug antibody study summary – Phase I   Safety 
Analysis Set
$SSURYHG
ues and 
es and
QTcF Abnormaliti
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O
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tatus – hift 
tokine - 
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Phase
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ine – Line plot
Line 
rmacokinetic
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C1D15 -
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Phase I PK
Phase I 
ummary of 
ary of 
munogenici
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