An Investigator-initiated Phase I Trial of an Armored and GPC3-targeted Autologous CAR T-cell Infusion C-CAR031 in Participants With GPC3+ Advanced/Metastatic Squamous Cell Lung Cancer
Phase: PHASE1
Conditions: Squamous Cell Lung Cancer
Sponsor: Shanghai AbelZeta Ltd.

Clinical Study Protocol  
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C-CAR031 - 0926-045 
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Study 
Intervention
C-CAR031 
Study Code 
0926-045 
Version 
1.0 
Date 
Jun 30, 2024 
 
 
 
 
 
 
 
An investigator-initiated Phase I trial of an armored and GPC3-
targeted autologous CAR T-cell infusion C-CAR031 in participants 
with GPC3+ advanced/metastatic squamous cell lung cancer 
 
 
 
 
Principal Investigator: 
 
 
 
Principal Study Institution: 
 
 
Collaborator: Shanghai AbelZeta Ltd. 
 
 
CONFIDENTIAL 
The information contained in this protocol is confidential and belongs to Shanghai AbelZeta Ltd. 
Except for the researchers listed in this protocol, any third party shall not copy and disseminate the 
relevant information of this document without the written permission of Shanghai AbelZeta Ltd. 
(referring to the signing of the cooperation agreement).  

Clinical Study Protocol  
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Clinical study protocol signature page 
(Collaborator) 
Signature page (Collaborator) 
I will strictly follow the Declaration of Helsinki, the principles of GCP, the principles of ICH-GCP 
and the established clinical study protocol, and earnestly fulfill my responsibilities as a collaborator. 
Agree with and be familiar with this protocol design and regulations to carry out this clinical study. 
 
 
 
 
Collaborator:                                            signature:                               date:                
Company name: Shanghai AbelZeta Ltd. 
Address: Bldg. 3, 85 Faladi Rd., Shanghai, China 
Zip Code: 201210 
Tel: (+86) 21-54069990 
Fax: (+86) 21-54069991 
E-mail: 
 
 

Clinical Study Protocol  
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C-CAR031 - 0926-045 
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Clinical study protocol signature page 
(Principal Investigator) 
 
Signature page (Principal Investigator) 
I have been familiar with the clinical study protocol and confirm that the protocol includes the 
necessary contents for the protocol implementation. I will carry out this study and perform my 
investigator duties in strict accordance with the Declaration of Helsinki, GCP principles, ICH-GCP 
principles and established clinical study protocol. 
 
 
 
 
Principal Investigator:                                            signature:                               date:                
Study Institutions: 
Address: 
Phone: 
E-mail: 
 
 

Clinical Study Protocol  
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C-CAR031 - 0926-045 
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Brief Title: 
A Phase I study to evaluate C-CAR031 in GPC3+ advanced/metastatic squamous cell lung 
cancer 
Study Phase: I  

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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 7 
LIST OF FIGURES ....................................................................................................................... 10 
LIST OF TABLES......................................................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................... 12 
1 
PROTOCOL SUMMARY.......................................................................................... 17 
1.1 
Synopsis ...................................................................................................................... 17 
1.2 
Schema ........................................................................................................................ 23 
1.3 
Schedule of Activities ................................................................................................. 27 
2 
INTRODUCTION ...................................................................................................... 36 
2.1 
Study Rationale ........................................................................................................... 36 
2.2 
Background ................................................................................................................. 38 
2.2.1 
Disease Background and Current Landscape ............................................................. 38 
2.2.2 
Glypican-3 as a Therapeutic Target in squamous cell lung cancer ............................ 41 
2.2.3 
Role of TGFβ in squamous cell lung cancer .............................................................. 42 
2.2.4 
Preclinical and Clinical Evidence of TGFβ-armoured CAR T-Cell Activity Against 
Solid Tumors ................................................................................................................................. 42 
2.2.5 
Summary of GPC3-Targeted CAR-T Clinical Trials Conducted to Date .................. 43 
2.2.6 
Summary of C-CAR031 preclinical study .................................................................. 45 
2.2.7 
Summary of C-CAR031 clinical study ....................................................................... 51 
2.3 
Benefit/Risk Assessment ............................................................................................ 53 
2.3.1 
Risk Assessment ......................................................................................................... 53 
2.3.2 
Benefit Assessment ..................................................................................................... 57 
2.3.3 
Overall Benefit/Risk Conclusion ................................................................................ 57 
3 
OBJECTIVES AND ENDPOINTS ............................................................................ 57 
4 
STUDY DESIGN ....................................................................................................... 59 
4.1 
Overall Design ............................................................................................................ 59 
4.2 
Scientific Rationale for Study Design ........................................................................ 61 
4.2.1 
Rationale for Lymphodepletion Chemotherapy ......................................................... 62 
4.3 
Justification for Dose .................................................................................................. 62 
4.3.1 
Dose for LDC ............................................................................................................. 62 
4.3.2 
Dose for C-CAR031 ................................................................................................... 63 
4.4 
End of the Main Study Definition .............................................................................. 63 
4.4.1 
Study Stopping Criteria .............................................................................................. 64 
5 
STUDY POPULATION ............................................................................................. 65 
5.1 
Inclusion Criteria ........................................................................................................ 65 
5.1.1 
Inclusion Criteria to be Met for Pre-screening ........................................................... 65 
5.1.2 
Inclusion Criteria to be Met for Screening ................................................................. 65 
5.2 
Exclusion Criteria ....................................................................................................... 67 
5.3 
Lifestyle Considerations ............................................................................................. 70 
5.4 
Screen Failures ............................................................................................................ 71 
5.5 
Criteria for Temporarily Delaying Enrolment/Administration of Study Intervention 72 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................ 72 
6.1 
Study Intervention(s) Administered ........................................................................... 72 
6.1.1 
Apheresis .................................................................................................................... 73 
6.1.2 
Bridging Therapy ........................................................................................................ 74 
6.1.3 
Lymphodepletion ........................................................................................................ 75 

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6.1.4 
C-CAR031 .................................................................................................................. 77 
6.1.5 
Exceptional Release Criteria....................................................................................... 78 
6.2 
Preparation, Handling, Storage, and Accountability .................................................. 79 
6.3 
Assignment to Study Intervention .............................................................................. 79 
6.4 
Blinding ...................................................................................................................... 79 
6.5 
Study Intervention Compliance .................................................................................. 79 
6.6 
Dose Modification ...................................................................................................... 80 
6.6.1 
Startin7 DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................. 89 
g Dose, Safety run-in and backfill Scheme and Stopping Criteria ................................................ 80 
6.6.2 
Dose Expansion .......................................................................................................... 82 
6.6.3 
Definition of DLT ....................................................................................................... 82 
6.6.4 
Definition of DLT-Evaluable Participant ................................................................... 84 
6.6.5 
Safety Review Committee .......................................................................................... 84 
6.6.6 
Risk Management Plan ............................................................................................... 85 
6.7 
Continued Access to Study Intervention After the End of the Study ......................... 86 
6.8 
Treatment of Overdose ............................................................................................... 86 
6.9 
Prior and Concomitant Therapy .................................................................................. 86 
6.9.1 
Rescue Medicine ......................................................................................................... 88 
7.1 
Discontinuation of Study Intervention ........................................................................ 89 
7.2 
Participant Discontinuation/Withdrawal From the Study ........................................... 89 
7.2.1 
Discontinuation from the Study Between Apheresis and Prior to CAR T-Cell  
Infusion       .................................................................................................................................... 89 
7.2.2 
Discontinuation from Stage 1 Follow-up ................................................................... 90 
7.2.3 
Discontinuation from Stage 2 Follow-up ................................................................... 90 
7.2.4 
Participant Withdrawal from the Study ...................................................................... 91 
7.3 
Lost to Follow-up ....................................................................................................... 91 
8 
STUDY ASSESSMENTS AND PROCEDURES...................................................... 92 
8.1 
Administrative and General/Baseline Procedures ...................................................... 93 
8.2 
Efficacy Assessments ................................................................................................. 93 
8.2.1 
Efficacy Endpoints ...................................................................................................... 93 
8.2.2 
Tumor Assessments .................................................................................................... 94 
8.2.3 
Survival Follow-up ..................................................................................................... 96 
8.2.4 
Subsequent Anticancer Treatment .............................................................................. 96 
8.2.5 
Clinical Outcome Assessments ................................................................................... 97 
8.3 
Safety Assessments ..................................................................................................... 97 
8.3.1 
Physical Examinations ................................................................................................ 97 
8.3.2 
ECOG Performance Status ......................................................................................... 97 
8.3.3 
Vital Signs and Oxygen Saturation ............................................................................. 98 
8.3.4 
Cardiac and Pulmonary Safety Assessments .............................................................. 98 
8.3.5 
Clinical Safety and Efficacy Laboratory Tests ........................................................... 99 
8.3.6 
Neurological Examination ........................................................................................ 101 
8.4 
AEs, SAEs, and Other Safety Reporting .................................................................. 102 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ..................... 103 
8.4.2 
Follow-up of AEs and SAEs ..................................................................................... 104 
8.4.3 
Causality Collection .................................................................................................. 104 
8.4.4 
AEs Based on Examinations and Tests .................................................................... 104 
8.4.5 
AEs Based on Signs and Symptoms ......................................................................... 105 

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8.4.6 
Adverse Events of Special Interest ........................................................................... 105 
8.4.7 
Specific AEs ............................................................................................................. 106 
8.4.8 
Hy’s Law .................................................................................................................. 106 
8.4.9 
Disease Progression .................................................................................................. 106 
8.4.10 
Reporting of SAEs .................................................................................................... 106 
8.4.11 
Pregnancy ................................................................................................................. 107 
8.4.12 
New Primary Malignancies ...................................................................................... 108 
8.4.13 
Positive RCL Results ................................................................................................ 108 
8.4.14 
Deaths ....................................................................................................................... 109 
8.4.15 
Reporting of Overdose .............................................................................................. 109 
8.5 
Pharmacokinetics ...................................................................................................... 110 
8.5.1 
Collection of Samples for Cellular Kinetics and Blood Cell  Immunophenotyping 110 
8.5.2 
Determination of C-CAR031 Blood Concentration ................................................. 111 
8.6 
Pharmacodynamics ................................................................................................... 111 
8.6.1 
Collection of Samples for Pharmacodynamics ......................................................... 111 
8.7 
RCL Detection .......................................................................................................... 111 
8.8 
Immunogenicity Assessments .................................................................................. 111 
8.8.1 
Collection of Samples for Immunogenicity Assessments ........................................ 112 
8.9 
Biomarkers ................................................................................................................ 112 
8.9.1 
Mandatory Biomarker Sample Collection ................................................................ 112 
8.9.2 
Optional Tumor Biopsy Sample Collection ............................................................. 114 
8.10 
Medical Resource Utilization and Health Economics .............................................. 115 
8.11 
Study Participant Feedback Questionnaire ............................................................... 115 
9 
STATISTICAL CONSIDERATIONS ..................................................................... 115 
9.1 
Statistical Hypotheses ............................................................................................... 115 
9.2 
Sample Size Determination ...................................................................................... 115 
9.3 
Populations for Analyses .......................................................................................... 116 
9.4 
Statistical Analyses ................................................................................................... 117 
9.4.1 
General Considerations ............................................................................................. 117 
9.4.2 
Safety Analyses ........................................................................................................ 118 
9.4.3 
Efficacy Analyses ..................................................................................................... 119 
9.4.4 
Pharmacokinetic Analysis ........................................................................................ 122 
9.4.5 
Exploratory Study Analyses ..................................................................................... 122 
9.5 
Data Monitoring Committee ..................................................................................... 123 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
 .................................................................................................................................. 123 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ...................... 123 
Appendix B 
AEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting ............................................................................................................ 129 
Appendix C 
Handling of Human Biological Samples ................................................. 132 
Appendix D 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................................ 134 
Appendix E 
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors) ................................... 140 
Appendix F 
Contraception Guidance .......................................................................... 152 
Appendix G 
Grading of CRS, ICANS, and ICE Scoring ............................................. 154 
11 
REFERENCES ......................................................................................................... 157 
 

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LIST OF FIGURES 
Figure 1 
Study Design ..................................................................................................... 23 
Figure 2 
Participant Flow Through the Study – Phase Ia and Phase Ib .......................... 25 
Figure 3 
Follow-up Schema for Stages 1-3  .................................................................... 26 
Figure 4 
The C-CAR031 CAR Construct ....................................................................... 36 
Figure 5     Expression of dnTGFβRII increases CAR-T in vivo efficacy against TGFβ     
expressing tumors.. .............................................................................................................. 47 
 
LIST OF TABLES 
Table 1 
Objectives and Endpoints ................................................................................. 19 
Table 2 
Schedule of Activities - Pre-screening to Stage 2 Follow-up ........................... 27 
Table 3 
Schedule of Activities (Stage 3 Follow-up)...................................................... 34 
Table 4 
GPC3-Targeted CAR T-Cell Clinical Trials .................................................... 43 
Table 5 
List of C-CAR031 Non-clinical Studies ........................................................... 45 
Table 6 
Primary Toxicology Study Results of C-CAR031 ........................................... 48 
Table 7 
Comparison of Safety and Efficacy Across Different Dose Groups (Safety      
Analysis Set) ........................................................................................................................ 51 
Table 8 
Risk Assessment ............................................................................................... 53 
Table 9 
Objectives and Endpoints ................................................................................. 58 
Table 10 
Study Intervention ............................................................................................ 72 
Table 11 
Pre-infusion Medications .................................................................................. 77 
Table 12 
C-CAR031 Phase Ia Scheme ............................................................................ 80 
Table 13 
Prohibited Concomitant Medications ............................................................... 87 
Table 14 
Permitted Concomitant Medications ................................................................ 88 
Table 15 
Laboratory Safety and Efficacy Variables (Local Laboratories) ...................... 99 
Table 16 
Clinical Laboratory Parameters to be Monitored During CRS ...................... 101 
Table 17 
Adverse Event Collection Window ................................................................ 103 
Table 18 
Description of Sample Collections for PK and Blood Cell             
Immunophenotyping .......................................................................................................... 110 

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Table 19 
Blood Samples and Purpose of Collection for Immunogenicity                  
Assessments ....................................................................................................................... 112 
Tabel 20    Study Populations ............................................................................................ 116 
Table 21 
Potential Hy’s Law Definitions ...................................................................... 134 
Table 22 
Summary of Imaging Modalities for Tumor Assessment ............................... 140 
Table 23 
RECIST 1.1 Evaluation of Target Lesions ..................................................... 148 
Table 24 
RECIST 1.1 Evaluation of Non-target Lesions .............................................. 149 
Table 25 
RECIST 1.1 Overall Visit Response .............................................................. 149 
Table 26 
Highly Effective Methods of Contraception ................................................... 152 
Table 27 
American Society for Transplantation and Cellular Therapy Consensus Grading 
Criteria For CRS ................................................................................................................ 154 
Table 28 
American Society for Transplantation and Cellular Therapy Consensus Grading 
Criteria for ICANS in Adults ............................................................................................. 155 
Table 29 
Immune Effector Cell-associated Encephalopathy (ICE) Score .................... 156 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Special 
Term 
Explanation 
ADA 
Anti-drug antibody 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic Lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase/transaminase 
ANC  
Absolute neutrophil count 
Anti-HBc 
Anti-hepatitis B core antibodies 
Anti-HBs 
Anti-hepatitis B surface antibodies 
Anti-HCV 
Anti-hepatitis C virus antibodies 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AST 
Aspartate aminotransferase/transaminase 
AUC 
Area under the curve 
BRAF 
V-Raf murine sarcoma viral oncogene homolog B 
CAR 
Chimeric antigen receptor 
CBC  
Complete blood cell count 
CDE 
Center for drug evaluation 
CDx 
Companion diagnostics 
CI 
Confidence interval 
CK 
Cellular kinetics 
Clast 
Last measurable concentration 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
COA 
Certificate of analysis 
CPIs 
Checkpoint inhibitors 
CR 
Complete response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSCO 
The Chinese Society of Clinical Oncology 
CSP 
Clinical study protocol 

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CSR 
Clinical study report 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CTLA-4 
Cytotoxic T lymphocyte associated protein 4 
DB 
Direct bilirubin 
DCR 
Disease control rate 
DIC 
Disseminated intravascular coagulation 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
DLT 
Dose-limiting toxicity 
DMSO 
Dimethyl sulfoxide 
DNA 
Deoxyribonucleic acid 
dnTGFβRII 
Dominant-negative transforming growth factor-beta receptor II 
DoR 
Duration of response 
DRR 
Durable response rate 
DUS 
Disease under study 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEG 
Electroencephalogram 
EGFR 
Epidermal growth factor receptor 
EMT 
Epithelial mesenchymal transition 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in one second 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GPC3 
Glypican-3 
Hb 
Hemoglobin 
HBA1c 
Haemoglobin A1c 
HBS 
Human biological sample(s) 
HBcAb 
Hepatitis B core antibody 
HBeAg 
Hepatitis B e antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 

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HIV 
Human immunodeficiency virus 
HL 
Hy’s Law 
HLH 
Haemophagocytic lymphohistiocytosis 
 
HR 
Hazard ratio 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICANS 
Immune effector cell-associated neurotoxicity syndrome 
ICE 
Immune effector cell encephalopathy 
iCRO 
imaging Contract Research Organization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
ILD 
Interstitial lung disease 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IRC 
Independent review committee 
IRR 
Infusion-related reaction 
ISH 
In Situ Hybridization 
IIT 
Investigator initiated trial 
IV 
Intravenous 
LDC 
Lymphodepleting chemotherapy 
LDH 
Lactate dehydrogenase 
LDLE 
Lymphoepithelioma-like carcinoma 
LLOD 
Lower limit of detection 
LLOQ 
Lower limit of quantification 
LTFU 
Long-term follow-up 
LVEF 
Left ventricular ejection fraction 
MAS 
Macrophage activation syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
Mesenchymal to epithelial transition factor 
MCV 
Mean corpuscular volume 
MS 
Mass spectrometry 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
Non evaluable 
NIMP 
Non-investigational Medicinal Product 
NL 
New lesion 
NMPA 
National Medical Products Administration 

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NOAEL 
No Observed Adverse Effect Level 
NSCLC 
Non–small cell lung cancer 
NTL 
Non-target lesion 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
PBMCs 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PET 
Positron emission tomography 
PHL 
Potential Hy’s Law 
PD 
Progressive disease 
PD 
Pharmacodynamics 
PD1 
Programmed death 1 
PD-L1 
Programmed death ligand 1 
PDX 
Patient-derived xenograft 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PLT 
Platelet 
PR 
Partial response 
PS 
Performance status 
PSMA 
Prostate-specific membrane antigen 
PT 
Preferred term 
PCR 
Polymerase chain reaction 
RDE 
Recommended dose for expansion 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RCL 
Replication-competent lentivirus  
RMP 
Risk management plan 
RNA 
Ribonucleic acid 
ROS1 
ROS proto-oncogene 1, receptor tyrosine kinase 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
scFv 
Single chain variable fragment 
SD 
Stable disease 
SIN 
Self-inactivated 
SoA 
Schedule of activities 
SoC 
Standard of care 
SOC 
System organ class 
SRC 
Safety Review Committee 

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TBL 
Total bilirubin 
SUSAR 
Suspected unexpected serious adverse reaction 
TACE 
Transarterial-chemoembolization 
TEAE 
Treatment-emergent adverse event 
TGFβ 
Transforming growth factor-beta 
TKI 
Tyrosine kinase inhibitors 
TL 
Target lesions 
Tlast 
Time of last measurable concentration 
TLS 
Tumor lysis syndrom 
Tmax 
Time to reach maximum concentration 
TPS 
Tumor proportion score 
TRAE 
Treatment-related adverse event 
QTc 
Corrected QT interval 
TTR 
Time to response 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: 
An investigator-initiated Phase I trial of an armored and GPC3-targeted autologous CAR T-
cell infusion C-CAR031 in participants with GPC3+ advanced/metastatic squamous cell lung 
cancer 
Brief Title: 
A Phase I study to evaluate C-CAR031 in GPC3+ advanced/metastatic squamous cell lung 
cancer 
 
Rationale: 
Glypican-3 (GPC3) is present on non–small cell lung cancer (NSCLC) tumor cells (23% of 
expression), further studies have shown that the positive expression is significantly higher in 
squamous cell lung cancer  (55% of expression) than that in adenocarcinoma (8% of expression) 
and virtually absent in normal adult tissues, making it an ideal target for chimeric antigen 
receptor (CAR) T-cell therapy (Aviel-Ronen et al 2008[1]). In addition, some studies have shown 
that GPC3 expression is significantly associated with poor prognosis of squamous cell lung 
cancer patients (Ning et al 2021[2]). 
 
C-CAR031 is an autologous CAR T-cell product that expresses a CAR specific for GPC3 and 
a dominant-negative transforming growth factor-beta receptor II (dnTGFβRII) as an armoring 
strategy. Expression of dnTGFβRII can block TGFβ signaling, protecting CAR-T cells from 
the immunosuppressive effect of this cytokine. Early clinical data of C-CAR031 has shown 
promise in an ongoing, open label, investigator-initiated Phase I trial (NCT05155189) to 
evaluate the safety and efficacy C-CAR031 in patients with advanced hepatocellular carcinoma 
(HCC) (Zhang et al 2024[3]). C-CAR031 is well tolerated in all the dose levels being explored. 
No grade 5 treatment-related adverse event (TRAE), dose-limiting toxicity (DLT) and immune 
effector cell-associated neurotoxicity syndrome (ICANS) were observed. Cytokine release 
syndrome (CRS) was observed in 22 (91.7%) participants with only 1 (4.2%) Grade 3 CRS. All 
CRS events were started within the first week post the infusion and resolved within 3 to 6 days 
of onset. C-CAR031 mono therapy demonstrated an objective response rate (ORR) of 56.5% 
across all dose levels and the ORR in the 4.0 ×106 CAR-T cells/kg dose cohort was 75% (6/8). 
The median target lesion reductions achieved 42.2% and the deep target lesion shrinkage can 
be observed in intra and extrahepatic lesions (70.8% of the participants have tumor lesions in 
lung). The median duration of response (DoR) was 7.4 months. Though there were 70.8% of 
participants had lung metastatic lesions, the pulmonary complications were not a safety concern 
in the HCC investigator-initiated trial (IIT). These data led to the hypothesis underlying this 
study: C-CAR031 mono therapy would provide clinical benefit with tolerable safety in GPC3 
expression solid tumors which supports the exploration of C-CAR031 in squamous cell lung 

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cancer.

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Objectives and Endpoints: 
 
Table 1 
Objectives and Endpoints 
 
Type 
Objectives 
Endpoints 
Primary 
Phase Ia: Safety run-in and backfill 
Phase Ib: Dose expansion  
Safety 
• 
To assess the safety and 
tolerability of C-CAR031 
in participants with GPC3+ 
advanced/metastatic 
squamous cell lung cancer 
• 
To determine the RDE 
(Phase Ia) 
• 
Incidence of AEs/SAEs/AESIs  
• 
Incidence and severity of DLTs (Safety run-in 
section of Phase Ia) 
• 
Changes from baseline in vital signs, physical 
examination, ECOG score, 12-lead ECGs, 
laboratory parameters that are abnormal and of 
clinically significance. 
Secondary 
Phase Ia: Safety run-in and backfill 
Phase Ib: Dose expansion 
Efficacy 
To estimate the anti-tumor 
activity of C-CAR031 in 
participants with GPC3+ 
advanced/metastatic 
squamous cell lung cancer 
• 
ORR, DCR, DoR, DRR, TTR, PFS and change 
in tumor size assessed by the investigator and 
evaluated according to RECIST 1.1 criteria 
• 
OS  
Pharmacokinetics 
To investigate the CK of C-
CAR031 by PCR in 
participants with GPC3+ 
advanced/metastatic 
squamous cell lung cancer 
• 
Quantification of CAR copies/μg DNA of C-
CAR031 in peripheral blood 
• 
CK parameters of C-CAR031, including but 
not limited to Tmax, Cmax, AUC0-28d, Tlast, Clast, 
and AUC last, as data allows 
Safety 
To assess the safety of C-
CAR031 in participants with 
GPC3+ advanced/metastatic 
squamous cell lung cancer 
• 
Presence of RCL in peripheral blood samples. 
Exploratory 
Phase Ia: Safety run-in and backfill 
Phase Ib: Dose expansion  
Pharmacokinetics  
To investigate the CK of C-
CAR031 by flow cytometry 
in participants with GPC3+ 
advanced/metastatic 
squamous cell lung cancer 
• 
Quantification of C-CAR031 CAR-T cells in 
peripheral blood  
• 
CK parameters of C-CAR031, including but 
not limited to Tmax, Cmax, AUC0-28d, Tlast, Clast, 
and AUClast as data allows 
Immunogenicity 
To assess the 
immunogenicity of C-
CAR031 
• 
Evaluation of humoral immunogenicity against C-
CAR031: incidence, and antibody levels as data 
allows. 
Biomarkers 
To assess intra-tumoral 
biomarkers of disease, 
pharmacodynamic 
biomarkers and biomarkers of 
clinical response to C-
CAR031 
• 
Presence or changes in tumoral biomarkers 
including, but not limited to levels of RNA, 
DNA, and protein analytes as well as imaging 
measurements. Specific assessments may 
include, but not be limited to expression of 
GPC3, immune markers (for example TGFβ, 
PD-L1, CD8) and CAR-T infiltration. 

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Biomarkers 
To assess systemic 
biomarkers of disease, 
pharmacodynamic 
biomarkers and biomarkers of 
clinical response to C-
CAR031 
• 
Presence and changes in peripheral DNA, 
RNA, immune cell phenotype, and protein 
biomarkers, which may include, but not limited 
to ctDNA, soluble and cellular analytes, gene 
expression, and immune markers pre- and post- 
treatment or on disease progression. 
AEs = adverse events; AESIs = adverse events of special interest; AUClast = area under the curve from time 0 to the 
time of the last quantifiable concentration; AUC0-28d = area under the curve 28 days after C-CAR031 infusion; CAR 
= chimeric antigen receptor; CD8 = cluster of differentiation 8; CK= cellular kinetics; Cmax = maximum observed 
concentration; Clast = last measurable concentration; ctDNA = circulating tumour DNA; DCR = disease control rate; 
DLTs = dose-limiting toxicities; DNA= deoxyribonucleic acid; DoR = duration of response; DRR = durable 
response rate; ECG = electrocardiogram; ECOG= Eastern Cooperative Oncology Group; GPC3 = glypican-3;  ORR 
= objective response rate; OS = overall survival; PFS = progression-free survival; PCR = polymerase chain reaction; 
RCL = replication-competent lentivirus; RDE = recommended dose for expansion; RECIST = Response Evaluation 
Criteria in Solid Tumours; RNA = ribonucleic acid; PD-L1= programmed death ligand 1; SAEs = serious adverse 
events; TGFβ = transforming growth factor-beta; Tlast = Time of Clast; Tmax = time to reach maximum concentration; 
TTR = time to response. 
 
Overall Design Synopsis: 
This single-arm, open-label, multicenter, Phase I study will evaluate the safety, tolerability, anti-
tumor 
activity, 
pharmacokinetics 
(PK)/pharmacodynamics 
(PD), 
biomarker, 
and 
immunogenicity of C-CAR031 in adult participants with GPC3+ advanced/metastatic squamous 
cell lung cancer, who are not amenable to curative therapy and have progressed or are intolerant 
to no more than 3 lines of prior systemic treatment including immune checkpoint inhibitors (CPIs) 
and platinum-based doublet chemotherapy, concurrently or sequentially. The study will be 
divided into two sections: safety run-in and backfill phase (Phase Ia) and dose expansion phase 
(Phase Ib). Phase Ia will determine the recommended dose for expansion (RDE) to be used in 
Phase Ib (dose expansion) of the study and evaluate the safety and efficacy in participants with 
GPC3 expression. Phase Ib will further evaluate the safety, tolerability, cellular kinetics (CK), 
biomarker, immunogenicity and efficacy of C-CAR031 at the RDE. 
The study will be conducted in the following steps: Participants will undergo pre-screening, 
screening, apheresis, bridging therapy (if appropriate) and lymphodepletion before receiving 
CAR T-cell (C-CAR031) infusion. Subsequent follow-up after C-CAR031 infusion is divided 
into three stages: Stage 1, 2, and 3.  
In Stage 1, participants will be followed up to 6 months post C-CAR031 infusion. Participants 
who have not progressed, discontinued prematurely from the study or started a new anticancer 
regimen will continue the follow-up in Stage 2 for up to 12 months post C-CAR031 infusion or 
until disease progression, or discontinued prematurely from the study or started a new anticancer 
regimen, whichever occurs first. Stage 3 is considered long term follow up (LTFU) up to 15 
years post C-CAR031 infusion based on the participants’ willingness and will be offered to all 
participants who received any dose of C-CAR031 infusion. 
Brief Summary: 
The purpose of this study is mainly to evaluate the safety, tolerability, CK and anti-tumor 
efficacy of C-CAR031 in participants with GPC3+ advanced/metastatic squamous cell lung 
cancer. The study is divided into: safety run-in and backfill phase (Phase Ia) and dose expansion 

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phase (Phase Ib). 
Eligible participants will undergo apheresis, bridging therapy (if appropriate), and 
lymphodepletion before receiving one dose of C-CAR031 on Day 0. Following C-CAR031 
infusion, participants will remain hospitalized for a minimum of 7days.  
Participants will complete all assessments as indicated in the Scheme of Activity (SoA) through 
6 months post C-CAR031 infusion, unless they experience disease progression, start a new 
anticancer regimen or discontinue due to participant or investigator decision, whichever occurs 
first (see Section 7.2.2). Participants who received C-CAR031  discontinue prematurely from 
the study in Stage 1 will undergo an early discontinuation visit (see SoA Table 2) and be offered 
to move to Stage 3 of the study (see SoA Table 3) for continued safety surveillance. The LTFU 
will start in Stage 3 of this study. After Stage 1 follow-up, participants who have not previously 
progressed, discontinued prematurely from the study or started a new anticancer regimen will 
continue to be followed in Stage 2 of the study for safety, efficacy, CK, immunogenicity and 
exploratory biomarkers up to 12 months post C-CAR031 infusion or until disease progression, 
start of new anticancer treatment, or discontinuation due to participant or investigator decision, 
whichever occurs first (see Figure 3, SoA Table 2, and Section 7.2.3). Participants who progress, 
start new anticancer treatment, or discontinue prematurely from the study in Stage 2 will undergo 
an early discontinuation visit and be offered to move to Stage 3 of the study (see SoA Table 3). 
 
At the end of the main study, defined as 12 months after the last participant has received his/her 
dose of C-CAR031(or sooner if: all the participants have progressed or stated a new anti-cancer 
therapy or death occurred, or have either withdrawn or are lost to follow-up, or investigator and 
AbelZeta aligned to terminate the study), all study participants who received any dose of C-
CAR031 infusion will be offered to transition to Stage 3 long-term follow-up up to 15 years post 
C-CAR031 based on their willingness. 
Disclosure Statement: This is a multicenter, single-arm, open-label, treatment, Phase I study. 
 
Number of Participants: 
Approximately 47~62 GPC3+ squamous cell lung cancer participants (assuming 20% of dropout 
rate due to the failures in apheresis, lymphodepletion, and manufacturing processes, etc.) will be 
enrolled to yield approximately 37~49 evaluable participants (up to 25 in Phase Ia, which is 
finally based on the practical escalated dose, and approximately 12 each cohort in Phase Ib, 
which will be adjusted based on the results of Phase Ia). 
Study Arms and Duration: 
This is a single-arm study with one infusion of C-CAR031. Prior to receiving C-CAR031, 
participants will undergo prescreening and screening (which may occur in parallel), apheresis 
(see Section 6.1.1), bridging therapy (if appropriate; see Section 6.1.2) and lymphodepletion (see 
Sections 6.1.3 ). Following C-CAR031 infusion (see Section 6.1.4), participants will remain 
hospitalized for a minimum of 7 days. The dose-limiting toxicity (DLT) observation period in 
Phase Ia (safety run-in section) is 28 days post C-CAR031-infusion.  
 
The follow-up period is divided into stage 1,2,3 which lasts for up to 6 months, 12 months and 

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15 years post C-CAR031 infusion (see Section 4.1). 
 
Data Monitoring Committee/Other Committee: Yes 
A safety review committee (SRC) will be appointed to review emerging data for the study. 
 
Phase Ia (safety run-in): The first 1~6 participants of each dose level will be evaluated as safety 
run-in phase. The SRC will review the totality of all adverse events (AEs), serious adverse events 
(SAEs), and laboratory safety data for participants in the DLT period and all other available 
relevant data prior to adjudicating on dose-escalation decisions according to the protocol (see 
Section 6.6.1). 
After each dose level during the safety run-in section (Phase Ia) of the study, once there are at 
least 3 evaluable participants (1 participant in dose level 1), the SRC will evaluate the safety, 
efficacy, tolerability, available CK and other available data of C-CAR031 to decide the dose for 
the next cohort of participants. SRC can suggest exploration of intermediate dose levels or 
additional higher or lower dose levels based on the available data but will not exceed the 3 times 
the current dose or the highest dose that has been determined safe by SRC (no more than 6.0 
×106 CAR-T cells/kg). If 1 out of the first 3 participants or 2 out of the first 6 participants (the 
first participant of dose level 1) in a dose cohort experience the DLT, the SRC cannot recommend 
a dose escalation to doses exceed this current dose cohort. 
Phase Ia (backfill): The SRC will evaluate the safety, efficacy, tolerability, available CK and 
other available data of C-CAR031 at not only the preset dose levels (0.75 ×106 CAR-T cells/kg , 
1.5 ×106 CAR-T cells/kg and 4.0 ×106 CAR- T cells/kg) but also the recommended additional 
intermediate/higher dose levels (Not exceeding 3 times the current dose or the highest dose that 
is determined safe by SRC) to determine the RDE of Phase Ib. Backfill will stop when up to 12 
evaluable participants have been filled in each dose level. The SRC can decide the early 
termination of the backfill phase of each dose level after the evaluation of available data and/or 
further explore additional intermediate/higher dose levels. And if a new dose  is to be explored, 
repeat the above steps of safety run-in of Phase Ia. The SRC will evaluate the safety, efficacy, 
tolerability, available CK and other available data of C-CAR031 at the new dose level to 
determine whether to continue to backfill phase. 
The SRC will determine the RDE based on the safety, efficacy, tolerability, available CK and 
other available data of Phase Ia and further evaluate the safety and efficacy in participants with 
GPC3 expression squamous cell lung cancer in phase Ib. 
Phase Ib (Dose expansion): Once RDE is determined by the SRC in Phase Ia, participants may 
be enrolled in Phase Ib at the RDE. If the SRC recommended more than one dose level as RDEs, 
approximately 12 evaluable participants will be enrolled in each RDE to further evaluate the 
safety, tolerability, CK, biomarker, immunogenicity and efficacy of C-CAR031 in squamous cell 
lung cancer participants with GPC3 expression.  
The SRC will also be responsible for reviewing on a regular basis all safety data beyond the DLT 
period in the study and can determine the numbers of participants with different levels of GPC3 

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expression in each dose group based on enrollment. 
Statistical Methods: 
For purposes of analysis, the study populations are defined as provided in Table 20. Safety and 
tolerability will be assessed in terms of AEs/SAEs, adverse events of special interest (AESIs), 
DLTs (Phase Ia safety run-in only), vital signs, laboratory data, physical examinations and 12-
lead electrocardiogram (ECG) changes, and replication-competent lentivirus (RCL) in peripheral 
blood. All safety analyses (other than DLT) will be performed on the safety analysis set (SS) and 
full analysis set (FAS). For the safety run-in phase in Phase Ia, DLTs analyses will be performed 
on the DLT evaluable analysis set (DLTAS). 
 The first cohort is treated with a starting dose which is considered safe based on extrapolation 
from other ongoing IIT, and the subsequent cohorts are treated at dose levels recommended by 
SRC which will not exceed 3 times the current dose level or the highest dose that is determined 
safe by SRC (no more than 6.0 ×106 CAR-T cells/kg). If 1 out of the first 3 participants or 2 out 
of the first 6 participants (the first participant of dose level 1) in a dose cohort experience the 
DLT, the SRC cannot recommend a dose escalation to doses exceed this current dose cohort.  
For the backfill phase in Phase Ia and the dose-expansion cohorts in Phase Ib safety and 
preliminary efficacy will be assessed. The dose for further study in the future will be selected in 
consultation with SRC based on an assessment of safety and preliminary efficacy data and all 
relevant clinical and nonclinical data available at that time.  
The assessment of efficacy endpoints will be conducted in efficacy analysis set (EAS), FAS and 
SS. Supplementary analysis will be performed in additional analysis sets as outlined in Table 20. 
Data will be presented by dose level; No direct statistical comparisons will be made between any 
2 dose levels. 
Descriptive statistics will be used for all variables. Continuous variables will be summarized by 
the number of observations, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized by frequency counts and percentages for each category. 
Time-to-event variables will be summarized using Kaplan-Meier estimates. 
1.2 
Schema 
The study design is shown in Figure 1. Participants will flow through the study from 
pre/screening to CAR T-cell infusion and subsequent follow-up (see Figure 2). 
Participants will undergo follow-up for safety, efficacy, CK, immunogenicity and 
biomarker analysis as described in Figure 3. 
Figure 1 
Study Design 
 
 

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Note: Additional intermediate or higher dose level may be recommended by SRC. 
         More than one RDEs may be recommended by SRC. 
DL = dose level; GPC3 = glypican-3; N = the number of evaluable participants as defined by the 
protocol; RDE = recommended dose for expansion. 
 
 
 
 
 

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Figure 2 
Participant Flow Through the Study – Phase Ia and Phase Ib 
 
 
CT = computed tomography; D = day; DLT = dose-limiting toxicity; GPC3 = Glypican-3; ICF = informed consent; LTFU = long-term follow-up; M = month; 
MRI = magnetic resonance imaging; PD = progressive disease; W = week; WD = withdrawal. 

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Figure 3 
Follow-up Schema for Stages 1-3  
 
a 
For specific AEs, refer to Section 8.4.7 
b 
Refer to Section 7.2.2 and Section 7.2.3 for full details on participant discontinuation from Stage 1 and 2 of the study 
c 
LTFU commences in Stage 3 of the CSP. AEs = adverse events; CAR = chimeric antigen receptor; CSP = clinical study protocol; DLT = dose-limiting 
toxicity; LTFU = long-term follow-up; PD = progressive disease; SAE = serious adverse even. 
 
 
 
DLT Period
(   days)
CAR-T
infusion
Day 0
   onths
post CAR T
Infusion
1  Years
post CAR T
Infusion
Study Follow-up
Collect all AEs
Stage 1 Follow-up
Stage 2 Follow-up
Stage 3 Follow-up c
Participants completes all
safety, efficacy, P ,
Immunogenicity and
biomarker assessments.
Participants transitions to Stage  
if meet all of 
 Participant has no PD
  o new anticancer therapy
  o premature discontinuation
Participants discontinues from Stage 1 and transition to Stage 3 for reasons including any of
b 
 Participant has PD
 Starts new anticancer therapy
 Participant/investigator decides to prematurely discontinue from Stage 1
Participants continues to
undergo safety, efficacy,
P , Immunogenicity and
biomarker assessments.
Participants discontinues from
Stage   and transition to Stage 3
for reasons including any of b 
 Participant has PD
 Starts new anticancer therapy
 Participant/investigator
decides to prematurely
discontinue
LTF of participant for
safety and survival.
Participants transition
to Stage 3 at end of
Stage   follow up
based on the
participants 
willingness
Participants can
receive other
anticancer therapy and
may  oin other clinical
trials
1  onths
post CAR T
Infusion
Collect specific AEs a and SAEs possibly
related to CAR T therapy

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1.3 
Schedule of Activities 
See Table 2 and Table 3 for the Schedule of Activities. 
 
Table 2 
Schedule of Activities - Pre-screening to Stage 2 Follow-up 
Procedure/Schedule 
Pre-Screening 
period 
Screening 
Apheresis 
Baseline 
LDC 
Infusion eligibility 
Cell Infusion 
Stage 1 follow-up1 
Stage 2 follow-up1 
Early discontinuation1 
Refer to CSP section 
 
Study Day 
 
≤28 days 
before 
Enrollment 
Enrollment 
D-7 D-5 D-4 D-3 D-2, 
D-1 D0 
D1 
(W1) 
D4 
(W1) 
D7 
(W1) 
D10 
(W2) 
D14 
(W2) 
D21 
(W3) 
D28 
(W4) 
W6 
W12 
W18 
M6 
M8 M10 
M12 
Procedure Window 
(days) 
N/A 
N/A 
N/A 
±2 
0 
0 
0 N/A N/A2 
0 
±1 
±1 
±1 
±1 
±2 
±2 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed pre- 
screening consent 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.1 
A2 
Informed consent 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.2 
A2 
Inclusion/Exclusion 
criteria 
 
× 
×3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Pre-Assessment of 
Peripheral white blood 
cell collection4 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.1 
Pre-Assessment of 
Lymphodepleting 
Chemotherapy  
 
 
 
×5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.3 
Eligibility check prior 
to C-CAR031 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.4.1 
Pre-screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Sample for 
GPC3 IHC Test 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.9.1.2 
Baseline 
characteristics and 
medical history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline characteristics 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1 

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Procedure/Schedule 
Pre-Screening 
period 
Screening 
Apheresis 
Baseline 
LDC 
Infusion eligibility 
Cell Infusion 
Stage 1 follow-up1 
Stage 2 follow-up1 
Early discontinuation1 
Refer to CSP section 
 
Study Day 
 
≤28 days 
before 
Enrollment 
Enrollment 
D-7 D-5 D-4 D-3 D-2, 
D-1 D0 
D1 
(W1) 
D4 
(W1) 
D7 
(W1) 
D10 
(W2) 
D14 
(W2) 
D21 
(W3) 
D28 
(W4) 
W6 
W12 
W18 
M6 
M8 M10 
M12 
Procedure Window 
(days) 
N/A 
N/A 
N/A 
±2 
0 
0 
0 N/A N/A2 
0 
±1 
±1 
±1 
±1 
±2 
±2 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
Medical/disease 
History 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1 
Concomitant 
Medications 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
6.9 
Study intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apheresis 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.1 
Bridging Therapy 
 
 
×6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.2 
Lymphodepleting 
Chemotherapy  
 
 
 
 
× 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.3.2 
Pre-C-CAR031 
infusion medication 
 
 
 
 
 
 
 
 
×7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.4.1.2 
C-CAR031 infusion 
 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.4.2 
Physical assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight8 
 
× 
× 
×5 
 
 
 
× 
 
 
 
 
 
 
 
×9 
×9 
×9 
×9 
×9 
×9 
×9 
×9 
×9 
8.3.1 
Full physical 
examination 
 
× 
 
×5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
× 
8.3.1 
Brief physical 
examination 
 
 
× 
 
× 
× 
× 
× 
×24 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
8.3.1 
Vital Sign 
 
× 
×3 
×5 
×11 ×11 ×11 
× 
×10 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
8.3.3 
Pulse Oximeter 
Oxygen Saturation 
 
× 
 
×5 
× 
× 
× 
× 
×24 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
 
 
 
8.3.3 
ECOG Performance 
Status 
 
× 
 
×5 
× 
 
 
× 
×24 
 
 
 
 
 
 
× 
× 
× 
× 
× 
 
 
× 
× 
8.3.2 

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Procedure/Schedule 
Pre-Screening 
period 
Screening 
Apheresis 
Baseline 
LDC 
Infusion eligibility 
Cell Infusion 
Stage 1 follow-up1 
Stage 2 follow-up1 
Early discontinuation1 
Refer to CSP section 
 
Study Day 
 
≤28 days 
before 
Enrollment 
Enrollment 
D-7 D-5 D-4 D-3 D-2, 
D-1 D0 
D1 
(W1) 
D4 
(W1) 
D7 
(W1) 
D10 
(W2) 
D14 
(W2) 
D21 
(W3) 
D28 
(W4) 
W6 
W12 
W18 
M6 
M8 M10 
M12 
Procedure Window 
(days) 
N/A 
N/A 
N/A 
±2 
0 
0 
0 N/A N/A2 
0 
±1 
±1 
±1 
±1 
±2 
±2 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
ICE Score12 
 
 
 
 
 
 
 
× 
×24 
× 
× 
× 
× 
× 
× 
× 
× 
As clinically indicated in case of suspected ICANS. 
8.3.6.2 
EEG 
 
 
 
 
 
 
 
 
 
As clinically indicated in case of suspected ICANS. 
 
 
 
 
8.3.6.3 
Neuroimaging 
 
As clinically indicated in case of suspected ICANS (Brain MRI or CT). 
8.3.6.1 
Cardiac and 
pulmonary 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
× 
 
×5 
 
 
 
× 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
8.3.4.1 
Echocardiography 
 
× 
 
×5 
As clinically indicated/ onitor in participants who develop CRS Grade ≥  . 
8.3.4.2 
Serum troponin 13 
 
As clinically indicated 
 
8.3.5 
NT-proBNP/BNP 13 
 
As clinically indicated 
 
8.3.5 
Pulmonary Function 
Test 
 
× 
As clinically indicated 
8.3.4.3 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology13 
 
× 
×3,14 
×5 
 
× 
× 
× 
×24 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
8.3.5 
Blood Chemistry 
Panel13 
 
× 
×3 
×5 
 
 
 
× 
×24 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
8.3.5 
TSH 
 
× 
 
×5 
 
 
 
 
×24 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
Urinalysis 
 
× 
 
×5 
 
 
 
 
×24 
 
 
× 
 
× 
 
× 
× 
× 
× 
× 
 
 
 
 
8.3.5 
Coagulation 
parameters13 
 
× 
 
×5 
 
 
 
 
×24 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
 
8.3.5 

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Procedure/Schedule 
Pre-Screening 
period 
Screening 
Apheresis 
Baseline 
LDC 
Infusion eligibility 
Cell Infusion 
Stage 1 follow-up1 
Stage 2 follow-up1 
Early discontinuation1 
Refer to CSP section 
 
Study Day 
 
≤28 days 
before 
Enrollment 
Enrollment 
D-7 D-5 D-4 D-3 D-2, 
D-1 D0 
D1 
(W1) 
D4 
(W1) 
D7 
(W1) 
D10 
(W2) 
D14 
(W2) 
D21 
(W3) 
D28 
(W4) 
W6 
W12 
W18 
M6 
M8 M10 
M12 
Procedure Window 
(days) 
N/A 
N/A 
N/A 
±2 
0 
0 
0 N/A N/A2 
0 
±1 
±1 
±1 
±1 
±2 
±2 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
Inflammation (CRP, 
ferritin)13 
 
× 
 
×5 
 
 
 
 
×24 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
 
 
 
8.3.5 
Infectious Virological 
Test15 
 
× 
As clinical indicated 
8.3.5 
Pregnancy Test 16 
 
× 
 
×5 
 
 
 
× 
 
 
 
 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
8.3.5 
Disease and efficacy 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging17 
 
×18 
 
×19 
 
 
 
 
 
 
 
 
 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
8.2.2 
E 
Survival status 
 
 
 
 
 
 
 
 
 
× 
8.2.3 
Collect anticancer 
medication 
 
 
 
 
 
 
 
 
 
× 
8.2.4 
Cellular kinetics  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood CAR 
Transgene DNA Copy 
Number20 
 
 
 
× 
 
 
 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
8.5.1 
Peripheral CAR-T 
Flow Cytometry21 
 
 
 
× 
 
 
 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
8.5.1 
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Humoral 
Immunogenicity, ADA 
22 
 
 
 
× 
 
 
 
 
×27 
 
 
 
 
 
 
× 
 
× 
× 
× 
 
 
× 
× 
8.8 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytokine13,23 
 
 
 
× 
 
 
 
 
×27 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
 
 
× 
8.9.1.1.2 

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Procedure/Schedule 
Pre-Screening 
period 
Screening 
Apheresis 
Baseline 
LDC 
Infusion eligibility 
Cell Infusion 
Stage 1 follow-up1 
Stage 2 follow-up1 
Early discontinuation1 
Refer to CSP section 
 
Study Day 
 
≤28 days 
before 
Enrollment 
Enrollment 
D-7 D-5 D-4 D-3 D-2, 
D-1 D0 
D1 
(W1) 
D4 
(W1) 
D7 
(W1) 
D10 
(W2) 
D14 
(W2) 
D21 
(W3) 
D28 
(W4) 
W6 
W12 
W18 
M6 
M8 M10 
M12 
Procedure Window 
(days) 
N/A 
N/A 
N/A 
±2 
0 
0 
0 N/A N/A2 
0 
±1 
±1 
±1 
±1 
±2 
±2 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
Soluble GPC3 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
8.9.1.1.2 
RCL25 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
 
× 
 
 
× 
× 
8.7 
Lentiviral vector 
genome integration site 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
× 
x 
8.9.1.1.1 
Blood immune 
associated genes 
signatures/ RNA seq  
 
 
 
× 
 
 
 
 
 
 
 
 
 
× 
× 
 
× 
× 
× 
× 
× 
 
× 
× 
8.9.1.1 
ctDNA 
 
 
×28 
 
 
 
 
 
 
 
 
 
 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
8.9.1.1.2 
Tumor Biopsy 
(optional)26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post Treatment and/or On Progression biopsy 
 
8.9.2.1 
Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
Collect all AEs29 
8.4 
 
The timing of C CAR031 infusion (treatment) may be appropriately delayed (up to a maximum of 7 days) by the researcher based on the physical condition of the participant after receiving 
chemotherapy pretreatment. The day of infusion (treatment) will be redefined as "Day 0" (D0). 
 
1. 
Early discontinuation  A participant who has received C CAR031 and discontinues from the study in Stage 1 will be asked to undergo an early discontinuation visit and will be offered 
to transition to Stage 3 (see Table 3). Participants (from Stage 1) who have completed a scheduled study visit within 14 days of decision to continue follow up in Stage 3 will not need 
to complete the early discontinuation visit (see Section 7.2.2). A participant who discontinues from Stage   will be asked to undergo an early discontinuation visit and will be offered to 
transition to Stage 3. Participants (from Stage  ) who have completed a scheduled study visit within 30 days of the decision to continue follow up in Stage 3 will not need to complete 
the early discontinuation visit (see Section 7. .3). Participants who received LDC but do not undergo C CAR031 infusion will be required to be followed for a minimum of 30 days post 
the last dose of lymphodepletion and/or bridging therapy, if applicable (or until AEs have returned to a minimum Grade  ) (see Section 7. .1), and be followed up only for AE, no blood 
samples to be collected unless clinical indicated. After Stage 1 follow up, participants who have not previously progressed, discontinued prematurely from the study or started a new 

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anticancer regimen will continue to be followed in Stage   of the study for safety, efficacy, C , immunogenicity and exploratory biomarkers up to 12 months post C-CAR031 infusion 
or until disease progression, start of new anticancer treatment, or discontinuation  due to participant or investigator decision (see Figure 3 and Section 7. .3). 
2. 
For participants who do not meet the criteria for undergoing C CAR031 infusion after 7 days of the last LDC dose, the investigator should contact the collaborator. Following discussion 
with the collaborator, these participants may receive C CAR031 7  1 days after LDC completion as long as they fulfil infusion eligibility criteria. For further details refer to Section 
 .1.4. . 
3. 
Pre apheresis (≤ 7 h prior to start of apheresis), and if apheresis is performed > 14 days after main screening, chemistry laboratory assessments should be repeated. For participants who 
require repeat apheresis (see Section  .1.1), screening assessments of weight, complete blood cell count (CBC) with differential and chemistry laboratory assessments, ECG (if clinically 
indicated), should be collected before the second apheresis. 
4. 
The routine blood test results pre apheresis (≤ 7 h prior to start of apheresis) can be used for pre assessment of peripheral white blood cell collection. 
5. 
After bridging therapy washout (if given) and ≤ 7 h prior to first dose of LDC. 
6. 
Post apheresis if agreed with the collaborator. For further details refer to Section  .1. . 
7. 
See Table 11 for timings of pre infusion medications. 
8. 
Convert the measurement results into Body Surface Area (BSA) to calculate the drug dosage required for LDC (based on baseline measurement data on the day of LDC or no more than 
3 days away from LDC) and the infusion dosage of C CAR031 (based on measurement data no more than 3 days before apheresis). The calculation of BSA uses the  osteller formula, 
BSA (m ) = ([Height (cm) × Weight (kg)]/3 00)1/ . 
9. 
Weight only. 
10. 
Vital signs  Perform at pre  C CAR031 infusion ( 1 ±  min), start of C CAR031 infusion (1 ±  min), end of C CAR031 infusion (+ 1 ±  min), 1 hr (±   mins), and   hrs (±   mins) 
post C CAR031 infusion. 
11. 
Vital signs  Perform pre LDC, post LDC. 
12. 
If neurotoxicity is noted, ICE should be performed until ICA S is resolved. 
13. 
These clinical laboratory parameters to also be monitored during CRS, or suspected CRS. In this case, it will be tested by clinically indicated in local laboratory. 
14. 
The CBC and classification examination must be conducted ≤ 7 h prior to apheresis，including the absolute lymphocyte count (ALC). 
15. 
Infectious disease virology testing  Includes HCV antibody and R A (Only if the HCV antibody is positive), HIV 1/  antibody, and syphilis spirochete antibody (TP Ab), HBV five 
items (HbsAg, HbsAb, HbeAg, HbeAb, HbcAb), HBV D A (only if the HbsAg is positive) and C V D A; HCV R A should be negative.   
16. 
Pregnancy testing will be conducted at least 1  months after the infusion of C CAR031 or as clinically indicated until blood C CAR031 CAR transgene D A is below the detectable 
level (end of exposure). Serum or urine tests are allowed. 
17. 
If PD occurs a subsequent scan should be performed preferably at the next scheduled imaging visit and no less than 4 weeks after the initial assessment of PD (in the absence of clinically 
significant deterioration). 
18. 
 se dynamic enhanced  RI or dynamic enhanced CT scan, which must include chest, abdomen, pelvic cavity, head and neck, and whole body bone scans. Qualified imaging results 
 udged by investigator can be used for screening within 4 weeks before signing the informed consent form. For participants with asymptomatic, treated, and radiologically stable brain 
metastases at enrolment, a brain  RI should be conducted as indicated. 
19. 
Scan can be done within 7 days of pre C CAR031 infusion as close as possible to infusion. Bone scan will be conducted if clinically indicated.  ote, scan must be conducted after 
bridging therapy, if given. The baseline radiological assessments should be done after the washout of bridging therapy.  
20. 
Peripheral blood CAR transgene D A  Collect samples according to the SOA table and use the PCR method in the analysis laboratory to detect C CAR031 transgene D A in peripheral 
blood. The test results are not recorded in the EDC. If C CAR031 CAR transgene D A were < lower limit of quantification (LLOQ) in two consecutive assessments, then following 
sampling may be stopped. Patient should be tested in case of second malignancy. 

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21. 
Peripheral blood CAR T cell percentage and the absolute number and immunophenotype  Collect samples according to the SoA table and detect by flow cytometry in the analysis 
laboratory. The detection results will not be recorded in the EDC. If two consecutive assessments of C CAR031 CAR T cells were < LLOQ, then following sampling of CAR T flow 
cytometry may be stopped. 
22. 
Immunogenicity  It will start before cell infusion and continue until withdrawal or completion of the main study.. The test results will not be recorded in the EDC. 
23. 
Cytokine：Collect samples for testing including but not limited to blood TGFβ,  IL  , IL 4, IL  , IL 10, IL 1 , T F α and I F γ according to the SoA table in the analysis laboratory. 
The test results will not be recorded in the EDC. 
24. 
The test is done before the infusion. 
25. 
RCL  It will be conducted until withdrawal of the study. Collection can be discontinued, if the testing results are all negative in the first year of infusion. If there were any clinical 
indication of suspected existence of RCL and at the diagnose of secondary malignancy. The test can be conducted per requirement and the results will not be recorded in the EDC. 
26. 
Optional on treatment tumor biopsy sample to be taken in a visit window of D 9 to week   inclusive and/or on disease progression, as clinically indicated. Tumor biopsy sample and 
blood draw is indicated to determine if malignancy is secondary to cell therapy. 
27. 
Can occur post last dose of LDC and ≤ 7 h prior to C CAR031 infusion. 
28. 
Should occur ≤ 72 h prior to apheresis. Buffy coat (white blood cells) together with plasma will be collected. 
29. 
Only AEs and SAEs related to study procedures will be collected in Pre screening period from the pre screening ICF signature. 
 

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Table 3 
Schedule of Activities (Stage 3 Follow-up) 
 
Study day 
(relative to C-CAR031 
infusion) 
M81 
(± 14 days) 2 
Y1, Y2 
(± 14 days) 2 
Y3, Y4, Y5 
(± 3 months) 3 
Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, Y15 
(± 6 months) 3 
Refer to CSP Section  
Assessment 
Informed consent 
×4 
A2 
Collection of concomitant 
medication information for 
mutagenic agents or 
anticancer therapies 
Document subsequent anticancer regimen post-CAR-T and/or mutagenic agents 
8.2.4 
Brief physical exam 
 
× 
Annual follow-up in-person 
Annual follow-up via in-person or telephone visit 
8.3.1 
Peripheral Blood CAR DNA 
Copy Number5 
× 
× 
× 
× 
8.5.1 
Peripheral CAR-T Flow 
Cytometry 5 
× 
× 
× 
× 
8.5.1 
Blood sample for RCL 
testing6 
× 
× 
× 
× 
8.7 
Lentiviral vector genome 
integration site 
 
× 
 
 
8.9.1.1.1 
 Tumor biopsy sample and 
blood draw to determine if 
malignancy is secondary to 
cell or gene therapy 
To be collected if new malignancy is detected 
8.9.2.1.1 
AE/SAE reporting 
Specific AEs ( Section 8.4.7 ), and SAEs deemed by the investigator as possibly related to the C-CAR031  
8.4 
Efficacy assessment 
Continue to collect as standard of care if progressive disease per applicable disease assessment criteria was not observed during the last 
disease assessment timepoint. Recommend to continue tumor evaluation in study site, if not applicable, every effort should be made to collect 
tumor evaluation result until disease progression or began new anticancer treatment. 
8.2 

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Study day 
(relative to C-CAR031 
infusion) 
M81 
(± 14 days) 2 
Y1, Y2 
(± 14 days) 2 
Y3, Y4, Y5 
(± 3 months) 3 
Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, Y15 
(± 6 months) 3 
Refer to CSP Section  
Survival status 
× 
× 
M12, M18, M24 
Annual follow-up via in-person or telephone visit 
8.2.3 
 
1. 
For participants who discontinue prematurely from Stage 1 before the W12 (M3) visit, the assessments listed for M8 (Stage 3 Schedule of Activities) should be 
completed at W12 (M3) and W24 (M6) (including tumour biopsy if a new malignancy is suspected). For participants who discontinue from Stage 1 before the W24 
(M6) visit, the assessments listed for M8 (Stage 3 Schedule of Activities) should be completed at W24 (M6). 
2. 
For participants who received any dose of C-CAR031 and discontinue from or complete the stage 1 or stage 2 and are willing to enter stage 3. 
3. 
If the participant decided to stop receiving medical care at the study site, every effort should be made to continue follow-up. When in person visits were not possible, 
assessments may be done via telephone, if there are no safety concerns. 
4. 
Once participants receiving C-CAR031 infusion withdrew before stage 3 or complete the stage 2 follow up, the participants can independently decide to sign a separate 
ICF of the long-term follow up in stage 3. Participants who refused at the time but were willing to sign the ICF at any subsequent time, will also be included in the 
long-term follow-up as much as possible. 
5. 
If two consecutive assessments of C-CAR031 blood CAR transgene DNA levels or blood CAR-T cell level were < LLOQ then following sampling may be stopped 
respectively. Patient should be tested for C-CAR031 blood CAR transgene DNA levels in case of second malignancy. 
6. 
Collection can be discontinued, if the testing results are all negative in the first year of C-CAR-031 infusion. And patient should be tested in case of second malignancy.

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2 
INTRODUCTION 
C-CAR031 is an autologous chimeric antigen receptor (CAR) T-cell product that expresses a 
CAR specific for Glypican-3 (GPC3) and a dominant-negative transforming growth factor-beta 
receptor II (dnTGFβRII) as an armouring strategy (see Figure 4). The GPC3-specific CAR 
construct consists of a scFv derived from a monoclonal antibody recognizing GPC3, an IgG4P 
hinge region, a CD28 transmembrane domain, and a 4-1BB and CD3ζ intracellular domain 
(Giardino Torchia et al 2022[4]). The armouring component dnTGFβRII is a truncated TGFβRII 
that lacks the intracellular domain necessary for downstream signalling (Chu et al 2022[5]). 
Expression of dnTGFβRII can block transforming growth factor-beta (TGFβ) signalling, 
protecting CAR-T cells from the immunosuppressive effect of this cytokine. 
 
Figure 4 
The C-CAR031 CAR Construct 
GPC3 = Glypican-3; ICD = intracellular domain; scFv = single chain variable fragment; TM= transmembrane 
domain. 
C-CAR031 is manufactured by Shanghai AbelZeta Ltd. It uses the patient's own fresh T cells, via 
a third-generation self-inactivated (SIN) lentiviral vector, in a serum-free culture process, utilizing 
a functionally closed system, such as the CliniMACS Prodigy® system (Miltenyi Biotec, Bergisch 
Gladbach, Germany). Semi-automated system is utilized in a strict Good Manufacturing Practice 
(GMP) environment. 
This single-arm study will assess the safety, tolerability, anti-tumor activity, pharmacokinetics 
(PK), biomarker, and immunogenicity of C-CAR031. 
 
2.1 
Study Rationale 
GPC3 is present on non–small cell lung cancer (NSCLC) tumor cells (23% of expression), 

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further studies have shown that the positive expression is significantly higher in squamous cell 
lung cancer (55% of expression) than that in adenocarcinoma (8% of expression) and virtually 
absent in normal adult tissues, making it an ideal target for CAR T-cell therapy (Aviel-Ronen 
et al 2008[1]). In addition, some studies have shown that GPC3 expression is significantly 
associated with poor prognosis of squamous cell lung cancer patients (Ning et al 2021[2]). 
Early clinical data of C-CAR031 has shown promise in an ongoing, open label, investigator-
initiated Phase I trial (NCT05155189) to evaluate the safety and efficacy C-CAR031 in 
patients with advanced hepatocellular carcinoma (HCC) (Zhang et al 2024[3]). C-CAR031 is 
well tolerated in all the dose levels being explored. No grade 5 treatment-related adverse event 
(TRAE), dose-limiting toxicity and immune effector cell-associated neurotoxicity syndrome 
(ICANS) were observed. Cytokine release syndrome (CRS) was observed in 22 (91.7%) 
participants with only 1 (4.2%) grade 3 CRS. All CRS events were started within the first 
week post the infusion and resolved within two to eight days of onset. C-CAR 031 mono 
therapy demonstrated an objective response rate (ORR) of 56.5% cross all dose levels and the 
ORR in the 4.0 ×106 CAR-T cells/kg dose cohort was 75% (6/8). The median target lesion 
reductions achieved 42.2% and the deep target lesion shrinkage can be observed in intra and 
extrahepatic lesions (70.8% of the participants have tumor lesions in lung). The median 
duration of response (DoR) was 7.4 months. Though there were 70.8% of participants had 
lung metastatic lesions, the lung complications were not a safety concern in the HCC IIT. 
These data support the exploration of C-CAR031 in squamous cell lung cancer. 
This is a Phase I study designed to evaluate the safety, tolerability, anti-tumor activity and 
immunogenicity of C-CAR031 in adult participants with GPC3+ advanced/metastatic 
squamous cell lung cancer, who are not amenable to curative therapy and have progressed or 
are intolerant to no more than  3 lines of prior systemic treatment including immune 
checkpoint inhibitors (CPIs) and platinum-based doublet chemotherapy, concurrently or 
sequentially. The study will also characterize the cellular kinetics (CK)/pharmacodynamics 
(PD) of C-CAR031 and explore its potential biological activity. 
 
The study will be divided into two sections: safety run-in and backfill phase (Phase Ia) and 
dose expansion phase (Phase Ib). Phase Ia will determine the recommended dose for 
expansion (RDE) to be used in Phase Ib (dose expansion) of the study and evaluate the safety 
and efficacy in participants with GPC3 expression. Phase Ib will further evaluate the safety, 
tolerability, CK, biomarker, immunogenicity and efficacy of C-CAR031 at the RDE. 
 
To better understand clinical efficacy in this patient population, where GPC3 tumor expression 
levels will be determined by immunohistochemistry (IHC), correlation analysis on ORR, 
progression-free survival (PFS) and overall survival (OS) versus GPC3 baseline tumor 
expression levels and soluble GPC3 levels in blood at baseline and post treatment will then be 
performed. 
 
The results from this study will inform decision-making regarding C-CAR031 CAR T-cell 
therapy in GPC3+ advanced/metastatic squamous cell lung cancer. 

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2.2 
Background 
2.2.1 
Disease Background and Current Landscape 
Lung cancer was identified as the first most common cancer in China and the world in 2022 
representing an estimated 12.4% of all new cancer cases. It was also the most common cause 
of death from cancer, with 1.817 million deaths which account for 18.7% of the total. The 2022 
global cancer statistics reported by the International Agency for Research on Cancer revealed 
that an estimated 1 0 0  00 new lung cancer diagnoses and 733 300 lung cancer‐related deaths 
occurred in China in 2022 (Freddie et al 2024[6]). Non-small cell lung cancer (NSCLC) 
accounts for the majority of all lung cancers (80%), of which 20%-30% are the squamous 
subtype (Barta et al 2019[7]). Patients with metastatic squamous cell lung cancer have a lower 
driven mutation positive rate than those with metastatic non-squamous cell lung, including in 
EGFR (2.8%), ALK/ROS1 (1.3%), BRAF (1.5%), and MET amplification or exon 14 skipping 
(5.1%) (Lam et al 2019[8], Mazieres et al 2019[9]).  
Up to two-thirds of NSCLC patients are diagnosed with advanced or metastatic NSCLC, and 
even among those with earlier stages of the disease, recurrence is frequent due to early 
micrometastatic dissemination (Passlick et al., 2001[10]). 
In the past two decades, the advances of NSCLC drugs mainly focus on non-squamous cell 
lung cancer, including pemetrexed maintenance therapy, anti-vascular endothelial growth 
factor (VEGF) monoclonal antibody, and tyrosine kinase inhibitors (TKI) drugs. The research 
and development of drugs for squamous has been stagnating due to the specific epidemiological, 
histopathological, and molecular characteristics. Therefore, new treatment models and drugs 
are urgently needed for advanced squamous cell lung cancer to improve the efficacy and 
survival. 
 
Platinum-based chemotherapy has been established as the classical treatment regimen for 
squamous cell lung cancer lacking driver gene mutations and exhibiting a performance status (PS) 
score of 0-1, often incorporating agents like gemcitabine or taxanes. In a randomized trial 
comparing two distinct chemotherapy regimens, cisplatin/gemcitabine demonstrated superior 
overall survival (OS) and progression-free survival (PFS) compared to cisplatin/pemetrexed; both 
analyses revealed statistically significant results favoring the gemcitabine arm (Scagliotti et al., 
2008[11]). Response rates have been documented in the range of 23-30%, with side effects such as 
thrombocytopenia and fatigue potentially necessitating treatment discontinuation (Langer et al., 
2016[12]).  
 
In addition to chemotherapy regimens, immunotherapy utilizing programmed death 1 (PD-1)/PD-
L1 inhibitors has emerged as a first-line standard treatment for squamous cell lung cancer. The 
PD-1 protein is a co-inhibitory receptor expressed on activated T-cells, which, upon binding to its 
ligand PD-L1, suppresses T-cell antitumor activity within the tumor microenvironment (Mittal et 
al., 2016[13]).  
 
 

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Atezolizumab, an anti–PD-L1 monoclonal antibody, has been approved by the National Medical 
Products Administration (NMPA) as a first-line monotherapy for metastatic NSCLC, suitable for 
patients assessed as having ≥ 0% tumor cell PD-L1 staining positivity (TC≥ 0%) or tumor-
infiltrating PD-L1 positive immune cells (IC) covering ≥10% of tumor area (IC≥10%). The 
approval of this clinical indication is based on analysis from the Impower 110 study, where 
atezolizumab significantly improves PFS (HR=0.63) and OS (HR=0.59) compared to 
chemotherapy in wild-type stage IV non-squamous or squamous cell lung cancer patients with 
high PD-L1 expression (TC≥ 0% or IC≥10%) (Herbst et al., 2020[14]). 
 
Pembrolizumab efficacy in squamous cell lung cancer was supported in the open-label Phase III 
KEYNOTE-024 study, which enrolled 305 patients with advanced NSCLC (including 
adenocarcinoma and squamous cell carcinoma) who had PD-L1 tumor proportion score (TPS) ≥ 
50% and wild-type EGFR/ALK. Pembrolizumab significantly prolonged PFS (hazard ratio 
[HR]=0.55 for adenocarcinoma subgroup and HR=0.35 for squamous cell carcinoma subgroup) 
and OS (HR=0.63) compared to chemotherapy, with a notably lower incidence of adverse reactions 
than the chemotherapy group (Reck et al., 2016[15]). Subsequently, the KEYNOTE-042 study 
further expanded the inclusion criteria to encompass patients with PD-L1 TPS ≥ 1%. The results 
indicated a 19% reduction in the risk of death with pembrolizumab compared to chemotherapy, 
although subgroup analyses suggested that the primary beneficiaries were patients with PD-L1 
TPS ≥  0% (Mok et al., 2019[16]). Based on the above results, theNMPA has approved 
pembrolizumab as a first-line therapy for NSCLC patients with PD-L1 TPS ≥ 1% in  019. And 
the Chinese Society of Clinical Oncology (CSCO) 2023 guidelines have designated 
pembrolizumab as a first-tier recommendation. 
 
In the KEYNOTE-407 study, 559 treatment-naive patients with metastatic squamous cell lung 
cancer were enrolled and randomized in a 1:1 ratio to receive pembrolizumab in combination with 
either carboplatin plus paclitaxel or nab-paclitaxel, or carboplatin plus paclitaxel/nab-paclitaxel 
alone. The results demonstrated that pembrolizumab in combination with chemotherapy 
significantly prolonged PFS (median, 6.4 months vs. 4.8 months, HR=0.56, P<0.001) and OS 
(median, 15.9 months vs. 11.3 months, HR=0.64, P<0.001), with no significant increase in adverse 
reactions (Paz-Ares et al., 2018[17]). Based on these results, NMPA has approved pembrolizumab 
in combination with carboplatin and paclitaxel/nab-paclitaxel for first-line treatment of metastatic 
squamous cell lung cancer. 
 
The RATIONALE 307 study demonstrated that in first-line treatment of advanced squamous cell 
lung cancer, compared to chemotherapy group, combination of tislelizumab with paclitaxel/nab-
paclitaxel significantly prolongs the PFS of patients (Wang et al., 2021[18]). NMPA has approved 
the combination of tislelizumab with carboplatin and paclitaxel/nab-paclitaxel for first-line 
treatment of advanced squamous cell lung cancer. 
 
Results from the CameL-sq study demonstrated that in comparison to chemotherapy, the 
combination of camrelizumab with paclitaxel and carboplatin significantly prolonged PFS of 
patients (median 8.5 months vs. 4.9 months, P<0.0001), with later follow-up indicating a median 

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OS of 27.4 months in the camrelizumab combination therapy group, extending almost a year 
beyond the chemotherapy group (Ren et al., 2022[19]). The GEMSTONE-302 study revealed that 
the combination of sugemalimab with carboplatin and paclitaxel significantly extends PFS 
(median 9.0 months vs. 4.9 months, HR=0.48, P<0.0001) compared to standard chemotherapy, 
with an increased objective response rate (63.4% vs. 40.3%) (Zhou et al., 2022[20]). These above 
treatments have all been approved by NMPA for first-line treatment of squamous cell lung cancer. 
 
The first-line treatment with dual immunotherapy (PD-1 inhibitors combined with CTLA-4 
inhibitors) have also been reported for positive results. The CheckMate-9LA study investigated 
the efficacy of nivolumab plus ipilimumab in combination with two cycles of chemotherapy 
compared to chemotherapy alone in advanced NSCLC. Results at a median follow-up of 13.2 
months demonstrated a significant extension in PFS with the combination of dual immunotherapy 
and chemotherapy compared to chemotherapy alone, regardless of PD-L1 expression levels and 
tumor histology (median 6.7 months vs. 5.0 months, HR=0.68) (Paz-Ares et al., 2021[21]). In 2020, 
the FDA approved nivolumab plus ipilimumab with two cycles of chemotherapy for first-line 
treatment of advanced or recurrent NSCLC, but this indication has not yet been approved in China. 
 
There is still a significant unmet medical need for most squamous cell lung cancer patients who 
have failed from or intolerant to previous CPIs and platinum-based doublet chemotherapy. Given 
the lack of randomized control trial evidence post CPI, the CSCO guidelines recommend second 
to late line therapy options for patients including nivolumab, tislelizumab, docetaxel, 
pembrolizumab, atezolizumab, afatinib and anlotinib.  
 
The CheckMate-078 study, conducted in a Chinese population with squamous or non-squamous 
cell lung cancer that had progressed during/after platinum-based doublet chemotherapy, 
demonstrated that nivolumab significantly prolongs OS (median 12.0 months vs. 9.6 months, 
P=0.0006) and improve ORR (16.6% vs. 4.2%, P<0.0001) when compared to docetaxel. Among 
those with squamous histology, median OS was 12.3 months with nivolumab versus 7.9 months 
with docetaxel and ORR was 21.1% vs. 1.5%. (Wu et al., 2019[22]). Consequently, the NMPA 
approved nivolumab for second-line treatment of NSCLC in 2018.  
 
Results from the RATIONALE 303 phase III clinical trial showed that compared to docetaxel, 
single-agent tislelizumab significantly extends OS in patients with advanced or metastatic 
squamous or non-squamous cell lung cancer in the second or third-line therapy (Zhou et al., 
2023[23]). This second-line indication has also been granted approval by the NMPA.  
 
Additionally, the KEYNOTE-010 study demonstrated that pembrolizumab provides superior OS 
benefit compared to docetaxel in late-stage CPIs naïve squamous or non-squamous cell lung cancer 
with positive PD-L1 expression. Subgroup analysis suggested that squamous cell lung cancer 
patients receiving pembrolizumab also significantly benefited in terms of OS (HR = 0.74) (Herbst 
et al., 2016[24]). Subgroup analysis of the OAK study showed a significant extension in median 
overall survival (8.9 months with atezolizumab vs. 7.7 months with docetaxel) with atezolizumab 

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as second-line treatment for patients with advanced squamous cell lung cancer (Rittmeyer et al., 
2017[25]). Based on these findings, the FDA approved pembrolizumab for second-line treatment of 
PD-L1-positive (PD-L1 TPS ≥ 1%) CPIs naïve lung squamous cell carcinoma and atezolizumab 
for second-line treatment of CPIs naïve metastatic NSCLC following platinum-based 
chemotherapy or after EGFR/ALK-TKI therapy in sensitive mutation patients. However, these 
indications have not yet been approved by the NMPA. 
 
Single-agent docetaxel is one of the options as second-line treatment approved based on the 
prolonged survival (7.0 months vs 4.6 months) compared with best supportive care. Grade 3 or 4 
neutropenia occurred in more than 65% of patients treated with docetaxel (Shepherd, et al 2023[26]
错误!未找到引用源。).  
 
In the third-line therapy, the ALTER 0303 study enrolled 439 patients with advanced NSCLC 
(including 86 cases of peripheral squamous cell lung cancer) post at least 2 lines of prior systemic 
therapies. The results indicated that anlotinib significantly prolonged PFS (median, 5.4 months vs. 
1.4 months, P<0.001) and OS (median, 9.6 months vs. 6.3 months, P=0.002), and significantly 
increased the ORR (9.2% vs. 0.7%, P<0.001) ( (Han et al., 2018[27])compared to placebo. Subgroup 
analysis showed that squamous cell lung cancer patients receiving anlotinib have benefits in terms 
of PFS (HR=0.37) only, no considerable OS improvement is seen. More patients experienced 
hypertension, hemoptysis, hand-foot syndrome in alotinib group. It can be considered as an 
optional regimen for third-line treatment of advanced NSCLC, limited to patients with peripheral 
squamous cell lung cancer. 
 
Currently there is limited data to determine the best regimen and optimal sequence of late-line 
therapy, with treatment depending on patients’ performance status, lung function, comorbidities 
and the choice of previous therapies. The outcome of CPIs naïve squamous cell lung cancer 
patients treated by CPI monotherapy or docetaxel is worse than that of non-squamous cell lung 
cancer patients. Checkmate-017 and checkmate-057 studies showed that two-year overall survival 
rates with nivolumab versus docetaxel were 23% versus 8% in squamous cell lung cancer and 29% 
versus 16% in non-squamous cell lung cancer. The median OS with nivolumab versus docetaxel 
were 9.2 months versus 6.0 months in squamous cell lung cancer and 12.2 months versus 9.5 
months in non-squamous cell lung cancer (Horn et al 2017[28]).  
 
Immunotherapy is becoming a pivotal role in the treatment of squamous cell lung cancer lacking 
driver gene mutations. But patients who experienced CPIs in prior lines are not recommended to 
received CPIs in later line, further limits the choice of patients who progressed from CPIs 
with/without platinum-based doublet chemotherapy. A huge unmet medical need still exists 
considering the moderate anti-tumor activity and significant toxicity of the recommended 
treatment options for 2L and beyond squamous cell lung cancer patients progressed from prior CPI 
and platinum-based doublet chemotherapy. Hence, there is an urgent need for innovative therapies 
in this disease setting to improve treatment outcome. 
 
2.2.2 
Glypican-3 as a Therapeutic Target in squamous cell lung cancer  

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GPC3 is present on NSCLC tumor cells (23% of expression). Further studies have shown that the 
positive expression is significantly higher in squamous cell lung cancer (55% of expression) than 
that in adenocarcinoma (8% of expression) and virtually absent in normal adult tissues, making it 
an ideal target for chimeric antigen receptor (CAR) T-cell therapy (Aviel-Ronen et al 2008[1]). In 
addition, some studies have shown that GPC3 expression is significantly associated with poor 
prognosis of squamous cell lung cancer patients (Ning et al 2021[2]). 
 
2.2.3 
Role of TGFβ in squamous cell lung cancer  
TGFβ is a cytokine belonging to a family of growth factors that regulate a variety of cellular 
functions, such as growth, differentiation, and morphogenesis, which are essential for the 
homeostasis of tissues and organs. TGFβ ligands have three isoforms  TGFβ1, TGFβ , and 
TGFβ3; TGFβ1 is the most abundant and is frequently upregulated in tumour cells (Dahmani and 
Delisle 2018[29]). A series of cell function experiments showed that GPC3 overexpression 
promoted the proliferation, migration, and invasion of squamous cell lung cancer cells (Ning et 
al 2023[30]). Some studies have demonstrated that TGFβ overexpression could be considered a 
potential predictive marker in lung cancer prognosis, and TGFβ inhibition has been shown to 
prevent lung cancer metastasis.  oreover, TGFβ inhibitors could be used in combination with 
chemo- and immunotherapy, thereby improving patient survival. ( Ramundo et al 2023[31]). 
TGFβ is a potent immunosuppressive cytokine, and tumor-associated TGFβ inhibits T cell-
mediated immune responses through a variety of mechanisms (Dahmani and Delisle 2018[29]). 
TGFβ can be blocked by using a dnTGFβRII, which is truncated and lacks the intracellular 
domain necessary for downstream signalling (Wieser et al 1993[32]) 
 
2.2.4 
Preclinical and Clinical Evidence of TGFβ-armoured CAR T-Cell 
Activity Against Solid Tumors 
Preclinical cell therapy studies have demonstrated that expression of the dnTGFβRII enhances 
antitumor immunity, and several clinical cell therapy studies using this armouring strategy are 
ongoing (NCT00368082, NCT04227275, NCT03089203, NCT02379520, NCT03198546, 
NCT04795882, NCT04526509, NCT03198052, NCT05489991, NCT05141253). One of these 
clinical trials ( CT003  0  ) testing the safety and efficacy of the dnTGFβRII receptor in 
Epstein-Barr virus-specific T cells for lymphoma, reported promising efficacy and no toxicity 
associated with the expression of this receptor (Bollard et al 2018[33]). In another study 
( CT030 9 03), testing a dnTGFβRII-armoured Prostate-specific membrane antigen (PSMA) 
CAR T-cell product in 13 patients with prostate cancer, one patient experienced severe CRS and 
had a fatal outcome. This death occurred at a high dose and could have been impacted by multiple 
factors including normal tissue PSMA expression (Gastrointestinal [GI] tract, brain, liver and 
kidney), lymphodepleting chemotherapy (LDC), the aforementioned high CAR T-cell dose, and 
patient factors such as age and/or comorbidities (Narayan et al 2022[34]). In a second study 
NCT04227275 (McKean et al 2022[35]), with the same CAR T-cell product in 9 patients with 
prostate cancer, 2 deaths were reported. In the first patient, 2 Grade 5 events of ICANS and multi-
organ failure with findings consistent with macrophage activation syndrome (MAS) were reported 
and in the second patient, severe immune mediated toxicity, with an equivocal cause of death with 

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contributing factors including metastatic prostate cancer, multi-organ failure and coagulopathy. 
Given a similar Grade 5 event was observed in an unarmoured PSMA CAR T cell trial 
NCT04249947 (Gergen 2020[36], Poseida 2020[37], Slovin et al 2022[38]), and the tolerability of 
dnTGFβRII armouring in  CT003  0   and  CT0 1  1 9 (G0 Bz GPC3 CAR C-CAR031) 
studies (described in Section 2.2.5), it is unclear if the toxicities noted are more related to the 
PSMA target, armouring of the CAR T-cell product or other factors.  
 
2.2.5 
Summary of GPC3-Targeted CAR-T Clinical Trials Conducted to Date 
CART-cell therapy has been highly effective in treating patients with relapsed/refractory B-cell 
malignancies and multiple myeloma; studies are ongoing across the globe to understand the best 
approaches to provide benefit to patients with solid tumors (Schroeder et al 2022[39]).  
Several autologous GPC3 CAR T-cell products have been tested in the clinic in the solid tumor 
mainly HCC(see Table 4). To date no studies have been reported in squamous cell lung cancer. 
The safety profile, observed thus far, between the different GPC3 CAR T-cell products appears 
similar, with the major toxicity being CRS, as is expected from autologous CAR T-cell products, 
with no reports of notable on-target off-tumor toxicities, potentially reflecting the inherent tumor 
specificity of GPC3 expression. In addition, most GPC3 CAR T-cell products have reported 
antitumor activity, supporting the further exploration of GPC3 CAR T-cell products in the 
treatment of squamous cell lung cancer. 
Table 4 
GPC3-Targeted CAR T-Cell Clinical Trials 
 
CAR T-cell 
therapy/clinical 
study/registry 
Number 
Participants and 
CAR T-cell dose 
range 
Safety findings (excl. haemalogical 
toxicities) 
Efficacy/ 
response 
findings 
Y035 CAR-GPC3 
unarmoured 
NCT02395250, 
NCT03146234 
(Shi et al 2020[40]) 
13 participants with 
GPC3+ advanced HCC 
7.0 × 108 to 92.5 × 108 
CAR-T cells 
Lowest dosed 
participant had a split 
infusion. 
• 
Tolerable 
• 
≥ Grade 3 AEs, including: 
• 
1 DLT Grade 5 CRS (20 × 108 
CAR-T) 
• 
1 Grade 3 pyrexia 
• 
1 Grade 4 and 1 Grade 3 bilirubin 
increase 
• 
1 Grade 4 abnormal hepatic function 
• 
1 Grade 3 blood albumin level 
decreased. 
2/13 PRs: 
PFS of 111 
days and 99 
days 
NCT03980288 
Armoured (unknown) 
(Fang et al 2021[41]) 
6 participants with 
GPC3+ advanced HCC 
2.5 × 108 
CAR T-cells. 
• 
Tolerable 
• 
No treatment-related SAEs or DLTs 
• 
≥ Grade 3 toxicities included: 
 
3 Grade 3 CRS 
 
1 Grade 3 abnormal liver 
function. 
 
 
1/6 PR 

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Ori-C101 
armoured (unknown) 
ChiCTR1900028121 
(Zhao et al 2021[42]) 
 
10 participants with 
GPC3+ advanced HCC 
via intravenous and 
intrahepatic routes. 
0.9 to 3.0 × 108 
CAR T-cells. 
• 
≥ Grade 4 non-haematological AEs 
included: 
 
2 Grade 4 CRS 
 
1 Grade 4 increased bilirubin 
 
1 Grade 4 decreased fibrinogen 
 
1 Grade 4 hypokalaemia 
• 
Other Grade 3 AEs included: LFT 
changes, blood chemistry changes, 
coagulation changes, fever, and 
other Grade 3 events, likely related 
to the patient’s underlying 
condition. 
4/9 PRs 
TAK-102 (IL- 
4 participants with 
GPC3+ advanced solid 
tumors 
1 × 107 to 
1 × 108 CAR-T cells. 
• 
Tolerable 
• 
No DLTs 
• 
≥ Grade 3 AEs included: 
• 
1 CD4 lymphocytes decrease 
• 
1 hypersensitivity reaction 
• 
1 gamma-glutamyl transferase 
increase 
• 
And events of disease progression. 
7/CCL19 armoured 
GPC3 CAR-T, 
0/4 PRs 
NCT04405778) 
(Koyama et al 2022[43]) 
CT0180; 
anti-GPC3 scFv-CD3ε 
engineered T cells 
NCT04756648 
(Zheng et al 2023[44]) 
IIT 
7 patients with 
hepatitis B virus-
related HCC were 
treated with 
CT0180 (one 
patient each at 
10×106 and 
30×106 DLs, 3 at 
100×106 DL, and 
2 at 300×106 DL) 
• 
Most common grade 3-4 AEs were 
hematologic toxicities, ie 
lymphopenia and neutropenia 
• 
No DTLs, immune effector cell-
associated neurotoxicity syndrome, 
or treatment-related deaths occurred. 
• 
Grade 1 CRS was observed in 6 
patients 
• 
tocilizumab was given in one patient 
and no glucocorticoids were used 
2/7 PRs (30×106 
and 300×106 
DL) 
3/7 SDs 
(10×106, 
100×106 and 
300×106 DL) 
11.6 months 
median OS with 
3 patients alive 
C-CAR031; 
dnTGFRII armoured 
GPC3 CAR-T 
NCT05155189 
IIT 
24 participants 
with GPC3+ HCC 
0.75 × 106/kg to 
4.0 × 106/kg 
• 
Tolerable 
• 
Reported 28-day DLT period 
 
No DLTs 
 
1  Grade 3 CRS 
 
No ICANS 
≥ Grade 3 related AEs in 9 
participants (37.5%, 9/24) 
included:Transient Grade 3 
AST increases、Grade 3 
Platelet count decreased, CRS 
and interstitial lung disease, the 
reported interstitial was 
considered CRS related and 
recovered from Grade 3 to 
Grade 2 within 6 days. 
13/24 PR cross 
all dose levels; 
6/8 PR at  4 × 
106/kg  
AE = adverse events; AST = Aspartate aminotransferase/transaminase; CAR = chimeric antigen receptor; CRS 
= cytokine release syndrome; DL = dose level; DLT = dose-limiting toxicity; GPC3+ = glypican-3 positive; 
dnTGFRII = dominant-negative transforming growth factor-beta receptor II; HCC = hepatocellular carcinoma; 
ICANS = immune effector cell-associated neurotoxicity syndrome; IIT = Investigator-initiated trial; LDC = 

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lymphodepleting chemotherapy; LFT = liver function test; ORR = objective response rate; PFS = progression-
free survival; PR = partial response; SAE = serious adverse event; SD = stable disease. 
 
2.2.6 
Summary of C-CAR031 preclinical study 
According to the requirements of the Technical Guidelines for the Studies and Evaluation of Cell 
Therapeutic Products (Tentative) (2017 No. 216) issued by The former China Food and Drug 
Administration (CFDA, 2017[45]), the Technical Guidelines for Non-Clinical Studies and 
Evaluation of Genetically Modified Cell Therapeutic Products (Tentative) (2021 No. 49) and 
other relevant technical guidelines issued by Center for Drug Evaluation, National Medical 
Products Administration (NMPA, 2021[46]), as well as the studies evaluating the efficacy and 
safety of CAR-T products approved at home and abroad, the following non-clinical studies had 
been conducted for C-CAR031. Of note AZD5851 utilizes the same construct as C-CAR031, but 
uses a different manufacturing process. 
Table 5 
List of C-CAR031 Non-clinical Studies 
Study type 
Study title 
Study number 
GLP 
compliant 
 ain 
pharmacodynamics 
Source and genetic payload of AZD   1 scFv 
O C   1 00  
 o 
C CAR031 in vitro pharmacodynamics test 
S000337 0311 
 o 
C CAR031 in vitro antigen specific proliferation test 
S000337 031  
 o 
AZD   1 in vitro functional identification  
O C   1 00  
 o 
AZD   1 in vivo efficacy and in vitro characterization 
O C   1 00  
 o 
Pharmacokinetics 
 ethodological validation for fluorescence quantitative PCR 
(Taq an probe method) for detecting C CAR031 gene copy 
number in whole blood and tissues of  OG tumor bearing 
mice 
  3 S1   P V 
 o 
Tissue distribution test of a single intravenous in ection of C 
CAR031 in  OG tumor bearing mice  
  3 S1    P  
 o 
Single dose toxicity 
Toxicity study of a single intravenous in ection of C 
CAR031 in  OG tumor bearing mice (subcutaneously 
transplanted with human hepatocellular carcinoma cell lines 
(Hep3B)) 
  3 S1   SD 
Yes 
Carcinogenicity 
CAR T cell lentiviral vector insertion site detection under the 
C CAR031 pro ect 
RP 49 04 04 
 o 
C CAR031 in vitro soft agar clonal growth test 
S000337 0313 
 o 
Evaluation of the functional gain of dnTGFβRII GPC3 CAR 
T in IL   independent in vitro proliferation test 
O C   1 009 
 o 
Local tolerability 
In vitro hemolysis test of C CAR031 on rabbit erythrocytes 
O 3 S1   HE 
Yes 
Local irritation test 
  3 S1   SD 
Yes 
Other toxicity studies 
Expression of GPC3 in normal human tissues 
O C   1 010 
 o 
Assessment of GPC3 expression in 1  human primary cells 
or cell lines 
O C   1 00   
 o 
Expression of Glypican 3 in adult peripheral nervous tissues 
O C   1 00 7 
 o 

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Study type 
Study title 
Study number 
GLP 
compliant 
Assessment of the binding properties of G0 scFv Fc using a 
human plasma membrane protein cell array 
RP 113 
 o 
A study of tissue cross reactivity of G0 ScFv hFc with 
normal human or  SG mouse tissues 
 030   7 
Yes 
GLP=Good Laboratory Practice; GPC3=glypican-3; PCR=polymerase chain reaction. 
Note: AZD585, targeting GPC3-armored CAR-T cells, is identical with C-CAR031 in the CAR sequence and 
DnTGFβRII sequence; G0 ScFv is the antigen recognition sequence of C-CAR031. 
Among them, the single-dose toxicity study, in vitro hemolysis test, local irritation test and tissue 
cross-reactivity test were all completed under GLP conditions (Table 5); other studies were 
conducted under non-GLP conditions by qualified operators in accordance with standardized 
procedures, so that the results produced are authentic and reliable. 
2.2.6.1 
C-CAR031 preclinical efficacy study results 
The specific scFv (clone number G08) targeting GPC3 in C-CAR031 is derived from the DP47 
phage display library (Groves et al 2012[47]) The scFv in this library consists of fully humanized 
antibody variable domain sequences, with VH and VL being connected through a 15- residue 
linker sequence (GGGGS) 3. The single-chain variable region segment is transformed into scFv-
Fc fusion protein, and its affinity with human and mouse GPC3 proteins is detected using surface 
plasmon resonance. It was observed in studies that the scFv recognizing GPC3 in C-CAR031 can 
bind to human and mouse GPC3 proteins, with a higher affinity to human GPC3 protein and the 
equilibrium dissociation constant (KD) of 73 nM and 138 nM, respectively. 
The specificity of CAR for the target antigen was evaluated in in vitro tests, including in vitro 
target antigen activation, cytokine secretion, antigen-dependent cell proliferation, and killing 
effect on GPC3-positive tumor cells. In addition, the blocking effect of dnTGFβRII on the TGFβ 
signaling pathway was evaluated. The test results showed that the lentiviral vector-transduced T 
cells co-expressed CAR and dnTGFβRII on their surface. Co-culture of CAR-T cells with a 
variety of tumor cells expressing GPC3 resulted in T cell activation, proliferation, production of 
IFN-γ and other effector cytokines, and target cytolysis. On the other hand, dnTGFβRII attenuates 
TGFβ-induced S AD /3 phosphorylation, thereby inhibiting the activity of the TGFβ signaling 
pathway. CAR-T cells armored with dnTGFβRII can maintain IL-2 transcription in the presence 
of TGFβ inhibitory molecules in the environment. 
In vivo, armored GPC3 CAR-T were more efficacious compared to the unarmored GPC3 CAR-
T cells in controlling the growth of a HCC cell line tumor model overexpressing TGFβ, achieving 
stronger and longer-lasting inhibitory effect even at low doses. On the Day 7 after treatment, a 
higher proportion of CAR-T cell infiltration was observed in tumor tissues of mice in the 
dnTGFβRII-armored CAR-T cell treatment group, indicating that armoring dnTGFβRII 
improved the infiltration ability of CAR-T cells in tumor tissues. Further flow cytometric analysis 
showed that compared with second-generation CAR-T cells, armored CAR-T cells expressed 
significantly lower levels of immunosuppressive molecules (e.g., LAG3 and PD1) in the tumor 
microenvironment, indicating the introduction of armoring dnTGFβRII enhanced the tolerability 
of CAR-T cells to immunosuppressive signals.  

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Furthermore, in vivo studies in HCC patient-derived xenograft (PDX) models showed that 
dnTGFβRII-armored CAR-T cell were able to control tumor growth of TGFβ positive tumors, 
while infusion of unarmored CAR-T cells did not result in significant tumor control. This shows 
that expression of dnTGFβRII does not affect the efficacy of GPC3 CAR-T cells in the absence 
of TGFβ but greatly improves it if TGFβ is present in the tumor. 
 
The efficacy of dnTGFβRII-armored CAR-T cell in squamous cell lung cancer was tested in vivo 
using PDX models. Models were selected based on GPC3 and TGFβ expression, evaluated by 
IHC. Infusion of dnTGFβRII-armored CAR-T cell resulted in tumor control and production of 
IFN regardless of TGFβ expression, while infusion of unarmored CAR-T cells did not result in 
significant tumor control or IFN production (Figure 5).  
Figure 5 Expression of dnTGFβRII increases CAR-T in vivo efficacy against TGFβ 
expressing tumors.  
 
Average tumor volume and IFN concentration (day 7 post-CAR-T infusion) are shown for a 
TGFβ positive and a TGFβ negative PDX model. This demonstrates that dnTGFβRII-armored 
CAR-T cell are efficacious in vivo against squamous cell lung cancer and further evidenced the 
rationality and necessity of armoring with dnTGFβRII, providing strong support for the efficacy 
of armored CAR-T cell therapies. 
2.2.6.2 
C-CAR031 preclinical pharmacokinetic study results 
Non-clinical pharmacokinetic study results showed that after a single caudal venous injection of 
5×106 CAR-T cells/mouse of C-CAR031 into tumor-bearing mice, CAR- T cells had been 
detectable in mouse tumor tissues at 24 hours post-treatment and then increased over time; C-
CAR031 in tumor tissues of male and female mice peaked on the Day 13 and Day 7 post-
treatment, respectively, indicating that C-CAR031 cells could infiltrate into tumor tissues after 
entering the mice and further expand after activation by the target antigen. The copy numbers of 
C-CAR031 in various tissues also gradually increased over time; C-CAR031-specific DNA 
peaked on the Day 13 post-treatment in the kidney tissues of male animals and the lung and 
kidney tissues of female animals, and on the Day 21-Day 28 post-treatment in the remaining 

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tissues, and the distribution level of C-CAR031 was the highest in the spleen. The change patterns 
of C-CAR031 cells in various organs were consistent with those in tumor tissues, and showed a 
trend towards decreasing in different degrees after peaking. 
Tissue distribution test results showed that after intravenous injection, C-CAR031 was mainly 
distributed in the spleen, lungs, whole blood, tumor tissues, liver, kidneys, and bone marrow, and 
the least distributed in the brain, gonads, heart and other tissues. It is worth noting that the spleen, 
lungs, liver, kidneys, bone marrow, etc. are all commonly affected organs in the mouse GvHD 
model. In the single-dose toxicity test, we also observed mononuclear cell infiltration in the 
histopathological examination of relevant tissues in animals in the T cell control group. Therefore, 
while the animal studies reflected the outcome, distribution and survival of C-CAR031 cells in 
the body to a certain extent, due to the limitations of the currently used animal models, it was not 
possible to distinguish GvHD-induced tissue distribution and cell proliferation of T cells in 
tumor-bearing mice in the studies, so that the study results may not be fully representative of the 
proliferation trend of this product in patients. 
2.2.6.3 
C-CAR031 results of preclinical safety studies 
As required in the Technical Guidelines for the Studies and Evaluation of Cell Therapeutic 
Products (Tentative) (2017 No. 216) issued by The former China Food and Drug Administration 
(CFDA, 2017[45]), the Technical Guidelines for Non-Clinical Studies and Evaluation of 
Genetically Modified Cell Therapeutic Products (Tentative) (2021 No. 49), and other relevant 
technical guidelines issued by Center for Drug Evaluation, National Medical Products 
Administration (NMPA, 2021[46]), we conducted a single-dose toxicity study in tumor-bearing 
mice, lentiviral insertion site detection, in vitro soft agar clonal growth, IL-2-independent in vitro 
proliferation, in vitro hemolysis, and local irritation tests, as well as targeted studies including 
GPC3 expression in normal tissues, membrane protein array, and tissue cross-reactivity, etc. The 
primary toxicology study results are summarized as follows: 
Table 6 
Primary Toxicology Study Results of C-CAR031 
Study type 
Species / study 
system 
Route of 
administration 
Dosing cycle / 
frequency, 
dosage 
Primary study results 
Single dose 
toxicity 
 OG mice, Hep3B 
subcutaneous tumor 
model, half males 
and half males 
Caudal venous 
in ection 
Single dose 
1×10  CAR T 
cells/animal 
 ×10  CAR T 
cells/animal 
During the    day observation period, no 
marked toxicities were observed other 
than the anti tumor effects and GvHD 
related reactions; 
The  OAEL was  ×10  CAR T 
cells/animal 
Lentivirus 
insertion 
site 
detection 
3 batches of C 
CAR031 prepared 
by the clinical 
process derived 
from healthy donors 
In vitro 
— 
The numbers of insertion sites detected 
in the three samples were  074 ,  37 0, 
and   7 1, respectively, and the 
Shannon indices were 9.  , 9.  , and 
9. 4, respectively, indicating 
polyclonality of insertion site 
distribution and random insertion. The 
insertion sites were mainly located in 

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intronic regions of the genome, followed 
by intergenic and peri gene regions. 
Insertion sites located in exon regions 
only accounted for  .13% to  .3 % of 
any insertion sites, and no sites with 
integration preference were identified. 
In vitro 
tumorigenici
ty 
  batches of C 
CAR031 prepared 
by the clinical 
process derived 
from healthy donors 
In vitro 
Inoculated at the 
densities of  00, 
 000, and 
 0,000 
cells/well 
Two batches of C CAR 031 showed no 
colony formation within the  1 day 
culture period, indicating no in vitro 
tumorigenicity of C CAR031 
IL   
independent 
in vitro 
proliferation 
test 
3 batches of 
armored CAR T 
prepared by the 
clinical process 
derived from 
healthy donors 
In vitro 
0. ×10   
cells/mL 
In the absence of exogenous 
recombinant human IL  , none of the 
three batches of armored CAR T cells 
exhibited abnormal growth/expansion. 
Over time, the total cell number, 
viability, and number of proliferating 
cells decreased. The results indicated a 
low risk of abnormal expansion or clonal 
proliferation of armored CAR T cells  
In vitro 
hemolysis 
test 
Rabbit red blood 
cells 
In vitro 
 . ×10 7 
cells/mL 
The C CAR031 preparation produced no 
hemolytic reaction in vitro at  . ×107 T 
cells/mL (higher than the maximum 
proposed clinical concentration) 
Local 
tolerability 
 OG mice, Hep3B 
subcutaneous tumor 
model, half males 
and half males 
Caudal venous 
in ection 
Single dose, 
 .7 ×10  
cells/mL and 
3.3 ×107 
cells/mL 
During the study, no local abnormalities 
at the administration site were observed 
in any animals; local irritation was not 
observed at the administration site in any 
animals upon pathological examination 
on D14 and D 9  
Off target 
toxicity 
studies 
Paraffin sections of 
33 types of normal 
human tissues from 
3 donors 
In vitro 
 /A 
GPC3 positive staining was observed in 
the cell membrane/cytoplasm of the 
placental trophoblast; localized positive 
staining, mainly in the cell membrane, 
was observed in the anterior pituitary 
gland 
1  types of human 
primary cells or cell 
lines 
In vitro 
 /A 
Compared with the hepatocellular 
carcinoma cell line HEP3B, the relative 
expression of GPC3 in motor neurons 
was low (9.   13.0%), and the relative 
expression of GPC3 was all very low 
(<0.4%) in any other primary cells 
Paraffin sections of 
tongue, stomach, 
small intestine, 
large intestine, 
heart, skin, and 
dorsal root ganglion 
In vitro 
 /A 
 0% of the ganglion cells in the colon 
sample expressed low levels of cell 
membrane localized GPC3 protein 

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Retrogenix cell 
microarray ( 101 
human membrane 
proteins, cell model 
anchored secreted 
proteins, and 39  
human 
heterodimeric 
proteins) 
In vitro 
 0 μg/mL 
At the concentration of  0 μg/mL, the 
antigen recognition region of C CAR031 
only interacted specifically with GPC3 
isoform 1, and no other interactions were 
observed. 
3  types of normal 
human frozen tissue 
sections from 3 
donors 
In vitro 
0.  μg/mL, 
  μg/mL 
At the concentration of   μg/mL, the 
antigen recognition region of C CAR031 
exhibited staining specific to the cell 
membrane and cytoplasm of human 
placental trophoblast cells, and the 
cytoplasm of 1/3 of the donor's external 
cervical oriface, renal tubules, and 
anterior pituitary epithelial cells; 
considering that cell therapeutic products 
would not come into contact with the 
cytoplasm components in the body, these 
stains located in the cytoplasm would be 
associated with a low risk of causing off 
target toxicity in clinical applications. 
GPC3=glypican-3; IL-2=interleukin 2; NOAEL=No Observed Adverse Effect Level. 
Toxicology studies showed that when C-CAR031 was given to NOG tumor-bearing mice by 
caudal venous administration at a dose of 1×106 CAR-T cells/ mouse and 5×106 CAR-T cells/ 
mouse, no marked toxicities other than the anti-tumor effects and GvHD-related reactions were 
observed, and the NOAEL was 5×106 CAR-T cells/animal, equivalent to the human dose of 
approximately 2×107 CAR-T cells/kg estimated based on the body surface area. Lentiviral 
insertion site detection for the 3 cases using C-CAR031 prepared with the clinical process showed 
that the insertion sites were mainly located in the intronic region of the genome, followed by 
intergenic and peri-gene regions, and the insertion sites located in the exon region accounting for 
only 2.13%-2.32% of any insertion sites; the distribution exhibited polyclonality, and no sites 
with integration preference were identified. C-CAR031 exhibited no tumorigenicity under in vitro 
culture conditions,and did not exhibit abnormal proliferation under culture conditions in the 
absence of exogenous recombinant human IL-2, indicating a low risk of abnormal expansion and 
clonal proliferation of C-CAR031 cells. 
C-CAR031 produced no hemolytic reactions in vitro at 2.8×107 T cells/mL; when administered 
as a single caudal venous injection at the concentrations of 6.76×106 cells/mL and 3.38×107 
cells/mL, C-CAR031 was observed with no local abnormalities at the administration site and no 
local irritation at the administration site upon pathological examination.Membrane protein array 
and tissue cross-reactivity tests indicated high specificity of the antigen recognition region of C-
CAR031 and a low risk of causing off-target toxicity in clinical applications. 
Expression of GPC3 in normal human tissues was investigated using a commercial mouse anti-
GPC3 antibody (1G12 clone- Sigma-Aldrich®). Samples included 2 TMAs covering 32 different 

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organs, with tissue cores from 3 different donors per tissue (Study No.: ONC5851-010). 
Furthermore, a GLP tissue cross reactivity study was conducted assessing binding of the G08 
binding part of CCAR031 to the full panel of 42 human tissues from 3 independent donors (Study 
No.:20308687). No binding to lung tissue was observed in any of these studies. Finally, a 
membrane protein array binding study (Retrogenix) was performed to assess any off-target 
binding of the G08 binding part. No off-target binding was observed. See Table 6 for list of 
studies assessing GPC3 expression and tissue/protein binding of the G08 binding part of C-
CAR031. 
In summary, the mechanism of action of C-CAR031 is well-established, the efficacy in terms of 
targeting GPC3-positive tumors in vitro and in vivo is well-documented, and armoring with 
dnTGFβRII improved the functioning of CAR-T cells in the immunosuppressive tumor 
microenvironment without increasing the safety risks (Bollard et al 2018[33], Narayan et al 
2022[34]). 
2.2.7 
Summary of C-CAR031 clinical study 
As of March 14, 2024, in the China IIT study of C-CAR031 for advanced HCC (NCT05155189), 
a total of 24 subjects had been infused in four dose cohorts of 0.75, 1.5, 2.5 and 4.0 (unit: ×106 
CAR-T cells/kg) as mono therapy in 1, 6, 9, and 8 participant, respectively, 70.8% participants 
had lung metastatic lesions. No DLT events were observed in all dose cohorts (0.75, 1.5, 2.5 
and 4.0); The maximum tolerated dose (MTD) had not been reached. The median follow-up 
time was 9.03 months. As shown in Table 7, the 0.75, 1.5, 2.5 and 4.0 doses (unit: ×106 CAR-
T cells/kg) were safe and well tolerated, and the efficacy of the 1.5, 2.5 and 4.0 doses was better 
than that of the 0.75 dose. The ORR at 4.0 doses (75%) was higher than that in 1.5 and 2.5 doses 
(50%), the DCR was similar across dose cohorts. The median PFS and DoR at 4.0 doses was 
not mature by the data cutoff date, participants at 1.5 and 2.5 doses had the comparable median 
PFS (4.27m vs. 4.17m). The median DoR of 1.5 doses appeared to be longer than that of 2.5 
doses numerically (7.36m vs. 4.44m, not compared statistically). 1 participant at 0.75 doses 
achieved a stable disease as the best of response, considered as a clinical benefit in this heavily 
treated patient population.  
Table 7 
Comparison of Safety and Efficacy Across Different Dose Groups (Safety Analysis 
Set) 
 
Safety 
0.75×106 /kg 
N=1 
n (%) 
1.5×106 /kg 
N=6 
n (%) 
2.5×106 /kg 
N=9 
n (%) 
4.0×106 /kg 
N=8 
n (%) 
Total 
N=24 
n (%) 
C-CAR031-related TEAEs  
1 (100) 
6 (100) 
9 (100) 
8 (100) 
24 (100) 
≥ Grade 3 C-CAR031-related TEAEs 
0 
3 (50.0) 
3 (33.3) 
3 (37.5) 
9 (37.5) 
TEAEs leading to withdrawal from 
study 
0 
0 
0 
0 
0 
SAEs 
1 (100) 
0 
2 22.2) 
2 (25.0) 
5 20.8) 
C-CAR031-related SAEs  
0 
0 
1 (11.1) 
1 (12.5) 
2 (8.3) 

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TEAEs leading to death 
1 (100) 
0 
0 
0 
1 (4.2) 
Grade 1/2 CRS 
1 (100) 
5 (83.3) 
8 (88.9) 
7 (87.5) 
21 (87.5) 
≥ Grade 3 CRS  
0 
0 
0 
1 (12.5) 
1 (4.2) 
Median Days to CRS Onset 
day (range) 
7 (7, 7) 
3 (2, 3) 
3 (2, 4) 
2 (1, 3) 
3 (1, 7) 
Median Days to CRS Resolution 
day (range) 
4 (4, 4) 
6 (4, 8) 
3 (2, 6) 
5 (3, 8) 
4 (2, 8) 
 ICANS 
0 
0 
0 
0 
0 
≥ Grade 3 infusion reactions 
0 
0 
0 
0 
0 
Efficacy 
N=1 
N=6 
N=8* 
N=8 
N=23 
ORR 
0 
3 (50.0) 
4 (50.0) * 
6 (75.0) 
13 (56.5) 
DCR 
1 (100) 
5 (83.3) 
8 (100) 
7 (87.5) 
21 (91.3) 
Median DoR (months) 
NE 
7.36 
4.44 
NE 
7.36 
Median PFS (months) 
NE 
4.27 
4.17 
NE 
4.30 
Note: CRS = cytokine release syndrome; ICANS = Immune effector cell-associated neurotoxicity syndrome; NE=not 
evaluable yet; TEAE = treatment-emergent adverse events. 
*Among the 24 participants, 1 (0921-02801C015) participantwas not included in efficacy analysis due to protocol 
deviations.  
As classified by preferred term, the most common treatment-emergent adverse events (TEAEs) 
were hematologic toxicities and CRS, no ICANS reported. TEAEs with an incidence ≥  0% 
included neutrophil count decreased (100%), lymphocyte count decreased (100%), white blood 
cell count decreased (100%), anemia (95.8%), CRS (91.2%, only 1 participant experienced G3 
CRS), fibrin D dimer increased (70.8%), platelet count decreased (62.5%), cough (58.3%), 
hypokalaemia (50.0%), productive cough (45.8%), alopecia (45.8%), hypoalbuminaemia 
(41.7%), coagulation test abnormal (41.7%),  aspartate aminotransferase increased (41.7%), 
hypoproteinemia (37.5%), proteinuria (37.5%), pyrexia (29.2%), hypotension (29.2%), blood 
glucose increased (29.2%), weight decreased (25.0%), myalgia (25.0%), nausea (25.0%), 
diarrhea (25.0%),  pleural effusion (20.8%), hyponatremia (20.8%) and hepatitis B virus DNA 
increased (20.8%). 9 (37.5%) participants experienced ≥ Grade 3 TEAEs related to C-CAR031 
infusion, including transient Grade 3 AST increases, Grade 3 Platelet count decreased, Grade 3 
CRS and Grade 3 interstitial lung disease (ILD), the ILD was considered CRS related and 
recovered from Grade 3 to Grade 2 within 6 days.  
A total of 2 (8.3%) participants experienced SAEs related to C-CAR031 infusion. 1 participant 
in 2.5 dose cohort experienced myelosuppression (Grade 4) assessed as definitely related to 
lymphodepleting chemotherapy and possibly related to C-CAR031 infusion. Another participant 
in 4.0 dose cohort experienced CRS and ILD (both Grade 3). The CRS post C-CAR031 infusion 
occurred more earlier at 1.5, 2.5 and 4.0 doses than in 0.75 doses (median onset days: 3, 3, 2 and 
7), but the duration of CRS was similar (4-6 days). Though there were more than 70.8% of 
participants had lung metastatic lesions, the lung complications were not a safety concern based 

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on the safety data. Only 1 ILD was reported in 4.0 dose cohort, it was considered associated with 
Grade 3 CRS and recovered from Grade 3 to Grade 2 within 6 days.  
 
After a single infusion of C-CAR031, the median Tmax was 10 days (range: 7-21 days); the median 
Cmax was 3.9×105 copies/µg gDNA (range: 7.1×103 , 8.3×105 copies/µg gDNA); the median AUC0-
28d was 4.5×106 copies/µg∙day (range  1.3×106, 14.3×106 copies/µg∙day); the median Tlast was 125+ 
days (range: 42, 271+ days). The study results indicate that C-CAR031 can effectively expand in 
the body in a durable manner; no other adverse events of special interest, such as uncontrolled T 
cell expansion or new or secondary tumors, were observed. 
 
2.3 
Benefit/Risk Assessment 
This section outlines the potential benefits, risks, and the mitigation strategies for this study. Table 
8 identifies the risks associated with C-CAR031 and mitigates the impact of these risks, while 
aiming to maximize the chance of therapeutic benefit to participants. More detailed information 
about the potential benefits, and risks and reasonably anticipated adverse events (AEs) of C-
CAR031 may be found in the C-CAR031 Investigator’s Brochure (IB). 
 
2.3.1 
Risk Assessment 
Risks related to the investigational intervention and study procedures with a brief description of 
strategies to mitigate these risks are summarized in Table 8. 
 
Table 8 
Risk Assessment 
Potential risk 
of clinical 
significance 
Summary of data/rationale for 
risk a 
Mitigation strategy 
Study intervention(s) C-CAR031 
CRS 
CRS is an acute systemic 
inflammatory syndrome associated 
with immunotherapy including CAR 
T-cell therapy. Elevated 
inflammatory cytokine levels 
leading to fever, hypotension, 
hypoxia and/or other organ system 
toxicities. 
• 
Participants with pre-existing autoimmune 
disorders (Section 5.2) 
• 
Pre-infusion medication (Section 
6.1.4.1.2 and Table 11) 
• 
Mandatory hospitalization (minimum 7 
days) post C-CAR031 infusion  
• 
Monitor closely for CRS, immediately 
hospitalize on first signs of CRS (such 
as fever), and follow the guidance for 
management of CRS (see RMP) 
• 
Access to ICU 
• 
Adequate supplies of supportive 
medications, including anti-IL-6 treatment 
(eg, tocilizumab), should be available on 
site prior to C-CAR031 infusion (Section 
6.9.1) 
• 
A participant wallet card will be 
implemented (Section 6.1.4.1.1) 

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HLH/MAS 
CAR T-cell therapy–induced 
HLH/MAS is a dysfunctional 
immune response leading to 
symptoms including fever, 
splenomegaly, lymphadenopathy, 
cytopenias, hyperferritinaemia. 
Considerable overlap with CRS 
symptoms. 
• 
Mandatory hospitalization (minimum 7 
days) post C-CAR031 infusion 
• 
Mitigations and clinical management 
mirrors the strategies used for managing 
CRS. Follow the guidance for management 
of HLH/MAS (see RMP) 
• 
A participant wallet card will be 
implemented (Section 6.1.4.1.1). 
Neurological 
disorders including 
ICANS 
Neurological complications 
including ICANS have been 
reported following CAR T-cell 
administration. A neurological 
condition characterized by 
confusion or delirium, expressive 
aphasia, weakness, tremor, seizures, 
and altered levels of consciousness. 
• 
Participants with select neurological 
disorders and autoimmune conditions that 
impact the CNS will be excluded (see 
Section 5.2) 
• 
Mandatory hospitalization (minimum 7 
days) post C-CAR031 infusion. Regular 
abbreviated neurological examination 
• 
Monitoring and management criteria for 
ICANS (see RMP) 
• 
A participant wallet card will be 
implemented (Section 6.1.4.1.1). 
IRRs including 
hypersensitivity 
and anaphylaxis 
Reaction to cell therapy product 
and/or excipients that may manifest as 
rash/erythema, hypotension, 
bronchospasm, and rarely anaphylaxis. 
• 
Exclusion criteria (Section 5.2) 
• 
Participants should receive pre-medication 
(Table 11) and be treated urgently per 
institutional standard, appropriate clinical 
practice guidelines and society guidelines, 
avoiding corticosteroid use if possible 
• 
See RMP for suggested management of 
IRRs. 
Transaminase elevation 
 
Reactivity of C-CAR031 with GPC3 
on liver metastatic tumor cells may 
cause elevation of liver transaminases. 
Transaminase elevation may also 
occur as part of CRS. 
• 
Exclusion criteria of HBV, and HCV 
infection (Section 5.2) 
• 
Regular monitoring of liver transaminases  
• 
See RMP for suggested management. 
New primary 
malignancy 
 Safety concern characterized by the 
risk of lentiviral induced insertional 
mutagenesis into a site that adversely 
affects the host cell genome, which 
could lead to genotoxicity and 
formation of new primary malignancy. 
Cases of new malignancies including 
T cell lymphomas have occurred 
following treatment with approved 
CAR-T products in haematological 
cancers. 
• 
Routine pharmacovigilance (see Section 
8.4). Monitoring to follow the 
recommendations set forth in the CDE 
Guidance for Industry (Technical 
guidelines for conducting long-term 
follow-up in clinical studies of gene 
therapy products, 2021) 
• 
New primary malignancies should be 
reported during the duration of the 
main study and LTFU study up to 15 
years irrespective of when they 
occur. 

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Enteric 
Autonomic 
Neuropathy 
Low levels of GPC3 expression on 
human colonic ganglia was detected 
by IHC with one antibody but the anti 
GPC3 scFv in C-CAR031 did not 
show reactivity. No toxicity or 
pathological findings were observed 
in the conducted safety study in mice. 
Reactivity of C-CAR031 may 
manifest with symptoms including 
constipation or diarrhea, but no AEs 
on colon related to C-CAR031 were 
reported in IIT to date. 
• 
Exclusion of neurological autoimmune 
conditions 
• 
Regular clinical examination of 
participants 
• 
See RMP for suggested management of 
enteric autonomic neuropathy 
Anterior pituitary 
dysfunction 
Low levels of GPC3 expression in 
human anterior pituitary gland was 
detected with one antibody but the 
anti GPC3 scFv in C-CAR031 did 
not show reactivity. No toxicity or 
pathological findings were observed 
in the conducted safety study in 
mice. Reactivity of C-CAR031 may 
cause hormonal imbalance affecting 
e.g. thyroid function, but no AEs on 
anterior pituitary gland related to C-
CAR031 were reported in IIT to date. 
• 
Regular clinical examination of 
participants 
• 
Regular monitoring of TSH 
• 
See RMP for suggested management. 
Infection with RCL 
Risk of recombination event during 
manufacturing/post-infusion could 
generate pathogenic RCL variants. 
• 
RCL testing of C-CAR031 product prior 
to release 
• 
Participant monitoring for RCL by 
mandatory viral testing (see Section 1.3, 
SoAs) 
• 
Monitoring of infections per local 
guidance. 
Uncontrolled T-cell 
proliferation 
Genetic engineering of participant T 
cells can increase the risk of T- cell 
clonal expansion or potentially 
malignant transformation via 
mechanisms such as insertional 
mutagenesis following lentiviral 
transduction or transgene expression. 
• 
Test of the lentiviral vector genome 
integration site of C-CAR031 
• 
Study participants will undergo regular 
blood sampling to monitor the 
proliferation of T cells. 
Adverse effects 
on embryo-
foetal 
development 
GPC3 is expressed in human placenta 
and the mesodermal layer of the 
developing foetus. It is unknown if 
C-CAR031 has the potential to be 
transferred to the foetus. 
• 
Exclusion criteria (Section 5.2), routine 
pharmacovigilance (Section 8.4), 
pregnancy testing and contraception 
guidelines (Section 5.1). 

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Immunogenicity 
of vector and 
transgene 
Humoral and cellular responses 
against components of the CAR-T, 
which may limit the efficacy of the 
product. 
• 
Routine pharmacovigilance (see Section 
8.4) 
• 
Clinical monitoring for symptoms of 
immunogenicity; regular measurement of 
anti-drug antibodies and assessment after 
C-CAR031 infusion (see Section 8.8). 
Study intervention(s): LDC associated with C-CAR031 therapy 
Cytopaenias 
Low haematological cell counts 
(neutrophils, lymphocytes, platelets, 
erythrocytes, etc.) associated with 
lymphodepletion leading to increased 
risk of infection, bleeding, and/or 
fatigue. 
• 
Participants with significant 
haematological imbalances are excluded 
(Section 5.2).  
• 
Frequent monitoring of haematological 
parameters and provision of supportive 
care (eg, irradiated blood and thrombocyte 
concentrates, granulocyte-colony 
stimulating factor for neutropenia) as 
outlined by institutional guidelines. 
Infections 
Immunosuppression secondary to 
lymphodepletion leading to increased 
risk of bacterial, viral, and/or fungal 
infection. 
In CAR-T therapy, the pretreatment 
with cyclophosphamide and 
fludarabine can induce 
immunosuppression, which may be 
the main cause for HBV reactivation. 
2 participants experienced virus 
reactivation post-infusion in HCC 
IIT to date. Both cases recovered to 
baseline levels within 4 weeks and 2 
weeks, respectively, following 
antiviral treatment. 
• 
Exclusion criteria of syphilis, HBV, 
HCV, CMV and HIV infection 
(Section 5.2) 
• 
Monitoring as clinically indicated; 
treatment as outlined by institutional 
guidelines 
• 
Prophylactic antimicrobial medication 
(including prophylaxis for pneumocystis 
jiroveci pneumonia) as clinically indicated 
and as outlined by institutional guidelines. 
Other risks associated 
with lymphodepleting 
chemotherapy 
• 
Fludarabine fevers, neurotoxicity, 
hemolysis. 
• 
Cyclophosphamide: haemorrhagic 
cystitis, myocarditis, pericarditis, 
pneumonitis, and neurotoxicity. 
Use of these agents may increase the risk 
of developing new primary 
malignancies; risk of fertility and 
embryo-fetal toxicity. 
Please see local product label for all 
product specific risks. 
• 
Relevant exclusion criteria (see 
Section 5.2), including uncontrolled 
intercurrent illness. 
• 
Close monitoring and clinical 
examinations during and after the 
procedure according to local practice. 
• 
Supportive care as outlined by 
institutional guidelines and local 
product label 
• 
Exclusion: Pregnant or breastfeeding 
(see Section 5.1). 
• 
Pregnancy test prior to study 
intervention. 
• 
Contraception guidance (see 
Appendix F) 
Study procedures 

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Apheresis 
Risks may include hypotension, 
faintness, blurry vision, dizziness, 
coldness, sweating, infection, 
abnormal blood clotting, allergic 
reaction, bleeding, seizures, 
abdominal cramps, and tingling in 
the limbs. 
Risks associated with placement of 
central venous catheter (if applicable) 
may include arterial puncture, 
pneumothorax, haemothorax, 
haematoma. 
• 
Participants will have risks explained 
according to local practice by the 
investigator during the consent process 
• 
Close monitoring and clinical examinations 
during and after the procedure according to 
local practice. 
Other 
Bridging therapy 
Risk associated with anticancer drugs 
used in the bridging regimen. Product-
specific risks as per local 
label. 
• 
Participants will have risks explained by the 
investigator according to the local product 
information during the consent process 
• 
Close monitoring and clinical examinations 
during and after the procedure according to 
local practice 
• 
Supportive care as outlined by institutional 
guidelines and local product label. 
 
a 
For a complete characterization for each risk associated with C-CAR031 refer to the C-CAR031 IB. 
AEs = adverse events; CAR = chimeric antigen receptor; CDE = center for drug evaluation; CMV = 
cytomegalovirus; CNS = central nervous system; CRS = cytokine release syndrome; GPC3 = glypican-3; HBV 
= hepatitis C virus; HCV = hepatitis C virus; HIV = Human immunodeficiency virus; HLH = haemophagocytic 
lymphohistiocytosis; ICANS = immune effector cell-associated neurotoxicity syndrome; ICU = intensive care 
unit; IL-6 = Interleukin- 6; IIT = investigator initiated trial; IRR = infusion-related reaction; LDC = 
lymphodepleting chemotherapy; LTFU = long-term follow-up; MAS = macrophage activation syndrome; RCL 
= replication-competent lentivirus; RMP = Risk Management Plan;; TSH = thyroid stimulating hormone. 
2.3.2 Benefit Assessment 
There remains a significant unmet need for additional treatment options for patients with 
GPC3+ advanced/metastatic squamous cell lung cancer, who are not amenable to curative 
therapy and have progressed or are intolerant to no more than 3 lines of systemic treatment 
including CPIs and platinum-based doublet chemotherapy, concurrently or sequentially (see 
Section 2.2.1). Early clinical data of C-CAR031 (Zhang et al 2024[3]) demonstrated promising 
safety and efficacy in other solid tumors support the exploration of C-CAR031 in patients with 
GPC3+ advanced/metastatic squamous cell lung cancer. 
 
2.3.3 Overall Benefit/Risk Conclusion 
Considering the measures taken to minimize the risks to the participants of this study, the potential 
risks associated with C-CAR031 are justified by the anticipated benefits that may be afforded to 
participants with GPC3+ advanced/metastatic squamous cell lung cancer, who are not amenable 
to curative therapy and have progressed or are intolerant to no more than 3 lines of systemic 
treatment including CPIs and platinum-based doublet chemotherapy, concurrently or sequentially. 
3 
OBJECTIVES AND ENDPOINTS 

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The objectives and endpoints are listed below in Table 9. 
Table 9 
Objectives and Endpoints 
Type 
Objectives 
Endpoints 
Primary 
Phase Ia: Safety run-in and backfill 
Phase Ib: Dose expansion  
Safety 
• 
To assess the safety and 
tolerability of C-CAR031 in 
participants with GPC3+ 
advanced/metastatic squamous 
cell lung cancer 
• 
To determine the RDE (Phase 
Ia)  
• 
Incidence of AEs/SAEs/AESIs 
• 
Incidence and severity of DLTs (Safety run-in section 
of Phase Ia) 
• 
Changes from baseline in vital signs, physical 
examination, ECOG score, 12-lead ECGs, laboratory 
parameters that are abnormal and of clinically 
significance. 
Secondary 
Phase Ia: Safety run-in and backfill 
Phase Ib: Dose expansion 
Efficacy 
To estimate the anti-tumor 
activity of C-CAR031 in 
participants with GPC3+ 
advanced/metastatic squamous 
cell lung cancer 
• 
ORR, DCR, DoR, DRR, TTR, PFS and change in 
tumor size assessed by the investigator and 
evaluated according to RECIST 1.1 criteria 
• 
OS  
Pharmacokinetics 
To investigate the CK of C-
CAR031 by PCR in participants 
with GPC3+ 
advanced/metastatic squamous 
cell lung cancer 
• 
Quantification of CAR copies/μg DNA of C-
CAR031 in peripheral blood 
• 
CK parameters of C-CAR031, including but not 
limited to Tmax, Cmax, AUC0-28d, Tlast, Clast, and AUC 
last, as data allows 
Safety 
To assess the safety of C-
CAR031 in participants with 
GPC3+ advanced/metastatic 
squamous cell lung cancer 
• 
Presence of RCL in peripheral blood samples. 
Exploratory  
Phase Ia: Safety run-in and backfill 
Phase Ib: Dose expansion  
Pharmacokinetics  
To investigate the CK of C-
CAR031 by flow cytometry in 
participants with GPC3+ 
advanced/metastatic squamous 
cell lung cancer 
• 
Quantification of C-CAR031 CAR-T cells in 
peripheral blood  
• 
CK parameters of C-CAR031, including but not 
limited to Tmax, Cmax, AUC0-28d, Tlast, Clast, and AUClast 
as data allows 
Immunogenicity 
To assess the immunogenicity of 
C-CAR031 
• 
Evaluation of humoral immunogenicity against C-
CAR031: incidence, and antibody levels as data 
allows. 
Biomarkers 
To assess intra-tumoral 
biomarkers of disease, 
pharmacodynamic biomarkers 
and biomarkers of clinical 
response to C-CAR031 
• 
Presence or changes in tumoral biomarkers 
including, but not limited to levels of RNA, DNA, 
and protein analytes as well as imaging 
measurements. Specific assessments may include, 
but not be limited to expression of GPC3, immune 
markers (for example TGFβ, PD-L1, CD8) and 

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CAR-T infiltration. 
Biomarkers 
To assess systemic biomarkers 
of disease, pharmacodynamic 
biomarkers and biomarkers of 
clinical response to C-CAR031 
• 
Presence and changes in peripheral DNA, RNA, 
immune cell phenotype, and protein biomarkers, 
which may include, but not limited to ctDNA, 
soluble and cellular analytes, gene expression, and 
immune markers pre- and post- treatment or on 
disease progression. 
AEs = adverse events; AESIs = adverse events of special interest; AUClast = area under the curve from time 0 to the time 
of the last quantifiable concentration; AUC0-28d = area under the curve 28 days after C-CAR031 infusion; CAR = chimeric 
antigen receptor; CD8 = cluster of differentiation 8; CK= cellular kinetics; Cmax = maximum observed concentration; Clast 
= last measurable concentration; ctDNA = circulating tumour DNA; DCR = disease control rate; DLTs = dose-limiting 
toxicities; DNA= deoxyribonucleic acid; DoR = duration of response; DRR = durable response rate; ECG = 
electrocardiogram; ECOG= Eastern Cooperative Oncology Group; GPC3 = glypican-3;  ORR = objective response rate; 
OS = overall survival; PFS = progression-free survival; PCR = polymerase chain reaction; RCL = replication-competent 
lentivirus; RDE = recommended dose for expansion; RECIST = Response Evaluation Criteria in Solid Tumours; RNA = 
ribonucleic acid; PD-L1= programmed death ligand 1; SAEs = serious adverse events;  TGFβ = transforming growth 
factor-beta; Tlast = Time of Clast; Tmax = time to reach maximum concentration; TTR = time to response. 
4 
STUDY DESIGN 
4.1 
Overall Design 
This single-arm, open-label, multicenter, Phase I study will evaluate the safety, tolerability, anti-tumor 
activity, PK/PD, biomarker, and immunogenicity of C-CAR031 in adult participants with GPC3+ 
advanced/metastatic squamous cell lung cancer, who are not amenable to curative therapy and have 
progressed or are intolerant to no more than 3 lines of prior systemic treatment including CPIs and 
platinum-based doublet chemotherapy, concurrently or sequentially. The study will be divided into 
two sections: safety run-in and backfill phase (Phase Ia) and dose expansion phase (Phase Ib). Phase 
Ia will determine the recommended dose for expansion (RDE) to be used in Phase Ib (dose expansion) 
of the study and evaluate the safety and efficacy in participants with GPC3 expression. Phase Ib will 
further evaluate the safety, tolerability, CK, biomarker, immunogenicity and efficacy of C-CAR031 at 
the RDE.  
 
The study will be conducted in the following steps: participants will undergo pre-screening, screening, 
apheresis, bridging therapy (if appropriate) and lymphodepletion before receiving C-CAR031 infusion 
and subsequent follow-up study schema is summarized in Figure 2 and Figure 3. 
 
• 
Study Consent: Each potential participant will provide informed consent prior to starting any 
study-specific procedures. This study has a 3-step consent process, with separate informed consent 
forms (ICF). 
• 
Pre-screening: Patients may consent to pre-screening only (see Section 5.1.1) Patients will be 
assessed for expression of GPC3 on the tumor via a validated IHC assay (performed at a central 
laboratory). The participant is required to provide tumor tissue sections (collection time 
requirements are detailed in the laboratory manual) or undergo a fresh tumor core biopsy for the 
testing of GPC3 expression. 
• 
Screening: Main screening consent is then required to enter the treatment period of the study (see 
Section 5.1.2). During screening, all patients will provide written consent for study participation 

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and will be screened for study eligibility within 28 days prior to apheresis. All eligibility criteria 
must be met prior to starting apheresis. Prescreening and screening may occur in parallel.  
• 
Apheresis: After meeting screening eligibility criteria, each participant will undergo apheresis for 
the collection of peripheral blood mononuclear cells (PBMCs). C-CAR031 will be generated from 
T cells selected from the apheresis. Participants for whom apheresis collection is unsuccessful or 
manufacturing is a failure may be allowed a second attempt at apheresis (see Section 6.1.1). 
• 
Bridging therapy: Bridging therapy between apheresis and baseline assessment (allowing at least 
5-half-lives washout of bridging therapy  prior to baseline assessment) will be permitted when 
clinically indicated following a discussion with the collaborator (see Section 6.1.2). 
• 
Lymphodepletion: After meeting eligibility criteria for receiving LDC (see Section 6.1.3.1), 
participants will be administered a conditioning regimen of IV cyclophosphamide 500 mg/m2 and 
fludarabine 25 mg/m2 daily for 3 days or per local standard (see Section 6.1.3.2). 
• 
C-CAR031 infusion: C-CAR031 will be administered on Day 0, approximately 7 days after the 
last dose of LDC (see Sections 6.1.3.2 and 6.1.4.2 for more information on C-CAR031 dosing 
window), at the dose levels specified in Figure 1. Following C-CAR031 infusion, participants will 
remain as inpatients for a minimum of 7 days (inclusive of D0) and participants should be within 
an approximate 2-hour travel time from the study site for approximately 28 days following C-
CAR031 infusion. 
The study is divided into two sections: safety run-in and backfill phase (Phase Ia) and dose expansion 
phase (Phase Ib): 
• 
Phase Ia (safety run-in and backfill): In each dose level of Phase Ia up to 12 evaluable 
participants  with GPC3+ advanced/metastatic squamous cell lung cancer, who are not amenable 
to curative therapy and have progressed or are intolerant to no more than 3 lines of prior systemic 
treatment including CPIs and platinum-based doublet chemotherapy, concurrently or sequentially 
will be evaluated. When enrolling is in progress, the eligible participant will preferentially be 
allocated to the 4.0 ×106 CAR -T cells/kg dose cohort if the two dose cohorts 1.5 ×106 CAR-T 
cells/kg and 4.0 ×106 CAR -T cells/kg are both open. This section aims to explore the RDE and 
consists of  preset dose levels, with flexibility to explore additional intermediate/higher dose levels. 
See Section 6.6.1 for the proposed dose levels to be explored. 
• 
Phase Ib (dose expansion): In Phase Ib approximately 12 evaluable participants each cohort at 
the RDE determined in Phase Ia will be evaluated to further evaluate the safety and tolerability, 
CK, biomarker, immunogenicity and explore efficacy of C-CAR031. 
• Follow-up and end of study: Follow-up of participants is divided into 3 stages in the study as 
described below (see Table 2, Table 3 and Figure 3). 
− 
Stage 1 Follow-up: Participants will complete all assessments as indicated in the SoA 
through 6 months post C-CAR031 infusion unless they experience confirmed disease 
progression, start a new anticancer regimen or discontinue  due to participant or investigator 
decision, whichever occurs first (see Section 7.2.2). For details of AE collection in Stage 1 

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see Table 17. Participants who received C-CAR031 discontinue prematurely from the study 
in Stage 1 will undergo an early discontinuation visit (see SoA Table 2) and be offered to 
move to Stage 3 of the study (see SoA Table 3) for continued safety surveillance. Participants 
who have completed a scheduled visit within 14 days of decision to be offered to move to 
Stage 3 will not need to complete the early study discontinuation visit. 
− 
Stage 2 Follow-up: Participants who have not previously progressed, discontinued 
prematurely from the study or started a new anticancer regimen after Stage 1 follow-up, will 
continue to be followed in Stage 2 of the study for safety, efficacy, CK, immunogenicity and 
exploratory biomarkers up to 12 months post C-CAR031 infusion or until disease progression, 
start of new anticancer treatment, or discontinuation due to participant or investigator decision, 
whichever occurs first (see SoA Table 2 and Section 7.2.3). For AE collection in Stage 2 see 
Table 17. 
Participants who progress, start new anticancer treatment, or discontinue prematurely from 
the study in Stage 2 will undergo an early discontinuation visit and be offered to move to 
Stage 3 of the study (see SoA Table 3) for continued safety surveillance. Participants who 
have completed a scheduled visit within 30 days of decision to be offered to move to Stage 3 
will not need to complete the early study discontinuation visit. 
The end of the main study is defined as 12 months after the last participant has received his/her 
dose of C-CAR031 (or sooner if: all the participants have progressed or stated a new anti-
cancer therapy or death occurred, or have either withdrawn or are lost to follow-up, or 
investigator and AbelZeta aligned to terminate the study). 
− 
Stage 3 Follow-up (Long-term Follow-up) – Once end of the main study is achieved (or 
before if appropriate follow-up has been completed),, all dosed with C-CAR031 participants 
will be offered to transition to, and continue to be monitored in stage 3 (the LTFU period) for 
up to 15 years from CAR-T infusion (see Figure 3) to assess for AEs as specified in Table 17, 
CK, RCL and OS (see Table 3). A separate ICF will be provided for the LTFU period. 
4.2 
Scientific Rationale for Study Design 
CAR T-cell therapy has been highly effective in treating patients with relapsed/refractory B-cell 
malignancies and multiple myeloma; studies are ongoing across the globe to understand the best 
approaches to provide benefit to patients with solid tumors (Schroeder et al 2022[39]). Several 
autologous GPC3 CAR T-cell products against other solid tumors have been tested in the clinic 
(summarized in Section 2.2.5 and Table 4). The safety profile observed thus far between the 
different GPC3 CAR T-cell products appears similar, with the major toxicity being CRS, as is 
expected from autologous CAR T-cell products, with no reports of notable on-target off-tumors 
toxicities. In addition, most GPC3 CAR T-cell products have reported anti-tumors activity, 
supporting the further exploration of differentiated GPC3 CAR T-cell products in the treatment 
of squamous cell lung cancer. 
 
This is a single-arm study primarily designed to evaluate the safety, tolerability and efficacy of 
C-CAR031 in patients with GPC3 + advanced/metastatic squamous cell lung cancer, who are not 

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amenable to curative therapy and have progressed or are intolerant to no more than 3 lines of prior 
systemic treatment including CPIs and platinum-based doublet chemotherapy, concurrently or 
sequentially. The study will also characterize the PK/PD and immunogenicity of C-CAR031 and 
explore potential biological activity by assessing pharmacodynamic and exploratory biomarkers 
and antitumor activity. The statistical design for this study is provided in Section 9. 
4.2.1 
Rationale for Lymphodepletion Chemotherapy 
LDC will be administered to all participants in this study prior to C-CAR031 infusion to induce 
lymphopenia to improve T-cell engraftment and persistence. Clinical studies of T-cell therapy for 
melanoma at the National Cancer Institute have demonstrated that administering LDC such as 
cyclophosphamide and fludarabine, or cyclophosphamide, fludarabine, and total body irradiation, 
prior to the transfer of 1010 to 1011 polyclonal melanoma-specific T cells improved the survival 
of a subset of the transferred T cells and antitumor efficacy (Dudley et al 2002[48], Dudley et al 
2005[49], Dudley et al 2008[50]). The size of the T-cell pool is subject to homeostatic regulation 
and the induction of lymphopenia results in less competition for cytokines, such as IL-15 and IL-
7, that promote lymphocyte proliferation and survival. Therefore, LDC leads to the proliferation 
of residual T cells, including those that are adoptively transferred. Lymphodepleting 
chemotherapy may also eliminate CD4+ and CD25+ regulatory T cells and activate antigen 
presenting cells that may promote the function of transferred T cells. Studies in murine models 
subsequently confirmed the human data indicating that lymphodepletion improves the persistence 
and antitumor efficacy of transferred effector T cells (Wrzesinski et al 2007[51]). 
 
Additionally, multivariate analyses from studies of CD19 CAR T-cell therapy have shown that 
outcomes in patients with B-cell malignancies are improved with high-intensity LDC containing 
fludarabine/cytarabine and with the incorporation fludarabine into LDC (Hay et al 2019[52], 
Hirayama et al 2019[53]). Pre-conditioning with cyclophosphamide has also been shown to modify 
the tumor microenvironment and enhance solid tumor CAR T-cell efficacy (Murad et al 2021[54]). 
 
These data suggest that lymphodepletion before CAR T-cell therapy effectively prolongs the 
persistence of infused cells and increases the effectiveness of the CAR-T cells in treating cancer. 
 
4.3 
Justification for Dose 
4.3.1 
Dose for LDC 
Cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily (for 3 days) is an often used LDC 
regimen and is used in many approved cell therapy products in the treatment of lymphoma 
(Kamdar et al 2022[55]) and multiple myeloma (Cohen et al 2022[56], Lin et al 2000[57], Munshi et 
al 2021[58], Usmani et al 2022[59]). In China IIT study of C-CAR031 against HCC, 
cyclophosphamide 500 mg/m2 and fludarabine 25 mg/m2 daily (for 3 days) were used and has 
shown to be safe, tolerable, and the promising antitumor activity of C-CAR031 for patients with 
GPC3+ advanced/recurrent HCC in the IIT trial. Based on this, cyclophosphamide 500 mg/m2 and 
fludarabine 25 mg/m2 doses will be used for LDC (daily for 3 days) in this study. Alternatively, 
local standards can also be followed, after discussion and alignment with the collaborator. 

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4.3.2 
Dose for C-CAR031 
The starting dose of C-CAR031 (DL1) for this study will be a single IV infusion of a dose of 
0.75 × 106 CAR- T cells/kg. This is based on the clinical precedence from previous GPC3-
targeted CAR-T therapies with active and safe doses evaluated in patients with 
advanced/recurrent HCC. This includes data from key trials summarized in Table 4 and below. 
• 
As of March 14, 2024, in the China IIT study of C-CAR031for advanced HCC 
(NCT05155189), a total of 24 subjects had been infused in four dose cohorts of 0.75, 1.5, 2.5 
and 4.0 (unit: ×106 CAR-T cells/kg) as mono therapy in 1, 6, 9, and 8 participant, respectively, 
70.8% participants had lung metastatic lesions. No DLT events were observed in all dose 
cohorts (0.75, 1.5, 2.5 and 4.0); The MTD had not been reached. The median follow-up time 
was 9.03 months. As shown in Table 7, the 0.75, 1.5, 2.5 and 4.0 doses (unit: ×106 CAR-T 
cells/kg) were safe and well tolerated, and the efficacy of the 1.5, 2.5 and 4.0 doses was better 
than that of the 0.75 dose. The ORR at 4.0 doses (75%) was higher than that in 1.5 and 2.5 
doses (50%), the DCR was similar across dose cohorts. The median PFS and DoR at 4.0 
doses was not mature by the data cutoff date, participants at 1.5 and 2.5 doses had the 
comparable median PFS (4.27m vs. 4.17m). The median DoR of 1.5 doses appeared to be 
longer than that of 2.5 doses numerically (7.36m vs. 4.44m, not compared statistically). 1 
participant at 0.75 doses achieved a stable disease as the best of response, considered as a 
clinical benefit in this heavily treated patient population. Though there were 70.8% of 
participants had lung metastatic lesions, the pulmonary complications were not a safety 
concern in the HCC IIT. 
• 
Other trials evaluating GPC3 CAR-T cells were considered but, unlike C-CAR031, those do 
not use the same armouring, have unknown vectors and manufacturing and therefore, were 
given less weight in these considerations. Dose ranges administered in these trials: Ori-C101; 
ChiCTR1900028121 (0.9 to 3.0 × 108) and NCT02395250, NCT03146234 (7.0 × 108 to 92.5 
× 108) were above the C-CAR031 starting dose and generally tolerated and demonstrated 
some signs of clinical activity. See Table 4 for further details. 
• 
The incidence of ≥Grade 3 pulmonary toxicity ranges 5-13.3% in CAR-T therapy for 
hematologic malignancy, the severe pulmonary complications are considered associated with 
CRS (Lee et al 2015[60] and Wudhikarn et al 2020[61]). Putting these available data of C-
CAR031 and other similar products together, 0.75×106 CAR- T cells/kg is chosen as the 
starting dose in this IIT for squamous cell lung cancer. 
 
Dose modifications are described in Section 6.6. 
 
The decision to proceed to the next dose level of C-CAR031 (either an increase or a decrease) 
will be made by the SRC based on safety, tolerability, and preliminary CK data obtained in at 
least 3 participants at the prior dose level (1 participant in dose level 1). See Section 6.6.1 for 
additional details. 
4.4 
End of the Main Study Definition 
The end of the main study is defined as 12 months after the last participant has received his/her 

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dose of C-CAR031 (or sooner if: all the participants have progressed or stated a new anti-cancer 
therapy or death occurred, or have either withdrawn or are lost to follow-up, or investigator and 
AbelZeta aligned to terminate the study). Once end of the main study is achieved (or before if 
appropriate follow-up has been completed), all ongoing participants will continue follow up in 
LTFU (Stage 3) (see also Section 4.1 and Figure 3) for monitoring based on their willingness. 
The total duration of follow-up for participants in both the main study and LTFU will be up to 15 
years (± 6 months) post-infusion of C-CAR031. A separate ICF will be provided for the LTFU 
period. 
 
A participant is considered to have completed the main study if he/she has received C-CAR031, 
completed Stage 2 follow-up and/or commenced Stage 3 (and continued to the point of the end 
of the main study as described above in Section 4.4). 
 
4.4.1 
Study Stopping Criteria 
The principal investigator and collaborator reserve the right to temporarily suspend or 
permanently terminate this study or components of the study at any time. The reasons for 
temporarily suspending or permanently terminating the study may include, but are not limited 
to the following: 
 
• 
Any death related to study treatment occurring within 60 days of receiving investigational 
product. 
• 
Occurrence of 2 or more participants with Grade 4 DLTs at a particular dose level that are 
not pre-existing or not due to the underlying malignancy, other concomitant medications, or 
another non drug related etiology. 
• 
Unexpected and life-threatening events deemed related to study therapy. 
• 
Principal investigator or collaborator decision that the study participants are placed at undue safety 
risk. See Section 6.6.1 and 6.6.2 for more details on pausing/stopping criteria for Phase Ia and Phase 
Ib, respectively. 
• 
Participant enrolment is unsatisfactory. 
• 
Noncompliance that might significantly jeopardize the validity or integrity of the study. 
• 
Principal investigator or collaborator decision to terminate development of the study intervention. 
 
If the  principal investigator or collaborator determines that temporary suspension or permanent 
termination of the study or components of the study is required, the principal investigator and 
collaborator will discuss and get alignment on the decision. The principal investigator and 
collaborator will discuss the reasons for taking such action with all participating investigators. 
When feasible, the principal investigator and collaborator will provide advance notice to all 
participating investigators of the impending action. 
 
If the trial is on hold and LDC has been initiated for any participant, a risk/benefit assessment will 
be conducted on a case-by-case basis between the investigator and collaborator to determine the 

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next steps and discussions with the study participant will be documented. Participants who have 
already been treated with C-CAR031 will continue in the study. 
 
5 
STUDY POPULATION 
Prospective approval of protocol deviations for recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
 
Investigators should keep a record (ie, patient screening log) of participants who entered 
prescreening and screening. 
Each participant must meet all the inclusion criteria and none of the exclusion criteria for this 
study prior to undergoing apheresis. 
 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria are met at 
screening and up to the time of apheresis. The latest result obtained prior to apheresis will be used 
to determine eligibility. A participant will be considered 'on study' when they have passed the 
clinical eligibility criteria at screening and undergone apheresis. 
 
5.1.1 
Inclusion Criteria to be Met for Pre-screening 
Tumor Tissue Sample 
To enable timely analysis and treatment, patients will sign a pre-screening consent for potential 
participant eligibility prior to enrollment. During this phase, subjects consent to pre-screening only 
and will be assessed for expression of GPC3 on the tumor via a validated IHC assay performed at 
the central laboratory. See Section 8.9.1.2 and Appendix C for further details. 
 
Criteria to be Met for Pre-screening: 
1 
Participant could reasonably be anticipated to be eligible in the study in the future based on 
medical / disease history. 
2 
Consent and provision of: 
(a) Squamous cell lung cancer tumor material to assess GPC3 expression and other 
correlative biomarkers of an archival tumor sample, collection time requirements are 
detailed in the laboratory manual. If a suitable archival sample is not available, a fresh 
tumor core biopsy may be collected (see Section 8.9.1.2). 
 
 
5.1.2 
Inclusion Criteria to be Met for Screening 
Participants will be eligible for the study only if all of the following criteria apply during screening 
and up until the time of apheresis: 
1. The participant voluntarily participates in the study, and the individual or their legal guardian 
signs the ICF. 

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2. 18 - 75 years of age at the time of signing ICF. 
3. Histologically or cytologically confirmed unresectable Stage IIIB ,IIIC or IV (Staging per 
American Joint Committee on Cancer [AJCC], Edition 8) squamous cell lung cancer 
(Histology according to 2021 WHO classification of thoracic tumor; adenosquamous 
carcinoma treated as squamous carcinoma is eligible), Lymphoepithelioma-like carcinoma 
(LELC) is excluded.  
4. Confirmed to express GPC3, as assessed by immunohistochemistry at a central lab This can be 
tested on archived tissue if available, although preferred tumor specimen is a biopsy after the 
most recent therapy. 
5. Participants who have progressed or intolerant to no more than three lines of prior systemic 
therapies for advanced/metastatic squamous cell lung cancer.  
a 
Must have been treated systemically with the immune checkpoint inhibitor and standard 
platinum-based doublet chemotherapy, concurrently or sequentially.  
b 
Previously received no more than two lines of systemic therapy containing cytotoxic 
regimen for advanced/metastatic squamous cell lung cancer . 
c 
If a systemic regimen of adjuvant/neoadjuvant therapy or part of multimodal (eg, 
chemoradiotherapy) treatment for locally advanced disease is also recommended as a 
standard care of systemic therapy for advanced/metastatic squamous cell lung cancer by 
guidelines of Chinese Society of Clinical Oncology (2024) and disease progression occurs 
within 6 months of the end of therapy, the systemic regimen is considered a line of therapy 
for advanced/metastatic squamous cell lung cancer. 
6. At least one measurable target lesion (as defined by RECIST v1.1). 
7. ECOG performance status score of 0 or 1.  
8.  inimal life expectancy ≥1  weeks, per the investigator’s discretion.  
9. The left ventricular e ection fraction (LVEF) measured by echocardiography ≥50% and 
reported as non-impaired. Measure must be within 28 days prior to apheresis. 
10. Sufficient pulmonary function： 
a. 
Oxygen saturation ≥ 92% without supplemental oxygen requirement.  
b. Forced expiratory volume in one second (FEV1) ≥ 1.0 liter or ≥ 50% of predicted normal 
value.  
c. 
 Diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 40% of predicted normal 
value. 
11. The laboratory testing results meet the following study requirements.  
Hematology 
a 
*Absolute  eutrophil Count (A C) ≥1.5×109/L. 
 
b 
Absolute Lymphocyte count ≥ 0.5×109/L. 
 

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c 
*Platelet count ≥ 100×109/L. 
 
d 
Hemoglobin ≥ 90g/L.  
*Hematological criteria cannot be met with ongoing or recent blood transfusions (within 28 
days prior to screening; within 14 days prior to apheresis) or required growth factor support 
(within 28 days prior to screening; within 21 days prior to apheresis). 
Blood biochemistry 
e 
Serum total bilirubin ≤ 1. × L  (upper limit of normal) in the absence of Gilbert’s 
syndrome, or ≤ 3.0× L  if the patient has Gilbert’s syndrome or liver metastases. 
f 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5×ULN, or ≤ .0×ULN 
if the patient has liver metastases. 
g 
*Calculated creatinine clearance ≥30 ml/min.  
*As determined by Cockcroft-Gault equation using actual body weight. (Cockcroft and 
Gault 1976[62]) or 24-hour urine creatinine clearance 
Coagulation 
h 
Prothrombin time International normalized ratio (PT-I R) ≤1.5×ULN. 
12. Female participants of childbearing potential must test negative for pregnancy in serum or urine; 
non-sterilized participants (males and females) agree to take effective contraceptive measures 
for at least 12 months and until CAR-T below lower limit of detection (LLOD) by PCR which 
occurs last after C-CAR031 infusion. (See details in section 5.3 and appendix F). 
 
5.2 
Exclusion Criteria 
Any potential participant who meets any of the following criteria up until apheresis will be excluded 
from participating in the study: 
1. 
known to harbor a driver mutation for which targeted standard therapy is recommended in 
accordance with local treatment guidelines. 
2. 
Known life-threatening allergies, hypersensitivity, or intolerance to the CAR-T product or its 
excipients, including dimethyl sulfoxide (DMSO). 
3. 
Known allergies  Contraindication to lymphodepleting agents, including fludarabine and/or 
cyclophosphamide. 
4. 
History of splenectomy or organ transplantation. 
5. 
Prior treatment with: 
a)  Any CAR-T therapy. 
  
OR 
b)  Any therapy that is targeting GPC3. 
6. 
Uncontrolled or intercurrent pulmonary disease, including but not limited to: 

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a) Chronic obstructive pulmonary disease with obvious symptoms,  
b) Moderate or above persistent asthma, 
c) Prior pneumonectomy, 
d) Previous history of ILD requiring corticosteroid therapy or history of non-infectious 
pneumonia or current/suspected ILD or pulmonary infectious pneumonia,  
e) History of deep vein thrombosis, pulmonary embolism, or any other significant 
thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis 
are not considered “significant”) during the 3 months prior to apheresis. 
7. 
Clinically meaningful ascites, defined as any ascites requiring non-pharmacologic intervention 
(eg, paracentesis) to maintain symptomatic control, within 6 months prior to apheresis. 
Participants on stable doses of diuretics for ascites for ≥   months prior to apheresis are eligible. 
8. 
Uncontrolled pleural effusion or pericardial effusion requiring recurrent drainage procedures 
(once monthly or more frequently). 
9. 
Cancer-related spinal cord compression, leptomeningeal disease, or 
a) brain metastases, unless asymptomatic, treated, and stable radiologically (defined as 2 
brain images, [both after treatment], should both be obtained at least 4 weeks apart and 
show no evidence of intracranial progression) and resolved or stable clinically; not 
requiring continuous corticosteroids at a dose of > 10 mg/day prednisone or equivalent for 
at least 4 weeks prior to apheresis. 
10. Received radiation therapy within 4 weeks of apheresis; or within 6 months or 3 half-lives 
(whichever is longer) if local radioactive particle implantation was performed. 
Note: Palliative radiotherapy to localized sites outside the lung (eg, for palliation of pain from a 
bone metastasis) is allowed with investigator’s approval if completed - ≥7 days prior to apheresis 
and no residual adverse effects >grade 1 attributed to the radiation. 
11. Received local treatment (such as: surgery, ablation) within 4 weeks of apheresis, or existence 
of unhealed wound. Or has surgery planned during the study, or within a minimum of 4 
weeks after study treatment administration. (Note: participants with planned surgical 
procedures to be conducted under local anesthesia may participate). 
12. Received inactivated or live attenuated vaccine within 4 weeks prior to apheresis. 
13. Blood transfusions within 14 days and/or growth factor support within 21 days prior to 
apheresis. 
14. Received systemic treatment and did not meet the minimum requirement for washout before 
apheresis: 
a 
Immune checkpoint inhibitor: within 5 half-lives or 3 weeks (whichever is shorter). 
b 
Chemotherapy, small molecule targeted therapy: within 5 half-lives or 2 weeks (whichever 
is longer). 
c 
Experimental anticancer drugs or other anti-cancer systemic treatment including Chinese 
herbal medicine, Chinese patent drug: within 5 half-lives or 2 weeks (whichever is longer). 
d 
Systemic dosing of steroid(s) (excluding: intranasal, inhaled, topical steroids or local 

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steroid injections [eg, intra-articular injection]; systemic corticosteroids at physiologic 
doses not exceed 10mg/day of prednisone or its equivalent; steroids as premedication for 
hypersensitivity reaction [eg, computed tomography [CT] scan premedication]) or other 
immunomodulators (eg. Interleukins, interferons, thymosins, etc.): within 5 half-lives or 2 
weeks (whichever is shorter). 
15. History of another primary malignancy except for: 
(a) Malignancy treated with curative intent and with no known active disease within 3 years 
before the apheresis and of low potential risk for recurrence. 
(b) Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of 
disease. 
(c) Adequately treated carcinoma in situ without evidence of disease. 
16. History of or with active autoimmune diseases (including but not limited to systemic lupus 
erythematosus, inflammatory bowel disease, rheumatoid arthritis, myasthenia gravis, Graves' 
disease, pituitary inflammation, multiple sclerosis, neuromyelitis optica spectrum disorders, 
Guillain-Barré syndrome, and chronic inflammatory demyelinating polyradiculoneuropathy, 
etc.; The following are exceptions: patients with vitiligo or alopecia, patients with 
hypothyroidism who have stabilized after hormone replacement therapy, any chronic skin 
disease that does not require systemic treatment, and other diseases that deemed not clinically 
significant per the investigator’s discretion). 
17. Patients with central nerve system (CNS) diseases: 
a. 
Stroke, intracranial haemorrhage, or seizure within 6 months prior to apheresis. 
b. Active uncontrolled epilepsy within 5 years prior to apheresis. 
c. 
Other diseases with obvious neurological symptoms (including mental illnesses). 
18. Active infection, including: 
a 
HBV infection defined as HBsAg [hepatitis B surface antigen] positive, or HBcAb 
[hepatitis B core antibody] positive and HBV DNA detectable. 
b 
HCV infection defined as HCV antibody positive and HCV RNA positive. 
c 
CMV infection defined as CMV DNA detectable. 
d 
Syphilis infection defined as syphilis antigen and antibody positive. 
e 
HIV infection defined as HIV 1/2 antibody positive. 
f 
Other persistent or active infections requiring systemic treatment (prophylactic use of anti-
infective drugs is allowed). 
19. History of cardiac arrhythmia (such as multifocal premature ventricular contractions, bigeminy, 
trigeminy, ventricular tachycardia), which is symptomatic or requires treatment ; unless 
controlled by pacemaker or medical management (discussion with the medical monitor 
required); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic 
sustained ventricular tachycardia; Fridericia formula-corrected QT interval (QTcF) ≥ 470 msec 

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et al. 
20. Uncontrolled or intercurrent cardiac diseases, including but not limited to: 
a) Unstable angina,  
b) Severe arrhythmia,  
c) Severe non-ischemic cardiomyopathy history  
d) Myocardial infarction  
e)  Cardiac vascular surgery treatment occurred within 6 months.  
21. Heart failure: heart function of Class III or IV per the New York Heart Association (NYHA) 
heart function classification standards. 
22. Patients using full-dose long acting oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic (as opposed to prophylactic) purpose. Use of short acting direct oral anticoagulants 
for therapeutic and prophylactic purposes are permitted. 
23. Obvious risk or tendency of bleeding or active bleeding (eg, clinically significant hemoptysis, 
tumor bleeding, etc.).  
24. Being in pregnancy or lactation period, or having plan to conceive during the study period. 
25. History or current evidence of any condition, therapy, or laboratory abnormality that, per the 
investigator’s discretion, might confound the results of the study, interfere with the participant’s 
safety and/or study compliance. 
26. Any unresolved toxicity  CI CTCAE ≥ Grade   from previous anticancer therapy with the 
exception of alopecia, vitiligo, and endocrine disorders stable on treatment. Participants with 
irreversible toxicity not reasonably expected to be exacerbated by treatment with study 
intervention including Grade 2 neuropathy maybe included after consultation with the 
collaborator. 
27. Patients with alcohol or drug abuse. 
28. Clear clinical evidence of dementia or changes in mental state. 
 
5.3 Lifestyle Considerations 
1 
Cell therapy may have a major influence on the ability of the participant to drive or operate 
machinery or engage in hazardous occupations or activities. The participant should be 
advised to refrain from these activities for 8 weeks post C-CAR031 infusion. 
2 
After C-CAR031 infusion, participants should not donate blood, organ tissue or cells 
(including ova and sperm donations) from Day 0 to until 12 months after C-CAR031 infusion 
or until the C-CAR031 CAR T-cell DNA is no longer detectable by PCR test, whichever 
occurs last. 
3 
Contraceptive use by males and females should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
(a) Male participants: 

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(i) Use of a condom from enrolment until 12 months after the infusion of C-CAR031 and until 
CAR T-cell DNA is no longer detectable by PCR, whichever occurs last. This applies to all 
sexual partners. 
(ii) Female partners of male participants, and of childbearing potential: use of one highly 
effective method of contraception (refer to Appendix F for definition) from enrolment of the 
male participant until 12 months after C-CAR031 infusion and until CAR T-cell DNA is no 
longer detectable by PCR, whichever occurs last. 
(b) For male participants that receive LDC but do not receive C-CAR031: 
(i) Use of a condom from enrolment, until 6 months after the last dose of LDC. 
(ii) For female partners of male participants (that receive LDC but do not receive C-CAR031), 
and of childbearing potential: use of one highly effective method of contraception from 
enrolment of the male participant until 6 months after the last dose of LDC. 
(c) Female participants: 
(i) Females of childbearing potential (refer to Appendix F for definition) must have a negative 
urine or serum pregnancy test at screening, prior to LDC (within 72 hours of the first dose of 
LDC) and a negative urine or serum pregnancy test prior to C-CAR031 infusion (Day 1). 
(ii) Female participants of childbearing potential who are sexually active with a nonsterilised 
male partner must agree to use one highly effective method of birth control (defined as one that 
can achieve a failure rate of less than 1% per year when used consistently and correctly; as 
described in Appendix F), from enrolment, where the contraceptive method must be effective 
prior to the first dose of LDC, until at least 12 months after the infusion of C-CAR031 and until 
CAR T-cell DNA is no longer detectable by PCR, whichever occurs last. It is strongly 
recommended for the male partner of a female participant to also use a male condom (plus 
spermicide, if available) from enrolment of the female participant until 12 months after C-
CAR031 infusion, and until CAR T-cell DNA is no longer detectable by PCR, whichever occurs 
last. Female participants who receive LDC but do not receive C-CAR031, who are sexually 
active with a non-sterilised male partner must agree to use one highly effective method of birth 
control (defined as one that can achieve a failure rate of less than 1% per year when used 
consistently and correctly) for 6 months after the last dose of LDC.  
 
5.4 
Screen Failures 
A pre-screen failure occurs where a patient is not eligible for the study screening. A screen failure 
occurs when a participant who has consented to participate in the clinical study, does not meet 
eligibility criteria at any point prior to apheresis and is not subsequently apheresed. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
 
Individuals who do not meet the criteria for participation in this study (pre-screening or 
screening failure) may be rescreened. Rescreening can be permitted in the study (after 

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agreement with the collaborator). Rescreened participants should be assigned the new 
participant number. 
 
Participants who meet eligibility and who are enrolled in the study but from whom it is not possible 
to collect adequate apheresis material or not possible to have a product successfully manufactured 
will be considered discontinuations and not screen failures. All screening data will be collected on 
these participants. 
 
Please note: pre-screen patients who do not sign the main ICF will have AEs and SAEs related 
to study procedures collected. 
 
5.5 
Criteria for Temporarily Delaying Enrolment/Administration of 
Study Intervention 
Not applicable. 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study interventions are all pre-specified, investigational medical products (IMPs) and non-
investigational medical products (NIMPs), medical devices and other interventions (eg, surgical 
and behavioral) intended to be administered to the study participants during the study conduct. 
 
6.1 
Study Intervention(s) Administered 
Table 10 
Study Intervention 
 
CAR-T cells 
Lymphodepletion 
Intervention 
name 
C-CAR031 
Cyclophosphamide 
Fludarabine 
Type 
Genetic. Autologous CAR 
T-cell therapy 
Drug: 
Lymphodepleting 
chemotherapy 
Drug: 
Lymphodepleting 
chemotherapy 
Dose formulation 
Cell suspension for 
infusion 
Solution for infusion 
Solution for infusion 
Unit dose 
strength(s) 
Number of CAR-positive 
viable T cells 
As per label 
As per label 
Dosage level(s) 
Phase Ia (safety run-
in and backfill): 
Starting dose 0.75×106 
CAR T cells/kg 
Phase Ib (dose 
expansion): cohort 
treated at RDE 
determined in Phase Ia 
500 mg/m2 
or per local standards 
25 mg/m2 
or per local standards 
Route of 
administration 
IV infusion 
IV infusion 
IV infusion 

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CAR-T cells 
Lymphodepletion 
Regimen 
Single dose 
Daily for 3 days 
Daily for 3 days 
Use 
Experimental 
Background 
intervention 
Background 
intervention 
IMP or 
NIMP/AxMP 
IMP 
NIMP 
NIMP 
Sourcing 
Collaborator product and 
intellectual property, 
provided centrally by 
collaborator 
Locally by the study 
site, subsidiary, or 
designee, or 
collaborator, if agreed. 
Locally by the study 
site, subsidiary, or 
designee, or 
collaborator, if 
agreed. 
Operation input 
C-CAR031 will be 
provided in a 
CryoMACS Freezing 
Bag in an aluminum 
cassette. It will be 
labelled according to 
the local labelling 
guidelines and 
requirements. 
Each IMP should be 
accompanied by: 
1        COA 
2        IMP Packaging 
and Shipping Form 
 
It will be labelled as 
required per country 
requirement 
Sourced from study 
site, no axillary 
labelling required 
If sourced from study 
site, no axillary 
labelling required.  
Current/former 
name(s) or 
alias(es) 
C-CAR031 
Cyclophosphamide 
Fludarabine 
Duration of 
infusion 
As per IMP Handling 
Manual guidance 
Per site’s internal SOPs 
Per site’s internal 
SOPs 
Order of infusion 
N/A 
Per site’s internal SOPs 
Per site’s internal 
SOPs 
AxMP = auxiliary medicinal product; CAR-T = chimeric antigen receptor T-cell; COA = Certificate of 
analysis; IMP = investigational medicinal product; NIMP = non-investigational medicinal product; IV = 
intravenous; N/A = not applicable; RDE = Recommended dose for expansion; SOP = standard operating 
procedure. 
 
6.1.1 
Apheresis 
Prior to apheresis, review of safety assessments should be completed per the SoA (Table 2). The 

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screening evaluation results of participants must meet the inclusion criteria and not meet the 
exclusion criteria. Vital signs, chemistry and hematology should be evaluated again within 3 days 
prior to apheresis. All the inclusion criteria of main screening (see Section 5.1.2) are met and none 
of the exclusion criteria of main screening (see Section 5.2) is met, and no other situations judged 
by investigator as unsuitable for apheresis, the participant can proceed to apheresis. 
Apheresis should be performed according to institutional standards and following the instructions 
for processing and shipping apheresis product provided in the collaborator Apheresis Handling 
Manual. 
 
If apheresis is performed > 14 days after main screening assessments, chemistry laboratory 
assessments should be repeated. 
 
For participants who require a repeat apheresis, sites should first discuss this with the 
collaborator and the following screening assessments should be collected before the second 
apheresis: 
 
• 
Weight 
• 
CBC with differential 
• 
Chemistry laboratory assessments 
• 
ECG (if clinically indicated) 
 
If the second apheresis falls outside of the 28-day screening window, all screening assessments 
(except tumor biopsy) must be repeated according to their applicable windows for completion. 
 
6.1.2 
Bridging Therapy 
If appropriate, the participants are permitted to receive bridging therapy if it is necessary to 
provide disease control (this is not considered a line of therapy), during the period between 
apheresis and baseline assessment, while the participant is waiting to receive C-CAR031. The 
investigator must contact the collaborator for confirmation prior to administering bridging 
therapy. Bridging therapy will be administered according to Prescribing Information or treatment 
guidance in general use by the investigating site. 
 
A treatment will be considered eligible as a bridging therapy if it meets the following criteria: 
 
1 
Favorable risk-benefit assessment for short duration of treatment, including no 
contraindications. 
2 
Bridging therapy with oral TKI locally approved for this indication e.g., afatinib (Half-life 
period is 8 days) may be utilized. Other agents are to be discussed with collaborator on a 
case-by-case basis. Long half-life drugs e.g., CPIs, antibodies, chemotherapy, TKIs with 
long half-life which couldn’t be eliminated within a short period (around 7 days) may not 
be used.  Must ensure an adequate washout period between the administration of the 
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prior to baseline assessment. 
 
6.1.3 
Lymphodepletion 
Prior to infusion of C-CAR031, all participants will undergo lymphodepletion per rationale in 
Section 4.2.1. 
 
6.1.3.1 
Lymphodepletion Criteria 
The investigator should contact the collaborator if evidence of rapid disease progression is 
observed between apheresis and lymphodepletion. Participants must meet the following criteria 
to proceed with lymphodepletion. 
1. 
No presence of active infection per investigator’s discretion. For participants requiring 
systemic anti-microbial treatment or with temperature ≥ 3 .0 °C within 7 days prior to 
the first dose of lymphodepletion, the investigator must receive confirmation to proceed 
from the collaborator. 
2. 
ECOG score 0~1. 
3. 
Within 3 days before lymphodepletion, the laboratory test must meet the following 
requirements: 
 
a Hemoglobin (Hb) ≥90 g/L; A C ≥1.5×109/L; Platelet (PLT) ≥100×109/L; White 
blood cell (WBC) > 1.0 × 109/L. 
b Total bilirubin (TBL) ≤ 1.5×UL  (≤3× for Gilbert’s syndrome or liver metastases), 
ALT and AST ≤2.5×ULN, or ≤5.0×ULN if the patient has liver metastases. 
c Calculated creatinine clearance ≥30 mL/min. 
4. 
Oxygen saturation ≥ 92% without supplemental oxygen use required.   
5. 
The participant needs to complete the relevant examinations according to the visit 
schedule before the administration of lymphodepletion, and the examination results can 
proceed with lymphodepletion after being evaluated by the investigator. 
6. 
C-CAR031 cells have been successfully prepared and meet the quality control 
standards. 
7. 
Negative pregnancy test (serum or urine) for females of child-bearing potential within 
72 hours prior to the first dose of lymphodepletion regimen. 
8. 
A repeat echocardiogram scan may be required for participants who received bridging 
therapy that included agents with known cardiac toxicity and verification of non- 
impaired cardiac function (LVEF ≥ 50%) performed. Note: If given, to be performed 
after completion of bridging therapy and prior to the first dose of the lymphodepletion 
regimen. 
9. 
 o cumulative dose of corticosteroids equivalent to ≥ 70 mg prednisone within the 7 
days prior to lymphodepletion. The collaborator should be contacted for confirmation 
if a participant receives corticosteroids at a dose > 10 mg per day in the week prior to 
the start of lymphodepletion. 

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10. No major surgery < 2 weeks prior to lymphodepletion. 
11. No active Grade 3 toxicity to any bridging therapy. 
12. No live attenuated vaccines within 30 days prior to lymphodepletion. 
13. No new arrhythmia or other cardiac AEs unless controlled with medical management 
and approved by the collaborator. 
14. There are no other situations judged by investigator(s) as unsuitable for 
lymphodepletion. 
6.1.3.2 
Administration of Lymphodepletion Regimen 
The preferred regimen of cyclophosphamide 500 mg/m2 and fludarabine 25 mg/m2 daily for three 
days will lead to lymphodepletion and help promote C-CAR031 CAR T-cell expansion in the 
participant. Participants will receive three daily doses of cyclophosphamide and fludarabine- 
based lymphodepletion on Days -5, -4, and -3 prior to CAR T-cell infusion (Section 4.3.1). 
Cyclophosphamide 500 mg/m2 and fludarabine 25 mg/m2 before C-CAR031 is consistent with 
the lymphodepletion regimen used in previous IIT study of C-CAR031. Alternatively, the 
dosage can also be adjusted per local standards after discussing and confirmation from 
collaborator. 
 
After meeting eligibility criteria for undergoing lymphodepletion, all participants should receive 
the following conditioning regimen: 
 
• 
Cyclophosphamide 500 mg/m2/day IV on Days -5, -4 and -3 
• 
Fludarabine 25 mg/m2/day IV on Days -5, -4 and -3 
 
Pre-medications for lymphodepletion should be given after confirmation with the collaborator per 
institutional standard. 
 
If renal deficiency or hepatic impairment is observed, consider dose reduction of fludarabine 
and/or cyclophosphamide per the local institutional standard. In cases where the participants’ 
hematological parameters do not meet the pre-specified laboratory criteria for undergoing 
lymphodepletion and/or the participant has a known intolerance to fludarabine or 
cyclophosphamide, the administration of alternative lymphodepletion regimens may be 
considered upon discussion with the collaborator. 
 
Refer to Section 6.1.4.1 for the evaluation of participant health status prior to administration of C-
CAR031. For those participants who do not meet the criteria for undergoing C-CAR031 infusion 
after 7 days of the last LDC dose, the investigator should contact the collaborator. 
 
Following discussion with the collaborator, these participants can be dosed after 7 days of LDC 
completion. However, these participants may need to be replaced. 
Of note, for participants with lymphocyte recovery, or 21 days post last dose of LDC, whatever 
is longer, administration of a repeat LDC course should be discussed with the collaborator (with 

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consideration to participant fitness, WBC count ≥ 1 × 109/L, and prior fludarabine exposure). 
6.1.4 
C-CAR031 
6.1.4.1 
Eligibility Check Prior to Administration of C-CAR031 
Participants will be evaluated for safety within 48 hours prior to C-CAR031 infusion (within 2 
days after the last dose of LDC). If a significant health status change (ie, clinical deterioration, 
rapidly progressing disease) occurs following the start of lymphodepletion, the investigator 
should contact the collaborator prior to C-CAR031 infusion. 
 
Infusion of C-CAR031 must be delayed if any of the following events occur: 
 
• 
Signs of active infection. Do not administer C-CAR031 to participants with active infection. 
For participants requiring systemic anti-microbial treatment, or with temperature ≥ 38.0 °C 
within 48 hours before C-CAR031 infusion, CAR T-cell infusion should be delayed until the 
infection has been successfully treated or controlled. 
• 
Non-hematologic toxicities of lymphodepletion (except for Grade 3 nausea, vomiting, 
diarrhea, or constipation) not recovered to < Grade 3; Grade 4 neutropenia and Grade 4 
thrombocytopenia not recovered to ≤ Grade 3. The investigator must consult with the 
collaborator prior to C-CAR031 dosing. 
• 
Oxygen saturation < 92% without supplemental oxygen .  
• 
ECOG score > 1. 
• 
The investigator assesses that the participants are unable or unwilling to comply with the 
study protocol. 
 
6.1.4.1.1 
Participant Wallet Card  
Before the infusion of C-CAR031 (ie, Day 0), participants will receive a participant wallet card 
that they must carry for a minimum of 56 days after the C-CAR031 infusion. The Participant 
Wallet Card is provided to increase participant awareness of the risks of CAR T-cell therapy, 
promote quick recognition and disclosure of any potential signs or symptoms during the study, 
and to inform participants about actions that must be taken if they are experiencing these 
symptoms or signs. At each on-site visit throughout the study, the investigators will ensure that 
the participant has the Participant Wallet Card with them. 
 
6.1.4.1.2 
Pre-infusion Supportive Therapy 
Prior to C-CAR031 infusion, participants should receive premedication as noted in Table 11 
to minimize the likelihood of an allergic reaction. Corticosteroids should not be used during 
pre- infusion. 
Table 11 
Pre-infusion Medications 
 
Medication 
Dose 
Administration 

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Antihistamine 
Diphenhydramine (50 mg) 
or equivalent 
Oral – administer 1 hour (±15 minutes) prior to C-
CAR031 OR 
IV or IM – start infusion/injection 30 minutes (±15 
minutes) prior to C-CAR031 infusion. 
Antipyretic 
Acetaminophen (650 mg to 
1000 mg) or equivalent 
Oral or IV – administer 30 minutes (±15 minutes) prior to 
C-CAR031 infusion. 
IM = intramuscular; IV = intravenous 
 
6.1.4.2 
C-CAR031 Administration 
C-CAR031 will be administered within 7 days after the last LDC dose. Participants will be 
evaluated for safety within 48 hours prior to C-CAR031 infusion (as described in Section 6.1.4.1). 
For participants who do not meet the criteria for undergoing C-CAR031 infusion after 7 days of 
the last LDC dose, the investigator should contact the collaborator. Following discussion with the 
collaborator, these participants may receive C-CAR031 7-21 days after LDC completion.  
 
C-CAR031 will be supplied by the collaborator for infusion and participants will receive 1 dose 
of C-CAR031. For details on dose preparation and administration please refer to the C-CAR031 
IMP Handling Manual. 
 
All planned assessments required for C-CAR031 administration (see SoA Table 2), including 
laboratory tests, must be completed and the results reviewed prior to the start of the C-CAR031 
infusion. Treatment decisions will be based on safety and disease assessments performed at the 
local laboratory. 
 
Following C-CAR031 administration, participants will remain hospitalized for a minimum of 7 
days and should be within an approximate 2-hour travel time from the study site for approximately 
28 days following C-CAR031 infusion.  
 
In the event of an allergic reaction, the infusion must be immediately stopped, and antihistamine 
treatment initiated, as per institutional guidelines (see risk management plan [RMP]). Acute mild 
respiratory distress developing during or immediately after (within 48 hours) C-CAR031 infusion 
can be managed with supportive care (see RMP). 
 
At the first signs of either CRS or neurotoxicity, participants should be hospitalized for 
monitoring and evaluation (see RMP). 
 
6.1.5 
Exceptional Release Criteria 
In the event a CAR T-cell therapy product that did not meet pre-specified release criteria is 
produced during the manufacturing procedures, the collaborator will evaluate the risk/benefit 
for administration of the affected product, and determine if the supply of the product could be 
considered. If administration of the Exceptional Release IMP is considered appropriate by the 
collaborator, the investigator will evaluate the risk/benefit and confirm administration of the 
affected product is for the participant’s interest. If the participant agrees, and it is filed or 

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approved by the Institutional Review Board or Independent Ethics Committee (IRB/IEC), the 
investigator should submit a formal request to collaborator including appropriate 
documentation required by health authorities (if required) prior to C-CAR031 infusion. 
 
If required, collaborator will seek approval from the relevant health authorities for use of the 
product. If an Out-of-Specification product is administered to the patient, this information will 
be captured in the CRF. 
 
6.2 
Preparation, Handling, Storage, and Accountability 
• 
The investigator or designee (eg, pharmacist) must confirm appropriate conditions (eg, 
temperature) have been maintained during transit for all study intervention received at the 
site and throughout the entire study until authorization is provided for on-site destruction or 
removal of the IMP, reflecting completion of the study. In the event of a temperature 
excursion detected at any time during the study, sites will follow the reporting procedures 
for notifying collaborator (or designated party); release of IMP for clinical use can only 
occur once the event has been reviewed and approval is provided by collaborator (or 
designated party). 
• 
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply, prepare, or administer study intervention. All study intervention must 
be stored in a secure, environmentally-controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator and 
authorized site staff. 
• 
The investigator, institution, the head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, reconciliation, and 
record maintenance (ie, receipt, reconciliation, and final disposition records). 
• 
Further guidance and information for the final disposition of unused study interventions are 
provided in the C-CAR031 IMP Handling Manual. 
• 
Refer to the C-CAR031 IMP Handling Manual for information on the procedure for product 
thawing and dose preparation. 
 
6.3 
Assignment to Study Intervention 
This is an open-label study. Once participants have signed the main screen ICF at a site they will 
be assigned medication according to the agreed participant number. 
 
6.4 
Blinding 
Not applicable. 
6.5 
Study Intervention Compliance 
Apheresis, infusion of LDC, and infusion of C-CAR031 will be conducted in the controlled 
environment of a qualified clinical site, under the direct observation of qualified study-site 
personnel. The details of apheresis, and administration of LDC and C-CAR031 will be recorded 

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in the source documents and recorded in the electronic Case Report Form (eCRF) (including date, 
dose, start, and stop times of the infusion, and volume infused). The dose of study intervention 
and study participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study intervention. 
 
Precautions associated with the use of the study treatment and concomitant medications will be 
reviewed by the collaborator. 
 
Refer to the Apheresis Handling Manual and the C-CAR031 IMP Handling Manual for a 
description of the chain of identity and chain of custody procedures associated with the apheresis 
product and C-CAR031. 
 
6.6 
Dose Modification 
6.6.1 
Starting Dose, Safety run-in and backfill Scheme and Stopping Criteria 
Starting Dose 
The starting dose of C-CAR031 for this study will be a single IV infusion of a dose of 0.75 × 106 
CAR T cells/kg (see Section 4.3). 
 
Table 12 shows the Phase Ia scheme. 
 
Table 12 
C-CAR031 Phase Ia Scheme 
 
Dose level cohort 
a 
Planned dose (106 CAR- T cells/kg) 
DL -1 
0.5 
 DL 1 
0.75 
DL 2 
1.5 
DL 3 
4.0 
a 
Additional intermediate/higher dose levels can be explored based on the available clinical data and not exceed 
the 3 times the current dose or the highest dose that has been determined safe by SRC. (no more than 6.0 ×106 
CAR-T cells/kg). CAR = chimeric antigen receptor; DL = Dose level. 
 
The DLT observation period is from infusion to 28 days post-infusion of C-CAR031 (Day 0 to 
Day 28). DLT observation is for the first 1-6 evaluable participants of each dose level cohort. 
After DLT observation period is complete for a minimum of 3 evaluable participants (1 
participant in dose level 1), relevant data will be reviewed by the SRC, and the SRC can approve 
to explore the next dose level and/or decide to start the backfill of current dose level; Or 
recommend to recruit 3 more evaluable participants in current dose level as safety run-in. The 
SRC can suggest exploration of intermediate or higher dose levels based on the available data. If 
1 out of the first 3 participants or 2 out of the first 6 participants (the first participant of dose level 
1) in a dose cohort experience the DLT, the SRC cannot recommend a dose escalation to doses 
exceed this current dose cohort. 
 
• 
An DLT evaluable participant in the safety run-in phase should have received C-CAR031 per 

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protocol, with no substantial protocol violations and completed the DLT period (or have 
experienced a DLT before the end of DLT period). Non evaluable (NE) participants will be 
replaced. 
• 
A minimum of 3 DLT evaluable participants are required in the dose level 2 and 3 unless 
unacceptable toxicity is encountered in the first 2 participants prior to enrolment of the third 
participant. For the dose level 1, 1 evaluable participant is required.  
 
The first 1-6 participants of each dose level will be evaluated as safety run-in phase. Backfill 
will stop when up to 12 evaluable participants have been filled in each dose level. The SRC can 
decide to proceed to the backfill phase; the early termination of the backfill phase of each dose 
level after evaluation of available data; and /or further explore additional intermediate/higher 
dose levels. And if a new dose is to be explored, repeat the above steps of safety run-in phase of 
Phase Ia. The SRC will evaluate the safety, efficacy, tolerability, available CK and other 
available data of C-CAR031 at the new dose level to determine whether to continue to backfill 
phase. 
 
To limit the number of participants who could be exposed to an unanticipated risk associated 
with C-CAR031 administration, a minimum of 14-days observation period between cell 
infusions for the first and second participant in each dose is required, if DLT occurred, all the 
other participants in this dose level will have minimum of 14-days observation period between 
each. 
 
Staggered administration of C-CAR031 will not be required for: 
 
• 
Dose levels assessed as tolerable by the SRC with a minimum of N = 3 evaluable 
participants (1 participant in dose level 1) 
• 
Backfill and dose expansion phase 
 
The RDE could be selected in consultation with the SRC based on an assessment of aggregate 
safety data and all relevant clinical and nonclinical data available at that time. The RDE for 
continued clinical development of C-CAR031 will be assessed as tolerable. 
The dose for subsequent cohorts or a decision to stop recruitment to dose expansion (Phase Ib) of 
the study will be agreed upon by the SRC after review of the data from each cohort (See Section 
6.6.5). 
  
SRC can suggest starting the enrollment of dose-expansion cohort during Phase Ia, when: 
1) The RDE has been determined safe in the Phase Ia. 
2) The benefit/risk ratio supports the early dose expansion after the aggregate safety data and all 
relevant clinical and nonclinical data available at that time being evaluated by SRC. 
Early dose-expansion and safety run -in to next dose level will be conducted in parallel in the 
circumstances. SRC will predefine the priority rules for participants allocation.  

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6.6.2 
Dose Expansion 
A dose-expansion phase, (Phase Ib) will begin at the RDE to confirm the safety, tolerability, 
CK/PD, efficacy of study intervention.  Phase Ib dose expansion will investigate C-CAR031 
in approximately 12 evaluable participants at each RDE. 
 
Intermediate dose levels may be explored if warranted by emerging safety, CK/PD, and efficacy 
data. During dose expansion, participants will be monitored for safety using the same DLT 
criteria employed during safety run-in. If during the treatment period, ≥ 30% of participants 
experience safety events that would meet the criteria for a DLT in the safety run-in Phase of the 
study, the SRC will review the study data to determine whether additional monitoring, alternate 
dose levels, or treatment schedules should be evaluated prior to further enrolment. 
 
Enrolment into the dose expansion cohort may be discontinued at the discretion of the 
investigator or collaborator or SRC based on emerging clinical or preclinical data suggest that 
continued treatment may not be beneficial to participants in a given cohort (see Section 4.4.1 
for study stopping criteria, and Section 6.6.5 for details on the SRC). 
 
Participants may be replaced if, for example, they are lost to follow-up, did not receive C-
CAR031 per protocol, violated the protocol, did not have acceptable tumor measurements, or 
were non-compliant. 
 
6.6.3 
Definition of DLT 
DLTs are defined as AEs that occur in the first 28 days after C-CAR031 infusion and meet the 
following criteria listed below. 
For DLT criteria, ASTCT consensus Grading will be used for CRS and ICANS (Lee et al 2019[63]) 
and CTCAE v5.0 for all other events. 
 
DLTs should be followed until improvement to full recovery (baseline, CTCAE Grade ≤ 1, or no 
further improvement expected). 
The DLT definition includes any of the following conditions: 
 
Hematologic Toxicities (not pre-existing, not related to underlying malignancy other 
concomitant medications, or another nondrug related etiology): 
• 
Grade 3 or greater  neutropenia lasting > 28 days with clinically significant complications. 
Note: If the Grade 3 event is not treated according to local guidance, the SRC will review the 
event and may determine the event as not a DLT despite being >28 days duration. 
• 
Grade 4 febrile neutropenia lasting > 72 hours with clinically significant complications. 
• 
Grade 3 febrile neutropenia > 14 days with clinically significant complications. 
Note: If the Grade 3 event is not treated according to local guidance, the SRC will review the 
event and may determine the event as not a DLT despite being >14 days duration. 

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• 
Grade 4 anemia lasting > 72 hours with clinically significant complications. 
• 
Grade 3 or greater thrombocytopenia lasting > 28 days without clinically significant bleeding or 
requiring platelet transfusion.  
Note: if the Grade 3 event is not treated according to local guidance, the SRC will review the event 
and may determine the event is not a DLT despite being > 28 days duration. 
• 
Grade 3 or greater thrombocytopenia with clinically significant bleeding. 
 
Non-hematologic Toxicities (not pre-existing, not related to underlying malignancy other 
concomitant medications, or another nondrug related etiology): 
• 
Any Grade 5 toxicity. 
• 
Any treatment-emergent Grade 4 CRS. 
• 
Any treatment-emergent Grade 3 CRS that does not resolve to ≤ Grade 2 within 7 days. 
• 
Any treatment-emergent Grade 4 ICANS. 
• 
Any treatment-emergent Grade 3 ICANS that does not resolve to ≤ Grade 2 within 72 hours. 
• 
Any treatment-emergent autoimmune toxicity ≥ Grade 3.  
• 
Grade 4 liver transaminase increase*. 
• 
In participants without liver metastases, Grade 3 AST or ALT increase, do not resolve to ≤ Grade 
2 within 10 days*. 
• 
In participants with liver metastases, Grade 3 AST or ALT increase, do not resolve to ≤ Grade 2 
within 10 days, if the baseline level was ≤1.5 × ULN*. 
• 
In participants with liver metastases, AST or ALT increases > 3x but ≤ 10x baseline, do not 
downgrade to ≤ 3x baseline within 10 days, if the baseline level was > 1.5 × ULN; Or AST or 
ALT increases > 10x baseline*. 
*Note: Before defining a DLT, the SRC should review cases where AST meets the DLT criteria, 
but ALT remains < 3x ULN or < 2x baseline to determine whether AST release from other 
organ system injury is confounding the assessment of liver safety. 
• 
Any confirmed Hy’s Law case (see Appendix D). 
• 
Grade 3 allergic reaction that does not downgrade to ≤ Grade 2 within 72 hours despite maximal 
supportive care (including systemic corticosteroids). 
• 
Grade 4 allergic reaction related to C-CAR031 infusion. 
• 
Any other Grade 3 treatment related AE that cannot resolve to ≤ Grade   within 7 days despite 
optimal supportive care (if event not otherwise specified as a DLT or a DLT exception). 
• 
Any other Grade 4 treatment related AE that cannot resolve to ≤ Grade 2 within 3 days despite 
optimal supportive care (if event not otherwise specified as a DLT or a DLT exception), should 
be assessed by SRC to determine whether it is a DLT. 
• 
Any other toxicity that is clinically significant and/or unacceptable and regarded to be a DLT by 
the SRC. 
 
The DLT definition excludes any of the following conditions: 

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• 
Grade 3 or 4 lymphocytopenia of any duration. 
• 
Grade 3 tumor lysis syndrome for < 14 days not associated with clinically significant 
complications. 
• 
Grade 3 electrolyte disorders requiring intravenous fluids not associated with clinically 
significant complications. 
• 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed 
with or without systemic corticosteroid therapy and/or hormone replacement therapy with 
resolution of the symptoms within 14 days after treatment onset. 
• 
Concurrent vitiligo or alopecia of any AE grade. 
• 
Fatigue of any AE grade. 
• 
Grade 3 or 4 hypoalbuminemia not associated with clinically significant complications. 
• 
Isolated Grade 3 laboratory abnormalities that are not associated with clinical signs or 
symptoms (eg, hyperlipasemia or hyperamylasaemia not associated with clinical signs or 
symptoms or radiographic features suggestive of pancreatitis). 
 
6.6.4 
Definition of DLT-Evaluable Participant 
An DLT-evaluable participant is defined as a participant who has received C-CAR031, and 
either: 
 
• 
has completed minimum safety evaluation requirements and has received at least 1 
completed infusion of C-CAR031 per protocol during the first 28 days. 
AND 
• 
has completed the DLT observation period without major protocol deviations 
OR 
• 
has experienced a DLT during the first 28 days post C-CAR031 infusion 
 
6.6.5 
Safety Review Committee 
The members of SRC include the investigators, an independent clinician, an AbelZeta’s medical 
delegate, and other relevant personnel may be added according to the specific needs of the study, 
including but not limited to the medical monitor, pharmacovigilance physician, clinical 
pharmacologist, statistician. All representatives from AbelZeta or other collaborators will be non-
voting members. 
A study specific SRC, in accordance with its charter, will provide ongoing safety surveillance of 
the study, with regularly scheduled reviews of safety, efficacy, CK, and other relevant data. The 
SRC may also meet to review data at other time points (ie, in response to AEs assessed as 
medically relevant by the investigator). The SRC may also advise on modifications in study 
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subsequent participants or stopping further enrolment if treatment-emergent toxicity is believed 
to result in an unfavorable risk-benefit profile. This committee will be responsible for making 
decisions regarding dose strategy and regarding further conduct of the study during all follow-up 
stages and parts of the study. 
 
The SRC will review the totality of all AEs, SAEs, and laboratory safety data for participants in 
the DLT period and all other available relevant data prior to adjudicating on dose decisions based 
on the protocol. 
 
After each dose level during the safety run-in (Phase Ia) section of the study, once there are at least 
3 evaluable participants (1 participant in dose level 1), the SRC will evaluate the safety, efficacy, 
tolerability, available CK and other available data of C-CAR031 to decide the dose for the next 
cohort of participants: 
 
• 
All available toxicity information (ie, AEs) and laboratory abnormalities in addition to the 
DLTs 
• 
All available CK and other available data 
• 
The dose recommendation  
• 
Any dose interruptions and reductions will be taken into account. 
 
The minimum data listed above will be extracted and confirmed for accuracy by the 
investigator ahead of the SRC. 
 
The decision may be to: 
 
• 
Proceed with dose escalation 
• 
Start the backfill phase/continue the safety run-in of current dose level but not to exceed the 
total number of evaluable patients at a single dose 
• 
De-escalate the dose either to a previous lower-dose level or to an intermediate lower-dose 
level 
• 
Stop the dose-escalation part of the study (see Section 4.4.1 and 6.6.1) for more details on 
pausing/stopping rules) 
• 
Initiate dose-expansion cohort(s). 
• 
Explore a new dose level. 
 
The SRC membership, purpose and frequency of SRC meetings, as well as the data and decision-
making process to be used by the SRC are described in the SRC Charter and Appendix A 5. All 
decisions by this committee will be clearly documented and communicated to all SRC members 
as defined in the SRC Charter. 
 
6.6.6 
Risk Management Plan 

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The C-CAR031 RMP has been developed to assist investigators with the recognition and 
management of toxicities associated with use of C-CAR031. These RMPs are applicable to the 
management of participants receiving C-CAR031 as specified in the protocol.  
The RMPs provide information for the management of CRS, ICANS, IRRs, and other reactions 
that may be observed with C-CAR031 treatment, with specific instructions for treatment 
interventions. These guidelines are provided as a recommendation to support investigators in the 
management of potential AEs. Investigators are advised however to use local practice guidelines 
and consult local references for the management of toxicities observed with C-CAR031 treatment. 
 
All AEs experienced will be graded for severity according to the NCI CTCAE v5.0 toxicity 
criteria with the exception of CRS and ICANS, which will be graded using ASTCT consensus 
grading (Appendix G). 
 
6.7 
Continued Access to Study Intervention After the End of the Study 
 
No intervention is planned after the end of the study.  
 
6.8 
Treatment of Overdose 
C-CAR031 CAR-T cells must be administered as a single dose by trained personnel at the 
investigational sites in this study. Infusion guidelines provided in the C-CAR031 IMP Handling 
Manual must be strictly followed, including premedication, duration of infusion, and vital sign 
monitoring. 
 
For this study, any dose of lymphodepleting agents or C-CAR031 greater than the defined dose 
will be considered an overdose. 
The collaborator does not recommend specific treatment for an overdose of C-CAR031. Overdose 
with LDC medications should be managed as per local standard and the product label. 
 
In the event of an overdose, the investigator/treating physician should: 
 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities as medically 
appropriate and at least until the next scheduled follow-up. Refer to Section 8.4.15 for 
details of AE/SAE reporting related to overdose. 
• 
Document the quantity of the excess dose as well as the duration of the overdose. 
 
In the event of an LDC overdose, the investigator/treating physician should evaluate the 
participant to determine whether the dose should be reduced. The overdose should be assessed 
and managed as per local guidance and product label. 
 
6.9 
Prior and Concomitant Therapy 
Any medication or vaccine (including over the counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest eg, 

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corticosteroids that the participant (except for screen failures) is receiving should be recorded 
after screening commences, until completion of Stage 2 follow-up and must be recorded along 
with: 
 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose, frequency and route 
 
The prohibited concomitant medications in the study are provided in Table 13. Permitted 
concomitant medications are provided in Table 14. 
 
The collaborator should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Table 13 
Prohibited Concomitant Medications 
Supportive medication/ 
class of drug 
Usage 
Corticosteroids 
Corticosteroid use should be avoided, except for the treatment of CRS or 
neurotoxicity or other adverse events where corticosteroids use is 
indicated. Dependent on timing of events relevant to CAR-T therapy and 
impact on potential efficacy, alternative therapies, if feasible, should be 
considered prior to corticosteroids. 
Other immunosuppressants 
Other immunosuppressant agents unless used as protocol-specified pre- 
or post-treatment medications to treat an adverse event (eg, CRS). 
Natural/herbal product 
That may have immune-modulating effects, have unknown toxicities or 
anticancer effects (unless agreed by the collaborator). 
GM-CSF 
Must not be used for 28 days after C-CAR031 infusion or until 
CRS resolved (whichever is later). 
Pegylated G-CSF 
Long acting pegylated G-CSF should not be used within 21 days before 
apheresis and 28 days after C-CAR031 infusion or until CRS resolved 
(whichever is later). 
G-CSF 
Consider holding until 10 days after infusion of C-CAR031 or until 
CRS has resolved (whichever is later). 
Any investigational therapy and 
anticancer therapy other than 
those under investigation in this 
study 
Any chemotherapy, hormonal (except non-cancer conditions), targeted 
treatments, anticancer immunotherapy, or experimental therapy, (except 
protocol-specific therapies) should not be given concomitantly while the 
patient is in Stage 1 and 2 of the study. Participants can receive these 
agents in Stage 3 of the study. 
 
Surgery and radiotherapy 
During stage 1, non-emergency surgery or radiotherapy is generally 
prohibited, but may be allowed in the absence of disease progression. 
Cases must be discussed and approved by the investigator. Local 
treatment of isolated lesions, excluding target lesions, for palliative 
intent is acceptable (eg, by local surgery or radiotherapy). Participants 
can receive these agents in Stage 3 of the study. 

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Live/attenuated vaccinations 
Should not be given within 30 days prior to lymphodepletion regimen, 
due to the immunosuppressed state of participants during this time frame, 
and for the 30 days following C-CAR031 infusion. 
CRS = cytokine release syndrome; G-CSF = granulocyte-colony stimulating factor; GM-CSF = granulocyte- 
macrophage colony-stimulating factor. 
Table 14 
Permitted Concomitant Medications 
 
Supportive medication/class of drug 
Usage 
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed in Table 13 
To be administered as prescribed by the investigator 
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy to 
non-target lesions, etc]) 
Should be used, when necessary, for all participants 
Hormonal therapy 
Should be used for non-cancer-related conditions only 
(eg, hormone replacement therapy) 
Growth factor support allowed with restrictions 
See Table 13 for restrictions 
Transfusions (irradiated blood products) are 
permitted to treat symptoms or signs of 
neutropenia, anemia, or thrombocytopenia 
To be administered according to local standards of care. 
Hydration 
Should be used, when necessary, for all participants 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
CYP450 substrates which have a narrow 
therapeutic window 
Given the expected pharmacology of C-CAR031, the 
release of cytokines in the immediate period post the first 
administration of C-CAR031 may potentially lead to 
secondary alteration of CYP450 enzymes, with risk of 
subsequent drug-DDIs. Based upon the known 
mechanism of action of other CAR-T therapies, this risk 
is highest during the first week, or longer in the event of 
a prolonged event of CRS, after the first administration. 
Participants at highest risk for DDIs are those receiving 
concomitant medications that are CYP450 substrates and 
have a narrow therapeutic window. As such, participants 
receiving medications fitting this description should be 
monitored closely and the dose adjusted as necessary. 
DDI = drug-drug interaction; CRS = cytokine release syndrome 
 
6.9.1 
Rescue Medicine 
CRS events that occur after C-CAR031 administration may require anti-IL-6 treatment (eg, 
tocilizumab) or corticosteroids. Emergency equipment must be available per participant prior to 

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infusion. Tumor necrosis factor-alpha antagonists are generally not recommended for 
management of CAR-T-associated CRS. In cases of CRS that is unresponsive to tocilizumab (or 
equivalent) or corticosteroids, additional interventions targeting cytokines may be considered 
based on institutional practice for management of unresponsive CRS. Refer also to RMP for 
further general supportive care guidance and for more information about management of CRS. 
 
Before C-CAR031 infusion, the on-site pharmacy should confirm that adequate doses of 
supportive medications, including anti-IL-6 treatment (eg, tocilizumab or equivalent) are 
available on site and for administration for each participant within 2 hours after C-CAR031 
infusion, if needed for CRS treatment. 
 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
Discontinuation of Study Intervention 
C-CAR031 is administered as a one-time infusion and therefore discontinuation of study 
treatment is not applicable in this study. The following sections describe different scenarios 
under which participants may discontinue from participating in specific parts of the study. It is 
important to follow participants treated with C-CAR031 for the durations defined in Section 1.3 
given the potential for delayed toxicities that may be associated with the administration of 
genetically modified cells. 
 
7.2 
Participant Discontinuation/Withdrawal From the Study 
7.2.1 
Discontinuation from the Study Between Apheresis and Prior to 
CAR T-Cell Infusion 
Participants who are enrolled into the study may not receive the C-CAR031 for the following 
reasons: 
 
• 
The investigator believes that for safety or tolerability reasons (ie, AEs, significant 
worsening of the participant’s clinical status) it is in the best interest of the participant not to 
receive C-CAR031 
• 
Participant decision 
• 
Manufactured C-CAR031 is out-of-specification and not suitable for infusion 
• 
Unexpected, significant, or unacceptable risk to the participants enrolled in the study 
• 
Investigator and AbelZeta aligned to termination of study for reasons including, but 
not limited to, unfavorable risk/benefit or change in drug development plan. 
 
Participants who do not undergo C-CAR031 infusion will be required to be followed for a 
minimum of 30 days post the last dose of lymphodepletion and/or bridging therapy if applicable 
(or until AEs have returned to a minimum of Grade 2) for AEs. These participants will be followed 
up per local standard of care (SoC), will undergo an early discontinuation/completion visit, and 

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will not enter Stage 3 follow-up. See Table 2 and Table 3 for data to be collected at the time of 
early discontinuation and follow-up and for any further evaluations that need to be completed. 
 
7.2.2 
Discontinuation from Stage 1 Follow-up 
Participants may discontinue from Stage 1 of the study for the following reasons: 
 
• 
Start of new anticancer treatment 
• 
Disease progression (clinical or radiologically confirmed) as defined in Section 8.2 
• 
Participant or investigator decision 
• 
Unexpected, significant, or unacceptable risk to the participants enrolled in the study 
• 
Non-compliance with the CSP (investigator or participant) 
• 
Investigator and AbelZeta aligned to termination of study for reasons including but not limited 
to unfavorable risk/benefit or change in drug development plan.  
 
A participant who discontinues from the study in Stage 1 will be asked to undergo an early 
discontinuation visit and will be offered to transition to Stage 3 to assess for AEs as described in 
Table 17, CK, RCL, and OS (Stage 3 follow-up described in Table 3). Participants who have 
completed a scheduled study visit within 14 days of decision to continue follow-up in Stage 3 will 
not need to complete the early discontinuation visit. 
 
Participants in Stage 3 are considered in long-term safety follow-up and will be allowed to start 
other anticancer treatments or other investigational clinical trials. 
 
7.2.3 
Discontinuation from Stage 2 Follow-up 
Participants who enter Stage 2 may discontinue from this stage of the study and continue to be 
followed in Stage 3 for the following reasons: 
 
• 
Disease progression (clinical or radiologically confirmed) as defined in Section 8.2 
• 
Participant or investigator decision 
• 
Non-compliance with the CSP (investigator or participant) 
• 
Start of a new anticancer treatment 
• 
Unexpected, significant, or unacceptable risk to the participants enrolled in the study 
• 
Investigator and AbelZeta aligned to termination of study for reasons including but not 
limited to unfavorable risk/benefit or change in drug development plan.  
 
A participant who discontinues from Stage 2 will be asked to undergo an early discontinuation 
visit and will be offered to transition to Stage 3 of the study to assess for AEs as described in 
Table 17, CK, RCL, and OS. Participants who have completed a scheduled study visit within 
30 days of the decision to continue follow-up in Stage 3 will not need to complete the early 
discontinuation visit. 

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Participants in Stage 3 are considered in long-term safety follow-up and will be allowed to start 
other anticancer treatments or other investigational clinical trials. 
 
7.2.4 
Participant Withdrawal from the Study 
Voluntary withdrawal from the study by the participant: 
• 
A participant may withdraw from the study at any time at the participant’s own request for 
any reason (or without providing any reason). 
• 
A participant who wishes to withdraw from the study must be informed by the investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records), and also the option to enter Stage 3 follow- 
up, which has limited assessments and allows the participant to start other anticancer 
treatments or other investigational clinical trials. 
• 
If the participant withdraws consent for disclosure of future information, the investigator 
may retain and continue to use any data collected before such a withdrawal of consent. 
• 
If the participant withdraws from the study, the investigator may retain and continue to use 
any samples collected before such a withdrawal of consent for the purposes the participant 
originally consented unless the participant withdraws consent for use of samples already 
collected. If the participant specifically withdraws consent for any use of samples, it must be 
documented in the site study records by the investigator. Destruction of any samples taken 
and not yet tested should be carried out in line with documented sample withdrawal wishes 
in conjunction with what was stated in the informed consent and local regulation. See also 
Appendix C 2. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
 
The following actions must be taken if a participant fails to return to the study site for a required 
study visit: 
 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible. The participant should be counselled on the importance of maintaining the assigned 
visit schedule. At this time ascertain whether the participant should or wishes to or continue 
in the study. Participants should be informed by the investigator about modified follow-up 
options (eg, telephone contact, a contact with a relative or treating physician, or information 
from medical records) and also the option to enter Stage 3 follow-up, which has limited 
assessments and allows the participant to start other anticancer treatments or other 
investigational clinical trials. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls, texts, emails, 
and if necessary, a certified letter to the participant’s last known mailing address or local 

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equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, the participant will be considered to have 
withdrawn from the study/been lost to follow-up. Site personnel, or an independent third 
party, will attempt to collect specific AEs (as per Table 17 and Section 8.4.7) and survival 
status of the participant within legal and ethical boundaries for all participants who receive 
the study intervention. Public sources may be searched for vital status information. If vital 
status is determined as deceased, this will be documented, and the participant will not be 
considered lost to follow-up. Collaborator personnel will not be involved in any attempts to 
collect vital status information. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures are provided in the following sections. 
 
• 
Study procedures and their timing are summarized in the SoA Section 1.3. Protocol waivers 
or exemptions are not allowed. 
• 
Urgent safety concerns should be discussed with the collaborator immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
(applicable for LDC only), study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants pre-screened and screened to confirm eligibility or record 
reasons for screening failure, as applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• 
Instructions for the collection and handling of Human biological sample(s) (HBS) will be 
provided in the study-specific Laboratory Manual. Samples should be stored in a secure 
storage space with adequate measures to protect confidentiality. For further details on 
handling of HBS see Appendix C. 
• 
The proposed days of all treatments and assessments are approximate and may vary due to 
scheduling, clinical or other factors. Results of tests and procedures conducted as per SoC 
purposes prior to screening may be used for research purposes if conducted within the 
protocol-defined window prior to apheresis or LDC. 
• 
If multiple assessments are scheduled for the same timepoint, it is recommended that 
procedures be performed in the following sequence: ECG, vital signs, blood draw. Blood 
collections for biomarkers and CK assessments should be kept as close to the specified time 

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as possible. Actual dates and times of assessments will be recorded in the source documents 
and the laboratory requisition form. 
• 
In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may be 
implemented by the collaborator or the investigator, as per local health authority/ethics 
requirements. 
• 
The amount of blood collected from each participant over the duration of the study may 
vary, however the maximum amount will not exceed 550 mL in an 8-week period. 
• 
Safety laboratory assessments will be performed locally at each center’s laboratory by 
means of their established methods. The number of samples/blood volumes is therefore 
subject to site-specific change. Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples. 
• 
Treatment decisions will be based on safety and disease assessments performed at the local 
laboratory. 
 
8.1 
Administrative and General/Baseline Procedures 
Demographic data will include gender, age, race, and ethnicity. A complete medical history 
should include all relevant prior and current medical history, and should also include anticancer 
therapies. 
 
Key baseline disease specific information including key clinical, histopathology, biomarkers, and 
key prognostic data will be collected including: 
 
• 
Dates of diagnosis and disease staging 
• 
Biomarker information (PD-L1/mutation testing and status/other) 
• 
Smoking status 
• 
Details of  histopathological assessments performed including grade, if appropriate at 
diagnosis and most recent biopsy 
• 
Tumor burden, ie, size, location, and number of tumors including CNS metastases at baseline  
• 
Details of prior anticancer treatments (including systemic, locoregional, and radiotherapy), 
best response to prior treatment, and date of progression 
• 
Dates and details of surgery, including lung resection 
 
8.2 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the Section 1.3 SoA. 
8.2.1 
Efficacy Endpoints 
Efficacy endpoints in the two parts of the study include ORR, durable response rate (DRR), DoR, 

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DCR, time to reponse (TTR), percentage change in tumor size, PFS, and OS. Please see Section 
9.4.3 for detailed definitions of endpoints. 
8.2.2 
Tumor Assessments 
RECIST 1.1 guidelines (Eisenhauer et al 2009[64]) for evaluating squamous cell lung cancer will 
be utilized for measurable, non-measurable, target lesions (TLs) and non-target lesions (NTLs) 
and the objective tumor response criteria are presented in Appendix E and will be performed 
according to the schedule presented in the SoA (Section 1.3). 
 
Standard radiographic imaging using RECIST is used to assess both response (in participants with 
measurable disease) and progression. An ORR as per RECIST 1.1 criteria requires confirmation 
of PR and complete response (CR) and must occur no fewer than 4 weeks after initial 
documentation of PR or CR. Disease progression will be defined as per RECIST 1.1. 
 
Throughout the research process, from the baseline period examination, the tumor imaging 
examination methods and parameters for the same participant must remain unchanged.  
 
Patients who terminate the study prematurely due to reasons other than disease progression 
(such as toxicity) will continue to undergo tumor assessments as originally planned, until the 
participant begins subsequent anti-cancer treatment, disease progression occurs (assessed 
according to RECIST 1.1), consent is withdrawn, lost to follow -up, death occurs, or until the 
study is terminated, whichever occurs first.  
 
All tumor assessments should include the following evaluations: physical examination and 
cross-sectional imaging using CT or Magnetic Resonance Imaging (MRI) scan. 
 
Physical Examination 
Lesions detected by physical examination will only be considered measurable if superficial, eg, 
skin nodules, and palpable lymph nodes and spleen. Documentation by colour photography 
including ruler is recommended for estimating the size of skin lesions. 
 
Imaging 
Use dynamic enhanced CT scan or dynamic enhanced MRI, which must include chest, abdomen, 
pelvic cavity, head and neck, and whole-body bone scans. CNS imaging is optional unless disease 
is known to be present at baseline. 
 
The preferred method of systemic disease assessment is CT with contrast; if CT with contrast is 
contraindicated, CT without contrast is preferred over MRI. The preferred method for CNS 
imaging is MRI; if CT scan is performed, CT with contrast is required. The same method should 
be followed for all subsequent tumor assessments. 
 
CT Scans 
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. Spiral CT 
should be performed using a 5-mm contiguous reconstruction algorithm. 

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MRI Scans 
MRI scan is acceptable for measurement of lesions provided that the same anatomical plane is 
used for serial assessments. If possible, the same imaging device should be used for serial 
evaluations. 
 
In addition to chest, abdomen, and pelvis cavity, head and neck, and whole-body bone scans, 
clinically indicated sites as determined by the treating investigator should be assessed at baseline. 
 
Brain Scans 
Brain scans are at the discretion of the investigator if CNS involvement is known/suspected. 
Post-baseline imaging of the brain will only be required in participants with brain metastases at 
baseline, while participants without brain metastases do not need additional brain scans for 
subsequent tumor assessments, unless clinically indicated. 
 
 
Assessment Schedule 
To confirm eligibility a radiological assessment during the screening period should be performed 
no more than 28 days before the start of apheresis. Scans obtained as part of standard clinical 
practice, prior to informed consent, but within the 28-day period are acceptable. 
 
Baseline radiological assessments can be done anytime within 7 days prior to C-CAR031 
infusion, ideally performed as close as possible to the start of study intervention on Day 0. If 
bridging therapy were conducted, the baseline radiological assessments should be done after 
the washout of bridging therapy.  
 
The methods of assessment used at baseline should be used at each subsequent follow-up 
assessment through to radiologically objective progressive disease (PD), as defined by RECIST 
1.1 and as determined by the investigator, or start a new anticancer treatment, or withdrawal of 
consent, lost to follow -up, death occurs, or until the study is terminated, whichever occurs first. 
Tumor assessments should be performed as per the SoA, until RECIST 1.1-defined radiological 
objective PD (see also Appendix E and Section 7.2). If scans are performed outside of scheduled 
visit window interval and the participant has not progressed, every attempt should be made to 
perform the subsequent scans at their scheduled visits. It is important to follow the SoA as closely 
as possible (see Section 1.3). 
 
Tumor assessments should continue on schedule until RECIST 1.1-defined radiological 
progression followed by a subsequent scan, unless clinically unfeasible, evaluated by 
Confirmation of Radiological Progression criteria. The subsequent scans should be performed 
preferably at the next scheduled imaging visit and no less than 4 weeks after the initial assessment 
of PD (in the absence of clinically significant deterioration). If repeated scans confirm progression, 
then the date of the initial scan should be declared as the date of progression. 
 
8.2.2.1 
Collection of Imaging Data for Secondary and Exploratory Analysis 

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Radiological examinations performed in the conduct of this study should be retained at site as 
source data. All treatment decisions will be based on site assessment of scans. Duplicates of all 
radiological examinations (redacted of personal identifiers to the participant) for participants must 
be available at the site in readiness to be sent for review, if requested by the collaborator. Images, 
including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
collaborator-appointed CRO for quality control, storage, and, if deemed appropriate by the 
collaborator, for IRC evaluation Digital copies of all original scans should be stored at the 
investigator site as source documents. Electronic image transfer from the sites to the CRO is 
strongly encouraged. IRC evaluation of images will be performed at the discretion of collaborator. 
Results of these independent reviews will not be communicated to investigators, and results of 
investigator tumor assessments will not be shared with the central reviewers. Further details of 
the IRC evaluation will be documented in an Independent Review Charter. Guidelines for imaging 
collection and storage will be provided in a separate document. 
 
8.2.3 
Survival Follow-up 
Participants will be followed up for survival status in this study as indicated in the SoA (Table 2 
and Table 3) until death, withdrawal of consent, lost to follow-up or the end of the study. Survival 
information may be obtained via telephone contact, email or through a clinic visit with the 
participant or the participant’s family, or by contact with the participant’s current physician. If the 
site becomes aware that a participant has died prior to the final analysis, the relevant eCRF on the 
database should be completed at that time. 
 
Additionally, other assessments, including subsequent anticancer therapy and time to second 
progression or death, are to be recorded. 
 
In order to support key efficacy endpoints of OS analyses, the survival status of all participants in 
the Full Analysis Set should be re-checked for those participants who withdrew consent or are 
classified as “lost to follow-up.” 
• 
Participants lost to follow-up – Site personnel should check hospital records and a publicly 
available death registry (if available), as well as checking with the participants’ current 
physician, to obtain a current survival status (the applicable eCRF modules will be updated) 
• 
In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. 
 
8.2.4 
Subsequent Anticancer Treatment 
The study site should maintain a record of the participant’s exposure to subsequent anticancer 
therapies (including mutagenic agents for C-CAR031-treated participants) in the CRF. For C-
CAR031-treated participants if they experience an AE (eg, new malignancy) that may either be 
possibly related to C-CAR031 treatment, a new anticancer regimen, or to exposure of a 

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mutagenic agent, then the site should enter the relevant treatment (ie, C-CAR031/mutagenic 
agent/anticancer therapy) into the appropriate CRF page. 
 
8.2.5 
Clinical Outcome Assessments 
Not applicable. 
 
8.3 
Safety Assessments 
Clinically relevant unfavorable changes occurring during the study must be recorded in the AE 
section of the eCRF. Clinically significant abnormalities persisting at the end of the 
study/withdrawal/study discontinuation will be followed by the investigator until resolution or 
until a clinically stable endpoint is reached. Safety monitoring assessments may be performed 
more frequently, if clinically indicated. 
 
Planned time points for all safety assessments are provided in the Section 1.3 SoA. 
 
8.3.1 
Physical Examinations 
A complete physical examination will be performed at timepoints as specified in Section 1.3 SoA 
and include assessments of the following; general appearance, respiratory, cardiovascular, 
abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, 
musculoskeletal (including spine and extremities), and neurological systems. Height and weight 
will be assessed at screening, apheresis, baseline and infusion eligibility, and weight only at 
follow-up. 
 
A brief physical examination will be performed at timepoints as specified in Section 1.3 SoA 
and include assessments, at a minimum, of the following: neurological, skin, lungs, 
cardiovascular system, abdomen (liver and spleen), and lymph nodes. 
 
8.3.2 
ECOG Performance Status 
Performance status will be assessed at timepoints as specified in Section 1.3 SoA according to 
ECOG criteria as follows: 
• 
0 = Fully active, able to carry out all pre-disease activities without restrictions. 
• 
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 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 self-care, totally confined to bed or chair. 
• 
5 = Dead. 
 

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Any significant change from baseline or screening must be reported as an AE. 
 
8.3.3 
Vital Signs and Oxygen Saturation 
Vital signs will be performed at timelines as specified in the Section 1.3 SoA. 
 
Vital signs will be measured after 5 minutes rest and will include temperature, systolic and 
diastolic blood pressure, pulse, respiratory rate. Blood oxygen saturation will be measured at 
thetimepoints specified in Section 1.3 SoA. Three readings of blood pressure and pulse will be 
taken and should be averaged to give the measurement to be recorded in the eCRF. 
 
Situations in which vital signs results should be reported as AEs are described in Section 8.4.4. 
 
Temperature should be checked at least twice a day by the participant after discharge until the 
end of the DLT period. Participants should be informed to contact their study doctor if any 
increase in temperature above 38 oC. 
For any AEs of infusion-related reactions, the vital signs values should be entered into the 
eCRF. 
8.3.3.1 
Vital Signs and Oxygen Saturation to be Collected During CRS 
Vital signs including body temperature and oxygen saturation should be monitored per 
institutional guidelines until values are normalized following a CRS event. 
 
8.3.4 
Cardiac and Pulmonary Safety Assessments 
8.3.4.1 
Electrocardiograms 
12-lead ECG will be performed at timepoints as specified in the Section 1.3 SoA. 
 
ECGs will be performed in triplicate (all 3 within a 5-minute time period, at least 1 minute apart) 
and the mean value of the triplicate measurement will be recorded as the baseline value. At all 
other time points, a single ECG will be obtained. All ECG recordings will be made with the subject 
in a supine position having rested in this position for at least 5 minutes before the start of the ECG. 
 
All ECGs will be recorded at a speed of 25 mm/second with amplitude recording of 100 mm/mV. At 
least 3 full complexes must be recorded. A multi-channel ECG machine should be used (equals 3 leads 
recorded simultaneously) and there must be amplitude index calibration for each lead. Digital copies 
of ECGs may be held centrally by a central ECG provider and stored for potential independent analysis 
during, or at the end of, the study at the collaborator’s discretion. 
 
Electronic software will be used to assess the following parameters: pulse rate, RR, QRS, QT, 
and QTc time intervals. All ECGs must be reviewed by the principal investigator or a medically 
qualified designee before the start of C-CAR031 infusion (for time points prior to the infusion) 
and before the participant is permitted to leave the clinic (for post-infusion time points). In case 
of a clinically significant ECG abnormality (eg, occurrence of de- or re-polarization disorders, 
arrhythmic disorders), including QTc interval prolongation by Fridericia’s formula of > 500 

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milliseconds, a minimum of 2 additional 12-lead ECGs should be obtained over a brief interval 
(eg, 30 minutes) to confirm the abnormality based on manual over-read by a medically qualified 
person. Such abnormalities and any obvious changes in ECG parameters from baseline will be 
assessed by the principal investigator for clinical significance. If clinically significant, the ECG 
abnormality should be recorded as an AE in the eCRF. Clinical interpretation and any associated 
management of participants related to ECG abnormalities will be done locally and will be based 
on interpretation by a medically qualified person at the site. 
 
8.3.4.2 
Echocardiography (ECHO) 
An ECHO to assess LVEF will be performed at the visits as shown in Section 1.3 SoA. The same 
modality should be used throughout the study for any given participant (ie, if ECHO is used for 
the screening assessment, then ECHO should also be used for subsequent assessments). 
Participants should also be examined using the same machine and operator whenever possible 
and quantitative measurements should be taken (ie, accurate to 1% and not estimated to 5%). All 
ECHO scans performed will be evaluated for the change in LVEF from baseline. 
 
If a participant has any clinically significant decrease in LVEF (greater than 10 percentage 
points to below 50%), there should be follow-up within 4 weeks until resolution. 
Situations in which ECHO results should be reported as AEs are described in Section 8.4.4. 
 
8.3.4.3 
 Pulmonary Function Test 
A pulmonary function test that measures breathing and how well the lungs are functioning will 
be done during the screening and as clinical indicated.  
 
8.3.5 
Clinical Safety and Efficacy Laboratory Tests 
• 
Blood and urine samples for determination of clinical chemistry, hematology,  coagulation, 
urinalysis, serology, and pregnancy will be taken at the visits indicated in Section 1.3 SoA. 
• 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units, and reference ranges) 
will be recorded on the appropriate eCRF. 
• 
The clinical chemistry, hematology, coagulation, urinalysis, serology, pregnancy 
assessments will be performed at a local laboratory at or near to the investigator site. Sample 
tubes and sample sizes may vary depending on laboratory method used and routine practice 
at the site. 
 
The following laboratory variables will be measured (see Table 15). 
 
Table 15 
Laboratory Safety and Efficacy Variables (Local Laboratories) 
 
Hematology (whole blood [B]) a 
Blood chemistry (serum [S] or plasma [P]) a 
B-Red blood count 
S/P-Glucose 
S/P-Alanine transaminase 

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B-White blood cell count with differential (including % 
neutrophils, B-Absolute lymphocyte, B-Absolute 
neutrophil, lymphocytes, monocytes, basophils, 
eosinophils) 
S/P-Aspartate transaminase S/P-Alkaline phosphatase 
B-Platelet count 
S/P-Gamma-glutamyl 
transpeptidase 
S/P-Bilirubin, total 
(including direct) 
B-Hemoglobin 
S/P-Total protein 
S/P-Albumin 
B-Hematocrit 
S/P-Creatinine 
Urinalysis (U) 
S/P-Uric acid 
S/P-Urea 
U-Ph 
S/P-Creatine kinase and its 
isoenzymes 
S/P–Lactate dehydrogenase 
U-Ketones 
S/P-Total cholesterol 
S/P-triglycerides 
U-Protein 
S/P-Sodium 
S/P-Potassium 
U-Glucose 
S/P-Calcium 
S/P-Chlorine 
U-Erythrocytes 
S/P-Phosphorus 
U-White blood cell 
S/P-Ferritin a 
S/P-C-reactive protein a 
U-Bilirubin 
TSH 
S-Troponin a, b 
U-Bilinogen 
NT-proBNP/BNP a, b 
Coagulation a 
Pregnancy test (females of childbearing potential 
only; local laboratories) 
International normalized ratio 
U-human chorionic 
gonadotropin 
S/P-human chorionic 
gonadotropin 
Activated partial thromboplastin time 
Prothrombin time 
Serology 
Fibrinogen 
Qualitative HBsAg, anti-HBc, anti-HBs, qualitative 
HBeAg, anti-HBs, Quantitative HBV-DNA, HCV, HCV 
RNA, anti-HCV, CMV DNA, and anti-HIV (1/2) 
serology, TPPA 
D-dimer 
Cytokine a, c (including but not limited to blood TGFβ, IL-2, IL-4, IL-6, IL-10, IL-18, TNF-α, INF-γ) 
a 
These clinical laboratory parameters to also be monitored during CRS, or suspected CRS. 
b 
To be conducted only if clinically indicated. 
c 
Cytokine will be tested in clinical sites when these clinical laboratory parameters are monitored during CRS, or 
suspected CRS. 
 
CMV = cytomegalovirus; DNA = Deoxyribonucleic acid; HBsAg = hepatitis B surface antigen; HBV = hepatitis 
B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; NT-proBNP= N-terminal pro-brain 
natriuretic peptide; TPPA = treponema pallidum particle assay. 
 
Additional laboratory safety variables that may be added include triiodothyronine (T3), thyroxine 
(T4), adrenocorticotropic hormone, cortisol, prolactin, luteinizing hormone, follicle stimulating 
hormone, mean corpuscular volume (MCV) and hemoglobin A1c (HbA1c). 
 
 B. In case a participant shows an AST or ALT ≥ 3 ×  L  together with TBL ≥  ×  L  
please refer to Appendix D, for further instructions and cases. 
 

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Table 16 
Clinical Laboratory Parameters to be Monitored During CRS 
 
Test category 
Test name 
Hematology 
Platelets 
Chemistry 
Creatinine, LDH, ALT, AST, TBL 
Coagulation 
PT and INR, aPTT, d-dimer, fibrinogen 
Inflammatory markers 
CRP, ferritin 
Cardiac 
Serum troponin, NT-proBNP/BNP 
ALT = alanine amino transferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BNP = B type natriuretic peptide; CRP = C-reactive protein; CRS = cytokine release 
syndrome; INR = international normalized ratio; LDH = lactate dehydrogenase; NT-proBNP = N-terminal 
pro B-type natriuretic peptide; PT = prothrombin time; TBL = total bilirubin. 
 
Minimal specific laboratory parameters described in Table 16 should be monitored following a 
CRS event until values are normalized. If multiple samples are taken, data from samples taken at 
key times in the CRS course should be entered into the EDC. At a minimum, the site should 
attempt to collect the laboratory parameters described in Table 16 at the beginning of CRS, at the 
peak of CRS symptoms, and after the resolution of CRS. 
 
8.3.6 
Neurological Examination 
8.3.6.1 
Brain MRI 
Brain MRI (or CT scan if MRI is not feasible) or neurology consultation should be considered 
for all participants as part of apheresis eligibility screening, if pre-existing disease is expected. 
For participants with prior pertinent neurologic disease (ie, stroke, encephalitis) consider baseline 
MRI of brain and/or an electroencephalogram (EEG) as clinically appropriate. Brain MRI may 
be performed as clinically indicated thereafter. At the first sign of neurotoxicity, neurology 
consultation and evaluation should be considered. CAR-T cell-related neurotoxicity (ie, ICANS) 
should be graded using ASTCT consensus grading (see Appendix G). Neurotoxicity that is not 
temporarily associated with CRS, or any other neurological events that do not qualify as ICANS 
will be graded by CTCAE v 5.0 criteria only. 
 
Findings from neurological testing that support CAR-T cell-related neurotoxicity (ie, ICANS) 
should be reported in the eCRF. 
 
8.3.6.2 
Immune Effector Cell Encephalopathy (ICE) Score 
The ICE score will be collected as denoted in Section 1.3 SoA (Table 2). For ICE scoring see 
Appendix G. The ICE test was developed to provide objectivity for the grading of multiple 
overlapping encephalopathy terms currently included on the approved CAR T products (Lee et 
al 2019[63]). 
 
8.3.6.3 
Electroencephalogram 
In case of suspected ICANS, EEG will be conducted as clinically indicated after C-CAR031 
infusion to the end of Stage 1 follow-up and findings reported in eCRF. 
 

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8.4 
AEs, SAEs, and Other Safety Reporting 
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
 
Participants (or, when appropriate, a caregiver, surrogate, or the participant’s legally authorized 
representative) must notify the investigator or designees of any symptoms. These must then be 
assessed by the investigator and if considered an SAE it will be reported by the investigator 
immediately (within 24 hours regularly) after awareness of SAE. 
 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
 
AE Variables 
The following variables will be collected for each AE: 
 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
AE grade/changes in AE grade (ASTCT consensus grading for CRS and ICANS; CTCAE 
for other AEs) 
• 
Whether the AE is SAE or not 
• 
Whether the AE is an AESI (yes/no) 
• 
Administration of treatment for the AE (yes/no) 
• 
Investigator causality rating against any of: apheresis, LDC, bridging therapy (if given) or, 
the IMP (yes or no) 
• 
Action taken with regard to IMP(s) 
• 
AE caused participant’s withdrawal from the study (yes/no) 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
 
• 
Date AE met criteria for SAE 
• 
Date investigator became aware of SAE 
• 
SAE description 
• 
At least one SAE seriousness criteria 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 

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• 
Date of death 
• 
Autopsy performed 
• 
Investigator causality rating against any of: apheresis, LDC, bridging therapy (if given), or 
the IMP (yes or no) 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
• 
Outcome 
• 
CTCAE grade 
 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be collected from time of signature of the study main ICF, throughout the 
treatment period and including the follow-up period. For patients who signed the pre-screening 
ICF, only AEs and SAEs related to study procedures will be collected during the pre-screening 
period. See AE/SAE collection requirements in Table 17 for details on collection window for 
AE/SAE, and see Appendix B 1 and B 2 for definitions of AE/SAE.  
 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a treated participant, the investigator 
shall, without undue delay, report the SAE to the collaborator within 24 hours. 
 
Table 17 
Adverse Event Collection Window 
 
AE collection period 
AE collection requirements 
Pre-screening period from the pre-screening ICF
signature 
Only AEs and SAEs related to study procedures will 
be collected  
From study main ICF signature until 6 months post 
C-CAR031 infusion (Stage 1 follow-up) 
Collect all AEs and SAEs. 
If the participant starts a new anticancer regimen, 
collect specific AEs (as described in Section 8.4.7) 
and any AE/SAE deemed by the investigator to be 
possibly related to C-CAR031 
From 6 months to 12 months post C-CAR031 
infusion (Stage 2 follow-up) 
 
Collect all AEs and SAEs. 
 
If the participant starts a new anticancer regimen, 
collect specific AEs (as described in Section 8.4.7) 
and any AE/SAE deemed by the Investigator to be 
possibly related to C-CAR031 

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From 12 months to a maximum of 15 years 
post C-CAR031 infusion (Stage 3 follow-up) 
Specific AEs (Section 8.4.7), and SAEs deemed by 
the investigator to be possibly related to the C-
CAR031 
 
Any ongoing AEs should be followed to resolution (or if no resolution, until stabilization). 
 
If a participant does not receive infusion of C-CAR031 after bridging therapy or LDC, all AEs will 
be collected for 30 days post last dose or until start of new anticancer regimen, until the study 
discontinuation (whichever occurs first). 
AE = adverse event; SAE = serious adverse event; ICF = informed consent form; LDC = lymphodepletion chemotherapy. 
 
8.4.2 
Follow-up of AEs and SAEs 
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically indicated, 
but without further recording in the eCRF. The collaborator retains the right to request additional 
information for any participant with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary. SAE Should be followed up until outcome of SAE was resolved, stable, death or 
participant was loss follow-up or the investigator could offer reasonable explanation. 
 
8.4.3 Causality Collection 
The investigator should assess causal relationship between the study intervention (apheresis, LDC, 
bridging therapy [if given] or C-CAR031) and each AE/SAE and answer ‘yes’ or ‘no’ to the 
question ‘Do you consider that there is a reasonable possibility that the event may have been 
caused by the study intervention?’ 
 
For SAEs causal relationship should also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
 
A guide to the interpretation of the causality question is found in Appendix B. 
 
8.4.4 AEs Based on Examinations and Tests 
Deterioration as compared to baseline in protocol-mandated laboratory values should only be 
reported as AEs if they meet any of the following: 
 
• 
fulfil any of the SAE criteria 
• 
are clinically relevant as judged by the investigator (which may include but is not limited to 
consideration as to whether intervention or non-planned visits were required). 
 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, the 
sign or symptom will be reported as an AE and the associated laboratory result/vital sign will be 
considered as additional information. Wherever possible the reporting investigator uses the 
clinical, rather than the laboratory term (eg, anemia vs low hemoglobin value). In the absence of 
clinical signs or symptoms, clinically relevant deteriorations in non-mandated parameters should 
be reported as AE(s). 
 

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Disease progression and deterioration of an event, which is unequivocally due to disease 
progression, should not be reported as an AE/SAE. 
 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE unless unequivocally related to 
the disease under study. 
 
The results from the protocol-mandated laboratory tests and vital signs will be summarized in the 
CSR. 
 
8.4.5 AEs Based on Signs and Symptoms 
All signs or symptoms spontaneously reported by the participant or reported in response to the 
open question from the study site staff  ‘Have you had any health problems since the previous 
visit/you were last asked?’, or revealed by observation will be collected and recorded in the 
eCRF. 
 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list 
of signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
 
8.4.6 Adverse Events of Special Interest 
An AESI is an AE of scientific and medical interest specific to understanding of a study 
intervention and may require close monitoring and rapid communication to the collaborator by 
the investigator. An AESI may be serious or non-serious. The reporting of AESIs allows ongoing 
surveillance of these events to characterize and understand them in association with the use of a 
study intervention. 
 
AESI will be recorded on the eCRF using a recognized medical term or diagnosis that accurately 
reflects the event. AESI will be assessed by the investigator for severity, relationship to the study 
intervention, possible etiologies, and whether the event meets criteria for an SAE. If an AESI 
evolves into a condition that meets the regulatory definition of “serious,” (see Appendix B for 
definitions) it will be reported as described in Section 8.4.10. 
 
Based on the available preclinical and clinical data, review of the cumulative literature, reported 
toxicities for the same class of agents and biological plausibility, the following events are 
considered to be AESIs for C-CAR031: 
 
• 
CRS 
• 
Neurological disorders including ICANS 
• 
Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 
• 
Any infection with RCL 

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• 
New primary malignancy 
 
8.4.7 
Specific AEs 
Specific AEs are defined as AEs that fall into the following categories as per FDA and NMPA 
guidance for long term follow-up after administration of human gene therapy products (FDA 
2020a[66], NMPA 2021[65]): 
 
• 
New malignancy(ies) 
• 
New incidence of infection (potentially product-related) 
• 
New incidence or exacerbation of a pre-existing neurologic disorder 
• 
New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder. 
 
8.4.8 Hy’s Law 
Cases where a participant shows elevations in liver biochemistry may require further evaluation, 
and occurrences of: 
• 
AST or ALT ≥ 3 ×  L  (if within normal range at baseline) together with TBL ≥   × ULN 
(if within normal range at baseline*) or 
• 
 AST or ALT ≥ 3 × baseline value or ≥ 10 ×  L  (if above normal range at baseline) 
together with TBL ≥   × ULN (if within normal range at baseline*) 
*If TBL is above normal range at baseline requires association with TBL ≥ 1.  × baseline value 
with direct bilirubin (DB) ≥  0% of the total, or any increase in DB ≥ 1 mg/dL over baseline may 
need to be reported as SAEs, unless caused by other underlying causes. 
 
Please refer to Appendix D for further instruction on cases of increases in liver biochemistry and 
evaluation of Hy’s Law. 
 
8.4.9 
Disease Progression 
Disease progression can be considered as a worsening of a participant’s condition attributable to 
the disease for which the IMP is being studied. It may be an increase in the severity of the Disease 
under study (DUS) and/or increases in the symptoms of the disease. The development of new or 
progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE. Events, which are unequivocally due to disease progression, 
should not be reported as AE/SAE during the study. 
 
8.4.10 
Reporting of SAEs 
SAEs must be reported according to SAE reporting requirements in protocol whether or not 
considered causally related to the study intervention. All SAEs will be recorded in the eCRF. 
 
If any SAE occurs during the study, the investigators or other site personnel need to conduct 

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timely emergency treatment to participants, filling in SAE/AESI form and inform the appropriate 
collaborator representatives immediately but no later than 24 hours and record in the eCRF . 
 
 
For fatal or life-threatening SAEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform the 
collaborator representatives of, and record in the eCRF, any follow-up information on a previously 
reported SAE also reported according to SAE reporting process by filling in SAE/AESI form 
immediately but no later than 24 hours of when he or she becomes aware of it. 
 
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated collaborator representative. 
If the EDC system is not available, then the investigator or other study site staff reports the SAE 
via secure method to the appropriate collaborator representative. 
 
When the EDC is temporarily not accessible, the collaborator Study Representative should 
confirm that the investigator/site staff enters the SAE in the collaborator EDC when access 
resumes. 
 
For further guidance on the definition of an SAE, see Appendix B. 
 
The reference document for definition of expectedness/listedness is the IB for the collaborator 
IMP C-CAR031. 
 
8.4.11 
Pregnancy 
Within 12 months post C-CAR031 infusion, and until CAR T-cell DNA is no longer detectable 
by PCR, whichever occurs last, all pregnancies and outcomes of pregnancy should be reported 
to the collaborator except if the pregnancy is discovered before the study participant has 
received any study intervention. 
 
8.4.11.1 Maternal Exposure 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/birth defects, stillbirth and spontaneous miscarriages should be reported and handled 
as SAEs. Elective abortions without complications should not be handled as SAEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly/birth defect, etc.) should be followed up and documented in the 
clinical trial pregnancy report form. Consent from the participant must be obtained before the 
Pregnancy Report Form is completed, even if the participant was discontinued from the study. 
 
If any pregnancy occurs from the date of C-CAR031 infusion until 12 months after the infusion 
of C-CAR031 and until CAR T-cell DNA is no longer detectable by PCR, whichever occurs last, 
then the investigator or other site personnel fill in clinical trial pregnancy report form and informs 

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the appropriate collaborator representatives immediately but no later than 24 hours after he or she 
or he becomes aware of it. 
 
The same timelines reporting apply when outcome information is available. 
 
Female participants must not donate ova from the Day 0 until 12 months after C-CAR031 infusion 
and until the C-CAR031 CAR T-cell DNA is no longer detectable by PCR test, whichever occurs 
last. 
 
When the eCRF module is used include the following: The PREGREP module in the eCRF is 
used to report the pregnancy and the paper based PREGOUT module is used to report the outcome 
of the pregnancy. 
8.4.11.2 
Paternal Exposure 
Male participants must not donate sperm from Day 0 until 12 months after C-CAR031 infusion 
and until the C-CAR031 CAR T-cell DNA is no longer detectable by PCR test, whichever occurs 
last. 
 
Pregnancy data will be collected for all female partners of male participants from the infusion of 
C-CAR031. If a male participant’s female spouse/partner becomes pregnant during the study, the 
same reporting procedure and timeline should be followed as mentioned in Section 8.4.11.1. 
 
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital anomaly, etc.), occurring from the date of C-CAR031 infusion until 12 months after 
the infusion of C-CAR031 and until CAR T-cell DNA is no longer detectable by PCR, whichever 
occurs last, should, if possible, be followed up and documented in the Pregnancy Report form. 
Consent from the pregnant partner must be obtained before the Pregnancy Report Form is 
completed. 
 
8.4.12 
New Primary Malignancies 
The development of a new cancer, including hematological malignancy, should be regarded as 
an SAE. New primary cancers are those that are not the primary reason for the administration of 
the study intervention, and have been identified after the participant’s inclusion in this study. 
They do not include metastases of the original cancer. New cancers that arise that are not the 
primary reason for the administration of the study intervention will be considered as potential 
secondary malignancies that require additional follow-up. 
 
8.4.13 
Positive RCL Results 
If any sample for RCL is positive, it must be reported to the collaborator according to SAE 
reporting process within 24 hours, and an ad hoc sample will be collected and analyzed to confirm 
the result. If the repeat test is also positive, this will be considered a confirmed positive result. 
The result of the repeat test, positive or negative, must be reported to the collaborator as a follow-

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up within 24 hours. 
 
8.4.14 
Deaths 
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of C-CAR031, must be reported as follows: 
 
• 
Death clearly resulting from disease progression should be reported to the appropriate 
collaborator representatives and should be documented in the eCRF. It should not be 
reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under study, the AE 
causing the death must be reported as an SAE within 24 hours after awareness. It should 
also be documented in the eCRF. The report should contain a comment regarding the 
co-involvement of disease progression, if appropriate, and should assign main and 
contributory causes of death. 
• 
Death with an unknown cause, or potentially related to C-CAR031, should always be 
reported as an SAE. It should also be documented in the eCRF. Autopsy may be helpful in 
the assessment of the cause of death, and if performed, a copy of the autopsy results should 
be forwarded to the collaborator or its representative within the usual time frames. 
 
Additionally, the death eCRF is provided immediately after the occurrence or outcome of death 
is reported. 
 
8.4.15 
Reporting of Overdose 
C-CAR031 T cells must be administered as a single dose by trained personnel at the 
investigational sites in this study. Infusion guidelines provided in the Product Handling Manual 
must be strictly followed, including premedication, duration of infusion, and vital sign 
monitoring. 
 
Refer to Section 6.8 for definition and treatment of overdose. 
 
• An overdose with associated AEs is recorded as the AE diagnoses/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose of an IMP or collaborator NIMP occurs in the course of the study, the investigator 
or other site personnel inform appropriate collaborator representatives immediately, but no later 
than 24 hours of when he or she becomes aware of it. 
 
If there is any untoward medical occurrence resulting from the overdose, associated AEs/SAEs 
will be recorded on the relevant modules in the eCRF (Section 8.4). 
 

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8.5 
Pharmacokinetics 
• 
Whole blood samples will be collected for measurement of whole blood concentrations, 
expansion, and persistence of  C-CAR031 as specified in the Section 1.3 SoA.  
• 
Samples may be collected at additional time points during the study if warranted and agreed 
upon between the investigator and collaborator, eg, for urgent safety reasons, and this will 
not be reflected as a protocol deviation. 
• 
The timing of sampling may be altered during the study based on newly available data (eg, 
to obtain data closer to the time of peak or trough C-CAR031 concentrations) to ensure 
appropriate monitoring. 
• 
Samples collected for analyses of C-CAR031 whole blood concentration, expansion, and 
persistence may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
• 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual. 
• 
For storage, re-use, and destruction of samples for CK see Appendix C. 
• 
The CK (DNA copy number) samples can be hold 6 months after completion of CSR. CK 
samples for flow cytometry cannot be stored after analysis and the remaining samples will 
be destroyed after completing the analysis. 
• 
Additional analyses may be conducted on the anonymized, pooled, or individual CK 
samples to further evaluate and validate the analytical method. Any results from such 
analyses may be reported separately from the CSR. 
 
8.5.1 
Collection of Samples for Cellular Kinetics and Blood Cell  
Immunophenotyping 
Blood samples will be collected for measurement of parameters listed in Table 18 at timepoints 
as listed in the SoA (Section 1.3). 
 
Table 18 
Description of Sample Collections for PK and Blood Cell Immunophenotyping 
 
Sample name 
Sample type 
Purpose of collection 
Cellular kinetics by 
PCR a 
Whole blood 
Characterization of expansion, and persistence of CAR-T product 
via detection of CAR transgene copies. 
Cellular kinetics by 
flow cytometry a 
Whole blood 
Characterization of expansion, and persistence of CAR-T product 
via detection of CAR-T percentage and absolute counts. 
Blood cell 
Immunophenotyping 
Whole blood 
Phenotyping of circulating lymphocytes; including but not 
limited to T cells, CAR T-cell subsets, B cells, and natural killer 
cells; and their relationship to clinical outcomes. 
a 
For the sampling beyond M6, if two consecutive assessments of C-CAR031 sample concentrations are < 
LLOQ, then sampling may be stopped. 
CAR-T = chimeric antigen receptor T-cell; CK = cellular kinetics; PCR = polymerase chain reaction; LLOQ = lower 

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limit of quantification. 
 
8.5.2 
Determination of C-CAR031 Blood Concentration 
Samples for determination of the CAR transgene by PCR or blood CAR-T cell numbers by flow 
cytometry for C-CAR-031 will be analyzed by an analysis lab using appropriately validated 
bioanalytical methods. Full details of the analytical method used will be described in a separate 
Bioanalytical Report. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples. The results from the evaluation, if performed, will be reported in a separate 
bioanalytical report. 
 
8.6 
Pharmacodynamics 
8.6.1 
Collection of Samples for Pharmacodynamics 
Tumor biopsies and peripheral blood will be collected to assess the pharmacodynamic activity 
of C-CAR031 (see Section 1.3). 
 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
For additional details on storage, re-use, and destruction of pharmacodynamic samples, see 
Appendix C. 
 
8.7 
RCL Detection 
The risk of infection with cell products manufactured with newer 2nd/3rd generation self-
inactivating lentiviral vectors has been shown to be very low. For the safety of study participants, 
C-CAR031 will be tested for RCL as part of product release criteria before infusion. 
 
Participants will also be tested for RCL at the baseline and following administration of C-
CAR031. A whole blood sample will be collected to detect the presence of lentiviral agent by 
PCR at timepoints stated in the SoA (Table 2 and Table 3). Collection of RCL samples may be 
discontinued for a participant if all samples tested during the first year after C-CAR031 infusion 
are negative. All positive RCL results should be reported as a medically significant SAE (see 
Section 8.4.13). 
 
Additionally, relevant clinical samples should be collected and tested for RCL if participants 
have AEs suggestive of a retroviral-associated disease, or if patients die of a suspected 
retroviral-associated disease or develop neoplasms within 15 years after C-CAR031 infusion. 
 
8.8 
Immunogenicity Assessments 
• 
Blood samples for determination of humoral immunogenicity will be assayed by an 
analysis lab, using an appropriately validated bioanalytical method. Full details of the 
methods used will be described in a separate report. 
• 
For storage, re-use, and destruction of immunogenicity samples see and Appendix C. 
• 
Remaining immunogenicity sample aliquots will be retained at the collaborator or its 

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designee for 1 year after completing CSR. Additional use includes but is not limited to 
further characterization of any immunogenicity, confirmation and/or requalification of the 
assay as well as additional assay development work. The results from future analysis will 
not be reported in the CSR. 
 
8.8.1 
Collection of Samples for Immunogenicity Assessments 
Blood samples will be collected for measurement of parameters per the timepoints listed in the 
SoA (Section 1.3). 
 
Table 19 
Blood Samples and Purpose of Collection for Immunogenicity Assessments 
 
Sample name 
Sample type 
Purpose of collection 
Humoral 
immunogenicity 
Blood (serum) 
Detection of anti-drug-antibody against and its impact on CK of 
CAR-T cells, and clinical efficacy and safety outcomes. 
CAR = Chimeric antigen receptor; CK = cellular kinetics. 
 
Further details on immunogenicity sample collection will be detailed in the Laboratory Manual. 
 
8.9 
Biomarkers 
8.9.1 
Mandatory Biomarker Sample Collection 
Blood and tumor tissues samples for biomarker analyses are required and will be collected as 
specified in the SoA (see Section 1.3). By consenting to participate in the study, the participant 
consents to the mandatory research components of the study within the scope of the protocol-
defined objectives (see Section 3 and below). Details regarding specimen collection, processing, 
and testing will be provided in the Laboratory Manual. 
 
8.9.1.1 
Collection of blood Samples 
To assess systemic biomarkers of disease, pharmacodynamic biomarkers and biomarkers of 
clinical response to C-CAR031, presence of and changes in peripheral DNA, RNA, ctDNA, 
immune cell phenotype, and protein biomarkers, which may include, but not limited to, soluble 
and cellular analytes, gene expression, and immune markers pre- and post- treatment will be 
studied. 
 
8.9.1.1.1 Collection of Blood for RNA and DNA 
A peripheral blood sample will be collected for RNA and DNA sample preparation. Baseline 
and on-treatment whole blood RNA and DNA will be collected at timepoints indicated in the 
SoA. Samples may be tested to evaluate the pharmacodynamics, potential candidate predictive 
biomarkers, early biomarkers of response, potential resistance mechanisms, and lentiviral vector 
genome integration site when applicable.| 
 
8.9.1.1.2 Collection of Serum and Plasma  

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A peripheral blood sample will be collected to provide serum and plasma for analysis of 
exploratory biomarkers, eg, ctDNA, soluble GPC3  and cytokines. Baseline and on-treatment 
serum and plasma will be collected at timepoints as specified in the SoA. For baseline ctDNA 
analysis, buffy coat (white blood cells) together with plasma will be collected. Details regarding 
specimen collection and processing will be provided in the Laboratory Manual. 
 
Cytokines, including but not limited to IL-2, IL-4, IL-6, IL-10, IL-18, TNF-α, and IF -γ, will be 
evaluated as potential pharmacodynamic markers for the activation of CAR-T cells. 
 
Blood TGFβ levels will also be examined to assess its impact on armored CAR-T cells.  
 
Soluble GPC3 baseline levels will be investigated to correlate with the baseline tumor expression 
levels of GPC3 and the clinical efficacy of C-CAR031, including ORR, PFS, and OS.  
 
ctDNA will be collected to evaluation of association of baseline ctDNA levels and kinetics of 
ctDNA changes with clinical outcome measures. We will evaluate the correlation between tumor 
and plasma mutational status.  
  
8.9.1.2 
Collection of Pre-screening Tumor Samples 
Provision of a tumor tissue at pre-screening is mandatory for all participants. Archived formalin-
fixed paraffin-embedded (FFPE) sample (see Section 5.1 for detailed sample requirement) or fresh 
core needle or excisional biopsies are acceptable, fine needle aspirated are not acceptable. 
 
Tumor Samples should have enough material to fulfil the requirements outlined in the Laboratory 
Manual. Where a participant has multiple existing tissue samples with sufficient tumor content 
available, the most recent sample is preferred. 
 
If no sample is available, tumor tissue from a new biopsy must be collected following SoC 
procedures, if the participant is willing and it is deemed safe and feasible by the investigator and 
if the biopsy is not expected to present any additional risk to the health, safety, and welfare of the 
participant. The fresh biopsy at baseline is highly encouraged to assess whether GPC3 expression 
is maintained after previous treatments. 
Expression of GPC3 will be evaluated in baseline tumor samples using a validated IHC assay in 
a central laboratory.  
In addition to participant selection, submitted mandatory tumor samples, if available, will be used 
for the development of the GPC3 companion diagnostic (CDx) or diagnostics(including digital 
diagnostics) and further support the regulatory filing if needed.  
Unstained tumor slides collected for GPC3 testing from participants will be repatriated or 
destroyed within 1 year of CSR completion. Stained tumor slides and IHC images will be stored 
for at least 5 years after clinical trial termination.  
Residual tissue samples will be used to address the exploratory biomarker objectives described in 

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Section 3. Analyses may include assessments of RNA, DNA, and protein, including image 
analysis, aimed at assessing biomarkers of disease, evaluating pharmacodynamics of the response 
and identifying potential predictive biomarkers and resistance mechanisms. The tumor samples, 
and derived results, may also be used for future diagnostic test development and/or validation. 
 
8.9.1.3 
Mandatory Biomarker Sample Storage, Re-use and Destruction 
For storage, re-use, and destruction of biomarker samples see Appendix C. 
 
8.9.2 
Optional Tumor Biopsy Sample Collection 
Collection of optional samples for biomarker research is also part of this study as specified in 
Section 1.3 SoA and is subject to agreement to optional consent. Participants will only undergo 
optional biopsy sampling when the risks are considered medically acceptable by their treating 
physicians and when the procedure will not cause undue risk to the participant. 
 
8.9.2.1 
 Tumor Biopsies 
8.9.2.1.1 On-treatment Tumor Biopsies 
On-treatment biopsies are critical to understanding whether C-CAR031 is able to infiltrate the 
tumor and mediating tumor killing. Assessment of intratumoral effects of C-CAR031 through 
on-treatment biopsies will enable further determination of whether pharmacodynamic effects in 
the periphery are indicative of pharmacodynamic effects within the tumor. On-treatment biopsies 
should be performed for participants as indicated in the SoA (Section 1.3). 
 
For consenting participants, an on-treatment biopsy should be taken  in a visit window of D29 
to week 6 inclusive and/or on disease progression, as clinically indicated. Tumor biopsy sample 
and blood draw is indicated to determine if malignancy is secondary to cell therapy (see Section 
1.3). 
 
Participants providing fresh tumor biopsies that can be biopsied at acceptable risk as judged by 
the investigator on a non-target, non-lymph node lesion that can be biopsied and is ≥   cm in 
longest diameter. Sites should confirm adequacy of tumor biopsy material at the time of the 
procedure. Associated pathology report(s) for fresh tumor samples will be required at screening 
and requested on-treatment for all participants enrolled into the study (details in the Laboratory 
Manual). Details for fresh tumor sample collection, processing, storage, and shipment are provided 
in the Laboratory Manual. 
 
Per institutional practice, image-guided fresh core needle tumor biopsies should be preferentially 
obtained from tumor tissues that are safely accessible as determined by the investigator. Fine-
needle aspirate specimens, bone specimens, or ascites are not acceptable. 
 
Tumor biopsies will be stored with a vendor selected by the collaborator. Biopsies may be used 
for correlative biomarker studies including assessments of protein, RNA and DNA. Specific 
analyses may include, but not be limited to, presence of C-CAR031 as determined by PCR or ISH, 

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assessment of protein expression on tumor cells and other cells in the microenvironment by IHC 
or proteomic methods (for example GPC3, CD8, and PD-L1), tumor mutation analysis, gene 
expression analysis, and immunodiversity. 
 
8.9.2.1.2 Disease Progression Tumor Biopsies 
Where possible, an on-study tumor biopsy sample from the progressing lesion should be taken at 
the time of documented RECIST 1.1 progression in participants that have provided the additional 
optional consent. Biopsies at progression may be particularly valuable when there is a marked 
phenotypic change in a particular lesion. 
 
The on-study provision of tumor tissue is encouraged only if clinically appropriate and not 
considered detrimental to participant care. The biopsied tumor must not be used as part of the 
RECIST 1.1 assessments. Participants will not be excluded from the study if these samples are 
not collected. 
 
Refer to the Laboratory Manual for further details of on-study tumor tissue collection, shipping, 
and storage. 
 
IHC study on changes in GPC3 expression levels, gene expression on TGFβ / Smad /3 signaling 
pathway or other protein, RNA or DNA changes in tumor tissue before and after C-CAR031 
infusion, and their relationship with efficacy may be studied. 
 
8.10 
Medical Resource Utilization and Health Economics 
Not applicable 
 
8.11 
Study Participant Feedback Questionnaire 
Not applicable. 
 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
Not applicable. 
 
9.2 
Sample Size Determination 
Approximately 47~62 GPC3+ squamous cell lung cancer participants (assuming 20% of 
dropout rate due to the failures in apheresis, lymphodepletion, and manufacturing processes, 
etc.) will be enrolled to yield 37~49 evaluable participants (up to 25 in Phase Ia, which is 
finally based on the practical escalated dose, and approximately 12 each cohort in Phase Ib, 
which will be adjusted based on the results of Phase Ia). Evaluability in the safety run-in 
section of Phase Ia will be determined based on inclusion in the DLT Evaluable Analysis Set 
(DLTAS), where participants who are not DLT evaluable may be replaced. 
 
Evaluability in Phase Ib and backfill section of Phase Ia will be determined based on inclusion in 

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the Efficacy Analysis Set (EAS). Any participants deemed unevaluable may be replaced. 
Phase Ia 
 
The primary objective of study Phase Ia is to investigate the safety and tolerability and thereby 
identify the RDE of C-CAR031 for further evaluation. Hence the number of participants has been 
based on the desire to obtain adequate tolerability, safety, CK/PD, efficacy and biological data 
while exposing as few participants as possible to the investigational product and study procedures. 
 
For the Phase Ia, up to 25 evaluable participants may be enrolled. Three dose levels are planned 
initially, with 1 participant in dose level 1 and 3 to 6 participants in dose level 2 and 3. Backfill 
will stop when up to 12 evaluable participants have been filled in each dose level to better 
characterize the safety, efficacy, and biological activity of C-CAR031 in these cohorts and explore 
the relationship between the efficacy and GPC3 expression levels. Assume 20% of patients will 
be non-evaluable or drop out. Approximately 32 patients will be enrolled. 
 
The total number of participants will depend on the number of non-evaluable participants, the 
number of toxicities and efficacy observed in each cohort and hence the number of dose levels 
necessary. Similarly, if additional dose levels are explored, the sample size may increase 
accordingly. 
 
Phase Ib 
 
A sample size of approximately 15 GPC3+ squamous cell lung cancer participants (assuming 
20% of dropout rate) is planned for the phase Ib. If the SRC recommended more than one dose 
level as RDEs, approximately 12 evaluable participants will be enrolled in each RDE to further 
evaluate the safety, tolerability and efficacy of C-CAR031 in squamous cell lung cancer 
participants with GPC3 expression. 
 
9.3 
Populations for Analyses 
The analyses will be performed for Phase Ia and Phase Ib separately. Some analyses may pool 
data from both Phase Ia and Phase Ib (eg, participants who were treated at the same dose may be 
pooled for analyses). Analysis details will be provided in the statistical analysis plan (SAP) (refer 
to SAP). 
 
For purposes of analysis, the study populations are defined as provided in Table 20. 
Tabel 20    Study Populations 
Population/analysis set 
Description 
Endpoint/output 
Safety analysis set (SS) 
All participants who receive C-CAR031 at 
any dose level 
Baseline and demography 
(supportive) Exposure 
Safety 
PFS, OS 
ORR, DoR, DRR, DCR, TTR 
(supportive) 

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DLT evaluable analysis 
set (DLTAS) 
Participants who received the target dose of 
C-CAR031 infusion without major protocol 
deviations and completed the 28-day DLT 
evaluation or experienced a DLT event. 
DLTAS is only used for safety run in 
section of phase Ia 
DLT 
Full analysis set (FAS) / 
apheresed set 
All participants who undergo apheresis 
Baseline and 
demography Feasibility 
Safety (supportive) 
OS (supportive) 
ORR, DRR, DCR 
(supportive) 
Efficacy analysis set 
(EAS) 
All participants who receive C-CAR031 
infusion per protocol with measurable 
disease at baseline 
ORR, DoR, DCR, DRR, TRR, 
change in tumor size,  
PFS, OS (supportive) 
Pharmcokinetic and 
pharmacodynamic 
analysis set (PKPDS) 
All participants who received C-CAR031 
infusion per protocol, and have at least 
completed 28 day post-cell infusion 
pharmacokinetic data collections 
CK/PD endpoints 
Immunogenicity 
All participants who receive C-CAR031 
with baseline and at least 1 reportable 
post-baseline immunogenicity 
measurement. 
Immunogenicity endpoints 
Biomarker analysis set 
(BAS) 
All participants who have received C-
CAR031 with baseline biomarker 
measurement. 
Biomarker endpoints 
BAS = biomarker analysis set; DCR = disease control rate; DLT = dose-limiting toxicity; DLTAS = DLT 
evaluable analysis set; DoR = duration of response; DRR = durable response rate; FAS = full analysis set; ICF 
= informed consent form; LDC = lymphodepletion chemotherapy; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PKPDS= Pharmacokinetics and pharmacodynamic analysis set; EAS 
= Efficacy analysis set; TTR = time to response. 
 
9.4 
Statistical Analyses 
 
The SAP will be finalized prior to the first SRC meeting and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary, secondary 
and some exploratory endpoints. 
 
9.4.1 
General Considerations 
Data will be presented by dose level. No direct statistical comparisons will be made between any 
2 dose levels. 
 
Descriptive statistics will be used for all variables. Continuous variables will be summarized by 
the number of observations, mean, standard deviation, median, minimum, and maximum. 

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Categorical variables will be summarized by frequency counts and percentages for each category. 
Unless otherwise stated, percentages will be calculated based on the population total, by dose 
level and by timepoint as appropriate. 
 
SAS® version 9.4 (as a minimum) will be used for analyses presented in the SAP. 
 
Baseline will be considered the last non-missing value prior to C-CAR031 infusion. Any 
information taken after the first dose of study intervention will be regarded as post-baseline 
information. Detailed rules for deriving baseline values will be described in the SAP. 
 
Unless otherwise stated, 2 sided confidence intervals (CIs) will be produced at 95%. 
 
Procedures for accounting for missing data, including missing dates, will be described in the SAP. 
9.4.2 
Safety Analyses 
The primary objective of the study is safety and tolerability. Safety and tolerability will be 
assessed in terms of AEs, SAEs, AESIs, DLTs (the safety run-in section of Phase Ia only), 
laboratory data, vital signs, physical examinations and ECG changes and RCL in peripheral blood. 
The assessment of safety endpoints will be conducted in safety analysis set (SS) and FAS, and 
the evaluation of DLT in Phase Ia safety endpoints will also be conducted in DLTAS. The data 
will be summarized and/or listed according to the endpoint (see Section 8.4). 
 
9.4.2.1 
Analysis of AEs/SAEs/AESIs 
AEs are coded using the Medical Dictionary for Regulatory Activities (MedDRA). Assessment 
of severity of CRS and ICANS are per the ASTCT standard (2019 version). Assessment of 
severity of AEs other than CRS and ICANS are per NCI CTCAE (V5.0). AE including DLT, 
TEAE, Post-LDC AEs SAE, ≥grade 3 AE, serious drug adverse reactions (ADR), AESI, AE 
leading to permanent discontinuation of cell infusion during the cell infusion period, AE leading 
to temporary discontinuation of cell infusion during the cell infusion period, AE leading to 
withdrawal from the study, and AE leading to death are summarized and calculated for each dose 
group, each stage, and the overall incidence according to the System Organ Class (SOC) / 
Preferred Term (PT). 
 
TEAEs are defined as:  
• 
All AEs with onset or worsen in severity on or after the C-CAR031 infusion through 6 months 
after the C-CAR031 infusion or the start of subsequent anticancer therapy, whichever is earlier 
• 
All specific AEs and AEs deemed by the investigator to be possibly related to C-CAR031 
infusion that occurred on or after the start of subsequent cancer therapy or after 6 months of C-
CAR031 infusion, whichever is earlier.  
  
Post-LDC AEs are defined as: 
• 
All AEs with onset or worsen in severity on or after the first dose of LDC but prior to C-CAR031 

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infusion.  
• 
All AEs with onset or worsen in severity on or after the first dose of LDC up to 30 days after the 
last dose of LDC or until the study discontinuation whichever occurs first for patients not 
receiving C-CAR031 infusion. 
AESI 
includes 
CRS, 
neurological 
disorders 
including 
ICANS, 
hemophagocytic 
lymphohistiocytosis/macrophage activation syndrome, any infection with RCL and new primary 
malignancy. 
 
Describe the number of CRS measures, number of cases, and the incidence rate. Summarize the 
number and percentage of CRS cases and CRS cases with severity ≥ grade 3 by severity. Analyze 
the symptoms of CRS, calculate the number of cases, and the incidence rate. Perform descriptive 
statistics on the time to CRS onset and the duration of CRS. Analyze the treatment of CRS, 
including the use of tocilizumab, corticosteroids, and TNF-α inhibitors, and calculate the number 
of cases and incidence rate. 
 
9.4.2.2 
Analysis of Other Safety Data 
Other AEs are statistically described and calculated for each AE's incidence rate by dose group, 
by stage, and overall. Other safety results will be summarized by the planned assessment time 
points, changes relative to baseline, and different categories of results, and assessed for clinical 
significance according to CTCAE grading (CRS and ICANS according to ASTCT, 2019 version). 
Abnormal and clinically significant results will be summarized and described for each assessment 
time point relative to baseline and the worst change. Data with only extreme evaluation results 
will be provided separately in the extreme analysis section. 
 
RCL status of patients will be summarized. 
 
9.4.3 
Efficacy Analyses 
 
 
The efficacy evaluation will be performed utilizing RECIST 1.1 (Eisenhauer et al 2009[64]) and 
assessed by the investigator. 
 
The assessment of efficacy endpoints will be conducted in EAS, FAS and SS. A summary of 
the antitumor efficacy of C-CAR031 assessed according to RECIST v1.1 criteria will be 
provided, including ORR, DRR, DCR, TTR, DoR, and PFS. OS and OS rates and PFS rates at 
different time points after cell infusion will also be assessed. 
 
The Clopper-Pearson method will be used to estimate the ORR and DCR and their 95% CI for 
each dose group. Time-to-event efficacy endpoints, such as DoR, PFS, and OS, will be plotted 
and described using the Kaplan-Meier method, providing the number and percentage of 
censored cases, median time and its 95% confidence interval, and survival rates at each 
assessment time point, as well as plotting the corresponding survival curves for each indicator. 

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The percentage of best change in tumor size compared to baseline will also be presented in a 
waterfall plot. 
 
For further details on analyses, refer to the SAP. 
9.4.3.1 
Primary Endpoint(s) 
Not applicable. 
 
9.4.3.2 
Secondary Endpoint(s) 
Objective Response Rate (ORR) 
The ORR is defined as the percentage of participants with a confirmed CR or PR per RECIST 1.1, 
with the denominator defined as the number of participants in the EAS. Objective response rate 
and its 95% CI will be summarized by dose level. Data obtained from infusion date until disease 
progression or the last evaluable assessment in the absence of progression, or initiation of 
subsequent anticancer treatment, will be included in the assessment of ORR. 
 
Durable Response Rate (DRR) 
DRR is defined as the percentage of participants who have a confirmed response (CR/PR) as 
determined by RECIST 1.1 with a duration of at least a specific number of months, the 
denominator is the number of participants in the EAS. Durable response will be summarized. The 
duration for DRR is from the date of first durable response to the date of first documented disease 
progression or the last evaluable assessment in the absence of progression or initiation of 
subsequent anticancer treatment prior to RECIST 1.1 progression. DRR and its 95% CIs will be 
summarized by dose level. 
Duration of Response (DoR) 
The DoR is defined as the time from the date of first documented objective response (which is 
subsequently confirmed) until date of first documented disease progression or the last evaluable 
assessment in the absence of progression or initiation of subsequent anticancer treatment prior to 
progression. 
 
The analysis will include all participants in the EAS who have a confirmed response. 
 
The measure of interest is the median and landmark estimates. DoR will be summarized using 
descriptive statistics and Kaplan-Meier plots, where there are sufficient numbers of responders. 
It may also be further summarized by best response (ie, CR and PR). 
 
Disease Control Rate (DCR) 
DCR is defined as the percentage of participants who have a best objective response of confirmed 
CR or PR or who have SD for at least 5 weeks after C-CAR031 infusion date per RECIST 1.1. 
Data obtained from infusion date up until progression, or the last evaluable assessment in the 
absence of progression, will be included in the assessment of DCR. 

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Participants with SD who receive any subsequent cancer therapy prior to week 5, will not be 
considered to have disease control in the analysis. 
 
The analysis will include all participants in the EAS. DCR and its 95% CI will be summarized 
by dose level. 
 
Time to Response (TTR) 
TTR is defined as the time from infusion date until the date of first documented objective 
response, which is subsequently confirmed as assessed by the investigator per RECIST 1.1. 
Only participants who have achieved confirmed response in the EAS are evaluated for TTR. 
 
TTR will be summarized by dose level using Kaplan- eier method.  edian TTR and it’s 
95% CI will be provided. Kaplan-Meier plots will be presented. 
 
Percentage Change in Tumor Size 
The best percentage change from baseline in tumor size is the largest decrease (or smallest 
increase) from baseline for a participant, using RECIST 1.1 assessments. 
 
The analysis will include all participants in the EAS. 
The percentage change in TL tumor size from baseline will be summarized using descriptive 
statistics by dose level and time point. Best percentage change will also be summarized. 
 
Waterfall plots showing the best percentage change from baseline in sum of the diameters of 
TLs will be produced. Spider plots showing the percentage change from baseline in TL tumor 
size for each participant in a dose level over time will be produced. 
 
Progression-free Survival (PFS) 
PFS is defined as the time from C-CAR031 infusion until the date of objective disease progression 
or death (by any cause in the absence of progression). If participants receive another anticancer 
therapy, the PFS will be censored. Participants 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 assessment. 
 
The PFS time will always be derived, based on scan/assessment dates, not visit dates. 
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied: 
 
• 
Date of progression will be determined, based on the earliest of the dates of the component 
that triggered the progression. 
• 
When censoring a participant for PFS, the participant will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
• 
If the participant progresses or dies immediately after two or more consecutive missed 

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visits, the PFS will be censored at the time of the latest evaluable assessment prior to the 
two missed visits. 
 
The analysis will include all participants in the SS, i.e. participants who receive C-CAR031 
at any dose level. 
PFS will be summarized by dose level and Kaplan-Meier plots will be provided. The measure of 
interest is the median and landmark estimates of PFS. 
 
Overall Survival (OS) 
OS is defined as the time from C-CAR031 infusion until death due to any cause. Any participant 
not known to have died at the time of analysis will be censored based on the last recorded date on 
which the participant was known to be alive. 
 
The analysis will include all participants in the SS. 
 
The measure of interest is the median and landmark estimates. OS will be summarized by 
dose level and Kaplan-Meier plots will be provided. 
 
9.4.4 
Pharmacokinetic Analysis 
Blood samples for determination of the level of CAR transgene by PCR and/or CAR-T blood 
concertation by flow cytometry for C-CAR031 will be tested by an analysis lab using 
appropriately validated bioanalytical methods. If data allows, CK parameters such as AUC0-28d, 
Cmax, Tmax, Tlast, Clast and AUClast will be analyzed. 
 
The calculation of CK parameters will use a non-compartmental model and actual sampling time. 
For data below the lower limit of cell concentration measurement, if it occurs before the first 
measurable concentration, it will be set as "0", otherwise, it will be set as 1/2 lower limit of 
quantification (LLOQ) (i.e., half of the LLOQ). 
 
The main CK parameters will be statistically summarized by dose group and phase. The statistical 
summary will use descriptive statistical methods, including number of cases, mean, standard 
deviation, median, minimum, maximum, coefficient of variation between participants, geometric 
mean, and geometric coefficient of variation between participants, except for Tmax and Tlast. The 
statistical description of Tmax and Tlast only includes the number of cases, median, minimum, and 
maximum. 
 
Relationship between CK parameters and efficacy/safety will be explored. CK parameter values 
will be described by category according to efficacy indicators whether clinical remission is 
achieved. CRS and ICANS will be classified by severity to evaluate the relationship between CK 
parameters and safety. Statistical charts for description will be applied where appropriate. 
 
9.4.5 
Exploratory Study Analyses 

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9.4.5.1 
Immunogenicity 
Humoral immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of participants who develop detectable ADAs. The potential impact on clinical 
efficacy and safety outcomes will be assessed if data allow. 
 
9.4.5.2 
Exploratory Biomarkers  
Biomarker exploratory analyses may be described in a separate analysis plan and may be reported 
either in the CSR itself or as an addendum, or separately in a scientific report or publication. 
 
9.4.5.3 
Long-term Data Analysis 
Any data obtained after the end of the stage 3 follow-up  will be analyzed as part of the LTFU data. 
 
For further details on analyses, refer to the SAP. 
 
9.5 
Data Monitoring Committee 
There will be no data monitoring committee for this study. A SRC will be appointed to review 
emerging data from each part of the study (refer to Section 6.6.5). 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Appendix A Regulatory, Ethical, and Study Oversight Considerations 
A 1 Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki as amended at 64th World Medical Association (WMA) 
General Assembly, Fortaleza, Brazil, October 2013 and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, revised protocol, ICF and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated. 
• 
Any revised protocol will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study participants. 
• 
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of ICH guidelines, the IRB/IEC, and all other 
applicable local regulations. 
 

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Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to collaborator of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• 
Collaborator has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
collaborator will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators. 
• 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and collaborator policy and forwarded to investigators as 
necessary. 
• 
An Investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from collaborator will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
 
Regulatory Reporting Requirements for Serious Breaches 
• 
Prompt notification by the investigator to collaborator of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met. 
− 
A ‘serious breach’ means a breach likely to affect to a significant degree the safety and 
rights of a participant or the reliability and robustness of the data generated in the 
clinical study. 
• 
If any (potential) serious breach occurs in the course of the study, investigators or other site 
personnel will inform the appropriate collaborator representatives immediately after he or 
she becomes aware of it. 
• 
The investigator should have a process in place to ensure that: 
− 
The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach 
− 
A (potential) serious breach is promptly reported to collaborator or delegated party, 
through the contacts (email address or telephone number) provided by collaborator. 
A 2 Informed Consent Process 
• 
The investigator or their representative will explain the nature of the study to the participant 
or their legally authorised representative and answer all questions regarding the study. 
• 
Participants must be informed that their participation is voluntary, and they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the 
study. Participants or their legally authorised representative will be required to sign a 
statement of informed consent that meets the requirements of local regulations, ICH 

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guidelines, privacy, and data protection requirements, where applicable, and the IRB/IEC or 
study centre. 
• 
Of note for this study, consent is a 3-step  process with a pre-screening, screening and 
stage 3 (the LTFU period) consent signature requirement. Pre-screening and screening 
may occur in parallel. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
• 
If new information requires changes to the ICF, consider if participants must be re-consented and if 
so, this must be to the most current version of the ICF(s) during their participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative. 
 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 60 days from the previous ICF signature date. 
 
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional HBS. The investigator or authorised designee will explain to each 
participant the objectives of the analysis to be done on the samples and any potential future use. 
Participants will be told that they are free to refuse to participate in any optional samples or the 
future use, and may withdraw their consent at any time and for any reason during the retention 
period. 
 
A 3 Data Protection 
• 
Participants will be assigned a unique identifier by the collaborator. Any participant records 
or datasets that are transferred to the collaborator will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that their personal study-related data will be used by the 
collaborator in accordance with local data protection law. The level of disclosure and use of 
their data must also be explained to the participant in the informed consent. 
• 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the collaborator, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• 
The participant must be informed that data will be collected only for the business needs. We 
will only collect and use the minimum amount of personal data to support our business 
activities and will not make personal data available to anyone (including internal staff) who 
is not authorised or does not have a business need to know the information. 
• 
The participant must be informed that in some cases their data may be pseudonymised. The 
General Data Protection Regulation (GDPR) defines pseudonymisation as the processing of 

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personal data in such a way that the personal data can no longer be attributed to a specific 
individual without the use of additional information, provided that such additional 
information is kept separately and protected by technical and organisational measures to 
ensure that the personal data are not attributed to an identified or identifiable natural person. 
 
A 4 Committees Structure 
 
The members of safety review committee (SRC) include the investigators, an independent clinician,  
an AbelZeta’s medical delegate, and other relevant personnel may be added according to the specific 
needs of the study, including but not limited to the medical monitor, pharmacovigilance physician, 
clinical pharmacologist, statistician. All representatives from AbelZeta or other collaborators will be 
non-voting members. 
 
The SRC membership should be recorded in the SRC Charter. 
A 5 Data Quality Assurance 
• 
All participant data relating to the study will be recorded on eCRF unless transmitted to 
collaborator or designee electronically (eg, laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by electronically signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy, including definition of study-critical data items and 
processes, methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are included in the 
Monitoring Plan(s) and contracts. 
• 
Investigator or designee is responsible for medical oversight throughout the conduct of the 
study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Medical monitor Plan. 
• 
Investigator or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
Investigator assumes accountability for actions delegated to other individuals (eg, CROs). 
• 
Study monitors will perform ongoing source data verification as per the Monitoring Plan(s) 
to confirm that data entered into the eCRF by authorised site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 

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be retained by the investigator as required by local regulations. No records may be destroyed 
during the retention period without the written confirmation of collaborator. No records may 
be transferred to another location or party without written notification to collaborator. 
 
A 6 Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• 
Definition of what constitutes source data and its origin can be found in source data 
acknowledgment or monitoring guidelines.  
A 7 Study Closure 
 
A study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
 
AbelZeta may terminate support for study at any time and for any reason including, but not limited 
to scientific misconduct, AbelZeta disbarment, emerging safety findings, and discontinuation of 
further research on the compound by AbelZeta. In the event a study is terminated, the appropriate 
ethical considerations will be made for the participants in the study. Study may provide decision 
making data for the AbelZeta drug development program. Therefore, if a decision is made to 
withdraw AbelZeta support there should be full consultation with all pertinent parties, including 
but not limited to the review committee, the Product Team, investigator, and/or the Alliance 
Partner (if any) before proceeding. The investigator is responsible for all closure activities 
pertaining to their Regulatory Authority, IRB/IEC, research participants, safety reconciliation.  
A 8 Publication Policy 
 
• 
Collaborator shall have the right to make and control all scientific or other publications of any 
materials or information relating in any way to the Compound, Product, Development Activities 
or Development Results 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
collaborator before submission to gain consent from collaborator. This allows the 
collaborator to protect proprietary information and to provide comments. 
• 
Collaborator will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the collaborator will generally 
support publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 

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• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 

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Appendix B AEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
B 1 Definition of AEs 
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether it’s considered related to the 
medicinal product. 
 
The term AE is used to include both serious and non-serious AEs and a deterioration of a pre- 
existing medical occurrence. An AE may occur at any time, even if no study intervention has been 
administered. 
 
B 2 Definition of SAEs 
An SAE is an AE occurring during any study phase, that fulfils one or more of the following 
criteria: 
 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
The above instruction applies only when the malignant tumor event in question is a new malignant 
tumor (ie, it is not the tumor for which entry into the study is a criterion and that is being treated 
by the study intervention and is not the development of new or progression of existing metastasis 
to the tumor under study). Malignant tumors that – as part of normal, if rare, progression – undergo 
transformation (eg, Richter’s transformation of B-cell chronic lymphocytic leukaemia into diffuse 
large B-cell lymphoma) should not be considered a new malignant tumor. 
 
Life-threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the medicinal product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 

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Hospitalization 
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it may 
be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered SAEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. Hospitalization or prolongation of existing hospitalization for study 
effectiveness assessment, hospitalization or prolongation of existing hospitalization for treatment 
of a disease covered by this study are not considered as SAE. 
 
Important Medical Event or Medical Treatment 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardise the participant or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
 
Simply stopping the suspect drug (if applicable) does not mean that it is an important medical 
event; medical judgment must be used. 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not an SAE unless it meets the criteria shown in Appendix B 2. 
On the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be an SAE when it satisfies the criteria shown in Appendix B 2. 
 
The grading scales found in the revised National Cancer Institute CTCAE version will be utilized 
for all events. This version will be used for the duration of the study. For those events without 
assigned CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate, 
and severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly. 
 
B 3 A Guide to Interpreting the Causality Question 
When assessing causality consider the following factors when deciding if there is a ‘reasonable 
possibility’ that an AE may have been caused by C-CAR031, and/or LDC and/or bridging therapy 
(if used). 
 
• 
Time Course. Exposure to suspect drug. Has the participant received the suspect drug? Did 
the AE occur in a reasonable temporal relationship to the administration of the suspect drug? 

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• 
Consistency with known drug profile. Was the AE consistent with the previous knowledge 
of the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological 
class? Or could the AE be anticipated from its pharmacological properties? 
• 
No alternative cause. The AE cannot be reasonably explained by another aetiology such as 
the underlying disease, other drugs, other host, or environmental factors. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
 
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With no available facts or arguments to suggest a causal 
relationship, the event(s) will be assessed as ‘not related’. 
 
Causal relationship in cases where the DUS has deteriorated due to lack of effect should be 
classified as ‘no reasonable possibility’. 

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Appendix C Handling of Human Biological Samples 
C 1 Chain of Custody 
A full chain of custody is maintained for all samples throughout their lifecycle. 
 
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at the site. 
 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
 
Investigator or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers. 
 
Samples retained for further use will be stored in the collaborator-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate collaborator team for the 
remainder of the sample life cycle. 
 
The immunogenicity sample should be retained 1 year after completing CSR. CK (DNA copy 
number) samples can be hold 6 months after completion of CSR. CK samples for flow 
cytometry cannot be stored after analysis and the remaining samples will be destroyed after 
completing the analysis.If required, collaborator will ensure that remaining biological samples 
are returned to the site according to local regulations or at the end of the retention period, 
whichever is the sooner. 
 
C 2 Withdrawal of Informed Consent for Donated Biological Samples 
Investigator ensures that biological samples are returned to the source or destroyed at the end of 
a specified period as described in the informed consent. 
If a participant withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed/repatriated, and the action documented. If samples are already analysed, 
the collaborator is not obliged to destroy the results of this research. 
 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
 
The investigator: 
 
• 
Ensures the participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the collaborator or delegate 

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• 
Ensures that relevant human biological samples from that participant, if stored at the study 
site, are immediately identified, disposed of as appropriate, and the action documented 
• 
Ensures that the participant and collaborator is informed about the sample disposal. 
 
Investigator or delegated representatives ensures the organization(s) holding the samples is/are 
informed about the withdrawn consent immediately and that samples are disposed of or 
repatriated as appropriate, and the action is documented, and study site is notified. 

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Appendix D Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
D 1 Introduction 
This appendix describes the process to be followed in order to identify and appropriately report 
potential Hy’s Law (PHL) cases and Hy’s law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
 
In studies where laboratory data are not routinely collected, the investigator should be vigilant 
for cases of PHL from ad hoc laboratory tests or AEs. Additional safety samples for example, 
liver chemistry tests to determine PHL cases, may be collected if clinically indicated at the 
discretion of the investigator. During the course of the study, the investigator will remain 
vigilant for increases in liver biochemistry. The investigator is responsible for determining 
whether a participant meets potential PHL criteria at any point during the study. 
 
All sources of laboratory data are appropriate for the determination of PHL and HL events; this 
includes samples taken at scheduled study visits and other visits including central and all local 
laboratory evaluations even if collected outside of the study visits; for example, PHL criteria could 
be met by an elevated ALT from a central laboratory and/or elevated TBL from a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations in 
liver biochemistry) for possible PHL events. 
 
The investigator participates, together with collaborator clinical project representatives, in review 
and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL criteria 
are met if there is no alternative explanation for the elevations in liver biochemistry other than 
drug-induced liver injury caused by the study intervention. 
 
The investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
SAEs and AEs according to the outcome of the review and assessment in line with standard safety 
reporting processes. 
D 2 Definitions 
Potential Hy’s Law 
 
Table 21 
Potential Hy’s Law Definitions 
 
Baseline lab values 
ALT and/or AST in normal 
range 
ALT and/or AST above ULN 
TBL in normal range 
AST or ALT ≥ 3 ×  L  together 
with TBL ≥   ×  L , may need to 
be reported as SAEs. 
AST or ALT ≥ 3 × baseline value 
or ≥ 10 ×  L , whichever occurs 
first, together with TBL ≥   × 
ULN, may need to be reported as 
SAEs. 

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TBL above ULN 
AST or ALT ≥ 3 ×  L , together 
with TBL ≥ 1.  × baseline value 
with DB ≥  0% of the total, or any 
increase in DB ≥ 1 mg/dL over 
baseline, may need to be reported 
as SAEs. 
AST or ALT ≥ 3 × baseline value 
or ≥ 10 ×  L , whichever occurs 
first, together with TBL ≥ 1.  × 
baseline value with DB ≥  0% of 
the total, or any increase in DB ≥ 1 
mg/dL over baseline, may need to 
be reported as SAEs. 
ALT = Alanine Aminotransferase/Transaminase; AST = Aspartate Aminotransferase/Transaminase; DB = direct 
bilirubin; SAE = Serious Adverse Events; TBL = total bilirubin; ULN = upper limit of normal. 
 
Hy’s Law 
Participants who have changes in transaminases and TBL/DBL in Table 21 above will be confirmed 
Hy’s Law cases where no other reason, other than the study intervention, can be found to explain 
the combination of increases, eg, elevated ALP indicating cholestasis, viral hepatitis, another drug. 
 
For Potential Hy’s Law and Hy’s Law the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur. 
 
D 3 Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination as detailed in Table 21. 
Local Laboratories Being Used 
 
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will: 
• 
Determine whether the participant meets PHL criteria (Appendix D 2) by reviewing 
laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory eCRF. 
 
D 4 Follow-up 
D 4.1 Potential Hy’s Law Criteria not met 
If the participant does not meet potential Hy’s Law criteria the investigator will 
 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the protocol. 
 
D 4.2 Potential Hy’s Law Criteria met 
If the participant does meet potential Hy’s Law criteria the investigator will: 
 

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• 
Determine whether potential Hy’s Law criteria were met at any study visit prior to starting 
study intervention (see Appendix D 6) 
• 
Notify the collaborator representative who will then inform the Study Team 
• 
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criterion “Important  edical Event” and causality assessment “yes/related” 
according to CSP process for SAE reporting 
• 
For participants that met PHL criteria prior to starting study intervention, the investigator 
is not required to submit a PHL SAE unless there is a significant change in the 
participant’s condition. 
 
• 
The medical monitor contacts the investigator, to provide guidance, discuss and agree 
an approach for the study participant’s follow-up (including any further laboratory 
testing) and the continuous review of data. 
• 
Subsequent to this contact the investigator will: 
− 
Monitor the participant until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long as 
medically indicated. Completes follow-up SAE Form as required. 
− 
Investigate the aetiology of the event and perform   investigations as 
discussed with the Study Physician. 
− 
Complete the eCRF as information becomes available. 
 
A “significant” change in the participant’s condition refers to a clinically relevant change 
in any of the individual’s liver biochemistry parameters (ALT, AST or TBL) in isolation or 
in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the investigator, 
this may be in consultation with the medical monitor if there is any uncertainty. 
 
D 5 Review and Assessment of Potential Hy’s Law Cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the medical 
monitor contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than drug-induced liver 
injury caused by the study intervention, to ensure timely analysis and reporting to health 
authorities within 15 calendar days from date PHL criteria was met. The collaborator 
Clinical Lead or equivalent and Safety Physician will also be involved in this review 
together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL 
elevations, a determination of whether the alternative explanation is an AE will be made 

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and subsequently whether the AE meets the criteria for a SAE: 
 
• 
If the alternative explanation is not an AE, record the alternative explanation on 
the appropriate eCRF 
• 
If the alternative explanation is an AE/SAE: update the previously submitted PHL 
SAE and AE eCRFs accordingly with the new information (reassessing event term; 
causality and seriousness criteria) following the  standard processes in protocol for 
AE/SAE reporting. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations 
other than the IMP: 
 
• 
Send updated SAE (report term ‘Hy’s Law’) according to standard processes in 
protocol for SAE reporting. 
− 
The ‘ edically Important’ serious criterion should be used if no other serious 
criteria apply 
− 
As there is no alternative explanation for the Hy’s Law case, a causality 
assessment of ‘related’ should be assigned. 
 
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether the case meets the criteria for Hy’s Law, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
 
• 
Provide any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to protocol process for SAE 
reporting. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are still met.  pdate the previously submitted potential Hy’s 
Law SAE report following protocol process for SAE reporting, according to the outcome 
of the review and amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined. 
D 6 Actions Required When Potential Hy’s Law Criteria are met Before and After 
Starting Study Intervention 
This section is applicable to participants who meet PHL criteria on study intervention, having 
previously met PHL criteria at a study visit prior to starting study intervention. 
At the first on-study intervention occurrence of PHL criteria being met, the investigator will 
determine if there has been a significant change in the participant’s condition compared with 
the last visit where PHL criteria were met. 
 

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• 
If there is no significant change, no action is required 
• 
If there is a significant change, notify the collaborator representative, who will inform the 
Study Team, then follow the subsequent process described in Appendix D 4.2. 
D 7 Actions Required for Repeat Episodes of Potential Hy’s Law 
 
This section is applicable when a participant meets PHL criteria on study intervention and 
has already met PHL criteria at a previous on study intervention visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
 
The investigator should determine the cause for the previous occurrence of PHL criteria 
being met and answer the following question: 
 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study eg, chronic or progressing malignant disease, severe infection or liver 
disease or did the participant meet PHL criteria prior to starting study intervention and at 
their first on study intervention visit as described in Section D 6  
If No: follow the process described in Appendix D 4.2 for reporting PHL as an SAE. 
 
If Yes  Determine if there has been a significant change in the participant’s condition compared 
with when PHL criteria were previously met. 
• 
If there is no significant change, no action is required 
• 
If there is a significant change, follow the process described in Appendix D 4.2 for 
reporting PHL as an SAE. 
 
D 8 Laboratory Tests 
List of  Hy’s Law Laboratory tests  
 
Additional standard chemistry and coagulation 
tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV 
HbsAg 
IgM and IgG anti-HBc 
HBV DNA a 
IgG anti-HCV 
HCV RNAb 
IgM anti-HEV 
HEV RNA 

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Other viral infections 
IgM and IgG anti-CMV 
IgM and IgG anti-HSV 
IgM and IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate-deficient transferrin c 
Autoimmune hepatitis 
Antinuclear antibody 
Anti-liver/kidney microsomal antibody 
Anti-smooth muscle antibody 
Metabolic diseases 
Alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin c 
Transferrin saturation 
a 
HBV DNA is only recommended when IgG anti-HBc is positive. 
b 
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive. 
c 
Carbohydrate-deficient transferrin and transferrin are not available in China. Study teams should amend this 
list accordingly. 
CMV = cytomegalovirus; DNA = deoxyribonucleic acid; EBV = Epstein-Barr virus; GGT = gamma-glutamyl 
transferase; HAV = hepatitis A virus; HBc = hepatitis B core antigen; HbsAg = hepatitis B surface antigen; 
HCV = hepatitis C virus; HEV = hepatitis E virus; HSV = herpes simplex virus; IgG = immunoglobulin G; 
IgM = immunoglobulin M; INR = international normalised ratio; LDH = lactate dehydrogenase; ribonucleic acid. 
D 9 References 
Aithal et al, 2011 
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 
2011; 89(6):806-15. 
 
FDA Guidance for Industry, July 2009 
FDA Guidance for Industry (issued July  009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda- 
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation 

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Appendix E Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria 
in Solid Tumors) 
Introduction 
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors v 
1.1 (RECIST 1.1) guidelines (Eisenhauer et al 2009[64]). iInvestigator assessments will use 
the RECIST 1.1 guidelines described in this appendix. 
 
Imaging Modalities and Acquisition Specifications for RECIST 1.1 
A summary of the imaging modalities that can be used for tumor assessment of TLs, NTLs, 
and NLs is provided in Table 22. 
 
Table 22 
Summary of Imaging Modalities for Tumor Assessment 
Target lesions 
Non-target lesions 
New lesions 
CT 
CT 
CT 
MRI 
MRI 
MRI 
Plain X-ray 
Plain X-ray 
Chest X-ray 
Chest X-ray 
Bone scan (Scintigraphy) 
FDG-PET/CT 
CT = Computed tomography; FDG-PET/CT = 18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI = Magnetic resonance imaging. 
 
 
CT and MRI 
Computed tomography (CT) with intravenous (IV) contrast is the preferred imaging modality 
(although magnetic resonance imaging [MRI] with IV contrast is acceptable if CT is 
contraindicated) to generate reproducible anatomical images for tumor assessments (ie, for 
measurement of TLs, assessment of NTLs, and identification of NLs). It is essential that the 
same correct imaging modality, image acquisition parameters (eg, anatomic coverage, imaging 
sequences, etc), imaging facility, tumor assessor (eg, radiologist), and method of tumor 
assessment (eg, RECIST 1.1) are used consistently for each patient throughout the study. The 
use of the same scanner for serial scans is recommended, if possible. It is important to follow 
the image collection/tumor assessment schedule as closely as possible (refer to the SoAs, see 
Section 1.3), and this on-study imaging schedule MUST be followed regardless of any delays 
in dosing or missed imaging visits. If an unscheduled assessment is performed (eg, to investigate 
clinical signs/symptoms of progression) and the patient has not progressed, every attempt 
should be made to perform the subsequent scan acquisitions at the next scheduled imaging visit. 

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Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artifacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse sequence. 
In general, local oncology diagnostic imaging parameters are applied for scan acquisition. It is 
beyond the scope of this appendix to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. 
 
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval. 
 
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up time points. This will enable better 
consistency not only of tumor measurements but also identification of new disease. 
 
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these timepoints are specified 
in the SoAs. Examples include the following: 
 
• IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis) 
• Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis) 
• IV contrast-enhanced CT or MRI of the head and neck 
• IV contrast-enhanced MRI (preferred) or CT of the brain 
 
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order 
of preference, with additional options (2 to 4) for consideration when patients have sensitivity 
to IV contrast or have compromised renal function: 
 
1 
Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred) 
2 
Chest CT without IV contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study 

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3 
Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the patient has compromised renal function 
4 
Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any 
time during the study 
 
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumors require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumor 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given patient. Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen and pelvis. 
 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤ -mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses >5 mm. If this occurs, 
the minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans. 
 
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study. 
 
Chest X-ray 
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs. 
 
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions. 
 
Isotopic Bone Scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or X-
ray at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray). 
 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 

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equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
or X-ray) of the same anatomical region shall not be the only trigger for a progressive disease 
(PD) assessment at that time point. 
 
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound will 
need to be assessed by correlative CT or MRI anatomical scan. 
 
 
 
 
 
 
 
 
 
1 A positive FDG-PET scan lesion should be reported only when an uptake (eg, standard uptake value) greater 
than twice that of the surrounding tissue or liver is observed. 

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Other Tumor Assessments  
Clinical Examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans. 
 
Endoscopy and Laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment. 
 
Histology and Cytology 
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1. 
 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1. 
 
Furthermore, an overall assessment of complete response (all other disease disappears/reverts 
to normal) would be changed to PR if an effusion remains present radiologically. 
 
Measurability of Tumor Lesions at Baseline  
RECIST 1.1 Measurable Lesions at Baseline: 
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥ 1  mm in short axis2 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. 
 
Non-measurable Lesions at Baseline: 
• Truly non-measurable lesions include the following: 
o Bone lesions (see exception below for soft tissue component) 
o Leptomeningeal disease 
o Ascites, pleural effusion, or pericardial effusion 
o Inflammatory breast disease 
• Lymphangitic involvement of skin or lung 
• All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥10 mm to <1  mm short axis diameter at baseline3) 
• Previously irradiated lesions4 
• Brain metastasis 
 
 

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Special Considerations Regarding Lesion Measurability at Baseline: 
• Bone lesions 
o Bone scan, PET scan, or plain X-ray are not considered adequate imaging 
techniques to measure bone lesions; however, these techniques can be used to 
confirm the presence or disappearance of bone lesions 
o Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability 
o Blastic lesions are considered non-measurable. 
• Cystic lesions thought to represent cystic metastases can be considered measurable lesions 
if they meet the criteria for measurability from a radiological point of view, but if non- 
cystic lesions are present in the same patient, these should be selected over cystic lesions 
as TLs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
The short axis is defined as the longest in-plane axis perpendicular to the long axis. 
 
3 
Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded 
or followed as NTLs. 
 
4 
Localised post-radiation changes that affect lesion size may occur. Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as 
part of the NTL assessment. 

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RECIST 1.1 TL Selection at Baseline: 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should 
be identified as TLs at baseline. TLs should be selected on the basis of their size (longest 
diameter for non-nodal lesions or short axis diameter for nodal lesions), but in addition should 
be those that lend themselves to reproducible repeated measurements. It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be selected. 
 
Lymph nodes, in any location (local/regional and distant), are collectively considered as a single 
organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), a 
segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ. 
 
The site and location of each TL should be documented, as well as the longest axis diameter for 
non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimeters. At baseline, the sum of the diameters for all TLs will be calculated and 
reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all TLs 
will be calculated and reported as the follow-up sum of diameters. 
 
Special Cases for TL Assessment at Baseline: 
• 
For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter. 
• 
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter. 
• 
Tumor lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least approximately 2 weeks after biopsy, allowing time for healing. 
• 
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan. 
 
• 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a New 
Lesion. 
 
RECIST 1.1 NTL Selection at Baseline: 
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 

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not required, but the presence or absence of each should be noted throughout follow-up. 
 
Evaluation of Tumor Response and Progression  
RECIST 1.1 TL Assessment at Follow-up 
This section defines the criteria used to determine objective tumor visit response for RECIST 
1.1-defined TLs (see also Table 23). The imaging modality, location, and scan date of each TL 
identified previously at baseline should be documented at follow-up visits with the long axis 
diameter for non-nodal lesions or short axis diameter for lymph node lesions. All measurements 
should be recorded in millimeters. The sum of the diameters for all TLs at each follow-up visit 
will be compared to the baseline sum of diameters (for response or stable disease) or to the 
smallest prior (nadir) sum of diameters (for progression). 
Special Cases for TL Assessment at Follow-up: 
• If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL. 
• If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded. 
• If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate mass, 
the vector of the longest diameter of the coalesced mass should be used to determine the 
perpendicular vector for the maximal short axis diameter. 
• If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm. 
• If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. The choice of “Too large to measure” in the case report form will trigger 
an overall visit response of PD. 
• When a TL has had any intervention (eg, definitive radiotherapy, embolisation, surgery, 
transarterial chemoembolisation, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 case report form 
for the current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm. 

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Table 23 
RECIST 1.1 Evaluation of Target Lesions 
 
Complete response (CR) 
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to <10 mm. 
Partial response (PR) 
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters. 
Stable disease (SD) 
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD. 
Progression of disease (PD) 
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir)—This includes 
the baseline sum if that is the smallest on study. In addition to the 
relative increase of 20%, the sum must demonstrate an absolute increase 
of at least 5 mm from nadir. 
Not evaluable (NE) 
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (eg, missing anatomy) or had a lesion intervention at this 
visit. Note: If the sum of diameters meets the PD criteria, PD overrides 
not evaluable as a TL response. 
Not applicable (NA) 
Only relevant if no TLs present at baseline. 
CR = complete response; NA = not applicable; NE = not evaluable; PD = progression of disease; PR = partial 
response; SD = stable disease; TL = target lesion. 
 
RECIST 1.1 NTL Assessment at Follow-up 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline (see Table 24). Measurements are not required for these lesions, but their status 
should be followed at subsequent visits. At each visit, an overall assessment of the NTL 
response should be recorded by the investigator. 
 
To achieve ‘unequivocal progression’ on the basis of  TLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, the 
overall tumor burden has increased sufficiently to merit unequivocal progression by NTLs. A 
modest ‘increase’ in the size of 1 or more  TLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PD of target disease will therefore be 
extremely rare. 

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Table 24 
RECIST 1.1 Evaluation of Non-target Lesions 
 
Complete response (CR) 
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
Non CR/non PD 
Persistence of 1 or more NTLs. 
Progression (PD) 
Unequivocal progression of existing NTLs. Unequivocal progression 
may be due to an important progression in 1 lesion only or in several 
lesions. In all cases, the progression MUST be clinically significant 
for the physician to consider changing (or stopping) therapy. 
Not evaluable (NE) 
Only relevant when 1 or some of the NTLs were not assessed and, in 
the investigator’s opinion, they are not able to provide an evaluable 
overall NTL assessment at this visit. 
Note: For patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression criteria 
have not been met. 
Not applicable (NA) 
Only relevant if no NTLs present at baseline 
CR = complete response; NE = not evaluable; NTL = non-target lesion; PD = progression of disease; TL = target 
lesion. 
 
RECIST 1.1 NL Identification at Follow-up 
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the case report form. The presence of 1 or more NLs is assessed as progression. 
The finding of a NL should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor. If a NL is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the previously (pre-existing) new lesion has been 
assessed as unequivocal at a follow-up visit, and then the progression date should be declared 
using the date of the initial scan when the NL first appeared. 
 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression. 
 
RECIST 1.1 Evaluation of Overall Visit Response at Follow-up 
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 25. 
Table 25 
RECIST 1.1 Overall Visit Response 
 
Target Lesions 
Non-target lesions 
New lesions 
Overall visit response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD 
No 
PR 
CR 
NE 
No 
PR 

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PR 
Non PD or NE or NA 
No 
PR 
SD 
Non PD or NE or NA 
No 
SD 
NA 
Non-CR/Non-PD 
No 
SD (non-CR/non-PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No 
NE 
NA 
NA 
No 
NED 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Non-CR/Non-PD for Overall Response if only non-target lesions (no TLs) are present at baseline. 
Note: An overall assessment of complete response (all other disease disappears/reverts to normal) would be changed 
to PR if ascites remains present radiologically. 
CR = complete response; NA = not applicable; NE = not evaluable; NED = no evidence of diseases; 
PD = progressive disease; PR = partial response; SD = stable disease. 
 
The following overall visit responses are possible depending on the extent of tumor disease 
at baseline: 
 
• For patients with TLs (at baseline): complete response (CR), partial response (PR), stable 
disease (SD), progression of disease (PD), or not evaluable (NE) 
• For patients with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE 
• For patients with no disease at baseline: NED (no evidence of disease; available as an 
option in the eCRF), PD, or NE 
 
Evaluation of Scans Subsequent to RECIST 1.1-defined Progression 
A follow-up scan is requested at least 4 weeks after a RECIST 1.1-defined radiological 
progression and no later than the next regularly scheduled imaging visit. The follow-up scans 
provide additional information to the investigator for patient management and further treatment 
decisions, and since the published RECIST 1.1 criteria (Eisenhauer 2009[64]) do not provide 
guidance on how to assess scans acquired after RECIST 1.1-defined PD, supplemental 
instructions for investigators on how to evaluate these follow-up scans are provided below. If 
the follow-up scan acquired after a RECIST 1.1 PD scan meets any of the following criteria, it 
will be assigned an overall visit response of PD, and if the scan does not meet any of these 4 
criteria, the timepoint assessment will be non-PD (ie, CR, PR, SD, or NE). 
• ≥  0% increase and at least a  -mm increase in the sum diameters of TLs compared with 
the nadir sum of diameters at   consecutive visits, and a further increase of ≥   mm in the 
sum of diameters at the follow-up timepoint compared with the immediate prior timepoint 
• significant progression (worsening) of NTLs at the follow-up scan timepoint compared 
with the immediate prior timepoint 
• significant progression (worsening) of previously new lesions (pre-existing new lesions) at 
the follow-up scan timepoint compared with the immediate prior timepoint 
• additional unequivocal brand-new lesions at the follow-up scan timepoint 
 

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Central Imaging 
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to a 
collaborator-appointed imaging Contract Research Organisation (iCRO) for quality control, 
storage, and for indepentent review committee (IRC) evaluation. Digital copies of all original 
scans should be stored at the investigator site as source documents. Electronic image transfer 
from the sites to the iCRO is strongly encouraged. A IRC evaluation of images will be 
performed at the discretion of collaborator. Results of these independent reviews will not be 
communicated to investigators, and results of investigator tumor assessments will not be shared 
with the central reviewers. The management of patients will be based in part upon the results of 
the tumor assessments conducted by the investigator. Further details of the IRC evaluation will 
be documented in an Independent Review Charter. 
References  
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 

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Appendix F 
Contraception Guidance 
F 1 
Definitions 
Females not of childbearing potential are defined as females who are either permanently 
sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are 
postmenopausal. Females will be considered postmenopausal if they have been amenorrhoeic 
for 12 months prior to the planned date of randomization without an alternative medical cause. 
The following age-specific requirements apply: 
 
Females < 50 years old would be considered postmenopausal if they have been amenorrhoeic 
for 12 months or more following cessation of exogenous hormonal treatment and follicle 
stimulating hormone levels in the postmenopausal range. 
 
Females ≥  0 years old would be considered postmenopausal if they have been amenorrhoeic 
for 12 months or more following cessation of all exogenous hormonal treatment. 
 
A highly effective method of contraception is defined as one that can achieve a failure rate of 
< 1% per year when used consistently and correctly. 
 
A highly effective method of contraception is defined as one that can achieve a failure rate of 
< 1% per year when used consistently and correctly. 
 
F 2 Highly Effective Methods of Contraception 
Table 26 
Highly Effective Methods of Contraception 
Non-hormonal methods 
Hormonal methods 
• 
Copper T intrauterine 
device 
• 
Levenorgestrel-releasing 
intrauterine system 
(eg, Mirena®) a 
• 
Bilateral tubal occlusion 
• 
Vasectomised sexual 
partner 
• 
Total sexual abstinence 
• 
Implants 
 
Etonorgestrel-releasing implants (eg, Implanon® or Norplan®) 
• 
Intravaginal devices 
 
Ethinylestradiol/etonorgestrel-releasing intravaginal devices 
(eg, NuvaRing®) 
• 
Injection 
 
Medroxyprogesterone injection: eg, Depo-Provera® 
• 
Combined pill 
 
Normal and low dose combined oral contraceptive pill 
• 
Patch 
 
Norelgestromin/ethinylestradiol-releasing transdermal system 
(eg, Ortho Evra®) 
• 
Minipill 
 
Progesterone based oral contraceptive pill using desogestrel 
 
Cerazette® is currently the only highly effective 
progesterone-based pill 
a 
Also considered a hormonal method 

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Birth control methods that are  OT highly effective (failure rate of ≥ 1% per year) include   ale 
or female condom with or without spermicide; cap, diaphragm, or sponge with spermicide, or 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action. A male condom plus cap, diaphragm, or sponge with spermicide (double barrier 
methods) are not highly effective birth control methods. 
 
The following are NOT acceptable methods of contraception: periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhoea. Female condom and male condom should not be used together. 
 
 

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Appendix G Grading of CRS, ICANS, and ICE Scoring 
CRS grading criteria are presented in Table 27. 
 
Table 27 
American Society for Transplantation and Cellular Therapy Consensus Grading 
Criteria For CRS 
CRS 
parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever a 
Temperature 
≥ 3 °C 
Temperature ≥ 3 °C 
Temperature ≥ 3 °C 
Temperature ≥ 3 °C 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors (excluding 
vasopressin) 
And/or b 
Hypoxia 
None 
Requiring low-flow 
nasal cannula a or 
blow-by 
Requiring high-flow 
nasal cannula c, face 
mask, non-rebreather 
mask, or Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
a 
Fever is defined as temperature 38°C not attributable to any other cause. In participants who have CRS 
then receive antipyretic or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer 
required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or 
hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other 
cause. For example, a participant with temperature of 39.5° C, hypotension requiring 1 vasopressor, and 
hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
c 
Low-flow nasal cannula is defined as oxygen delivered at ≤   L/min. Low flow also includes blow-by 
oxygen delivery, sometimes used in paediatrics. High-flow nasal cannula is defined as oxygen delivered 
at > 6 L/min. 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS 
grading. 
Grading of CRS events is based on ASTCT consensus Grading (Lee et al 2019[63]). 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bilevel positive airway 
pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; 
CTCAE = Common Terminology Criteria for Adverse Events 
 
ICANS grading criteria are presented in Table 28. 

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Table 28 
American Society for Transplantation and Cellular Therapy Consensus Grading 
Criteria for ICANS in Adults 
Neurotoxicity 
domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE score a 
7-9 
3-6 
0-2 
0 (participant is unarousable and 
unable to perform ICE 
assessment) 
Depressed level of 
consciousness b 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to 
tactile stimulus 
Participant is unarousable or 
requires vigorous or repetitive 
tactile stimuli to arouse. Stupor 
or coma. 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalised 
that resolves rapidly 
or nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening prolonged 
seizure (> 5 min); or repetitive 
clinical or electrical seizures 
without return to baseline in 
between 
Motor findings c 
N/A 
N/A 
N/A 
Deep focal motor weakness such 
as hemiparesis or paraparesis 
Elevated increased 
intracranial 
pressure/cerebral 
oedema d 
N/A 
N/A 
Focal/local oedema 
on neuroimaging 
Diffuse cerebral oedema on 
neuroimaging; decerebrate or 
decorticate posturing; or cranial 
nerve VI palsy; or papilloedema; 
or Cushing’s triad 
a 
A participant with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, 
but a participant with an ICE score of 0 may be classified as Grade 4 ICANS if unarousable. 
b 
Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). 
c 
Tremors and myoclonus associated with immune effector cell therapies may be graded according to 
CTCAE v5.0, but they do not influence ICANS grading. 
d 
Intracranial hemorrhage with or without associated oedema is not considered a neurotoxicity feature and 
is excluded from ICANS grading. It may be graded according to CTCAE v5.0. 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor 
findings, raised ICP/cerebral oedema) not attributable to any other cause; for example, a participant with an 
ICE score of 3 and a generalized seizure is classified as having grade 3 ICANS. 
Grading of ICANS events is based on ASTCT consensus Grading (Lee et al 2019[63]). 
ASTCT = American Society for Transplantation and Cellular Therapy; CTCAE = Common Terminology 
Criteria for Adverse Events; ICANS = Immune Effector Cell-Associated Neurotoxicity Syndrome; ICE = 
Immune Effector Cell Encephalopathy; EEG = electroencephalogram; N/A = not applicable. 
 
ICE scoring is presented in Table 29. 

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Table 29 
Immune Effector Cell-associated Encephalopathy (ICE) Score 
 
ICE assessment 
Score 
Orientation 
Orientation to year, month, city, hospital 
1 point each 
Naming 
Name 3 objects (eg, clock, pen, button) 
1 point each 
Following commands 
(eg, show me 2 fingers, or close your eye and stick out your 
tongue) 
1 point 
Writing 
Ability to write a standard sentence (eg, our national bird is the 
bald eagle) 
1 point 
Attention 
Count backwards from 100 by 10 
1 point 
ICE scoring 
Score 10 
No impairment 
Score 7-9 
Grade 1 ICANS 
Score 3-6 
Grade 2 ICANS 
Score 0-2 
Grade 3 a ICANS 
Score 0 (due to participant 
unarousable and unable to 
perform ICE assessment) 
Grade 4 ICANS 
a 
A participant with an ICE score of 0 may be classified as having Grade 3 ICANS if the participant is 
awake with global aphasia or may be classified as having Grade 4 ICANS if the participant is 
unarousable. 
ICANS = Immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-associated 
Encephalopathy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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