Randomized, Open-label, Phase 3 Study of SAR408701 Versus Docetaxel in Previously Treated, Metastatic Nonsquamous, Non-small-cell Lung Cancer Patients With CEACAM5-positive Tumors
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer Metastatic
Sponsor: Sanofi

 
 
 
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Based on Template: Sanofi OneDocument Version 1.0, dated 1-JUL-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 06 
Protocol title: 
Randomized, open-label, Phase 3 study of SAR408701 
versus docetaxel in previously treated, metastatic, 
nonsquamous, non–small-cell lung cancer patients with 
CEACAM5-positive tumors 
Protocol number: 
EFC15858 
Amendment number: 
06 
Compound number 
(INN/Trademark): 
SAR408701 
(tusamitamab ravtansine/NA) 
Study phase: 
Phase 3 
Short title: 
SAR408701 versus docetaxel in previously treated, 
carcinoembryonic antigen-related cell adhesion 
molecule 5 (CEACAM5)-positive, metastatic 
nonsquamous non–small-cell lung cancer patients 
(CARMEN-LC03) 
Sponsor name: 
Sanofi-aventis recherche & développement 
Legal registered 
address: 
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin, France  
Monitoring Team’s 
Representative Name 
and Contact Information 
  
Regulatory agency identifier number(s): 
IND: 
144484 
EudraCT: 
2019-001273-81 
NCT: 
NCT04154956 
WHO: 
U1111-1233-0781 
Other: 
Not applicable 
Approval date: 
13-Mar-2023 
Total number of pages: 133 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/ 
countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial protocol 06 
All 
Date: 13-Mar-2023, version 1 (electronic 10.0) 
Amended Clinical Trial protocol 05 
All 
Date: 18-Oct-2022, version 1 (electronic 9.0) 
Amended Clinical Trial protocol 04 
All 
Date: 21-Jul-2021, version 1 (electronic 5.0) 
Amended Clinical Trial protocol 03 
All 
Date: 20-Jul-2020, version 1 (electronic 4.0) 
Amended Clinical Trial protocol 02 
All 
Date: 13-Dec-2019, version 1 (electronic 3.0) 
Amended Clinical Trial protocol 01 
All 
Date: 27-Sep-2019, version 1 (electronic 2.0) 
Original Protocol 
 
Date: 26-June-2019, version 1 (electronic 1.0) 
AMENDED PROTOCOL 06 (13-MAR-2023) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union because 
it may impact the scientific value of the study.  
OVERALL RATIONALE FOR THE AMENDMENT 
Due to a higher dropout rate for progression-free survival (PFS) than initially assumed, the 
anticipated number of PFS events by the time of the first interim analysis (IA) of overall survival 
(OS; with 50% information fraction) planned in amended protocol 05 is anticipated to be 
significantly lower than the expected 221 PFS events.  
To maintain an adequate power for PFS analysis while not considerably delaying the futility 
analysis on OS planned at the same time, the cut-off date for the first IA of OS is now redefined 
as the time when approximately 221 PFS events or approximately 210 deaths (approximately 58% 
information fraction) are observed, whichever comes first. The futility threshold based on the OS 
hazard ratio to be applied at the time of this analysis is now also updated from 0.95 to 0.90.  
Beside these changes, further modifications to protocol wording as detailed in the Summary of 
Changes table were implemented.  
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Section # and Name Description of Change 
Brief Rationale 
1.1 Synopsis; 4.4 End of 
study definition; 
9.2 Sample size 
determination 
The information fraction at the first IA of OS 
was updated from 50% to 58%.   
To reflect increased dropout rate for PFS 
1.1 Synopsis; 4.4 End of 
study definition; 
9.2 Sample size 
determination; 
9.4 Statistical analyses; 
9.5 Interim analyses 
Respective cut-off dates for the first IA, second 
IA, and final analysis of OS were updated from 
33 months, 44 months, and 53 months to 
40 months, 48 months, and 58 months.  
To reflect increased dropout rate for PFS 
1.1 Synopsis; 9.2 Sample 
size determination 
The estimated power for the first analysis of 
OS was updated from 82% to 81%; and the 
expected number of OS events was increased 
from 183 deaths to 210 deaths. 
To reflect increased dropout rate for PFS 
1.1 Synopsis; 9.2 Sample 
size determination 
The PFS probablility of dropout rate by 
4 months was updated from 10% to 17% 
To reflect the PFS probability of dropout rate 
1.1 Synopsis; 9.2 Sample 
size determination; 
9.4.1 Efficacy analyses; 
9.5 Interim analyses 
Definition of the cut-off date for final analysis 
of PFS was updated from “total of 221 PFS 
events (approximate number of PFS events 
anticipated to be observed when 
approximately 183 deaths will be observed)” to 
“approximately 221 PFS events or 
approximately 210 deaths ... , whichever 
comes first.”  
To reflect increased dropout rate for PFS 
1.1 Synopsis; 
9.4. Statistical analyses; 
9.4.1.1.1 Progression 
free survival; 
9.4.1.1.2 Overall survival 
Time from cut-off date for final analysis of PFS 
to planned cut-off date for final analysis of OS 
was updated from 20 months to 18 months, 
and time to cut-off for IA of OS at 80% IF was 
changed from approximately 11 months to 
8 months  
To reflect increased dropout rate for PFS 
1.1 Synopsis; 
9.6 Multiplicity 
For overall response rate (ORR) and health-
related quality of life (HRQoL) time to 
deterioration (TTD) endpoints, the Lan-DeMets 
O'Brien-Fleming α-spending function is 
replaced by a user-defined α-spending 
function. 
Due to uncertainty regarding the information 
fraction and overall α level available for testing 
those key secondary endpoints 
1.3.2 Crossover phase; 
5.1 Inclusion criteria; 
5.2 Exclusion criteria 
Modified headers for crossover phase 
schedule of activities and crossover phase 
inclusion/exclusion criteria to clarify that these 
would be implemented only if certain 
prespecified efficacy criteria are met  
To clarify that implementation of the crossover 
phase is conditional 
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Section # and Name Description of Change 
Brief Rationale 
1.3.2 Crossover phase; 
8.2.5 Clinical safety 
laboratory assessments 
Troponin assessments were added to the 
schedule of activities for the crossover phase, 
and a corresponding footnote d was added to 
describe details of timing. Statement that 
troponin would not be assessed in crossover 
participants was deleted from safety laboratory 
assessments, and timing of troponin 
assessments was described here. 
To keep same safety measurement as in main 
study phase  
4.1.1 Duration of the 
study period 
Total estimated enrollment duration was 
updated from 43 months to 50 months.  
Updated per realized enrollment  
4.1.2 Crossover 
treatment phase 
Added statement that Sponsor will notify sites 
in writing if the crossover phase is 
implemented. 
To clarify how crossover phase implementation 
would be communicated to sites 
6.6. Dose modification  
Dose levels for second dose reductions 
(requiring case-by-case discussion with 
sponsor) were added to table, and additional 
language added to text and table footnote.  
For clarity  
8.1 Efficacy assessments 
Description of tumor assessment procedures 
for participants who have EOT visits due to 
reasons other than PD “until documented PD” 
was corrected by adding “or OS study cut-off’” 
For clarity 
8.2.5 Clinical safety 
laboratory assessments 
Deleted statement that troponin will not be 
assessed during the crossover treatment 
phase, and added description of assessments 
for crossover participants. 
To keep same rule of troponin assessment 
during crossover treatment phase, if 
implemented  
9.2 Sample size 
determination 
Updated previous estimate of enrollment rate 
from 12 to 10 participants per month, and 
removed previously provided alternative 
estimate based on 10 participants per month 
as redundant. 
To reflect new statistical assumption 
9.5 Interim analyses 
Table 7 was updated with probabilities of 
crossing the futility boundary. 
To reflect updated information fraction due to 
increased dropout rate for PFS 
9.5 Interim analyses 
Added statement that predictive power for the 
final OS analysis given the IA data could be 
used as supportive information in the futility 
decision. 
To clarify considerations to be used in the futility 
decision 
9.6 Multiplicity 
Boundary properties for planned analyses of 
PFS (Table 8) and OS (Table 9) were 
updated.  
To reflect updated information fraction due to 
increased dropout rate for PFS 
10.1.3 Informed consent 
process 
Deleted erroneous reference to a legally 
authorized representative. 
This reference has been removed as not 
applicable for this study. 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 06 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 19 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 20 
1.3.1 
Main study phase ........................................................................................................................... 20 
1.3.2 
Crossover phase (if implemented) ................................................................................................. 24 
2 
INTRODUCTION ............................................................................................................................ 26 
2.1 
STUDY RATIONALE...................................................................................................................... 26 
2.2 
BACKGROUND ............................................................................................................................. 27 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 27 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 28 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 29 
4 
STUDY DESIGN ............................................................................................................................ 30 
4.1 
OVERALL DESIGN ........................................................................................................................ 30 
4.1.1 
Duration of the study period ........................................................................................................... 30 
4.1.2 
Crossover treatment phase (if implemented) ................................................................................. 31 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 32 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 33 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 33 
5 
STUDY POPULATION .................................................................................................................. 35 
5.1 
INCLUSION CRITERIA .................................................................................................................. 35 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 37 
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5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 41 
5.4 
SCREEN FAILURES...................................................................................................................... 41 
6 
STUDY INTERVENTION ............................................................................................................... 42 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 44 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 44 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 45 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 45 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 46 
6.6 
DOSE MODIFICATION .................................................................................................................. 47 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 48 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 49 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 49 
7.1.1 
Definitive discontinuation ............................................................................................................... 49 
7.1.2 
Temporary discontinuation ............................................................................................................. 50 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 50 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 51 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 52 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 52 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 53 
8.2.1 
Physical examinations ................................................................................................................... 53 
8.2.2 
Specific ocular test ......................................................................................................................... 54 
8.2.3 
Vital signs ....................................................................................................................................... 54 
8.2.4 
Electrocardiograms ........................................................................................................................ 54 
8.2.5 
Clinical safety laboratory assessments .......................................................................................... 55 
8.2.6 
Guideline for management of adverse event ................................................................................. 55 
8.2.6.1 
Hypersensitivity reactions .............................................................................................................. 55 
8.2.6.2 
Ocular toxicity ................................................................................................................................. 56 
8.2.6.3 
Management of anemia ................................................................................................................. 57 
8.2.6.4 
Management of neutropenia .......................................................................................................... 57 
8.2.6.5 
Liver function tests ......................................................................................................................... 57 
8.2.6.6 
Peripheral neuropathy .................................................................................................................... 57 
8.2.6.7 
Gastrointestinal toxicity .................................................................................................................. 58 
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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 58 
8.3.1 
Adverse event of special interest ................................................................................................... 58 
8.3.2 
Time period and frequency for collecting AE and SAE information ............................................... 59 
8.3.3 
Method of detecting AEs and SAEs ............................................................................................... 59 
8.3.4 
Follow-up of AEs and SAEs ........................................................................................................... 60 
8.3.5 
Regulatory reporting requirements for SAEs ................................................................................. 60 
8.3.6 
Pregnancy ...................................................................................................................................... 60 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 60 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 61 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 61 
8.5 
PHARMACOKINETICS .................................................................................................................. 61 
8.6 
PHARMACODYNAMICS ............................................................................................................... 64 
8.6.1 
Circulating CEA .............................................................................................................................. 64 
8.7 
GENETICS ..................................................................................................................................... 64 
8.8 
BIOMARKERS ............................................................................................................................... 65 
8.8.1 
CEACAM5 expression in tumor tissue samples ............................................................................ 65 
8.9 
IMMUNOGENICITY ....................................................................................................................... 65 
8.10 
HEALTH ECONOMICS .................................................................................................................. 65 
8.11 
PATIENT-REPORTED OUTCOMES ............................................................................................. 66 
8.11.1 
EORTC QLQ-C30 .......................................................................................................................... 66 
8.11.2 
EORTC QLQ-LC13 ........................................................................................................................ 66 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 67 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 67 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 67 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 69 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 69 
9.4.1 
Efficacy analyses ........................................................................................................................... 70 
9.4.1.1 
Analysis of multiple primary efficacy endpoints ............................................................................. 70 
9.4.1.2 
Analysis of secondary efficacy endpoints ...................................................................................... 72 
9.4.1.3 
Analysis of exploratory efficacy endpoints ..................................................................................... 74 
9.4.2 
Safety analyses .............................................................................................................................. 74 
9.4.2.1 
Analyses of adverse events ........................................................................................................... 75 
9.4.2.2 
Deaths ............................................................................................................................................ 76 
9.4.2.3 
Analyses of clinical laboratory evaluations .................................................................................... 76 
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9.4.3 
Other analyses ............................................................................................................................... 77 
9.5 
INTERIM ANALYSES .................................................................................................................... 77 
9.5.1 
Data Monitoring Committee (DMC) ................................................................................................ 78 
9.6 
MULTIPLICITY ............................................................................................................................... 78 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 82 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 82 
10.1.1 
Regulatory and Ethical considerations........................................................................................... 82 
10.1.2 
Financial disclosure........................................................................................................................ 82 
10.1.3 
Informed consent process .............................................................................................................. 83 
10.1.4 
Data protection ............................................................................................................................... 83 
10.1.5 
Committees structure ..................................................................................................................... 84 
10.1.6 
Dissemination of clinical study data ............................................................................................... 85 
10.1.7 
Data quality assurance .................................................................................................................. 85 
10.1.8 
Source documents ......................................................................................................................... 86 
10.1.9 
Study and site closure .................................................................................................................... 86 
10.1.10 Publication policy ........................................................................................................................... 86 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 87 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 89 
10.4 
APPENDIX 4: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS ......................................................... 93 
10.5 
APPENDIX 5: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 98 
10.6 
APPENDIX 6: GENETICS ........................................................................................................... 101 
10.7 
APPENDIX 7: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 ....... 101 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 108 
10.8.1 
Safety run-in in China................................................................................................................... 109 
10.8.2 
PK assessment in China .............................................................................................................. 109 
10.8.3 
Assessment of ATA, circulating CEA in China ............................................................................ 110 
10.8.4 
Circulating tumor DNA and germline DNA ................................................................................... 110 
10.9 
APPENDIX 9: CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE (NTR) .............. 110 
10.10 
APPENDIX 10: STRONG CYP3A INHIBITORS .......................................................................... 111 
10.11 
APPENDIX 11: PROTOCOL AMENDMENT HISTORY .............................................................. 112 
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10.11.1 AMENDED PROTOCOL 05 (18-OCT-2022) ............................................................................... 112 
10.11.2 Amended protocol 04 (21-Jul-2021) ............................................................................................ 115 
10.11.3 Amended protocol 03 (20-Jul-2020) ............................................................................................ 117 
10.11.4 Amended protocol 02 (13-Dec-2019)........................................................................................... 120 
10.11.5 Amended protocol 01 (27-Sep-2019)........................................................................................... 123 
10.12 
APPENDIX 12: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 128 
10.12.1 Remote prescreening process ..................................................................................................... 128 
10.12.2 Screening procedures .................................................................................................................. 129 
10.12.3 Study intervention ........................................................................................................................ 129 
10.12.4 Study procedures ......................................................................................................................... 129 
10.13 
APPENDIX 13: ABBREVIATIONS ............................................................................................... 130 
11 
REFERENCES ............................................................................................................................. 132 
 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 28 
Table 2 - Overview of study interventions administered ............................................................................... 44 
Table 3 - Pharmacokinetic and antitherapeutic antibody sampling times and labeling ................................ 63 
Table 4 - Populations for analyses ................................................................................................................ 69 
Table 5 - Efficacy analyses ........................................................................................................................... 70 
Table 6 - Safety analyses .............................................................................................................................. 74 
Table 7 - Probabilities of crossing the futility boundary on overall survival under different assumptions for 
the true hazard ratio ...................................................................................................................................... 77 
Table 8 - Boundary properties for planned final analysis of PFS .................................................................. 79 
Table 9 - Boundary properties for planned analyses of OS .......................................................................... 80 
Table 10 - ORR hypothesis testing level ....................................................................................................... 81 
Table 11 - Protocol-required safety laboratory assessments (local laboratory) ............................................ 88 
Table 12 - Recommended dose modification or discontinuation .................................................................. 93 
Table 13 - Response criteria ....................................................................................................................... 104 
Table 14 - Response in patients with target disease .................................................................................. 107 
Table 15 - Response in patients with non-target disease only.................................................................... 107 
Table 16 - PK sampling schedule for 12 tusamitamab ravtansine treated patients in China ...................... 109 
Table 17 - List of CYP substrates with narrow therapeutic range ............................................................... 110 
Table 18 - List of strong CYP3A inhibitors .................................................................................................. 111 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 19 
Figure 2 - Type I error reallocation strategy .................................................................................................. 79 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: Randomized, open-label, Phase 3 study of SAR408701 versus docetaxel in 
previously treated, metastatic, nonsquamous non-small-cell lung cancer patients 
with CEACAM5-positive tumors  
Short title: 
SAR408701 versus docetaxel in previously treated, carcinoembryonic antigen-
related cell adhesion molecule 5 (CEACAM5)-positive, metastatic, nonsquamous 
non–small-cell lung cancer patients (CARMEN-LC03) 
Rationale: 
Despite recent progress in the treatment of advanced non–small-cell lung cancer (NSCLC), there 
remains a need for effective new treatment at the time of disease progression.  
Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC) combining 
hu769_4D4 (SAR408377), a humanized antibody that recognizes selectively the A3-B3 
extracellular domain of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), 
a tumor-associated carcinoembryonic antigen, with the potent cytotoxic maytansinoid derivative 
(DM)4, that inhibits microtubule assembly. SAR408701 is expected to selectively deliver DM4 to 
cancer cells expressing the CEACAM5 antigen, such as colon, stomach and its signet-ring cell 
subtype, as well as NSCLC (adenocarcinoma). 
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was first described in 
1965 as a tumor-associated antigen in human colon cancer tissue extracts (1). High levels of 
CEACAM5 expression have since been observed in several epithelial tumors while in normal 
adult tissue, its expression is limited to few tissues (2, 3). Immunostaining of CEACAM5 in a 
large panel of human tumor tissue microarray samples has shown the highest prevalence of cell 
surface CEACAM5 expression in adenocarcinoma of the colon, the stomach and its subtype 
signet ring cell as well as in nonsquamous NSCLC. 
In the first-in-human study (TED 13751), a cohort of patients with pretreated nonsquamous 
NSCLC with membrane CEACAM5 expression ≥2+ in intensity in at least 50% of the tumor cell 
population were treated with tusamitamab ravtansine at the recommended dose of 100 mg/m² 
every 2 weeks. Preliminary results on the first 32 evaluable patients treated, showed encouraging 
antitumor activity and were associated with a response rate of 25% (90% CI 14.70%-39.20%). 
The accrual continued to obtain 64 patients treated to ensure a minimum of 30 patients pretreated 
with anti-programmed death 1/program death ligand 1 (PD-1/PD-L1). 
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Objectives and endpoints  
 
Objectives 
Endpoints 
Primary 
Study is designed with 2 primary endpoints that will be analyzed on 
randomized participants at the time of the cut-off date for each given 
analysis (progression free survival [PFS] and overall survival [OS]). 
Study success is defined either on PFS or OS. 
 
• 
The primary objective is to determine whether tusamitamab 
ravtansine improves the progression free survival (PFS) 
when compared to docetaxel in participants with metastatic 
nonsquamous NSCLC expressing CEACAM5 ≥2+ in 
intensity in at least 50% of the tumor cell population and 
previously treated with standard-of-care platinum-based 
chemotherapy and an immune checkpoint inhibitor (ICI)  
• 
The primary endpoint is PFS as assessed by 
independent blinded review committee (IRC) 
and based on RECIST 1.1 assessments. PFS 
will be defined as the time from randomization 
to the date of the first documented disease 
progression or death due to any cause, 
whichever comes first. 
• 
The primary objective is to determine whether tusamitamab 
ravtansine improves the overall survival (OS) when 
compared with docetaxel in participants with metastatic 
nonsquamous NSCLC expressing CEACAM5 ≥2+ in 
intensity in at least 50% of the tumor cell population and 
previously treated with standard-of-care platinum-based 
chemotherapy and an immune checkpoint inhibitor.  
• 
The primary endpoint is OS and defined as the 
time from randomization to the date of death 
due to any cause. 
 
Secondary 
• 
To compare the objective response rate (ORR) to 
tusamitamab ravtansine with docetaxel 
• 
Objective response rate will be defined as the 
proportion of participants who have a complete 
response (CR) or partial response (PR), as best 
overall response derived from Overall 
Response (OR) determined by the IRC per 
RECIST 1.1 
• 
To compare the health-related quality of life (HRQOL) to 
tusamitamab ravtansine with docetaxel 
• 
HRQOL will be analyzed through three different 
endpoints: 
- 
Time to deterioration (TTD) in disease 
related symptoms (composite endpoint of 
cough, chest pain and dyspnea) as 
determined by EORTC QLQ-LC13 
- 
TTD in physical function as determined by 
EORTC QLQ C-30 
- 
TTD in role function as determined by 
EORTC QLQ C30  
 
The TTD is defined as the time from baseline until the first 
≥10 point change from baseline up to the end of 
treatment. 
• 
To evaluate the safety of tusamitamab ravtansine 
compared to docetaxel 
• 
Incidence of TEAEs and SAEs and laboratory 
abnormalities according to NCI CTCAE v5.0 
• 
To assess the duration of response (DOR) to tusamitamab 
ravtansine as compared with docetaxel 
• 
Duration of response (DOR) is defined as the 
time from first documented evidence of CR or 
PR until progressive disease (PD) determined 
per RECIST 1.1 or death from any cause, 
whichever occurs first 
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Overall design: 
This is a Phase 3, randomized, open-label, multicenter, efficacy and safety study of tusamitamab 
ravtansine versus docetaxel in patients with metastatic nonsquamous NSCLC whose tumors 
express CEACAM5 (measured using the CEACAM5 immunohistochemistry [IHC]769 assay). 
CEACAM5 positivity in this study is defined as membranous CEACAM5 expression in the most 
recent formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (or if not available in fresh 
tumor tissue) sample as ≥2+ in intensity in at least 50% of the tumor cell population, 
demonstrated prospectively by central IHC evaluation. 
Once participants have signed a prescreening informed consent form (ICF), the prescreening 
phase will correspond to the timing of sending archival tumor material and IHC analyses to allow 
determination of CEACAM5 status by central laboratory. Prescreening for CEACAM5 status 
could be performed in advance during prior anticancer therapy. During the study screening phase, 
only nonsquamous NSCLC CEACAM5 positive participants determined by central assay will go 
through protocol study procedures. 
The study will have 3 main periods: screening, study treatment and follow up. After being 
screened the eligible patients will be randomized (1:1) to one of the following treatment arms: 
• Treatment A: tusamitamab ravtansine every 2 weeks (Q2W cycle) at the dose of 
100 mg/m2. 
• Treatment B: docetaxel every 3 weeks (Q3W cycle) at the dose of 75 mg/m2. 
Treatment allocation will be performed by an Interactive Response Technology (IRT). All eligible 
patients will be randomly assigned to either of the experimental arm or the control arm in 
a 1:1 proportion. Allocation to the 2 treatment arms will be done using stratified randomization 
based on Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), previous 
immune checkpoint inhibitors (ICI) treatment (sequential versus combination with chemotherapy) 
and geographical region (Asia versus Western Europe+Australia+North America versus Rest of 
the World [RoW]). 
Participants will continue to receive their assigned treatment until objective disease progression, 
unacceptable toxicity, or upon participant’s request to stop treatment, or Investigator decision, 
whichever occurs first. 
After discontinuing randomized study intervention, the participant will enter the follow up period. 
During the follow-up period, participants may be treated with standard of care per investigator 
discretion, and the details will be collected as post-study treatment. In case the crossover phase is 
implemented after the time of the 58% interim analysis of OS, participants enrolled to the 
docetaxel treatment arm may also be allowed to receive crossover treatment with tusamitamab 
ravtansine after documented disease progression.  
The study is designed with 2 primary endpoints that will be analyzed on randomized participants 
at the time of the cut-off date for each given analysis (PFS and OS). Regardless of the outcome of 
PFS analysis, enrollment will continue to have the final analysis of OS, unless the result of either 
interim analysis of OS is overwhelming for efficacy or futility. 
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An independent DMC will periodically assess the progress of the clinical trial, review the safety 
data and will advise the study principal Investigator (s) and Sponsor regarding patient safety, as 
well as the course of action regarding the conduct of the trial. The DMC will also be in charge of 
reviewing the final analysis of PFS and the formal statistical interim analyses for OS. 
An independent radiological review committee (IRC; blinded to study intervention arms) will 
review the tumor assessment data as central reading for PFS and ORR analyses for the main study 
phase. 
Disclosure Statement: This is a Parallel, Treatment study with 2 Arms that are unblinded for 
previously treated metastatic nonsquamous non–small-cell lung cancer. 
Number of participants: 
Approximately 450 randomized patients (225 in each arm) would be adequate to achieve the 
targeted number of events for both PFS and OS. Assuming an accrual rate as detailed in 
Section 9.2, cut-off dates for final analysis of PFS and final analysis of OS will be approximately 
40 and 58 months after first patient in (FPI) respectively. 
Approximately 3534 patients will be prescreened for CEACAM5 status, of whom 530 patients 
will be screened to achieve 450 randomized patients with estimated failure rates of 85% for 
prescreening and 15% for screening. 
Intervention groups and duration: 
The duration of the study for a participant will include a period for screening of up to 28 days. 
Once successfully screened, participants may receive study intervention until disease progression, 
unacceptable AE, participant’s or investigator's decision to stop the treatment. After discontinuing 
study intervention, participants will return to the study site approximately 30 days (±5 days) after 
the last investigational medicinal product (IMP) administration or before the participant receives 
another anticancer therapy, whichever is earlier, for end-of-treatment assessments. For a 
participant who has progressive disease who does not enter the crossover treatment phase, 
follow-up visits will be performed every 12 weeks until the OS cut-off date or death (whichever 
comes first). A participant who stops treatment before documented progressive disease (achieving 
SD, CR, PR) should undergo a tumor assessment and a follow-up visit every 8 weeks until 
radiological disease progression, death, final study cut-off (OS cut-off date), or withdrawal of 
participant’s consent, whichever comes first. Participants who enter the crossover phase to receive 
tusamitamab ravtansine treatment after radiological progression should come to the site every 
2 weeks for treatment and to be followed for safety.   
The expected duration of study intervention for participants who benefit from study intervention 
may vary, based on progression date; but median expected duration of study per participant is 
estimated as median 9 months in docetaxel arm (1 month for screening, 4 months for treatment, 
and 4 months for the EOT and follow-up visits) and 12.5 months in the tusamitamab ravtansine 
arm (1 month for screening, 6.5 months for treatment, and 5 months for end of treatment 
follow-up). 
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If a participant is treated (including in the crossover treatment phase) and continues to benefit 
from treatment after the OS analysis cut-off date, the participant may continue until unacceptable 
toxicity, progression, participant’s request to stop treatment, or Investigator decision, whichever 
occurs first. For cycles completed after the OS cut-off date, all ongoing SAEs (related or not), all 
related nonserious AEs ongoing at the cut-off date, and all new related AEs (serious or not) 
occurring post-cut-off date and associated concomitant medication, as well as IMP 
administrations and reason for EOT will continue to be collected. A safety follow-up visit will be 
performed approximately 30 (+5) days from last dose of tusamitamab ravtansine, even after study 
cut-off dates. In the case that an expanded access program is initiated, participants continuing 
tusamitamab ravtansine treatment at the OS cut-off date may be switched to this access program, 
depending on program details.  
Study intervention(s) 
Investigational medicinal product(s) 
Tusamitamab ravtansine: 
• Formulation: tusamitamab ravtansine (SAR408701) is supplied as a 25 mL extractable 
volume of concentrate for solution for infusion of 125 mg contained in a 30 mL clear glass 
vials fitted with a white plastic flip-off cap. 
• Route(s) of administration: intravenous (IV) infusion 
• Dose regimen: tusamitamab ravtansine will be administered on Day 1 as 100 mg/m2 given 
via 1 hour 30 min IV infusion and repeated every 2 weeks. Each administration will be 
preceded of a pre-medication to prevent hypersensitivity reactions. The duration of one 
cycle will be 14 days (1 administration of tusamitamab ravtansine per cycle). 
Docetaxel:  
• Formulation:  docetaxel is supplied as a 4 mL extractable volume of concentrate for 
solution for infusion of 80 mg contained in a 7 mL clear colorless glass vial with a 
magenta plastic flip-off cap. 
• Route(s) of administration: IV infusion 
• Dose regimen: Docetaxel will be administered on Day 1 as 75 mg/m² given via 1 hour IV 
infusion and repeated every 3 weeks. Each administration will be preceded of a 
premedication (as per the approved product label) to prevent hypersensitivity reaction. The 
duration of one cycle will be 21 days (1 administration of docetaxel per cycle). 
Non-investigational medicinal product(s) 
Premedication: 
Both tusamitamab ravtansine and docetaxel have a potential risk of an infusion related allergic 
reaction and premedication should be used as detailed in Section 6. 
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Statistical considerations: 
• Sample size calculations: The sample-size calculation incorporates multiplicity 
adjustment for the analyses of the multiple primary efficacy endpoints: progression free 
survival and overall survival. 
• Multiplicity of primary endpoints to calculate the sample size is taken into account using 
Bonferroni adjustment with different weights assigned to endpoints: PFS is tested at the 
1-sided 0.01 level and OS is tested at the 1-sided 0.015 level for a strong control of the 
overall type-I error at the 2.5% level. The graphical method of Maurer and Bretz will be 
applied to provide a strong type-I error control for multiple hypotheses. 
- 
Overall Survival: Assuming proportional hazards, a total of 363 death events will be 
needed to detect a hazard ratio of 0.72 using a log-rank test at the 1-sided 0.015 level 
with an 81% power, or at the 1-sided 0.0249 level with approximately 86% power. 
Based on an anticipated median OS time of 9 months in the docetaxel arm, this is 
expected to correspond to a median OS of 12.5 months in the tusamitamab ravtansine 
arm. The sample size calculation takes into account a first IA on OS for futility and 
efficacy when approximately 58% of OS events (approximately 210 deaths) will be 
observed; and a second IA on OS for efficacy when approximately 80% of events 
(approximately 290 deaths) will be observed. 
- 
Progression Free Survival: Assuming proportional hazards, a total of 221 PFS events 
would be needed to detect a hazard ratio of 0.615 using a log rank test at the 1-sided 
0.01 level with a 90% power or at the 1-sided α-level of 0.02485 with approximately 
95% power. Based on an anticipated median PFS time of 4 months in the docetaxel 
arm, this is expected to correspond to a median PFS of 6.5 months in the tusamitamab 
ravtansine arm. 
- 
A maximum of 450 randomized participants (225 in each arm) would be adequate to 
achieve the targeted number of events for both PFS and OS. The cut-off dates for final 
analyses of PFS and OS are predicted to be ~ 40 months for PFS and ~58 months for 
OS respectively after FPI. These cutoffs assume a probability of dropout (censoring 
reason other than cut-off reached) of 17% at 4 months for the final analysis of PFS, 
and a probability of dropout of 3% at 58 months for the final analysis of OS.  
• Main analysis populations: 
- 
Intent-to-treat (ITT) population: this population will include all participants who have 
given their informed consent and who have had a treatment kit number allocated and 
recorded in the IRT. This population is the primary population for all efficacy 
parameters. All analyses using this population will be based on the treatment assigned 
at randomization. 
- 
Safety population: this population will include all participants randomly assigned to 
study intervention and who have received at least 1 dose of study intervention. 
Participants will be analyzed according to the treatment arm they received. This 
population is the primary population for the analysis of all safety parameters.  
- 
Pharmacokinetic population: this population will include safety participants who have 
received at least 1 dose or a part of a dose of tusamitamab ravtansine with at least 
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1 concentration postbaseline with adequate documentation of dosing and sampling 
dates and times. 
- 
Immunogenicity population: this population will include safety participants who have 
received at least 1 dose or a part of a dose of tusamitamab ravtansine with at least 
1 evaluable ATA result postbaseline. 
• Analysis of primary efficacy endpoints: 
- 
PFS in the tusamitamab ravtansine arm will be compared to the docetaxel arm using 
the log-rank test procedure stratified by stratification factors as entered in the IRT. See 
Section 9.6 for details about the type-I error level to be used for statistical testing.  
- 
The estimates of the hazard ratio and corresponding 95% and α-adjusted 2-sided 
confidence intervals (CIs) will be provided using the Cox proportional hazard model 
stratified by stratification factors as entered in the IRT. The median PFS and 
probabilities of being progression free at different time points calculated using the 
Kaplan-Meier methods as well as corresponding CI will be presented by treatment 
arm. The Kaplan-Meier PFS curves will also be provided. 
- 
The cut-off date for final analysis of PFS will be the date when approximately 221 PFS 
events or approximately 210 deaths are observed, whichever comes first. 
- 
OS in the tusamitamab ravtansine arm will be compared to the docetaxel arm using the 
log-rank test procedure stratified by stratification factors as entered in the IRT. See 
Section 9.6 for details about the type I error to be used for statistical testing.   
- 
The estimates of the hazard ratio and corresponding 95% and α-adjusted 2-sided CI 
will be provided using the Cox proportional hazard model stratified by stratification 
factors as entered in the IRT. The median OS and probabilities of being alive at 
different time points calculated using the Kaplan-Meier methods as well as 
corresponding CI will be presented by treatment arm. Kaplan-Meier OS curves will 
also be provided. 
- 
The final OS analysis (based on approximately 363 deaths) is expected to be 
performed approximately 18 months after the final PFS/58% IA-OS analysis cut-off 
date. 
• Analysis of secondary efficacy endpoint: 
- 
Objective response rate (ORR) will be summarized using descriptive statistics and 
95% CIs. The ORR will be compared between treatment groups using the Cochran-
Mantel-Haenszel stratified method at the significance level defined in the multiplicity 
section in Section 9.6.  
- 
Time to deterioration (TTD) in disease-related symptoms (as determined by 
EORTC-QLQ-LC13) in the SAR408701 arm will be compared to the docetaxel arm 
using the log-rank test procedure stratified by stratification factors as entered in the 
IRT at the significance level defined in the multiplicity section in Section 9.6.  
- 
The estimates of the hazard ratio and corresponding CI will be provided using the Cox 
proportional hazard model stratified by stratification factors as entered in the IRT. The 
median TTD and corresponding 95% CI will be presented by treatment arm. The 
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Kaplan-Meier time to deterioration in disease-related symptoms curves will also be 
provided. 
- 
Same analyses will be provided for the TTD in physical function and for the TTD in 
role function (as determined by EORTC-QLQ-C30). 
- 
Details of subscales from EORTC QLQ-LC13 and EORTC QLQ-C30 and list of items 
to be used for disease-related symptoms, physical function and role function will be 
provided in the statistical analyses plan. 
- 
The duration of response (DOR) will only be summarized on the subgroup of 
participants who have achieved objective response. DOR for the 2 treatment arms will 
be summarized using Kaplan-Meier methods and displayed graphically, if appropriate. 
The median DOR and associated 95% CI will be provided. 
• Analysis of safety endpoints:  
- 
Number (%) of patients experiencing treatment-emergent adverse events (TEAEs) and 
SAEs by primary system organ class and preferred term will be summarized by 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0 (all grades and Grade ≥3) for the safety population. The same 
table will be prepared for drug-related TEAEs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose modification, serious TEAEs, and TEAEs 
with fatal outcome. For patients with multiple occurrences of the same AE within the 
on-treatment period, the worst grade will be used. 
- 
Hematology and blood chemistry results will be graded according to the CTCAE v5.0, 
when applicable. Number (%) of patients with laboratory abnormalities (ie, all grades 
and Grade ≥3) using the worst grade during the on-treatment period will be provided 
for the safety population. 
- 
Immunogenicity: incidence of anti-therapeutic antibodies will be provided for the 
immunogenicity-evaluable population. 
• Interim Analysis 
- 
The cut-off date for the final analysis of PFS and the first IA for assessment of efficacy 
and futility on OS will occur when approximately 221 PFS events or approximately 
58% of the targeted number of deaths (ie, approximately 210 deaths) will be available, 
whichever comes first. 
- 
The second IA for efficacy assessment on OS will occur when 80% of the targeted 
number of deaths are available (ie, approximately 290 deaths). 
- 
 Control of the type I error will be ensured using an O’Brien and Fleming spending 
function for type I error. The nonbinding futility assessments will be based on the 
observed OS HR using a Cox proportional-hazard model stratified by the stratification 
factors. A user-defined α-spending function will also be applied on type I error for key 
secondary endpoints (ORR, HRQOL TTD). See Section 9.6 for further details. 
Data Monitoring Committee: Yes
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
Treatment period 
Stratification factorsb
• ECOG
• Geographical
region
• ICI treatment
Randomization
(1:1) 
Arm A
Arm B
tusamitamab ravtansine
100 mg/m2 Q2W;  n=225
docetaxel 
75 mg/m2 Q3W;  n=225
Treatment until PD/ 
unacceptable toxicity
Follow-up Periodc
Prescreeninga
Screening
EOT visit
(30 5 days after last IMP)
-28
-3
C1D1
Until death/ 
cut-off
tusamitamab ravtansine
100 mg/m2 Q2W
Off study treatment; SOC per 
investigator discretion
Treatment until PD/ 
unacceptable toxicity
EOT visit
(30 5 days after last IMP)
PD
PD
Crossover treatment 
period
Follow-up period 
 
 
a. Patients’ tumor tissue (Archival or if not available as new fresh biopsy) will be analyzed for CEACAM5 expression, and only participants with tumors showing CEACAM5 expression level of 2+ intensity in 50% of 
tumor cells will be screened. Patients who have additional tumor tissue samples available during the prescreening phase may be re-assessed for CEACAM5 expression level; the most recent tissue sample assessed 
for CEACAM5 expression will be used to determine eligibility of participants for screening.    
b. Stratification factors: ECOG (Eastern Cooperative Oncology Group) 0 vs 1; Geographical Region (Asia vs Western Europe+Australia+NA vs ROW); prior ICI (immune checkpoint inhibitors) treatment: Sequential 
versus combination with chemotherapy 
c. A participant discontinuing main study treatment due to a reason other than PD will be followed every 8 weeks until documented disease progression. After disease progression, the participant may be treated with 
SOC or, if treated under docetaxel arm and if the crossover phase is implemented, tusamitamab ravtansine, per investigator discretion.  
Abbreviations: C1D1=treatment Cycle 1 Day 1; ECOG=Eastern Cooperative Oncology Group; EOT=End of Treatment; ICI=immune checkpoint inhibitor; IMP=investigational medicinal product; NA=North America; 
PD=progressive disease; Q2W=every 2 weeks; Q3W=every 3 weeks; ROW=rest of world. 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
1.3.1 Main study phase 
 
Procedure 
Pre- 
screeninga Screeningb 
Treatment cycle 1 
Treatment Cycle 2 
and subsequent 
End of 
treatment 
(Day 30 
±5 days 
after last 
infusion) 
Follow-up 
periodd 
Notes 
Day 
 
Days prior 
to initial 
infusion 
D1 
D3 
(24-72 h 
after 
Infusion) 
 
 
 
 
 
Pre-
infusionc 
EOI 
 
Pre-
infusionc 
Every 
8 weeks 
CEACAM5 expression statusa (archival or 
fresh tumor tissue) – central IHC/ 
prescreening Informed consent 
X 
 
 
 
 
 
 
 
 
See Section 8.8.1 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
≤28 
X 
 
 
 
 
 
 
See Section 5.1 and Section 5.2 
Demography and medical/surgical/disease 
history/smoking history 
X 
≤28 
 
 
 
 
 
 
 
See Section 8 
PS, VS, Body Weight/Height 
 
≤7 
X 
 
 
X 
 
 
PS only  
(if on-site visit)  
See Section 8.2.1 and  
Section 8.2.3.  
Height only at Screening visit, 
before the IRT call. 
Physical examination/  
signs and symptoms 
 
≤7 
X 
 
 
X 
 
X 
X 
See Section 8.2.1 
Hematology 
 
≤7 
X 
 
 
X 
 
X 
 
See Section 8.2.5 and 
Appendix 2 Section 10.2 
Coagulation 
 
≤7 
X 
 
 
X 
 
X 
 
See Section 8.2.5 and 
Appendix 2 in Section 10.2 
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Procedure 
Pre- 
screeninga Screeningb 
Treatment cycle 1 
Treatment Cycle 2 
and subsequent 
End of 
treatment 
(Day 30 
±5 days 
after last 
infusion) 
Follow-up 
periodd 
Notes 
Day 
 
Days prior 
to initial 
infusion 
D1 
D3 
(24-72 h 
after 
Infusion) 
 
 
 
 
 
Pre-
infusionc 
EOI 
 
Pre-
infusionc 
Every 
8 weeks 
Blood chemistry 
 
≤7 
X 
 
 
X 
 
X 
 
See Section 8.2.5 and 
Appendix 2 in Section 10.2 
Troponin 
 
≤7 
 
 
 
X 
 
X 
 
During study treatment:  
for SAR408701 arm:  
at end of Cycle 4  
for Docetaxel arm:  
at end of Cycle 3 
HBV & HCV serology and HIV test (only if 
required at country level)  
 
X 
 
 
 
 
 
 
 
See Appendix 2 in  
Section 10.2 
Serum pregnancy test 
 
≤7 
 
 
 
X 
 
X 
 
Mandatory serum test at 
screening and EOT and if 
required per local regulations, 
serum/ urine test during study 
treatment period. See 
Appendix 2 in  
Section 10.2 
12-lead ECG 
 
≤7 
X 
X 
 
X 
 
X 
 
See Section 8.2.4 
Specific ocular tests 
 
≤28 
 
 
 
 
 
X 
 
EOT ocular assessment 
required only for ongoing 
corneal event or ocular 
symptoms at EOT visit.  
See Section 8.2.2 
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Procedure 
Pre- 
screeninga Screeningb 
Treatment cycle 1 
Treatment Cycle 2 
and subsequent 
End of 
treatment 
(Day 30 
±5 days 
after last 
infusion) 
Follow-up 
periodd 
Notes 
Day 
 
Days prior 
to initial 
infusion 
D1 
D3 
(24-72 h 
after 
Infusion) 
 
 
 
 
 
Pre-
infusionc 
EOI 
 
Pre-
infusionc 
Every 
8 weeks 
Tusamitamab ravtansine/Docetaxel 
administration 
 
 
X 
 
 
X 
 
 
 
See Section 6.1 
AE assessment 
X 
X 
Continuously throughout the study period 
See Section 8.2, Section 8.3, 
Section 10.3 
Concomitant medication 
 
X 
Continuously throughout the study period 
See Section 6.5 
Tumor assessment 
 
≤28 
 
 
 
 
X 
X 
X 
See Section 8.1 
ePRO  
(EORTC QLQ-C30 and EORTC-LC13)e 
 
 
Xe 
 
 
X 
 
X 
X 
See Section 8.11 
Plasma for tumor cfDNA and whole blood for 
germline DNA 
 
 
X 
 
 
 
 
 
 
See Section 8.7 
Circulating CEA 
 
≤28 
 
 
 
 
X 
X 
X 
See Section 8.6.1 
Further anticancer therapyf 
 
 
 
 
 
 
 
 
X 
 
Survival status  
 
 
 
 
 
 
 
 
X 
Assessed every 12 weeks 
See Section 7.1.1 
Tusamitamab ravtansine pharmacokinetics 
 
 
X  
X 
X 
X--------------------------X 
 
 
See Section 8.5 
Tusamitamab ravtansine immunogenicity 
 
 
X-----------------------------------------------------------------X 
 
See Section 8.9 
a Prescreening:A prescreening Informed Consent will be signed by the patient for this purpose. For analyses of CEACAM5 expression. Limited patient & diseases characteristics will be collected in patients who are 
not eligible for screening; ie, CEACAM5 negative or CEACAM5 positivity below the threshold value: gender, race, ethnicity, smoking status, age, histology and stage at diagnosis and biomarkers when available 
(tumor mutation status [eg, EGFR, ALK, ROS, MET, RET, BRAF], PD-L1 and circulating CEA value) 
b Screening: Informed consent should be signed before any study specific procedures. It can be signed more than 28 days prior to randomization. Screening time indicates the timeframe relative to first IMP 
administration in which exams used to support eligibility have to be done prior to randomization. All the tests or procedures on D1 should be done at predose time unless otherwise stated. Assessments must be 
performed prior to first IMP administration: patients must have confirmed CEACAM5 expression as assessed centrally. Baseline evaluation should be completed within 1 week prior to initiation of therapy, except 
for tumor assessment and ocular tests that may be performed within 4 weeks prior to the first IMP administration. Results of these tests should be reviewed by the Investigator prior to randomization. 
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c D1 predose: Cycle 1 D1 refers to the day the patient receives the initial dose of IMP. D1 of Cycle 2 and of each subsequent cycle corresponds to D15 if patient allocated to tusamitamab ravtansine 
pharmacokinetics (respectively to D22 if allocated to Docetaxel arm) of the previous cycle. During treatment, D1 assessment can be done on the day of infusion (before infusion) or the day before. C1D1 
hematology, blood chemistry and coagulation tests may be omitted if baseline test performed within 7 days are normal. If baseline tests are abnormal should be repeated within 2 days of first study intervention. 
d Follow-up period: during the follow-up period, SAEs (regardless of relationship with study treatment) and IMP-related AEs ongoing at the end of study treatment, and any new IMP-related AE/SAE/AESI will be 
followed until resolution or stabilization (stabilization is defined as an event ongoing without any change for at least 3 months).  Date of disease progression and further anticancer treatment will be collected at the 
follow-up visits. Patients who stopped treatment before documented progressive disease (achieving stable disease, complete or partial response) should undergo a tumor assessment and a follow-up visit every 
8 weeks until radiological disease progression, death, OS cut-off date, or withdrawal of patient’s consent, whichever comes first. Patients with documented disease progression should attend a follow-up visit every 
12 weeks until OS study cut-off date or death (whichever comes first). For participants who progress on docetaxel and cross over to receive tusamitamab ravtansine treatment, refer to schedule in Section 1.3.2).  
e ePRO to be completed at site visit prior to any tests/medications and prior to any discussion of health status with healthcare personnel at the site. C1D1 assessment can be done up to -3 days, just after 
randomization call. The estimated time to complete the EORTC QLQ-C30 and the EORTC QLQ LC13 is approximately 10 to 15 minutes 
f 
Participants enrolled to tusamitamab ravtansine can be treated with local standard of care per investigator discretion. Participants enrolled to the doxetaxel arm can be treated either with local standard of care or, 
if the crossover phase is implemented, with tusamitamab ravtansine, per investigator discretion. Eligibility for crossover treatment is detailed in Section 5, and related study procedure and safety follow-up 
requirements are detailed in Section 1.3.2.   
 
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1.3.2 Crossover phase (if implemented) 
Procedure 
Assessmenta 
C1cb and subsequent 
cycles 
End of treatment- crossover 
Follow-up 
periodc 
Notes 
Day 1 
(30 ±5 days after last infusion) 
Day 
Days before 
initial infusion 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Eligibility for crossover 
≤7 
 
 
 
See Section 5.1 and Section 5.2 
PS, VS, Body Weight 
≤7 
X 
 
Only PS if 
on-site visit 
See Section 8.2.1 and Section 8.2.3.  
Physical examination/signs + symptoms 
≤7 
X 
X 
 
See Section 8.2.1 
Hematology 
≤7 
X 
X 
 
See Section 8.2.5 and Appendix 2 Section 10.2 
Coagulation 
≤7 
X 
X 
 
See Section 8.2.5 and Appendix 2 in Section 10.2 
Blood chemistry 
≤7 
X 
X 
 
See Section 8.2.5 and Appendix 2 in Section 10.2 
Troponin 
≤7 
Xd 
Xd 
 
 
Serum pregnancy test 
≤7 
 
X 
 
Mandatory serum test before the start of tusamitamab ravtansine 
crossover treatment and EOT, and as required per local 
regulations; serum/urine test during study treatment period. 
See Appendix 2 in Section 10.2. 
12-lead ECG 
≤7 
X 
X 
 
Before administration at each cycle for first 4 cycles, and then 
every other cycle 
Specific ocular tests 
≤7 
 
X 
 
Mandatory before start of crossover treatment, whenever ocular 
symptoms are observed, and at EOT. (Section 8.2.2.) 
Tusamitamab ravtansine administration 
 
X 
 
 
See Section 6.1 
AE assessment 
 
Continues throughout treatment from first dose up to 30 days after last dose 
See Section 8.2, Section 8.3, Section 10.3 
Concomitant medication 
 
Continues throughout treatment from first dose up to 30 days after last dose 
See Section 6.5 
Circulating CEA 
≤28 
X 
X 
X 
See Section 8.6.1 
Further anticancer therapy 
 
 
 
X 
 
Survival status 
 
 
 
X 
Assessed every 12 weeks; see Section 7.1.1 
Abbreviations: AE=adverse event; C=cycle; c=crossover; CEA=carcinoembryonic antigen; ECG=electrocardiogram 
a If within the specified window before first crossover infusion, assessments at the EOT visit can be used as pre-assessment before starting the crossover treatment.  
b Cycle 1 assessment can be omitted if pre-assessment values are either normal, or abnormal values within eligibility for crossover treatment and considered by the investigator as not clinically significant.  
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c A participant who discontinues crossover treatment due to PD should be followed every 12 weeks for survival status.   
d Troponin will be measured before the first dose of the crossover phase, after the end of Cycle 4-crossover (before administration of tusamitamab ravtansine at the Cycle 5-crossover visit), and at the End of 
Treatment-crossover visit (see Section 8.2.5). 
 
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2 
INTRODUCTION  
Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC) combining 
hu769_4D4 (SAR408377), a humanized antibody that recognizes selectively the A3-B3 
extracellular domain of CEACAM5, a tumor-associated carcinoembryonic antigen, with the 
potent cytotoxic maytansinoid derivative, DM4, that inhibits microtubule assembly. Tusamitamab 
ravtansine is expected to selectively deliver DM4 to cancer cells expressing the CEACAM5 
antigen, such as colon, stomach, and its signet-ring cell subtype, as well as nonsquamous NSCLC. 
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was first described in 
1965 as a tumor-associated antigen in human colon cancer tissue extracts (1). High levels of 
CEACAM5 expression have since been observed in several epithelial tumors while in normal 
adult tissue, its expression is limited to few tissues (2, 3). Immunostaining of CEACAM5 in 
a large panel of human tumor tissue microarray samples has shown the highest prevalence of cell 
surface CEACAM5 expression in adenocarcinoma of the colon, the stomach and its subtype 
signet-ring cell, as well as in nonsquamous NSCLC.  
2.1 
STUDY RATIONALE  
Despite recent progress in the treatment of advanced NSCLC, there remains a need for effective 
new treatment at the time of disease progression. Tusamitamab ravtansine, an antibody conjugate 
to the cytotoxic (DM4), is expected to selectively deliver DM4 to cancer cells expressing the 
CEACAM5 and thus could bring a clinical benefit and improved safety profile over the existing 
chemotherapy option.  
In first in human study TED13751, a cohort of patients with heavily pretreated nonsquamous 
NSCLC with tumor cell membranes shown to be CEACAM5 positive (≥2+ in intensity in at least 
50% of the tumor cell population) have been treated with tusamitamab ravtansine at the 
recommended dose of 100 mg/m² every 2 weeks. Results from the first 32 patients treated showed 
encouraging antitumor activity associated with a response rate of 25% (90% confidence interval 
[CI]: 14.70% to 39.20%; 4); this cohort was expanded to include a total of 64 high CEACAM5 
expressers and 28 moderate expressers. Of the high expressers, 13 participants had PR (ORR, 
20.3%); an additional 28 patients (43.8%) had SD as BOR.  
Data from 11 patients (9 high expressers and 2 moderate expressers) treated long term 
(ie, ≥12 months of tusamitamab ravtansine treatment) showed that 7 patients (64%) had 
a confirmed PR, and 4 (36%) had SD as best overall response (5). Almost half of (7 of 15) 
patients with nonsquamous NSCLC who achieved a confirmed PR maintained the response after 
1 year of treatment, suggesting that response to tusamitamab ravtansine in heavily pretreated 
patients was durable and frequently sustained. No new or unexpected safety signals were 
observed; none of these patients on long-term treatment discontinued the treatment because of 
drug-related AEs, and corneal AEs were manageable with dose modification. 
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2.2 
BACKGROUND  
Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-
related mortality worldwide (6). Non-small-cell lung cancer (NSCLC) accounts for 80% to 
85% of all lung cancers and is composed of several histopathological subtypes, the most common 
of which are adenocarcinoma (40% to 60%) and squamous-cell carcinoma (10% to 15%). 
The majority of patients with NSCLC present at an advanced stage at the time of diagnosis. These 
patients have a median overall survival (OS) of up to 8 to 12 months and a 5 year survival rate of 
approximately 18% (6, 7). About 15%-20% of patients with NSCLC have key genomic alterations 
such as epidermal growth factor receptor gene (EGFR) mutations and ROS1 and anaplastic 
lymphoma kinase (ALK) rearrangements that are amenable to targeted therapy. 
Until recently the only available treatment option, for advanced or metastatic nonsquamous 
NSCLC that lacks targetable mutations, was chemotherapy. Systemic therapy with platinum-
based doublet regimens, with or without maintenance therapy, is the current first-line treatment 
for patients with advanced NSCLC (8). The addition of bevacizumab a monoclonal antibody 
against vascular endothelial growth factor (VEGF) or necitumumab an antibody that targets 
EGFR produced modest improvement in survival (9, 10). In second line treatment the standard of 
care has been docetaxel (11). 
More recently immunotherapy has become a new paradigm for the treatment of NSCLC. In 
particular, monoclonal antibodies targeting the programmed death-1 receptor (PD-1)/PD ligand 1 
(PD-L1) pathway and have emerged as powerful new therapeutic tools in several clinical trials. 
Three drugs targeting the PD-1 pathway (nivolumab, pembrolizumab and atezolizumab) have 
been approved for the treatment of both chemotherapy-naïve and previously treated advanced 
stage NSCLC (12, 13, 14, 15), however only small subset of patients (20%-30%) respond to 
treatment. Despite recent improvement of outcome following initial therapy lines, including the 
new antibodies anti PD-1/PD-L1, the disease often progresses.  
In this situation, the main therapeutic options remain docetaxel, however its efficacy is modest 
and offset by substantial toxic effects (12, 13, 14). Therefore, newer therapeutic approaches are 
needed to improve the clinical efficacy and health-related quality of life (HRQOL) in patients 
with advanced NSCLC. 
2.3 
BENEFIT/RISK ASSESSMENT  
Based on the available data, the main risk observed during clinical development is corneal toxicity 
presenting as microcystic keratopathy, which is reversible and manageable with dose delay and 
dose reduction in some patients. Peripheral neuropathy is identified risk in patients that have been 
previously exposed to neurotoxic drugs. Other potential risks include gastro-intestinal toxicity, 
bone marrow toxicity, liver enzyme increased, cardiotoxicity, as well as hypersensitivity 
(infusion) reactions for tusamitamab ravtansine. Based on the current data on efficacy and safety 
obtained in the ongoing studies of tusamitamab ravtansine (TED13751 and TCD15054) supports 
its continued clinical development. More detailed information about the known and expected 
benefits and risks and reasonably expected adverse events of tusamitamab ravtansine may be 
found in the Investigator’s Brochure.  
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
Study is designed with 2 primary endpoints that will be analyzed on 
randomized participants at the time of the cut-off date for each given 
analysis (progression free survival [PFS] and overall survival [OS]). 
Study success is defined either on PFS or OS 
• 
The primary objective is to determine whether 
tusamitamab ravtansine improves the progression free 
survival (PFS) when compared to docetaxel in participants 
with metastatic nonsquamous NSCLC expressing 
CEACAM5 ≥2+ in intensity in at least 50% of the tumor cell 
population and previously treated with standard-of-care 
platinum-based chemotherapy and an immune checkpoint 
inhibitor (ICI)  
• 
The primary endpoint is PFS as assessed by 
independent blinded review committee (IRC) 
and based on RECIST 1.1 assessments. PFS 
will be defined as the time from randomization 
to the date of the first documented disease 
progression or death due to any cause, 
whichever comes first. 
• 
The primary objective is to determine whether 
tusamitamab ravtansine improves the overall survival (OS) 
when compared with docetaxel in participants with 
metastatic nonsquamous NSCLC expressing CEACAM5 
≥2+ in intensity in at least 50% of the tumor cell population 
and previously treated with standard-of-care platinum-
based chemotherapy and an immune checkpoint inhibitor.  
• 
The primary endpoint is OS and defined as the 
time from randomization to the date of death 
due to any cause. 
Secondary 
• 
To compare the objective response rate (ORR) to 
tusamitamab ravtansine with docetaxel 
• 
Objective response rate will be defined as the 
proportion of participants who have a complete 
response (CR) or partial response (PR), as best 
overall response derived from Overall 
Response (OR) determined by the IRC per 
RECIST 1.1 
 
• 
To compare the health-related quality of life (HRQOL) with 
tusamitamab ravtansine with docetaxel 
• 
HRQOL will be analyzed through three different 
endpoints: 
• 
Time to deterioration (TTD) in disease related 
symptoms (composite endpoint of cough, chest 
pain and dyspnea) as determined by EORTC 
QLQ-LC13 
• 
TTD in physical function as determined by 
EORTC QLQ C-30 
• 
TDD in role function as determined by EORTC 
QLQ C30 
The TTD is defined as the time from baseline (Cycle 1, 
Day 1) until the first ≥10-point change from baseline up to 
the End-of-Treatment assessment 
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Objectives 
Endpoints 
• 
To evaluate the safety of tusamitamab ravtansine 
compared to docetaxel 
• 
Incidence of TEAEs and SAEs and laboratory 
abnormalities according to NCI CTCAE v5.0 
• 
To assess the duration of response (DOR) to tusamitamab 
ravtansine as compared with docetaxel 
• 
Duration of response (DOR) is defined as the 
time from first documented evidence of CR or 
PR until progressive disease (PD) determined 
per RECIST 1.1 or death from any cause, 
whichever occurs first 
Tertiary/exploratory 
• 
To characterize the pharmacokinetic (PK) of tusamitamab 
ravtansine  
• 
Plasma concentrations of tusamitamab 
ravtansine during the treatment period 
• 
To assess the potential immunogenicity of tusamitamab 
ravtansine  
• 
Incidence of anti-therapeutic antibodies (ATAs) 
against tusamitamab ravtansine  
• 
To assess the relationship between the tumor mutation 
profiles detected in the circulating free DNA (cfDNA) at 
baseline with efficacy outcome 
• 
Plasma analysis for tumor cfDNA at baseline 
• 
To explore modulations of circulating CEA as a potential 
pharmacodynamics biomarker of response to tusamitamab 
ravtansine treatment 
• 
Circulating CEA at baseline and during the 
treatment period 
• 
To explore PK and pharmacodynamics (PD) (PK/PD) 
relationship 
• 
Exploration of relationship between relevant 
safety and efficacy endpoints with PK 
parameters during treatment period 
• 
To identify disease and patient characteristics that could 
be associated to CEACAM5 expression 
• 
To evaluate disease and patient characteristics 
in each CEACAM5 expression group 
(CEACAM5 positive ≥50%; CEACAM5 positive 
1% to <50%; and CEACAM5 negative) and 
CEACAM5 expression patterns 
Tertiary endpoints associated with the crossover population: 
• 
To assess safety of tusamitamab ravtansine in terms of 
TEAEs, SAEs, and treatment-related AEs in participants 
previously treated with docetaxel 
• 
Incidence of TEAEs, SAEs, treatment-related 
AEs, and laboratory abnormalities according to 
NCI CTCAE v5.0 in the crossover treatment 
phase 
• 
To assess tusamitamab ravtansine efficacy in terms of 
ORR in participants receiving crossover tusamitamab 
ravtansine treatment after documented disease 
progression on docetaxel 
• 
Objective response rate in the crossover 
treatment phase, defined as the proportion of 
participants who have a complete response 
(CR) or partial response (PR), as best overall 
response reported by the investigator per 
RECIST 1.1 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy, safety and QoL assessments chosen for use in this study is considered well 
established and relevant in an oncology study setting.  
In addition, suitable steps have been built into each of these assessments to ensure their reliability 
and accuracy and to minimize any risks to participant safety. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 3, randomized, open-label, multicenter study comparing tusamitamab ravtansine 
100 mg/m² (Arm A) and docetaxel 75 mg/m² (Arm B) in patients with metastatic nonsquamous - 
NSCLC expressing CEACAM5 and previously treated with platinum-based chemotherapy and 
an immune checkpoint inhibitor. 
To identify nonsquamous NSCLC patients with CEACAM5 positive tumors, there is 
a prescreening phase to perform prospective analyses of CEACAM5 expression on the most 
recent archival tumor tissue. An in vitro diagnostic medical device manufactured for Sanofi is 
provided by a third party. This in vitro diagnostic medical device is a qualitative 
immunohistochemical assay under performance evaluation, called CEACAM5 IHC 769 assay. 
For this analysis, at least 5 × 4 µm slides from FFPE archival tissue should be sent to the central 
laboratory designated by the Sponsor. If less material is available, a participant could be eligible 
only after discussion with the Sponsor, who will confirm that there may be sufficient material for 
key CEACAM5 expression analyses. In case of unavailable archival tissue, a fresh biopsy can be 
considered in participants who have reachable lesion that is suitable for biopsy. This prescreening 
activity can be performed in advance, when participant may be on prior anticancer therapy due to 
the progression of their underlying disease condition.   
Screening visit should be performed in patient whose tumor tissue analyses at central laboratory 
meets the CEACAM5 expression of ≥2+ in intensity involving ≥50% of the tumor cell population.   
The study will have 3 main periods: screening, treatment and follow up. After being screened the 
eligible patients will be randomized (1:1) to one of the following treatment arms: 
• Treatment A: tusamitamab ravtansine (SAR408701) every 2 weeks (Q2W cycle) at the 
dose of 100 mg/m2. 
• Treatment B: Docetaxel every 3 weeks (Q3W cycle) at the dose of 75 mg/m2. 
Treatment allocation will be performed by an Interactive Response Technology (IRT). All eligible 
patients will be randomly assigned to either of the experimental arm or the control arm in 
a 1:1 proportion. Allocation to the 2 treatment arms will be done using stratified randomization 
based on Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), previous 
ICI treatment (sequential versus combination with chemotherapy) and geographical region 
(Asia versus Western Europe + Australia + North America versus Rest of the World [RoW]).  
4.1.1 Duration of the study period  
The duration of the study for a participant prescreened and CEACAM5 positive will include 
a period for screening of up to 28 days. The cycle duration is 14 days for tusamitamab ravtansine 
and 21 days for docetaxel therapy.  
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The expected treatment period for participants who benefit from study intervention may vary, 
based on progression date.  
After discontinuation of study intervention, participants will return to the study site approximately 
30 days (±5 days) (for end-of-treatment [EOT] assessments) after the last IMP administration or 
before the start of another anticancer therapy, whichever is earlier.  
After the EOT visit, during the FU visits, the participants will be monitored for all ongoing related 
AEs and regardless of relationship all the SAEs and adverse event of special interest (AESIs) until 
resolution or stabilization (ie, an event ongoing without any change for at least 3 months). 
All new related AEs, SAEs, or Events of Special Interest, including deaths will be followed until 
resolution or stabilization. 
For participants who have progressive disease, follow up visits will be performed every 12 weeks 
until OS study cut-off date or death (whichever comes first), unless the participant is allocated to 
crossover tusamimatab ravtansine treatment. In addition, if the participant discontinues study 
intervention for reasons other than progression, the participant should undergo a tumor assessment 
and a follow-up visit every 8 weeks until radiological disease progression, death, final study cut-
off (OS cut-off date), or withdrawal of participant’s consent, whichever comes first. 
The total estimated duration of enrollment will be approximately 50 months. The expected 
duration of treatment for participants who benefit from study intervention may vary, based on 
progression date; but median expected duration of study per participant is estimated as median 
9 months in docetaxel arm (1 month for screening, 4 months for treatment, and 4 months for the 
EOT and follow-up visits) and 12.5 months in the tusamitamab ravtansine arm (1 month for 
screening, 6.5 months for treatment, and 5 months for EOT follow-up), excluding any potential 
impact of the crossover phase.  
4.1.2 Crossover treatment phase (if implemented)  
Crossover to tusamitamab ravtansine treatment may be implemented by the Sponsor for 
participants randomized to docetaxel upon progression, in the case that: 
• the final PFS outcome is statistically significant, and  
• statistical power for final analysis of the primary endpoint of OS is expected to not be 
significantly altered 
The decision to implement the crossover phase will be communicated to sites by the Sponsor in 
writing after the final analysis of PFS/IA of OS at 58% IF. The decision for each participant to 
receive crossover treatment with tusamitamab ravtansine will be based on the Investigator’s 
discretion after documented PD per RECIST 1.1 as assessed by the Investigator and confirmed by 
the Sponsor after review of the eCRF data.  
Intolerance to chemotherapy, withdrawal of consent, or clinical progression without documented 
radiological progression per RECIST 1.1 is not sufficient for eligibility for crossover to 
tusamitamab ravtansine. Participants allocated to crossover tusamitamab ravtansine treatment will 
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come to the clinic every 2 weeks for treatment and follow-up procedures as detailed in 
Section 1.3.2. 
Treatment with tusamitamab ravtansine during the crossover phase will continue until disease 
progression, unacceptable AEs, participant’s decision to discontinue the study, or Investigator 
discretion, whichever occurs first. An EOT visit will be performed 30 (±5) days after the last 
crossover dose for safety follow-up.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Lung cancer is the leading cause of death and only 18% of all lung cancer patients are alive 
5 years or more after initial diagnosis. Based on histology, therapy and prognosis, lung cancer is 
divided into 2 major classes: small-cell lung cancer (SCLC) and non–small-cell lung cancer 
(NSCLC). NSCLC accounts 80% of lung cancer and it includes 2 major subtypes: nonsquamous 
carcinoma (including adenocarcinoma, large-cell carcinoma, and other subtypes) and squamous-
cell (epidermoid) carcinoma. Adenocarcinoma is the most common subtype of nonsquamous 
NSCLC (11).  
The past decade has dramatically changed the approach on diagnosis and treatment of lung cancer 
with the concept of personalized medicine, which led discovery of several therapeutic options that 
are only approved for treatment of patients with specific histopathologic characteristics (16). 
Accurate pathologic assessment with tumor mutation profile and staging are essential for 
treatment decision. In general, systemic therapy is recommended for patients with metastatic 
(stage IV) disease, especially with disseminated metastasis. The type of systemic therapy depends 
on the histologic type, whether there are genetic alterations that can be targeted for therapy, and 
the performance status of the patient.  
In the advanced setting, platinum-based chemotherapy was considered the gold standard, with 
evidence of improved survival, symptom control, and superior quality of life compared to best 
supportive care.  After improvement of biomarker testing for genetic alterations, the number of 
available targeted therapies has been increasing, and targeted therapy has been shown to decrease 
tumor burden, decrease symptoms, and dramatically improve the quality of life for patients with 
specific genetic alterations.   
Doublet chemotherapy regimens are recommended as first-line chemotherapy for nonsquamous 
NSCLC patients whose tumors are negative for ALK and ROS1 re-arrangement and sensitizing 
EGFR mutations and have PD-L1 expression <50% or unknown. Based on genetic profiling, 
targeted therapies maybe considered as first line before, or as second line therapy after, 
platinum-based chemotherapy.  
Immune-check point inhibitors are recommended as subsequent therapy for all patients, with 
reported data on improved survival, longer response duration and better safety profile when 
compared to chemotherapy. Current data suggest that patients with EGFR mutations or ALK 
rearrangement have a low response rate to PD-1 or PD-L1 inhibitors when compared with patients 
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without these alterations; so not considered as recommended subsequent treatment in patients with 
these alterations.  
Docetaxel is still considered as the best control arm in patients with relapsed advanced NSCLC 
patients after platinum-based chemotherapy and ICI, if indicated. The Phase 3 study in subsequent 
therapy for NSCLC, comparing docetaxel in combination with ramucirumab versus docetaxel 
alone reported slightly increased overall survival (10.5 versus 9.1 months, HR 0,86, 
95% CI 0.75-0.98; p<0.023), which is considered as not clinically relevant (11). Docetaxel is 
determined as the control arm in this study as still considered as widely used standard of care in 
the targeted patient population.   
4.3 
JUSTIFICATION FOR DOSE  
In a first-in-human study (TED13751), the dose-escalation phase explored doses between 5 and 
150 mg/m2 administered in cycles once every 2 weeks, and the recommended dosage was 
determined as 100 mg/m2 administered every 2 weeks. There is an ongoing cohort of heavily 
pretreated nonsquamous NSCLC patients with CEACAM5-positive tumors treated with 
tusamitamab ravtansine at the recommended dose of 100 mg/m² every 2 weeks. Preliminary 
results from the first 32 evaluable patients treated showed encouraging antitumor activity in 
heavily pretreated patients with nonsquamous NSCLC CEACAM5 ≥50% (4). This antitumor 
activity was associated with a response rate of 25% per RECIST 1.1 (90% CI 14.70%-39.20%) in 
the response-evaluable population. 
4.4 
END OF STUDY DEFINITION  
There are 3 planned cut-off dates for the study: 
The estimated first trial cut-off date, for the final analysis of PFS and 58% interim analysis of OS 
will be approximately 40 months after FPI 
The estimated second cut-off date for 80% interim analysis of OS will be approximately 
48 months after the FPI. 
The estimated third cut-off date for the final analysis of OS will be approximately 58 months after 
FPI. 
The primary analysis of OS corresponds either to the positive OS interim analysis or the final OS 
analysis.  
Secondary efficacy endpoints will be analyzed and tested at the time of the final PFS analysis if 
PFS and/or 58% IA of OS is significant; if not, at the time of the 80% interim OS (if OS is 
statistically significant), otherwise at the time of the final analysis of OS. 
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the Schedule of Activities for the last participant in the trial 
globally. It will occur at the final study cut-off planned at 58 months after the first participant is 
randomized or when all participants have had the opportunity to complete the EOT visit 30 days 
after the last study treatment administration (main study or crossover treatment), whichever is the 
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latest. In the case that an expanded access program is initiated, participants continuing 
tusamitamab ravtansine treatment at the OS cut-off date may be switched to this access program, 
depending on program details.  
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be ≥18 years of age (or country’s legal age of majority if >18 years) at the 
time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Histologically or cytologically proven diagnosis of nonsquamous NSCLC metastatic 
disease at study entry; - meeting all 3 of the following criteria:  
a) Having progressive disease during or after platinum-based chemotherapy (at least 
2 cycles). 
Maintenance therapy following platinum-based chemotherapy is not considered as a 
separate regimen. Adjuvant/neoadjuvant treatment for a patient who had a relapse with 
metastatic disease during or within 6 months of completion of treatment will be considered 
as first line treatment. 
AND 
b) Having progressive disease during or after one immune checkpoint inhibitor 
(anti-PD-1/PD-L1); this could be given as monotherapy or in combination with platinum-
based chemotherapy (whatever the order).  
AND 
c) Participant with EGFR sensitizing mutation or BRAF mutation or ALK/ROS alterations 
must be able to demonstrate progression of the disease on approved treatments for these 
conditions, in addition to platinum-based chemotherapy and immune checkpoint inhibitor. 
I 03. Participants with CEACAM5 expression of ≥2+ in intensity in archival tumor sample (or if 
not available fresh biopsy sample) involving at least 50% of the tumor cell population as 
demonstrated prospectively by a centrally assessed ICH assay. At least 5 × 4 µm slides 
from FFPE tumor tissue are required. If less material is available, patient could still be 
eligible after discussion with the Sponsor who will assess and confirm that there is 
sufficient relevant material for key evaluations. 
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I 04. At least one measurable lesion by RECIST v1.1 as determined by local site investigator 
/radiology assessment. Irradiated lesion can be considered measurable only if progression 
has been demonstrated on irradiated lesion.   
I 05. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
Sex 
I 06. Male or female 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of highly effective contraception for those participating in clinical studies. 
a) Male participants 
Male participants: A male participant must agree to use contraception methods 
(see Appendix 5, Section 10.5) during the intervention period and for at least 6 months 
after the last dose of study intervention. Men being treated with docetaxel should be 
advised to seek advice on conservation of sperm prior to treatment. 
b) Female participants 
Female participants: A female participant is eligible to participate if she is not pregnant 
(see Appendix 5, Section 10.5), not breastfeeding, and at least one of the following 
conditions applies: 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 
(Section 10.5). 
OR 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 
(Section 10.5) during the intervention period and for at least 7 months after the last 
dose of study intervention. 
Informed Consent 
I 07. Capable of giving signed informed consent as described in Appendix 1, Section 10.1.3, 
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.  
Inclusion criteria added with amendment 5 for eligibility for the crossover treatment phase (if 
implemented as detailed in Section 4.1.2): 
Retesting of tumor CEACAM5 status is not required. Participants will be considered eligible for 
crossover tusamitamab ravtansine treatment if they meet all the following criteria.  
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I 801. Documented radiological progression per RECIST v1.1 as assessed by the Investigator 
during or after study treatment with docetaxel. 
I 802. Written ICF for the crossover treatment phase is signed by the participant in compliance 
with the requirements and restrictions listed in the ICF and in this protocol (Appendix 1, 
Section 10.1.3).  
I 803. At least one measurable lesion by RECIST v1.1 as determined by local site 
investigator/radiology assessment. An irradiated lesion can be considered measurable only 
if progression has been demonstrated on the irradiated lesion. 
I 804. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
I 805. Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of highly effective contraception for those participating in clinical studies. 
a) Male participants 
Male participants: A male participant must agree to use contraception methods 
(see Appendix 5, Section 10.5) during the intervention period and for at least 6 months 
after the last dose of study intervention. Men being treated with docetaxel should be 
advised to seek advice on conservation of sperm prior to treatment. 
b) Female participants 
Female participants: A female participant is eligible to participate if she is not pregnant 
(see Appendix 5, Section 10.5), not breastfeeding, and at least one of the following 
conditions applies: 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 
(Section 10.5). 
OR 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 
(Section 10.5) during the intervention period and for at least 7 months after the last 
dose of study intervention. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Untreated brain metastases or history of leptomeningeal disease. Patients with previously 
treated brain metastases may participate provided they are stable (ie, without evidence of 
progression) by imaging performed at least 4 weeks after CNS-directed treatment and at 
least 2 weeks prior to the first administration of study intervention, and any neurologic 
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symptoms have returned to baseline; and there is no evidence of new or enlarging brain 
metastases; and the patient does not require any systemic corticosteroids for management 
of brain metastases within 2 weeks prior to the first dose of study intervention. 
E 02. Significant concomitant illnesses, including all severe medical conditions which, in the 
opinion of the investigator or Sponsor, would impair the patient’s participation in the study 
or interpretation of the results. 
E 03. History within the last 3 years of an invasive malignancy other than the one treated in this 
study, with the exception of resected/ablated basal or squamous-cell carcinoma of the skin 
or carcinoma in situ of the cervix, or other local tumors considered cured by local 
treatment. 
E 04. History of known acquired immunodeficiency syndrome (AIDS) related illnesses or 
known HIV disease requiring antiretroviral treatment, or active hepatitis A, B (defined as 
either positive HBs antigen or positive hepatitis B viral DNA test above the lower limit of 
detection of the assay), or C (defined as a known positive hepatitis C antibody result and 
known quantitative HCV RNA results greater than the lower limits of detection of the 
assay) infection. HIV serology at screening will be tested only for participants enrolled in 
German sites and any countries where mandatory as per local requirements. 
E 05. Nonresolution of any prior treatment related toxicity to < Grade 2 according to NCI 
CTCAE v5.0, except for alopecia, vitiligo and active thyroiditis controlled with hormonal 
replacement therapy. 
E 06. Unresolved corneal disorders or any previous corneal disorder that considered by 
ophthalmologist that patient may have higher risk of drug induced keratopathy. The use of 
contact lenses is not permitted. Patients using contact lenses who are not willing to stop 
wearing them for the duration of the study intervention. 
E 07. Medical conditions requiring concomitant administration of medications with narrow 
therapeutic window, metabolized by CYPs (See Appendix 9, Section 10.9) and for which 
a dose reduction cannot be considered. 
E 08. Medical conditions requiring concomitant administration of strong CYP3A inhibitor 
(see Appendix 10, Section 10.10), unless it can be discontinued at least 2 weeks before 
first administration of study intervention. 
Prior/concomitant therapy 
E 09. Concurrent treatment with any other anticancer therapy. 
E 10. Prior treatment with docetaxel  
E 11. Prior therapy targeting CEACAM5 
E 12. Prior maytansinoid treatment (DM1 or DM4 antibody drug conjugate) 
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E 13. Washout period before the first administration of study intervention of less than 3 weeks or 
less than 5 times the half-life, whichever is shorter, for prior antitumor therapy 
(chemotherapy, targeted agents, immunotherapy and radiotherapy, or any investigational 
treatment. 
E 14. Any major surgery within the preceding 3 weeks of the first study intervention 
administration. 
E 15. Contraindication to use of corticosteroid premedication 
Prior/concurrent clinical study experience 
E 16. Previous enrollment in this study and current participation in any other clinical study 
involving an investigational study treatment or any other type of medical research  
Diagnostic assessments 
E 17. Poor organ function as defined by any one of the following: 
• Serum creatinine >ULN and eGFR <50 mL/min/1.73 m2 as estimated using the aMDRD 
formula. Participants with elevated creatinine are eligible if eGFR ≥50 mL/min/1.73 m2.  
• Total bilirubin >1.0 × ULN. 
• AST, ALT >2.5 × ULN or AST, ALT >1.5 × ULN concomitant with ALP >2.5 × ULN. 
ALP >5 × ULN with normal ALT/AST for patients with bone metastases. 
• Neutrophils <1.5 × 109/L or platelet count <100 × 109/L or hemoglobin <9 g/dL 
Other exclusions 
E 18. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or subjects who are legally institutionalized 
E 19. Any country-related specific regulation that would prevent the subject from entering the 
study - (country specific requirements)  
E 20. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures 
E 21. Participants who are dependent on the Sponsor or Investigator (in conjunction with 
Section 1.61 of the ICH-GCP Ordinance E6) 
E 22. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals 
E 23. Any specific situation during study implementation/course that may raise ethics 
considerations 
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E 24. Hypersensitivity to any of the study interventions, or components thereof (EDTA), or drug 
(paclitaxel, polysorbate 80) or other allergy that, in the opinion of the Investigator, 
contraindicates participation in the study 
Criterion added with amendment 3: 
E 25. Patients treated in advanced stage with any further chemotherapy/immunotherapy in 
addition to the therapies defined in I02 
Exclusion criteria added with amendment 5 for eligibility for the crossover treatment phase (if 
implemented as detailed in Section 4.1.2) 
A participant will be considered ineligible for the crossover treatment phase if any of the 
following criteria apply:  
Medical conditions 
E 801. Untreated brain metastases or history of leptomeningeal disease. Participants with newly 
diagnosed active brain metastases should be treated with local therapy (such as stereotactic 
radiosurgery), and treatment-related acute toxicities should be resolved before allocation to 
crossover tusamitamab ravtansine treatment. 
E 802. Significant concomitant illnesses, including all severe medical conditions which, in the 
opinion of the investigator or Sponsor, would impair the patient’s participation in the study 
or interpretation of the results. 
E 803. Nonresolution of any prior treatment related toxicity to Grade <2 according to NCI 
CTCAE v5.0, except for alopecia, vitiligo, and active thyroiditis controlled with hormone 
replacement therapy. 
E 804. Unresolved corneal disorders or any previous corneal disorder considered by an 
ophthalmologist to place the patient at higher risk of drug-induced keratopathy. The use of 
contact lenses is not permitted. 
E 805. Medical conditions requiring concomitant administration of medications with a narrow 
therapeutic window that are metabolized by CYPs (See Appendix 9, Section 10.9) and for 
which a dose reduction cannot be considered. 
E 806. Medical conditions requiring concomitant administration of strong CYP3A inhibitor 
(see Appendix 10, Section 10.10), unless it can be discontinued at least 2 weeks before 
first administration of study intervention. 
Prior/concomitant therapy 
E 807. Participant received further line of anticancer treatment after docetaxel. 
E 808.  Concurrent treatment with any other anticancer therapy 
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E 809. Washout period before the first administration of tusamitamab ravtansine of less than 
3 weeks from the last dose of docetaxel. 
E 810. Any major surgery within the 3 weeks preceding the first crossover tusamitamab 
ravtansine treatment. 
Prior/concurrent clinical study experience 
E 811. Current participation in any other clinical study involving an investigational study 
treatment or any other type of medical research 
Diagnostic assessment 
E 812. The retreatment criteria as detailed in Section 6.6 are not met. 
E 813. Poor renal function as eGFR <50 mL/min/1.73 m2 per aMDRD formula 
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable.  
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. 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 (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
reasons, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) and for 
whom resolution of the screen failure reason may not be expected within a reasonable time frame, 
the screen failure will be performed. In case the participant is a temporary screen failure  
(ie, prolonged screening), there is no need to have participant re-consent (ie, new ICF signed) 
if the participant finally participates in the trial. However, if the reason for temporary screen 
failure is a reason that might have altered the initial given agreement of the participant to 
participate, the Investigator should ensure the willingness of the participant to continue or redo 
some screening procedures and his/her participation to the trial. This oral agreement should be 
documented in the participant’s chart. All the tests out of protocol window should be repeated and 
entered to the additional pages. If the participant screen failed, he/she may be rescreened; in this 
situation, the rescreened participant should sign a new study ICF (Section 10.1.3). 
During a regional or national emergency declared by a governmental agency, the Investigator/site 
should assess the site’s capacity to conduct procedures for a new participant to be enrolled into the 
study before initiating any screening procedures. Site capacity also should be ensured before 
randomization of a participant. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
intended to be administered to a study participant according to the study protocol. Crossover 
tusamitamab ravtansine treatment will be handled in the same manner as treatment in the main 
study phase, as detailed below.  
Infusion via a central line is preferred, if available. In case of participants with local intolerance 
after peripheral IV infusion, the decision to use a central line is left to the Investigator’s decision. 
Using an infusion-controlled pump, tusamitamab ravtansine will be administered by IV infusion 
over 1hour 30 minutes and docetaxel will be administered by IV infusion over 1 hour.   
Prior to dosing, each participant's dose will be individually prepared by the study pharmacist and 
labeled with protocol number, participant number, and treatment description. 
On Day 1 of each treatment cycle, the patient’s BSA will be determined using the current weight 
and baseline height; dose may not be adjusted if body weight change is ≤5%. For patients with 
a BSA >2.2 m2, the dose will be calculated based on 2.2 m2 BSA. After first study intervention of 
tusamitamab ravtansine, patients should be observed for acute reactions at site up to 4 hours 
depending on any sign of drug induced allergic reaction 
Detail instructions for dilution and administration of the IMP is provided in Pharmacy Manual  
Non-investigational medicinal product 
Premedication 
• Premedication for tusamitamab ravtansine: 
Both SAR408701 and docetaxel had potential risk of infusion related allergic reaction and 
premedication should be used. All the drugs used as premedication will be entered to the 
concomitant premedication page. 
Premedication with histamine H1 antagonist (diphenylhydramine 50 mg PO or equivalent 
[eg, dexchlorpheniramine] given approximately 1 hour before tusamitamab ravtansine 
administration) is required for all participants. If a participant has previously experienced an 
infusion related reaction in a previous tusamitamab ravtansine administration, premedication 
will also include dexamethasone 10 mg IV for future infusions. In case participant does not 
experience any hypersensitivity reactions after 4 cycles, the pre-medications can be 
discontinued at the discretion of the investigator. 
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• Premedication for docetaxel: 
Premedication consisting of oral corticosteroid, such as dexamethasone 16 mg per day 
(eg, 8 mg BID dexamethasone or equivalent corticosteroids) for 3 days starting 1 day prior to 
docetaxel administration, unless contraindicated, can reduce the incidence and severity of 
fluid retention as well as the severity of hypersensitivity reactions. For docetaxel 
premedication, product leaflet or site guidance on administration of docetaxel will be 
followed.
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6.1 
 STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
ARM name 
Tusamitamab ravtansine 
Docetaxel 
Intervention name 
Tusamitamab ravtansine 
Docetaxel 
Type 
Drug 
Drug 
Dose formulation 
Concentrate for solution for intravenous 
infusion 
Concentrate for solution for intravenous 
infusion 
Unit dose strength(s) 
5 mg/mL 
125 mg/25mL 
20 mg/mL 
80 mg/4mL 
Dosage level(s) 
Tusamitamab ravtansine IV 100 mg/m² 
day 1 every 2 weeks 
Docetaxel IV 75 mg/m² day 1 every 
3 weeks 
Route of administration 
intravenous (IV) infusion 
intravenous (IV) infusion 
IMP and Ninvetigation 
IMP 
IMP 
Packaging and labeling 
Tusamitamab ravtansine (SAR408701) is 
supplied in a 30 mL type I glass vial with a 
white plastic flip-off cap. Each IMP kit contains 
1 vial of 125 mg/25 mL of tusamitamab 
ravtansine, labeled with multilingual booklets. 
The content of the labeling at vial and box level 
is in accordance with the local regulatory 
specifications and requirements. 
Docetaxel is supplied in a 7 mL clear 
colorless glass vial with a magenta plastic 
flip-off cap. Each IMP kit contains 1 vial of 
80 mg/4 mL of Docetaxel, labelled with 
multilingual booklets. The content of the 
labeling at vial and box level is in 
accordance with the local regulatory 
specifications and requirements. 
Current/Former name(s) 
or alias(es) 
Tusamitamab ravtansine 
TAXOTERE 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site staff 
may supply 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 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). Partially used and used study treatments 
will be destroyed at the study site according to the standard practices of the site after an accurate 
accountability has been performed and signed by the Investigator (or the pharmacist). A detailed 
treatment log form of the destroyed study treatment will be established with the Investigator 
(or the pharmacist) and countersigned by the Investigator and the Monitoring Team. 
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The Investigator must not destroy the unused IMP unless Sanofi provides written authorization. 
Further guidance and information for the final disposition of used and unused study interventions 
are provided in the pharmacy manual and/or monitoring plan. 
Any quality issue noticed with the receipt or use of an IMP/ non-investigational medicinal product 
(NIMP) (deficiency in condition, appearance, pertaining documentation, labeling, expiration date, 
etc) must be promptly notified to the Sponsor. Some deficiencies may be recorded through 
a complaint procedure (see Section 8.3.8). 
A potential defect in the quality of IMP/NIMP may be subject to initiation of a recall procedure 
by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall the IMP/NIMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party, allow the 
IMP/NIMP to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
• The randomized intervention kit number list is generated centrally by Sanofi. 
• The IMPs are packaged in accordance with this list. 
• The IRT generates the participant randomization list and allocates the intervention number 
and the corresponding intervention kits to the participants according to it. 
• During the trial, administration of tusamitamab ravtansine will be open-label, and no 
attempts will be made to blind administration. An IRT centralized randomization system 
will be used to prevent the investigators from knowing in advance the study intervention 
assignment, as the randomization is the best method to avoid bias. 
• Despite the open-label administration of tusamitamab ravtansine, assessment of outcomes 
will be based on objectively collected data, which are radiological assessments for tumor 
response that will be reviewed by an IRC blinded to study intervention arms.  
• Blinding rules for the Sponsor study team will be detailed in a separate document. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Administration of the IMP will be supervised by the Investigator or Sub-investigator. The person 
responsible for drug dispensing is required to maintain adequate records of the IMPs. These 
records (eg, drug movement form) include the date the IMPs are received from the Sponsor, 
dispensed to the participant, and destroyed or returned to the Sponsor. The packaging batch 
number (IP number) and the treatment number on the vial must be recorded on the drug 
accountability form. The person responsible for drug administration to the participant will 
precisely record the date and the time of the drug administration to the participant. Deviation(s) 
from the prescribed dosage regimen should be recorded in the eCRF. 
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6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Route of use 
• Dates of administration including start and end dates 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient's welfare and are unlikely to interfere with the IMP, they may 
be given at the discretion of the investigator and recorded in the e-CRF. Concomitant medication 
will be recorded in the eCRF from 28 days prior to the first study intervention administration, 
before every cycle during the study treatment period, and for up to 30 days after the final dose of 
study intervention. Once the participant has withdrawn from study treatment, concomitant 
medication should only be recorded if used to treat new or unresolved study treatment-related 
adverse events. 
Concomitant medication may be considered on a case-by-case basis by the Investigator, in 
accordance with the following guidelines:  
• Docetaxel is a CYP3A4 substrate. In vivo studies showed that the exposure of docetaxel 
increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of 
CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of 
docetaxel.  Concomitant use of docetaxel and drugs that inhibit CYP3A4 may increase 
exposure to docetaxel and should be avoided.  
• Palliative radiotherapy may be given for control of pain for palliative intents. Sponsor 
should be notified to obtain prior approval prior to treatment if palliative radiotherapy is 
being considered, and prior to resuming therapy on the study. The irradiated area should 
be as small as possible and should never involve more than 20% of the bone-marrow in 
any given 3-week period. In all such cases, the possibility of tumor progression should be 
ruled out by physical and radiological assessments of the tumor. If the only evaluable 
lesions are to be irradiated, the participant will stop the study intervention. The irradiated 
area cannot be used as a parameter for response assessment. 
• Any background therapy taken by the participant for concomitant illnesses other than 
cancer (eg, hormone-replacement therapy, statin, antihypertensive medication) is allowed.  
• Bone-targeting approved drugs (eg, bisphosphonate or denosumab) are allowed if there is 
no dose increase within 12 weeks prior to the randomization in the current study, and the 
patient remains at the same dosage throughout the study treatment. 
• Supportive treatment as medically indicated for the patient's well-being may be prescribed 
at the Investigator's discretion. Every medication or treatment taken by the patient during 
the trial and the reason for its administration must be recorded on the eCRF. 
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The following concomitant treatments are not permitted during this study: 
• Concurrent treatment with other investigational drugs. 
• Concurrent treatment with any other anticancer therapy not specified in the protocol, 
including immunotherapy, hormonal therapy, targeted therapy or biological therapies. 
• The primary prophylactic use of Granulocyte-Colony Stimulating Factor is not allowed 
during the first cycle but secondary prophylaxis or therapeutic administration are allowed 
as detailed in Section 6.6. 
• The use of prophylactic erythropoietin during the first cycle.  
• Patients treated or intended to be treated with the following drugs presented as CYP 
substrates with narrow therapeutic range (NTR) should be carefully monitored 
(See Appendix 9 Table 17 [Section 10.9]). 
• Concomitant use of strong CYP3A inhibitors should be avoided from 2 weeks before 
tusamitamab ravtansine administration up to the last tusamitamab ravtansine 
administration (See Section 10.10, Appendix 10 Table 18). 
• The use of contact lenses will not be permitted during the study treatment period. 
6.6 
DOSE MODIFICATION  
For the retreatment of patients on Day 1 of each subsequent cycle, the following conditions should 
be met: 
• Neutrophils count ≥1.5 x 109/L. 
• Platelets ≥100 x 109/L. 
• Total bilirubin ≤1.5 x ULN. 
• AST, ALT ≤2.5 x ULN or ≤5 x ULN in case of documented liver metastasis. 
• No IMP-related toxicity Grade >1 (except for alopecia) or baseline severity. 
Dose adjustment and/or cycle delay are permitted in case of adverse reaction. In case of toxicity, 
cycle delays and dose modifications should be implemented according to Appendix 4 
(Section 10.4). Every effort will be made to administer the full dose regimen and maximize dose 
intensity. 
Dose adjustments will be made according to the worst grade of adverse reaction observed within 
a cycle. If a participant experiences several adverse reactions and there are conflicting 
recommendations, the most conservative dose adjustment recommended should be followed. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other AE that, in the opinion of the Investigator, 
warrants discontinuation. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor unless required for immediate participant safety. 
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All changes to study treatment administration must be recorded in the eCRF. 
In the event of neutropenia, therapeutic G-CSF should be administered according to the current 
American Society of Clinical Oncology (ASCO) guidelines (8). In case of neutropenia or febrile 
neutropenia, prophylactic G-CSF should be started and in case of second episode beside 
prophylactic G-CSF, then dose should be reduced.   
The acceptable treatment windows for tusamitamab ravtansine and docetaxel administrations are 
3 days and 4 days respectively.   
One dose reduction is allowed for a participant in either arm in the main study or for 
a tusamitamab ravtansine crossover participant for a safety reason. Dose delay is allowed for 
safety management. Retreatment of patients that require more than 1 month dose delay need to be 
justified with case-by-case risk-benefit assessment. See Table 12 in Appendix 4 (Section 10.4) for 
guidance in dose modification or discontinuation. Approved product label should be followed for 
patient receiving docetaxel treatment for supportive care and dose modification requirement due 
to not listed adverse events. During the conduct of the study, if a second dose reduction may be 
needed, it should be decided upon case-by-case discussion with the Sponsor.    
In case a dose reduction is necessary, the study intervention will be administered as follows:  
Drug name 
Starting dose 
Reduced dose 1 
Reduced dose 2a 
Tusamitamab ravtansine 
100 mg/m2 Q2W 
80 mg/m2 Q2W 
65 mg/m2 Q2W 
Docetaxel 
75 mg/m2 Q3W 
60 mg/m2 Q3W 
50 mg/m2 Q3W 
a A second dose reduction for a participant for toxicity should be implemented only after discussion of the case with the Sponsor. 
The same rules for study intervention dose modifications as well as safety management 
(Appendix 4 [Section 10.4]) are applicable for crossover tusamitamab ravtansine treatment.  
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
As per discretion of the Investigator. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
The study intervention should be continued until the documented progressive disease whenever 
possible. Permanent study intervention discontinuation before disease progression should be 
discussed with the investigator. Any study intervention discontinuation must be fully documented 
in the eCRF. 
If study intervention is permanently discontinued, the participant will remain in the study for 
tumor assessment until PD and to be evaluated for survival status until OS cut-off date. See the 
SoA (Section 1.3) for data to be collected at the time of discontinuation of study intervention. 
Study intervention should be discontinued in any of the following cases: 
1. Unacceptable AE. 
2. Disease progression. 
3. Poor compliance to the study protocol. 
4. Other such as concurrent illness, that prevents further administration of study intervention. 
For the patients who discontinue all study treatment after documented PD during or after main 
study treatment or crossover tusamitamab ravtansine treatment, survival status will be assessed 
every 12 weeks up to the OS study cut-off date. See the SoA (Section 1.3) for data to be collected 
at the time of intervention discontinuation and follow-up and for any further evaluations that need 
to be completed. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including 
tumor assessment, safety laboratory assessment and immunogenicity sample, if appropriate. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
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7.1.2 Temporary discontinuation  
Temporary intervention discontinuation (ie, prolonged cycle delay) may be considered by the 
Investigator because of suspected AEs or disruption of the clinical trial due to a regional or 
national emergency declared by a governmental agency (Appendix 12 [Section 10.12]). For all 
temporary intervention discontinuations (ie, prolonged cycle delay), the duration should be 
recorded by the Investigator in the appropriate pages of the eCRF. 
If the temporary discontinuation corresponds to more than 1 month delay of study intervention, all 
measures should be taken to ensure the participant’s wellbeing, and the management plan for each 
ongoing patient should be guided by the clinical judgment of the treating physician based on an 
individual benefit-risk assessment and the evolving emergency situation.  
During a regional or national emergency declared by a governmental agency, reinitiation of IMP 
after temporary discontinuation can occur only once the Investigator has determined, according to 
his/her best judgment, that the participant would likely benefit from continued study treatment, 
and the IMP(s) was unlikely to contribute to the occurrence of an event of epidemic 
(eg, COVID-19). The Investigator should discuss the restart of IMP after prolonged cycle delay 
with Sponsor’s Medical Monitor. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study intervention, if possible, an end of treatment 
visit should be conducted, as shown in the SoA (Section 1.3). See SoA for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• The participant who withdrawn from the study will be permanently discontinued both 
from the study intervention and from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
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All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to participate in the study. Participant 
decision to stop intervention should be distinguished from withdrawal of consent for follow-up 
visits and from withdrawal of consent for non-participant contact follow-up, eg, medical record 
checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized in the study or allocated 
to crossover tusamitamab ravtansine treatment. Their inclusion and intervention numbers must not 
be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 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 and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Discontinuation of specific sites or of the study, as a whole, are handled as part of 
Appendix 1 (Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. For a regional or national emergency declared by 
a governmental agency, contingency measures are included in Appendix 12, 
Section 10.12). 
• 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 screened and 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. 
• In patients who prescreened failed limited information will be collected as detailed 
in Section 1.3, to characterize patients that are most likely to express CEACAM5. 
During screening period, demography, medical/surgical and disease history was evaluated. 
Demography includes age, gender, race, and ethnicity. Medical/surgical history includes relevant 
history of previous pathologies and surgeries. Disease history includes the histologic types, stage 
at diagnosis and disease extend at study entry, specific mutations including PD-L1 expression 
status and previous antitumor therapy (type, start and end dates, reason for discontinuation and 
response to the therapy) and smoking history. 
Demographic data (age, gender, race, ethnicity, smoking status); age, histology and stage at 
diagnosis and biomarkers when available [tumor mutation status including PD-L1 expression 
status and circulating CEA) that collected during prescreening visit will be used for baseline 
demographic (except for age at prescreening) and disease characteristics analysis. Age, disease 
extend at study entry and previous antitumor therapy (type, start and end dates, reason for 
discontinuation and response to the therapy) and change in smoking history will be collected at 
screening visit. Age at screening will be considered as baseline demographic. 
8.1 
EFFICACY ASSESSMENTS   
The assessment of PFS and OS with tusamitamab ravtansine compared to docetaxel are primary 
objectives. 
All participants treated must have at least 1 measurable lesion as per RECIST 1.1for inclusion 
based on tumor assessment defined in SoA (see Section 1.3).  
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Tumor assessments will be made at every 8 weeks interval (±5 days window), and scheduled 
assessment time points will not be modified in case of a cycle delay. Thoracic-abdominal-pelvic 
CT-scan or MRI and any other examinations as clinically indicated will be performed to assess 
disease status at baseline, then every 8 weeks during the study treatment period until radiological 
disease progression or OS study cut-off, whichever comes first, and at the end of study treatment, 
except if already done at last cycle. Participants who have EOT visits due to other reasons than 
PD should continue tumor assessment until documented PD or OS study cut-off. Tumor 
assessment should be performed at EOT for patients and without imaging performed within past 
4 weeks. Brain CT-scan or MRI should be performed at baseline and followed only for patients 
with brain lesions at baseline Imaging assessments are to be scheduled using the randomization 
date as the reference date for all time-points and are not to be scheduled based on the date of the 
previous imaging time-point. Imaging assessment delay to conform to treatment delay is not 
permitted. The same tumor assessment technique must be used throughout the study for a given 
lesion/participant. 
The tumor assessment images, excluding those performed during crossover treatment phase, will 
be transferred to the Independent Radiological review Committee for tumor response evaluation.  
Secondary efficacy variables will include the overall response rate (ORR) and the duration of 
response (DoR). 
The RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) criteria will be followed for 
assessment of tumor response, see Appendix 7 (Section 10.7) for details. 
For participants who crossed over to tusamitamab ravtansine after progression on docetaxel 
treatment, tumor assessment will be performed per site local practice starting from first dose of 
crossover tusamitamab ravtansine treatment.  There will be no central reading of tumor imaging, 
and efficacy assessments will be performed by the Investigator per RECIST 1.1. The Investigator 
will report the BOR and date of progression in the eCRF.   
8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SoA (Section 1.3). Safety 
assessments for participants receiving crossover tusamitamab ravtansine treatment will be 
performed per SoA detailed in Section 1.3.2, and crossover safety analyses will be conducted 
separately from those for the main study phase.  
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
(at screening only) and weight will also be measured and recorded.  
• ECOG performance status should be assessed before each IMP administration and at the 
follow-up visit.  
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• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new adverse 
event 
8.2.2 Specific ocular test  
Specific complete ocular tests at baseline and before the start of crossover tusamitamab ravtansine 
treatment will include the following: assessment of ocular/visual symptoms and ocular exams 
including visual acuity, slit lamp under dilatation, and Schirmer’s test.  
Standard specific ocular tests include: 
• Assessment of ocular/visual symptoms, (ie, blurred vision, photophobia, dry eye) at each 
visit before each study intervention.  
• Visual acuity at screening and whenever clinically indicated. 
• Slit lamp under dilatation at screening and whenever clinically indicated. 
• Schirmer’s test at screening and whenever clinically indicated. 
• In participants with any ocular/visual symptom(s) (eg, blurred vision, photophobia) the 
complete ocular tests will be repeated at the time of the occurrence of the ocular toxicity, 
if any regardless of the grade. Then, visual acuity, slit lamp examination under dilatation, 
and Schirmer’s test will be repeated once weekly (if not recommended to have less 
frequent assessment by ophthalmologist based on lesion characteristics) until resolution to 
Grade 1. In case of recurrent ocular toxicity observed in subsequent cycles, visual acuity 
and slit lamp examination under dilatation, and Schirmer’s test will be performed at the 
time of the event onset, then weekly until resolution to Grade 1. Schirmer’s test is 
mandatory for baseline assessment; it can be omitted from further ocular assessments if 
not considered a required examination per reported events category (ie, no 
symptom/findings of dry eye). 
8.2.3 Vital signs  
• Temperature and blood pressure will be assessed. 
• For blood pressure assessment, manual techniques will be used only if an automated 
device is not available. 
• Blood pressure measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones). 
8.2.4 Electrocardiograms  
• Single 12-lead ECG is required at baseline, at each cycle during first 4 cycles of 
tusamitamab ravtansine arm and 3 cycles for docetaxel arm and then every other cycle 
during treatment period (even cycles for tusamitamab ravtansine and odd cycles for 
docetaxel) and at end of treatment for both arms as outlined in the SoA (see Section 1.3). 
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ECG is to be repeated as clinically indicated.  This test can be performed before the study 
intervention administration on the same day or the day before. 
• In addition to before the infusion assessment, single 12-lead ECG is also required within 
30 minutes after the EOI (End of Infusion) at Cycle 1 only for the tusamitamab ravtansine 
arm (see Section 1.3).  
• Single 12-lead ECG will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, and QT intervals. 
8.2.5 Clinical safety laboratory assessments  
• See Appendix 2 at Section 10.2 for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency.  
• These tests will be done at each cycle. During first 2 treatment cycles of the main study 
phase as well as the crossover treatment phase, hematology, and liver function tests 
(ie, ALT, AST, ALP, and total and direct bilirubin) will be assessed weekly.  If Grade 4 
neutropenia occurs, assess ANC every 2-3 days until ANC ≥0.5 x 109/L. In case of 
Grade ≥3 liver function abnormal tests, additional tests will be done every 2 to 3 days until 
recovery to baseline value. Additional tests will be performed when clinically appropriate. 
Tests can be performed on the same day or within the 2 days before initiating study 
intervention. 
• Troponin will be tested at baseline (at screening within 7 days of C1D1), at end of Cycle 4 
for tusamitamab ravtansine and Cycle 3 for docetaxel, and at EOT visit. If the crossover 
treatment phase is implemented, troponin will be tested before the first dose of 
tusamitamab ravtansine at the Cycle 1-crossover visit; after the end of Cycle 4-crossover 
(before administration of tusamitamab ravtansine at the Cycle 5-crossover visit), and at the 
EOT-crossover visit. 
• The Investigator must review the laboratory report, document this review.  
• All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA.  
8.2.6 Guideline for management of adverse event  
The docetaxel label should be followed for management of docetaxel specific adverse event 
if otherwise not specified in the protocol. 
8.2.6.1 Hypersensitivity reactions  
Premedication treatments provided for treatment of hypersensitivity reactions are detailed 
in Section 6.1. 
In case of event of hypersensitivity reactions, please refer to the recommended dose modification 
or discontinuation table (Table 12) in Appendix 4 (Section 10.4). 
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8.2.6.2 Ocular toxicity  
It is recommended that topical artificial tears (and/or hyaluronic ophthalmic gel) are used 
regularly in all patients treated with tusamitamab ravtansine during the study treatment period.  
The patient should be asked about ocular/visual symptoms at each visit, and ocular evaluation 
including visual acuity, slit lamp examination under dilatation, and Schirmer’s test should be 
carried on according to Study Procedures (Section 1.3). Ocular evaluation will be performed at 
baseline (during the screening period and as a baseline safety assessment before the start of the 
crossover treatment), as required during the treatment and at the EOT visit (ie, occurrence of 
ocular symptoms such as blurred vision, photophobia, pain), and when relevant, at FU visit(s). 
The outcome of the examination should be available before infusion of the next cycle. If ocular 
symptoms are present, then a formal ocular examination should be performed. In patients with any 
ocular/visual symptom(s) (eg, blurred vision, photophobia) the ocular evaluation should be 
repeated once weekly if not less frequent assessment recommended by ophthalmologist, until 
resolution to Grade 1. Then the patient should be followed with ocular exam (Slit Lamp and 
visual acuity) at each cycle until total resolution of the event. 
Photographs of the cornea are recommended to be taken at the site, if possible, when ocular 
findings are first documented and to follow progression when relevant. Tonometry and additional 
ocular assessment can be performed at discretion of ophthalmologist when applicable. 
After resuming study treatment, the patient who had Grade ≥2 keratopathy/keratitis should be 
followed with standard ocular exams (ie, Slit Lamp examination under dilatation and Visual 
acuity) by every two cycles, even with no reported symptoms. If no recurrent event during the 
next four cycles, then regular follow-up (ie, symptom assessment at each visit with standard 
ocular exam in case of any ocular sign/symptom) is applied.  
8.2.6.2.1 Keratopathy/keratitis management  
Reversible non-inflammatory, microcystic keratopathy was identified as the DLT during the dose 
escalation process in TED13751 study with tusamitamab ravtansine. At slit-lamp examination, it 
presents as lesions consisting of 100s to 1000s microcysts and/or deposits that are initially 
observed at the periphery of the cornea, the limbus being preserved. The lesions have a centripetal 
distribution and evolve towards the center of the corneal upon resolution, following the natural 
keratinocyte regeneration process. 
For standardization of AE verbatim, keratopathy should be preferred term unless otherwise 
specified by ophthalmologist due to inflammatory findings on eye exams leading to diagnosis of 
keratitis.   
The potential ocular/visual toxicity symptoms could include, but are not limited to, blurred vision, 
dry eye, and photophobia. Curative treatment may be used as recommended by an 
ophthalmologist. 
No primary prophylaxis is recommended but prevention of dry eye with artificial tears and 
avoidance of using contact lenses should be ensured during treatment period. Corticosteroid 
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containing ocular drugs are recommended in case ocular symptom occurs for the management of 
keratopathy/keratitis either and treatment will be performed based on discretion of 
ophthalmologist. Dose modification and recommendations are further described in  
Appendix 4 (Section 10.4).  
8.2.6.3 Management of anemia  
Patients should not start Cycle 1 treatment if hemoglobin is <9.0 g/dL. Red blood cell transfusion 
is allowed during the screening window, but a 2 weeks washout period should be applied. During 
the treatment, erythrocyte transfusion can be given, upon Investigator decision. Erythropoietin can 
be given based on the discretion of the Investigator, except during screening and first cycle. 
Current clinical guidelines should be followed for management of anemia.  
8.2.6.4 Management of neutropenia  
In patients who experienced either febrile neutropenia, neutrophil count <500 cells/mm3 for more 
than 1 week during study intervention, the prophylactic G-CSF should be implemented to ensure 
dose intensity and the dose should be reduced in case of recurrent event even after prophylactic 
G-CSF use.  
If the patient continues to experience these reactions at lower dose, the treatment should be 
discontinued (see Section 6.6). 
8.2.6.5 Liver function tests  
Hepatic enzyme increase has been reported with tusamitamab ravtansine and docetaxel 
administration as monotherapy. Patients should be carefully followed and in case of Grade ≥3 
abnormal liver function tests, additional liver function tests will be done every 2-3 days until 
recovery to baseline value. Tusamitamab ravtansine should be permanently discontinued in case 
of drug induced Grade 4 liver enzyme increase. For stopping rules for docetaxel administration, 
current product leaflet should be followed. 
Grade ≥3 increase events should be reported as adverse events of special interest (AESI). 
8.2.6.6 Peripheral neuropathy  
Patients with a known history of peripheral neuropathies and/or patients taking medications 
(eg, prior anti-tubulin, platinum, and/or taxanes treatments) known to cause peripheral 
neuropathies are at high risk of developing neuropathy. Peripheral neuropathies potentially 
present as signs and symptoms of sensory (paresthesia, dysesthesias, pain, and change in 
proprioception), motor (weakness), and neural dysfunctions. 
There is no further recommendation beyond routine guidance on prevention and treatment of 
peripheral neuropathy.  Cycle delays or modifications should be compliant with Section 10.4.  
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8.2.6.7 Gastrointestinal toxicity  
Based on the clinical observation in TED13751 study, the following side effects have been 
observed regardless of causality: abdominal pain, colitis, constipation, diarrhea, dry mouth, 
erosive colitis (including ulcerative and hemorrhagic), nausea, stomatitis, and vomiting.  
The monitoring of patients for GI toxicities will rely on careful evaluation by routine history and 
physical examination, and standard laboratory examination. Close surveillance of any signs and 
symptoms is required with additional routine blood hematology workup, Hemoglobin, hematocrit, 
WBC with differential, platelet counts, whenever indicated. As 1 case of Grade 4 erosive colitis 
reported, it is recommended to close surveillance of any diarrhea event with further exams when 
clinically indicated. Treatment is per patient condition based on investigator discretion.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
8.3.1 Adverse event of special interest  
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified, or removed during a study by protocol amendment. 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in 
a female partner of a male subject entered in a study with IMP/NIMP; 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3, Section 10.3). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 5, 
Section 10.5) 
• Grade ≥3 keratopathy/keratitis 
• Bundle branch blocks or any conduction defects 
• Grade ≥3 liver enzyme increased (symptomatic or asymptomatic) 
• Symptomatic overdose (serious or nonserious) with IMP/ NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant and defined as at least 
30% above the intended administered dose at each cycle expressed in unit per body 
surface. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).  
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AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (Section 7).  
8.3.2 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the screening ICF at the time points specified in 
the SoA (Section 1.3) and until at least D30 after the last study intervention administration. 
All AE will be collected from the signing of the screening ICF at the time points specified in the 
SoA (Section 1.3) and until at least D30 after the last study intervention administration. 
For participant who was prescreened and had fresh biopsy, only the Adverse Events related to the 
fresh biopsy procedure itself should also be reported in eCRF as general requirement of AE/SAE 
with the reporting time frame interval of 1 month for prescreening period after fresh biopsy). 
For participants in Treatment Arm B crossing over to tusamitamb treatment during the Follow-up 
period, all AEs/SAEs/AESI will be reported starting from the date of the first dose of crossover 
tusamitamab ravtansine treatment up to 30 days after the last dose of tusamitamab ravtansine.  
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
During follow-up period, SAEs regardless of relationship to IMP and IMP-related AEs, which are 
ongoing at the end of study treatment, and new IMP related AE/SAE, will be followed until 
resolution or stabilization. 
8.3.3 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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8.3.4 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  At the pre-specified study end-date, all SAEs, and 
non-serious AEs of special interest (as defined in Section 8.3.1), will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.2). Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.5 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a 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. 
• The Sponsor 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 Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• Adverse events that are considered expected will be specified in the reference safety 
information. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.6 Pregnancy  
• Details of all pregnancies in [female participants and, if indicated, female partners of male 
participants] will be collected after the start of study intervention and until one year after 
the birth. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5 
(Section 10.5). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
The following disease related events (DREs) are common in participants with cancer and can be 
serious/life threatening: 
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• Progression of underlying disease, as it is the study endpoint. 
• Death due to progression of underlying disease, if it occurs after 30 days of the last IMP 
administration. All death that occurs within the 30 days of last study intervention should 
be reported as a SAE. 
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the event 
may meet the definition of a SAE. These events will be recorded on the corresponding page in the 
participant’s eCRF within the appropriate time frame. Lack of efficacy will not be reported as an 
AE/SAE, as it is part of efficacy analysis, but signs and symptoms due to lack of efficacy will be 
reported as AEs/SAEs as detailed in Section 10.3.  
8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint from within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
Guidance and information (contact and complaint form) are provided in the pharmacy manual 
and/or monitoring plan. 
8.4 
TREATMENT OF OVERDOSE  
There is no specific antidote for treatment of overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities  
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
• For patients treated with tusamitamab ravtansine during the main study phase, samples of 
approximately 1 mL will be collected for measurement of plasma concentrations of 
tusamitamab ravtansine during Cycle 1 at predose (within 48 hours before Start of 
Infusion), end-of-infusion (EOI; ±10 min), and at D3 (ie, whenever between 24 hours and 
72 hours after administration), at predose (within 24 hours before infusion) from Cycle 2 
to Cycle 7, then every 6 cycles (ie, Cycles 13, 19, 25, etc…). At Cycle 3, in addition to the 
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predose sample, an EOI+1 hour (±10 minutes) sample will be collected. Instructions for 
the collection and handling of biological samples will be provided by the Sponsor. The 
actual date and time of each sample will be recorded. These samples will be tested by the 
Sponsor's designee. Pharmacokinetic sampling times are summarized in Table 3. 
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Table 3 - Pharmacokinetic and antitherapeutic antibody sampling times and labeling 
Cycle  
Day within 
cycle 
All participants treated with tusamitamab ravtansine in the main study phasea 
Time point 
Relative nominal 
timeb 
PK Sample ID ATA sample ID 
Time window allowance 
Cycle 1 
(first cycle of tusatumumab ravtansine) 
1 
SOI 
0 
P00 
AB00 
Within 24 hours before SOI 
EOI 
1.5 
P01 
- 
±10 minutes around the EOI 
3 
48 hours 
48 
P04 
- 
Whenever between 24 and 72 hours 
Cycle 2 
1 
SOI 
0 
P00 
AB00 
Within 24 hours before SOI. Sample must be 
collected even if tusamitamab ravtansine is not 
administered at this visit 
Cycle 3 
1  
SOI 
0 
P00 
AB00 
Within 24 hours before SOI 
EOI+1 hour 
2.5 
P01 
- 
±10 minutes 
Cycle 4 
1 
SOI  
0 
P00 
- 
Within 24 hours before SOI 
Cycle 5 
1 
SOI  
0 
P00 
- 
Within 24 hours before SOI 
Cycle 6 
1 
SOI  
0 
P00 
- 
Within 24 hours before SOI 
Cycle 7 
1 
SOI  
0 
P00 
AB00 
Within 24 hours before SOI 
Cycle 13 and every 6 cycles thereafter 
1 
SOI 
0 
P00 
AB00 
Within 24 hours before SOI 
ATA=antitherapeutic antibody; EOI=end of infusion (ie, when the pump beeps before flush), PK=pharmacokinetic; SOI=start of infusion. 
a Samples will be collected from all participants in the main study phase except the first 12 intensive PK participants treated in China  
b Relative nominal times are calculated based on a theoretical infusion duration of 1 hour. 
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• Data from plasma concentrations of tusamitamab ravtansine will be used for population 
PK analysis by non-linear mixed effects modeling.  Data from previously conducted 
studies might be added for model development. This analysis will involve an estimation of 
inter-patient PK variability, the determination of the population PK parameters estimates 
and the quantitative evaluation of potential effect of patient characteristics on the main PK 
parameters. Empirical Bayesian estimation of individual exposure parameters such as 
maximum concentration (Cmax), trough concentration (Ctrough) and area under the curve 
(AUC) will also be performed. Those individual exposure parameters will then be 
investigated as predictive factors for clinical outcomes including safety and efficacy 
endpoints, if possible.  
The remaining plasma volume may also be used study for further exploratory analysis if deemed 
relevant.  
8.6 
PHARMACODYNAMICS  
8.6.1 Circulating CEA  
Circulating CEA levels collected at baseline and during the treatment and follow-up period at the 
time of laboratory assessment as close as to tumor assessment (and no more than 1-2 weeks) until 
disease progression will be assessed using local testing.  
Venous blood samples of approximately 3 mL (volume may change depending on local laboratory 
assay) will be collected for measurement at the local laboratory. 
Circulating CEA will be collected during the crossover tusamitamab ravtansine treatment every 
4 cycles (ie, end of C4, C8, etc) at the time of routine safety lab assessment, before the next cycle.  
8.7 
GENETICS  
A 20 mL blood sample corresponding to about 10 mL of plasma for tumor cfDNA isolation and 
an additional 2 mL blood sample for germline DNA will be collected at pre infusion of Cycle 1 
Day 1 from participants to perform the required genetic tests (unless not allowed by local 
authorities). Samples are planned to be transferred to a centralized laboratory for cfDNA/DNA 
extraction and mutational profiling of key cancer genes to understand the significance of existing 
or acquired mutation during tusamitamab ravtansine treatment.  
Fragmented cfDNA is released from the tumor in the plasma and can readily be extracted and 
analyzed for mutation of common cancer genes. Subtractive mutation analysis will be performed 
with germline DNA data to identify tumor specific somatic genetic aberrations. Mutation profiling 
analysis will be performed and the potential correlation of specific mutation(s) with clinical 
outcomes will be assessed. 
List (not exhaustive) of the genes that could be mutated is: AKT1, ALK, BRAF, CDKN1B, 
CDKN2A, CDKN2D, EGFR, ESR1, FGFR4, HER2, HRAS, KRAS, MDM2, MED1, MET, NRAS, 
PIK3CA, PTEN, RB1, RET, ROS1, TP53. 
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8.8 
BIOMARKERS  
8.8.1 CEACAM5 expression in tumor tissue samples  
At prescreening, determination of CEACAM5 positivity in tumors will be performed by IHC on 
FFPE slides collected from the most recent available tumor samples or if not available from a 
fresh biopsy. The tumor tissue samples could be from primary tumor biopsy or metastatic site, but 
bone lesions should be avoided, wherever possible. The level of CEACAM5 expression in tumor 
tissues at prescreening will be determined centrally using an in vitro diagnostic medical device 
provided by a third party. CEACAM5 IHC 769 assay is a qualitative immunohistochemical assay 
using monoclonal mouse anti-CEACAM5, Clone 769 intended for use in the detection of 
CEACAM5 protein in FFPE nonsquamous NSCLC tissue using EnVision FLEX visualization 
system on Dako Omnis platform. Analysis will be performed in a central laboratory and will be 
used to assess clinical validity of IHC assay to select patients with CEACAM5 high expression.  
For the analysis, at least 5 × 4 µm slides from FFPE tissue block (ie, archive tumor tissue at 
diagnosis, archive tumor tissue at surgery, or most recent tumor sample) are required.   
The positivity of CEACAM5 is defined by IHC with membrane staining at ≥2+ intensity of 
≥50% of tumor cells. 
8.9 
IMMUNOGENICITY  
For patients treated with tusamitamab ravtansine during the main study phase, blood samples of 
approximately 6 mL will be collected for measurement of antitherapeutic antibodies (ATAs) 
against tusamitamab ravtansine in plasma collected from all participants at predose Cycles 1, 2, 3, 
and 7, and then every 6 cycles (ie, at predose Cycles 13, 19, 25, …). It is required to collect the 
ATA samples at the same time of PK sampling of respective cycles. Additionally, blood samples 
should also be collected at the final visit from participants who discontinued study intervention or 
were withdrawn from the study (end-of-treatment (EOT). These samples will be tested by the 
Sponsor's designee or the sponsor himself.  
Plasma samples will be screened for antibodies binding to tusamitamab ravtansine and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify the 
stability of antibodies to tusamitamab ravtansine and/or further characterize the immunogenicity 
of tusamitamab ravtansine by evaluating for their ability to neutralize the activity of tusamitamab 
ravtansine. Table 3 summarizes sample collection times for immunogenicity assessments. 
8.10 
HEALTH ECONOMICS  
Not applicable. 
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8.11 
PATIENT-REPORTED OUTCOMES  
Participants will complete electronic patient-reported outcomes (ePROs) at predose on Day 1 of 
Cycle 1 (up to within 3 days), then on Day 1 of every 2 docetaxel Cycles, or every 3 tusamitamab 
ravtansine Cycles (ie, every 6 weeks) at the end of treatment visit and one more time at first 
follow-up visit. Completed questionnaires (ePROs) are always considered source document and 
must be filed accordingly. Participants must complete ePROs in clinic (ePRO devices cannot be 
taken home) and prior to having any tests and to any discussion of their progress with healthcare 
personnel at the site. The instruments will be given to the participant in the appropriate language 
for the site. The time estimated to complete the EORTC QLQ-C30 and the EORTC QLQ LC13 is 
approximately 10 to 15 minutes. 
There will be no ePRO assessment during the crossover tusamitamab ravtansine treatment phase.  
8.11.1  EORTC QLQ-C30  
The EORTC QLQ-C30 (C30) is a validated, self-administered, 30-item, cancer specific health 
related quality of life (HRQOL) questionnaire. (17). The C30 is a secondary endpoint in this 
study. The recall period for the C30 is the past week. The C30 assesses global health status/health-
related quality of life (GHS/QoL), functioning, symptoms and financial difficulties due to disease 
or treatment related to cancer. For the GHS/QoL scale and the five functional scales (physical, 
role, emotional, cognitive, and social) higher scores indicate better GHS/QoL or function (higher 
scores better). C30 also assesses symptoms commonly reported by cancer patients and financial 
difficulties due to disease or treatment. For the three C30 symptom scales (fatigue, nausea & 
vomiting, and pain), five symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea 
and perceived financial difficulties item); lower scores indicate fewer symptoms/difficulties 
(lower scores better). Items on the C30 were scored using the C30 scoring algorithms which 
standardize the raw scores to a 0-100 range (18).  
8.11.2 EORTC QLQ-LC13  
The EORTC QLQ-LC13 (LC13) is the lung cancer module of the C30. The LC13 is a secondary 
endpoint in this study. The recall period for the LC13 is the past week. The LC13 assesses 
lung-cancer-associated symptoms (cough, dyspnea, pain, hemoptysis) and side-effects from 
conventional chemotherapy and radiotherapy (sore mouth, hair loss, dysphagia and neuropathy) 
that can impact the HRQOL of lung cancer patients (18). The EORTC QLQ-LC13 contains 
13 items. Items on the LC13 were scored using the LC13 scoring algorithms which standardize 
the raw scores to a 0-100 range (18). Lower scores indicate lower symptomology/symptom 
burden (lower scores better). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
This study is designed to test the following statistical set of hypotheses on PFS and on OS 
respectively as multiple primary endpoints: 
H0:  the survival distribution function of the tusamitamab ravtansine treatment group is lower or 
the same as the survival distribution function for the docetaxel treatment group   
SDF (tusamitamab ravtansine) ≤SDF (docetaxel) 
Versus 
H1: the survival distribution function of tusamitamab ravtansine treatment group is superior to the 
survival distribution function of docetaxel treatment group  
SDF(tusamitamab ravtansine) > SDF (docetaxel) 
where SDF denotes the survival distribution function of the parameter PFS or OS respectively. 
9.2 
SAMPLE SIZE DETERMINATION  
The sample size calculation incorporates multiplicity adjustment for the analyses of the multiple 
primary efficacy endpoints: progression free survival and overall survival.   
Multiplicity of primary endpoints to calculate the sample size is taken into account using 
Bonferroni adjustment with different weights assigned to endpoints: PFS is tested at the 1-sided 
0.01 level and OS is tested at the 1-sided 0.015 level for a strong control of the overall type-I error 
at the 2.5% level. The graphical method of Maurer and Bretz will be applied to provide a strong 
type-I error control for multiple hypotheses (Section 9.6).  
Overall survival:  
For OS, the following assumptions were used: 
• OS has an exponential distribution in both treatment arms. 
• The Docetaxel arm will have a median OS of 9 months. 
• The tusamitamab ravtansine arm will have 28% risk reduction in hazard rate in 
comparison to Docetaxel arm. The targeted HR is 0.72, which corresponds to an 
improvement in the true median OS time from 9 months to 12.5 months. 
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• The first interim analysis for futility and efficacy assessment on OS is planned when 
approximately 221 PFS events or approximately 58% of OS events (approximately 
210 deaths) are observed, whichever comes first.  
• A second interim analysis of OS for assessment of efficacy is planned when 80% of the 
OS events (ie, approximately 290 deaths) are observed. Control of the type I error will be 
ensured using an O’Brien and Fleming spending function. 
• A randomization ratio of 1:1.  
With a total of 363 deaths, a log-rank test at an overall 1-sided 1.5% significance level will have 
81% power to detect a risk reduction of 28% for tusamitamab ravtansine compared to docetaxel in 
OS. 
Progression-free Survival: 
For PFS, the following assumptions were used: 
• Progression-free survival has an exponential distribution in both treatment arms. 
• The docetaxel arm will have a median PFS of 4 months. 
• The tusamitamab ravtansine arm will have 38.5% risk reduction in hazard rate in 
comparison to the docetaxel arm. The targeted HR is 0.615, which corresponds to an 
improvement in the true median PFS time from 4 months to 6.5 months. 
• A randomization ratio of 1:1  
With a total of 221 PFS events, a log-rank test at a 1-sided 1% significance level will have 90% 
power to detect a HR of 0.615 for tusamitamab ravtansine compared to docetaxel in PFS.  
In case or reallocation of α following the multiplicity rules defined in Section 9.6,  
• with 363 OS events at final OS analysis the study has ~86% power for detecting a HR of 
0.72 at a 1-sided α of 0.0249 (see Table 9). 
• with 221 PFS events at final PFS analysis the study has ~95% power for detecting a HR of 
0.615 at a 1-sided α of 0.02485 (see Table 8). 
Approximately 450 randomized participants (225 in each arm) would be adequate to achieve the 
targeted number of events for both PFS and OS. 
Approximately 3534 participants will be prescreened for CEACAM5 status, of whom 530 patients 
will be screened to achieve 450 randomized patients with estimated failure rates of 85% for 
prescreening and 15% for screening. 
Calculations assume the observed current enrollment at 3 participants per month during the first 
7 months and assume 10 participants per month afterwards based on observed enrollment in the 
following year. Based on these enrollment assumptions, cut-off dates (CODs) for final analyses of 
PFS and OS would be approximately 40 and 58 months after FPI, respectively. These cut-offs 
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assume a dropout rate (censoring reason other than cut-off reached) of 17% at 4 months for the 
final analysis of PFS, and a probability of dropout of 3% at 58 months for the final analysis of OS. 
Based on these assumptions, cut-off dates for 58% and 80% IAs of OS are planned approximately 
40 months and 48 months after FPI, respectively.  
Calculations were made using East 6.5.2 software. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 4): 
Table 4 - Populations for analyses  
Population 
Description 
Prescreened 
All participants who signed the prescreening informed consent for CEACAM5 assay 
assessment of their biopsy 
Screened 
All participants who signed screening informed consent for study participation. 
Intent-to-treat (ITT) 
All participants who have given their informed consent and who have had a treatment kit 
number allocated and recorded in the IRT. All analyses using this population will be 
based on the treatment assigned at randomization 
Safety 
All participants randomly assigned to study intervention and who have actually received at 
least 1 dose of study intervention. Participants will be analyzed according to the treatment 
arm they actually received. 
Crossover - treated  
All participants randomized to docetaxel arm and who have received at least 1 dose of 
tusamitamab ravtansine in the crossover phase. Analyses of safety and efficacy on the 
crossover phase will be performed in this population. 
Pharmacokinetic 
All participants from the safety population who have actually received at least 1 dose or 
a part of a dose of tusamitamab ravtansine in the main phase of the study with at least 
1 evaluable concentration postbaseline with adequate documentation of dosing and 
sampling dates and times. 
Immunogenicity 
All participants from the safety population who have actually received at least 1 dose or 
a part of a dose of tusamitamab ravtansine in the main phase of the study with at least 
1 evaluable postbaseline ATA result.  
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before the FPI and will describe the 
participant populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. 
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Planned date for analysis cut-off 
The estimated COD is anticipated to be approximately 40 months after FPI for the final 
PFS/58% OS analyses. The CODs for the 80% OS interim analysis (at approximately 
290 observed deaths) and final analysis of OS (at approximately 363 deaths observed) are 
anticipated to be approximately 8 and 18 months after the final PFS/58% OS COD, respectively 
(48 and 58 months after FPI). 
9.4.1 Efficacy analyses  
All efficacy analyses will be performed on the ITT population unless stated otherwise. All 
primary and secondary efficacy endpoints based on radiological assessments of tumor burden 
(ie, PFS, Objective Response Rate [ORR], and duration of response [DOR]) will be derived using 
the IRC tumor assessment. Analysis based on local radiologist’s/Investigator’s assessment will be 
considered as supportive analyses. A summary of efficacy analyses is provided in Table 5. 
Table 5 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary: 
PFS, OS 
Stratified log-rank for statistical testing. 
Stratified Cox proportional hazard model for HR. 
Kaplan-Meier method for probabilities of being event free at different time points. 
Secondary 
Key secondary 
 
ORR 
Descriptive statistics by treatment arm and Clopper-Pearson method for CI 
calculation. 
Cochran-Mantel Haenszel for statistical testing. 
Time to deterioration (EORTC QOL-C30 and 
LC13) 
Stratified log-rank for statistical testing. 
Stratified Cox proportional hazard model for HR. 
Kaplan-Meier method for median time to deterioration 
Other secondary 
DOR 
Kaplan-Meier method for median duration of response 
Exploratory 
Biomarkers (including CEACAM 5 
expression at study entry) 
Will be described in the SAP 
 CI = confidence interval; DOR = duration of response; HR = hazard ratio; OS = overall survival; ORR = objective response rate; 
PFS = progression-free survival; SAP = statistical analysis plan 
9.4.1.1 Analysis of multiple primary efficacy endpoints  
9.4.1.1.1 Progression Free Survival  
Progression-free survival is defined as the time from the date of randomization to the date of the 
first documentation of objective PD according to RECIST 1.1 definitions or death due to any 
cause before the study cut-off date, whichever occurs first. Primary efficacy analysis will consist 
of PFS comparison between the tusamitamab ravtansine arm and Docetaxel arm through 
a log-rank test procedure stratified by the stratification factors as entered in the IRT. 
See Section 9.6 for details about the type-I error level to be used for statistical testing. 
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The primary analysis of PFS will be based on the following censoring rules: 
• If progression and death are not observed before the PFS analysis cut-off date, PFS will be 
censored at the date of the last valid disease assessment before the cut-off date with no 
evidence of a disease progression performed prior to the initiation of any posttreatment 
anticancer therapies. 
• A participant without an event (death or disease progression) and without any valid 
postbaseline disease assessments will be censored at the day of randomization (Day 1). 
The cut-off date for final analysis of PFS will be the date when approximately 221 PFS events or 
approximately 210 deaths are observed, whichever comes first.  
The HR estimates and corresponding 95% and α-adjusted 2-sided CIs will be provided using the 
Cox proportional hazard model stratified by the same stratification factors as those used for the 
log-rank test described above. Progression-free survival for the 2 treatment arms will be 
summarized using Kaplan-Meier methods and displayed graphically. The median PFS times and 
associated 95% CI will be provided, along with probabilities of being progression-free at different 
time points. 
Sensitivity analyses (eg, different censoring rules and PFS assessed by the Investigator) and 
subgroup analyses of PFS will be specified in the SAP. 
9.4.1.1.2 Overall Survival  
Overall survival is defined as the time from date of randomization to date of death due to any 
cause. If death is not observed before the OS analysis cut-off date, data on OS will be censored at 
the date the participant is known to be alive or at the OS cut-off date, whichever occurs first.  
The cut-off date for the first IA will be the date when approximately 221 PFS events or 
approximately 210 deaths are observed, whichever comes first. Cut-off dates for the second 
interim and final analyses of OS will be when approximately 290 and approximately 363 deaths 
are observed, respectively.  
Primary efficacy analysis will consist of OS comparison between the tusamitamab ravtansine arm 
and Docetaxel arm through a log-rank test procedure stratified by the stratification factors as 
entered in the IRT. See Section 9.6 for details about the type-I error level to be used for statistical 
testing. 
The HR estimates and corresponding 95% and α-adjusted 2-sided CIs will be provided using the 
Cox proportional hazard model stratified by the same stratification factors as those used for the 
log-rank test described above. Overall survival for the 2 treatment arms will be summarized using 
Kaplan-Meier methods and displayed graphically. The median survival times and associated 
95% CI will be provided, along with probabilities of being alive at different time points. 
The significance levels at the interim and final analyses will be determined using O’Brien and 
Fleming α-spending function (see Section 9.5 and Section 9.6). 
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Sensitivity analyses and subgroup analyses of OS will be specified in the SAP. If the crossover 
tusamitamab ravtansine treatment phase is implemented, these may include especially analyses 
adjusting OS for switch to further systemic anticancer therapies (eg, using inverse probability of 
censoring weighting [IPCW] or Rank Preserving Structural Failure Time Model [RPSFTM] 
methods). 
9.4.1.2 Analysis of secondary efficacy endpoints  
Analysis of response-based endpoints (ie, ORR and DOR) and quality of life will be performed 
primarily on the ITT population. 
9.4.1.2.1 Key secondary endpoints:  
See Section 9.6 for details about the level of significance to be used for the CIs of the key 
secondary endpoints.  
9.4.1.2.1.1 Objective response rate 
The ORR on each randomized treatment arm will be estimated by dividing the number of 
participants with objective response (CR or PR as BOR, according to RECIST 1.1) by the number 
of participants from the analysis population of the respective treatment arm.  
BOR is the best tumor response observed from the date of the randomization until disease 
progression, death, cut-off date, initiation of posttreatment anticancer therapy (including 
tusamitamab ravtansine initiated during the crossover), whichever occurs first. 
ORR will be summarized for the ITT population with descriptive statistics at the time of the 
analysis of PFS. In addition, 2-sided CIs will be computed using the Clopper-Pearson method. 
Comparison between the tusamitamab ravtansine arm and the docetaxel arm will be performed 
using Cochran-Mantel Haenszel test with the stratification factors as entered in the IRT. 
See Section 9.6 for details about the type-I error level to be used for statistical testing. 
9.4.1.2.1.2 Time to deterioration in disease-related symptoms, time to deterioration in physical 
function, time to deterioration in role function 
The time to deterioration (TTD) analyses will be conducted on the ITT population. 
Health-related Quality of life (HRQL) is analyzed as TTD through 3 different secondary 
endpoints: 
• TTD in disease related symptoms (composite endpoint of cough, chest pain and dyspnea) 
as determined by EORTC QLQ-LC13 
• TTD in physical function (PF) as determined by EORTC QLQ-C30 
• TTD in role function (RF) as determined by EORTC QLQ-C30 
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The TTD is defined as the time from baseline (Cycle 1, Day 1) until the first ≥10-point change 
from baseline (considered as clinically meaningful change) up to the end of treatment assessment 
before the initiation of further anticancer therapy and the analysis cut-off date.  
For the TTD in disease-related symptoms (cough, dyspnea, pain) from EORTC QLQ LC-13, 
a deterioration will be defined as an increase from baseline score of at least 10 points in any 1 of 
these 3 symptoms. For TTD in PF and RF from EORTC QLQ-C30, a deterioration will be defined 
as a decrease of at least 10 points from baseline score.   
Participants with a non-missing baseline assessment will be censored at the last assessment up to 
end of treatment before the start of further anticancer therapy or before the analysis cut-off date 
(whichever is earlier), provided their symptoms/functional scale had not deteriorated up to that point 
before the analysis cut-off date. A participant without a baseline or postbaseline PRO questionnaire 
or whose baseline scores do not allow further deterioration will be censored at the first 
administration intake (or at randomization date if the participant is randomized and not treated).  
Efficacy analysis will consist of time to deterioration comparison between the tusamitamab 
ravtansine arm and docetaxel arm through a log-rank test procedure stratified by the stratification 
factors as entered in the IRT. See Section 9.6 for details about the type-I error level to be used for 
statistical testing. 
The HR estimates and corresponding 2-sided CIs will be provided using the Cox proportional 
hazard model stratified by the same stratification factors as those used for the log-rank test 
described above. Time to deterioration for the 2 treatment arms will be summarized using 
Kaplan-Meier methods and displayed graphically. The median time to deterioration and 
associated 95% CI will be provided.  
Sensitivity analyses and supportive analyses of the 3 TTD endpoints will be specified in the SAP. 
9.4.1.2.2 Other secondary endpoints:  
9.4.1.2.2.1 Duration of response 
The DOR will only be summarized on the subgroup of participants who have achieved objective 
response in the ITT population.  
The duration of response (DOR) will be defined as the time from the date of first initial 
occurrence of a CR or PR to the date of first documentation of objective PD according to 
RECIST 1.1 before the initiation of any posttreatment anticancer therapy or death due to any 
cause, whichever occurs first.  
For participants with ongoing response at the time of the analysis, DOR will be censored at the 
date of the last valid disease assessment not showing disease progression performed before the 
initiation of any posttreatment anticancer treatment or the analysis COD, whichever occurs first. 
Duration of response for the 2 treatment arms will be summarized using Kaplan-Meier methods 
and displayed graphically, if appropriate. The median DOR and associated 95% CI will be 
provided.  
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9.4.1.3 Analysis of exploratory efficacy endpoints 
The ORR based on local radiologist’s/Investigator’s assessment on the crossover period will be 
summarized in the crossover treated population. For crossover participants, BOR will be reported 
by the Investigator.   
9.4.2 Safety analyses  
All safety analyses will be primarily performed on the Safety Population by actual treatment 
group. For participants who enter the crossover phase to receive tusamitamab ravtansine 
treatment, analyses on the safety population will include all data reported up to the crossover date. 
Safety analyses will be performed separately on the crossover treated population. Summary of 
safety data will be performed by participant. For each of the safety parameters, a baseline value 
will be defined as the last value or measurement taken up to the first dose in the study. For a 
participant who crosses over to tusamitamab ravtansine, a crossover baseline value will be defined 
as the last value or measurement taken up to the first dose of tusamitamab ravtansine in the 
crossover phase. 
A summary of safety analyses is provided in Table 6. 
Table 6 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
No primary endpoint is defined for safety analyses. 
Secondary 
AEs/SAEs and laboratory abnormalities 
 
Descriptive statistics 
Exploratory 
Immunogenicity 
Will be described in the SAP 
AE = adverse event; SAE = serious adverse event; SAP = statistical analysis plan. 
The observation period will be divided into 4 segments:  
• The prescreening period is defined as the time from when the participants give 
prescreening informed consent to the day before the screening informed consent. 
• The screening period is defined as the time from when the participants give screening 
informed consent to the first administration of the IMP. 
• The treatment period is defined as the time from the first dose of IMP up to 30 days after 
the last dose of IMP. For participants randomized to docetaxel who enter the crossover 
phase to receive tusamitamab ravtansine treatment, the treatment period is defined as the 
time from the first dose of IMP up to the last dose of IMP before the crossover +30 days, 
or up to the first dose of tusamitamab ravtansine –1 day, whichever is earlier. 
• The crossover treatment period is defined as the time from the first dose of tusamitamab 
ravtansine after crossover up to 30 days after the last dose of tusamitamab ravtansine.  
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• The posttreatment period is defined as the time starting 31 days after the last dose of IMP 
(including the crossover treatment phase) to study closure or death, whichever comes first. 
9.4.2.1  Analyses of adverse events  
Adverse events will be graded according to NCI-CTCAE v5.0 and classified by system organ 
class (SOC) / preferred term (PT) according to the last available version of the MedDRA 
dictionary.  
• Prescreening AEs are defined as AE occurring during the prescreening period. 
• Screening AEs are defined as any AE occurring during the screening period. 
• Treatment-emergent AEs are defined as AEs that develop, worsen (according to the 
Investigator’s opinion), or become serious during the treatment period.  
• Crossover treatment-emergent AEs are defined as AEs that develop, worsen (in the 
opinion of the Investigator), or become serious during the crossover treatment phase. 
• Posttreatment AEs are defined as AEs that are reported during the posttreatment period.  
The grade will be taken into account in the summary. For participants with multiple occurrences 
of the same PT, the maximum grade will be used  
The primary focus of AE reporting will be on TEAEs. Prescreening, screening, and posttreatment 
AEs will be described separately.  
9.4.2.1.1 Treatment-emergent adverse events 
An overall summary of TEAEs will be provided. The number and percentage of participants who 
experience any of the following will be provided:  
• Treatment-emergent AEs 
• Grade ≥3 TEAEs 
• Grade 5 TEAEs (any TEAE with a fatal outcome during the treatment period) 
• Serious TEAEs 
• Treatment-emergent AEs leading to definitive treatment discontinuation 
• Treatment-related TEAEs 
• Treatment-related TEAEs Grade ≥3 
• Serious treatment-related TEAEs 
• AESI 
Number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE v5.0 grade (all grades and Grade ≥3) for the safety population. 
Similar summaries will be prepared for treatment-related TEAEs, TEAEs leading to definitive 
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discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, 
AESIs, and AEs/SAEs occurring during the posttreatment period. 
In addition, an overview of Grade 5 AEs will be provided summarizing the number (%) of 
participants with any:  
• Grade 5 AE (TEAE and posttreatment) 
• Fatal TEAE 
• Grade 5 TEAE (TEAE with a fatal outcome during the treatment period) 
• Any grade TEAE with a fatal outcome during the posttreatment period. 
• Posttreatment Grade 5 AE (excluding a TEAE that worsened to Grade 5 during the 
posttreatment period) 
Selected summaries of crossover TEAEs will be provided for the crossover treated population. 
9.4.2.2 Deaths  
The following summaries of deaths will be generated: 
•  Number (%) of participants who died by study period (treatment, crossover treatment 
[if applicable], posttreatment) and reasons for death (disease progression, AE, or other 
reason). 
• Deaths in non-randomized participants or randomized but not treated participants. 
• All TEAEs leading to death by primary SOC and PT showing number (%) of participants. 
Similar outputs will be provided for the crossover treated population. 
9.4.2.3 Analyses of clinical laboratory evaluations  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Hematology and blood chemistry results 
will be graded according to the NCI-CTCAE v5.0, when applicable. Number and percentage of 
participants with laboratory abnormalities (ie, all grades and by grade) using the worst grade 
during the treatment period (or crossover treatment period, as applicable) will be provided for the 
safety population (and crossover treated population, as applicable). 
When the NCI-CTCAE v5.0 grading scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
9.4.2.3.1 Analysis of immunogenicity  
Incidence of ATAs will be provided for the immunogenicity-evaluable population. 
Immunogenicity analysis and the potential impact on PK, safety and efficacy will be described in 
the SAP. 
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9.4.3 Other analyses  
The population PK analyses will be described in the Population PK analysis plan (PAP) provided 
by PKDM Modeling and Simulation group. The results of the population PK analysis will be 
presented separately from the main clinical study report (CSR). 
Biomarker analyses (including CEACAM5 at study entry) and exploratory PK relationship with 
efficacy, safety and other biomarker will be described in the SAP. 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
9.5 
INTERIM ANALYSES 
The Statistical Analysis Plan will describe the planned IAs in greater detail.   
A first IA for efficacy and futility assessment on OS will be performed when approximately 
221 PFS events or approximately 210 deaths (58% of OS events) are observed, whichever comes 
first. At that time, final PFS analysis will also be performed. The cut-off date for final analysis of 
PFS and 58% IA of OS will be approximately 40 months after FPI. A second IA for efficacy 
assessment of OS will be performed when approximately 80% of targeted number of deaths will 
be available (ie, approximately 290 deaths). The cut-off date for the second IA of OS will be 
approximately 48 months after FPI. 
The futility rule of the first IA is described below. Of note, the stopping boundaries for the 
nonbinding futility assessment will be based on the observed OS HR using a Cox proportional-
hazard model stratified by the stratification factors as entered in the IRT. If the observed OS HR is 
>0.90, then the study may be stopped (nonbinding futility assessment). Table 7 summarizes the 
probabilities of crossing the futility boundary under different assumptions for the true HR.  In 
addition, the predictive power for the final analysis of OS given the interim data could be used as 
supportive information to guide the decision.  
Table 7 - Probabilities of crossing the futility boundary on overall survival under different 
assumptions for the true hazard ratio 
H0 (HR=1) 
HR=0.95 
HR=0.85 
HR=0.80 
H1 (HR=0.72) 
77.7% 
65.2% 
33.9% 
19.7% 
5.3% 
 
Abbreviations: H0=null hypothesis (nonsuperiority of tusamitamab ravtansine treatment to docetaxel treatment); H1: superiority of 
tusamitamab ravtansine treatment to docetaxel treatment; HR=hazard ratio. 
The stopping boundaries for efficacy on the OS endpoint will be derived based on the O’Brien 
and Fleming α-spending function for type I error and will depend on the actual number of events 
observed at the time of each interim analysis.   
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If exactly 210 deaths are observed (58% information fraction), and exactly 290 deaths (80% 
information fraction) are observed respectively at the time of the first and second IAs of OS, 
boundary properties for the planned IAs of overwhelming efficacy for OS are detailed in Table 9.  
The 1-sided nominal significance level to declare superiority of tusamitamab ravtansine at the 
final analysis (approximately 363 deaths) is 0.0130 (the corresponding threshold for the observed 
HR to reach this significance level is 0.792).  
The analysis on PFS will not be updated at the time of any subsequent OS analysis. If this primary 
analysis on PFS is significant, this analysis will be used to support registration of tusamitamab 
ravtansine. Regardless of the PFS data, the study will continue until the final analysis of OS, 
unless either interim analysis of OS shows overwhelming efficacy or futility. Note that if futility 
is shown, the Sponsor may still decide to continue the study (nonbinding properties). 
At the time of the 58% interim analysis of OS, the conditional power for final analysis of OS 
based on the observed OS data until that time point will be examined, considering the potential 
impact on the power for the final OS analysis, to assess whether the tusamitamab ravtansine 
crossover phase can be implemented. 
9.5.1 Data Monitoring Committee (DMC)  
This study will use an independent DMC. Details on DMC structure and role are presented in 
Section 10.1.5. 
The first DMC meeting will be set up to review early safety results (eg, after approximately 
50 participants enrolled into the study or after 6 months after first participant randomized 
whichever comes earlier), and then periodically. Ad hoc DMC meetings may also be held if a 
significant safety issue or an issue deemed important for discussion arises on this or other 
tusamitamab ravtansine studies. After each meeting, the DMC will make recommendations to the 
Sponsor’s representatives regarding the continued safety of treating ongoing and future study 
participants, as well as the course of action regarding the conduct of the study. 
During the course of the study, an external statistician (independent from the sponsor) will 
perform the unblinded final analysis of PFS and interim analyses of OS, as well as unblinded 
interim safety and efficacy analyses for the purpose of the DMC data review. Access to these data 
and analyses will be restricted to the DMC members and to limited personnel from the Sponsor 
involved in the submission, if applicable. 
For the final analysis of PFS and the IAs of OS, after review of the results by arm, the DMC will 
make recommendations on continuation of the study or not, and on unblinding or not according to 
the criteria prespecified by the Sponsor.  
9.6 
MULTIPLICITY 
The trial uses the graphical method of Maurer and Bretz (19) to provide a strong type-I error 
control for multiple hypotheses. Figure 1 shows the initial 1-sided α-allocation for each 
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hypothesis (in the ellipse) on the endpoints of PFS, OS, ORR and QoL. The weights for 
reallocation from each hypothesis to the others are represented in the boxes on the lines 
connecting hypotheses.  
Figure 2 - Type I error reallocation strategy  
 
*If both PFS and OS are significant, based on the graphical testing procedure, the entire α=0.025 will be reallocated to the testing of ORR. 
Abbreviations: ORR=objective response rate (complete response +partial response ) OS=overall survival; PFS=progression-free survival; 
QoL=quality of life. 
PFS 
PFS hypothesis will be tested at α=0.01. When OS test is significant, the PFS hypothesis may be 
tested at α=0.02485 (0.99*0.015+0.01) (re-allocated α). 
Table 8 demonstrates the bounds and boundary properties for PFS hypothesis testing. The HR of 
PFS between the experimental group and control group is assumed to be 0.615. 
Table 8 - Boundary properties for planned final analysis of PFS  
Boundary 
α=0.01 
α=0.02485 
IF: 100% 
Critical value 
-2.326 
-1.963 
N: 351 
Events: 221 
Threshold for the observed HR to be significant 
0.731 
0.768 
Months:40 
Prob of significant if true HR=0.615 
0.901 
0.951 
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With 221 PFS events at final analysis the study has ~95% power for detecting a HR of 0.615 at 
a 1-sided α of 0.02485.  
OS 
The OS hypothesis will be tested at α=0.015. When PFS test is significant, the OS hypothesis may 
be tested at α=0.0249 (0.99*0.01+0.015) (re-allocated α). Table 9 demonstrates the bounds and 
boundary properties for OS hypothesis testing. The HR of OS between the experimental group 
and control group is assumed to be 0.72.  The table summarizes the α spending for interim and 
final analyses based on the planned number of events. The actual α spending will be based on the 
actual number of events included in the analyses and determined by the Lan-DeMets O'Brien-
Fleming spending function at the time of interim and final analyses. 
Table 9 - Boundary properties for planned analyses of OS  
Analysis 
Boundary 
α=0.015 
α=0.0249 
First IA 
 
 
 
IF: 58% 
Critical value 
-2.992 
-2.728 
N: 351 
Significance level (1-sided) 
0.0014 
0.0032 
Events: 210  
Threshold for the observed HR to be significant 
0.662 
0.686 
Months: 40 
Prob significant if true HR=1 
0.0014 
0.0032 
 
Prob significant if true HR=0.72 
0.2702 
0.3641 
Second IA 
 
 
 
IF: 80% 
Critical value 
-2.508 
-2.287 
N: 436 
Significance level (1-sided) 
0.0061 
0.0111 
Events: 290 
Threshold for the observed HR to be significant 
0.745 
0.764 
Months: 48 
Cumulative prob significant if true HR=1 
0.0065 
0.0120 
 
Cumulative prob significant if true HR=0.72 
0.6178 
0.6997 
Final 
 
 
 
IF: 100% 
Critical value 
-2.227 
-2.031 
N: 450 
Significance level (1-sided) 
0.0130 
0.0211 
Events: 363 
Threshold for the observed HR to be significant 
0.792 
0.808 
Month: 58 
Cumulative prob of significant if true HR=1 
0.0145 
0.0236 
 
Cumulative prob of significant if true HR=0.72 
0.8143 
0.8573 
Abbreviations: IA=interim analysis; IF=information fraction; HR=hazard ratio; prob=probability. 
ORR 
Following the graphical testing procedure, the ORR hypothesis will be tested at the following 
α level shown in Table 10 depending on the results from testing PFS and OS. ORR will be tested 
if either PFS or OS is significant. 
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Table 10 - ORR hypothesis testing level  
α level for testing ORR hypothesis 
Condition 
0.0001 
if only PFS is significant, and OS is not significant 
0.00015 
if only OS is significant at either IA or final analysis, and PFS is not significant 
0.025 
if PFS is significant and OS is significant at either IA or final analysis 
Abbreviations: IA=interim analysis; OS=overall survival; PFS=progression-free survival. 
Then, a user-defined spending function will be applied to the α level using a fixed α level of 
0.00001 for ORR hypothesis testing at each IA, and a fixed α level for final analysis, computed as 
(α level for testing ORR [as defined in Table 10] - 2 × 0.00001). 
TTD endpoints for QoL  
If ORR is significant, then QoL key secondary endpoints will be tested at the same significance 
level as ORR following a hierarchical order: TTD in disease-related symptoms, TTD in physical 
function, TTD in role function. The procedure, including the user-defined α-spending function, is 
similar to the hypothesis testing of ORR.  
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 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 and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, 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 amendments to the 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 the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
• 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 authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented 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 
authorized representative. 
A participant who requires prolongation of the screening period (temporary screen failure) is not 
required to sign another ICF. Participants who screen failed and then rescreen need to re-sign 
a new screening ICF; there will be no re-prescreening for CEACAM5 expression and initial value 
will be applicable, with respect to maximum allowed window for prescreening.  
The ICF will contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens analysis to be used for exploratory research. Participants who 
decline to participate in this optional research will not provide this separate signature. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation). 
Data collected must be adequate, relevant, and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
several regulatory agencies (eg, on afro American population for the FDA or on Japanese 
population for the Pharmaceuticals and Medical Devices Agency in Japan). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
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names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Committees structure  
Data Monitoring Committee (DMC):  
Independent from the Sponsor and Investigators, the DMC role will include 3 external members 
(2 oncologists and 1 statistician) and will meet regularly to: 
• Review progress of the trial 
• Review the safety of data 
• Advise the sponsor and the study chairmen on potential modifications or communications 
that may be necessary to ensure the participant safety or protect the scientific integrity of 
the trial. 
The DMC will also be in charge of reviewing the formal interim analysis for OS and the final 
analyses for PFS (please see Section 9.5.1). 
Specific details regarding composition, roles and responsibilities, governance, requirements, and 
documentation of DMC reports will be described in the DMC charter.  
DMC may invite ad hoc experts (eg, ophthalmologist) for safety follow-up, when relevant. 
Independent Radiological review committee (IRC): 
Independent from the Sponsor and Investigators, the IRC will review the tumor assessment data 
as central reading for response evaluation in blinded manner. 
All the tumor assessment imaging performed during the main study phase will be sent for central 
review. The same modality of tumor assessment should be used throughout the study for each 
individual patient. Treatment continuation will be decided by investigator according to response 
evaluation by local radiologist/ Investigator but statistical analyses for efficacy parameters of the 
main study phase will be performed based on IRC. 
Process will be defined in related manuals.  
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10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, clinicaltrialsregister.eu, and sanofi.com, as well as some 
national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance, and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to https://vivli.org. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: https://vivli.org. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of 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. 
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• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• Every data point recorded in the CRF must have a source document (SD).  The 
investigator/ delegated site staff will report all the original data in the participant’s medical 
chart or in a study specific SD created by him/her. If such document is used, the template 
should be reviewed by the CRA. A list of SD and their location will be filed in the 
Investigator Study File. 
• 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 reported on the CRF or 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. 
10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
10.1.10 
Publication policy  
• 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 Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
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• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 11 will be performed by the local laboratory 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations 
• Pregnancy testing will be performed in all WOCBP at baseline and at end of treatment 
visit, as detailed in SoA (Section 1.3). Women of Childbearing potential must have 
a negative serum pregnancy test result within 7 days prior to the initial intervention and at 
the end of treatment evaluation (between D22 and D30 after the last IMP administration). 
The serum/urine pregnancy test will also be performed before each cycle, only in countries 
where it is a regulatory requirement. 
 
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Table 11 - Protocol-required safety laboratory assessments (local laboratory)  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Coagulation 
INR 
 
 
Blood chemistrya 
Urea or Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose  
 
LDH 
 
Albumin 
 
Potassium 
 
Sodium 
 
Calcium 
 
Phosphate 
 
Chloride 
 
Magnesium 
 
Bicarbonateb 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total bilirubin and conjugated bilirubin 
 
Total protein 
 
Troponin 
Other screening tests 
• 
Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
• 
Highly sensitive [Serum or urine] human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)c   
• 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg] ± Hepatitis B core 
Antigen or Hepatitis B Viral DNA, and hepatitis C virus antibody or other tests) if 
applicable as per local regulatory requirement] 
The results of each test must be entered into the CRF 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are given in 
Section 8.2.6.5. All events of grade ≥3 AST/ALT increase should be reported as adverse events of special interest (AESI). 
b Bicarbonate may be omitted at countries where its assay is not performed as part of the routine chemistry panel.  
c Serum pregnancy test will be performed at screening and end of treatment. If required to repeat during treatment period, local urine testing will 
be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, blood chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg: 
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
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• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
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immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Monitoring team in lieu of completion of the Sanofi/AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
Sanofi. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
Monitoring team. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories NCI CTCAE v5.0: 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
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• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Sanofi. However, it is very important that 
the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Monitoring Team. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Monitoring 
Team to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAES 
SAE reporting to Sanofi via an electronic data collection tool 
• The primary mechanism for reporting an SAE to Monitoring Team will be the electronic 
data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Monitoring Team by telephone. 
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• Contacts for SAE reporting can be found in Investigator Study File. 
SAE reporting to Sanofi via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Monitoring Team. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in Investigator Study file. 
10.4 
APPENDIX 4: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS  
Table 12 - Recommended dose modification or discontinuation  
Event 
Symptoms 
severity (Nadir)  
(NCI CTCAE v5.0) 
Management of 
IMP dosing 
(tusamitamab 
ravtansine) 
Management of 
IMP dosing 
(Docetaxel) 
(20;21) 
Supportive care 
guidelines 
Infusion related 
reaction  
Mild-moderate 
Eg, Grade ≤2 nausea, 
headache, tachycardia, 
hypotension, rash, 
shortness of breath. 
Interrupt tusamitamab 
ravtansine infusion. 
SAR408701 may be 
resumed only after 
patient recovery, at 
half the previous 
infusion rate.a 
Interrupt Docetaxel 
infusion and start 
appropriate treatment.   
Give diphenhydramine 
50 mg IV and/or 
dexamethasone 10 mg IV. 
Docetaxel label should be 
followed 
Dexamethasone can be added 
as premedication for upcoming 
cycles for SAR408701 
 
Severe 
Eg, symptomatic 
bronchospasm, 
urticaria lesions 
covering >30% BSA, 
hypotension, 
angioedema. 
Interrupt tusamitamab 
ravtansine infusion 
and definitively 
discontinue 
tusamitamab 
ravtansine. 
Interrupt docetaxel 
infusion and 
definitively 
discontinue docetaxel 
Give diphenhydramine 
50 mg IV and/or 
dexamethasone 10 mg IV 
and/or epinephrine and any 
required treatment per 
investigator judgement. 
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Event 
Symptoms 
severity (Nadir)  
(NCI CTCAE v5.0) 
Management of 
IMP dosing 
(tusamitamab 
ravtansine) 
Management of 
IMP dosing 
(Docetaxel) 
(20;21) 
Supportive care 
guidelines 
Ocular toxicity:  
Keratopathy/kerat
itisb associated 
with tusamitamab 
ravtansine 
(Cystoid macular 
edema 
associated with 
docetaxel) 
Grade 1 – 
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated . 
Next infusion of 
tusamitamab 
ravtansine at the same 
dose, with or without 
cycle delay, depending 
on the 
recommendation from 
the ophthalmologist 
(nature and extent of 
the lesion). 
Cystoid macular 
edema has been 
reported with 
docetaxel. Patients 
with impaired vision 
should undergo a 
prompt and complete 
ophthalmologic 
examination. In case 
CMO is diagnosed, 
docetaxel treatment 
should be 
discontinued and 
appropriate treatment 
initiated (21) 
Standard ocular examination is 
planned as recommended by 
the ophthalmologist. 
 
Grade 2 
Symptomatic, 
moderate decrease in 
visual acuity (best 
corrected visual acuity 
20/40 and better or 3 
lines or less decreased 
vision from known 
baseline)  
 
1st episode: 
tusamitamab 
ravtansine cycle delay 
until resolution to 
Grade 1 
(asymptomatic) and 
restart tusamitamab 
ravtansine at the same 
dose. 
2nd episode:  delay 
cycle until resolution to 
grade 1 
(asymptomatic) and 
tusamitamab 
ravtansine dose 
reduction. 
Standard ocular examination 
weekly until resolution c, d 
Start curative treatment per 
ophthalmologist 
recommendation.  
After resuming study 
treatment, participant should 
be followed with standard 
ocular examination by every 
2 cycles, even asymptomatic 
during next 4 cycles. If no 
recurrence, standard process 
with follow-up with ocular 
symptom is resumed, as 
detailed in Section 8.2.6.2.  
 
Management of study drug and 
follow-up process upon 
recurrence to be discussed 
according to Grade of the 
event at recurrence, clinical 
benefit from study drug and 
recommendation from the 
ophthalmologist. 
 
Grade 3 
Symptomatic with 
marked decrease in 
visual acuity (best 
corrected visual acuity 
worse than 20/40 or 
more than 3 lines of 
decreased vision from 
known baseline, up to 
20/200); corneal ulcer; 
limiting self-care ADL  
 
1st episode: 
tusamitamab 
ravtansine cycle delay 
until resolution 
(asymptomatic) and 
restart  
tusamitamab 
ravtansine with dose 
reduction. 
2nd episode: definitive 
discontinuation of 
tusamitamab 
ravtansine.   
 
Grade 4 
Perforation, best 
corrected visual acuity 
of 20/200 or worse in 
the affected eye  
 
Definitive 
discontinuation of 
tusamitamab 
ravtansine. 
 
Complete the corneal 
examination as recommended 
by ophthalmologist. Repeat the 
standard ocular examination 
weeklyc until resolutiond. 
Start curative treatment per 
ophthalmologist 
recommendation.  
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Event 
Symptoms 
severity (Nadir)  
(NCI CTCAE v5.0) 
Management of 
IMP dosing 
(tusamitamab 
ravtansine) 
Management of 
IMP dosing 
(Docetaxel) 
(20;21) 
Supportive care 
guidelines 
Conduction 
disorder 
associated with 
tusamitamab 
ravtansine 
Grade 1 
Mild symptoms 
tusamitamab 
ravtansine 
administration to be 
continued upon 
decision by the 
Investigator and 
Sponsor, depending 
on the nature of the 
conduction disorder. 
Not expected 
ECG performed once weekly 
until event resolution. 
Additional evaluations such as 
LVEF and Holter monitoring 
should be performed when 
relevant. 
 
Grade ≥2 
Definitive 
discontinuation of 
tusamitamab 
ravtansine. 
 
ECG to be repeated twice 
weekly until event resolution. 
Prompt cardiology consultation 
Additional evaluations such 
LVEF and Holter monitoring 
should be performed when 
relevant. 
Neutrophil count 
decreased 
Grade 1 
<LLN – 1500/mm3; 
<LLN – 1.5 × 109/L 
No change in IMPs 
administration. 
No change in IMPs 
administration  
No intervention. 
 
Grade 2 
<1500 – 1000/mm3; 
<1.5 – 1.0 × 109/L 
Delay the cycle until 
recovery of absolute 
neutrophil count 
>1500/mm3. 
Restart at the same 
dose. 
Delay the cycle until 
recovery of absolute 
neutrophil count 
>1500/mm3. 
Restart at the same 
dose. 
No intervention. 
 
Grade 3 
<1000 – 500/mm3;  
<1.0 – 0.5 × 109/L 
Or 
Grade 4 
<500/mm3; <0.5 × 109/L 
Delay the cycle. 
Restart the treatment 
when absolute 
neutrophil count 
>1500/mm3 at the 
same dose. 
Prophylactic G-CSF 
can be considered in 
all subsequent cycle 
Delay the cycle. 
Restart the treatment 
when absolute 
neutrophil count 
>1500/mm3 at the 
same dose and add 
G-CSF to provide 
prophylactic coverage 
in all subsequent 
cycles. If reoccurred 
under the prophylactic 
G-CSF treatment, 
dose reduction might 
be considered case 
by case manner 
(eg, Asian patient with 
higher risk of 
hematologic toxicity) 
Follow ASCO guidelines on 
usage G-CSF and 
antibiotherapy (22). Repeat the 
test every 3 days.  
 
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Event 
Symptoms 
severity (Nadir)  
(NCI CTCAE v5.0) 
Management of 
IMP dosing 
(tusamitamab 
ravtansine) 
Management of 
IMP dosing 
(Docetaxel) 
(20;21) 
Supportive care 
guidelines 
 
Grade 4 >7days 
<500/mm3; <0.5 × 
109/L 
Delay the cycle until 
absolute neutrophil 
count >1500/mm3. 
1st episode administer 
next cycle at the same 
dose and administer 
growth factors 
2nd episode: 
administer 
tusamitamab 
ravtansine at reduced 
dose 
3rd episode: definitive 
discontinuation 
Delay the cycle until 
absolute neutrophil 
count >1500/mm3. 
1st episode 
administer next cycle 
at the same dose and 
prophylactic G-CSF 
should be 
implemented   
2nd episode: 
administer docetaxel 
at reduced dose 
3rd episode: definitive 
discontinuation 
Follow ASCO guidelines on 
usage G-CSF and 
antibiotherapy (22). Repeat the 
test every 3 days.  
 
Febrile 
neutropenia 
Grade 3 
Absolute neutrophil 
count <1000/mm3 with 
a single temperature of 
>38.3ºC (101ºF) or a 
sustained temperature 
of ≥38ºC (100.4ºF) for 
more than 1 hour 
Delay cycle until 
absolute neutrophil 
count >1500/mm3. 
1st episode administer 
next cycle at the same 
dose and administer 
G-CSF 
2nd episode: 
administer 
tusamitamab 
ravtansine at reduce 
dose 
3rd episode: definitive 
discontinuation  
Delay cycle until 
absolute neutrophil 
count >1500/mm3. 
1st episode 
administer next cycle 
at the same dose and 
administer G-CSF 
2nd episode: 
administer docetaxel 
at reduce dose 
3rd episode: definitive 
discontinuation  
To ensure relative dose 
ıntensity, G-CSF is 
recommended as secondary 
prophylaxis in all patients with 
Grade ≥3 febrile neutropenia  
ASCO guideline is 
recommended for supportive 
treatment if there are no 
defined clinical standards (22). 
 
Grade 4 
Life-threatening 
consequences 
Administration 
changes to be decided 
at the Investigator’s 
discretion: 
1st episode: 
administer next cycle 
at reduced dose and 
administer G-CSF or 
definitively discontinue 
2nd episode: definitive 
discontinuation 
Administration 
changes to be 
decided at the 
Investigator’s 
discretion: 
1st episode: 
administer next cycle 
at reduce dose and 
administer G-CSF or 
definitively 
discontinue 
2nd episode: 
definitive 
discontinuation 
 
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Event 
Symptoms 
severity (Nadir)  
(NCI CTCAE v5.0) 
Management of 
IMP dosing 
(tusamitamab 
ravtansine) 
Management of 
IMP dosing 
(Docetaxel) 
(20;21) 
Supportive care 
guidelines 
Peripheral 
neuropathy 
Grade 1:  
Asymptomatic 
No action 
No action 
Patient who has ongoing grade 
1 neuropathy has high risk of 
worsening of his/her symptoms 
and should be closely followed. 
Grade 2:   
Moderate symptoms; 
limiting instrumental 
Activities of Daily 
Living 
Delay cycle, dose 
reduction if no 
improvement with 
dose delay 
Delay cycle, dose 
reduction if no 
improvement with 
dose delay 
Grade 3:  
Severe symptoms; 
limiting self care 
Activities of Daily 
Living 
Definitive 
discontinuation 
Definitive 
discontinuation 
Grade 4: 
Life-threatening 
consequences; urgent 
intervention indicated 
Definitive 
discontinuation 
Definitive 
discontinuation 
a Tusamitamab ravtansine is stable at least 7.5 hours in the infusion bag at room temperature. If necessary, a new infusion should be prepared 
with the remaining dose to be administered. 
b The NCI CTCAE v5.0 grading is to be applied to keratopathy. 
c Standard ocular examination per protocol includes visual acuity, slit lamp examination, Schirmer’s test, and enquiring for ocular/visual 
symptoms. 
d When possible at the site, photographs should be done when findings are first documented and to follow progression when relevant. Any 
additional relevant ocular examination can be done if indicated. 
Abbreviations: ASCO = American Society of Clinical Oncology, ASOCT = Anterior segment optical coherence, BSA = Body surface area,  
ECG = Electrocardiogram, G-CSF = Granulocyte colony-stimulating factor, Hb = Hemoglobin, IMP = Investigational medicinal product, 
IV = Intravenous; LLN = Lower limit of normal, LVEF = Left ventricular ejection fraction, NCI CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events, RBC = Red blood cell. 
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10.5 
APPENDIX 5: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
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CONTRACEPTION GUIDANCE: 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:  
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used consistently and 
correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) b 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
− oral 
− intravaginal 
− transdermal 
− injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
− oral 
− injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant.) 
ACCEPTABLE METHODSd 
• 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action 
• 
Male or female condom with or without spermicidee 
• 
Cervical cap, diaphragm, or sponge with spermicide 
• 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier methods)c 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
d Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception.  
e Male condom and female condom should not be used together (due to risk of failure with friction). 
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COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date but may last up to one year. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date but may 
last up to one year. Any termination of pregnancy will be reported, regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as 
an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described 
in Section 8.3.5. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.  
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10.6 
APPENDIX 6: GENETICS  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants. 
• DNA samples will be used for research related to tusamitamab ravtansine or nonsquamous 
NSCLC and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to CEACAM5 targeting drugs and nonsquamous NSCLC. Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of 
genetic markers throughout the genome (as appropriate). 
• DNA samples will be analyzed for determination of tumor mutation profile on plasma 
cfDNA. Subtractive mutation analysis will be performed with germline DNA data to identify 
tumor-specific somatic genetic aberrations. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to tusamitamab ravtansine or study interventions of this class to 
understand study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• The samples will be retained while research on tusamitamab ravtansine, CEACAM5 target 
or lung cancer continues but no longer than 15 years or other period as per local 
requirements. 
10.7 
APPENDIX 7: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1  
Details provided in bibliographic reference (23). 
Measurability of tumor at baseline 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. 
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
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• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as non-measurable lesions. 
Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
• Bone lesions: 
1. Bone scan, positron emission tomography scan or plain films 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. 
2. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
3. Blastic bone lesions are non-measurable. 
• Cystic lesions: 
4. Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
5. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
• Lesions with prior local treatment: 
6. Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
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Method of assessment 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers. For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may be 
reviewed at the end of the study. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. 
• Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol. 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements. 
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Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. All 
other pathological nodes (those with short axis ≥10 mm but <15 mm) should not be considered 
non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or ‘unequivocal progression’. In addition, 
it is possible to record multiple non-target lesions involving the same organ as a single item on the 
case (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria 
Response criteria are described in Table 13. 
Table 13 - Response criteria  
Response criteria 
Evaluation of target lesions 
CR 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum 
diameters. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
SD 
Neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
Special notes on the assessment of target lesions 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded and should be measured in the same anatomical plane as the baseline examination, even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of <10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
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Target lesions that become ‘too small to measure’: All lesions (nodal and non-nodal) recorded at 
baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (eg, 2 mm). However, sometimes lesions or lymph nodes which are recorded as 
target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being ‘too small to measure’. When this 
occurs, it is important that a value be recorded on the CRF. If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion 
is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’. 
Evaluation of non-target lesions 
While some non-target lesions may be measurable, they need not be measured and instead should 
be assessed only qualitatively at the time points specified in the protocol. 
• CR: Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
• Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• Progressive Disease: Unequivocal progression of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
The concept of progression of non-target disease requires additional explanation as follows: 
When the participant also has measurable disease; in this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. 
When the participant has only non-measurable disease; to achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial worsening such 
that the overall tumor burden has increased sufficiently to merit discontinuation of therapy. 
A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
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increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to 
a 20% increase diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to widespread, 
or may be described in protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that point. 
New lesions 
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the participant’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The participant’s brain metastases are considered to be constitute PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents new disease. If repeat scans confirm that there is 
a new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments need 
additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
A) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
B) No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a preexisting site of disease on CT that is not progressing 
on the basis of the anatomic images, this is not PD. 
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Evaluation of best overall response 
Time point response: At each protocol specified time point, a response assessment should occur.   
Table 14 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
Table 14 - Response in patients with target disease  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.  
When patients have non-measurable (therefore non-target) disease only, Table 15 is to be used. 
Table 15 - Response in patients with non-target disease only  
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Inevaluable  
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
Missing assessments and inevaluable designation: When no imaging/measurement is done at all at 
a particular time point, the patient is not evaluable (NE) at that time point. 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the contribution 
of the individual missing lesion(s) would not change the assigned time point response. This would 
be most likely to happen in the case of PD. 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that patients with CR may not have 
a total sum of ‘zero’ on the CRF. 
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In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as 
a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. 
The objective response status of such patients is to be determined by evaluation of target and 
non-target disease. For equivocal findings of progression (eg, very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Duration of response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
Reproduced from: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria 
in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47 (23). 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
It is expected that sites in China will enroll 15% of the global study population. If enrollment of 
this proportion of the study participants at Chinese sites is not achieved at the time of completion 
of global enrollment, randomization may remain open for sites in China in order to achieve 
approximately 15% of the total study population.   
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10.8.1 Safety run-in in China  
At the time of Protocol Amendment02 submission, there is no experience with tusamitamab 
ravtansine in Chinese patients. However, based on available data, no ethnic difference in the 
tusamitamab ravtansine safety profile is expected between Chinese and non-Chinese patients.  
A safety run in step will consist in the sequential treatment of 6 patients with tusamitamab 
ravtansine (ie, approximately 12 randomized patients); none of the first 3 patients of tusamitamab 
ravtansine arm will be treated for first dose on the same day. The safety review will occur when 
6 Chinese patients have been exposed to tusamitamab ravtansine and completed a minimum of 
2 cycles duration (~4 weeks) of treatment. If 0-1 of 6 evaluated patients had treatment related 
AESI or treatment related AE leading to the treatment discontinuation, enrollment will continue in 
China. Otherwise, enrollment will be on-hold in China and further safety and PK assessment will 
be performed 
10.8.2 PK assessment in China  
In the first 12 patients in China treated with tusamitamab ravtansine after implementation of the 
Protocol Amendment02, blood samples will be collected for measurement of plasma 
concentrations of tusamitamab ravtansine as listed in Table 16. These PK concentrations will be 
used to calculate, in these patients, the pharmacokinetic parameters using non-compartmental 
methods.  
PK samples from subsequent participants treated with tusamitamab ravtansine in China as well as 
from participants enrolled and treated with tusamitamab ravtansine before implementation of the 
Protocol Amendment02 will be collected as described in Section 8.5. 
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
in a separate document. The actual date and time of each sample will be recorded. These samples 
will be tested by the Sponsor's designee.   
Table 16 - PK sampling schedule for 12 tusamitamab ravtansine treated patients in China  
Cycle  
Day 
Sampling timepoints 
Time window allowance 
Cycle 1 
Day 1 
SOI 
Within 48h before SOI 
 
 
EOI 
±10 min around the EOI 
 
 
EOI+4h 
±30 min 
 
Day 2 
24h 
±5 h 
 
Day 3 
48h,  
±10 h 
 
Day 4 
72h 
±10 h 
 
Day 8 
168h 
± 24 h 
Cycle 2 
 
SOI 
Within 24h before SOI. Sample must be collected even if the 
patient is not administered with tusamitamab ravtansine at this 
visit 
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Cycle  
Day 
Sampling timepoints 
Time window allowance 
Cycle 3 
 
SOI 
Within 24h before SOI 
 
 
EOI+1h 
±10 min 
Cycles 4, 5, 6 and 7 
 
SOI  
Within 24h before SOI 
From Cycle 13 
 
SOI every 6 cycles 
Within 24h before SOI 
EOI : end of infusion (ie, when the pump beeps before flush), SOI : start of infusion 
10.8.3 Assessment of ATA, circulating CEA in China  
ATA samples will be collected as described in Section 8.9, to assess the immunogenicity in 
Chinese patients. Circulating CEA samples will be collected at baseline and during treatment as 
described in Section 8.6.1, to assess circulating CEA as a potential pharmacodynamics biomarker 
of response to tusamitamab ravtansine treatment and as a potential impact on PK of tusamitamab 
ravtansine.  
10.8.4 Circulating tumor DNA and germline DNA  
Samples for Circulating tumor DNA and Germline DNA will not be collected in Chinese patients.  
10.9 
APPENDIX 9: CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE (NTR)  
Table 17 - List of CYP substrates with narrow therapeutic range  
In vivo CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A Narrow Therapeutic Range 
(NTR) Substrates 
CYP enzyme 
NTR Substratesa 
CYP1A2 
Theophylline, tizanidine 
CYP2C8 
Paclitaxel 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP2D6 
Thioridazine 
CYP3A 
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, quinidine, sirolimus, 
tacrolimus, cisapride, astemizole, terfenadine, pimozide 
a CYP Substrates with a Narrow Therapeutic Range – drugs with an exposure-response relationship that indicates that relatively small 
increases in their exposure levels by co-administered CYP inhibitors may lead to safety concerns 
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10.10 APPENDIX 10: STRONG CYP3A INHIBITORS  
Table 18 - List of strong CYP3A inhibitors  
STRONG CYP3A INHIBITORS 
CYP3A 
inhibitors 
Precipitant therapeutic class 
Victim (oral, unless otherwise 
specified) 
AUC 
Ratio 
Potent CYP3A Inhibitors (yielding substrate AUC ratio >5) 
VIEKIRA PAK 
Antivirals 
Tacrolimus 
55.76 
Telaprevir 
Antivirals 
Midazolam 
13.5 
Indinavir/RIT 
Protease inhibitors 
Alfentanil 
36.50 
Tipranavir/RIT 
Protease inhibitors 
Midazolam 
26.91 
Ritonavir 
Protease inhibitors 
Midazolam 
26.41 
Cobicistat 
(GS-9350) 
none 
Midazolam 
19.03 
Indinavir 
Protease inhibitors 
Vardenafil 
9.67 
Ketoconazole 
Antifungals 
Midazolam 
17.08 
Troleandomycin 
Antibiotics 
Midazolam 
14.80 
Saquinavir/RIT 
Protease inhibitors 
Midazolam 
12.48 
Itraconazole 
Antifungals 
Midazolam 
10.80 
Voriconazole 
Antifungals 
Midazolam 
9.63 
Mibefradil 
Calcium Channel Blockers 
Midazolam 
8.86 
Clarithromycin 
Antibiotics 
Midazolam 
8.39 
Danoprevir/RIT 
Antivirals 
Midazolam 
13.42 
Lopinavir/RIT 
Protease inhibitors 
Alfentanil 
11.47 
Elvitegravir/RIT 
Treatments of AIDS 
Midazolam 
12.8 
Posaconazole 
Antifungals 
Midazolam 
6.23 
Telithromycin 
Antibiotics 
Midazolam 
6.2 
Conivaptan 
Diuretics 
Midazolam 
5.76 
Nefazodone 
Antidepressants 
Midazolam 
5.44 
Nelfinavir 
Protease inhibitors 
Midazolam 
5.29 
Saquinavir 
Protease inhibitors 
Midazolam 
5.18 
Boceprevir 
Antivirals 
Midazolam 
5.05 
idelalisib 
Kinase inhibitors 
Midazolam 
5.15 
LCL161 
Cancer treatments 
Midazolam 
8.80 
Mifepristone 
Antiprogestins 
Simvastatin 
9.55  
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STRONG CYP3A INHIBITORS 
CYP3A 
inhibitors 
Precipitant therapeutic class 
Victim (oral, unless otherwise 
specified) 
AUC 
Ratio 
Potent CYP3A Inhibitors (yielding substrate AUC ratio >5) 
Ceritinib 
Kinase Inhibitors 
Midazolam 
5.84 
Ribociclib 
Kinase Inhibitors 
Midazolam 
5.17 
Josamycin 
Antibiotics 
Ivabradine 
7.70 
Tucatinib 
Kinase Inhibitors 
Midazolam 
5.74 
List extracted from the Drug Interaction Database from the University of Washington (Home Page: www.druginteractioninfo.org; 
https://didb.druginteractionsolutions.org/resources/list-of-substrates-inhibitors-and-inducers/?Oid=1130), updated in January 2021 and from FDA 
(https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm) updated in June 
2020. 
Abbreviations: AIDS = Acquired immune deficiency syndrome, AUC = Area under the curve, CYP = Cytochrome P450, RIT = Ritonavir. 
10.11  APPENDIX 11: PROTOCOL AMENDMENT HISTORY  
Five previous amendments were created. The Protocol Amendment Summary of Changes Table 
for the current amendment is located directly before the Table of Contents (TOC). 
10.11.1 
AMENDED PROTOCOL 05 (18-OCT-2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union because 
it may impact the scientific value of the study.  
OVERALL RATIONALE FOR THE AMENDMENT 
Based on regulatory authority input, the nonsquamous non-small-cell lung cancer (NSCLC) 
treatment landscape, and Sponsor considerations, assumptions for calculation of sample size for 
analysis of the primary endpoint, overall survival (OS), are being revised, prompting decreases in 
proposed sample size from 554 to 450 participants and number of OS events at final analysis from 
452 to 363 deaths while maintaining adequate statistical power for the final analysis of OS. Final 
progression-free survival (PFS) analysis will be conducted with a lower number of events than 
initially planned, while maintaining adequate statistical power for this final analysis. In addition, 
the interim analysis (IA) of PFS at 60% information fraction has been removed, as it is anticipated 
that data will be immature at this time, leaving the final analysis of PFS as the only planned 
analysis of PFS. Due to the earlier timing of the cut-off date for IA for OS concurrent with the 
final PFS analysis, at 50% of the anticipated total OS events, an additional IA for OS was added at 
80% OS information fraction, when enrollment is expected to be complete. 
As the futility rules for OS became too stringent following the above-mentioned changes, the 
beta-spending function for OS futility analysis was replaced by a criterion based on observed 
hazard ratio (HR), using a criterion based on observed HR similar to that planned with the initial 
design. 
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In the anticipated case that analysis of PFS shows a statistically significant advantage of 
tusamitamab ravtansine over docetaxel, participants randomized to docetaxel may be expected to 
benefit from the access to treatment with tusamitamab ravtansine after objective disease 
progression. This amendment therefore includes provisional implementation, under conditions 
detailed in the protocol, of a crossover tusamitamab ravtansine treatment phase for participants 
with documented progressive disease during or after the docetaxel treatment.  
Beside these changes, further modifications to protocol wording as detailed in the Summary of 
Changes table were implemented.  
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Section # and Name Description of Change 
Brief Rationale 
1.1 Synopsis, 
1.2 Schema; 9.2 Sample 
size determination, 
9.5 Interim analyses 
The total sample size, the number of OS 
events at the interim and final analyses of OS, 
and the corresponding statistical power and 
efficacy boundaries were revised.  
To reflect the revised OS hypothesis. 
1.1 Synopsis, 
1.2 Schema; 9.2 Sample 
size determination 
The number of participants to be randomized 
to each arm was updated from 277 to 225 
To reflect the revised sample size. 
1.1 Synopsis, 4.4 End of 
study definition, 
9.2 Sample size 
determination, 
9.4 Statistical analyses; 
9.5 Interim analyses; 
9.6 Multiplicity 
The estimated cut-off dates and timelines for 
the final analysis of progression-free survival 
(PFS) and interim and final analyses of overall 
survival (OS) were updated. 
Timelines were adjusted based on the reduced 
total sample size, the addition of the 80% OS 
interim analysis, and the current enrollment 
curve. 
1.1 Synopsis, 4.4 End of 
study definition; 
9.2 Sample size 
determination; 
9.4 Statistical analyses; 
9.5 Interim analyses; 
9.5.1 Data Monitoring 
Committee (DMC); 
9.6 Multiplicity  
Removed PFS IA at 60% information fraction 
Based on regulatory authority input, PFS data 
are anticipated to be immature at this cut-off 
date  
1.1 Synopsis, 9.2 Sample 
size determination 
Estimated rate of dropout for sample size 
calculation was increased to 3% 
Adjustment to match observed dropout rates 
9.2 Sample size 
determination 
Rounded enrollment assumptions from 
11.89 participants/month to 
12 participants/month, and added alternative 
cut-off date projections based on 
10 participants/month  
To provide estimated cut-off date projections 
that better reflect observed enrollment rates 
1.1 Synopsis, 9.2 Sample 
size determination, 
9.5 Interim analyses 
The beta-spending function planned to be 
used for the assessment of futility at the time 
of the first IA of OS was removed and replaced 
by a rule based on observed OS HR; added 
Table 7. 
To maintain the same futility criterion based on 
observed HR as initially planned  
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Section # and Name Description of Change 
Brief Rationale 
1.1 Synopsis; 9.2 Sample 
size determination; 
9.4.1.1.2 Overall survival; 
9.5 Interim analyses; 
9.6 Multiplicity 
The number of OS events at the 50% 
information fraction IA of OS was updated, and 
a new IA of OS at 80% information fraction 
was added 
Based on a new strategy for interim analyses of 
OS and adjustments to the total number of 
events for the final OS analysis, the estimated 
number of events at the 50% information 
fraction IA of OS changed, and a second IA of 
OS was added.  
1.1 Synopsis, 
1.2 Schema; 
1.3 Schedule of activities 
newly specified 
1.3.1 Main phase and 
new 1.3.2 Crossover 
phase; 3 Objectives and 
endpoints; new 
4.1.2 Crossover phase; 
5.1 Inclusion criteria; 
5.2 Exclusion criteria; 
6.6 Dose modification; 
9.3 Populations for 
analyses; 
9.4.1.3 Analysis of 
exploratory efficacy 
endpoints; minor wording 
changes throughout 
document 
Subsections added under Section 5.1 and 
5.2 to define minimal entrance criteria for 
allocation to crossover treatment phase 
Specified that dose reductions/delays and 
retreatment criteria for crossover participants 
would be according to the same rules for 
participants in the main study phase.  
Added text in other sections, wherever 
needed, describing provisional crossover 
treatment phase, required assessments and 
analyses of safety and efficacy for crossover 
treatment participants; wording adjusted as 
necessary throughout to reflect distinction 
between main study phase and newly added 
crossover phase.  
To reflect addition of new provisional 
tusamitamab ravtansine crossover treatment 
phase for participants who progress during or 
after docetaxel treatment in the main study 
phase 
2.1 Study rationale 
Updated data based on results for 
nonsquamous NSCLC patients in first-in-
human study TED13751 
To provide data from a study of tusamitamab 
ravtansine as a treatment in this patient 
population 
2.3 Benefit/risk 
assessment 
Added cardiotoxicity to potential risks 
To reflect the current safety information in the 
Investigator Brochure, edition 9. 
3 Objectives and 
endpoints 
Tertiary objectives and endpoints were added 
to specify safety and efficacy analysis for 
participants in the tusamitamab ravtansine 
crossover treatment phase 
To reflect anticipated analyses for the crossover 
population.  
5.1 Inclusion criteria I03; 
4.1 Overall design; 
8.8.1 CEACAM5 
expression in tumor 
tissue samples 
Reduced required number of slides from 7 to 5 
To expand the number of eligible participants, 
as the sample size required for validation of the 
assay for tumor CEACAM5 expression was met 
5.2 Exclusion criteria  
Exclusion criterion E17 was modified to 
decrease minimally required eGFR (MDRD) 
for participants with elevated creatinine from 
60 mL/min to 50 mL/min; additionally, 
participants with elevated creatinine but eGFR 
≥50 mL/min/1.73 m2 are now eligible.  
As minimal urinary excretion of SAR408701 and 
its metabolites was observed in mice; population 
PK analysis from clinical study TED13751 did 
not identify creatinine clearance as a significant 
covariate for PK of SAR408701, DM4, or 
Me-DM4; and no major renal safety concern has 
been observed in clinical studies with 
tusamitamab ravtansine; modification of 
requirements to broaden the study population to 
include participants with minimal renal 
impairment is appropriate.   
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Section # and Name Description of Change 
Brief Rationale 
8.5 Pharmacokinetics 
Added PK and ATA sampling schedule 
Table 3  
To clarify sampling times for the main study 
phase. 
9.3 Populations for 
analyses 
Clarified Screened population as those 
participants who signed screening informed 
consent 
To simplify definition, as only those whose 
tumors meet CEACAM5 immunohistochemical 
criteria in prescreening are asked to sign 
screening informed consent 
9.4.1.2.1.2 Time to 
deterioration in disease-
related symptoms, time 
to deterioration in 
physical function, time to 
deterioration in role 
function 
Modified description of analysis population and 
censoring rules for data analyses of time to 
deterioration in PRO endpoints 
Clarification of how PRO data will be handled if 
data are missing or not evaluable. 
10.8 Appendix 8: 
Country-specific 
requirements 
Specified continuation of enrollment in China 
after the study cut-off date, if the minimum 
required sample size is not reached by the 
time global enrollment is complete.  
To meet a local requirement for registration of 
tusamitamab ravtansine in China.   
11 References 
Added reference citations for presentations 
based on preliminary findings from 
Study TED13751 
To provide further detail for study rationale 
Throughout document 
Minor typographical and grammatical 
corrections 
To improve readability and consistency in the 
document 
 
10.11.2 
Amended protocol 04 (21-Jul-2021) 
Amended protocol 04 (amendment 04) is considered to be nonsubstantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it does not significantly impact the safety or physical/mental integrity of 
participants or the scientific value of the study. The added interim analysis will be used as early 
assessment of safety and preliminary efficacy. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of this amendment is to add an interim analysis on the PFS to occur when 60% 
of anticipated events (ie, disease progression or death) have been recorded.  
The goal of this interim PFS analysis is to provide preliminary efficacy data. No predetermined 
stopping rule is to be applied to this interim analysis of PFS. 
Regardless of this interim PFS outcome, the study will continue until the planned final analysis of 
PFS and then final analysis of OS, unless the interim analysis of OS at the time of final PFS 
analysis showed overwhelming efficacy or futility. 
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An external independent statistician will perform the unblinded interim analysis of PFS for the 
purpose of the DMC data review. Access to these data and analyses will be restricted to the DMC 
members and to limited personnel from the Sponsor involved in the submission if the analysis is 
positive and DMC recommends unblinding. DMC recommendation will be based on statistical 
criteria for PFS, as pre-specified in this protocol, and on benefit/risk considerations. 
SAR408701 has been granted the INN name as tusamitamab ravtansine and throughout the 
document is replaced with the INN name.  
Beside this change, further modifications to protocol wording were implemented, as detailed 
below.  
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Sponsor address added 
Administrative update 
1.1 Synopsis 
Predicted cut-off dates for final PFS and OS 
analyses were modified. Number of PFS events at 
final analysis and corresponding power were also 
updated. 
Based on the current enrollment 
curves and the adding of interim PFS 
analysis at 60% of information 
fraction 
Updated the number of patients treated in 
TED13751 
Based on realization of the 
enrollment 
4.1.1 Duration of the study 
period 
Estimated duration of enrollment period updated 
from 40 to 44 months 
Based on current projection 
4.4 End of Study definition 
 
New cut-off date for interim PFS analysis was 
added and timing of cut-off dates for final PFS and 
final OS analysis were updated  
Based on current projection 
5.2 Exclusion criteria  
Typo error corrected for E01 as “Untreated brain 
metastases or history of leptomeningeal disease”  
For clarity 
9.2 Sample size determination 
Section updated by adding new interim PFS 
analysis and assumption per current status. Timing 
of cut-off dates for final PFS and final OS analysis 
were updated 
To reflect new interim PFS analysis 
and consider current status.  
9.4 Statistical analyses 
Planned cut-off dates are updated by adding cut-off 
dates for interim PFS and updating assumption for 
final PFS and final OS analysis  
To reflect new interim PFS analysis 
and consider current status. 
9.4.1.1.1 Progression free 
survival  
Number of required events for interim PFS analysis 
added and significance levels at interim and final 
analyses are updated 
To reflect new interim PFS analysis. 
9.4.1.1.2 Overall survival 
Erroneously missed OS interim analysis details are 
added to this section 
Typo error correction. 
9.5 Interim analyses 
Section updated by adding details related to the 
interim analysis for PFS. Timing of cut-off dates for 
final PFS and final OS analyses were updated. 
To reflect new interim PFS analysis 
and consider current status. 
9.5.1 Data Monitoring 
Section updated by adding interim analysis for PFS 
To reflect new interim PFS analysis. 
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Section # and Name 
Description of Change 
Brief Rationale 
Committee 
9.6 Multiplicity 
Section updated and a table (Table 6) is added to 
detail PFS hypothesis testing. Previous Table 6 
and all tables afterwards renumbered. Table 7 
(former Table 6) is updated with current cut-off 
dates and estimations   
For clarity and to reflect new interim 
PFS analysis and consider current 
status. 
10.1.5 Committees Structure – 
Data Monitoring Committee 
(DMC) 
Section updated by adding the interim PFS 
analysis  
To reflect new interim PFS analysis 
10.10 Appendix 10: Strong 
CYP3a inhibitors  
Table updated with current up-to-date version 
Version change on reference table 
Throughout document 
Added INN tusamitamab ravtansine to compound 
identifier 
New INN issued 
Minor formatting and typographical updates 
Editorial changes 
10.11.3 
Amended protocol 03 (20-Jul-2020) 
This amended protocol 03 (amendment 03) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants or the scientific value of the study. 
The main purpose of this amendment is to clarify protocol wording; in particular, to clarify the 
inclusion criteria regarding prior anticancer therapies. To ensure a homogenous study population 
limited to a single line of prior chemotherapy in advanced setting, the wording on inclusion 
criterion I02 has been modified, and a new exclusion criterion E25 added.  
Beside this change, further modifications to protocol wording were implemented, as detailed 
below. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis (Objectives and 
endpoints), Section 3 Objectives 
and endpoints 
Disease related symptoms and definition of Time 
to Deterioration added for health-related quality of 
life endpoint 
For clarity 
1.2 Schema 
Wording added to footnote a as below 
“a … Patients who have additional tumor tissue 
samples available during the prescreening phase 
may be re-assessed for CEACAM5 expression 
level; the most recent tissue sample assessed for 
CEACAM5 expression will be used to determine 
eligibility of patients for screening.” 
To allow re-assessment for 
CEACAM5 expression in case a 
patient had an additional tumor 
tissue sample available   
1.3 Schedule of activities (SOA) 
Clarification added that height is measured only at 
screening visit, before the IRT call 
For clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities (SOA); 
10.2 Table 8   
“HBsAgV & HCV serology” is updated as HBV & 
HCV serology; specific HBV serology also noted in 
Table 8 
For consistency between protocols 
in study schedule terminology 
1.3 Schedule of activities (SOA) 
Footnote b was updated to clarify that time 
windows are based on first infusion  
For clarity  
5.1 Inclusion criteria 
Criterion I02 further modified 
For clarity  
5.1 Inclusion criteria 
I06 criterion modified as:  
-Wording added to remind investigator regarding 
recommendation of sperm conservation for 
docetaxel  
For clarity to reflect the docetaxel 
label.  
 
 
- To cover both men and women, highly effective” 
deleted from section specifically for male patients 
and added to the first sentence of criterion  
Typographical error corrected, as 
this wording had been erroneously 
added to the section pertaining 
solely to men instead of the section 
for both sexes   
5.2 Exclusion criteria 
Criterion E01 updated to define assessment 
imaging window as “at least 4 weeks after CNS 
directed treatment and at least 2 weeks prior to 
first administration of study intervention.” 
To clarify the timing of required 
confirmatory scan for non-
progression and also to allow 
patients diagnosed with brain 
metastasis to be enrolled with 
prolonged screening window   
5.2 Exclusion criteria 
E25 criterion added  
Added as supportive criterion for 
clarity on I02 criteria 
5.4 Screen failures 
Section modified to allow prolonged screening 
period for temporary screen failure reason and 
detail the condition requiring screen failure and 
rescreening process.  
To reflect and define operational 
process 
6.5 Concomitant therapy 
Details added for bone-targeted treatments; 
corrected link to Appendix 9 (Section 10.9) 
To ensure standardization across 
studies; typographical correction 
7.1.2 temporary discontinuation 
Section updated to include details of guidance in 
case of regional or national emergency; link to new 
Appendix 12  
As guidance for standardization 
across studies  
Section 8 
Information regarding measures in case of 
temporary discontinuation added; link to new 
Appendix 12 detailing changes to procedures in 
the case of regional or national emergency  
 
8.2.2 Specific ocular tests 
Text added to allow omitting Schirmer’s test during 
treatment period and follow-up, if considered not 
required per ophthalmologist.  
Test is not routinely done in some 
sites  
8.2.3 Vital signs 
Pulse measurement deleted 
To correct typographical error 
8.2.4 Electrocardiograms 
"..(even cycles for SAR408701 and odd cycles for 
docetaxel)”.. added  
“For the SAR408701 arm” added to clarify that end 
of infusion ECG is required only in SAR408701 
arm 
For clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.5 Clinical Safety laboratory 
assessment 
added “..ie ALT, AST,ALP, total and direct 
bilirubin)..” added to clarify the liver function test for 
weekly assessment 
Also, section updated to allow laboratory tests to 
be performed within 2 days before the IMP 
administration  
For clarity  
 
Per operational need at site  
8.3.7 Disease-related events 
and/or disease-related outcomes 
not qualifying as AEs or SAEs 
Sentence added to clarify that lack of efficacy is 
not reported as AE/SAE as part of efficacy analysis 
For clarity on related section  
8.5 Pharmacokinetics 
Section updated to add time windows for each PK 
sample 
For clarity 
8.7 Genetics 
Below wording added to clarify that genetic tests 
are mandatory  
“..to perform the required genetic tests (unless not 
allowed by local authorities)..” 
For clarity 
8.9 Immunogenicity 
Wording added to clarify that ATA samples are 
collected at the same time with PK samples   
For clarity 
9.4.1.2.1.2 Time to deterioration in 
disease-related symptoms, time to 
deterioration in physical function, 
time to deterioration in role 
functions 
Section updated to detail HRQOL endpoints and 
statistical analysis 
For clarity  
9.4.3 Other analysis  
Wording added related to analysis on impact of the 
regional or national emergency situation 
For clarity  
10.1.3 Informed consent process 
Section updated to reflect prolonged screening 
window and requirement of reconsent in case of 
rescreening. 
For clarity 
 
10.1.3 Informed consent process 
“..and sample for cfDNA analysis.”  deleted as 
cfDNA are mandatory assessment unless not 
allowed by local authorities  
 
For clarity  
10.2 Clinical Laboratory tests 
Erroneously added “Non-fasting” deleted to allow 
site to follow the correct process  
To correct typographical error 
10.3 Adverse events: definitions 
and procedures for recording, 
evaluating, follow-up and reporting 
Last bullet removed from Events meeting the AE 
definition  
Removed as it was repeated text as 
in above bullet 
10.8.2 PK assessment in China 
Table 13 updated with time window for C1D1 
predose as within 48h,  
Table updated by adding column with study days 
for cycle 1 sampling and creating a separate row 
for each 72h samples (previously on same row 
with 48h sample)  
To allow flexibility to site to get 
sample with baseline laboratory 
assessment 
For clarity 
10.12 Contingency measures for a 
regional or national emergency 
that is declared by a governmental 
agency 
New appendix added to detail contingency 
measures for a regional or national emergency   
To harmonize across sites actions 
taken in response to regional or 
national emergency.  
Throughout 
Minor editorial, typographical error corrections and 
standardization of wording. 
For Clarity 
 
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10.11.4 
Amended protocol 02 (13-Dec-2019) 
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall rationale for amendment 02 
The protocol has been amended to add one additional ECG assessment at the approximate time of 
SAR408701 Cmax in the SAR408701 arm for the purpose of more intense cardiac safety 
assessment. In addition, the protocol is updated to clarify the management of patients who were 
exposed to SAR408701 after an ocular event.  
At the time of amendment 02, there is no experience with SAR408701 in Chinese patients. No 
ethnic difference in SAR408701 safety profile is expected between Chinese and non-Chinese 
patients. The protocol is updated to add a safety run-in assessment phase and pharmacokinetic 
run-in phase for the SAR408701 arm in Chinese patients to secure safety as well as to obtain 
safety and pharmacokinetic data as detailed below. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Statistical 
consideration 
Paragraph for Pharmacokinetic population modified as “ this population 
will include safety participants who have actually received at least one 
dose or a part of a dose of SAR408701 with at least one concentration 
post baseline with adequate documentation of dosing and sampling dates 
and times. “ 
For clarity 
 
1.3 Schedule of 
Activity  
The X added for 12-Lead ECG before the infusion at Cycle 1 and for 
blood chemistry for EOT visits  
Correction of typo errors 
1.3 Schedule of 
Activity  
The X added for 12-Lead ECG after EOI at Cycle 1. 
 
EOI assessment added for 
collection of the 12-Lead  
ECG at the estimated 
SAR408701 Cmax 
 
1.3 Schedule of 
Activity  
Footnote a – PD1 updated as PD-L1 and typo error corrected  
Footnote d – “On-site” wording deleted for follow-up visits. 
Typo error correction  
 
To allow phone contact in case 
the patient’s general condition 
is not suitable for on-site visit 
3 Objectives and 
Endpoints 
Secondary endpoint definition is updated by adding “… derived from 
Overall Response (OR)….” 
For clarity. Best Overall 
Response (BOR) will 
be programmatically derived 
by sponsor following RECIST 
1.1 algorithm from 
OR determined by the IRC per 
RECIST 1.1. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion  
I06 – The duration of contraception for male participant updated as 6 
months instead of 4 months 
For clarity, to cover docetaxel 
related fertility 
recommendation as a 
requirement in some countries   
5.2 Exclusion 
Criteria 
E17 updated as “[…or 1.0 – 1.5x ULN with eGFR < 60mL/min/1.73m2 as 
estimated using aMDRD formula” by replacing CrCL with eGFR. 
Typo error correction, for 
clarity to reflect formula  
Study Intervention 
Premedication for docetaxel arm: 
Text deleted “an iv histamine H1 antagonist given as predose and” 
To reflect current docetaxel 
labels  
8.2.4 
Electrocardiograms 
 
The addition of the 12-Lead ECG after EOI at Cycle 1 only. Below 
wording added: 
In addition to before the infusion assessment, “Single 12-lead ECG is 
also required within 30 minutes after the EOI (End Of Infusion) at Cycle 1 
only (see section 1.3).” 
The collection of the 12-Lead 
ECG at the time of estimated 
SAR408701 Cmax. 
8.2.6 Guideline for 
management of 
adverse event 
 
Section updated by adding below text: 
“The docetaxel label should be followed for management of docetaxel 
specific adverse event if otherwise not specified in the protocol.”  
For clarity 
8.2.6.2 Ocular 
toxicity 
 
Section updated by adding below texts: 
“...Then patient should be followed with ocular exam (Slit Lamp and 
visual acuity) at each cycle until total resolution of the event ….” 
….. 
“After resuming study treatment, the patient who had Grade ≥2 
keratopathy/keratitis should be followed with standard ocular exams (ie 
Slit Lamp examination under dilatation and Visual acuity) by every two 
cycles, even with no reported symptoms. If no recurrent event during the 
next four cycles, then regular follow-up (ie, symptom assessment at each 
visit with standard ocular exam in case of any ocular sign/symptom) is 
applied.” 
For clarity, as a guidance on 
safety management and 
follow-up of the patient 
8.2.6.3 
Management of 
anemia 
Hemoglobin unit was updated from mg/dL to g/dL  
Text added “Current clinical guidelines should be followed for 
management of anemia”  
The text deleted “Cycle delays or modifications should be compliant with 
Appendix 10.4. 
Typo error 
 
For clarity 
Typo error 
8.2.6.5 Liver 
function tests  
Grade 4 updated as Grade ≥3  
Typo error 
8.2.6.6 Peripheral 
neuropathy 
”Section added to detail recommendation on peripheral neuropathy 
For clarity, as a guidance on 
safety management and 
follow-up of the patient 
8.2.6.7 
Gastrointestinal 
toxicity  
Section added to detail recommendation on gastrointestinal toxicity 
For clarity, as a guidance on 
safety management and 
follow-up of the patient 
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Section # and 
Name 
Description of Change 
Brief Rationale 
8.3.1 Adverse 
Event of Special 
Interest 
Keratopathy updated as “keratopathy/keratitis” 
Grade 4 liver enzyme increase modified to Grade ≥3 
For clarity to cover drug 
induced keratitis 
Typo error  
8.5 
Pharmacokinetics 
Section updated by adding below text: 
“For patients randomized to the SAR408701 arm” 
Section was updated to add PK samples every 6 cycles after Cycle 7 (ie, 
at pre-dose Cycles 13, 19, 25,…). 
To collect time-matched PK 
samples with immunogenicity 
samples beyond Cycle 13. 
8.9 
Immunogenicity  
 
Section updated by adding below text: 
“For patients randomized to the SAR408701 arm” 
For clarity 
9.3 Populations for 
Analysis 
 
Definition of Intent to Treat (ITT) population is updated that it will be 
based on allocated treatment kit numbers in the IRT 
For clarity 
 
Pharmacokinetic section updated by adding below text: 
with adequate documentation of dosing and sampling dates and times. 
For clarity 
 
10.2 Appendix 2: 
Clinical Laboratory 
Tests 
Table 8 footnote a, last sentence wording has been modified as below: 
All events of grade ≥3 AST/ALT increase should be reported as adverse 
events of special interest (AESI). 
For consistency 
10.4 Appendix 4: 
Recommended 
Supportive Care 
and/or Dose 
Modification 
Guidelines for 
Drug-Related 
Adverse Events 
Ocular toxicity:  
The supportive column was revised as merged for Grade 2 and Grade 3 
and updated as below:   
Standard ocular examination weekly until resolution. 
Start curative treatment per ophthalmologist recommendation 
After resuming study treatment, participant should be followed with 
standard ocular examination by every two cycles, even asymptomatic 
during next four cycles. If no recurrence, standard process with follow-up 
with ocular symptom is resumed, as detailed in Section 8.2.6.2. 
Management of study drug and follow-up process upon recurrence to be 
discussed according to Grade of the event at recurrence, clinical benefit 
from study drug and recommendation from the ophthalmologist. 
Febrile neutropenia:  
Below paragraph added to Management of dosing column for 
SAR408701 under Grade 4 Life-threatening consequences:  
“1st episode: administer next cycle at reduced dose and administer G-
CSF or definitively discontinue 
2nd episode: definitive discontinuation” 
For clarity on safety 
management 
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Section # and 
Name 
Description of Change 
Brief Rationale 
10.4 Appendix 4: 
Recommended 
Supportive Care 
and/or Dose 
Modification 
Guidelines for 
Drug-Related 
Adverse Events 
 
Below paragraph added to Management of dosing column for Docetaxel 
under Grade 4 Life-threatening consequences: 
“1st episode: administer next cycle at reduce dose and administer G-CSF 
or definitively discontinue 
2nd episode: definitive discontinuation” 
Grade 3 changed to Grade ≥3 on Supportive Care Guideline Column 
 
Peripheral Neuropathy:  
Section added for recommendation on dose modification and supportive 
care for peripheral neuropathy  
For clarity on safety 
management 
 
10.8 Appendix 8: 
Country Specific 
Requirement 
Section updated to detail safety run-in step and pharmacokinetic run-in 
with 12 SAR408701 treated participants with full PK sampling at Cycle 1 
for China. 
To secure safety and well-
being of Chinese patients as 
well as to obtain safety and 
pharmacokinetic data in 
EFC15858 study. 
10.11.5 
Amended protocol 01 (27-Sep-2019)  
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the amendment 
The treatment landscape in nonsquamous, non–small-cell lung cancer is rapidly evolving with the 
integration of immune check point inhibitors (ICI) that are more and more widely marketed and 
are becoming fully part of the therapeutic strategy, used either in front line metastatic setting in 
combination with platinum-based chemotherapy or as monotherapy, eg, after relapse of 
chemotherapy (or targeted therapy for patients having genetic mutation of their cancer). In this 
context and to have a homogeneous patient population, the study is amended to include only 
patients who have received prior treatment with one platinum-based chemotherapy and an anti-
PD-1/PD-L1 monoclonal antibody. Based on this modification, a stratification factor related to 
prior ICI treatment was adopted, specifically, whether prior ICI treatment was given in 
combination with chemotherapy or sequentially as monotherapy. 
In order to provide additional evidence of clinically meaningful efficacy, timing of the final 
progression free survival (PFS) analysis was amended to be performed at the time when 50% of 
OS events have occurred. This will allow for OS data to be more robust than in the original plan at 
the time of the final PFS analyses. 
With further analyses of availability of validated scales by country and the operational feasibility 
feedbacks, a reassessment of the Health Related Quality of Life (HRQOL) scales to be 
administered in the study was performed. It has been considered to adapt HRQOL related sections 
with perspective of focusing on secondary endpoints only and deleting tertiary endpoints. This is 
mainly in the context of unavailability of culturally validated translation of NSCLC SAQ and 
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VisQoL scales in all countries targeted for the study, as well as the limitation of interpretability of 
PRO data in an open label study design. Disease related symptoms will be captured from EORTC 
QLQ-LC13 and the impact of the ocular toxicity will be gathered by analyses of overall safety 
impact, general physical and role functional quality of life assessment of the EORTC QLQ-C30 as 
well as analysis of ocular symptoms and adverse events.    
Additional modification implemented for clarification around protocol wording, as detailed on 
summary of changes table below. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title page 
“in previously treated” added to Short title 
To reflect original protocol 
1.1 Primary 
objective; 3.0 Table 
1 
The “doublet” and “if indicated” wording deleted  
 
To reflect the study population 
1.1 overall design; 
1.2 footnote b; 
4.1 Overall design;  
Stratification factor related to prior ICI treatment 
updated as Sequential versus combination with 
chemotherapy instead of Yes versus No  
To reflect the study population. This criterion 
considered as best reflect the study population in 
terms of prior PD-L1 expression level.  
1.1 Statistical 
considerations -
sample size 
consideration 
Final Overall Survival analysis assumption updated 
as 452 events instead of 446 with consideration of 
one Interim analysis (IA) for Overall survival (OS) 
when 50% of events (226 deaths) will be observed.  
Final Progression Free Survival analysis assumption 
updated at the time of 50% of OS event as 275 
events instead of 221 events with log-rank test at 
one-sided 0.01 level and power of approximately 
95.5%    
Timelines of final PFS analysis updated as 31 months 
instead of 26 months and final OS analysis at 
51 months instead of 50 months after first participant 
in the study.   
Updated to reflect new design of final PFS 
analyses at the time of 50% of OS events instead 
of 38% of OS events, with consideration of 
achieving more mature OS interim analysis at the 
time of final PFS analysis.  
1.1 Statistical 
considerations  
Analysis of 
secondary efficacy   
endpoints 
Below sentence added to HRQOL related analysis of 
secondary endpoints 
Details of subscales from EORTC QLQ-LC13 and 
EORTC QLQ-C30 and list of items to be used for 
disease-related symptoms, physical function and role 
function will be provided in the statistical analyses 
plan 
For clarity 
1.1 Interim analysis, 
statistical 
considerations 
Timing of OS interim analysis updated as 50% of 
events (ie, approximately 226 deaths) instead of 
about 38% (ie. 169 deaths) 
To reflect new statistical design as detailed 
above  
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activity  
The X added to prescreening for Demography, 
medical/surgical/disease history and smoking history 
X deleted from C1D1 assessment of serum 
pregnancy test, 12-Lead ECG and ocular tests 
NSCLC SAQ and VisQoL scales deleted from ePRO 
row 
Footnote e added for ePRO related description. 
Sentence added to footnote c:  C1D1 hematology, 
blood chemistry and coagulation tests may be omitted 
if baseline test performed within 7 days are normal. If 
baseline test are abnormal should be repeated within 
2 days of first study intervention. 
For consistency 
 
To prevent frequent tests 
 
 
 
For clarity 
3 Objective and 
Endpoints 
 
 
 
3.1 Appropriateness 
of measurements 
Tertiary/exploratory – Two HRQOL related endpoints 
were deleted as NSCLC SAQ and VisQoL deleted  
Tertiary- “CEACAM5 pattern” is added to the endpoint 
of last objective 
 
This sentence deleted: The NSCLC-SAQ (SAQ) is an 
FDA qualified clinical outcome assessment to 
measure symptoms of non-small cell lung cancer.  
As described on Amendment rational.  
 
For analysis of CEACAM5 pattern beside 
CEACAM5 expression level 
 
To reflect amendment 
4.4 End of Study 
Definition  
Timelines of Final PFS and interim OS analyses 
updated as 31 months instead of 26 months and final 
OS analysis 51 months instead of 50 months  
For consistency to reflect new statistical design 
5 Study population  
I02 criterion updated with  
- subsection bullets changed from i, ii, iii to a, b, c 
- deletion of sentence linked to waiver on prior ICI 
treatment 
- addition of below sentence to bullet i to allow prior 
refractory population to be enrolled 
“Patient who had adjuvant / neoadjuvant treatment 
and relapsed as metastatic disease during or within 
6 months of treatment will be considered as first 
line treatment” 
- Bullet iii updated  
E01 updated as “Untreated brain metastases and 
history of leptomeningeal disease. […]” and 
corticosteroid washout decreased to 2 weeks from 4 
weeks 
E04 Definition of active hepatitis B updated with 
correction of or instead of and as “…. either positive 
HBsAg or positive hepatitis B viral DNA test above 
the lower limit…” 
E06 Updated as “Unresolved corneal disorders or any 
previous corneal disorder that considered by 
ophthalmologist that patient may have risk of drug 
induced keratopathy. 
 
For clarity 
To reflect new restriction of participant population 
to previously ICI treated patients  
For clarity  
 
 
 
For clarity 
For clarity  
 
 
 
Typo error  
 
 
 
For clarity per feasibility feedbacks  
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Section # and 
Name 
Description of Change 
Brief Rationale 
6 Study intervention; 
6.5 Concomitant 
therapy 
Premedication of docetaxel updated as “…(eg, 8 mg 
BID dexamethasone or equivalent corticosteroids)..” 
Use of prophylactic erythropoietin limited to “first 
cycle” rather than “first two cycles” 
To reflect possibility of equivalent corticosteroid 
use per site process.  
To take into account docetaxel and use of G-CSF 
8 Study 
assessments and 
procedures 
Specified that, with the exception of age, 
demographic data (gender, race, ethnicity, smoking 
status); histology and stage at diagnosis; and 
biomarkers [tumor mutation status including PD-1 
expression, circulating CEA] when available) 
collected during prescreening will be used for 
analyses of baseline demographic and disease 
characteristics. Age, disease extent at study entry, 
and previous antitumor therapy (type, start and end 
dates, reason for discontinuation, and response to the 
therapy) and change in smoking history will be 
collected at Screening, and will be considered as 
baseline data. 
To clarify the use of prescreening data to prevent 
double data entry  
8.2.6.2 Ocular 
toxicity;  
Clarified that artificial tears are recommended only for 
participants treated with tusamitamab ravrtansine. 
For clarity 
8.2.6.3 Management 
of anemia  
Section updated to allow erythropoietin use after the 
first cycle, instead of after the first 2 cycles. 
As guidance for management of participant 
safety 
8.5 
Pharmacokinetics 
Removed duplicated statement referring to nonlinear 
mixed-effects modeling for population PK analysis. 
To reduce repetition 
8.11 Patient 
Reported Outcome 
The window to fill electronic patient report outcomes 
(ePROs) at pre-dose on Day 1 of Cycle 1 was 
changed from (up to within 7 days)  to (up to within 3 
days) 
Adapted to reflect randomization window to 
ensure data collected in randomized participant 
only 
8.11.3 VisQoL 
Section was deleted 
To reflect amendment 
8.11.4 NSCLC SAQ 
Section was deleted 
To reflect amendment 
9.2 Sample Size 
Determination  
Section updated to reflect new statistical design on 
timing of final PFS (with assumption of 275 PFS 
events) and OS analysis at 31 months at the time of 
50% of OS events and final OS analysis with a total of 
452 deaths 
To reflect amendment as detailed on amendment 
rational  
 
9.2 Sample Size 
Determination  
Phrase below: 
“achieve 554 randomly assigned to study 
intervention” replaced with “for CEACAM5 status, of 
whom 650 patients will be screened to achieve 554 
randomized patients with estimated failure rates of 
80% for pre-screening and 15% for screening” 
For clarity 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.4 Statistical 
analyses 
Estimated cut-off dates updated  
To reflect amendment 
9.4.1 Table 4 
QoL SAQ, VisQoL deleted from Exploratory endpoint 
To reflect amendment 
9. 4.1.1.1 
progression free 
survival 
Censoring rules updated: For patients alive without 
PD at the COD, PFS will be censored at the date of 
the last valid assessment before the COD without 
taking into account the response of the tumor 
assessment after the COD if any. PFS will not be 
censored at the COD anymore  
To avoid to introduce informative censoring and 
bias in the estimated treatment effect in case of 
imbalance of informative censoring between 
arms and to not favor the arm with more 
informative censoring 
9.4.1.1.2 Overal 
survival  
Text added “The cut-off date for the final analysis of 
OS will be the date when 452 deaths are observed 
To clarify and to reflect amendment 
9.4.3 Other 
Analyses 
Text added: “The results of the population PK 
analysis will be presented separately from the main 
clinical study report (CSR).” 
For clarity 
9.5 Interim Analyses 
Section updated with new statistical assumption 
To reflect amendment 
9.5.1 DMC 
Below wording deleted  
“and have completed at least 9 weeks after first study 
intervention” 
For clarity  
9.6 Multiplicity  
Below sentence updated  
“With 275 PFS events at final analysis the study has 
~98% power for detecting a HR of 0.615 at one –
sided alpha 0.02485” 
Table 6 updated to reflect new statistical assumptions  
To reflect amendment  
10.2 Clinical 
laboratory test 
Below sentence added as footnote to Table 8 
“Bicarbonate may be omitted at countries where its 
assay is not performed as part of the routine 
chemistry panel." 
Based on feasibility feedback, in countries where 
routine venous blood blood chemistry assay is 
not used for this assessment 
10.4 Recommended 
Supportive Care 
Ocular toxicity; Definition of grades was updated with 
NCI CTCAE V5.0 wording 
For clarity 
10.5 Contraception 
Section updated to allow up to 1 year of data 
collection on status of child. 
To allow further data collection on baby of a 
female participant or a partner of a male 
participant in case of a need per PV requirement. 
Throughout 
Minor editorial, typographical error corrections and 
standardization of wording. 
For Clarity 
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10.12 APPENDIX 12: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or legally authorized 
representative should be informed verbally prior to initiating any change that is to be implemented 
for the duration of the emergency (eg, study visit delays, use of back-up sites for safety laboratory 
or tumor assessment). 
As the situation may evolve differently by country, by region, or by site, each site should define 
its business continuity plan, and inform the Sponsor of its plan as early as possible. Some 
guidance to be considered in formulating a contingency plan during a regional or national 
emergency is provided in this section.  
10.12.1 
Remote prescreening process  
If there is no other way to conduct prescreening procedures during a regional or national 
emergency declared by a governmental agency (eg, due to a COVID-19 pandemic), the site may 
consider implementing for only those participants who have enough archival samples a remote 
prescreening ICF process compliant with country/site requirements.  
The process should be compliant with accepted principals of patients’ rights and global, national, 
and local regulatory requirements. Requireed protection of personal data (including security of 
e-mail interactions) and confidentiality of study data should be ensured.  
If remote prescreening is planned to be implemented at site:  
• The Investigator/delegate should contact each participant to inquire regarding the 
participant’s willingness to participate in the prescreening process. 
• If participant agrees to prescreening, the Investigator/delegate should send the 
prescreening ICF via e-mail to the participant’s personal e-mail address (as allowed by 
local regulation) or by postal mail. The Investigator/delegate should provide an overview 
of the study (eg, SAR408701 mechanism of action; design of the study in terms of 
treatment groups, visits, and prescreening procedures; and rationale for assessment of 
CEACAM5 expression).  The Investigator/delegate should respond to any question raised 
by a participant, and this correspondence should be documented in detail in the 
participant’s source file. 
• If a participant agrees to participate in the prescreening phase, the participant should print 
out, sign, and date 2 copies of the ICF. A scan of a signed ICF should be sent via secured 
email (if available), and 1 of the signed original ICFs to be filed in the Investigator Study 
File should be sent via postal mail.  
• The Investigator/delegate should review each received signed ICF (or a printout of an 
electronically submitted, scanned copy), sign and date it, and archive it in the Investigator 
Study File.  It is mandatory for the Investigator to ensure the collection of the original 
signed ICF sent by mail; the signed original should be attached to any previously filed 
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signed printout of an electronically submitted signed ICF. After properly documenting this 
consent process, the site may proceed to prepare and send the slides for CEACAM5 
assessment. 
10.12.2 
Screening procedures 
The Investigator/site should assess the site’s capacity to conduct study procedures throughout the 
study for each participant before starting any screening procedure. If the site cannot guarantee an 
accurate follow-up in the context of the trial, alternative treatment outside the clinical trial should 
be proposed. This assessment, per the Investigator’s medical judgement and depending on the 
country/site status, should be communicated to the participant. The participant should satisfy all 
eligibility criteria before enrolling to the study; no protocol waiver is acceptable. Remote 
signature of main study ICF is not acceptable in any circumstance.  
10.12.3 
Study intervention  
During a regional or national emergency declared by a governmental agency, all contingency 
plans should be implemented to ensure compliance to study treatment, based on a case-by-case 
benefit–risk assessment. Administration (or, in case of temporary interruption, re-initiation) of the 
IMP can occur only once the Investigator has determined, according to his/her best judgement, 
that the contribution of the IMP(s) to the occurrence of the epidemic event (eg, COVID-19) was 
unlikely. 
During a regional or national emergency due to pandemic (eg, COVID-19), the Investigator’s 
choice, based on a benefit–risk assessment, to initiate prophylactic G-CSF treatment at Cycle 1 for 
a patient in the docetaxel arm should be considered acceptable.  The Investigator’s decision to 
initiate G-CSF should be detailed in the source data and reported on eCRF.   
Any further safety measure (eg, interim laboratory assessment such as neutrophil count 
monitoring; regular contact with site staff) to follow the safety of patients during the regional or 
national emergency period can be considered.  
10.12.4 
Study procedures  
Depending on site status, if needed, Cycle 1 and Cycle 2 weekly safety laboratory assessment 
(hematology [differential WBC] and liver function tests [AST, ALT, total and direct bilirubin, 
ALP]) can be arranged to be performed either at a laboratory certified to perform these tests that is 
close to patient home, or via sampling at patient’s home.  
All efforts should be made to ensure that measurements of key parameters for efficacy endpoints 
can be performed at the site.  If the Investigator is unable to guarantee that the protocol-required 
efficacy assessments can be conducted, no participant should be screened until the site confirms 
its capacitiy to perform the assessments.  
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As part of a site’s contingency plan, a back-up site should be identified in advance in the case that 
the site delegated to perform the radiological tumor assessment is prevented from performing the 
assessment by a regional or national emergency situation (eg, COVID-19 outbreak). The 
Investigator should ensure that the back-up site conducts the RECIST assessment in same manner 
as that used for baseline tumor assessments.  
In the case that the primary tumor assessment site is incapacitated, ongoing patients would then be 
referred to the back-up site for tumor assessment. The Investigator/delegate should ensure the 
information on baseline assessment methods is shared with the back-up site’s radiologist to ensure 
same method is followed for scans to be sent to IRC. 
10.13 APPENDIX 13: ABBREVIATIONS  
 
AESI: 
adverse event of special interest 
CEACAM5: 
carcinoembryonic antigen-related cell adhesion molecule 5  
CI: 
confidence interval 
CR: 
complete response 
DM4: 
maytansinoid derivative 4 
DMC: 
data monitoring committee 
DOR: 
duration of response 
ECOG: 
Eastern Cooperative Oncology Group 
EOI: 
end of infusion 
EOT: 
end of treatment 
ePROs: 
electronic patient report outcome 
FDG-PET: 
fluorodeoxyglucose-positron emission tomography 
FFPE: 
formalin-fixed paraffin embedded 
FPI: 
first patient in 
FSH: 
follicle stimulating hormone 
GHS/QoL: 
global health status/quality of life 
HRQOL: 
health-related quality of life 
HRT: 
hormonal replacement therapy 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
IRC: 
radiological review committee 
IRT: 
interactive response technology 
ITT: 
intent to treat 
IV: 
intravenous 
NCI-CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Event 
NE: 
not evaluable 
NIMP: 
non investigational medicinal product 
NSCLC: 
non small cell lung cancer 
ORR: 
objective response rate 
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OS: 
overall survival 
PD: 
progressive disease 
PD1/PDL1: 
programmed death 1/ programmed death ligand 1 
PF: 
Physical function 
PFS: 
progression free survival 
Q2W: 
every 2 weeks 
Q3W: 
every 3 weeks 
RF: 
Role function 
RoW: 
Rest of the World 
SAE: 
serious adverse event 
TEAE: 
treatment-emergent adverse event 
TTD: 
time to deterioration 
WOCBP: 
woman of childbearing potential 
 
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11 
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