Open-label, Phase 2 Study, Evaluating the Efficacy and Safety of Tusamitamab Ravtansine in Non-squamous Non-small-cell Lung Cancer (NSQ NSCLC) Participants With Negative or Moderate CEACAM5 Expression Tumors and High Circulating CEA
Phase: PHASE2
Conditions: Non-squamous Non-small Cell Lung Cancer
Sponsor: Sanofi

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According to Template: Sanofi OneDocument Version 6.0, dated 25-JUN-2021 
Page 1 
CLINICAL TRIAL PROTOCOL 
Protocol title: 
Open-label, Phase 2 study, evaluating the efficacy and safety 
of tusamitamab ravtansine in non-squamous non-small-cell 
lung cancer (NSQ NSCLC) participants with negative or 
moderate CEACAM5 expression tumors and high circulating 
CEA 
Protocol number: 
ACT17241 
Amendment number: 
Not Applicable 
Compound number 
(INN/Trademark): 
SAR408701 
tusamitamab ravtansine/NA 
Brief title: 
Tusamitamab ravtansine in NSQ NSCLC participants with 
negative or moderate CEACAM5 expression tumors and high 
circulating CEA 
Acronym: 
CARMEN-LC06 
Study phase: 
Phase 2 
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: 
2021-004423-32 
NCT: 
Not applicable 
WHO: 
U1111-1264-2828 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Date: 
27-Sep-2021 
Total number of pages: 116 
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NCT Number: NCT05245071

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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ....................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 7 
1 
PROTOCOL SUMMARY ................................................................................................................. 8 
1.1 
SYNOPSIS ....................................................................................................................................... 8 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 16 
1.3.1 
Study flow chart.............................................................................................................................. 16 
1.3.2 
PK/ATA flow chart .......................................................................................................................... 24 
2 
INTRODUCTION............................................................................................................................ 25 
2.1 
STUDY RATIONALE ..................................................................................................................... 25 
2.2 
BACKGROUND ............................................................................................................................. 26 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 27 
2.3.1 
Risk assessment ............................................................................................................................ 27 
2.3.2 
Benefit assessment ........................................................................................................................ 32 
2.3.3 
Overall benefit/risk conclusion ....................................................................................................... 32 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ......................................................................... 33 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 35 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 37 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 37 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 37 
5 
STUDY POPULATION .................................................................................................................. 38 
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5.1 
INCLUSION CRITERIA .................................................................................................................. 38 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 40 
5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 42 
5.4 
SCREEN FAILURES ..................................................................................................................... 42 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ............................................................................... 43 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 44 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 44 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 46 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 46 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 47 
6.5 
DOSE MODIFICATION .................................................................................................................. 47 
6.5.1 
Retreatment criteria ....................................................................................................................... 48 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY ...................... 48 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 48 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 49 
6.8.1 
Rescue medicine............................................................................................................................ 50 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 51 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 51 
7.1.1 
Permanent discontinuation ............................................................................................................ 51 
7.1.2 
Temporary discontinuation ............................................................................................................. 52 
7.1.3 
Rechallenge ................................................................................................................................... 52 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 52 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 53 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 54 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 54 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 55 
8.2.1 
Physical examinations ................................................................................................................... 55 
8.2.2 
Specific ocular tests ....................................................................................................................... 55 
8.2.3 
Vital signs ....................................................................................................................................... 56 
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8.2.4 
Electrocardiograms ........................................................................................................................ 56 
8.2.5 
Clinical safety laboratory tests ....................................................................................................... 56 
8.2.6 
Guidelines for management of adverse events ............................................................................. 57 
8.2.6.1 
Hypersensitivity reactions .............................................................................................................. 57 
8.2.6.2 
Ocular toxicity ................................................................................................................................. 57 
8.2.6.3 
Keratopathy/keratitis management ................................................................................................ 58 
8.2.6.4 
Management of anemia ................................................................................................................. 59 
8.2.6.5 
Management of neutropenia .......................................................................................................... 59 
8.2.6.6 
Liver function tests ......................................................................................................................... 59 
8.2.6.7 
Peripheral neuropathy .................................................................................................................... 59 
8.2.6.8 
Colitis (including hemorrhagic) ....................................................................................................... 60 
8.2.7 
Pregnancy testing .......................................................................................................................... 60 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 60 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 61 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 61 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 61 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 61 
8.3.5 
Pregnancy ...................................................................................................................................... 62 
8.3.6 
Cardiovascular and death events .................................................................................................. 62 
8.3.7 
Adverse events of special interest ................................................................................................. 62 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 63 
8.4 
PHARMACOKINETICS .................................................................................................................. 63 
8.5 
GENETICS ..................................................................................................................................... 64 
8.5.1 
Circulating tumor DNA analysis ..................................................................................................... 64 
8.5.2 
Tumor DNA and RNA analyses ..................................................................................................... 64 
8.6 
BIOMARKERS ............................................................................................................................... 65 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 65 
8.8 
HEALTH ECONOMICS .................................................................................................................. 66 
8.9 
PATIENT-REPORTED OUTCOMES ............................................................................................. 66 
8.9.1 
NSCLC-SAQ .................................................................................................................................. 66 
8.9.2 
PGIS-LCS and PGIC-LCS ............................................................................................................. 67 
8.9.3 
FACT-GP5 ..................................................................................................................................... 67 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 67 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 69 
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9.1 
POPULATIONS FOR ANALYSES ................................................................................................. 69 
9.2 
STATISTICAL ANALYSES ............................................................................................................ 70 
9.2.1 
General considerations .................................................................................................................. 70 
9.2.2 
Primary endpoint analyses ............................................................................................................. 71 
9.2.3 
Secondary endpoints analyses ...................................................................................................... 71 
9.2.3.1 
Progression-free survival ............................................................................................................... 72 
9.2.3.2 
Disease control rate ....................................................................................................................... 73 
9.2.3.3 
Duration of response ...................................................................................................................... 73 
9.2.4 
Tertiary/exploratory endpoint(s) analyses ...................................................................................... 74 
9.2.5 
Safety analyses .............................................................................................................................. 74 
9.2.5.1 
Adverse events .............................................................................................................................. 74 
9.2.5.2 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 75 
9.2.6 
Other analyses ............................................................................................................................... 76 
9.3 
INTERIM ANALYSES  ................................................................................................................... 76 
9.4 
SAMPLE SIZE DETERMINATION................................................................................................. 77 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 78 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 78 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 78 
10.1.2 
Financial disclosure ....................................................................................................................... 79 
10.1.3 
Informed consent process .............................................................................................................. 79 
10.1.4 
Data protection ............................................................................................................................... 80 
10.1.5 
Committees structure ..................................................................................................................... 82 
10.1.6 
Dissemination of clinical study data ............................................................................................... 82 
10.1.7 
Data quality assurance .................................................................................................................. 83 
10.1.8 
Source documents ......................................................................................................................... 84 
10.1.9 
Study and site start and closure ..................................................................................................... 84 
10.1.10 Publication policy ........................................................................................................................... 85 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 85 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 87 
10.3.1 
Definition of AE .............................................................................................................................. 87 
10.3.2 
Definition of SAE ............................................................................................................................ 89 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 90 
10.3.4 
Reporting of SAEs ......................................................................................................................... 92 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 93 
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10.4.1 
Definitions ...................................................................................................................................... 93 
10.4.2 
Contraception guidance ................................................................................................................. 93 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 94 
10.6 
APPENDIX 6: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS ......................................................... 95 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................... 98 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 98 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 98 
10.9.1 
Remote pre-screening process ...................................................................................................... 99 
10.9.2 
Screening procedures .................................................................................................................. 100 
10.9.3 
Study intervention ........................................................................................................................ 100 
10.9.4 
Study procedures ......................................................................................................................... 100 
10.9.5 
Statistical analyses and deviation ................................................................................................ 101 
10.9.6 
Informed consent process ............................................................................................................ 101 
10.10 
APPENDIX 10: DEFINITION OF WELL CONTROLLED HUMAN IMMUNODEFICIENCY 
VIRUS INFECTION ...................................................................................................................... 101 
10.11 
APPENDIX 11: CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE AND 
STRONG CYP3A INHIBITORS ................................................................................................... 102 
10.12 
APPENDIX 12: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 ..... 104 
10.12.1 Measurability of tumor at baseline ............................................................................................... 104 
10.12.2 Special considerations regarding lesion measurability ................................................................ 104 
10.13 
APPENDIX 13: ABBREVIATIONS ............................................................................................... 111 
10.14 
APPENDIX 14: PROTOCOL AMENDMENT HISTORY .............................................................. 113 
11 
REFERENCES............................................................................................................................. 114 
 
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LIST OF TABLES  
Table 1 - Risk assessment ............................................................................................................................ 28 
Table 2 - Objectives and endpoints ............................................................................................................... 33 
Table 3 - Summary of primary estimands for main endpoints....................................................................... 34 
Table 4 - Study intervention(s) administered ................................................................................................ 44 
Table 5 - Study arm(s) ................................................................................................................................... 45 
Table 6 - Individual tusamitamab ravtansine dose reduction ........................................................................ 48 
Table 7 - Population for analyses .................................................................................................................. 69 
Table 8 - 
.......................... 77 
Table 9 - Protocol-required laboratory tests .................................................................................................. 86 
Table 10 - Recommended Dose Modification or Discontinuation for SAR40870 ......................................... 95 
Table 11 - List of CYP substrates with narrow therapeutic range ............................................................... 102 
Table 12 - List of strong CYP3A inhibitors .................................................................................................. 102 
Table 13 - Response criteria ....................................................................................................................... 107 
Table 14 - Response in participants with target disease ............................................................................. 109 
Table 15 - Response in participants with non-target disease only .............................................................. 110 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 15 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
Open-label, Phase 2 study, evaluating the efficacy and safety of tusamitamab ravtansine in non-squamous 
non-small-cell lung cancer (NSQ NSCLC) participants with negative or moderate CEACAM5 expression 
tumors and high circulating CEAOpen-label, Phase 2 study, evaluating the efficacy and safety of 
tusamitamab ravtansine in non-squamous non-small-cell lung cancer (NSQ NSCLC) participants with 
negative or moderate CEACAM5 expression tumors and high circulating CEA 
Brief title: 
 
Tusamitamab ravtansine in NSQ NSCLC participants with negative or moderate CEACAM5 expression 
tumors and high circulating CEA 
Rationale: 
Tusamitamab ravtansine is an antibody (anti-CEACAM5) conjugate to the cytotoxic maytansinoid 
agent DM4. In the first in human (FIH) TED13751 study, a cohort of 64 participants with heavily 
pretreated non-squamous non-small-cell-lung-cancer (NSQ NSCLC) with high carcinoembryonic 
antigen-related cell adhesion molecule 5 (CEACAM5) expression using immunohistochemistry 
(IHC) method applied at pre-screening on archived tumor sample (defined as ≥2+ in intensity in at 
least 50% of the tumor cells) have been treated with tusamitamab ravtansine at 100 mg/m² every 
2 weeks (Q2W). Tusamitamab ravtansine has shown encouraging anti-tumor activity which was 
associated with an overall response rate of 20.3% (13 participants who had partial response [PR]) 
per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 (95% CI: 12.27%–31.71%), 
warranting further development of tusamitamab ravtansine to treat this patient population.  
CEACAM5 is one of the 7 members of the carcinoembryonic antigen (CEA) family and 
circulating CEA is the shed form of membranous proteins. 
In this cohort of NSQ NSCLC participants with high CEACAM5 expression on tumor (≥2+ in 
intensity in ≥50% of tumor cells), 10 out of the 13 responding participants had high baseline 
circulating CEA (≥100 ng/mL). Potential responses to tusamitamab ravtansine have also been 
evaluated in a cohort of NSQ NSCLC participants with moderate CEACAM5 expression on 
tumor (≥2+ in intensity in ≥1% and <50% of tumor cells) but only a limited number of 
participants (7 out of 28 participants) presented high circulating CEA levels at baseline. 
No anti-tumor activity response data are available from the negative CEACAM5 expression on 
tumor by IHC (intensity 1+ whatever the percentage of stained tumor cells or <1% of tumor cells) 
with high circulating CEA level (≥100 ng/mL) cohort. 
The CEACAM5 expression status may differ between the initial tumor at diagnosis and the tumor 
at the time of the enrollment in the clinical trial.  
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Even though a correlation is expected between circulating CEA and CEACAM5 expression status 
on tumor, there are no available data on concomitant CEACAM5 expression on fresh tumor 
biopsy and circulating CEA.  
The aim of this study is to evaluate, if participants with high circulating CEA level at baseline 
could benefit from tusamitamab ravtansine treatment despite negative or moderate CEACAM5 
expression on archival biopsy, assuming that a high circulating CEA level reflects a high 
CEACAM5 expression on tumor at the time of the enrollment. To this end, the anti-tumor activity 
will be assessed in participants with NSQ NSCLC with high circulating CEA levels despite 
negative or moderate CEACAM5 expression on tumor by IHC testing on archived biopsy in 
third- or fourth-line treatment. 
Objectives and endpoints: 
  
Objectives 
Endpoints 
Primary 
 
• 
To assess the anti-tumor activity of tusamitamab 
ravtansine when given every 2 weeks (Q2W) in 
non-squamous non-small-cell-lung-cancer (NSQ 
NSCLC) participants with negative or moderate 
CEACAM5 expression tumors and high circulating 
carcinoembryonic antigen (CEA) levels 
• 
Objective Response Rate (ORR) of tusamitamab 
ravtansine, defined as the proportion of participants 
who have a confirmed complete response (CR) or 
partial response (PR) as best overall response 
(BOR) per Response Evaluation Criteria In Solid 
Tumors (RECIST) v1.1 
Secondary 
 
• 
To assess the safety and tolerability of tusamitamab 
ravtansine 
• 
Incidence of participants with treatment-emergent 
adverse events (TEAEs), serious adverse events 
(SAEs) and laboratory abnormalities according to 
the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) 
v5.0 
• 
To assess other efficacy parameters of 
tusamitamab ravtansine 
• 
Progression-free survival (PFS), defined as the time 
from the date of first tusamitamab ravtansine 
administration to the date of the first documented 
disease progression or death due to any cause, 
whichever comes first. 
• 
Disease control rate (DCR), defined as the 
percentage of participants who have achieved 
confirmed CR or PR, or stable disease as BOR per 
RECIST v1.1 
• 
Duration of response (DOR), defined as the time 
from first documented evidence of CR or PR until 
progressive disease (PD) determined per RECIST 
v1.1 or death from any cause, whichever occurs first 
• 
To evaluate the immunogenicity of tusamitamab 
ravtansine 
• 
Incidence of participants with anti-therapeutic 
antibodies (ATAs) against tusamitamab ravtansine 
• 
To document the pharmacokinetics (PK) of 
tusamitamab ravtansine  
• 
Tusamitamab ravtansine concentrations 
 
 
 
 
 
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Overall design: 
This is a Phase 2, open-label, multi-center study assessing efficacy (anti-tumor activity), safety, 
and pharmacokinetic (PK) of tusamitamab ravtansine single agent in NSQ NSCLC participants 
with negative or moderate CEACAM5 expression tumors and high circulating CEA (≥100 ng/mL) 
at screening.  
Moderate CEACAM5 expression is defined as intensity ≥2+ in ≥1% and <50% of tumor cells. 
Negative CEACAM5 expression is defined as intensity 1+ whatever the percentage of stained 
tumor cells or <1% of tumor cells. 
During the pre-screening phase, participants who were pre-screen failed in EFC15858 Phase 3 
trial with available CEACAM5 status (central assessment by IHC) as negative or moderate 
expression on archival tumor tissue can be pre-screened. Participants with high circulating CEA 
(≥100 ng/mL) will be screened and will go through protocol screening procedures. 
After being screened, the eligible participants will receive tusamitamab ravtansine as single agent 
treatment at the dose of 100 mg/m² Q2W. 
Brief summary:  
This is an open label single group, Phase 2, one-arm study for treatment to evaluate efficacy, 
safety, and PK of tusamitamab ravtansine in NSQ NSCLC participants with negative or moderate 
CEACAM5 expression tumors and high circulating CEA. 
Participants who will be enrolled, will receive tusamitamab ravtansine as monotherapy at 
100 mg/m2 Q2W until disease progression, unacceptable adverse event (AE), initiation of a new 
anticancer therapy, or the participant’s or Investigator’s decision to stop the treatment, whichever 
comes first. A total of approximately 38 participants are planned to be treated. An interim analysis 
is planned after 20 participants treated are evaluable for anti-tumor activity. If at least 2 confirmed 
objective responses are reported, the recruitment will continue to achieve a total of 38 evaluable 
treated participants. 
Number of participants: 
Approximately 285 participants will be pre-screened to achieve approximately 38 treated 
participants, based on an estimated pre-screening failure rate of 84% and an estimated study 
screening failure rate of 15%. 
Intervention groups and duration: 
• Pre-screening period: a pre-screening informed consent will be signed in order to collect 
available CEACAM5 expression results on archival tumor tissue from EFC15858 study 
and the circulating CEA value. 
The duration of the study for a participant will include: 
• Screening period: up to 28 days. 
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• Treatment period: once successfully screened, enrolled participants may receive study 
intervention until disease progression, unacceptable AE, initiation of a new anticancer 
therapy, or the participant’s or Investigator’s decision to stop the treatment, whichever 
comes first. Each cycle of treatment will have a duration of 2 weeks. After discontinuing 
study intervention, participants will return to the study site approximately 30 days after the 
last investigational medicinal product (IMP) administration or before the participant 
receives another anticancer therapy, whichever is earlier, for end-of-treatment (EOT) 
assessments. 
• Follow-up period: a safety follow-up visit will be performed approximately 90 days after 
the last dose of IMP 
- 
Participants who discontinue the study treatment due to documented progressive 
disease (PD), do not need further follow-up visit, if any ongoing related AE/ adverse 
events of special interest (AESI)/serious adverse event (SAE) is resolved or stabilized. 
Otherwise follow-up visits will be performed every 12 weeks, 
- 
Participants who stop treatment before documented PD should undergo a tumor 
assessment and a follow-up visit every 12 weeks (±7 days) after the last tumor 
assessment until radiological disease progression, start of a new anticancer therapy, 
study cut-off date for secondary endpoints, or withdrawal of participant’s consent, 
whichever comes first. After documented PD or a start of new anticancer therapy, the 
participant will be followed until any ongoing IMP related AE/AESI/SAE is resolved 
or stabilized. 
The study cut-off date for the interim analysis corresponds to the date when the first 20 evaluable 
treated participants have had at least 2 postbaseline tumor assessments, experienced confirmed 
objective response, or have discontinued the study treatment for any reason. For participants with 
2 postbaseline tumor assessments and occurrence of response at the second postbaseline tumor 
assessment, the confirmatory assessment will also be included. 
The study cut-off for analysis of the primary endpoint, objective response rate (ORR), 
corresponds to the date on which all evaluable treated participants have had at least 2 postbaseline 
tumor assessments, experienced confirmed objective response, or have discontinued the study 
treatment for any reason. For participants with 2 postbaseline tumor assessments and occurrence 
of response at the second postbaseline tumor assessment, the confirmatory assessment will also be 
included. This study cut-off can be up to approximately 20 weeks (16 weeks for 2 tumor 
assessments and 4 weeks for confirmation of response, if needed) after the last participant’s first 
IMP administration. Of note, disease control rate (DCR) will be also assessed at this cut-off. 
The final study cut-off for analysis of the secondary efficacy endpoints, which include duration of 
response (DOR) and progression-free survival (PFS), will be 4 months after the cut-off date for 
the primary analysis. At that time, the primary analysis of ORR and DCR will also be updated.  
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Study intervention(s) 
Investigational medicinal product(s) 
• Formulation: tusamitamab ravtansine is supplied as a 25 mL extractable volume of 
concentrate for solution for infusion of 125 mg contained in a 30 mL Type I glass vials. 
• Route(s) of administration: Intravenous infusion (IV). 
• Dose regimen: tusamitamab ravtansine will be administered on Day 1 as 100 mg/m2 given 
via IV infusion and repeated Q2W. The duration of 1 cycle will be 14 days 
(1 administration of tusamitamab ravtansine per cycle). For participants with a body 
surface area (BSA) >2.20 m², the dose will be calculated based on a BSA of 2.20 m². 
Noninvestigational medicinal products (NIMP) 
Premedication with histamine H1 antagonist (diphenhydramine 50 mg or equivalent 
[eg, dexchlorpheniramine] given approximately 15 minutes [IV] to 1 hour [oral] before 
tusamitamab ravtansine administration) is required for all participants before administration of 
tusamitamab ravtansine. After first study intervention of SAR408701, patients should be observed 
for acute reactions at site up to 4 hours depending on any sign of drug-induced allergic reaction. 
Detailed instructions for dilution and administration of the IMP are provided in Pharmacy 
Manual. If a participant has experienced an infusion reaction in a previous tusamitamab ravtansine 
administration, premedication will also include dexamethasone 10 mg IV for future infusions. If 
the case participant does not experience any hypersensitivity reactions after 4 cycles, the 
premedication can be discontinued at the discretion of the Investigator. 
Posttrial access to study medication: Not applicable. 
Duration of study intervention 
The expected duration of study intervention for participants may vary, based on disease 
progression date; median expected duration of study per participant is estimated as 40 weeks (up 
to 4 weeks for screening, a median of 24 weeks for treatment, and a median of 12 weeks for end 
of treatment assessments and the safety follow-up visit. 
Statistical considerations: 
• Sample size calculations: 
- 
Assuming a pre-screening failure rate of 84% and a study screening failure rate of 
15%, approximately 285 participants will be pre-screened to achieve approximately 38 
treated participants in the study. The initial plan is to treat a total of 38 participants 
evaluable for anti-tumor activity (at least 1 postbaseline tumor assessment, early 
clinical progression, or death due to disease progression).  
• Main analysis population: 
- 
All-treated population: All enrolled participants exposed to the study treatment, 
regardless of the amount of treatment administered. All safety analyses will be 
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performed on this population, which is also the primary population for analysis of all 
efficacy parameters. 
- 
Activity population: All-treated participants who have measurable disease at study 
entry and at least 1 postbaseline evaluable tumor assessment. Participants with no 
postbaseline evaluable tumor assessment but with an early clinical progression or who 
died from disease progression will also be included in this set. This population is the 
secondary population for analysis of efficacy parameters. 
- 
Pharmacokinetic population: All participants from the all-treated population with at 
least 1 postbaseline PK concentration with adequate documentation of dosing and 
sampling dates and times. 
- 
Anti-therapeutic antibodies (ATA) population: All participants from the all-treated 
population with at least 1 postbaseline ATA result (negative, positive, or inconclusive). 
• Analysis of primary endpoint: 
- 
Objective response rate (ORR) will be summarized for the all-treated population using 
descriptive statistics and 95% exact CI will be provided using the Clopper-Pearson 
method. As a supplementary analysis, ORR will also be summarized on the activity 
population. 
• Analysis of secondary efficacy endpoints: 
- 
Duration of response (DOR) will be summarized for the subgroup of participants who 
achieved confirmed objective response for the all-treated population with descriptive 
statistics using Kaplan-Meier methods. The median DOR and associated 95% CI will 
be provided, 
- 
Progression-free survival (PFS) will be summarized for the all-treated population using 
Kaplan-Meier methods. The median PFS and associated 95% CI will be provided, 
along with probabilities of being progression-free at different time points, 
- 
Disease control rate (DCR) will be summarized for the all-treated population using 
descriptive statistics and 95% CI will be provided using the Clopper-Pearson method. 
As a supplementary analysis, DCR will also be summarized on the activity population. 
• Analysis of safety endpoints: 
- 
Number and percentage of participants experiencing treatment-emergent adverse 
events (TEAEs) by primary system organ class (SOC) and preferred term (PT) will be 
summarized by National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) V5.0 Grade (all grades, and Grade ≥3) for the all-treated 
population. Similar summaries will be prepared for TEAEs related to IMP, TEAEs 
leading to permanent study intervention discontinuation, TEAEs leading to dose 
modification or dose interruption, serious TEAEs, TEAEs with fatal outcome, AESIs, 
and AEs/SAEs occurring during the post-treatment period. In addition, the number (%) 
of participants with any Grade 5 AE (TEAE and post-treatment) will be summarized, 
- 
Hematology and clinical chemistry results will be graded according to the 
NCI-CTCAE V5.0, when applicable. Number and percentage of participants with 
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laboratory abnormalities (all grades and by grade) using the worst grade during the 
on-treatment period will be provided on the all-treated population. 
Data Monitoring/Other committee: No
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
Prescreening
Screening
Treatment Period
Follow-up
CEACAM5 negative – moderate and high circulating CEA levels 
(≥100 ng/mL) NSQ NSCLC participants
Tusamitamab ravtansine 100 mg/m2 Q2W (N = 38)
N = 38 (N = 20 -> Interim analysis -> N = 18)
Treatment will be continued until documented disease progression, unacceptable toxicity, new 
anticancer therapy initiation, or the participant’s or investigator's decision to stop the treatment.





Prescreening ICF
-42 days 
Screening ICF
-28 days 
C1D1
EOT
30±5 days
of last IMP
Follow-up 
90±7 days 
of last IMP
 
Moderate CEACAM5 expression is defined as intensity ≥2+ in ≥1% and <50% of tumor cells. Negative CEACAM5 expression is defined as intensity 1+ whatever the percentage of stained tumor cells or <1% of tumor 
cells 
Abbreviations: C =cycle; CEA = carcinoembryonic antigen; CEACAM5 = carcinoembryonic antigen-related cell adhesion 5, D = Day, EOT = end-of-the-treatment, ICF = informed consent form, IMP = investigational 
medicinal product, N = number of participants, NSQ NSCLC = non-squamous non-small-cell lung cancer, Q2W = every 2 weeks. 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
 
1.3.1 Study flow chart  
 
 
Procedure 
Pre-
screeninga 
Screeningb 
Treatment Cycle 1 
 
 
Subsequent Cycles 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upd 
Notes 
Day(D) 
Days prior to 
initial 
infusion 
Days prior to 
initial 
infusion 
D1 
Pre-
infusion 
D8 
D1 Pre-
infusionc 
(±2 days) 
Every 
8 weeks 
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after 
last 
infusion 
(±7 days) 
 
 
Available CEACAM5 
expression status 
(archival tumor tissue) 
after pre-screening 
informed consenta 
≤42 
 
 
 
 
 
 
 
Available CEACAM5 
expression results 
from EFC15858 
Study assessed by 
central IHC will be 
used after pre-
screening informed 
consent will be 
signed. 
Informed consent 
 
X 
 
 
 
 
 
 
 
Circulating CEAe 
≤42 
≤7 
 
 
 
 
 
 
 
X 
X 
X 
At pre-screening, 
after pre-screening 
informed consent 
signed. Then after 
informed consent 
signed. On infusion 
days, to be 
performed before 
infusion or the day 
before 
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Procedure 
Pre-
screeninga 
Screeningb 
Treatment Cycle 1 
 
 
Subsequent Cycles 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upd 
Notes 
Day(D) 
Days prior to 
initial 
infusion 
Days prior to 
initial 
infusion 
D1 
Pre-
infusion 
D8 
D1 Pre-
infusionc 
(±2 days) 
Every 
8 weeks 
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after 
last 
infusion 
(±7 days) 
 
 
CEACAM5 expression 
status and RNA/DNA 
analysis on fresh tumor 
tissuef 
 
≤28 
 
 
 
 
 
 
After informed 
consent signed. 
Fresh biopsy at 
screening is optional. 
IgG 
 
 
X 
 
 
 
 
 
Will be collected at 
C1D1 pre-infusion 
only. 
Plasma for Circulating 
CEACAM5g 
 
≤7 
 
 
 
X 
 
 
 
Plasma for tumor cfDNA 
and whole blood for 
germline DNA 
 
 
X 
 
 
 
 
 
 
IRT contact 
X 
X 
X 
 
X 
 
X 
X 
 
Inclusion and exclusion 
criteria 
 
≤28 
X 
 
 
 
 
 
 
Demography 
 
≤28 
 
 
 
 
 
 
 
Medical/surgical/disease 
historyh 
Xi 
≤28 
 
 
 
 
 
 
 
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Procedure 
Pre-
screeninga 
Screeningb 
Treatment Cycle 1 
 
 
Subsequent Cycles 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upd 
Notes 
Day(D) 
Days prior to 
initial 
infusion 
Days prior to 
initial 
infusion 
D1 
Pre-
infusion 
D8 
D1 Pre-
infusionc 
(±2 days) 
Every 
8 weeks 
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after 
last 
infusion 
(±7 days) 
 
 
Physical examination, 
ECOG performance 
status 
 
≤7 
X 
 
X 
 
X 
X 
Examination of major 
body systems 
including 
cardiovascular, 
central nervous 
system, respiratory 
system, 
gastrointestinal 
system, 
hepatomegaly, 
splenomegaly, 
lymphadenopathy. 
Height 
 
≤7 
 
 
 
 
 
 
 
Weight 
 
≤7 
X 
 
X 
 
X 
 
On Day 1 of each 
treatment cycle 
Vital signs 
 
≤7 
X 
 
X 
 
X 
 
Temperature, blood 
pressure, and pulse 
rate 
Serum or urine pregnancy 
test (WOCBP only)j  
 
≤7 
 
 
Every 
4 weeks 
 
X 
 
Mandatory serum 
test at screening and 
EOT. Serum or urine 
test every 4 weeks 
during study 
treatment period. 
HBV & HCV serology; 
HIV test (only required at 
country level) 
 
X 
 
 
 
 
 
 
 
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Procedure 
Pre-
screeninga 
Screeningb 
Treatment Cycle 1 
 
 
Subsequent Cycles 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upd 
Notes 
Day(D) 
Days prior to 
initial 
infusion 
Days prior to 
initial 
infusion 
D1 
Pre-
infusion 
D8 
D1 Pre-
infusionc 
(±2 days) 
Every 
8 weeks 
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after 
last 
infusion 
(±7 days) 
 
 
Laboratory assessmentsk 
 
≤7 
Xl 
 
X 
X 
 
X 
 
During first 2 cycles, 
hematology and liver 
function tests will be 
assessed weekly. 
12-lead ECG 
 
≤7 
X 
 
X 
 
X 
 
 
Specific ocular test 
 
≤28 
 
 
 
 
X 
 
Performed by the 
ophthalmologist 
include visual acuity, 
slit-lamp under 
dilatation, and 
Schirmer’s test at 
screening, EOT and 
whenever clinically 
indicated 
Assessment of 
ocular/visual symptomsm 
 
≤28 
X 
 
X 
 
X 
 
 
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Procedure 
Pre-
screeninga 
Screeningb 
Treatment Cycle 1 
 
 
Subsequent Cycles 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upd 
Notes 
Day(D) 
Days prior to 
initial 
infusion 
Days prior to 
initial 
infusion 
D1 
Pre-
infusion 
D8 
D1 Pre-
infusionc 
(±2 days) 
Every 
8 weeks 
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after 
last 
infusion 
(±7 days) 
 
 
Study intervention 
 
 
X 
 
X 
 
 
 
Participants should 
receive study 
intervention until 
documented disease 
progression, 
unacceptable 
toxicity, new 
anti-cancer therapy 
initiation, or the 
participant’s or 
Investigator’s 
decision to stop the 
treatment, whichever 
comes first. 
AE assessment 
 
Xn 
==========================================================→ 
 
Concomitant medication 
review 
 
X 
==========================================================→ 
 
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Procedure 
Pre-
screeninga 
Screeningb 
Treatment Cycle 1 
 
 
Subsequent Cycles 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upd 
Notes 
Day(D) 
Days prior to 
initial 
infusion 
Days prior to 
initial 
infusion 
D1 
Pre-
infusion 
D8 
D1 Pre-
infusionc 
(±2 days) 
Every 
8 weeks 
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after 
last 
infusion 
(±7 days) 
 
 
Tumor assessment - 
RECIST v1.1 - CT/MRIo 
 
28 
 
 
 
X 
X 
X 
Imaging 
assessments are to 
be scheduled using 
the C1D1 date as 
the reference for all 
time points and are 
not to be scheduled 
based on the date of 
the previous imaging 
time point. Please 
refer to Section 8.1 
for further 
information. 
Tusamitamab ravtansine 
PK 
 
 
Refer to PK/ATA flowchart Section 1.3.2 
 
 
 
Section 8.4 
Tusamitamab ravtansine 
Immunogenicity (ATA)  
 
 
Refer to PK/ATA flowchart Section 1.3.2 
 
X 
 
Section 8.7 
NSCLC-SAQ, PGIS- LCS, 
FACT-GP5p 
 
 
X 
X 
X 
 
X 
X 
Baseline: Data 
collected on device 
at site pre-infusion 
on C1D1. 
Post-baseline: Data 
collected on device 
at site on C1D8 and 
on D1 pre-infusion of 
subsequent cycles 
during treatment; at 
EOT; and at the first 
follow-up visit. 
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Procedure 
Pre-
screeninga 
Screeningb 
Treatment Cycle 1 
 
 
Subsequent Cycles 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upd 
Notes 
Day(D) 
Days prior to 
initial 
infusion 
Days prior to 
initial 
infusion 
D1 
Pre-
infusion 
D8 
D1 Pre-
infusionc 
(±2 days) 
Every 
8 weeks 
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after 
last 
infusion 
(±7 days) 
 
 
PGIC-LCSp 
 
 
 
X 
X 
 
X 
X 
Post-baseline: Data 
collected on device 
at site pre-infusion (if 
applicable) on C1D8 
and on D1 of 
subsequent cycles 
during treatment; at 
EOT; and at the first 
follow-up visit. 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; ALT = alanine aminotransferase; ANC = absolute neutrophil count; ALP = alkaline phosphatase; AST = aspartate aminotransferase; ATA = 
anti-therapeutic antibody; BUN = blood urea nitrogen; C = cycle; CEA = carcinoembryonic antigen; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; cfDNA = circulating free DNA; CT = 
computed tomography; D = Day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; eGFR = estimated glomerular filtration 
rate ; EOT = end-of-treatment; FACT-GP5 = Functional Assessment of Cancer Therapy Item GP-5; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent 
form; IgG = immunoglobulin G; IHC = immunohistochemistry; IMP = investigational medicinal product; IRT = interactive response technology; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; 
NSCLC-SAQ = Non-Small-Cell Lung Cancer Symptom Assessment Questionnaire; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PK = pharmacokinetics;  PRO = patient 
reported outcomes; RBC = red blood cells; RECIST = response evaluation criteria in solid tumors; RNA = ribonucleic acid; SAE = serious adverse event; WBC = white blood cell; WES = whole exome sequencing; 
WOCBP = woman of childbearing potential. 
a Pre-screening Informed Consent will be signed by the participant for the use of CEACAM5 assay results on archival tumor tissue (central assessment by IHC) obtained in study EFC15858 and who had negative or 
moderate expression status. Participants who were pre-screened in study EFC15858 using a fresh biopsy cannot be pre-screened in Study ACT17241 unless the fresh specimen is older than 6 months at the time 
of pre-screening. Circulating CEA will be assessed at the pre-screening visit no more than 42 days prior to initiation of therapy.  
b Informed consent should be signed before any study specific procedures. Only participants with high circulating CEA (≥100 ng/mL) at pre-screening will be screened and will go through protocol screening 
procedures. Informed consent can be signed more than 28 days prior to initiation of therapy. Screening time indicates in which timeframe exams used to support eligibility have to be done prior to initiation of 
therapy. Routine baseline tests performed prior to ICF signature do not need to be repeated as long as they are within the screening-defined timeframe. Assessments must be performed prior to first IMP 
administration. Baseline evaluation should be completed within 1 week prior to initiation of therapy, except for tumor assessment, assessment of ocular/visual symptoms, and specific 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 initiation of therapy.  
c D1 of each subsequent cycle corresponds to D15 of the previous cycle (±2 days). Procedures can be done on the day of infusion (before infusion) or the day before.  
d All participants should attend an on-site follow-up visit 90 days (±7 days) after the last IMP administration. SAEs/AESIs (regardless of relationship with study treatment) and IMP-related AEs ongoing at the end of 
study treatment, and any new IMP-related AEs/SAEs/AESIs will be followed until resolution or stabilization (stabilization is defined as an event ongoing without any change for at least 3 months). If ongoing IMP-
related AEs/SAEs/AESIs are resolved or stabilized, no further safety follow-up visit is needed. If IMP related AEs/SAEs/AESIs ongoing, an on-site follow up visit will be performed every 12 weeks (±7 days). 
Participants who stopped treatment before documented progressive disease should undergo a tumor assessment and an on-site follow-up visit every 12 weeks (±7 days) until radiological disease progression, the 
start of new anti-cancer therapy, withdrawal of participant’s consent, or cut-off date for secondary efficacy endpoints, whichever comes first. After documented progressive disease or the start of a new anti-cancer 
therapy, participants will be followed until any ongoing IMP related AEs/SAEs/AESIs are resolved or stabilized. Further anticancer treatment will be collected, including date of progression if any.  
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e Circulating CEA: As per local laboratory, at pre-screening (no more than 42 days prior to initiation of therapy); at screening (within 7 days prior to initiation of therapy), then during treatment every 8 weeks, at EOT 
and at the follow-up visit. At screening and first tumor assessment, an additional sample for circulating CEA is requested for central assessment. 
f 
A fresh tumor biopsy at screening (optional) could be proposed for CEACAM5 expression assessment by IHC (retrospective, results not needed for screening and IMP treatment), WES and RNA sequencing.: 
Block (preferred option) or 5 slides at 5 µm thickness for IHC and 3 slides at 10 µm thickness (or equivalent quantity) for DNA/RNA evaluation are requested. 
g Plasma for Circulating CEACAM5 (central assessment) at screening within 7 days prior to initiation of therapy (the same day and time as sample for local circulating CEA assessment) and at first tumor 
assessment (the same day and time as sample for local circulating CEA assessment). 
h Includes histologic types, stage at diagnosis, disease extent at study entry. 
i 
Smoking history, tumor mutation status and PD-L1 expression. 
j 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. 
k See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed. If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 x 109/L). In case of Grade ≥3 liver function abnormal 
tests, additional tests will be repeated every 2-3 days until recovery to baseline value. During first 2 cycles, hematology, and liver function tests will be assessed weekly. 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 
l 
Cycle 1 Day 1 hematology and blood chemistry tests may be omitted if screening tests performed within 7 days are normal. If screening tests are abnormal, they should be repeated within 2 days of first study 
intervention. 
m Ocular/visual symptoms must be assessed by the Investigator at screening, before each IMP infusion and at EOT, and whenever clinically indicated. If any visual symptom is reported, an ophthalmologist visit must 
be scheduled. 
n Only AEs related to the fresh biopsy procedure (if applicable) and occurring within 1 month after the fresh biopsy will be recorded in the eCRF. 
o Chest, abdomen, pelvic CT-scan or MRI and any other examinations as clinically indicated will be performed to assess disease status at screening and then every 8 weeks until EOT, and also every12 weeks 
during follow-up period until progressive disease or new anti-cancer therapy if the discontinuation is due to other reason than progressive disease. Bone CT-scan or MRI and other examinations should be 
performed if clinically indicated. Brain CT-scan or MRI should be performed at screening only for known stable lesions or if clinically indicated and followed during treatment only for participants with brain lesions at 
screening. 
p PRO assessments: NSCLC-SAQ, PGIS-LCS, PGIC-LCS, and FACT-GP5 are completed by each study participant after informed consent and prior to any treatment- or study-related activities, including 
administration of IMP, laboratory work, radiological assessments, discussion with the participant regarding their treatment or health status, and similar activities. 
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1.3.2 PK/ATA flow chart  
PK/ATA flowchart of Tusamitamb ravtansine 
Cycle  
Day within cycle 
Relative Nominal time 
PK Sample IDb 
ATA Sample 
ID 
Time window allowance 
Cycle 1 
1 
SOI 
P00a 
AB00a 
Within 24h before SOI 
EOI 
P01 
- 
±10 min around the EOI 
3 
48h 
P02 
- 
Whenever between 24 and 72h 
Cycle 2 
1 
SOI 
P00a 
AB00a 
Within 24h before SOI 
Cycle 3 
1 
SOI 
P00a 
AB00a 
Within 24h before SOI 
EOI+1h 
P01 
- 
±10 min 
Cycle 4 
1 
SOI  
P00a 
- 
Within 24h before SOI 
Cycle 5 
1 
SOI  
P00a 
- 
Within 24h before SOI 
Cycle 6 
1 
SOI  
P00a 
- 
Within 24h before SOI 
Cycle 7 
1 
SOI  
P00a 
AB00a 
Within 24h before SOI 
Cycle 13 
1 
SOI  
P00a 
AB00a 
Within 24h before SOI 
Cycle 19 then every 
6 Cycles 
1 
SOI 
- 
AB00a 
Within 24h before SOI 
EOT  
30 
EOT 
- 
ABF00 
30 ±5 days after last IMP 
ATA = anti-therapeutic anti bodies; EOI = end of infusion (ie, when the pump beeps before flush); EOT = End of Treatment; IMP = investigational medicinal product; PK= pharmacokinetics; SOI = start of infusion.  
a  Samples collected strictly before start of infusion (SOI). 
b No more PK samples will be collected after the cut-off for analysis of the primary endpoint. 
Note: The sampling time-points for PK and ATA may be reduced during the course of the study based on the updated knowledge of drug behavior, upon notification from the Sponsor. 
 
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2 
INTRODUCTION  
Despite recent progress in the treatment of advanced NSCLC, there remains a need for effective 
new treatment at the time of disease progression after the first-line therapy. Current therapeutic 
approaches for subsequent systemic options consist of a combination of an inhibitor of 
angiogenesis with a systemic cytotoxic agent such as docetaxel that entails serious hematological 
and other toxicities or docetaxel, pemetrexed or gemcitabine as single cytotoxic agent with very 
limited other options (1) therefore, targeted cytotoxic therapies may offer an improvement in 
safety and tolerability as well as efficacy. 
One feature that can be used to target some tumor cells is surface expression of 
carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), first described in 1965 
as a tumor-associated antigen in human colon cancer tissue extracts (2). High levels of 
CEACAM5 expression have since been observed in several epithelial tumors, whereas in normal 
adult tissue, its expression is limited to few tissues (3, 4). Immunostaining of CEACAM5 in a 
large panel of human tumor tissue microarray samples has shown the highest prevalence of cell 
surface CEACAM5 expression in adenocarcinomas of the colon and of the stomach and its 
signet ring cell subtype as well as NSQ NSCLC. 
Maytansinoids are antimitotic agents that inhibit microtubule formation to act as very potent 
cytotoxic agents against tumor cell lines in vitro, with IC50 values 100- to 1000-fold more potent 
than conventional tubulin binding compounds, including docetaxel. Tusamitamab ravtansine 
(SAR408701) is an antibody to CEACAM5 conjugated to the cytotoxic maytansinoid agent, 
(DM4). Encouraging preliminary anti-tumor activity of tusamitamab ravtansine in participants 
heavily pre-treated for NSQ NSCLC has been demonstrated in an ongoing study (TED13751). 
2.1 
STUDY RATIONALE  
In the FIH, TED13751 study, a cohort of 64 participants with heavily pre-treated NSQ NSCLC 
with high CEACAM5 expression using the IHC method applied at pre-screening on archived 
tumor sample (defined as ≥2+ in intensity in at least 50% of the tumor cells) were treated with 
tusamitamab ravtansine at 100 mg/m² Q2W. Tusamitamab ravtansine has shown an encouraging 
anti-tumor activity which was associated with an overall response rate of 20.3% (13 participants 
who had PR) per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 (95% CI: 
12.27%-31.71%) (5). These data warranting further development of tusamitamab ravtansine and 
being the basis for the start of a pivotal phase 3 study (EFC15858) to treat this patient population. 
In the TED13751 study the cohort of NSQ NSCLC participants with high CEACAM5 expression 
on tumor (≥2+ in intensity in ≥50% of tumor cells), 10 out of 13 responding participants had high 
baseline circulating CEA (≥100 ng/mL). Potential responses to tusamitamab ravtansine have also 
been evaluated in a cohort of NSQ NSCLC participants with moderate CEACAM5 expression on 
tumor (≥2+ in intensity in ≥1% and <50% of tumor cells) but only a limited number of 
participants (7 out of 28 participants) presented high circulating CEA levels at baseline. 
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No anti-tumor activity response data are available from the negative CEACAM5 expression on 
tumor by IHC (intensity 1+ whatever the percentage of stained tumor cells or <1% of tumor cells) 
with high circulating CEA level (≥100 ng/mL) cohort.  
The CEACAM5 expression status may have differed between the initial tumor at diagnosis and 
the tumor at the time of the enrollment in the clinical trial. Even though a correlation is expected 
between circulating CEA and CEACAM5 expression status on tumor, there are no available data 
on concomitant CEACAM5 expression on fresh tumor biopsy and circulating CEA. Biomarkers 
in oncology are most accurate and best correlated with clinical outcomes when they are assessed 
immediately prior to therapy. 
Participants are pre-screened in the EFC15858 Phase 3 study in second or third-line therapy based 
on the expression of CEACAM5 that is assessed on archival biopsy at the time of diagnosis, prior 
to first-line therapy, which can be months or years before enrollment. This is potentially important 
for participants who are pre-screened in the EFC15858 and whose diagnostic biopsies are 
negative, but who could have high CEACAM5 expression at the time of a fresh biopsy, either due 
to heterogeneous expression of CEACAM5 or upregulation of CEACAM5 expression after 
first-line therapy. In this study ACT17241, a fresh biopsy will be proposed (optional) at screening 
to explore the relationship between CEACAM5 expression at diagnosis and at the time of 
enrollment as well as the relationship between high circulating CEA and high CEACAM5 
expression at the time of enrollment. The fresh biopsy will be assessed retrospectively as due to 
the heterogenicity of tumors, participants with negative CEACAM5 expression may have high 
expression on other tumor locations.   
The aim of this study is to evaluate if participants with high circulating CEA level at baseline 
could benefit from tusamitamab ravtansine treatment despite negative or moderate CEACAM5 
expression on archival biopsy, assuming that a high circulating CEA level reflects a high 
CEACAM5 expression on tumor at the time of the enrollment. To this end, the anti-tumor activity 
will be assessed in participants with NSQ NSCLC with high circulating CEA levels despite 
negative or moderate CEACAM5 expression on tumor by IHC testing in third- or fourth-line 
treatment. 
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 85% of 
all lung cancers (7) and comprises several histopathological subtypes, of which adenocarcinoma 
(60%) and squamous-cell carcinoma (15%) are the most common (8). 
The majority of patients with NSCLC present an advanced stage at the time of diagnosis. These 
patients have a median overall survival of up to 8 to 12 months (9), and in 2015, a 5 year survival 
rate of approximately 25% (10). About 15% to 20% of patients with NSCLC have tumors with 
key genomic alterations that are amenable to targeted therapy, which include epidermal growth 
factor receptor (EGFR) mutations and ROS receptor tyrosine kinase 1 (ROS1) and anaplastic 
lymphoma kinase (ALK) rearrangements (11). 
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Until recently the only available treatment option for advanced or metastatic NSQ NSCLC 
lacking targetable mutations was chemotherapy. Systemic therapy with platinum-based doublet 
regimens, with or without maintenance therapy, was the current first-line treatment for patients 
with advanced NSCLC (12).  
More recently, immunotherapy has initiated 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 have emerged as powerful new therapeutic tools in several clinical trials. Four 
drugs targeting the PD-1 pathway (nivolumab, pembrolizumab, atezolizumab, and cemiplimab) 
have been approved for the treatment of both chemotherapy-naïve and/or previously treated 
advanced stage NSCLC (13, 14, 15, 16), however only a small subset (20% to 30%) of patients 
responds to these treatments. Despite an improvement in outcomes with newer lines therapy, 
including anti-PD-1/PD-L1 antibodies, the disease often progresses.  
The standard second-line treatment for NSCLC has been docetaxel (17); docetaxel’s activity was 
found to be enhanced by the addition of ramucirumab (18). There are other available options as 
single agent treatment such as docetaxel, pemetrexed or gemcitabine, however, there is an unmet 
medical need for subsequent systemic therapy (1).  
Additional therapeutic options are needed to improve the clinical efficacy in patients with 
advanced/metastatic NSCLC. 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of tusamitamab ravtansine may be found in the Investigator’s brochure (IB). 
2.3.1 Risk assessment  
To date, efficacy and safety data from ongoing studies of tusamitamb ravtansine (TED13751, 
TCD15054, and EFC15858) support the continued clinical development of tusamitamb 
ravtansine. Based on available safety data, the main anticipated risk to patients is corneal toxicity 
presenting as microcystic keratopathy, which is reversible and manageable with dose delay and 
dose reduction in some patients. Peripheral neuropathy is an identified risk in patients previously 
exposed to neurotoxic drugs. 
Other potential risks were observed in a limited number of patients, and clinical pictures were 
consistent with a presentation in patients with underlying relevant risk factors. These potential 
risks include colitis ([including hemorrhagic], mainly in participants with a known history of 
colitis or gastrointestinal tract conditions), cardiotoxicity (myocardial or conduction 
abnormalities), hematologic cytopenias, and hepatotoxicity, as well as systemic acute 
hypersensitivity reactions (including anaphylaxis; Table 1). 
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Table 1 - Risk assessment  
Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention: tusamitamab ravtansine 
Microcystic 
keratopathy/Keratitis 
Nonclinical: Mitotic arrest/single cell necrosis in the 
cornea of the eye in mice and monkeys. In addition, 
brown discoloration of the cornea associated, 
microscopically, with minimal dark pigmentation in cornea 
epithelial cells in monkeys. Findings considered related to 
the cytotoxic properties of DM4. 
Clinical: Reversible non-inflammatory, microcystic 
keratopathy/keratitis. Main dose-limiting toxicity (DLT) in 
the dose escalation part of study TED13751. 
Observations in the different phases of the clinical trial 
showed nonserious, mild to moderate AEs, no Grade 4-5 
AEs were reported. The corneal TEAEs were 
manageable and reversible.  
Corneal TEAEs appeared:  
- In TED13751 study in 30.1% of patients (56/186) in the 
pool of patients at 100 mg/m2 Q2W, 32.1% of patients 
(9/28) in the Loading dose cohort, and 40.0% of patients 
(6/15) in the Dose Escalation Q3W phase.  
- In TCD15054, in 50% of patients in the main dose 
escalation (3/6 patients) and in 50% of patients in the 
loading dose (8/16 patients).  
Regarding the ongoing studies ACT16525, ACT16146, 
ACT16432, EFC15858 among the patients treated there 
was no serious TEAE of keratopathy/keratitis. 
Careful collection of medical history 
and physical examination. 
Assessment of ocular/visual 
symptoms at each visit before IMP 
administration. Specific ocular tests 
at screening, whenever clinically 
indicated and at EOT. 
Wearing of contact lenses is 
forbidden. 
Preventive instillation of artificial tears 
or hyaluronic ophthalmic gel drops. 
Curative action: dose delay and 
reduction; artificial tears, 
corticosteroid eye drops and 
symptomatic treatment; 
ophthalmologist follow-up. 
Peripheral neuropathy 
Nonclinical: Nerve fiber degeneration in the peripheral 
nervous system and spinal cord in mice and monkeys. 
Effects attributed to the tubulin binding properties of DM4 
and inhibition of microtubule assembly. 
Clinical: Symptoms may be sensory (paresthesia, 
dysesthesias, pain, change in proprioception), motor 
(weakness), and neural dysfunctions. TEAEs 
In TED13751 study peripheral neuropathy was observed 
in 26.3% (49/186) of patients in the pool of patients at  
100 mg/m² Q2W, 21.4% of patients (6/28 patients) in the 
loading dose cohort and 33.3% of patients (5/15 patients) 
in the Dose Escalation Q3W phase. In the loading dose 
escalation cohort and the Q3W cohort, there was no SAE 
and only grade 1 AEs of Keratopathy/keratitis were 
reported. TCD15054 study, TEAEs appeared in 1 patient 
(16.7%) in the main dose escalation part at DL 
100 mg/m2, Q2W, and 1 patient (6.3%) in the loading 
dose part.  
No serious TEAE were reported in ACT16525, 
ACT16146, ACT16432, and EFC15858 studies. 
Close surveillance of any signs and 
symptoms of peripheral 
neuropathies. 
This AE is managed by dose 
delay/reduction as well as treatment 
discontinuation in case of Grade 3-4. 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Colitis (including 
hemorrhagic) in patients 
with a known history of 
colitis or gastrointestinal 
tract conditions 
Preclinical: Mitotic arrest/single cell necrosis observed in 
the gastrointestinal tract (tongue, esophagus, stomach, 
duodenum, jejunum, ileum, cecum, colon and/or rectum) 
in mice and monkeys. Therefore, degeneration and villous 
atrophy was noted in the intestinal mucosa as well as 
mucosal erosions and/or ulcers. Findings related to the 
cytotoxic properties of DM4. 
Clinical: Based on clinical observations, patients with 
known underlying colitis or gastrointestinal tract 
conditions are noted to be at highest risk for such events. 
In the TED13751 study relevant symptoms of colitis were 
observed in 1 patient (0.5%) in the pooled data of 
patients treated at 100 mg/m2 Q2W and developed by 
2 additional patients in the main dose escalation phase.  
No relevant observation were made in TCD15054 study, 
ACT16525, ACT16146, ACT16432, EFC15858. 
Close surveillance of any diarrhea 
event and further investigation when 
clinically indicated. 
Hematologic cytopenias 
Nonclinical: Following a single or a weekly IV 
administration for 5 weeks of tusamitamab ravtansine in 
mice and/or cynomolgus monkeys, transient decreases in 
red blood cells and WBC, decreases/increases in 
reticulocytes and decreases/increases in platelets. In 
addition, mitotic arrest/single cell necrosis associated with 
a decreased cellularity in the bone marrow and lymphoid 
tissues. Findings considered related to the cytotoxic 
properties of DM4. 
Clinical: Hematologic cytopenias (including clinically 
relevant alteration and/or laboratory data abnormalities) 
are frequently observed with ADC in general, and in 
tusamitamab ravtansine clinical development program. 
The observations were in favor of a higher risk in patients 
with a known history of cytopenias (leucopenia, 
neutropenia, thrombocytopenia, or anemia) due to 
previous cytotoxic drugs treatment. The incidence of 
TEAEs grade ≥3 was low as follows: 
TED13751: Pooled data at DL 100 mg/m2 Q2W: 
Grade≥ 3 in 5 patients (2.7%) under blood and lymphatic 
system disorders SOC, 2 patients (1.1%) under 
Investigations SOC with platelet count decreased. 
Regarding laboratory data, the following abnormalities 
were observed: anemia Grade 3 in 10 patients (5.4%), 
platelet count decreased Grade 3 in 1 patient (0.5%) and 
Grade 4 in 4 patients (2.2%), lymphocyte count 
decreased Grade 3 in 20 patients (10.9%) and Grade 4 in 
2 patients (1.1%). 
- Loading dose: 1 patient (3.6%) had Anemia ≥Grade 3 
and 1 patient (3.6%) was reported with Platelet count 
decreased (Grade≥ 3).  
- Dose Escalation Q3W: no Grade 3 or 4 Hematologic 
cytopenias. 
 
Exclusion criterion (see Section 5.2). 
 
Close surveillance of any signs and 
symptoms. 
 
Routine blood hematology workup, 
Hemoglobin, hematocrit, WBC with 
differential, platelet counts. These 
tests will be performed before IMP 
administration at each visit. During 
the first 2 cycles, they will be 
performed on weekly basis. If Grade 
4 neutropenia, assess ANC every 2 
to 3 days until ANC ≥0.5 x 109/L. 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
TCD15054 study: 2 patients with Grade 3 Lymphocyte 
count decreased. 
 
ACT16525, ACT16146, ACT16432 studies: no serious 
TEAEs of Hematologic cytopenias reported. 
 
EFC15858 study: 4 patients (3.3%) reported with serious 
AE of febrile neutropenia Grade 3- 4, 1 patient with 
serious AE of Neutropenia, 1 patient was reported with 
serious AE of Grade 4 neutrophil count decreased, 1 
patient with serious AE of Grade 3 anaemia. 
Cardiotoxicity (myocardial or 
conduction abnormalities) 
Nonclinical: Occasional minimal or mild 
degeneration/necrosis in the heart observed in single- 
and repeat-dose weekly for 5 weeks toxicity studies in 
monkeys. Compound-related effects on ECG parameters 
observed in some monkeys at the top dose 
(7 mg/kg/adm) using an external telemetric methodology 
were reversible marked increase in HR and 
non-reversible long-lasting episodes of bundle branch 
block suggesting an alteration in ventricular conduction 
which could nevertheless not be evidenced quantitatively 
(no widening of QRS complex duration) in the present 
experimental conditions. 
Clinical:  
TED13751 study:  
- Pooled data at 100 mg/m² Q2W: 2 patients with BBB 
right (1.1%), 1 patient (0.5%) with each of the following 
AEs: angina pectoris, atrioventricular block first degree. 
ECG QT prolonged in 2 patients [1.1%]), none of them 
was Grade 3 or 4.  
EFC15858 study: 1 patient (0.8%) experienced 2 
Myocardial infarctions considered as not related to the 
study treatment, another patient (0.8%) with underlying 
cardiovascular risk factors (Hypercholesterolemia, 
hypertension, coronary bypass and angioplasty) 
developed serious Grade 3 Angina pectoris + serious 
Grade 1 Troponin T increased.  
Cardiovascular examination. 
Monitoring of potential cardiac 
conduction defects by regular ECG. 
Hepatotoxicity 
Nonclinical: Following a single IV administration of 
tusasmitamab ravtansine in mice and/or cynomolgus 
monkeys, increased aspartate AST, alanine ALT, ALP 
and/or GLDH have been noted. In addition, this was 
associated with mitotic arrest/single cell necrosis 
observed in the liver. These findings are considered 
related to the cytotoxic properties of DM4. 
Clinical:  
No “Hy's law” cases have been observed. Grade ≥3 
TEAEs were observed as follows: 
In TED13751 study:  
- Pooled  data at 100 mg/m² Q2W: Hepatic cytolysis in 2 
patients (1.1%), AST increased in 4 patients (2.2%), 
Exclusion criterion (see Section 5.2). 
Close surveillance of any signs and 
symptoms of hepatotoxicities. 
Liver function tests will be performed 
before IMP administration at each 
visit. During the first 2 cycles, they 
will be performed on a weekly basis. 
In case of Grade ≥3 liver function 
abnormal tests, additional tests will 
be repeated every 2-3 days until 
recovery to baseline value. 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Transaminases increased in 2 patients (1.1%), ALT 
increased in 2 patients (1.1%), 
Gammaglutamyltransferase increased in 2 patients 
(1.1%), Blood ALP increased in 1 patient (0.5%), Blood 
bilirubin increased in 1 patient (0.5%). The analysis of 
clinical laboratory data showed ALT increased Grade 3 in 
3 patients (1.6%) and Grade 4 in 2 patients as well 
(1.1%); AST increased Grade 3 in 9 patients (4.9%) and 
Grade 4 in 3 patients (1.6%); ALP increased Grade 3 in 
15 patients (8.2%) and blood bilirubin increased Grade 3 
in 7 patients (3.8%). 
- Loading dose: no Grade ≥3 TEAEs. 
- Dose Escalation Q3W: ALT increased Grade 3 in 1 
patient (6.7%), AST increased Grade 3 in 3 patients 
(20.0%), and ALP increased Grade 3 in 2 patients 
(13.3%). 
In TCD15054 study: 2 patients (12.5%) reported with AST 
increased, 1 patient (6.3%) reported with ALT increased, 
1 patient (6.3%) reported with Blood ALP increased and 1 
patient (6.3%) reported with Gamma-glutamyltransferase 
increased. 
The analysis of clinical laboratory data showed 1 patient 
(7.7%) reported with ALT increased Grade 4 (none with 
Grade 3), 1 patient (9.1%) reported with AST increased 
Grade 4. and 1 patient (14.3%) reported with ALP 
increased Grade 3. 
ACT16146: 1 patient (12.5%) with serious Grade 3 TEAE 
of Hepatic enzyme increased. 
EFC15858 study: 1 patient reported with serious AE of 
Grade 3 Transaminases increased. 
ACT16525, ACT16432: no serious TEAEs of 
Hepatotoxicity reported. 
Systemic acute 
hypersensitivity reactions 
(including anaphylaxis) 
Nonclinical: Not observed. 
Clinical:  
ADCs are known to have the potential for hypersensitivity. 
In tusamitamab ravtansine development program very 
limited number of patients developed this profile of 
reactions. 
Premedication with histamine H1 
antagonist. 
If a patient has previously 
experienced an infusion-related 
reaction in a previous tusamitamab 
ravtansine administration, 
premedication will also include 
dexamethasone 10 mg IV for future 
infusions. 
Target infusion time is 1.5 h. In case 
of an infusion reaction, the flow rate 
can be decreased; minimum 
authorized flow rate is  
33 mL/h. Recommended curative 
action: In case of infusion reaction 
≥ Grade 2, tusamitamab ravtansine 
administration will be interrupted. The 
infusion may be resumed at half of 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
the previous infusion rate after the 
recovery.  
Abbreviations: ADC = anti-body drug conjugate; AE = adverse events; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BBB= Bundle branch block; 
DLT = dose-limiting toxicity; ECG = electrocardiogram; EOT = end-of-the-treatment; GI = gastrointestinal; GLDH = glutamate 
dehydrogenase; HR = heart rate; IMP = Investigational medicinal product; IV = Intravenous; Q2W = every 2 weeks; Q3W = every 
3 weeks; SAE = serious adverse event; SOC = system organ classes; TEAE = treatment-emergent adverse events; WBC = white 
blood cells.  
2.3.2 Benefit assessment  
Based on the current data obtained in the ongoing monotherapy studies of tusamitamab ravtansine 
(TED13751 and TCD15054) in NSQ NSCLC participants, anticipated benefits in the treatment 
support continued clinical development in this indication. 
Participants with high circulating CEA level at baseline could benefit from tusamitamab 
ravtansine treatment despite negative or moderate CEACAM5 expression on archival biopsy, 
assuming that a high circulating CEA level reflects a high CEACAM5 expression on tumor at the 
time of the enrollment. 
2.3.3 Overall benefit/risk conclusion  
Considering the measures taken to minimize risk to participants of this study, the potential risks 
identified in association with tusamitamab ravtansine are justified by the anticipated benefits that 
may be afforded to participants with NSQ NSCLC in third- or fourth-line treatment with high 
unmet medical need. 
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 2 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the anti-tumor activity of tusamitamab 
ravtansine when given every 2 weeks (Q2W) in 
non-squamous non-small-cell-lung-cancer (NSQ 
NSCLC) participants with negative or moderate 
CEACAM5 expression tumors and high circulating 
carcinoembryonic antigen (CEA) levels 
• 
Objective Response Rate (ORR) of tusamitamab 
ravtansine, defined as the proportion of participants 
who have a confirmed complete response (CR) or 
partial response (PR) as best overall response 
(BOR) per Response Evaluation Criteria In Solid 
Tumors (RECIST) v1.1 
Secondary 
 
• 
To assess the safety and tolerability of tusamitamab 
ravtansine 
• 
Incidence of participants with treatment-emergent 
adverse events (TEAEs), serious adverse events 
(SAEs) and laboratory abnormalities according to 
the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) 
v5.0 
• 
To assess other efficacy parameters of 
tusamitamab ravtansine 
• 
Progression-free survival (PFS), defined as the time 
from the date of first tusamitamab ravtansine 
administration to the date of the first documented 
disease progression or death due to any cause, 
whichever comes first. 
• 
Disease control rate (DCR), defined as the 
percentage of participants who have achieved 
confirmed CR or PR, or stable disease as BOR per 
RECIST v1.1 
• 
Duration of response (DOR), defined as the time 
from first documented evidence of CR or PR until 
progressive disease (PD) determined per RECIST 
v1.1 or death from any cause, whichever occurs first 
• 
To evaluate the immunogenicity of tusamitamab 
ravtansine 
• 
Incidence of participants with anti-therapeutic 
antibodies (ATAs) against tusamitamab ravtansine 
• 
To document the pharmacokinetics (PK) of 
tusamitamab ravtansine  
• 
Tusamitamab ravtansine concentrations 
Tertiary 
 
 
 
• 
To evaluate patient-reported outcomes (PROs) 
• 
Time to deterioration in the overall severity of 
disease-related symptoms (cough, pain, dyspnea, 
fatigue, appetite) as measured by the NSCLC- 
Symptom Assessment Questionnaire (SAQ) 
• 
Patient global impression of severity (PGIS) and 
patient global impression of change (PGIC) in 
disease-related symptoms will be measured by 
generic PGIS lung cancer symptom (PGIS-LCS) 
and PGIC lung cancer symptom (PGIC-LCS) scales 
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• 
Change from baseline in overall side effect impact 
as measured by the Functional Assessments of 
Cancer Therapy Item GP-5 (FACT-GP5) 
• 
To explore modulations of circulating CEA as a 
potential pharmacodynamic biomarker of response 
to tusamitamab ravtansine treatment and to 
evaluate circulating CEA levels at pre-screening 
and its correlation with CEACAM5 tumor expression 
on fresh biopsy (if available) 
• 
Circulating CEA at pre-screening, screening, during 
the treatment period and during the follow-up 
period; tumor CEACAM5 expression (on fresh 
biopsy tumor sample, if available) 
• 
To explore the relationship between CEACAM5 
expression in archived and fresh biopsy at 
screening (if available) 
• 
CEACAM5 expression on archived and fresh biopsy 
at screening 
• 
To explore the relationship between the tumor 
mutation profiles detected in the circulating free 
DNA (cfDNA) at baseline with efficacy outcome 
• 
Mutation analysis for tumor cfDNA at baseline 
• 
To explore potential sets of biomarkers including 
tumor mutation profiles from tumor DNA and RNA 
analyses on fresh biopsy (if available), beside target 
expression, as potential biomarkers of response to 
tusamitamab ravtansine treatment. 
• 
Mutation analysis and biomarker annotation for 
tumor DNA and RNA on fresh biopsy at screening 
(if available). 
 
 
 
 
 
 
Primary estimand defined for primary efficacy endpoint is summarized in Table 3 below. More 
details are provided in Section 9.2. 
For this estimand, the study intervention of interest will be tusamitamab ravtansine. 
Table 3 - Summary of primary estimands for main endpoints  
Endpoint 
Estimands 
Category 
(estimand) 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level summary  
(Analysis and missing data 
handling) 
Primary objective: To assess the anti-tumor activity of tusamitamab ravtansine Q2W in NSCLC participants with negative 
or moderate CEACAM5 expression tumors and high circulating CEA levels 
Primary 
endpoint 
(primary 
estimand) 
Confirmed 
objective 
response 
(confirmed CR 
or PR as BOR), 
determined 
according to 
RECIST v1.1 
All-treated 
population 
Regardless of investigational 
medicinal product IMP 
discontinuation (treatment policy 
strategy) 
Based on tumor assessments done 
before initiation of further 
anticancer therapy (“while not 
initiating anticancer therapy” 
strategy)  
Objective response rate defined as 
rate of participants with confirmed 
objective response and two-sided 
95% confidence interval (CI) using 
the Clopper-Pearson method. 
In the absence of confirmed 
objective response, participants will 
be considered as non-responders, 
whatever the reason (including 
participants with non-evaluable 
BOR). 
 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy or anti-tumor activity and safety assessments chosen for use in this study are 
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 single group, Phase 2, open-label, multi-center study assessing efficacy (anti-tumor 
activity), safety, and PK of tusamitamab ravtansine single agent in NSQ NSCLC participants with 
negative or moderate CEACAM5 expression tumors and high circulating CEA (≥100 ng/mL) at 
baseline. 
Moderate CEACAM5 expression is defined as intensity ≥2+ in ≥1% and <50% of tumor cells. 
Negative CEACAM5 expression is defined as intensity 1+ whatever the percentage of stained 
tumor cells or <1% of tumor cells. 
During the pre-screening phase, participants who were pre-screen failed in the EFC15858 Phase 3 
trial with available CEACAM5 status (central assessment by IHC) as negative or moderate 
expression on archival tumor tissue can be pre-screened. Participants with high circulating CEA 
(≥100 ng/mL) will be screened and will go through protocol screening procedures. 
After being screened, the eligible participants will receive tusamitamab ravtansine as a single 
agent treatment at the dose of 100 mg/m² Q2W until disease progression, unacceptable AE, 
initiation of a new anticancer therapy, or the participant’s or Investigator’s decision to stop the 
treatment, whichever comes first. A total of approximately 38 participants are planned to be 
treated. An interim analysis is planned after 20 participants treated are evaluable for anti-tumor 
activity or efficacy. If at least 2 confirmed objective responses are reported, the recruitment will 
continue to achieve a total of 38 evaluable treated participants. 
The duration of the study for a participant will include: 
• Pre-screening period: a pre-screening informed consent will be signed in order to collect 
available CEACAM5 expression results on archival tumor tissue from EFC15858 study 
and the circulating CEA value. 
• Screening period: up to 28 days. 
• Treatment period: once successfully screened, enrolled participants may receive study 
intervention until disease progression, unacceptable AE, initiation of a new anticancer 
therapy, or the participant’s or Investigator’s decision to stop the treatment, whichever 
comes first. Each cycle of treatment will have a duration of 2 weeks. After discontinuing 
study intervention, participants will return to the study site approximately 30 days after the 
last IMP administration or before the participant receives another anticancer therapy, 
whichever is earlier, for end-of-treatment (EOT) assessments. 
• Follow-up period: a safety follow-up visit will be performed approximately 90 days after 
the last dose of IMP. 
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- 
Participants who discontinue the study treatment due to documented PD, do not need 
further follow-up visit, if any ongoing related AE/AESI/SAE is resolved or stabilized. 
Otherwise, follow-up visits will be performed every 12 weeks, 
- 
Participants who stop treatment before documented PD should undergo a tumor 
assessment and a follow-up visit every 12 weeks (±7 days) after the last tumor 
assessment until radiological disease progression, start of a new anticancer therapy, 
study cut-off date for secondary endpoints, or withdrawal of participant’s consent, 
whichever comes first. After documented PD or a start of new anticancer therapy, the 
participant will be followed until any ongoing IMP related AE/AESI/SAE is resolved 
or stabilized. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of 
cancer-related mortality worldwide (6). Despite recent progress in the treatment of advanced 
NSCLC, there remains a need for effective new treatment at the time of disease progression after 
the first and second-line therapies. 
The primary endpoint for this efficacy single arm signal seeking study is ORR. This will allow an 
earlier efficacy assessment with small sample size. 
4.3 
JUSTIFICATION FOR DOSE  
In the main dose-escalation phase of the first-in-human study TED13751 exploring 5 to 
150 mg/m2 SAR408701 doses administered once every 2 weeks, the recommended dose was 
determined to be 100 mg/m2 administered every 2 weeks. A cohort of heavily pretreated NSQ 
NSCLC patients with CEACAM5-positive tumor at the membrane (≥2+ in intensity involving at 
least 50% of the tumor cell population) have been treated with SAR408701 at the recommended 
dose of 100 mg/m² every 2 weeks. The 64 treated patients showed encouraging anti-tumor activity 
and was associated with a response rate of 20.3% (95% CI: 12.27%-31.71%); 28 (43.8%) had 
stable disease. The recommended dose of 100 mg/m2 will be used in this study. 
4.4 
END OF STUDY DEFINITION  
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 (SoA) (Section 1.3) for the last 
participant in the study globally. 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the last visit or the last scheduled procedure shown in the SoA. 
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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 the legal age of consent in the jurisdiction in 
which the study is taking place), at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Histologically or cytologically proven diagnosis of NSQ NSCLC metastatic disease at 
study entry. 
I 03. Documented disease progression after at least 1 prior first chemotherapy line that must 
contain platinum-based chemotherapy (at least 2 cycles) and an immune checkpoint 
inhibitor (ICI, can be given as combined with chemotherapy or sequential, whatever the 
order) but no more than 2 prior chemotherapies lines are allowed. Maintenance therapy 
following platinum-based chemotherapy is not considered as a separate regimen. 
Adjuvant/neoadjuvant treatment for a participant who had a relapse with metastatic disease 
during or within 6 months of completion of treatment will be considered as first 
chemotherapy line treatment. 
I 04. For a tumor genotype with a sensitizing EGFR mutation or BRAF mutation or ALK/ROS 
alteration, demonstrated disease progression while receiving approved treatment for that 
genotype in addition to platinum-based chemotherapy and ICI. 
I 05. Moderate or negative CEACAM5 expression assessed by a central IHC assay in an 
archival tumor sample. Moderate CEACAM5 expression is defined as intensity ≥2+ in 
≥1% and <50% of tumor cells. Negative CEACAM5 expression is defined as intensity 1+ 
whatever the percentage of stained tumor cells or <1% of tumor cells. 
I 06. Circulating CEA levels ≥100 ng/mL at pre-screening. 
I 07. Measurable disease by RECIST v1.1 (Section 10.12), as determined by the Investigator. At 
least 1 measurable lesion is required. A previously irradiated tumor lesion is considered 
measurable if progression has been demonstrated in the lesion. The lesion must be ≥10 mm 
in the longest diameter (except lymph nodes, which must have a short axis ≥15 mm) as 
imaged in computed tomography (CT; preferred) or magnetic resonance imaging (MRI) 
scans. 
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I 08. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
Weight 
Not Applicable. 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 09. All participants (male and female) 
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 4 months after the last dose of study intervention 
• Refrain from donating sperm 
• Plus either: 
o Be abstinent from heterosexual or homosexual intercourse as their 
preferred and usual lifestyle (abstinent on a long term and persistent 
basis) and agree to remain abstinent  
Or  
o Must agree to use contraception/barrier as detailed below: 
Agree to use male condom when engaging in any activity that allows 
for passage of ejaculate to another person 
b) Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies: 
• Is not a woman of childbearing potential (WOCBP) 
Or 
• Is a WOCBP and agrees to use a contraceptive method that is highly effective 
(with a failure rate of <1% per year), preferably with low user dependency, as 
described in Appendix 4 (Section 10.4) of the protocol during the intervention 
period and for at least 7 months after the last dose of study intervention and 
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during 
this period. 
• A WOCBP must have a negative highly sensitive pregnancy test (serum) 
before the first dose of study intervention. Additional requirements for 
pregnancy testing during and after study intervention are located in Appendix 4 
(Section 10.4) of the protocol. The Investigator is responsible for review of 
medical history, menstrual history, and recent sexual activity to decrease the 
risk for inclusion of a woman with an early undetected pregnancy. 
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Informed Consent 
I 10. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) of 
the protocol which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Untreated brain metastases that may be considered active or history of leptomeningeal 
disease. Patients with previously treated brain metastases may participate provided they are 
stable (ie, without evidence of progression by imaging for at least 4 weeks prior to the first 
administration of study intervention, and any neurologic 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 4 
weeks prior to the first dose of study intervention. 
E 02. Life expectancy less than 3 months. 
E 03. Significant concomitant illness, including any severe medical condition that, in the opinion 
of the Investigator or Sponsor, would impair the participant’s participation in the study or 
interpretation of the results. 
E 04. 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 05. Any major surgery within 3 weeks prior to Day 1 of first study intervention administration. 
E 06. Known uncontrolled infection with human immunodeficiency virus (HIV). Participants 
with well controlled HIV infection/disease (Section 10.10) must be on antiretroviral 
therapy (ART) to be eligible.  
E 07. Active infection with 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 
known positive result for antibodies to hepatitis C and known quantitative hepatitis C virus 
[HCV] RNA results greater than the lower limit of detection of the assay). 
E 08. Nonresolution of any prior treatment-related toxicity to <Grade 2 according to NCI 
CTCAE v5.0, with the exception of alopecia, vitiligo, or active thyroiditis controlled with 
hormone replacement therapy (HRT). 
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E 09. Unresolved corneal disorder or any previous corneal disorder considered by an 
ophthalmologist to predict higher risk of drug-induced keratopathy.  
E 10. Use of contact lenses that the participant is unwilling to stop for the duration of the study 
intervention. The use of contact lenses is not permitted. 
Prior/concomitant therapy 
E 11. Medical condition requiring concomitant administration of a medication with a narrow 
therapeutic window, that is metabolized by cytochrome P450 (CYP450) (see Appendix 11 
[Section 10.11]), and for which a dose reduction cannot be considered. 
E 12. Medical conditions requiring concomitant administration of strong CYP3A inhibitor (see 
Appendix 11 [Section 10.11]), unless it can be discontinued at least 2 weeks before the 
first administration of study intervention. 
E 13. Concurrent treatment with any other anticancer therapy. 
E 14. 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 anti-tumor therapy 
(chemotherapy, targeted agents, immunotherapy and radiotherapy, or any investigational 
treatment), if palliative radiotherapy washout period of less than 2 weeks. 
E 15. Any prior therapy targeting CEACAM5. 
E 16. Prior maytansinoid treatment (DM1 or DM4 anti-body drug conjugate [ADC]). 
Prior/concurrent clinical study experience 
E 17. Previous enrollment in this study, current participation in any other clinical study 
involving an investigational study treatment, or any other type of medical research. 
Diagnostic assessments 
E 18. Poor organ function as defined by any 1 of the following prior to IMP administration: 
a) Serum creatinine >1.5 × upper limit of normal (ULN) or estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m2 as estimated using a Modification of Diet 
in Renal Disease (MDRD) formula.  
b) Total bilirubin >1.0 × ULN (excluding congenital conjugation disorders [Gilberts], for 
whom total bilirubin ≤3.0 × ULN, with direct bilirubin ≤1.5 × ULN, is allowed). 
or 
aspartate aminotransferase (AST), alanine aminotransferase (ALT) >2.5 × ULN (in 
case of documented liver metastasis, AST, ALT <5 × ULN is allowed).  
c) Neutrophils <1.5 × 109/L, platelet count <100 × 109/L, or hemoglobin <9 g/dL (blood 
infusion-free for at least 2 weeks). 
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Other exclusions 
E 19. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized  
E 20. Any country-related specific regulation that would prevent the participant from entering 
the study – see Appendix 8 (Section 10.8) of the protocol (country-specific requirements) 
E 21. 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 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 (in 
conjunction with Section 1.61 of the International Conference on Harmonisation –Good 
Clinical Practice (ICH-GCP) Ordinance E6) 
E 23. Any specific situation during study implementation/course that may raise ethics 
considerations 
E 24. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
 
5.3 
LIFESTYLE CONSIDERATIONS  
Not Applicable. 
5.4 
SCREEN FAILURES  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently enrolled. 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 SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number by IRT for 
every screening event. 
In case the participant is a temporary screen failure, there is no need to have participant reconsent 
(ie, new ICF signed) if the participant finally participates in the trial. However, if the reason for 
the temporary screen failure might have altered the participant’s initial given agreement to 
participate, the Investigator should ask the participant and confirm the participant’s willingness to 
continue or redo some screening procedures and participate in the trial. This oral agreement 
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should be documented in the participant’s chart. All the tests outside protocol-specified window 
should be repeated and entered to the additional pages. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Appendix 9 (Section 10.9) Contingency measures for a regional or national emergency that is 
declared by a governmental agency should be considered for pre-screening/screening/enrollment 
administration of study intervention. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol.  
Using an infusion-controlled pump, tusamitamab ravtansine will be administered by IV infusion 
over 1 hour 30 minutes.  
Prior to dosing, each participant’s dose will be individually prepared by the study pharmacist or 
delegate and labeled with protocol number, participant number and treatment description.  
One Day 1 of each treatment cycle, the patient’s BSA will be determined using the current weight 
and baseline height. For patients with a BSA >2.20 m², the dose will be calculated on the basis of 
2.20 m² BSA. After first administration of tusamitamab ravtansine, patients should be observed 
for acute reactions at site up to 4 days depending on any sign of drug allergic reaction.  
Detailed instructions for dilution and administration of the IMP are provided in the Pharmacy 
Manual. 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 4 - Study intervention(s) administered  
Intervention label 
Tusamitamab ravtansine  
Intervention name 
Tusamitamab ravtansine 
Intervention description 
Tusamitamab ravtansine, Intravenous infusion 100 mg/m² Day 1 
every 2 weeks 
Type 
Drug 
Dose formulation 
Concentrate for solution for Intravenous (IV) infusion 
Unit dose strength(s) 
5 mg/mL  
125 mg/25 mL  
Dosage level(s) 
Tusamitamab ravtansine Intravenous (IV) infusion 100 mg/m² 
Day 1 every 2 weeks 
Route of administration 
Intravenous infusion 
Use 
experimental 
IMP and NIMP 
IMP 
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Packaging and labeling 
Tusamitamab ravtansine is supplied in a 30 mL type I glass vial. 
Each IMP kit contains 1 vial of 125 mg/25 mL of tusamitamab 
ravtansine labeled with a multilingual booklet. 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 
Abbreviations: IMP = investigational medicinal product; NIMP = noninvestigational medicinal product 
Table 5 - Study arm(s)  
Arm title 
Tusamitamab ravtansine 
Arm type 
Experimental 
Arm description 
Participants will receive intravenous (IV) administration 
100 mg/m2 every 2 weeks (Q2W) 
Associated intervention labels 
Not applicable 
The tusamitamab ravtansine may be supplied at the site or from the PI/site/Sponsor to the 
participant via a Sponsor-approved courier company where allowed by local regulations and 
agreed upon by the participant.  
After the study cut-off date for the secondary efficacy endpoints, participants with observed 
clinical benefit who are still receiving study treatment can continue on study treatment. 
Study intervention will be administered until documented disease progression, unacceptable 
toxicity, new anti-cancer therapy initiation, or the participant’s or Investigator’s decision to stop 
the treatment, whichever comes first. 
Noninvestigational medicinal product (NIMP): Premedication for tusamitamab ravtansine 
Tusamitamab ravtansine has a potential risk of infusion-related reaction (IRR) and premedication 
should be used. All the drugs used as premedication will be entered to the concomitant 
premedication page. 
Premedication with histamine H1 antagonist (diphenhydramine 50 mg or equivalent [eg, 
dexchlorpheniramine] given approximately 15 minutes [IV] to 1 hour [oral] before tusamitamab 
ravtansine administration) is required for all participants before administration of tusamitamab 
ravtansine. After first study intervention of SAR408701, patients should be observed for acute 
reactions at site up to 4 hours depending on any sign of drug-induced allergic reaction. Detailed 
instructions for dilution and administration of the IMP are provided in Pharmacy Manual. If a 
participant has experienced an IRR in a previous tusamitamab ravtansine administration, 
premedication will also include dexamethasone 10 mg IV for future infusions. If the participant 
does not experience any hypersensitivity reactions after 4 cycles, the premedication can be 
discontinued at the discretion of the Investigator. 
Target infusion time is 1.5 hour. In case of an IRR ≥ Grade 2, tusamitamab ravtansine 
administration will be interrupted. The infusion may be resumed at half of the previous infusion 
rate after the recovery. The flow rate can be decreased; minimum authorized flow rate is 33 mL/h.  
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For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 9 (Section 10.9): Contingency measures for a regional or national emergency that is 
declared by a governmental agency. 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
1. 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. 
2. 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. 
3. 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). 
4. Partially-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 treatments will be established with the Investigator (or the pharmacist) 
and countersigned by the Investigator and the Monitoring Team.  
5. The Investigator must not destroy the unused IMP unless sanofi provides written 
authorization.  
6. Further guidance and information for the final disposition of 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 (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 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 and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable as this is a single-arm, nonrandomized, open-label study; however, the specific 
study intervention to be taken by a participant will be assigned using an interactive response 
technology (IRT). The site will contact the IRT prior to the start of the study intervention 
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administration of each participant. The site will record the study intervention assignment on the 
applicable case report form. 
6.4 
STUDY INTERVENTION COMPLIANCE  
• Methods used by the Investigator or his/her delegate to ensure that the IMP was 
administered.  
- 
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. 
• IMP compliance: 
- 
The Investigator records the dosing information on the appropriate page(s) of the case 
report form (CRF) 
- 
The monitor in charge of the study then checks the CRF data by comparing them with 
the IMP which he/she has retrieved and intervention log forms 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention. 
6.5 
DOSE MODIFICATION  
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 the Appendix 6 
(Section 10.6). 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 electronic CRF (eCRF).  
The acceptable treatment window for tusamitamab ravtansine administrations is 2 days. 
One dose reduction is allowed for safety reason. Dose delay is allowed for safety management. 
Retreatment of patients that require more than one-month dose delay need to be justified with case 
by case risk benefit assessment. See Table 10 in Appendix 6 (Section 10.6) for guidance in dose 
modification or discontinuation. During the conduct of the study, second dose reduction may be 
needed, and need to be decided on a case by case basis following discussion with the sponsor. 
If a dose reduction is necessary, the study intervention will be administered as follows:  
Table 6 - Individual tusamitamab ravtansine dose reduction  
Drug name 
Dose 
Reduced dose 
Tusamitamab ravtansine 
100 mg/m2 Q2W 
80 mg/m2 Q2W 
 
6.5.1 Retreatment criteria  
All participants entered into the study will be treated at Day 1. A participant may receive 
additional study interventions if he/she meets retreatment criteria as determined by the 
Investigator and agrees to be retreated. Throughout the study, study intervention will be 
unblinded. 
On Day 1 of each subsequent cycle, the participant must meet all of the following criteria to be 
eligible for retreatment: 
• Neutrophils count ≥1.5 × 109/L. 
• Platelets ≥100 × 109/L. 
• Total bilirubin ≤3.0 × ULN, with direct bilirubin ≤1.5 × ULN. 
• AST, ALT ≤2.5 × ULN or ≤5 × ULN in case of documented liver metastasis. 
• No IMP-related toxicity Grade >1 (except for alopecia) or baseline severity. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Not applicable. 
6.7 
TREATMENT OF OVERDOSE  
For this study, any dose of tusamitamab ravtansine greater than at least 30% above the intended 
administered dose expressed in units per BSA or any dose administered in less than half the 
recommended duration of administration, will be considered an overdose. 
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In the event of an overdose, the Investigator should: 
• Contact the Sponsor immediately. 
• Evaluate the participant to determine, in consultation with the Sponsor, whether study 
intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
• Obtain a plasma sample for PK analysis as soon as possible, if requested by the Sponsor 
(determined on a case-by-case basis). 
• Document appropriately in the CRF.  
6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, 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. 
• Dates of administration including start and end dates. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins, 
recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the Investigator and 
Sponsor, the medication will not interfere with the study. 
Concomitant medication may be considered on a case-by-case basis by the Investigator, in 
accordance with the following guidelines: 
• Participants with well controlled HIV infection (Appendix 10 [Section 10.10]) must 
receive a stable ART regimen containing no antiretroviral medication other than the 
following: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, and/or 
tenofovir. 
• Palliative radiotherapy may be given for control of pain (for palliative intent). If palliative 
radiotherapy is being considered, the Sponsor should be contacted for approval prior to 
initiating treatment, and prior to resuming therapy on the study.  
The irradiated area should be as small as possible and should involve no 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. The irradiated area 
cannot be used as a parameter for response assessment. If the only evaluable lesions are to be 
irradiated, the participant will stop the study intervention.  
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• Any background therapy taken by the participant for concomitant illnesses other than 
cancer (eg, HRT, statin, antihypertensive medication) is allowed. 
• Supportive treatment as medically indicated for the participant's well-being may be 
prescribed at the Investigator's discretion. Every medication or treatment taken by the 
participant during the trial and the reason for its administration must be recorded on the 
eCRF. 
The following 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. Secondary prophylaxis or therapeutic administrations are allowed. 
• Use of prophylactic erythropoietin during the first 2 cycles. 
• Participants treated or intended to be treated with drugs identified as CYP450 substrates 
with narrow therapeutic range (NTR) (Appendix 11 [Section 10.11]) should be carefully 
monitored. 
• Concomitant use of strong CYP3A inhibitors (Appendix 11 [Section 10.11]) should be 
avoided from 2 weeks before tusamitamab ravtansine administration up to the last 
tusamitamab ravtansine administration. 
6.8.1 Rescue medicine  
Not applicable. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1 
(Section 10.1.9). 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
• Discontinuation of study intervention for abnormal liver function should be considered by 
the Investigator when a participant meets one of the conditions outlined in the dose 
modification and toxicity management guidelines or if the Investigator believes that it is in 
best interest of the participant.  
• If a clinically significant finding on electrocardiogram (ECG) is identified after 
enrollment, the Investigator or qualified designee will determine if the participant can 
continue in the study and if any change in participant management is needed. This review 
of the ECG printed at the time of collection must be documented. Any new clinically 
relevant finding should be reported as an AE. 
• 
Any potentially clinically significant abnormal laboratory value or ECG parameter will be 
immediately rechecked for confirmation and repeated after 24 hours to document 
evolution before making a decision of permanent intervention discontinuation for the 
concerned participant.  
7.1.1 Permanent discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for safety and disease progression status, when applicable. See the SoA for 
data to be collected at the time of discontinuation of study intervention and follow-up and for any 
further evaluations that need to be completed. 
Study intervention should be discontinued in any of the following cases: 
• Unacceptable AE. 
• Disease progression. 
• Poor compliance to the study protocol. 
• Other such as concurrent illness, that prevent further administration of study intervention. 
Handling of participants after permanent 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. 
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If possible, and after the permanent discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including a 
pharmacokinetics sample and immunogenicity assessments, if appropriate. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation 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 9 [Section 10.9]): Contingency measures for a regional or 
national emergency that is declared by a governmental agency). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
CRF or eCRF.  
7.1.3 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned AE was unlikely 
and if the selection criteria for the study are still met (refer to Section 6.5.1). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9 (Appendix 9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency).  
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 or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. 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. 
• 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. 
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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. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF 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 stop participating in the study. 
Withdrawal of consent for 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 reallocated (treated) in the study. 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, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether 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. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 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, urine tests) 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 timeframe defined in the SoA. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
8.1 
EFFICACY ASSESSMENTS   
Planned timepoints for all efficacy assessments are provided in the SoA. 
The assessment of antitumor activity of tusamitamab ravtansine with regard to ORR per 
RECIST v1.1 is the primary efficacy objective. 
All participants treated must have at least 1 measurable lesion as per RECIST v1.1 for inclusion 
based on tumor assessment defined in the SoA (Section 1.3) 
Tumor assessment will be made every 8 weeks (±7 days window), and a scheduled assessment 
time point 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 screening; then every 8 weeks during the study treatment period until radiological disease 
progression, initiation of further anticancer therapy, death, or study cut-off for secondary 
endpoints, whichever comes first. Confirmatory radiological evaluation will be performed at least 
4 weeks after initial documentation of response. After IMP discontinuation, tumor assessment 
should be performed at EOT for participants without imaging performed within past 4 weeks.  
A participant who stops treatment before documented progressive disease should undergo a tumor 
assessment and a follow-up visit every 12 weeks (±7 days) after the last tumor assessment until 
radiological disease progression, start of a new anticancer therapy, study cut-off for secondary 
endpoints, or withdrawal of participant’s consent, whichever comes first.  
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Brain CT-scan or MRI should be performed at screening only for known stable lesions or if 
clinically indicated and followed during treatment only for participants with brain lesions at 
screening.  
Imaging assessments during the on-treatment period are to be scheduled using the Cycle 1, Day 1 
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. Delay of an imaging assessment to conform to treatment delay is not 
permitted. The same tumor assessment technique must be used throughout the study for a given 
lesion/participant. 
Secondary efficacy endpoints will include DOR, PFS, and DCR. 
The RECIST v1.1 criteria will be followed for assessment of tumor response, see Appendix 11 
(Section 10.12). 
8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than AE which are presented in Section 8.3. 
Planned timepoints for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height (only at 
screening) and weight will also be measured and recorded. 
• Performance status will be evaluated using ECOG scale (19).  
• 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 AE. 
8.2.2 Specific ocular tests  
Specific complete ocular tests will include: assessment of ocular/visual symptoms and ocular 
exams. 
Ocular/visual symptoms must be assessed by the Investigator at screening, at each visit before 
study treatment administration (including C1D1), at EOT, and whenever clinically indicated. If 
any visual symptom is reported, an ophthalmologist visit must be scheduled. 
Specific ocular tests performed by the ophthalmologist at screening, at EOT, and whenever 
indicated will include:  
• Visual acuity. 
• Slit lamp under dilatation. 
• Schirmer’s test. 
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In participants with any ocular/visual symptom (eg, blurred vision, photophobia), complete ocular 
tests will be repeated at the time of the occurrence of the ocular toxicity, if any, regardless of the 
grade. Thereafter, 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, pulse rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device, unless an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded. 
8.2.4 Electrocardiograms  
• Single 12-lead ECG(s) will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT 
intervals. 
• ECG can be performed on the same day before the study intervention administration or on 
the day before when requested on Day 1 pre-infusion. An ECG is to be repeated as 
clinically indicated. 
• ECGs will be interpreted by a qualified physician at the site as soon after the time of ECG 
collection as possible, and ideally while the patient is still present, should additional ECGs 
be performed or for immediate patient management should any clinically relevant findings 
be identified. 
8.2.5 Clinical safety laboratory tests  
• See Appendix 2 (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 the first 2 cycles, hematology, and liver function tests (ie, alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], 
total and direct bilirubin) will be assessed weekly. 
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• If Grade 4 neutropenia occurs, assess absolute neutrophil count (ANC) every 2 to 3 days 
until ANC ≥0.5 × 109/L.  
• In case of Grade ≥3 abnormal liver function tests, additional tests will be done every 2 to 
3 days until recovery to the baseline value. Additional tests will be performed when 
clinically appropriate. This test can be performed before the study intervention 
administration on the same day or the day before. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator. 
- 
If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified and the 
Sponsor notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
- 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded.  
8.2.6 Guidelines for management of adverse events  
Management of AEs related to tusamitamab ravtansine is summarized in Appendix 6 
(Section 10.6). 
8.2.6.1 Hypersensitivity reactions  
Premedication treatments provided as prophylactic treatment for 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 10 (Section 10.6). 
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. 
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• 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 out on according to SoA (Section 1.3). Ocular evaluation will be 
performed at screening, as required during the treatment (ie, on occurrence of ocular 
symptoms such as blurred vision, photophobia, pain), at the EOT visit, and when relevant 
at follow-up 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, unless less frequent 
assessment is recommended by an ophthalmologist, until resolution to Grade 1. 
Subsequently, the participant 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 the discretion of an ophthalmologist 
when applicable. 
8.2.6.3 Keratopathy/keratitis management  
• Reversible non-inflammatory, microcystic keratopathy was identified as the dose limiting 
toxicity (DLT) during the dose escalation process in study TED13751with 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 the preferred term unless 
otherwise specified by an ophthalmologist due to inflammatory findings on eye exams 
leading to a 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 other than prevention of dry eye with artificial tears and/or 
hyaluronic ophthalmic gel is recommended; the use of contact lenses is not permitted 
during the treatment period. Corticosteroid-containing ocular drugs are recommended for 
the management of keratopathy/keratitis in the case that ocular symptoms occur, and 
treatment will be performed based on discretion of ophthalmologist. Dose modification 
and recommendations are further described in Appendix 6 (Section 10.6). 
• After resuming study treatment, a patient who had Grade ≥2 keratopathy/keratitis should 
be followed with standard ocular exams (ie, slit lamp examination under dilatation and 
visual acuity) every 2 cycles, even if symptoms are no longer reported. If no event recurs 
during the next 4 cycles, then regular follow-up (ie, symptom assessment at each visit with 
standard ocular exam in case of any ocular sign/symptom) is applied.  
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8.2.6.4 Management of anemia  
• Close surveillance of any signs and symptoms is required: a routine blood hematology 
workup, including red blood cells (RBC) counts, hemoglobin, hematocrit, white blood 
cells (WBC) with differential, and platelet counts will be done weekly during the first 2 
cycles, and thereafter each treatment cycle before IMP administration. Patients should not 
start Cycle 1 treatment if hemoglobin is <9.0 g/dL. To be eligible for the study and to 
receive the first study treatment, the participant must have been transfusion-free for 2 
weeks. During the treatment period, erythrocyte transfusion can be given, upon 
Investigator decision. Erythropoietin can be given at the discretion of the Investigator, 
except during screening and the first 2 cycles. Cycle delays or modifications should be 
compliant with Appendix 6 (Section 10.6). 
8.2.6.5 Management of neutropenia  
• In patients who experienced either Grade 3 or 4 febrile neutropenia or Grade 4 decreased 
neutrophil count (<500 cells/mm3) for more than 1 week during study intervention, 
prophylactic Granulocyte colony-stimulating factor (G-CSF) should be implemented per 
American Society of Clinical Oncology (ASCO) guidelines (20) to ensure dose intensity 
(Appendix 6, (Section 10.6). Doses of tusamitamab ravtansine should be reduced in case 
of recurrent events even after prophylactic G-CSF use. 
• If the patient continues to experience these reactions at a lowered dose, the treatment 
should be discontinued (Section 7.1). 
8.2.6.6 Liver function tests  
• Hepatic enzyme increase has been reported with tusamitamab ravtansine administration. 
Patients should be carefully followed and in case of Grade ≥3 abnormal liver function 
tests, additional liver function tests will be done every 2 to 3 days until recovery to 
baseline value. Tusamitamab ravtansine should be permanently discontinued in case of 
drug-induced Grade 4 liver enzyme increase. 
• Grade ≥3 (ie, >5 × ULN) increased liver enzyme events should be reported as AESIs. 
8.2.6.7 Peripheral neuropathy  
• Participants with a known history of peripheral neuropathies and/or patients having 
received medications known to cause peripheral neuropathies (eg, prior antitubulin, 
platinum and/or taxanes) 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 
Appendix 6 (Section 10.6). 
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8.2.6.8 Colitis (including hemorrhagic)  
In study TED13751 evaluating tusamitamab ravtansine in patients with several cancer types, a 
limited number of participants developed colitis. Based on clinical observations, patients with 
known underlying colitis or gastrointestinal tract conditions are noted to be at highest risk for such 
events. The monitoring of patients for gastrointestinal toxicities will rely on careful evaluation by 
routine history, physical examination, and standard laboratory examination. Close surveillance of 
any signs and symptoms is required, with additional routine hematology workup (hemoglobin, 
hematocrit, and WBC with differential and platelet counts) whenever indicated. As 1 Grade 4 case 
of colitis erosive has been reported, it is recommended to conduct close surveillance of any 
diarrhea event, with further exams when clinically indicated. Treatment is per patient condition, 
based on Investigator discretion. 
8.2.7 Pregnancy testing  
Refer to Section 5.1 for pregnancy testing criteria. The Investigator is responsible for review of 
medical history, menstrual history, and recent sexual activity to decrease the risk of including a 
female participant with an early undetected pregnancy. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted 
every 4 weeks during intervention (at study visits and if needed, at home in between visits) 
as described in Section 1.3. 
• Pregnancy testing (urine or serum as required by local regulations) must be conducted 
corresponding with the time frame for female participant contraception.  
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the subject’s participation in the study. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). The definition of 
AESI is provided in Section 8.3.7. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative) 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 (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
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8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until at least 30 days 
after the last study intervention at the timepoints specified in the SoA (Section 1.3).  
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 information on AEs or SAEs 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. 
8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 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 AEs of 
special interest (as defined in Section 8.3.7), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 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. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information in the IB.  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
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• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 7 months after the last 
intervention (See Section 5.1). 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
pregnancy. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant/pregnant 
female partner after obtained informed consent and the neonate and the information will 
be forwarded to the Sponsor. 
• 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 8.3.4. While the Investigator is not obligated to actively seek this information in 
former participant/pregnant female partner, 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 or be withdrawn from the study.  
Prior to continuation of study intervention following pregnancy, the following must occur: 
• The Sponsor and the relevant IRB/IEC give written approval. 
• The participant gives signed informed consent. 
• The Investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring. 
8.3.6 Cardiovascular and death events  
Cardiovascular and death events will be treated as regular events. 
8.3.7 Adverse events of special interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
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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 participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP;  
- 
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 4 
[Section 10.4]) 
• Symptomatic overdose (serious or nonserious) with IMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as an increase of at least 30% of the dose to be administered in the 
specified duration or if the dose is administered in less than half the recommended 
duration of administration.  
• Grade ≥3 keratopathy/keratitis. 
• Bundle branch blocks or any conduction defects. 
• Grade ≥3 liver enzyme increased (symptomatic or asymptomatic).  
8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form 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. 
8.4 
PHARMACOKINETICS  
• Whole blood samples will be collected for measurement of plasma concentrations of 
tusamitamab ravtansine as specified in the PK/ATA flowchart (Section 1.3.2). 
• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor’s designee in a separate document. The actual date and time of each sample will 
be recorded. Pharmacokinetic samples will be tested by the Sponsor or Sponsor's designee. 
• 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 
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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. 
• Pharmacokinetic samples could be used for testing analytical method performance such as 
comparability and incurred sample reproducibility and for possible exploratory analysis of 
drug metabolites. The exploratory data will not be included in the study report but will be 
kept on file. 
8.5 
GENETICS  
8.5.1 Circulating tumor DNA analysis  
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 preinfusion of Cycle 1 
Day 1. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.  
Samples are planned to be transferred to a central laboratory for cfDNA/DNA extraction and 
mutational profiling of key cancer genes to understand the significance of existing 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. 
8.5.2 Tumor DNA and RNA analyses  
Although high circulating CEA levels at baseline reflecting concomitant CEACAM5 tumor 
expression may be an important parameter driving the activity of an anti-CEACAM5 ADC such 
as tusamitamab ravtansine, other factors may significantly contribute. Tumor tissue from a fresh 
tumor biopsy at screening will therefore also be proposed to explore the potential relationship 
between clinical endpoints following tusamitamab ravtansine therapy and potential sets of 
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biomarkers besides target expression that could be predictive of response. For that purpose, a 
tissue block (preferred option) or 3 × 10 μm slides (or equivalent such as 6 × 5 μm or other) is 
requested at screening. The samples may serve to investigate other potential biomarkers of 
response. In tumor tissue, biomarker annotation could include, but may not be restricted to, 
genomic annotation by sequencing, gene copy number variation, gene expression (messenger 
RNA [mRNA] and microRNA [miRNA]), and proteomic profiling. See Appendix 5 
(Section 10.5) [Genetics] for information regarding genetic research]. Details on processes for 
collection and shipment and destruction of these samples can be found in the study laboratory 
manual. 
8.6 
BIOMARKERS  
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA: 
• Tumor tissue samples will be collected at screening (optional) and assayed for CEACAM5 
expression centrally. 
• Blood samples for circulating CEA will be collected for local assessment. At screening 
and first tumor assessment, an additional sample (2 mL of blood, corresponding to 1 mL 
of serum) for circulating CEA is requested for central assessment.  
• Plasma for Circulating CEACAM5 (central assessment) will be collected. For this test 
1 mL of blood will be collected, corresponding to 500 µL of plasma. 
• Blood sample will be collected for IgG dosage to explore impact of immunoglobulin G 
(IgG) level on PK of tusamitamab ravtansine. For this test 2 mL of blood will be collected, 
corresponding to 1 mL of serum. 
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
in a separate laboratory manual. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
• Antibodies to tusamitamab ravtansine will be evaluated in plasma samples collected from 
all participants as specified in the PK/ATA flowchart (Section 1.3.2). 
• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor's designee in a separate document. These samples will be tested by the Sponsor or 
Sponsor's designee. 
• A 3-tiered approach will be employed to assess the immunogenicity of tusamitamab 
ravtansine when applicable: Samples will be screened and then confirmed for antibodies 
binding to tusamitamab ravtansine and the titer of confirmed positive samples will be 
reported. Other analyses may be performed to further characterize the immunogenicity of 
tusamitamab ravtansine. 
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8.8 
HEALTH ECONOMICS  
No health economics data will be collected. 
8.9 
PATIENT-REPORTED OUTCOMES  
All patients enrolled in the trial are expected to fill out the patient-reported outcome (PRO) 
assessments at clinic sites according to the pre-defined schedule in the SoA (Section 1.3). There 
are no PRO-specific eligibility criteria for the trial. As stated in the SoA (Section 1.3), PRO 
assessments are to be administered to each study participant after informed consent and prior to 
any treatment- or study- related activities, including administration of IMP, laboratory work, 
radiological assessments, discussion with the participant regarding their treatment or health status, 
and other similar activities. The administration schedule for PRO assessments must be adhered to 
as much as possible, regardless of protocol deviations. Four PRO measures will be used in this 
trial: the Non-Small-Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ), 
patient global impression of severity- lung cancer symptom (PGIS-LCS), patient global 
impression of change- lung cancer symptom (PGIC-LCS), and Functional Assessments of Cancer 
Therapy Item GP-5 (FACT-GP5). Together, these assessments include a total of 10 items, which 
is estimated to take approximately 5 minutes to complete. The PRO assessments will always be 
administered in the following standardized order: NSCLC-SAQ, PGIS-LCS, PGIC-LCS, and 
FACT-GP5.  
All PRO assessments are designed for self-completion. The primary mode of administration is via 
electronic clinical outcome assessment (eCOA) using an application on participants’ own devices. 
If the eCOA application fails, a web-based eCOA platform will be used as a back-up option. 
Provisioned back-up devices will be available at each site for participants without their own 
devices. The clinical report forms will include a question whether the PRO assessments have been 
filled in, and if not, the reason why. It is recommended that a key person (eg, research nurse) not 
directly involved in the participant’s clinical care at each institution should be responsible for 
questionnaire data collection in order to optimize the participant compliance and to ensure the 
completeness of the data.  
In case patients are not be able to physically attend hospital visits due to unforeseen restrictions 
(eg, Coronavirus disease-2019 [COVID-19] pandemic restrictions), the PRO measures can be 
collected by electronic assessment at home. Patients should be instructed to complete the PRO 
assessments within the intended timepoint (according to protocol SoA). Where participants 
completed their PRO assessment (ie, home versus site) will be documented.  
8.9.1 NSCLC-SAQ  
The NSCLC-SAQ assesses patient-reported symptom severity associated with NSCLC (21). The 
NSCLC-SAQ is a qualified clinical outcome assessment (COA) through the FDA’s Drug 
Development Tool program (DDT COA #000009) (21, 22, 23), and has shown adequate evidence 
of content validity and cross-sectional measurement properties in adult patients with NSCLC (24). 
The 7 items of the NSCLC-SAQ assess 5 different cardinal NSCLC-related symptom concepts 
over a 7 day recall period: cough (1 item), pain (2 items), dyspnea (1 item), fatigue (2 items), and 
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appetite (1 item). The measure uses a 5-point Likert-type, verbal rating scales ranging from “No 
<symptom> at All” to “Very severe <symptom>” for cough and pain items and from “Never to 
Always” for dyspnea, fatigue, and appetite items. Domain scores are calculated based on the scale 
developer’s procedures to form a total score, where higher scores indicate higher NSCLC 
symptom severity (23, 24). The NSCLC-SAQ is estimated to take approximately 2-3 minutes to 
complete. The instrument has been translated in 50 languages according to a standardized 
translation procedure (25). 
8.9.2 PGIS-LCS and PGIC-LCS  
The Patient Global Impression scale (PGI) is the patient-reported counterpart to the Clinical 
Global Impressions scale (CGI) which was published in 1976 by the US National Institute of 
Mental Health (26). Over the years, PGI scales were used in a broad range of diseases and were 
modified for the purpose of clinical settings. In this study, the PGIS and PGIC (1 item each) based 
on the CGI are adapted to the current setting. The PGIS-LCS measures severity in lung cancer 
symptoms at the time of assessment; while the PGIC-LCS measures change in lung cancer 
symptoms over time. 
8.9.3  FACT-GP5  
The FACT-GP5 (“I am bothered by side effects of treatment”) is a single-item from the 
Functional Assessment of Cancer Therapy-General (FACT-G) scale assesses the overall impact of 
treatment side effects (27). Responses are given on a 5-point Likert-type scale recalling the past 
7 days. Higher scores indicate a higher degree of side effect bother (28). The FACT-GP5 has been 
translated in over 50 languages according to a standardized translation procedure (29). 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, mechanism of action, or possible toxicity, and can help identify new drug targets or 
biomarkers that predict participant response to treatment. Therefore, data and biological samples 
will be stored and used for future research when consented to by participants (see Section 10.1.3) 
unless prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will 
not be included in the local ICF). For participants who consent to the storage and use of their data 
and remaining (leftover) and/or extra (additional) clinical samples, data and samples may be used 
for future research related either to the drug, the mechanism of action, and the disease or its 
associated conditions. Such research may include, but is not limited to, performing assessments on 
DNA, RNA, proteins or metabolites.  If future research on genetic material is performed, this will 
also be limited to the purpose of addressing research questions related to the drug, the mechanism 
of action, the disease or its associated conditions. 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct at 
a given timepoint (eg, at randomization visit) as defined in the study protocol. 
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In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. Data and 
samples will be used in alignment with the information provided to participants in the ICF Part 2 
(future research). For future research projects, all biological samples and relating data to be used 
will be coded such that no participant direct identifiers will be linked to them. These coded data 
and samples may be transferred to a Sponsor site (or a subcontractor site), which may be located 
outside of the country where the study is conducted. The Sponsor adopts safeguards for protecting 
participant confidentiality and personal data (see Section 10.1.4). 
Relating data and biological samples for future research will be stored for up to 25 years after the 
end of the study. Any samples remaining at the end of retention period will be destroyed. If a 
participant requests destruction of his/her samples before the end of the retention period, the 
Investigator must notify the Sponsor (or its contract organization) in writing. In such case, 
samples will be destroyed and related coded data will be anonymized unless otherwise required by 
applicable laws. 
Participant’s coded datasets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
This study is designed to obtain preliminary efficacy, safety, and PK data on tusamitamab 
ravtansine administered as 100 mg/m² Q2W to participants with NSQ NSCLC tumors with 
CEACAM5 moderate-negative tumor expression and high circulating CEA levels. 
As this study is not intended to explicitly test a hypothesis, calculations of power and Type I error 
were not considered in the study design. 
9.1 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined:  
Table 7 - Population for analyses  
Population 
Description 
Pre-screened 
All participants who signed the pre-screening informed consent. 
Screened 
All participants who signed the screening informed consent for study participation. 
Enrolled 
All participants from screened population who have been allocated to intervention 
regardless of whether the intervention was received or not. 
All-treated 
All enrolled participants exposed to the study treatment, regardless of the amount of 
treatment administered. All safety analyses will be performed on this population, 
which is also the primary population for analysis of all efficacy parameters. 
Activity 
All-treated participants who have measurable disease at study entry and at least 
1 postbaseline evaluable tumor assessment. Participants with no postbaseline 
evaluable tumor assessment but with an early clinical progression or who died from 
disease progression will also be included in this set. This population is the 
secondary population for analysis of efficacy parameters. 
PK 
All participants from the all-treated population with at least 1 postbaseline PK 
concentration with adequate documentation of dosing and sampling dates and 
times. 
ATA 
All participants from the all-treated population with at least 1 postbaseline ATA 
result (negative, positive, or inconclusive). 
Abbreviations: ATA = anti-therapeutic antibody; PK = pharmacokinetic. 
Note: In practice, a participant will be included in the enrolled population if the question “Will the subject continue in the treatment phase?” has 
been answered as “Yes” in the “Completion of screening phase” electronic case report form page. 
Participants exposed to study intervention before or without being enrolled will not be considered 
enrolled and will not be included in any analysis population. The safety experience of these 
participants will be reported separately. 
Enrolled participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the “all-treated” population. 
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For any participant enrolled more than once, only the data associated with the first enrollment will 
be used in any analysis population. The safety experience associated with any later enrollment 
will be reported separately. 
9.2 
STATISTICAL ANALYSES  
The statistical analysis plan will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical analyses of 
the most important endpoints including primary and key secondary endpoints. 
9.2.1 General considerations  
This study is not intended to explicitly test a hypothesis. For the primary and secondary efficacy 
endpoints, 95% CIs will be provided. 
All efficacy endpoints based on radiological assessments of tumor burden (ie, ORR, DOR, PFS, 
and DCR) will be derived using the local radiologist’s/Investigator’s assessment. 
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation, median, Q1, Q3, minimum, and maximum. Categorical and ordinal data will 
be summarized using the count and percentage of participants. 
The baseline value is defined as the last available value before the first dose of IMP. 
The study cut-off for analysis of the primary endpoint, ORR, corresponds to the date on which all 
evaluable treated participants have had at least 2 postbaseline tumor assessments, experienced 
confirmed objective response, or have discontinued the study treatment for any reason. For 
participants with 2 postbaseline tumor assessments and occurrence of response at the second 
postbaseline tumor assessment, it will also include the confirmatory assessment. This study 
cut-off can be up to approximately 20 weeks (16 weeks for 2 tumor assessments and 4 weeks for 
confirmation of response, if needed) after the last participant’s first IMP administration. Of note, 
DCR will be also assessed at this cut-off. 
The final study cut-off for analysis of the secondary efficacy endpoints, which include DOR and 
PFS, will be 4 months after the cut-off date for the primary analysis. At that time, the primary 
analysis of ORR and DCR will also be updated. 
Observation period 
The observation period will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
- 
The pre-screening period is defined as the period from the pre-screening informed 
consent to the day before the screening informed consent. 
- 
The screening period is defined as the period from the screening informed consent up 
to the first IMP administration.  
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• The on-treatment period (ie, treatment-emergent period) is defined as the period from the 
first IMP administration to 30 days after the last IMP administration.  
• The post-treatment period is defined as the period from the end of the on-treatment 
period. 
9.2.2 Primary endpoint analyses  
The primary analysis will be based on a primary estimand introduced in Section 3. It is defined 
according to the following attributes: 
• The primary endpoint is confirmed objective response (confirmed CR or PR as BOR) as 
per RECIST v1.1 (30). The best overall response (BOR) will be derived according to 
RECIST v1.1 definitions based on the Investigator’s assessment. The BOR is the best 
overall response observed from the date of the first administration of IMP until 
documented disease progression, death, start of an anticancer therapy, or analysis cut-off 
date, whichever occurs first. 
• The treatment condition of interest is tusamitamab ravtansine. 
• The analysis population is the all-treated population (defined in Section 9.1). 
• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. Confirmed objective response will be assessed based on 
tumor assessments regardless of study intervention discontinuation. 
- 
The further anticancer therapy intercurrent event will be handled with the “while not 
initiating further anticancer therapy” strategy. Confirmed objective response will be 
assessed based on tumor assessments done up to the time of initiation of further 
anticancer therapy.    
• The population-level summary will be the ORR, defined as the rate of participants with 
confirmed objective response and two-sided 95% CI using the Clopper-Pearson method. 
In the absence of confirmed objective response before the analysis cut-off date (taking into 
account the intercurrent event handling strategies), participants will be considered as 
non-responders, whatever the reason (including participants with non-evaluable BOR). 
As a supplementary analysis, ORR as per RECIST v1.1 will also be summarized on the activity 
population (defined in Section 9.1). The same analytical approach as described above will be 
used. 
9.2.3 Secondary endpoints analyses  
The secondary efficacy endpoints detailed in this section are other efficacy parameters (PFS, DCR 
and DOR). Analyses of other secondary endpoints are described separately with safety analyses 
(AEs and laboratory variables, vital signs and electrocardiograms) or other analyses 
(pharmacokinetic, immunogenicity). 
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9.2.3.1 Progression-free survival  
Analysis of PFS will be based on an estimand defined according to the following attributes: 
• The endpoint is PFS, defined as the time from the date of the first administration of IMP to 
the date of the first documentation of objective PD according to RECIST v1.1 or death due 
to any cause, whichever comes first. 
• The treatment condition of interest is tusamitamab ravtansine. 
• The analysis population is the all-treated population (defined in Section 9.1). 
• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. PFS will be assessed based on tumor assessments regardless 
of study intervention discontinuation. 
- 
The further anticancer therapy intercurrent event will be handled with the hypothetical 
strategy. PFS will be assessed based on tumor assessments had a further anticancer 
therapy not being taken. PFS will be assessed based on tumor assessments up to the 
time of initiation of further anticancer therapy. 
- 
Two or more consecutive missing/unevaluable tumor assessments immediately before 
documented PD or death will be handled with the hypothetical strategy. PFS will be 
assessed based on tumor assessments had 2 consecutive tumor assessments not been 
missed immediately before documented PD or death. PFS will be assessed based on 
tumor assessments up to the last evaluable tumor assessment documenting no 
progression. 
• The population-level summary will include: 
- 
Kaplan-Meier estimates of the 25th, 50th, and 75th percentiles and their associated 
95% CIs. The method of Brookmeyer and Crowley and a log log transformation of the 
survival function will be used to construct 95% CIs. 
- 
Number (%) of participants at risk as well as the probabilities of being event-free at 
least at 2, 4, 6, 8, and 10 months with 95% CIs using the Kaplan-Meier method and a 
log log approach based on a normal approximation following Greenwood’s formula. 
- 
Kaplan-Meier curves including the number of participants at risk at key time points. 
In addition, the number (%) of participants with an event and the type of event 
(documented disease progression or death without documented disease progression) and 
the number (%) of censored participants and reason for censoring (no baseline tumor 
assessment, no evaluable postbaseline tumor assessment, alive without documented 
disease progression, event occurred after 2 or more non-evaluable tumor assessments, or 
initiation of further anticancer therapy) will be analyzed. 
In the absence of documented disease progression or death before the analysis cut-off date 
(taking into account the intercurrent event handling strategies), PFS will be censored at the 
date of the last evaluable tumor assessment (not showing documented disease progression) 
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performed before the analysis cut-off date, or at the date of the first administration of IMP 
(Day 1) if no baseline tumor assessment or no evaluable postbaseline tumor assessment. 
9.2.3.2 Disease control rate  
Analysis of the DCR will be based on an estimand defined according to the following attributes: 
• The endpoint is disease control response (confirmed CR or PR, or SD as BOR) as per 
RECIST v1.1. 
• The treatment condition of interest is tusamitamab ravtansine. 
• The analysis population is the all-treated population (defined in Section 9.1). 
• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. Disease control response will be assessed based on tumor 
assessments regardless of study intervention discontinuation, 
- 
The further anticancer therapy intercurrent event will be handled with the “while not 
initiating further anticancer therapy” strategy. Disease control response will be 
assessed based on tumor assessments done up to the initiation of further anticancer 
therapy. 
• The population-level summary will be the DCR, defined as the rate of participants with 
disease control response and two-sided 95% CIs using the Clopper-Pearson method. 
In the absence of disease control response before the analysis cut-off date (taking into 
account the intercurrent event handling strategies), participants will be considered as 
non-responders, whatever the reason (including participants with non-evaluable BOR). As 
a supplementary analysis, DCR as per RECIST v1.1 will also be summarized on the 
activity population (defined in Section 9.1). The same analytical approach as described 
above will be used. 
9.2.3.3 Duration of response  
Analysis of the DOR will be based on an estimand defined according to the following attributes: 
• The endpoint is DOR, defined as the time from the date of first initial occurrence of the 
confirmed CR or PR to the date of first documentation of objective PD according to 
RECIST v1.1 or death due to any cause, whichever occurs first. 
• The treatment condition of interest is tusamitamab ravtansine. 
• The analysis population is the subgroup of participants from the all-treated population 
(defined in Section 9.1) who achieved a confirmed objective response. 
• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. DOR will be assessed based on tumor assessments 
regardless of study intervention discontinuation, 
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- 
The further anticancer therapy intercurrent event will be handled with the hypothetical 
strategy. DOR will be assessed based on tumor assessments had a further anticancer 
therapy not being taken. DOR will be assessed based on tumor assessments up to the 
time of initiation of further anticancer therapy, 
- 
Two or more consecutive missing/unevaluable tumor assessments immediately before 
documented PD or death will be handled with the hypothetical strategy. DOR will be 
assessed based on tumor assessments had 2 consecutive tumor assessments not been 
missed immediately before documented PD or death. DOR will be assessed based on 
tumor assessments up to the last evaluable tumor assessment documenting no 
progression. 
• The population-level summary will include the median DOR and associated 95% CI using 
Kaplan-Meier methods. 
In the absence of documented disease progression or death before the analysis cut-off date 
(taking into account the intercurrent event handling strategies), DOR will be censored at 
the date of the last evaluable tumor assessment (not showing documented disease 
progression) performed before the analysis cut-off date. In the absence of confirmed 
objective response before the analysis cut-off date (taking into account the intercurrent 
event handling strategies), DOR will not be derived. 
9.2.4 Tertiary/exploratory endpoint(s) analyses  
Analyses of PRO outcomes, circulating CEA and CEACAM5 expression will be described in the 
statistical analysis plan (SAP). 
9.2.5 Safety analyses  
Except if otherwise mentioned, all safety analyses will be conducted on the all-treated population. 
9.2.5.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed worsened or became serious during the 
pre-treatment period. 
• TEAEs: AEs that developed, worsened or became serious during the treatment-emergent 
period. 
• Post-treatment AEs: AEs that developed, worsened or became serious during the 
post-treatment period.  
Similarly, deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
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Summaries will be provided for all grades combined and for Grade ≥3 (including Grade 5). 
Missing grades, if any, will be included in the “all grades” category.  
Analysis of all adverse events 
Adverse event incidence table will be provided for all types of TEAEs: all TEAEs, all treatment 
emergent AESI (defined with a PT or a prespecified grouping), all treatment emergent SAEs and 
all TEAEs leading to permanent study intervention discontinuation. 
The AE summaries will be generated with number (%) of participants experiencing at least 1 
event.  
Deaths will also be analyzed. 
9.2.5.2 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Quantitative analyses 
When relevant, for vital signs and ECG variables, descriptive statistics for results and changes 
from baseline will be provided for each planned visit and at the worst value (minimum and/or 
maximum value depending on the parameter) during the on-treatment period. These analyses will 
be performed using local measurements.  
Analyses according to Potentially clinically significant abnormality (PCSA) and NCI 
grading 
For laboratory variables, analyses according to NCI grading will be made based on NCI-CTCAE 
version 5.0. In addition, for laboratory variables for which NCI-CTCAE scale is not applicable, 
vital signs and ECG variables, PCSA analyses will be performed based on the PCSA list currently 
in effect at Sanofi at the time of the database lock. 
Analyses according to PCSA and NCI grading will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables, vital signs and ECG variables, the incidence of participants with at least 
one PCSA during the treatment-emergent period will be summarized regardless of the baseline 
level and according to the following baseline status categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
For laboratory variables graded by NCI-CTCAE version 5.0. 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade.   
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• The number (%) of participants with abnormal laboratory tests during the 
treatment-emergent period will be summarized by grade. When appropriate, the number 
(%) of participants with abnormality of any grade and with Grade 3-4 abnormalities will 
be provided. 
9.2.6 Other analyses  
Pharmacokinetic 
The population PK analyses will be reported separately from the main clinical study report (CSR). 
Immunogenicity 
Immunogenicity analyses and the potential impact on PK, safety and efficacy will be described in 
the SAP and will be performed on the ATA population. 
Biomarkers 
Other exploratory biomarkers analyses will be described in the SAP. 
Other 
For regional or national emergency declared by a governmental agency, contingency measures are 
included in Appendix 9 (Section 10.9.5): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
9.3 
INTERIM ANALYSES   
An interim analysis based on the number of confirmed objective responses observed in the 
activity population will be performed. 
The study cut-off date for the interim analysis corresponds to the date on which the first 20 
evaluable treated participants have had at least 2 postbaseline tumor assessments, experienced 
confirmed objective response, or have discontinued the study for any reason. For participants with 
2 postbaseline tumor assessments and occurrence of response at the second postbaseline tumor 
assessment, the confirmatory assessment will also be included. 
If 0 or 1 confirmed objective response is observed among the first 20 treated participants 
evaluable for anti-tumor activity, the enrollment will be stopped. Otherwise, the enrollment will 
continue with the 18 additional evaluable participants. 
The statistical analysis plan will describe the planned interim analyses in greater detail. 
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9.4 
SAMPLE SIZE DETERMINATION  
Assuming a pre-screening failure rate of 84% and a study screening failure rate of 15%, 
approximately 285 participants will be pre-screened to achieve approximately 38 treated 
participants in the study. 
The initial plan is to treat a total of 38 participants evaluable for anti-tumor activity (at least 1 
postbaseline tumor assessment, early clinical progression, or death due to disease progression). 
Estimated ORR and 95% exact CIs by number of responders from a sample size of 38 evaluable 
participants for anti-tumor activity are listed in Table 8.  
Table 8 - 
 
 
 
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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 (eg, data protection law as General Data Protection 
Regulation - GDPR). 
• The protocol, protocol amendments, ICF, IB, [IDFU], 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. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation 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,  
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
- 
The return of such information to the study participant (and/or his/her 
designated healthcare professional, if so designated by the participant) is 
consistent with all applicable national, state, or regional laws and regulations in 
the country where the study is being conducted, and 
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- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical 
validity,  
- 
The participant in a clinical study has the right to opt out of being notified by 
the Investigator of such incidental findings. In the event that the participant has 
opted out of being notified and the finding has consequences for other 
individuals, eg, the finding relates to a communicable disease, Investigators 
should seek independent ethical advice before determining next steps, 
- 
In case the participant has decided to opt out, the Investigator must record in 
the site medical files that she/he does not want to know about such findings. 
- 
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 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
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. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participants, and answer all questions regarding the study, 
including what happens to the participant when his/her participation ends (post-trial access 
strategy for 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, Privacy and Data Protection requirements including 
those of the GDPR and of the French law, where applicable, and the IRB/IEC or study 
center.  
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• 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. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s).Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc.). 
• A copy of the ICF(s) must be provided to the participant, where applicable.  
The participants who will be rescreened need to resign new screening ICF; there will be no re-pre-
screening for CEACAM5 expression and the initial value will be applicable. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future 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. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR. The study Sponsor is the Sanofi company responsible for ensuring compliance with this 
matter, when processing data from any individual who may be included in the Sanofi databases, 
including Investigators, nurses, experts, service providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
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. 
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Participant race and ethnicity will be collected in this study because they are required by 
regulatory agencies (eg, on African American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan). They will not be collected in the 
countries where this is prohibited by local regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• 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. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study,  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
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• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
Not applicable. 
10.1.6 Dissemination of clinical study data  
Study participants 
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, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants are required to be submitted to 
peer-reviewed journals following internal company review for accuracy, fair balance and 
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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 
clinicalstudydatarequest.com. 
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: clinicalstudydatarequest.com. 
Professionals involved in the study or in the drug development program 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “The European 
Federation of Pharmaceutical Industries and Associations (EFPIA) Code on Disclosure of 
Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and Healthcare 
Organisations”. 
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. 
• Guidance on completion of CRFs will be provided in CRF completion instructions.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These pre-defined parameters 
will be monitored during the study and important deviations from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
• Monitoring details describing strategy, including definition of study critical data items and 
processes (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). 
• 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 
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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  
• 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. 
• Every data point recorded in the CRF must have a source document. The 
Investigator/delegated site staff will report all the original data in the participant’s medical 
chart or in a study specific source document created by him/her. If such document is used, 
the template should be reviewed by the clinical research associate (CRA). A list of source 
document and their location will be filed in the Investigator Study File.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 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. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open is considered the first act of recruitment and will 
be the study start date. 
Study/Site termination 
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. 
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Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio, 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
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 or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator, 
- 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
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. 
• 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 9 will be performed by the local laboratory with the exception 
PK/Circulating CEACAM5, ATA, cfDNA/Germline DNA, and tumor DNA/RNA analysis 
and some additional circulating CEA, which will be performed in the central laboratory or 
another external laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
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• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• Pregnancy testing should be conducted in all WOCBP at Screening, then every 4 weeks 
from Cycle 2 before each IMP administration, and at the EOT, as detailed in the 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 EOT evaluation (30 ±5 days 
after the last IMP administration). 
Table 9 - Protocol-required laboratory tests  
 
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophilsa 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Coagulation 
International normalized ration (INR) 
Clinical chemistryb 
 
 
Urea or Blood urea nitrogen (BUN) 
 
Creatinine-eGFR (estimated glomerular filtration rate) 
 
Glucose 
 
Potassium 
 
Sodium 
 
Phosphate  
 
Chloride  
 
Calcium 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Lactate dehydrogenase (LDH) 
 
Alkaline phosphatase (ALP) 
 
Total and direct bilirubin 
 
Total protein 
Albumin 
 
Circulating carcinoembryonic antigen (CEA) (local assessment) 
Pregnancy testing 
• 
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)c 
Other screening tests 
• 
Serology (Human immunodeficiency virus [HIV] antibody, hepatitis B surface 
antigen [HBsAg] or hepatitis B viral DNA, and hepatitis C virus antibody or 
Hepatitis C virus [HCV], RNA), and immunoglobulin G [IgG] if applicable as per 
local regulatory requirement 
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Laboratory tests 
Parameters 
• 
Additional circulating carcinoembryonic antigen (CEA) and circulating CEACAM5 
(central assessment) 
• 
Fresh biopsy as optional, for CEACAM5 expression status and DNA/RNA analysis 
(central assessment).  
• 
cfDNA/Germline DNA analysis on blood (central) 
• 
PK samples and anti-therapeutic antibody (ATA) (Central) 
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
nonchildbearing potential only). 
NOTES: 
a If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 x 109/L. 
b Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Section 8.2.6.6. All events of ≥ Grade 3 ALT/AST increase must be reported as an adverse event of special interest (AESI).  
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or Institutional review 
board/Independent Ethics Committee. In addition, serum pregnancy test is mandatory for screening and end-of the treatment (EOT) 
evaluation 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 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. 
Definition of unsolicited and solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a participant 
diary and that is communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and nonserious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, emergency room visit, or visit to/by a health care provider). The 
participants will be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant concern. Detailed information about reported unsolicited AEs will be collected 
by qualified site personnel and documented in the participant’s records. 
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• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participants and by review of 
available medical records at the next visit. 
• Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participants in their diary. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical 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 condition 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 fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill the definition of an AE or SAE. Also, lack of 
efficacy or failure of expected pharmacological action also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that 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. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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• 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. 
10.3.2 Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more 
of the criteria listed: 
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 admitted (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 or significant 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) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
g) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that 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, 
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- 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm,   
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc), 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse,  
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic 
ALT increase >10 × ULN,  
- 
Suicide attempt or any event suggestive of suicidality,  
- 
Syncope, loss of consciousness (except if documented as a consequence of 
blood sampling),  
- 
Bullous cutaneous eruptions.   
10.3.3 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. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. 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 the Sponsor’s representative. 
• 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 one of the following categories according to NCI-CTCAE v5.0. 
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
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• Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). Instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self care 
ADL. Self care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
An event is defined as “serious” when it meets at least 1 of the pre-defined 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. The Investigator will use clinical judgment to determine 
the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• 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 the Sponsor. 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 the monitoring team. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an 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 the Sponsor’s 
representative 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. 
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• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any postmortem findings 
including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative 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) 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 
offline 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 
offline, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in in the Investigator study file. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• 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 data collection tool within the designated reporting timeframes. 
• Contacts for SAE reporting can be found in in the Investigator study file. 
 
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10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive 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 HRT.  
• 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. 
Permanent sterilization methods include: 
• 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, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
10.4.2 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 ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia 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 
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contraception should be used. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
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. 
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. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should not be used 
together (due to risk of failure with friction). 
 
10.5 
APPENDIX 5: 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/RNA analysis from consenting participants. 
• DNA/RNA samples will be used for research related to tusamitamab ravtansine or 
non-squamous NSCLC and related diseases. They may also be used to develop 
tests/assays including diagnostic tests related to CEACAM5 targeting drug and NSQ 
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/RNA samples will be analyzed for determination of tumor mutation profile on 
plasma cfDNA and tumor DNA/RNA. Subtractive mutation analysis will be performed 
with germline DNA data to identify tumor-specific somatic genetic aberrations. 
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• 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 study intervention continues but no longer 
than 15 years or other period as per local requirements. 
10.6 
APPENDIX 6: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS  
Table 10 - Recommended Dose Modification or Discontinuation for SAR40870  
Event 
Symptoms severity 
(NCI-CTCAE v5.0) 
Dose modification  
Supportive care guidelines 
Infusion-related 
reaction  
Grade 1-2 
eg, Grade ≤2 nausea, 
headache, tachycardia, 
hypotension, rash, shortness 
of breath. 
Interrupt SAR408701 infusion. 
SAR408701 may be resumed 
only after participant recovery, 
at half the previous infusion 
ratea. 
Give diphenhydramine 50 mg IV 
and/or dexamethasone 10 mg IV.  
Dexamethasone can be added as 
premedication for upcoming cycles 
for SAR408701 
Grade 3-4 
eg, symptomatic 
bronchospasm, urticaria 
lesions covering >30% BSA, 
hypotension, angioedema. 
Interrupt SAR408701 infusion 
and definitively discontinue 
SAR408701. 
Give diphenhydramine 50 mg IV 
and/or dexamethasone 10 mg IV 
and/or epinephrine and any 
required treatment per Investigator 
judgment. 
Ocular toxicity:  
Keratopathy/keratitisb 
associated with 
SAR408701 
Grade 1 
Asymptomatic, Corneal 
lesions only observed on 
routine ocular examination 
and not requiring topical 
treatment. 
Next infusion of SAR408701 at 
the same dose, with or without 
cycle delay, depending on the 
recommendation from the 
ophthalmologist (nature and 
extent of the lesion). 
Standard ocular examination is 
planned as recommended by the 
ophthalmologist. 
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Event 
Symptoms severity 
(NCI-CTCAE v5.0) 
Dose modification  
Supportive care guidelines 
 
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: SAR408701 cycle 
delay until resolution to 
Grade 1 (asymptomatic) and 
restart SAR408701 at the 
same dose. 
2nd episode: delay cycle until 
resolution to Grade 1 
(asymptomatic) and 
SAR408701 dose reduction. 
Standard ocular examination 
weekly until resolutionc. 
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 four cycles. If no 
recurrence, standard process with 
follow-up with ocular symptom is 
resumed.  
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: SAR408701 cycle 
delay until resolution 
(asymptomatic) and restart 
SAR408701 with dose 
reduction. 
2nd episode: definitive 
discontinuation of SAR408701.  
 
Grade 4 
Perforation, best corrected 
visual acuity of 20/200 or 
worse in the affected eye 
Definitive discontinuation of 
SAR408701. 
 
Complete the corneal examination 
as recommended by 
ophthalmologist. Repeat the 
standard ocular examination 
weeklyc until resolution. 
Start curative treatment per 
ophthalmologist recommendation.  
Conduction disorder 
associated with 
SAR408701 
Grade 1 
Mild symptoms 
SAR408701 administration to 
be continued upon decision by 
the Investigator and Sponsor, 
depending on the nature of the 
conduction disorder. 
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 
SAR408701. 
 
ECG to be repeated twice weekly 
until event resolution. 
Prompt cardiology consultation 
Additional evaluations such as 
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 intervention. 
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Event 
Symptoms severity 
(NCI-CTCAE v5.0) 
Dose modification  
Supportive care guidelines 
Grade 2 
<1500-1000/mm3; 
<1.5-1.0 × 109/L 
Delay the cycle until recovery 
of ANC >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 
ANC >1500/mm3 at the same 
dose. Prophylactic G-CSF can 
be considered in all 
subsequent cycles 
Follow ASCO guidelines on usage 
G-CSF and antibiotherapy (20). 
Repeat the test every 3 days.  
 
Grade 4 >7 days 
<500/mm3; <0.5 × 109/L 
Delay the cycle until 
ANC >1500/mm3. 
1st episode: administer next 
cycle at the same dose and 
administer growth factors 
2nd episode: administer 
SAR408701 at reduced dose 
3rd episode: definitive 
discontinuation 
Follow ASCO guidelines on usage 
G-CSF and antibiotherapy (20). 
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 
ANC >1500/mm3. 
1st episode: administer next 
cycle at the same dose and 
administer G-CSF 
2nd episode: administer 
SAR408701 at reduced dose 
3rd episode: definitive 
discontinuation  
To ensure relative dose intensity, 
G-CSF is recommended as 
secondary prophylaxis in all 
participants with Grade ≥3 febrile 
neutropenia  
ASCO guideline is recommended 
for supportive treatment if there are 
no defined clinical standards (20). 
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  
 
Hepatic enzyme 
increase 
Grade 1-2 
Administer SAR408701 as 
planned. 
No intervention. 
Grade 3 
Delay the cycle. 
Restart the treatment until 
recovery to Grade 1. 
Additional liver function tests will 
be done every 2-3 days until 
recovery to baseline value. 
Grade 4 
SAR408701 should be 
permanently discontinued. 
Additional liver function tests will 
be done every 2-3 days until 
recovery to baseline value. 
Peripheral 
neuropathy  
Grade 1 
Asymptomatic  
No action  
Participant who has ongoing grade 
1 neuropathy has high risk of 
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Event 
Symptoms severity 
(NCI-CTCAE v5.0) 
Dose modification  
Supportive care guidelines 
Grade 2 
Moderate symptoms; limiting 
instrumental Activities of Daily 
Living  
Delay cycle, dose reduction if 
no improvement with dose 
delay  
worsening of his/her symptoms 
and should be closely followed.  
Grade 3 
Severe symptoms; limiting 
self-care Activities of Daily 
Living  
Definitive discontinuation  
 
Grade 4 
Life-threatening 
consequences; urgent 
Definitive discontinuation 
 
 
 
 
ASCO = American Society of Clinical Oncology; BSA = Body surface area; ECG = Electrocardiogram; G-CSF = Granulocyte colony-stimulating 
factor; 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; and RBC = Red blood cell. 
a SAR408701 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. 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Serology for HBsAg, HCV, or HIV will be performed at screening only if required at the country 
level. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency: 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, and terrorist attack) may prevent access to the clinical trial 
site. 
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Contingency procedures are suggested below and in Section 5.5, Section 7.1.2, Section 8, 
Section 9.2.6, and Section 10.1.3 for an emergency that prevents access to the study site, to ensure 
the safety of the participants, to consider continuity of the clinical study conduct, protect trial 
integrity, and assist in maintaining compliance with GCP in Conduct of Clinical Trials Guidance. 
Sponsor agreement MUST be obtained prior to the implementation of these procedures for the 
duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and 
pre-screening/screening/enrollment/administration of study intervention may be temporarily 
delayed/halted (see Section 5.5). 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study.   
Contingencies implemented due to emergency will be documented. 
10.9.1 Remote pre-screening process  
If there is no other way to conduct pre-screening procedures during a regional or national 
emergency declared by a governmental agency (eg, due to a COVID-19 pandemic), the site may 
consider implementing a remote pre-screening ICF process compliant with country/site 
requirements for only those participants who have enough archival samples.  
The process should be compliant with accepted principals of patients’ rights and global, national, 
and local regulatory requirements. Required protection of personal data (including security of 
e-mail interactions) and confidentiality of study data should be ensured.  
If remote pre-screening 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 pre-screening process. 
• If participant agrees to pre-screening, the Investigator/delegate should send the 
pre-screening 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, tusamitamab ravtansine mechanism of action; design of the study in terms 
of treatment groups, visits, and pre-screening 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 pre-screening 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 
e-mail (if available), and 1 of the signed original ICFs to be filed in the Investigator Study 
File should be sent via postal mail. 
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• 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 
signed printout of an electronically submitted signed ICF. After properly documenting this 
consent process, the site may proceed to obtain Circulating CEA value. 
10.9.2 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 judgment 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; and no protocol waiver is acceptable. Remote 
signature of main study ICF is not acceptable in any circumstance.  
10.9.3 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, reinitiation) of the 
IMP can occur only once the Investigator has determined, according to his/her best judgment, that 
the contribution of the IMP(s) to the occurrence of the epidemic event (eg, COVID-19) was 
unlikely. 
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.  
10.9.4 Study procedures  
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 capacity to perform the assessments.  
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 
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information on baseline assessment methods is shared with the back-up site’s radiologist to ensure 
same method is followed for scans. 
Depending on-site status, if needed, Cycle 1 and Cycle 2 weekly safety laboratory assessment 
(hematology [hemoglobin, hematocrit, RBC, WBC with differential, and platelet counts] 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 the patient’s home, or via sampling 
at the patient’s home.  
10.9.5 Statistical analyses and deviation  
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. 
10.9.6 Informed consent process  
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant 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). 
10.10 APPENDIX 10: DEFINITION OF WELL CONTROLLED HUMAN IMMUNODEFICIENCY 
VIRUS INFECTION  
Well controlled HIV infection is defined as meeting all of the following criteria: 
• CD4+ T-cell count >350 cells/mm3 at time of screening.  
• Virologic suppression, defined as confirmed HIV RNA level <50 copies/mL or the lower 
limit of quantification (below the limit of detection) using a locally available assay, 
achieved and maintained for at least 12 weeks prior to screening. 
• On a stable ART regimen, without changes in drugs or dose modification, for at least 
4 weeks prior to study entry (Day 1).  
• On a combination ART regimen containing no antiretroviral medication other than the 
following: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, and/or 
tenofovir. 
 
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10.11 APPENDIX 11: CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE AND 
STRONG CYP3A INHIBITORS  
Table 11 - 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 Cytochrome (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. 
 
Table 12 - 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 
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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) 
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  
Ceritinib 
Kinase Inhibitors 
Midazolam 
5.84 
Ribociclib 
Kinase Inhibitors 
Midazolam 
5.17 
Josamycin 
Antibiotics 
Ivabradine 
7.70 
Tucatinib 
Kinase Inhibitors 
Midazolam 
5.74 
Abbreviations: AIDS = Acquired immune deficiency syndrome; AUC = Area under the curve; CYP = Cytochrome P450; RIT = Ritonavir. 
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 website (https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm) 
updated in June 2020. 
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10.12 APPENDIX 12: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
VERSION 1.1  
Details provided in bibliographic reference (30). 
10.12.1 
Measurability of tumor at baseline  
At baseline, tumor lesions/lymph nodes will be categorized as 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). 
• 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 the short axis when assessed by CT-scan (CT-scan slice thickness 
recommended to be no greater than 5 mm). At baseline and at 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 truly non-measurable 
lesions. Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
10.12.2 
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. 
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• Cystic lesions: 
1. 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. 
2. “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 participant, these are preferred for selection as 
target lesions. 
• Lesions with prior local treatment: 
1. 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. 
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. 
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• 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. 
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. 
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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 of 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 of 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 <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. 
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 actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
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• 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 participants 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 
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 participant 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 pre-existing 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 
participant 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. 
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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: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up. 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT-scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing 
on the basis of the anatomic images, this is not PD. 
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 
participants who have measurable disease at baseline. 
Table 14 - Response in participants 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 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.  
When participants have non-measurable (therefore non-target) disease only, Table 15 is to be 
used. 
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Table 15 - Response in participants 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 
CR = complete response; PD = progressive disease.. 
Missing assessments and inevaluable designation: When no imaging/measurement is done at all at 
a particular time point, the participant 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 participants with CR may not 
have a total sum of “zero” on the CRF. 
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 participant with time point responses of PR-NE-PR as a 
confirmed response. 
Participants 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 participants 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. 
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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. 
 
10.13 APPENDIX 13: ABBREVIATIONS  
 
ADC: 
anti-body drug conjugate 
ADL: 
activities of dialy living 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALK: 
anaplastic lymphoma kinase 
ALT: 
alanine aminotransferase 
ART: 
antiretroviral therapy 
AST: 
aspartate aminotransferase 
ATA: 
anti-therapeutic antibodies 
BOR: 
best overall response 
BSA: 
body surface area 
CEA: 
carcinoembryonic antigen 
CEACAM5: 
carcinoembryonic antigen-related cell adhesion molecule 5 
CI: 
confidence interval 
COVID-19: 
coronavirus disease-2019 
CR: 
complete response 
CSICF: 
Core Study Informed Consent Form 
CT: 
computed tomography 
CYP450: 
cytochrome P450 
DCR: 
disease control rate 
DOR: 
duration of response 
ECG: 
electrocardiogram 
eCOA: 
electronic clinical outcome assessment 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
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eGFR: 
estimated glomerular filtration rate 
EGFR: 
epidermal growth factor receptor 
EOT: 
end-of-treatment 
FDG-PET: 
fluorodeoxyglucose-positron emission tomography 
FIH: 
first in human 
G-CSF: 
Granulocyte colony stimulating factor 
GDPR: 
General Data Protection Regulations 
HIV: 
human immunodeficiency virus 
HRT: 
hormone replacement therapy 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
ICH-GCP: 
International Conference on Harmonisation- Good Clinical Practice 
ICI: 
immune checkpoint inhibitor 
IEC: 
Independent Ethics Committees 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRR: 
infusion-related rate 
IRT: 
interactive response technology 
IV: 
intravenous infusion 
MRI: 
magnetic resonance imaging 
NCI-CTCAE: 
National Cancer Institute- Common Terminology Criteria for Adverse Events  
NE: 
not evaluable 
NIMP: 
noninvestigational medicinal product 
NSCLC-SAQ: 
Non-Small-Cell Lung Cancer Symptom Assessment Questionnaire 
NSQ NSCLC: 
non-squamous non-small-cell lung cancer 
NTR: 
narrow therapeutic range 
ORR: 
objective response rate 
PCSA: 
potentially clinically significant abnormality 
PD: 
progressive disease 
PD-1: 
programmed death-1 
PD-L1: 
programmed death ligand-1 
PFS: 
progression-free survival 
PGIC-LCS: 
patient global impression of change-lung cancer symptom 
PGIS-LCS: 
patient global impression of severity-lung cancer symptom 
PK: 
pharmacokinetics 
PR: 
partial response 
PRO: 
patient-reported outcome 
Q2W: 
every 2 weeks 
QTL: 
quality tolerance limit 
RBC: 
red blood cells 
RECIST: 
Response Evaluation Criteria in Solid Tumours 
ROS1: 
ROS receptor tyrosine kinase 1 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
stable disease 
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SoA: 
schedule of activities 
SUSAR: 
suspected unexpected serious adverse reaction 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
WBC: 
white blood cells 
WOCBP: 
woman of childbearing potential 
 
10.14 APPENDIX 14: PROTOCOL AMENDMENT HISTORY  
Not applicable. 
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