Clinical trial NCT04659603
Conditions: Breast Cancer Metastatic Pancreatic Carcinoma Metastatic
Sponsor: Sanofi
Start date: 2021-03-29; Completion date: 2025-01-19
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

* For Cohort A, Cohort B, and Cohort C Part 2: To assess the antitumor activity of tusamitamab ravtansine in metastatic breast cancer (mBC) and tusamitamab ravtansine monotherapy and in combination with gemcitabine in metastatic pancreatic adenocarcinoma (mPAC)
* For Cohort C Part 1: Confirmation of the recommended tusamitamab ravtansine dose when administered in combination with gemcitabine

Secondary Objectives:

* To assess the safety and tolerability of tusamitamab ravtansine administered as monotherapy and in combination with gemcitabine
* To assess other efficacy parameters of tusamitamab ravtansine administered as monotherapy and in combination with gemcitabine
* To assess the immunogenicity of tusamitamab ravtansine
* To assess the pharmacokinetics (PK) of tusamitamab ravtansine and gemcitabine when given in combination

Detailed description:
The expected duration of study intervention for participants may vary, based on progression date and the cohort; median expected duration of study per participant is estimated at 8 months for Cohort A/C and 6 months for Cohort B (up to 1 month for screening, a median of 4 or 2 months for treatment in Cohort A/C and Cohort B respectively, a median of 1 month for EOT, and follow-up visit 90 days after the last IMP administration).

Arms: arm 1: tusamitamab ravtansine every 2 weeks administered via intravenous infusion (IV) arm 2: tusamitamab ravtansine every 2 weeks administered via intravenous infusion (IV) arm 3: tusamitamab ravtansine every 2 weeks combined with gemcitabine on Day 1, Day 8 and Day 15 every 4 weeks administered via intravenous infusion (IV)
Interventions: intervention 1: tusamitamab ravtansine intervention 2: Gemcitabine
Intervention descriptions: intervention 1: Pharmaceutical form:Concentrated solution for IV;

Route of administration: IV infusion intervention 2: Pharmaceutical form: Lyophilized powder for reconstitution or as a solution for infusion;

Route of administration: IV infusion

Protocol documents:
Prot_000.pdf: 
 
 
 
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affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 4.0, dated 27-JUL-2020 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL 02 
Protocol title: 
Open-label, multi-cohort, Phase 2 trial, evaluating the 
efficacy and safety of tusamitamab ravtansine 
(SAR408701) monotherapy and in combination in 
patients with CEACAM5-positive advanced solid 
tumors 
Protocol number: 
ACT16432 
Amendment number: 
02 
Compound number 
(INN/Trademark): 
SAR408701 
tusamitamab ravtansine/Not applicable 
Brief title: 
Tusamitamab ravtansine monotherapy and in 
combination in patients with CEACAM5-positive 
advanced solid tumors  
(CARMEN-BT01)  
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: 
2020-003096-18 
NCT: 
NCT04659603  
WHO: 
U1111-1244-1644 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
 
Date: 
25-Jul-2022 
Total number of pages: 127 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial protocol 02 
All 
Date: 25-Jul-2022, version 1 (electronic 3.0) 
Amended Clinical Trial protocol 01 
All 
Date: 01-Oct-2021, version 1 (electronic 1.0) 
Original Protocol 
 
Date: 23-Sep-2020, version 1 (electronic 1.0) 
AMENDMENT 02 (25 July 2022) 
This amended protocol 02 (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The purpose of this amendment is to add a new cohort (Cohort C) to evaluate tusamitamab 
ravtansine, an anti-CEACAM5 antibody-drug conjugate [ADC] containing the cytotoxic 
antitubulin agent DM4, in combination with gemcitabine in participants with pancreatic 
adenocarcinoma (mPAC).   
Additionally, the interim analysis for the metastatic breast cancer (mBC) Cohort A has been 
removed, as enrollment has been stopped due to the low prevalence of CEACAM5-positive 
tumors in participants with mBC (3.9%, compared to the expected 10% to 15%). Modifications to 
protocol wording were implemented as detailed in the following table.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Modified title and abbreviated title 
To reflect addition of new combination 
cohort 
1.1 Synopsis, rationale, 1.2 Schema 
Added clarifications for Cohorts A and B, 
and added Cohort C 
To reflect study design change  
1.1 Synopsis, Objectives and endpoints; 
3 Objectives and endpoints 
Added objectives and endpoints of 
Cohort C 
To reflect new cohort  
1.1 Synopsis, Overall design; 
4.1 Overall design 
Added overall study design of Cohort C, 
including numbers of participants to be 
prescreened, screened, treated, and 
evaluable; new Figure 2 for Cohort C dose 
escalation 
To reflect new cohort design  
1.1 Synopsis, study intervention; 
1.2 Schema, 6.1 Study intervention(s) 
administered 
Added gemcitabine to the interventions 
To reflect Cohort C of combination 
treatment 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, study intervention; 
6.1 Study intervention(s) administered 
Added reference to guidelines for 
antiemetic premedication  
To provide complete information for 
gemcitabine intervention 
1.1 Synopsis, 1.2 Schema, 9.1 Sample 
size determination 
Updated calculated sample sizes 
To reflect additional participants to be 
enrolled in Cohort C 
1.1 Synopsis, 9.2 Populations for 
analyses 
Added definitions of DLT-evaluable 
population and PK population  
To define populations for analysis of 
primary endpoint (DLT) in Cohort C 
Part 1, and new PK analyses for 
Cohort C  
1.1 Synopsis, 9.3.2 Primary endpoint(s) 
Added paragraph describing primary 
endpoint for Part 1 of Cohort C 
To specify DLTs as new primary 
endpoint for Part 1 of Cohort C  
1.3.2 Study procedures flowchart for 
Cohort C 
Added new flowchart  
To reflect study procedures for Cohort 
C 
1.3.3 PK/ATA flow charts for 
tusamitamab ravtansine and 
gemcitabine samples for Cohort C 
Added new sampling schedules  
To reflect PK analysis of combination 
treatment and immunogenicity of 
tusamitamab ravtansine for Cohort C  
2.1 Study rationale 
Added rationale for Cohort C 
To reflect study rationale for Cohort C 
2.2 Background 
Added background for combination 
treatment 
To reflect background for Cohort C 
2.3 Benefit/risk assessment 
Added benefit/risk assessment for 
gemcitabine and combination  
To reflect study design change 
4.2 Scientific rationale for study design, 
9.3.1 General considerations, 9.4 
Interim analyses 
Removed mention of interim analysis for 
Cohort A 
The mBC cohort stopped enrollment 
4.2 Scientific rationale for study design, 
9.3.1 General considerations, 
9.4 Interim analyses 
Added interim analysis for Cohort C 
To describe process for deciding to 
continue enrolling new Cohort C 
4.2 Scientific rationale for study design 
Updated scientific rationale  
To reflect new cohort  
5.1 Inclusion criteria, I 12 
Specified Cohort B for inclusion criterion 
12 
To distinguish from criterion for 
Cohort C 
5.1 Inclusion criteria I 13 
Added requirement for contraceptive use 
“at least 6 months after the last dose of 
gemcitabine” for all male participants 
In accordance with male 
contraception guidance for 
chemotherapy 
5.1 Inclusion criteria, new I 15 
Added prior fluoropyrimidine containing 
chemotherapy requirement for Cohort C 
To define appropriate patient 
population for new combination 
treatment cohort  
5.2 Exclusion criteria, new E 27 
Added exclusion of participants with 
previous systemic taxane or gemcitabine 
treatment from Cohort C   
To define appropriate patient 
population for new combination 
treatment cohort 
6.1 Study intervention(s) administered 
Added gemcitabine to the interventions 
To reflect Cohort C of combination 
treatment 
6.5.1 Determination of recommended 
dose for Cohort C 
New section added to describe 
recommended dose determination for 
gemcitabine combination treatment 
To reflect Cohort C dose selection 
scenario 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5.2 Individual dose adjustment/dose 
delay: Cohort A, Cohort B and Cohort C 
Part 2 
Added rules for individual dose 
modification in text and additional row in 
Table 9 describing dose reduction of 
gemcitabine for participants receiving 
combination treatment  
To clarify dose modification for 
participants in the combination 
treatment cohort 
6.5.3 Retreatment criteria 
Added retreatment criteria for Day 8 and 
Day 15 
To specify retreatment criteria for 
gemcitabine 
8.3.8 Adverse event of special interest 
Added dose-limiting toxicity (DLT) to list of 
adverse events of special interest (AESI) 
To report of DLT events as AESI 
8.3.10 Guidelines for managing specific 
adverse events 
Added guidelines for managing specific 
adverse events of gemcitabine 
To reflect Cohort C of combination 
treatment 
8.4 Pharmacokinetics 
Added new section 
To reflect PK analysis of Cohort C of 
combination treatment 
8.6.2 Other biomarkers 
Specified Cohort A and Cohort B for DNA 
analyses 
To clarify that circulating tumor DNA 
analysis will not be assessed for 
Cohort C 
8.6.2 Other biomarkers 
Added pre-infusion IgG sample at Cycle 1 
To explore the impact of IgG on PK 
parameters 
9.3.1 General considerations 
Described gemcitabine combination 
regimen for Cohort C 
To reflect new cohort design 
9.3.3 Secondary endpoint(s) 
Added PK analysis to secondary endpoint 
analyses 
To reflect PK analysis for Cohort C 
(gemcitabine combination treatment) 
10.1.5 Committee structure  
Added study committee in Cohort C Part 1 
To confirm the recommended 
tusamitamab ravtansine dose when 
administered in combination with 
gemcitabine 
10.6 Appendix 6: Recommended 
supportive care and/or dose 
modification guidelines for drug-related 
adverse events 
Added dose modification for gemcitabine 
To reflect addition of gemcitabine to 
tusamitamab in combination regimen 
in Cohort C 
10.9 Appendix 9 Contingency measures 
for a regional or national emergency 
that is declared by a governmental 
agency: 10.9.4 Study procedures  
Specified “for Cohorts A and B”  
To clarify for which cohorts 
contingency measures may apply  
10.10 Appendix 10 
Updated list of strong CYP3A inhibitors 
To provide current list drugs with 
potential for PK interaction 
11 References 
Added new references (Von Hoff  et al, 
Hesketh et al, Mita et al) 
Added references for Cohort C design 
and premedication for gemcitabine  
throughout 
typographical, grammatical, and style edits 
Clarity and consistency 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 20 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 21 
1.3.1 
Study procedures flowchart for Cohort A and B ............................................................................ 21 
1.3.2 
Study procedures flowchart for Cohort C ....................................................................................... 25 
1.3.3 
PK/ATA flow charts for tusamitamab ravtansine and gemcitabine samples for Cohort C ............. 28 
1.3.3.1 
First 10 participants ........................................................................................................................ 28 
1.3.3.2 
Participants enrolled after the first 10 ............................................................................................ 30 
2 
INTRODUCTION ............................................................................................................................ 31 
2.1 
STUDY RATIONALE...................................................................................................................... 33 
2.2 
BACKGROUND ............................................................................................................................. 34 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 36 
2.3.1 
Risk assessment ............................................................................................................................ 36 
2.3.2 
Benefit assessment ........................................................................................................................ 38 
2.3.3 
Overall benefit:risk conclusion ....................................................................................................... 39 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 40 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 41 
4 
STUDY DESIGN ............................................................................................................................ 42 
4.1 
OVERALL DESIGN ........................................................................................................................ 42 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 43 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 44 
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4.4 
END OF STUDY DEFINITION ....................................................................................................... 44 
5 
STUDY POPULATION .................................................................................................................. 45 
5.1 
INCLUSION CRITERIA .................................................................................................................. 45 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 48 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 50 
5.4 
SCREEN FAILURES...................................................................................................................... 51 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT ...................................................... 51 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 52 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 52 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 53 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 54 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 54 
6.5 
DOSE MODIFICATION .................................................................................................................. 55 
6.5.1 
Determination of recommended dose for Cohort C ....................................................................... 55 
6.5.2 
Individual dose adjustment/dose delay: Cohort A, Cohort B and Cohort C Part 2 ........................ 56 
6.5.3 
Retreatment criteria........................................................................................................................ 57 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 58 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 58 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 58 
6.8.1 
Rescue medicine ............................................................................................................................ 59 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 60 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 60 
7.1.1 
Definitive discontinuation ............................................................................................................... 60 
7.1.2 
Temporary discontinuation ............................................................................................................. 61 
7.1.2.1 
Rechallenge ................................................................................................................................... 61 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 61 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 62 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 63 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 63 
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8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 64 
8.2.1 
Physical examinations ................................................................................................................... 64 
8.2.2 
Vital signs ....................................................................................................................................... 64 
8.2.3 
Electrocardiograms ........................................................................................................................ 64 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 65 
8.2.5 
Pregnancy testing .......................................................................................................................... 65 
8.2.6 
Performance status ........................................................................................................................ 65 
8.2.7 
Specific ocular test ......................................................................................................................... 66 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 66 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 66 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 67 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 67 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 67 
8.3.5 
Pregnancy ...................................................................................................................................... 68 
8.3.6 
Cardiovascular and death events .................................................................................................. 68 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 68 
8.3.8 
Adverse event of special interest ................................................................................................... 69 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 69 
8.3.10 
Guidelines for managing specific adverse events ......................................................................... 70 
8.3.10.1 Hypersensitivity reactions .............................................................................................................. 70 
8.3.10.2 Ocular toxicity ................................................................................................................................. 70 
8.3.10.3 Management of anemia ................................................................................................................. 71 
8.3.10.4 Management of neutropenia .......................................................................................................... 71 
8.3.10.5 Liver function tests ......................................................................................................................... 71 
8.3.10.6 Peripheral neuropathy .................................................................................................................... 71 
8.3.10.7 Colitis (including hemorrhagic) ....................................................................................................... 72 
8.3.10.8 Management of thrombocytopenia ................................................................................................ 72 
8.3.10.9 Pulmonary toxicity and respiratory failure ...................................................................................... 72 
8.3.10.10 Hemolytic uremic syndrome ........................................................................................................... 72 
8.3.10.11 Capillary leak syndrome ................................................................................................................. 72 
8.3.10.12 Posterior reversible encephalopathy syndrome ............................................................................. 73 
8.4 
PHARMACOKINETICS .................................................................................................................. 73 
8.4.1 
Noncompartmental analysis ........................................................................................................... 73 
8.4.2 
Population approach ...................................................................................................................... 73 
8.5 
GENETICS ..................................................................................................................................... 74 
8.5.1 
Circulating tumor DNA analysis ..................................................................................................... 74 
8.5.2 
Tumor DNA and RNA analyses ..................................................................................................... 74 
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8.6 
BIOMARKERS ............................................................................................................................... 74 
8.6.1 
Pharmacodynamics........................................................................................................................ 75 
8.6.2 
Other biomarkers ........................................................................................................................... 75 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 75 
8.8 
HEALTH ECONOMICS .................................................................................................................. 76 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 76 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 77 
9.1 
SAMPLE SIZE DETERMINATION ................................................................................................. 77 
9.2 
POPULATIONS FOR ANALYSES ................................................................................................. 78 
9.3 
STATISTICAL ANALYSES ............................................................................................................ 79 
9.3.1 
General considerations .................................................................................................................. 79 
9.3.2 
Primary endpoint(s) ........................................................................................................................ 80 
9.3.3 
Secondary endpoint(s) ................................................................................................................... 81 
9.3.3.1 
Adverse events .............................................................................................................................. 81 
9.3.3.2 
Deaths ............................................................................................................................................ 82 
9.3.3.3 
Clinical laboratory evaluations ....................................................................................................... 82 
9.3.3.4 
Progression-free survival ............................................................................................................... 82 
9.3.3.5 
Disease control rate ....................................................................................................................... 83 
9.3.3.6 
Duration of response ...................................................................................................................... 83 
9.3.3.7 
Immunogenicity .............................................................................................................................. 83 
9.3.3.8 
Pharmacokinetics ........................................................................................................................... 83 
9.3.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 83 
9.3.5 
Other analyses ............................................................................................................................... 84 
9.4 
INTERIM ANALYSES  ................................................................................................................... 84 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 85 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 85 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 85 
10.1.2 
Financial disclosure........................................................................................................................ 86 
10.1.3 
Informed consent process .............................................................................................................. 86 
10.1.4 
Data protection ............................................................................................................................... 87 
10.1.5 
Committees structure ..................................................................................................................... 89 
10.1.6 
Dissemination of clinical study data ............................................................................................... 89 
10.1.7 
Data quality assurance .................................................................................................................. 90 
10.1.8 
Source documents ......................................................................................................................... 90 
10.1.9 
Study and site start and closure ..................................................................................................... 91 
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10.1.10 Publication policy ........................................................................................................................... 92 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 92 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 94 
10.3.1 
Definition of AE .............................................................................................................................. 94 
10.3.2 
Definition of SAE ............................................................................................................................ 95 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 97 
10.3.4 
Reporting of SAEs.......................................................................................................................... 98 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 99 
10.4.1 
Definitions ...................................................................................................................................... 99 
10.4.2 
Contraception guidance ............................................................................................................... 100 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 100 
10.6 
APPENDIX 6: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS ....................................................... 101 
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 .................................................................. 107 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 107 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 107 
10.9.1 
Remote prescreening process ..................................................................................................... 108 
10.9.2 
Screening procedures .................................................................................................................. 109 
10.9.3 
Study intervention ........................................................................................................................ 109 
10.9.4 
Study procedures ......................................................................................................................... 109 
10.9.5 
Statistical analyses and deviation ................................................................................................ 110 
10.9.6 
Informed consent process ............................................................................................................ 110 
10.10 
APPENDIX 10: CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE AND 
STRONG CYP3A INHIBITORS ................................................................................................... 110 
10.11 
APPENDIX 11: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 ..... 112 
10.11.1 Measurability of tumor at baseline ............................................................................................... 112 
10.11.2 Special considerations regarding lesion measurability ................................................................ 112 
10.12 
APPENDIX 12: ABBREVIATIONS ............................................................................................... 119 
10.13 
APPENDIX 13: PROTOCOL AMENDMENT HISTORY .............................................................. 121 
11 
REFERENCES ............................................................................................................................. 125 
 
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LIST OF TABLES  
Table 1 - Approximate number of participants per study arm ....................................................................... 15 
Table 2 - Risk assessment ............................................................................................................................ 37 
Table 3 - Objectives and endpoints ............................................................................................................... 40 
Table 4 - Dose levels for Part 1 (safety run-in) ............................................................................................. 42 
Table 5 - Overview of study interventions administered ............................................................................... 52 
Table 6 - Arms and associated interventions ................................................................................................ 53 
Table 7- Dose-limiting toxicities ..................................................................................................................... 56 
Table 8 - Dose modification for toxicity ......................................................................................................... 57 
Table 9 - List of pharmacokinetic parameters and definitions ....................................................................... 73 
Table 10 -
 .......................... 77 
Table 11 - 
 ......................... 78 
Table 12 - 
 .................................... 78 
Table 13 - Populations for analyses .............................................................................................................. 78 
Table 14 - Protocol-required laboratory tests ................................................................................................ 93 
Table 15 - Recommended dose modification or discontinuation for tusamitamab ravtansine.................... 101 
Table 16 - List of CYP substrates with narrow therapeutic range ............................................................... 110 
Table 17 - List of strong CYP3A inhibitors .................................................................................................. 111 
Table 18 - Response criteria ....................................................................................................................... 115 
Table 19 - Response in participants with target disease ............................................................................. 117 
Table 20 - Response in participants with non-target disease only .............................................................. 118 
 
LIST OF FIGURES  
Figure 1 - Decision tree for tusamitamab ravtansine loading dose in Cohort C............................................ 14 
Figure 2 - Graphical study design ................................................................................................................. 20 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
Open-label, multi-cohort, Phase 2 trial, evaluating the efficacy and safety of 
tusamitamab ravtansine (SAR408701) monotherapy and in combination in patients 
with CEACAM5-positive advanced solid tumors 
Brief title: 
 
Tusamitamab ravtansine monotherapy and in combination in patients with CEACAM5-positive 
advanced solid tumors  
Rationale: 
The carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is one of the 
7 members of the CEACAM subgroup of a family of glycoproteins involved in cell adhesion (1). 
It was 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, 
while in normal adults, its expression is limited to only a few tissues (1, 3). Immunostaining of 
CEACAM5 in a large panel of human tumor tissue microarray samples has shown the highest 
prevalence of cell surface CEACAM5 expression in adenocarcinoma of the colon and the 
stomach, and in its subtype signet ring cells as well as in non-squamous (NSQ) non-small-cell 
lung carcinoma (NSCLC). 
Tusamitamab ravtansine is an antibody-drug conjugate (ADC) combining hu769_4D4 
(SAR408377), a humanized antibody that recognizes selectively the A3-B3 extracellular domain 
of CEACAM5, with the potent cytotoxic maytansinoid derivative ravtansine (DM4), which 
inhibits microtubule assembly. Tusamitamab ravtansine is expected to selectively deliver DM4 to 
cancer cells expressing the CEACAM5 antigen. 
In the first-in-human study TED13751, 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 tusamitamab ravtansine 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% confidence interval [CI]: 12.27%-31.71%); 
28 (43.8%) had stable disease. Patients were heavily pretreated with a median of 3 prior 
treatments (1 to 10 lines) for advanced disease, including antitubulin agents (60.9%) and anti-
programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) (70.3%).   
Tusamitamab ravtansine is being developed in NSQ NSCLC. The randomized Phase 3 EFC15858 
trial is currently ongoing to evaluate the efficacy and the safety of tusamitamab ravtansine versus 
docetaxel in previously treated metastatic NSQ NSCLC patients with CEACAM5-positive 
tumors. The combination therapy with tusamitamab ravtansine is also currently being studied in 
2 Phase 2 trials in patients with NSQ NSCLC in second or third-line and first-line settings, 
ACT16525 in combination with ramucirumab in patients with CEACAM5 positive tumors 
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previously treated with platinum-based chemotherapy and an immune checkpoint inhibitor, and 
ACT16146 in combination with pembrolizumab in first-line in patients with CEACAM5-positive 
and PD-L1-positive tumors.  
Other tumor types also express CEACAM5 in tumor cells. The efficacy and the safety of 
tusamitamab ravtansine will be explored in other indications for which the tumor expresses 
CEACAM5 and which are also known to be sensitive to anti-tubulin agents such as the metastatic 
breast cancer (mBC) and the pancreatic adenocarcinoma (PAC). 
The prevalence of the high expression (defined as ≥2+ in intensity involving at least 50% of the 
tumor cells) is 10% in all mBC types in which no high expression was identified in the primary 
tumors, 14% in triple-negative breast cancer (TNBC), and 15% in pancreatic cancer.  
Taxanes are very active agents in the treatment of breast cancer and have shown clinical benefit 
both in the metastatic and (neo) adjuvant setting (4, 5). Nab-paclitaxel in combination with 
gemcitabine is one of the two recommended combination therapies in first-line treatment for 
metastatic pancreatic cancer (6, 7). 
The aim of this multi-cohort study is to evaluate the safety and efficacy of tusamitamab ravtansine 
to potentially improve the efficacy with a favorable safety profile in participants with mBC 
(Cohort A [monotherapy]) and metastatic pancreatic adenocarcinoma (mPAC; Cohort B 
[monotherapy] and Cohort C [in combination with gemcitabine]) CEACAM5-positive tumors 
known to be sensitive to taxanes, which leads to a higher hematological toxicity than tusamitamab 
ravtansine.  
Objectives and endpoints  
 
 
Objectives 
Endpoints 
Primary 
• 
For Cohort A, Cohort B, and Cohort C 
Part 2: To assess the antitumor activity 
of tusamitamab ravtansine in mBC and 
tusamitamab ravtansine monotherapy 
and in combination with gemcitabine in 
mPAC 
• 
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 per 
Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 
• 
For Cohort C Part 1: Confirmation of 
the recommended tusamitamab 
ravtansine dose when administered in 
combination with gemcitabine 
• 
Incidence of dose-limiting toxicites (DLTs) in the 28 Day DLT 
observation period (Cycle 1) 
Secondary 
• 
To assess the safety and tolerability of 
tusamitamab ravtansine administered 
as monotherapy and in combination 
with gemcitabine  
• 
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 
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• 
To assess other efficacy parameters of 
tusamitamab ravtansine administered 
as monotherapy and in combination 
with gemcitabine 
• 
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, confirmed PR or 
stable disease as per RECIST v1.1 
• 
Duration of response (DOR), defined as the time from first 
documented evidence of confirmed CR or confirmed PR until 
progressive disease determined per RECIST v1.1 or death from 
any cause, whichever occurs first 
• 
To assess the immunogenicity of 
tusamitamab ravtansine 
• 
Incidence of participants with antitherapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
• 
To assess the pharmacokinetics (PK) 
of tusamitamab ravtansine and 
gemcitabine when given in combination 
• 
Pharmacokinetic parameters of tusamitamab ravtansine and 
gemcitabine 
 
 
 
 
Overall design: 
This is a Phase 2, open-label, multi-cohort, multi-center study assessing efficacy (anti-tumor 
activity), safety, and immunogenicity of tusamitamab ravtansine single agent in participants with 
mBC (Cohort A) and mPAC (Cohort B) with CEACAM5-positive tumors (defined as CEACAM5 
immunohistochemistry [IHC] intensity ≥2+ in ≥50% of tumor cells), and also assessing efficacy 
(antitumor activity), safety, tolerability, PK, and immunogenicity of tusamitamab ravtansine 
combined with gemcitabine in participants with mPAC (Cohort C) with CEACAM5-positive 
tumors.  
During the prescreening phase, participants’ tumor samples will be collected to evaluate 
CEACAM5 status (central assessment by IHC). During the screening phase, only participants 
with mBC and mPAC determined to be CEACAM5-positive will go through protocol screening 
procedures. 
Treatment allocation will be performed using an interactive response technology (IRT). After 
being screened, the eligible participants will receive tusamitamab ravtansine as single agent 
treatment or receive tusamitamab ravtansine and gemcitabine combined treatment.  
In Cohorts A and B, participants will receive a tusamitamab ravtansine loading dose at 170 mg/m² 
on Day 1 of Cycle 1, followed by 100 mg/m² every 2 weeks (Q2W) from Cycle 2 and in all other 
cycles.  
In Cohort C, each treatment cycle will be 28 days (4 weeks). Cohort C will comprise 2 parts:  
Part 1 (Safety Run-In): In Part 1, participants will receive a 170 mg/m² tusamitamab ravtansine 
loading dose on Day 1, followed by 100 mg/m² every 2 weeks (Q2W); participants will also 
receive gemcitabine 1000 mg/m2 on Day 1, Day 8, and Day 15 every 4 weeks (Q4W). In the case 
that it is decided to reduce the initial loading dose of tusamitamab ravtansine to DL-1 (Figure 1), a 
tusamitamab ravtansine loading dose of 135 mg/m2 will be administered to participants on Day 1 
of Cycle 1.  
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Figure 1 - Decision tree for tusamitamab ravtansine loading dose in Cohort C  
 
The starting dose for tusamitamab ravtansine is selected as the maximum tolerated dose (MTD) 
used in studies evaluating tusamitamab ravtansine as loading-dose monotherapy. Enough 
participants will be enrolled in Part 1 to achieve 3 to 12 participants evaluable for DLTs to 
confirm the recommended dose. The tolerability of the combination is assessed in Part 1 
according to the algorithm illustrated in Figure 1. The DLT observation period is the first cycle 
(approximately 28 days). A DLT-evaluable participant must have completed 1 cycle of treatment 
or have been discontinued from study treatment because of a DLT; DLT-nonevaluable 
participants will be replaced. A minimum delay of 1 week is required between the initial dose in 
the first participant treated in a DL cohort and dosing of the next 2 participants treated at the same 
DL. 
In Part 2 of the study, the recommended dose confirmed in Part 1 will be evaluated for activity in 
24 to 27 additional participants. A total of 30 participants, including participants treated at the 
recommended dose in Part 1, will be evaluated for activity. 
Brief summary:  
This is a single group, treatment, Phase 2, no masking, 3 arm study to evaluate efficacy (antitumor 
activity), safety, and immunogenicity of tusamitamab ravtansine in male and female participants 
aged 18 years or more with mBC (Cohort A [monotherapy]) and mPAC (Cohorts B 
[monotherapy] and C [in combination with gemcitabine]) with CEACAM5-positive tumors 
(defined as CEACAM5 IHC intensity ≥2+ in ≥50% of tumor cells).  
 
 
3 participants
Starting dose
170 mg/m²
3 participants
DL - 1
135 mg/m²
+ 3 participants
Starting dose
170 mg/m²
1/3 DLT
+ 3 participants
DL - 1
135 mg/m²
≥ 2/3 DLTs
≤ 1/3 DLT
≥ 2/3 DLTs
Alternative 
dosage or STOP
≥ 2/6 DLTs
≤ 1/6 DLT
≥ 2/6 DLTs
RP2D = 170 mg/m²
GO to Part 2*
RP2D = 135 mg/m²
GO to Part 2*
≤ 1/6 DLT
* Only applicable to Cohort C
0/3 DLT
0/3 DLT
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Number of participants: 
Approximately 118 participants will be screened to achieve 94 participants enrolled to study 
intervention and evaluable. The table below provides the approximate number of participants 
prescreened, screened, treated and evaluable per study arm: 
Table 1 - Approximate number of participants per study arm  
Approximate number of 
participants 
mBC 
mPAC 
Cohort A 
Cohort B 
Cohort C 
Prescreened 
440 
242 
90 
Screened 
44 
36 
38 
Treated and Evaluable 
35 
29 
30 
 
 
Intervention groups and duration: 
• Prescreening period: Prescreening Informed Consent will be signed by the participant 
and participants’ tumor samples will be collected to evaluate CEACAM5 status. 
The duration of the study for a participant, irrespective of the study cohort, will include: 
• Screening period: up to 28 days.  
• Treatment period: once successfully screened, enrolled participants may receive study 
intervention until documented disease progression, unacceptable toxicity, new anticancer 
therapy initiation, or the participant’s or Investigator’s decision to stop the treatment. Each 
cycle of treatment will last for 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 anti-cancer therapy, whichever is 
earlier, for end-of-treatment (EOT) assessments. 
• Safety follow-up visit: Serious adverse events/adverse events of special interest (AESIs) 
(regardless of relationship with study treatment) and IMP-related adverse events (AEs) 
ongoing at the end of study treatment, and any new IMP-related AEs/SAEs/AESIs will be 
followed until resolution or stabilization. The follow-up visit will be performed 90 days 
after the last IMP administration. If ongoing IMP-related AEs/SAEs/AESIs are resolved or 
stabilized, no further safety follow-up visit will be needed, otherwise an on-site follow-up 
visit will be performed every 12 weeks. 
Participants who stop treatment before documented progressive disease (achieving stable disease, 
or CR or PR) should undergo a tumor assessment and an on-site follow-up visit every 12 weeks 
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 anticancer therapy, participants will be 
followed until any ongoing IMP-related AEs/SAEs/AESIs are resolved or stabilized. 
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The cut-off date for the interim analysis corresponds to the date when the first 15 treated 
evaluable participants in Cohort C 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. 
The study cut-off for the primary analysis (ORR) for each cohort corresponds to the date on which 
all treated evaluable participants of the cohort 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. The cut-off can 
be up to approximately 20 weeks after the date of the first IMP administration of the last 
participant of the cohort: 16 weeks for 2 tumor assessments and at least 4 weeks if a confirmation 
of response is needed.  
The analysis cut-off date for secondary efficacy endpoints including DOR and PFS (final cut-off 
date) will be 6 months after the cut-off date of the primary analysis. The primary analysis of ORR 
and DCR will also be updated at that time. 
After the cut-off date for the secondary efficacy endpoints, participants with observed clinical 
benefit who are still receiving study treatment can continue study treatment until progressive 
disease, unacceptable toxicity, new anticancer therapy initiation, or the participant’s or 
Investigator’s decision to stop the treatment, and will continue to undergo all assessments as per 
the study flow chart. 
The expected duration of study intervention for participants may vary, based on progression date 
and the cohort; median expected duration of study per participant is estimated at 8 months for the 
mBC cohort and 6 months for the mPAC cohorts (up to 1 month for screening, a median of 4 or 
2 months for treatment in the mBC and mPAC cohorts respectively, a median of 1 month for 
EOT, and follow-up visit 90 days after the last IMP administration). 
Study interventions 
Study intervention is tusamitamab ravtansine (SAR408701) administered as monotherapy or in 
combination with gemcitabine. 
Investigational medicinal product(s) 
Tusamitamab ravtansine 
• Formulation: tusamitamab ravtansine (SAR408701) is supplied as a 25 mL extractable 
volume of concentrate for solution for infusion of 125 mg contained in a 30 mL Type I 
glass vial. 
• Route(s) of administration: intravenous (IV) infusion. 
• Dose regimen: For Cohorts A and B, tusamitamab ravtansine (SAR408701) loading dose 
at 170 mg/m² will be administered via IV infusion over 1 hour 30 minutes on Day 1 of 
Cycle 1, followed by 100 mg/m² Q2W from Cycle 2 and in all other cycles. For Cohort C, 
tusamitamab ravtansine (SAR408701) loading dose at 170 mg/m² (or 135 mg/m2) will be 
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administered via IV infusion over 1 hour 30 minutes on Day 1 of Cycle 1, followed by 
100 mg/m² Q2W. To prevent hypersensitivity reactions, premedication will be given 
before each administration (see below).  
For participants with a body surface area (BSA) >2.20 m², the dose will be calculated 
based on a BSA of 2.20 m². 
Gemcitabine 
• Formulation: gemcitabine is supplied as lyophilized powder for reconstitution or as a 
solution for infusion. 
• Route(s) of administration: intravenous (IV) infusion. 
• Dose regimen: For Cohort C, gemcitabine at 1000 mg/m² will be administered via IV 
infusion over 30 minutes on Day 1, Day 8, and Day 15 of each cycle (Q4W). If 
gemcitabine is administered on the same day as tusamitamab ravtansine, gemcitabine 
administration will be started after tusamitamab ravtansine infusion.  
Noninvestigational medicinal products (NIMP) 
Premedication: 
• Premedication with Histamine H1 antagonist (oral diphenhydramine 50 mg or equivalent 
[eg, dexchlorpheniramine] given approximately 15 minutes to 1 hour before tusamitamab 
ravtansine administration depending on the administration form IV or oral [15 minutes 
prior for IV and 1 hour prior for oral]) is required for all participants before administration 
of tusamitamab ravtansine. 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. In case participant does not experience any 
hypersensitivity reactions after 4 cycles, the premedication can be discontinued at the 
discretion of the Investigator.  
• Premedication for gemcitabine: Antiemetic preventive therapy must be given according to 
ASCO guidelines and the local practice. Gemcitabine is known as a low-emetic-risk 
antineoplastic agent. According to ASCO anti-emetics guidelines updated on May 6th, 
2020, adults treated with low-emetic-risk antineoplastic agents should be offered a single 
dose of a 5-HT3 receptor antagonist or a single 8◦mg dose of dexamethasone before 
antineoplastic treatment (8). 
  
Posttrial access to study medication:  
Interventions should be decided by the Investigator per clinical practice. 
Statistical considerations: 
• Sample size calculations:  
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. Assuming prescreening failure rates 
of 90% for mBC Cohort A, 85% for mPAC Cohort B, 58% for mPAC Cohort C, and a 
screening failure rate of 20% for the 3 cohorts, approximately 440 participants will be 
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prescreened to achieve up to 35 treated evaluable participants in mBC Cohort A; 
approximately 242 participants will be prescreened to achieve up to 29 treated evaluable 
participants in mPAC Cohort B; and approximately 90 participants will be prescreened to 
achieve up to 30 treated evaluable participants in mPAC Cohort C. These participants will 
be evaluable for activity (at least 1 postbaseline tumor assessment, early progression, or 
death due to progressive disease). 
• Main analysis population: 
- 
All-treated population: All registered participants exposed to the study treatment, 
regardless of the amount of treatment administered. This population is the primary 
population for 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. 
- 
ATA population: All treated participants with at least 1 postbaseline ATA result 
(negative, positive, or inconclusive). 
- 
DLT-Evaluable (Cohort C Part 1): Participants who received 1 cycle with at least 
80% of the intended dose for both tusamitamab ravtansine at each of the first 
2 infusions and gemcitabine at each of the 3 first infusions unless they discontinued the 
study intervention before the end of Cycle 1 due to a DLT. 
- 
PK population: All treated participants with at least 1 postbaseline PK result with 
adequate documentation of dosing and sampling dates and times. 
• Analysis of primary endpoint: 
- 
Objective response rate will be summarized for the All-treated population using 
descriptive statistics and 95% exact CIs will be provided using the Clopper-Pearson 
method. 
- 
Objective response rate will also be summarized on the activity population as a 
supplementary analysis.  
- 
For Part 1 of Cohort C, DLTs observed during the 28 day DLT observation period 
(Cycle 1) will be summarized on the DLT-evaluable population, by dose level. 
• Analysis of secondary efficacy endpoints: 
- 
Progression-free survival will be summarized on the All-treated population using 
Kaplan-Meier methods. The median PFS time and associated 95% CI will be provided 
along with probabilities of being progression-free at different time points. 
- 
The DCR will be summarized for the All-treated population with descriptive statistics. 
In addition, 2-sided 95% CIs will be computed using the Clopper-Pearson method. 
- 
The DOR will only be summarized on the subgroup of participants who have achieved 
confirmed objective response in the All-treated population with descriptive statistics 
using Kaplan-Meier methods. The median DOR and associated 95% CI will be 
provided. 
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• Analysis of safety endpoints: 
- 
Number and percentage of participants experiencing TEAEs by primary system organ 
class (SOC) and preferred term (PT) will be summarized by NCI-CTCAE v5.0 grade 
(all grades and Grade ≥3) for the All-treated population. Similar summaries will be 
prepared for treatment-related TEAEs, TEAEs leading to definitive discontinuation, 
TEAEs leading to dose modification, 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 
laboratory abnormalities (all grades and by grade) using the worst grade during the 
treatment period will be provided for the All-treated population. 
Data Monitoring/Other committee: No 
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1.2 
SCHEMA  
Figure 2 - Graphical study design  
Cohort C: 
Metastatic pancreatic 
adenocarcinoma (mPAC)
combination tusamitamab ravtansine + gemcitabine
N=30 (N=15 => interim analysis => add 15)
tusamitamab ravtansine
tusamitamab ravtansine
N=35
Treatment period
 
C = cycle; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; D = Day; EOT = end-of-treatment; ICF = informed consent form; IMP = investigational medicinal product; mBC = metastatic breast 
cancer, mPAC = metastatic pancreatic adenocarcinoma, N = number of participants. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
1.3.1 Study procedures flowchart for Cohort A and B  
 
Procedure 
Prescreeninga 
Screeningb 
Treatment 
Cycle 1 
Treatment Cycle 2 and 
subsequent 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upc 
Notes 
Day(D) 
 
(Days prior to 
initial 
infusion) 
D1 Pre-
infusion 
D1 Pre-
infusiond 
(±2 days) 
Every 
8 weeks  
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after last 
infusion 
(±7 days) 
 
CEACAM5 expression status 
(archival or fresh tumor tissued) 
after prescreening informed 
consent 
X 
 
 
 
 
 
 
Assessed by central IHC after 
prescreening informed consent. 
CEACAM5 expression status for 
mBC on primary tumor (archival, if 
available)f 
 
X 
 
 
 
 
 
FFPE sections for RNA and DNA 
analysis (archival or fresh tumor 
tissue)g  
 
X 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
IRT contact 
X 
X 
X 
X 
 
X 
X 
 
Inclusion and exclusion criteria 
 
≤28 
X 
 
 
 
 
 
Demography 
 
≤28 
 
 
 
 
 
 
Medical/surgical/disease history 
 
≤28 
 
 
 
 
 
Includes histologic types, stage at 
diagnosis, disease extent at study entry 
and specific mutations 
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 
 
 
 
 
 
 
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Procedure 
Prescreeninga 
Screeningb 
Treatment 
Cycle 1 
Treatment Cycle 2 and 
subsequent 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upc 
Notes 
Day(D) 
 
(Days prior to 
initial 
infusion) 
D1 Pre-
infusion 
D1 Pre-
infusiond 
(±2 days) 
Every 
8 weeks  
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after last 
infusion 
(±7 days) 
 
Weight, BSA 
 
≤7 
X 
X 
 
X 
 
On Day 1 of each treatment cycle, the 
participant’s BSA will be determined 
using the current weight and baseline 
height. 
Vital signs 
 
≤7 
X 
X 
 
X 
 
Temperature, blood pressure, and 
pulse rate 
Serum or urine pregnancy test 
(WOCBP only)h  
 
≤7 
 
Every 4 weeks 
 
X 
 
Mandatory serum test at screening and 
EOT, serum or urine test during study 
treatment period. 
HBV & HCV serology; 
HIV test (only if required at 
country level) 
 
X 
 
 
 
 
 
 
Laboratory assessmentsi 
 
≤7 
Xj 
X 
 
X 
 
During first 2 cycles, hematology and 
liver function tests will be assessed 
weekly. 
12-lead ECG 
 
≤7 
 
X 
 
X 
 
 
Specific ocular tests 
 
28 
 
 
 
X 
 
Include assessment of ocular/visual 
symptoms and ocular exams including 
visual acuity, slit-lamp under dilatation, 
and Schirmer’s test at screening, EOT 
and whenever clinically indicated 
Assessment of ocular/visual 
symptoms 
 
 
X 
X 
 
 
 
 
Tusamitamab ravtansine 
intervention 
 
 
X 
X 
 
 
 
Participants should receive study 
intervention until documented disease 
progression, unacceptable toxicity, new 
anticancer therapy initiation, or the 
participant’s or Investigator’s decision 
to stop the treatment 
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Procedure 
Prescreeninga 
Screeningb 
Treatment 
Cycle 1 
Treatment Cycle 2 and 
subsequent 
(14 ±2 days from 
previous infusion) 
End of 
treatment 
Follow-upc 
Notes 
Day(D) 
 
(Days prior to 
initial 
infusion) 
D1 Pre-
infusion 
D1 Pre-
infusiond 
(±2 days) 
Every 
8 weeks  
(±7 days) 
D30 after last 
infusion 
(±5 days) 
D90 after last 
infusion 
(±7 days) 
 
AE assessment 
Xk 
==========================================================→ 
Xc 
 
Concomitant medication review 
 
==========================================================→ 
 
 
Tumor assessment - RECIST v1.1 
- CT/MRIl 
 
28 
 
 
X 
X 
X 
Imaging assessments are to be 
scheduled using the Cycle 1, Day 1 
date as the reference for all time points 
and are not to be scheduled based on 
the date of the previous imaging time 
point. 
Circulating CEA 
X 
28 
 
 
X 
X 
X 
On infusion days, to be performed 
before infusion or the day before 
Whole blood for circulating 
tumoral cells (CTC) 
 
 
X 
 
 
 
 
To be performed on Cycle 1 Day 1 
before infusion or the day before. 
Samples will be taken from 
approximately 5 participants per 
indication (mBC, mPAC). 
Plasma for tumor cfDNA and 
whole blood for germline DNA 
 
 
X 
 
 
 
 
To be performed on Day 1 before 
infusion or the day before 
tusamitamab ravtansine 
immunogenicity (ATA)m 
 
 
Xm 
Xm 
 
X 
 
On infusion days, to be performed 
before infusion or the day before 
AE = adverse event; AESI = adverse event of special interest; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AP = alkaline phosphatase; AST = aspartate aminotransferase; ATA = anti-therapeutic 
antibody; BSA = body surface area; BUN = blood urea nitrogen; CEA = carcinoembryonic antigen; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; cfDNA = circulating free deoxyribonucleic 
acid; CT = computed tomography; CTC = circulating tumoral cells; CR = complete response; D = Day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
eCRF = electronic case report form; EOT = end-of-treatment; FFPE = formalin-fixed paraffin embedded; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; 
IHC = immunohistochemistry; IMP = investigational medicinal product; IRT = interactive response technology; LDH = lactate dehydrogenase; mBC = metastatic breast cancer; mPAC = metastatic pancreatic 
adenocarcinoma; MRI = magnetic resonance imaging; PR = partial response; RECIST = response evaluation criteria in solid tumors; RNA = ribonucleic acid; SAE = serious adverse event; WBC = white blood cell; 
WOCBP = woman of childbearing potential. 
a Prescreening Informed Consent will be signed by the participant before CEACAM5 assay on archival or fresh tumor tissue. 
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b Informed consent should be signed before any study specific procedures. It 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: participants must have confirmed CEACAM5 expression as assessed centrally. Baseline evaluation should be completed within 1 week prior to initiation of 
therapy, except for tumor assessment, circulating CEA, and ocular tests that may be performed within 4 weeks prior to the first IMP administration. Results of these tests should be reviewed by the Investigator 
prior to initiation of therapy.  
c At the follow-up visit, 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). Further anti-cancer treatment will be collected at the follow-up visit, including date of progression if 
any. Participants who stopped treatment before documented progressive disease (achieving stable disease, or CR or PR) should undergo a tumor assessment and an on-site follow-up visit every 12 weeks 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. Participants with documented disease progression should 
attend an on-site follow-up visit 90 days after the last IMP administration. 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. 
d D1 of Cycle 2 and of each subsequent cycle corresponds to D15 of the previous cycle (±2 days). As of Cycle 2, procedures can be done on the day of infusion (before infusion) or the day before. 
e mBC: At the metastatic site (mandatory); mPAC: Preferably at the metastatic site; Cell collections (eg, from pleural effusion) processed as FFPE blocks are acceptable. 
f 
If available, 3 x 5 µm slides from the surgery material at the breast cancer diagnosis (primary tumor or local lymph nodes) are requested for CEACAM5 assessment. 
g At least 3 x 10 μm slides (best) or 6 x 5 μm slides (or equivalent to the same total amount of material) from FFPE tissue (from same sample as the one used for CEACAM5 expression status if possible) from 
treatment start for both mBC and mPAC (only screened participants).  
h Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. A pregnancy test (urine or serum as required by local regulations) will be 
repeated every 4 weeks before each IMP administration and at the EOT evaluation (30 ±5 days after the last IMP administration). 
i 
Hematology: hemoglobin, hematocrit, RBC, WBC with differential, platelet counts (If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 x 109/L). Liver function tests: AST, ALT, total bilirubin, 
conjugated bilirubin, AP. Renal function tests: urea (or BUN) and creatinine. Electrolytes: sodium, potassium, calcium, phosphate, chloride. Others: glucose, LDH, albumin and total proteins. In case of Grade ≥3 
liver function abnormal tests, additional tests will be repeated every 2-3 days until recovery to baseline value. Additional tests will be performed when clinically appropriate. Tests can be performed on the same day 
or within the 2 days before initiating study intervention. 
j 
Day 1 hematology, blood chemistry and coagulation tests may be omitted if baseline test performed within 7 days are normal. If baseline tests are abnormal, they should be repeated within 2 days of first study 
intervention. 
k 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. 
l 
Chest, abdomen, pelvic CT-scan or MRI and any other examinations as clinically indicated will be performed to assess disease status at baseline and then every 8 weeks (±7 days) until EOT, and then every 
12 weeks until progressive disease, new anticancer therapy, death, withdrawal of participant’s consent, or study cut-off date for secondary efficacy endpoints, whichever comes first. Bone CT-scan or MRI and 
other examinations should be performed if clinically indicated. Brain CT scan or MRI should be performed at baseline and followed during treatment only for participants with brain lesions at baseline. 
m Tusamitamab ravtansine ATA samples will be collected before start of infusion of each cycle until C3, at C7, and thereafter every 6 cycles (ie, C13, C19, etc). The remaining plasma volume may also be used for 
further investigations including pharmacokinetics if deemed relevant in case of ATA positive results. 
 
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1.3.2 Study procedures flowchart for Cohort C  
Procedure 
Prescreeninga Screeningb 
Treatment Cycle 1 and subsequent 
(28±3 days from previous infusion) 
End of 
treatment 
Follow-upc 
Notes 
Day(D) 
 
(Days prior 
to initial 
infusion) 
D1 Pre-
infusiond 
D8 Pre-
infusion 
(±1 day) 
D15 Pre-
infusion 
(±2 days) 
Every 
8 weeks 
(±7 days) 
30 days after 
last infusion 
(±5 days) 
90 days after 
last infusion 
(±7 days) 
 
CEACAM5 expression status 
(archival or fresh tumor 
tissuee 
X 
 
 
 
 
 
 
 
Assessed by central IHC after prescreening informed 
consent. 
FFPE sections for RNA and 
DNA analysis (archival or 
fresh tumor tissue)f 
 
X 
X (if not 
obtained 
during 
screening) 
 
 
 
 
 
If not done during Screening, to be performed on 
Cycle 1 Day 1 before infusion 
Informed consent 
 
X 
 
 
 
 
 
 
 
IRT contact 
X 
X 
X 
 
X 
 
X 
X 
 
Inclusion and exclusion 
criteria 
 
≤28 
X 
 
 
 
 
 
Only to be performed on Cycle 1 Day 1 
Demography 
 
≤28 
 
 
 
 
 
 
 
Medical/surgical/ disease 
history 
 
≤28 
 
 
 
 
 
 
Includes histologic types, stage at diagnosis, disease 
extent at study entry and specific mutations 
Physical examination, ECOG 
performance status 
 
≤7 
X 
X 
X 
 
X 
X 
Examination of major body systems including 
cardiovascular, central nervous system, respiratory 
system, gastrointestinal system, hepatomegaly, 
splenomegaly, lymphadenopathy. 
Height 
 
≤7 
 
 
 
 
 
 
 
Weight, BSA 
 
≤7 
X 
X 
X 
 
X 
 
On each treatment cycle, the participant’s BSA will be 
determined using the current weight and baseline 
height. 
Vital signs 
 
≤7 
X 
X 
X 
 
X 
 
Temperature, blood pressure, and pulse rate 
Serum or urine pregnancy 
test (WOCBP only)h  
 
≤7 
X 
 
 
 
X 
 
Mandatory serum test at Screening and EOT; serum or 
urine test during study treatment period. 
HBV & HCV serology; 
(HIV test if required at 
country level) 
 
X 
 
 
 
 
 
 
 
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Procedure 
Prescreeninga Screeningb 
Treatment Cycle 1 and subsequent 
(28±3 days from previous infusion) 
End of 
treatment 
Follow-upc 
Notes 
Day(D) 
 
(Days prior 
to initial 
infusion) 
D1 Pre-
infusiond 
D8 Pre-
infusion 
(±1 day) 
D15 Pre-
infusion 
(±2 days) 
Every 
8 weeks 
(±7 days) 
30 days after 
last infusion 
(±5 days) 
90 days after 
last infusion 
(±7 days) 
 
Laboratory assessmentsi 
 
≤7 
Xi 
X 
X 
 
X 
 
 
12-lead ECG 
 
≤7 
X 
 
X 
 
X 
 
D1 ECG performed only from Cycle 2 
Specific ocular tests 
 
28 
 
 
 
 
X 
 
Include assessment of ocular/visual symptoms and 
ocular exams including visual acuity, slit-lamp under 
dilatation, and Schirmer’s test at screening, EOT, and 
whenever clinically indicated 
Assessment of ocular/visual 
symptoms 
 
 
X 
 
X 
 
 
 
 
Tusamitamab ravtansine 
intervention 
 
 
X 
 
X 
 
 
 
Participants should receive study intervention until 
documented disease progression, unacceptable toxicity, 
new anticancer therapy initiation, or the participant’s or 
Investigator’s decision to stop the treatment 
Gemcitabine intervention 
 
 
X 
X 
X 
 
 
 
AE assessment 
Xj 
===============================================================→ 
Xc 
 
Concomitant medication 
review 
 
===============================================================→ 
 
 
Tumor assessment - 
RECIST v1.1 - CT/MRIk 
 
28 
 
 
 
X 
X 
X 
Imaging assessments are to be scheduled using the 
Cycle 1, Day 1 date as the reference for all time points, 
and are not to be scheduled based on the date of the 
previous imaging time point. 
Circulating CEA 
X 
28 
 
 
 
X 
X 
X 
To be performed pre-infusion or the day before, and at 
EOT visit 
Plasma for tumor cfDNA and 
whole blood for germline 
DNA 
 
 
X 
 
 
 
 
 
To be performed only pre-infusion on Cycle 1 Day 1 or 
the day before 
Immunoglobulin G 
 
 
X 
 
 
 
 
 
To be performed only pre-infusion on Cycle 1 Day 1 or 
the day before 
Tusamitamab ravtansine PK 
and gemcitabine PK ; 
immunogenicity (ATA);  
 
 
====================================→ 
 
 
Refer to PK/ATA flowcharts in Section 1.3.3; see also 
Section 8.4; Section 8.7 
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AE = adverse event; AESI = adverse event of special interest; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AP = alkaline phosphatase; AST = aspartate aminotransferase; ATA = antitherapeutic 
antibody; BSA = body surface area; BUN = blood urea nitrogen; CEA = carcinoembryonic antigen; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; cfDNA = circulating free deoxyribonucleic 
acid; CT = computed tomography; CTC = circulating tumoral cells; CR = complete response; D = Day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
eCRF = electronic case report form; EOT = end-of-treatment; FFPE = formalin-fixed paraffin embedded; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; 
IHC = immunohistochemistry; IMP = investigational medicinal product; IRT = interactive response technology; LDH = lactate dehydrogenase; mBC = metastatic breast cancer; mPAC = metastatic pancreatic 
adenocarcinoma; MRI = magnetic resonance imaging; PK = pharmacokinetics; PR = partial response; RECIST = response evaluation criteria in solid tumors; RNA = ribonucleic acid; SAE = serious adverse event; 
WBC = white blood cell; WOCBP = woman of childbearing potential. 
a Prescreening Informed Consent will be signed by the participant before CEACAM5 assay on archival or fresh tumor tissue. 
b Informed consent should be signed before any study specific procedures. It 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: participants must have confirmed CEACAM5 expression as assessed centrally. Baseline evaluation should be completed within 1 week prior to initiation of 
therapy, except for tumor assessment, circulating CEA, and ocular tests that may be performed within 4 weeks prior to the first IMP administration. Results of these tests should be reviewed by the Investigator 
prior to initiation of therapy.  
c At the follow-up visit, 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). Further anticancer treatment will be collected at the follow-up visit, including date of progression, if 
any. Participants who stopped treatment before documented progressive disease (achieving stable disease, or CR or PR) should undergo a tumor assessment and an on-site follow-up visit every 12 weeks until 
radiological disease progression, the start of new anticancer 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 anticancer therapy, participants will be followed until any ongoing IMP-related AEs/SAEs/AESIs are resolved or stabilized. Participants with documented disease progression should 
attend an on-site follow-up visit 90 days after the last IMP administration. 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. 
d D1 of Cycle 2 and of each subsequent cycle corresponds to D29 of the previous cycle (±3 days). As of Cycle 2, procedures can be done on the day of infusion (before infusion) or the day before. 
e mPAC: Preferably at the metastatic site; cell collections (eg, from pleural effusion) processed as FFPE blocks are acceptable. 
f 
At least 3 × 10 μm slides (best) or 6 × 5 μm slides (or equivalent to the same total amount of material) from FFPE tissue (from same sample as that used for CEACAM5 expression status, if possible) from 
treatment start for mPAC (only screened participants).  
g Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. A pregnancy test (urine or serum as required by local regulations) will be 
repeated every 4 weeks before each IMP administration and at the EOT evaluation (30±5 days after the last IMP administration). 
h Hematology: hemoglobin, hematocrit, RBC, WBC with differential, platelet counts (If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 × 109/L). Liver function tests: AST, ALT, total bilirubin, 
conjugated bilirubin, AP. Renal function tests: urea (or BUN) and creatinine. Electrolytes: sodium, potassium, calcium, phosphate, chloride. Others: glucose, LDH, albumin and total proteins. In case of Grade ≥3 
liver function abnormal tests, additional tests will be repeated every 2-3 days until recovery to baseline value. Additional tests will be performed when clinically appropriate. Tests can be performed on the same day 
or within the 2 days before initiating study intervention. 
i 
Day 1 hematology, blood chemistry and coagulation tests may be omitted if baseline test performed within 7 days are normal. If baseline tests are abnormal, they should be repeated within 2 days of first study 
intervention. 
j 
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. 
k Chest, abdomen, pelvic CT scan or MRI and any other examinations as clinically indicated will be performed to assess disease status at baseline and then every 8 weeks (±7 days) until EOT, and then every 
12 weeks until progressive disease, new anticancer therapy, death, withdrawal of participant’s consent, or study cut-off date for secondary efficacy endpoints, whichever comes first. Bone CT scan or MRI and 
other examinations should be performed if clinically indicated. Brain CT scan or MRI should be performed at baseline and followed during treatment only for participants with brain lesions at baseline. 
 
 
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1.3.3 PK/ATA flow charts for tusamitamab ravtansine and gemcitabine samples for Cohort C  
1.3.3.1 First 10 participants  
1.3.3.1.1 Cycle 1  
Intervention period 
C1 
Day 
D1 
D4  
D8 
D15 
tusamitamab ravtansine 
IV infusion  
X------------ ---------X 
  
 
 
 
  
 
  
X 
Sample RNT (hours) 
Ref. tusamitamab SOI SOI 
EOI 
EOI +3 h 
 
 
 
72 h 168 h 
 
 
 
 
 
336 h 
(SOI) 
Sample time window  (-24 h, SOI) ±10 min ±30 min  
 
 
±5 h ±24 h 
 
 
 
 
 
±48 h 
PK sample ID 
(SAR408701) 
P00a 
P01 
P02 
 
 
 
P03 
P04 
 
 
 
 
 
P05a,b 
ATA sample ID  
AB00a 
 
 
 
 
 
 
 
 
 
 
 
 
AB01a,
b
gemcitabine 
IV infusion  
X-------------- ----------X 
 
 
 
 
 
X------------- ----------X 
 
 
 
 
 
Sample RNT (hours) 
Ref. gemcitabine SOI  
SOI 
EOI 
EOI 
+15 min 
1 h 
1 h 30 min 
2 h 
 
SOI 
EOI 
EOI + 
15 min 
1h 
1 h 30 min 
2 h 
 
Sample time window  
(-24h, SOI) 
within 
5 min of 
EOI 
±5 min ±10 min 
±10 min ±20 min 
 
(-24 h, SOI) 
within 
5 min of 
EOI 
±5 min ±10 min ±10 min ±20 min 
 
PK sample ID 
(gemcitabine, dFdU)  
PG00a 
PG01 
PG02 
PG03 
PG04 
PG05 
 
PG06a 
PG07 
PG08 
PG09 
PG10 
PG11 
 
Abbreviations: ATA = antitherapeutic antibody; C = cycle; D = day; dFdU=metabolite of gemcitabine; EOI = End of infusion time (ie, for tusamitamab ravtansine: when the pump beeps before 
flush = 1.5 hour, for gemcitabine = 30 min); EOT = End-of-treatment; h = hour ; IMP = investigational medicinal product; IV = intravenous; min = minutes ; PK = pharmacokinetics; RNT = relative nominal 
time; SOI = start of infusion.  
a Samples collected strictly before start of infusion (SOI), when applicable, tusamitamab ravtansine and gemcitabine predose samples can be collected at the same time before tusamitamab ravtansine 
administration. 
b Sample must be collected even if the infusion planned is not done or delayed on C1D15 and on C2D29 (corresponding to C3D1). 
Note: Sampling for PK and ATA may be reduced or stopped during the course of the study upon notification from the Sponsor.    
 
 
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1.3.3.1.2 Cycles 2 through 4, Cycle 7, and End of Treatment visit  
Intervention period 
C2 
C3 
C4 
C7 
EOT  
Day 
D1 
D15 
D18 
D22 
D29 
D15 
D1 
D1 
30±5 days after last 
IMP 
tusamitamab ravtansine 
IV infusion  
X 
X-- 
---X 
 
 
 
X 
X 
X 
X 
 
Sample RNT (hours)  
Ref. tusamitamab SOI  
SOI 
SOI 
EOI 
EOI+3 h 
72 h 
168 h 336 h (SOI) 
SOI 
SOI 
SOI 
 
Sample time window  
(-24 h, 
SOI) 
(-24 h, 
SOI) 
±10 
min 
±30 
min 
±5 h 
±24 h 
±48 h 
(-24 h, 
SOI) 
(-24 h, 
 
SOI) 
(-24 h, 
SOI) 
 
PK sample ID 
(SAR408701) 
P00a 
P01a 
P02 
P03 
P04 
P05 
P06a,b 
P07a 
P00a 
P00a 
 
ATA sample ID  
AB00a 
 
 
 
 
 
 
 
AB00a 
AB00a,c  
ABF00 
Abbreviations: ATA = antitherapeutic antibody; C = cycle; D = day; EOI = End of infusion time (ie, for tusamitamab ravtansine: when the pump beeps before flush = 1.5 hour, for gemcitabine = 30 min); 
EOT = End-of-treatment; h = hour ; IMP = investigational medicinal product; IV = intravenous; min = minutes ; PK = pharmacokinetics; RNT = relative nominal time; SOI = start of infusion.  
a Samples collected strictly before start of infusion (SOI), when applicable, tusamitamab ravtansine and gemcitabine predose samples can be collected at the same time before tusamitamab ravtansine 
administration. 
b Sample must be collected even if the infusion planned is not done or delayed  on C1D15 and on C2D29 (corresponding to C3D1). 
c tusamitamab ravtansine ATA samples will be collected at SOI at Cycle 7 and thereafter every 3 cycles (ie, C10, C13, 16…) 
Note: Sampling for PK and ATA may be reduced or stopped during the course of the study upon notification from the Sponsor. 
 
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1.3.3.2 Participants enrolled after the first 10  
 
Cycle  
 
C1 
 
C2 
C3 
C4 
C7 
EOT 
 
Day  
D1 
D15 
D1 
D15 
D1 
D15 
D1 
D1 
30±5 days 
after last IMP  
tusamitamab ravtansine 
IV infusion  
X---- 
---X  
X 
X  
 
X 
X  
X 
X  
X 
  
Sample RNT (hours) 
Ref. SAR408701 SOI  
SOI  
EOI 
SOI  
SOI 
EOI+1h  
SOI  
SOI  
SOI  
SOI  
SOI 
  
Sample time window  
(-24 h, SOI)  ±10 min (-24 h, SOI) (-24 h, SOI) ±10 min  (-24h, SOI) (-24 h, SOI) (-24h, SOI) (-24 h, SOI)  (-24 h, SOI) 
  
PK sample ID  
(SAR408701) 
P00a 
P01  
P02a 
P00a 
P01  
P02a 
P00a 
P01a 
P00a 
P00a 
  
ATA sample ID  
AB00a  
  
AB01a 
AB00a 
 
 
 
 
AB00 
AB00a,b 
ABF00  
Abbreviations: ATA = antitherapeutic antibody; C = cycle; D = day; EOI = end of infusion time (ie, for tusamitamab: when the pump beeps before flush = 1.5 hour); EOT = End-of-treatment visit; IMP = investigational 
medicinal product; IV = intravenous; PK = pharmacokinetics; RNT = relative nominal; SOI = start of infusion.  
a Samples collected strictly before start of infusion (SOI) 
b  tusamitamab ravtansine ATA samples will be collected at SOI at Cycle 7 and thereafter every 3 cycles (ie, C10, C13, 16…) 
Note: Sampling for PK and ATA may be reduced or stopped during the course of the study upon notification from the Sponsor. 
 
 
 
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2 
INTRODUCTION  
The CEACAM5 is one of the 7 members of the CEACAM subgroup of a family of glycoproteins 
involved in cell adhesion (1). It was 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, while in normal adults, its expression is limited to only a 
few tissues (1, 3). Immunostaining of CEACAM5 in a large panel of human tumor tissue 
microarray samples has shown the highest prevalence of cell surface CEACAM5 expression in 
adenocarcinoma of the colon and the stomach, and in its subtype signet ring cells as well as in 
NSQ NSCLC. 
Tusamitamab ravtansine is an ADC combining hu769_4D4, a humanized antibody that recognizes 
selectively the A3-B3 extracellular domain of CEACAM5, with the potent cytotoxic maytansinoid 
derivative DM4, which inhibits microtubule assembly. Tusamitamab ravtansine is expected to 
selectively deliver DM4 to cancer cells expressing the CEACAM5 antigen. 
In the completed main escalation phase of the first-in-human Study TED13751, 31 participants 
have been treated with tusamitamab ravtansine across 8 dose levels ranging from 5 to 150 mg/m². 
Treatment-emergent adverse events were seen in 29 of 31 participants in the main dose-escalation 
phase. Grade ≥3 TEAEs related to tusamitamab ravtansine were seen in 7 participants (22.6%) 
and were reported as SAEs in 2 participants (6.5%).  
The most frequent (in ≥4 of 31 participants [≥12.9%]) all-cause TEAE PTs were asthenia, nausea, 
and decreased appetite (8 participants [25.8%] each); keratopathy (8 participants [25.8%] any 
grade; 6 participants [19.4%] Grade ≥3); diarrhea and constipation (7 participants [22.6%] each); 
diarrhea/colitis combined (9 participants [29%]); fatigue (6 participants [19.4%]); abdominal pain 
(5 participants [16.1%]); dry eye and xerophthalmia combined (7 participants [22.6%]); and 
blurred vision and cough (4 participants [12.9%] each). Nervous system disorders occurred in 
8 participants; these included paresthesia in 4 participants (12.9%) and peripheral sensory 
neuropathy in 2 participants (6.5%). Infectious conditions, which included 3 Grade ≥3 events, 
were observed in 5 participants (16.1%). Except for keratopathy, these events were predominantly 
of low severity (Grade 1/Grade 2).  
The main clinically relevant laboratory abnormality was thrombocytopenia (51.6% [versus 9.7% 
at baseline]). Neutropenia has been observed in 5 participants (16.1%); 3 had Grade >3 events. 
Events possibly linked to allergic processes were documented in 2 participants (1 patient with 
Grade 2 infusion reaction, and 1 patient with Grade 1 eczematous lesions). 
During the assessment of preliminary safety data, extracted from the ongoing expansion cohorts, 
among 114 participants treated at 100 mg/m² tusamitamab ravtansine and treated with right-eye 
prophylaxis in the expansion phase, TEAEs of the cornea were reported in 31 participants; 
29 participants had clear laterality assessments. Preliminary results showed that approximately 
93% of corneal events (27 of 29 events) were bilateral, and thus were not impacted by 
prophylactic treatment. Based on this preliminary result, it was decided to discontinue primary 
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ocular prophylaxis, and instead consider secondary prophylaxis on a case-by-case basis following 
an ophthalmologist’s recommendation based on assessment of an individual patient. 
As of 17 June 2020, 28 patients were treated in the escalation bis loading dose cohort. Median age 
was 59.5 years (range: 36 to 73 years) and 19 (67.9%) were male. Sixteen patients (57.1%) had 
Eastern Cooperative Oncology Group (ECOG) performance status was as 1 at the time of study 
entry. Three patients were treated at the intended dose level 120 mg/m2, 4 patients at dose level 
135 mg/m2, 8 patients at dose level 150 mg/m2, and 13 patients at dose level 170 mg/m2. No dose-
limiting toxicity (DLT) was observed at the 120, 135, and 150 mg/m2 doses. Among the 9 patients 
evaluable for DLT, 2 patients presented with DLT at the 170 mg/m2 dose: 1 patient presented with 
a Grade 2 event of keratitis during Cycle 2 that led to drug withdrawn and the event was resolved 
after 31 days; 1 patient presented with Grade 2 event of keratopathy during Cycle 2, that was 
resolved after 33 days and leading to cycle delay and dose reduction. The maximum tolerated 
dose (MTD) was identified to be 170 mg/m2 at Cycle 1 followed by 100 mg/m2 from Cycle 2. 
Treatment-emergent adverse events have been reported in 28 patients (100%) with 19 (67.9%) 
TEAEs were treatment related. The most frequent all-grade TEAEs excluding laboratory AEs 
(≥3 patients; ≥10%), regardless of relationship to study medication were corneal events including 
keratopathy and keratitis (10 patients, 35.7%), nausea (6 patients; 21.4%), peripheral neuropathy 
(6 patients, 21.4%), asthenia (6 patients; 21.4%), abdominal pain (5 patients; 17.9%), dry eye 
(4 patients; 14.3%), dyspnoea (4 patients; 14.3%), diarrhoea (4 patients; 14.3%), decreased 
appetite (3 patients; 10.7%), cough (3 patients; 10.7%), and fatigue (3 patients; 10.7%). Among 
13 patients treated at the dose of 170 mg/m2 at Cycle 1, 8 patients had all grades corneal events 
and 3 patients had Grade 3 corneal event, 3 patients had all grades peripheral neuropathy and none 
of the patient experienced Grade 3 and 4 or treatment discontinuation due to neuropathy. 
The main laboratory abnormalities were Grade 3 anemia (1 patient, 3.7%), thrombocytopenia 
(1 patient, 3.7%), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase 
(1 patient, 3.7%), and AST increase (1 patient, 3.7%). No neutropenia and Grade 3 or 4 renal 
abnormalities were reported. 
Pooled analyses were performed for the 160 patients treated at 100 mg/m² Q2W. 
Treatment-emergent adverse events have been reported in 157 out of 160 treated patients (98.1%): 
the most frequent all-grade TEAEs (≥16 patients; ≥10% PT) excluding laboratory based AE 
regardless of relatedness to study medication were asthenia (35.6%), corneal events (31.9%), 
peripheral neuropathies (26.9%), decreased appetite (22.5%), diarrhea (21.3%), dyspnea (18.8%), 
nausea (16.9%), constipation (14.4%), abdominal pain (12.5%), cough (11.9%) and vomiting, 
fatigue (10% each). Among the patients who experienced corneal side effect, 32 patients had an 
event that led to dose modification (dose delay [24.4%]), and 1 event led to permanent treatment 
discontinuation. The median duration until recovery of the observed corneal events was 19 days 
(range: 8 to 264 days). The first occurrence of corneal event was within the first 4 cycles of 
treatment for 41 patients (80.4% of patients with corneal event).  
Based on laboratory data, the Grade 3 to Grade 4 hematological abnormalities included anemia in 
8 patients (5.1%), platelets count decrease in 4 patients (2.5%), and no patient with neutropenia. 
Grade 3 to Grade 4 liver enzymes elevation (AST/ALT) was observed in 9 patients (5.7%) and no 
“Hy’s law” cases have been observed in this cohort. 
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The safety and PK of tusamitamab ravtansine administered IV Q2W as monotherapy is being 
further evaluated in Japanese patients with advanced malignant solid tumors in a Phase 1/1b study 
(TCD15054). As of 17 June 2020, 9 patients have been treated in the main dose-escalation phase 
(3 patients at the dose level of 80 mg/m² and 6 patients at the dose level of 100 mg/m²) and 
8 patients in the ongoing loading dose-escalation cohort. In the main escalation phase, TEAEs 
have been reported in 8 patients (88.9%) and 2 (22.2%) of them were reported as Grade ≥3 events. 
Treatment-emergent AEs related to tusamitamab ravtansine were reported in 6 patients (66.7%); 
only 1 patient (11.1%) had a Grade ≥3 treatment-related event (gastrointestinal hemorrhage). One 
patient permanently discontinued study treatment due to an AE (Grade 1 blurred vision event). 
2.1 
STUDY RATIONALE  
In the first-in-human study TED13751, 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) has been treated with tusamitamab ravtansine at the recommended dose of 
100 mg/m² every 2 weeks. In the 64 treated patients, tusamitamab ravtansine showed encouraging 
anti-tumor activity and was associated with a response rate of 20.3% (95% CI: 12.27% to 
31.71%); 28 participants (43.8%) had stable disease. Patients were heavily pretreated with a 
median of 3 prior treatments (1 to 10 lines) for advanced disease, including anti-tubulin agents 
(60.9%) and anti-PD1/PD-L1 (70.3%).   
Tusamitamab ravtansine is being developed in NSQ NSCLC. The randomized Phase 3 EFC15858 
trial is currently ongoing to evaluate the efficacy and the safety of tusamitamab ravtansine versus 
docetaxel in previously treated metastatic NSQ NSCLC patients with CEACAM5-positive 
tumors. The use of combination therapy with tusamitamab ravtansine is also currently being 
studied in 2 Phase 2 trials in patients with NSQ NSCLC in second or third-line and first-line 
settings: tusamitamab ravtansine in combination with ramucirumab in patients with 
CEACAM5-positive tumors previously treated with platinum-based chemotherapy and an 
immune checkpoint inhibitor (Study ACT16525), and tusamitamab ravtansine in combination 
with pembrolizumab as first-line treatment in patients with CEACAM5-positive and 
PD-L1-positive tumors (Study ACT16146).  
Other tumor types also express CEACAM5 in tumor cells. The efficacy and the safety of 
tusamitamab ravtansine will be explored in other indications such as mBC and PAC, for which the 
tumor expresses CEACAM5, and which are also known to be sensitive to antitubulin agents. 
The prevalence of high CEACAM expression (defined as ≥2+ in intensity involving at least 50% 
of the tumor cells) is 10% in all mBC types in which no high expression was identified in the 
primary tumors, 14% in TNBC, and 15% in pancreatic cancer.  
Taxanes are very active agents in the treatment of breast cancer and have shown clinical benefit 
both in the metastatic and (neo) adjuvant settings (4, 5). Nab-paclitaxel in combination with 
gemcitabine is 1 of the 2 recommended combination therapies in first-line treatment for metastatic 
pancreatic cancer (6, 7).   
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The aim of this multi-cohort study is to evaluate the safety and efficacy of tusamitamab ravtansine 
single agent to potentially improve the efficacy with a favorable safety profile in patients with 
mBC and mPAC CEACAM5-positive tumors known as sensitive to taxanes, which are associated 
to a higher hematological toxicity than tusamitamab ravtansine. 
Cohort C has been added to evaluate tusamitamab ravtansine (containing the cytotoxic antitubulin 
agent DM4) in combination with gemcitabine in participants with pancreatic cancer. The 
preliminary results of mPAC monotherapy cohort in this study showed the prevalence of 
CEACAM5 high expression was 42%, so the combination of tusamitamab ravtansine and 
gemcitabine in 2L taxane naïve population may add a new treatment option in pancreatic 
adenocarcinoma, an indication with a high unmet medical need. When participants with mPAC 
were treated with tusamitamab ravtansine monotherapy, DCR was about 29% and long treatment 
duration (4 to 7.5 months) was observed in 8 of 26 patients.  
Gemcitabine is approved as first-line treatment for patients with locally advanced or metastatic 
pancreatic adenocarcinoma. According to National Comprehensive Cancer Network guidelines, 
gemcitabine in combination with nab-paclitaxel remains the preferred option for subsequent 
therapy following fluoropyrimidine-based therapy for mPAC. Substituting tusamitamab 
ravtansine for nab-paclitaxel in a combination regimen with gemcitabine may improve efficacy 
and offer a better safety profile, particularly with regard to hematological toxicity, as compared to 
the combination of gemcitabine and nab-paclitaxel.  
2.2 
BACKGROUND  
Metastatic breast cancer: 
Breast cancer remains the most common cancer type in women, with 271,270 new cases and 
42 750 deaths in the United States (US) in 2019 (9). Overall survival for women with mBC has 
improved over recent decades. Long-term survival, however, remains poor (10, 11), highlighting 
the unmet need for a therapy that is effective, improves quality of life (QoL), and prolongs 
survival.  
Anthracycline- or taxane-based regimens are commonly used in the treatment of breast cancer, 
often in the (neo) adjuvant and first-line metastatic settings (12). Hormonal therapy and human 
epidermal growth factor receptor 2 (HER2) targeted therapy in combination with chemotherapy 
are also standard of care depending on the tumor type. However, treatment decisions in 
subsequent lines are increasingly difficult (13). There is no single accepted standard of care after 
failure of anthracycline and taxane therapy (14). 
Triple-negative breast cancer accounts for 12% to 20% of all breast cancers diagnosed in the US 
(15, 16). Compared to patients with hormone receptor (HR)-positive or HER2-positive tumors 
where average survival exceeds 50 months, survival for women with metastatic TNBC (mTNBC) 
is considerably shorter, ranging from 11 to 17.8 months (17, 18). Triple-negative breast cancer 
carries a poor prognosis. Chemotherapy is the standard of care. More importantly, there is no clear 
standard of care in the second-line setting. Response rates are low (approximately 14% for 
single-agent chemotherapy) and, although they improve with combination therapies, no treatment 
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regimen has demonstrated definitive improvement in outcomes (19). Recent data demonstrate that 
immunotherapy and ADC can improve outcomes. Sacituzumab govitecan, which is an ADC, has 
shown promising anti-cancer activity in patients with mTNBC previously treated with at least two 
prior lines of systemic therapy based on a single-arm Phase 1/2 clinical trial (20, 21). The 
confirmatory Phase 3 ASCENT study exploring sacituzumab govitecan in patients with mTNBC 
has been stopped due to “compelling evidence of efficacy” and the United States Food and Drug 
Administration (FDA) granted accelerated approval. Nevertheless, survival remains poor. There 
remains an unmet medical need for TNBC after first-line chemotherapy treatment (19). 
Pancreatic adenocarcinoma: 
Pancreatic adenocarcinoma is an aggressive gastrointestinal cancer with an estimated annual 
incidence of over 45 000 cases and an expected death toll of over 38 000 deaths in 2013 in the 
US, making it the fourth leading cause of cancer death for both men and women. Five-year 
survival rate is around 6% (22).  
Pancreatic adenocarcinoma is characterized by extensive local growth and early metastasis, 
making surgical control of disease uncommon. As a result, chemotherapeutic agents are often 
employed in an effort to control growth and spread of the cancer, as well as to prolong life and 
maximize function for patients with pancreatic cancer.  
Currently, the preferred first-line therapy options for patients with mPAC include the combination 
therapy of 5-fluorouracil/leucovorin plus oxaliplatin and irinotecan (FOLFIRINOX) and nab-
paclitaxel plus gemcitabine, or single-agent gemcitabine (6). FOLFIRINOX was approved by the 
FDA in 2010 after a large randomized Phase 3 trial showed a significant improvement in OS 
compared with gemcitabine monotherapy (11.1 versus 6.8 months, hazard ratio for death 0.57; 
95%CI 0.45 to 0.73; p <0.001) (23). 
There was an improvement in the duration of OS with nab-paclitaxel in combination with 
gemcitabine (8.5 months) as compared with gemcitabine alone (6.7 months; hazard ratio for death 
0.72; 95% CI 0.62 to 0.83; p <0.001). The response rate was significantly higher with nab-
paclitaxel plus gemcitabine than with gemcitabine alone (23% [95% CI 19 to 27] versus 7% 
[95% CI 5 to 10]; p <0.001) (7). 
For those patients previously treated with fluoropyrimidine-based therapy, the recommended 
second-line options are gemcitabine-based therapy, the combination of 5-fluorouracil, leucovorin, 
and liposomal irinotecan (if no prior irinotecan), or clinical trial participation (6). Second-line 
gemcitabine plus nab-paclitaxel after FOLFIRINOX failure for patients with advanced pancreatic 
cancer could be more effective than gemcitabine alone. The ORR was 13.3%, with a median 
follow-up time of 9.3 months. Median OS and PFS were 7.6 and 3.8 months, respectively (24).   
Despite advances in first-line therapy for mPAC, OS remains poor, and second-line treatments 
remain an unmet medical need; there is currently no optimal treatment for patients whose disease 
progresses after their initial treatment. 
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2.3 
BENEFIT/RISK ASSESSMENT  
The benefit-risk assessment incorporates an evaluation of the key safety and efficacy information 
that is presently available. 
More detailed information about the known and anticipated benefits and risks and reasonably 
expected adverse events of tusamitamab ravtansine may be found in the Investigator’s Brochure 
(IB). Information regarding known and expected benefits and risks for gemcitabine may be found 
in prescribing information for gemcitabine. 
2.3.1 Risk assessment  
Based on the available data, the main important identified risks observed during clinical 
development of tusamitamab ravtansine are corneal toxicity presenting as keratitis/microcystic 
keratopathy, which is reversible and manageable with dose delay and dose reduction in some 
patients. Peripheral neuropathy is an important identified risk in patients previously exposed to 
neurotoxic drugs. These main important identified and potential risks and respective mitigation 
strategies are described in Table 2. Other important potential risks were observed in a limited 
number of patients exposed to tusamitamab ravtasine, and clinical pictures were consistent with a 
presentation in patients with underlying relevant risk factors. These important 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 and local infusion site reactions.  
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Table 2 - Risk assessment  
Main important 
potential risk   
Summary of data/rationale for risk 
Mitigation strategy 
Keratitis/microcystic 
keratopathy 
Preclinical: Mitotic arrest/single cell necrosis was 
observed 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 was 
noted in monkeys. 
Clinical: Identified as a risk during the 
dose-escalation process in the TED13751 study; it 
was the main DLT. In the TED13751 study pooled 
data: among the 160 patients treated at a dose 
level of 100 mg/m2, Q2W, there were 51 patients 
(31.9%) with a corneal TEAE, of which 13 patients 
(8.1%) had events ≥ Grade 3. 
In the TCD15054 study there were 3 patients 
(50%) reported with a corneal TEAE, of which 1 
patient (16.7%) had keratitis and another patient 
(16.7%) had punctate keratitis. 
Careful history and physical 
examination. The monitoring of patients 
for ocular toxicities will be done with 
regular extensive ocular examination.  
No primary prophylaxis is 
recommended but prevention of dry 
eye with artificial tears and avoidance 
of using contact lenses during the 
treatment period.  
Corticosteroids containing ocular drugs 
in case ocular symptoms occur.  
Curative action: dose delay and dose 
reduction in some patients and 
symptomatic treatment; 
ophthalmologist follow-up.  
Peripheral neuropathy 
Preclinical: Nerve fiber degeneration was 
observed in the peripheral nervous system and 
spinal cord in mice and monkeys. 
Clinical: In the TED13751 study among the 
160 patients treated at a dose level of 100 mg/m2, 
Q2W, 43 patients (26.9%) had at least one 
peripheral neuropathy TEAE.  
In the TCD15054 study, of the 6 patients treated at 
a dose level of 100 mg/m2, Q2W, there was 
1 patient (16.7%) with peripheral sensory 
neuropathy. 
Close surveillance of any signs and 
symptoms of peripheral neuropathies.  
Peripheral neuropathies potentially 
presenting as signs and symptoms of 
sensory (paresthesia, dysesthesias, 
pain, change in proprioception), motor 
(weakness), and neural dysfunctions. 
This AE is managed by dose 
delay/reduction as well as treatment 
discontinuation in case of Grade 3-4. 
DLT = dose-limiting toxicity; Q2W = every 2 weeks; TEAE = treatment-emergent adverse event. 
Additional potential risks were observed during preclinical studies and are anticipated to be 
associated with DM4. At this stage of the clinical development a limited number of patients 
presented these adverse reactions and the clinical pictures were consistent with a presentation in 
patients with underlying relevant risk factors. These potential risks included the following: 
• Cardiotoxicity (myocardial or conduction abnormalities) in patients with underlying 
cardiovascular risk factors which are confounding factors. 
• Colitis (including hemorrhagic) in patients with a known history of colitis or 
gastrointestinal tract conditions, which would not be unexpected and is consistent with 
their underlying pathology. 
• Hepatotoxicity in patients with a known history of hepatotoxicity or patients taking 
medications known to cause hepatotoxicity or patients with a history of liver abnormalities 
(symptomatic or asymptomatic). 
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• Hematologic cytopenias in patients with a known history of cytopenias (leucopenia, 
neutropenia, thrombocytopenia, or anemia) due to previous treatment with cytotoxic 
drugs. 
• Local infusion site reactions. 
• Systemic acute hypersensitivity reactions (including anaphylaxis) which is not supported 
by preclinical data but rather by very rare occurrences in clinical development. 
The current data on efficacy and safety obtained in the ongoing studies of tusamitamab ravtansine 
(TED13751 and TCD15054) support its continued clinical development. 
Gemcitabine 
Gemcitabine is a nucleoside metabolic inhibitor indicated as a single agent for the treatment of 
pancreatic cancer. Potential and identified risks associated with gemcitabine in pancreatic cancer 
are summarized here. 
The most common adverse reactions for the single agent (≥20%) are nausea/vomiting, anemia, 
increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), 
neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, 
thrombocytopenia, dyspnea, and edema.  
In a Phase 3 study of efficacy and safety of the combination of nab-paclitaxel and gemcitabine as 
compared to gemcitabine monotherapy in patients with metastatic pancreatic cancer (7), the most 
commonly reported AEs of Grade 3 or higher severity were neutropenia 
(nab-paclitaxel/gemcitabine combination therapy, 38%; gemcitabine monotherapy, 27%), fatigue 
(combination therapy, 17%; monotherapy, 7%), and neuropathy (combination therapy, 17%; 
monotherapy, 1%). Febrile neutropenia occurred in 3% of patients receiving the combination in 
this study, as compared to 1% of the patients receiving gemcitabine alone. 
Safety profile for the combinationof tusamitamab ravtansine with gemcitabine 
Potentially overlapping risks associated with tusamitamab ravtansine and gemcitabine treatment 
are the following:  
• hematologic cytopenias (anemia, neutropenia, or thrombocytopenia) 
• hepatotoxicity (increased ALT, AST, or alkaline phosphatase) 
Given the risks of adverse effects including neutropenia, anemia, and infection associated with 
paclitaxel, the combination of tusamitamab ravtansine with gemcitabine may represent a treatment 
regimen with an improved safety profile as compared to the approved combination of paclitaxel 
and gemcitabine. 
2.3.2 Benefit assessment  
Based on the current data obtained in the ongoing monotherapy studies of tusamitamab ravtansine 
(TED13751 and TCD15054), the perceived balance between the anticipated benefits and the 
reported risks of tusamitamab ravtansine in the treatment of advanced malignancies is acceptable 
and supports the continued clinical development of the agent in other indications, such as mBC 
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and mPAC, that express CEACAM5 on tumor cells and are historically known to be sensitive to 
antitubulin agents, which are associated with significant toxicity.   
2.3.3 Overall benefit:risk conclusion  
Considering the measures taken to minimize risks to participants in this study, the important 
identified and potential risks observed in association with tusamitamab ravtansine and 
gemcitabine are justified by the anticipated benefits that may be afforded to participants with 
mBC and mPAC. To date, the important risks for tusamitamab ravtansine are considered 
manageable based on the risk minimization measures currently utilized in the clinical studies in 
conjunction with Sanofi routine pharmacovigilance activities.  
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3 
OBJECTIVES AND ENDPOINTS  
Table 3 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
For Cohort A, Cohort B, and Cohort C 
Part 2: To assess the antitumor activity 
of tusamitamab ravtansine in mBC and 
tusamitamab ravtansine monotherapy 
and in combination with gemcitabine in 
mPAC 
• 
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 per 
Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 
• 
For Cohort C Part 1: Confirmation of 
the recommended tusamitamab 
ravtansine dose when administered in 
combination with gemcitabine 
• 
Incidence of dose-limiting toxicites (DLTs) in the 28 Day DLT 
observation period (Cycle 1) 
Secondary 
• 
To assess the safety and tolerability of 
tusamitamab ravtansine administered 
as monotherapy and in combination 
with gemcitabine  
• 
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 administered 
as monotherapy and in combination 
with gemcitabine 
• 
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, confirmed PR or 
stable disease as per RECIST v1.1 
• 
Duration of response (DOR), defined as the time from first 
documented evidence of confirmed CR or confirmed PR until 
progressive disease determined per RECIST v1.1 or death from 
any cause, whichever occurs first 
• 
To assess the immunogenicity of 
tusamitamab ravtansine 
• 
Incidence of participants with antitherapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
• 
To assess the pharmacokinetics (PK) 
of tusamitamab ravtansine and 
gemcitabine when given in combination 
• 
Pharmacokinetic parameters of tusamitamab ravtansine and 
gemcitabine 
Tertiary/exploratory 
• 
To explore CEACAM5 expression on 
circulating tumoral cells (CTCs) 
• 
CEACAM5 expression assessment on CTCs from participants 
with positive CEACAM5 expression on tumor tissue 
• 
To explore modulations of circulating 
CEA as a potential pharmacodynamics 
biomarker of response to tusamitamab 
ravtansine treatment and to evaluate 
circulating CEA levels at prescreening 
• 
Circulating CEA at prescreening, baseline and during the 
treatment period 
• 
To assess 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 
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Objectives 
Endpoints 
• 
To explore potential sets of biomarkers 
from tumor DNA and RNA analyses, 
beside target expression, as potential 
biomarkers of response to 
tusamitamab ravtansine treatment  
• 
Biomarker annotation for tumor DNA and RNA at baseline 
 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy 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 Phase 2, open-label, multi-cohort, multi-center study assessing the efficacy (antitumor 
activity), safety, and immunogenicity of tusamitamab ravtansine in the treatment of participants 
with mBC (Cohort A [monotherapy]), mPAC (Cohort B [monotherapy] and Cohort C [in 
combination with gemcitabine]) with CEACAM5-positive tumors (defined as CEACAM5 IHC 
intensity ≥2+ in ≥50% of tumor cells).  
Treatment allocation will be performed using an IRT. After being screened, the eligible 
participants will receive tusamitamab ravtansine as single agent treatment (Cohorts A and B) or in 
combination with gemcitabine (Cohort C) until documented disease progression, unacceptable 
toxicity, new anticancer therapy initiation, or the participant’s or Investigator’s decision to stop 
the treatment.  
In Cohort A and B, participants will receive a tusamitamab ravtansine loading dose at 170 mg/m² 
on Day 1 of Cycle 1, followed by 100 mg/m² Q2W from Cycle 2 and in all other cycles.  
In Cohort C, each treatment cycle will be 28 days (4 weeks). Cohort C will comprise 2 parts:  
Part 1 (Safety Run-In): In Part 1, participants will receive a tusamitamab ravtansine loading 
dose at 170 mg/m² on Day 1, followed by 100 mg/m² every 2 weeks (Q2W); participants also will 
receive gemcitabine 1000 mg/m2 on Day 1, Day 8, and Day 15 every 4 weeks (Q4W). In the case 
that it is decided to reduce the initial loading dose of tusamitamab ravtansine to DL-1 (Table 4), a 
tusamitamab ravtansine loading dose of 135 mg/m2 will be administered to participants on Day 1 
of Cycle 1. 
Table 4 - Dose levels for Part 1 (safety run-in)  
Dose level (DL) 
Tusamitamab ravtansine 
Gemcitabine 
Starting dose 
170 mg/m2 on D1; 100 mg/m2 Q2W thereafter 
1000 mg/m2 on D1, D8, and D15 Q4W 
Minus -1 (DL -1) 
135 mg/m2 on D1; 100 mg/m2 Q2W thereafter 
1000 mg/m2 on D1, D8, and D15 Q4W 
BSA = body surface area; DL -1=dose level -1; Q2W = every 2 weeks; Q4W = every 4 weeks. 
For participants with a BSA >2.2 m2, the tusamitamab ravtansine dose will be calculated based on a BSA of 2.2 m2. 
The starting dose for tusamitamab ravtansine is selected as the maximum tolerated dose (MTD) 
used in studies evaluating tusamitamab ravtansine as loading-dose monotherapy. Enough 
participants will be enrolled in Part 1 to achieve 3 to 12 participants evaluable for DLTs to 
confirm the recommended dose. The tolerability of the combination is assessed in Part 1 
according to the algorithm illustrated in Figure 1. The DLT observation period is the first cycle 
(approximately 28 days). A DLT-evaluable participant must have completed 1 cycle of treatment 
or have been discontinued from study treatment because of a DLT; DLT-nonevaluable 
participants will be replaced. A minimum delay of 1 week is required between the initial dose in 
the first participant treated in a DL cohort and dosing of the next 2 participants treated at the same 
DL. 
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In Part 2 of Cohort C, the recommended dose confirmed in Part 1 will be evaluated for activity in 
24 to 27 additional participants. A total of 30 participants, including participants treated at the 
recommended dose in Part 1, will be evaluated for activity. 
The expected duration of study treatment for participants may vary, based on the progression date 
and cohort; the median expected duration of the study per participant is estimated to be 8 months 
for Cohorts A and C and 6 months for Cohort B (up to 1 month for screening, a median of 4 or 
2 months for treatment in Cohorts A/C and Cohort B, respectively, a median of 1 month for EOT, 
and a follow-up visit 90 days after the last IMP administration). 
Serious adverse events/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 (defined as an event ongoing without any change for at 
least 3 months). A safety follow-up visit will be performed 90 days after the last IMP 
administration. If ongoing IMP-related AEs/SAEs/AESIs are resolved or stabilized, no further 
safety follow-up visit will be needed, otherwise an on-site follow-up visit will be performed every 
12 weeks. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The efficacy and the safety of tusamitamab ravtansine will be explored in indications for which 
the tumor expresses CEACAM5 and which are also known to be sensitive to antitubulin agents 
such as mBC and PAC. 
The prevalence of high CEACAM expression (defined as ≥2+ in intensity involving at least 50% 
of the tumor cells) is 10% in all mBC types in which no high expression was identified in the 
primary tumors, 14% in TNBC, and 15% in pancreatic cancer. 
Assuming a prescreening failure rate of 90% for Cohort A, 85% for Cohort B, and 58% for 
Cohort C, and a screening failure rate of 20% for the 3 cohorts, approximately 440 participants for 
Cohort A, 242 participants for Cohort B, and 90 participants for Cohort C will be prescreened to 
achieve up to approximately 35 treated participants evaluable for activity (at least 1 postbaseline 
tumor assessment, early progression, or death due to progressive disease) in Cohort A, 29 treated 
participants evaluable for activity in Cohort B, and 30 treated participants evaluable for activity in 
Cohort C.  
An interim analysis will be performed when the first 15 treated evaluable participants in Cohort C 
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. For Cohort C, if 1 or 0 confirmed responses are 
observed among these first 15 treated participants, the cohort will be closed. Once 15 participants 
have been treated, the enrollment may be paused until a decision regarding the interim analysis 
can be made. 
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4.3 
JUSTIFICATION FOR DOSE  
In the main dose-escalation phase of the first-in-human study TED13751 exploring 5 to 
150 mg/m2 tusamitamab ravtansine 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 tumors at the membrane (≥2+ in intensity 
involving at least 50% of the tumor cell population) have been treated with tusamitamab 
ravtansine at the recommended dose of 100 mg/m² every 2 weeks. The 64 treated patients showed 
encouraging antitumor activity associated with a response rate of 20.3% (95% CI: 
12.27%-31.71%); 28 (43.8%) had stable disease. An escalation bis cohort using a loading dose is 
ongoing. The recommended dose is 170 mg/m2 at Cycle 1 Day 1 followed by 100 mg/m2 from 
Cycle 2 and will be used in Cohorts A and B in this study. The increase of the initial exposure at 
Cycle 1 may increase the efficacy. 
For Cohort C, the starting dose of tusamitamab ravtansine to be administered in combination with 
gemcitabine will be 170 mg/m² at Cycle 1 Day 1 followed by 100 mg/m2 Q2W. If DLT is 
observed and after discussion with the study committee, the tusamitamab ravtansine dose may be 
decreased to 135 mg/m² at Cycle 1 Day 1 followed by 100 mg/m2 Q2W. The rules for this 
decision are described in Section 6.5.1. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the EOT visit and the Follow-Up visit approximately 90 days after the last IMP 
administration.  
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 trial globally.   
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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 at least 18 years of age (or country’s legal age of majority if 
>18 years), at the time of signing the informed consent.  
Type of participant and disease characteristics 
I 02. Participants with at least one measurable lesion according to the RECIST v1.1 criteria that 
has not been irradiated (ie, newly arising lesions in previously irradiated areas are 
accepted). The lesion must be ≥10 mm in the longest diameter (except lymph nodes, which 
must have short axis ≥15 mm) with computed tomography (CT) (preferred) or magnetic 
resonance imaging (MRI) scans. 
I 03. Participants with ECOG performance status 0 to 1. 
I 04. Evidence of metastatic disease. 
Cohort A: mBC 
I 05. Histological or cytologic diagnosis of breast cancer.  
I 06. Expression of CEACAM5 as demonstrated prospectively by a centrally assessed IHC 
assay of ≥2+ in intensity involving at least 50% of the tumor cell population in archival or 
fresh tumor sample at the metastatic site (mandatory) including distant lymph nodes. At 
least 5 fresh cut slides of formalin-fixed paraffin embedded (FFPE) tumor tissue sectioned 
at a thickness of 4 to 5 µm are required. Cell collections (eg, from pleural effusion) 
processed as FFPE blocks are acceptable. If less material is available, the participant could 
still be considered eligible after discussion with the Sponsor, who may assess and confirm 
that the available material is sufficient for key evaluations. 
I 07. Have received at least 2 prior cytotoxic chemotherapy regimens for non-TNBC tumor type 
or at least 1 for TNBC tumor type but not more than 4 in the locally recurrent or metastatic 
setting. 
I 08. Participants with non-TNBC tumor type (either at primary diagnostic or at metastatic site) 
is defined as any estrogen receptor (ER) and/or progesterone receptor positive (≥1% tumor 
staining by IHC) and/or HER2 positive (IHC [3+] or IHC [2+] and in situ hybridization 
[ISH] positive based on single-probe average HER2 copy number ≥6.0 signals/cell or dual-
probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number ≥4.0 signals/cell) 
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disease status. Participants must be no longer eligible for hormonal therapy or HER2-
targeted therapy. 
I 09. Participants with TNBC tumor type (either at primary diagnostic or at metastatic site) is 
defined as ER/Progesterone receptor negative (<1% tumor staining by IHC), and HER2 
nonoverexpressing by IHC (0, 1+) or ISH-negative based on single-probe average HER2 
copy number <4.0 signals/cell or dual-probe HER2/CEP17 ratio <2.0 with an average 
HER2 copy number <4.0 signals/cell. 
Note: 
1. Adjuvant/neo-adjuvant chemotherapy will be counted as a prior chemotherapy for 
metastatic/recurrent disease if the participant had a progression/recurrence within 
6 months after completion of the treatment. 
2. Prior hormonal, biologic (eg, bevacizumab) or immunotherapy, without a cytotoxic agent, 
are allowed and are not counted as a line of therapy. 
3. A chemotherapy line in advanced/metastatic disease is an anti-cancer regimen that 
contains at least 1 cytotoxic chemotherapy agent and was discontinued due to progression. 
If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease 
progression then this regimen does not count as a “prior line of chemotherapy” unless this 
regimen was discontinued after at least 2 cycles of treatment. 
Cohorts B and C: mPAC 
I 10. Have confirmed diagnosis of pancreatic ductal adenocarcinoma.  
I 11. Expression of CEACAM5 as demonstrated prospectively by a centrally-assessed IHC 
assay of ≥2+ in intensity involving at least 50% of the tumor cell population in archival 
tumor sample (or, if not available, a fresh biopsy sample). At least 5 fresh cut slides of 
FFPE tumor tissue sectioned at a thickness of 4 to 5 µm are required. Cell collections (eg, 
from pleural effusion) processed as FFPE blocks are acceptable. If less material is 
available, the participant could still be considered eligible after discussion with the 
Sponsor, who may assess and confirm that the available material is sufficient for key 
evaluations. 
Cohort B: mPAC 
I 12. Cohort B: Have documented radiographic progression or documented intolerance after at 
least 1 prior systemic chemotherapy line which included either gemcitabine (or relapsed 
within 6 months of completion of gemcitabine adjuvant therapy) or a 5-fluorouracil based 
regimen (including capecitabine) but no more than 2 prior chemotherapy lines for locally 
advanced/metastatic disease. 
  
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Sex 
I 13. All (male and female) 
Contraceptive use by men or 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 tusamitamab ravtansine, and 
at least 6 months after the last dose of gemcitabine:  
• Refrain from donating sperm 
Plus either:  
• 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 
• 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 one 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 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 (urine or serum as 
required by local regulations) before the first dose of study intervention. 
• Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2 (Section 10.2) 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 14. Capable of giving signed informed consent as described in Appendix 1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.  
Criterion added in amended protocol (only for participants in Cohort C) 
I 15. Have documented radiographic progression or documented intolerance after 1st line 
fluoropyrimidine-containing chemotherapy (or relapsed within 6 months of completion of 
chemotherapy as adjuvant therapy) for locally advanced/metastatic disease. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Medical condition requiring concomitant administration of a medication with a narrow 
therapeutic window, that is metabolized by cytochrome P450 (CYP450) (see Appendix 10; 
Section 10.10), and for which a dose reduction cannot be considered. 
E 02. Medical conditions requiring concomitant administration of strong CYP3A inhibitor 
(see Appendix 10; Section 10.10), unless it can be discontinued at least 2 weeks before the 
first administration of study intervention. 
E 03. Life expectancy less than 3 months. 
E 04. Untreated brain metastases or history of leptomeningeal disease. Participants with 
previously treated brain metastases may participate provided that: 
- 
they are stable (ie, without evidence of progression by imaging for at least 4 weeks 
prior to the first administration of study treatment, and any neurologic symptoms have 
returned to baseline); 
- 
there is no evidence of new or enlarging brain metastases; 
- 
and the participant does not require any systemic corticosteroids to manage brain 
metastases within 3 weeks prior to the first dose of study intervention.  
E 05. 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 06. 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.  
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E 07. History of known acquired immunodeficiency syndrome (AIDS) related illnesses or 
known human immunodeficiency virus (HIV) disease requiring antiretroviral treatment, or 
active hepatitis A, B (defined as either positive HBsAg or positive hepatitis B viral 
deoxyribonucleic acid [DNA] test above the lower limit of detection of the assay), or C 
(defined as a known positive hepatitis C antibody result and known quantitative hepatitis C 
virus [HCV] RNA results greater than the lower limits of detection of the assay) infection. 
HIV serology will be tested at screening only for participants enrolled in any country 
where mandatory per local requirements.  
E 08. Non-resolution 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).  
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. Participants using contact lenses who are not willing to stop wearing 
them for the duration of the study intervention are excluded. 
Prior/concomitant therapy 
E 11. Concurrent treatment with any other anti-cancer therapy. 
E 12. 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).  
E 13. Any prior therapy targeting CEACAM5. 
E 14. Prior maytansinoid DM4 treatment (ADC). 
E 15. Any major surgery within the preceding 3 weeks of the first study intervention 
administration. 
Prior/concurrent clinical study experience 
E 16. Previous enrollment in this study or current participation in any other clinical study 
involving an investigational study treatment or any other type of medical research. 
Diagnostic assessments 
E 17. Poor renal function as defined by serum creatinine >1.5 × upper limit of normal (ULN) or 
1.0 to 1.5 × ULN with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² as 
estimated using a modification of diet in renal disease (MDRD) formula. 
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E 18. Poor hepatic function as defined by total bilirubin >1.5 × ULN (except participants with 
Gilbert's syndrome, for whom total bilirubin ≤3.0 × ULN with direct bilirubin ≤1.5 × ULN 
is allowed). 
E 19. Poor hepatic function as defined by AST, ALT, or alkaline phosphatase (AP) >2.5 × ULN, 
except participants with liver metastases for whom AST, ALT, or AP ≤5 × ULN is allowed 
or participants with bone metastases for whom AP ≤5 × ULN is allowed. 
E 20. Poor bone marrow function as defined by neutrophils <1.5 × 109/L or platelet count 
<100 × 109/L or hemoglobin <9 g/dL (no blood and blood product transfusion within 
2 weeks before screening). 
Other exclusions 
E 21. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 22. Any country-related specific regulation that would prevent the participant from entering 
the study - see Appendix 8 (Section 10.8) of the protocol for country-specific 
requirements. 
E 23. 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 24. 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 Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH)-Good Clinical Practice (GCP) 
Ordinance E6). 
E 25. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 26. 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. 
Criterion added in amended protocol (only for participants in Cohort C) 
E 27. Any previous systemic therapy with taxane or gemcitabine (for Cohort C only). 
 
5.3 
LIFESTYLE CONSIDERATIONS  
No restrictions are required. 
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5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure reasons, 
eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) and for 
whom resolution of the screen failure may not be expected within a reasonable time frame, the 
screen failure will be recorded. Individuals who do not meet the criteria for participation in this 
study (screen failure) may be rescreened. Rescreened participants should be assigned a different 
participant number to the initial screening, and all the screening procedures will be repeated and 
entered in the screening visit pages. In case the participant is a temporary screen failure and 
requires prolongation of the screening period, there is no need to have participant re-consent 
(ie, new ICF signed) if the participant finally participates in the trial. However, if the reason for 
the temporary screen failure is one that might have altered the participant’s initial given 
agreement to participate, the Investigator should ensure the willingness of the participant to 
continue or redo some screening procedures and his/her participation to the trial. This oral 
agreement should be documented in the participant’s chart. All the tests out of protocol window 
should be repeated and entered to the additional pages. The participants who will be rescreened 
after this period need to resign new screening ICF; there will be no re-prescreening for 
CEACAM5 expression and the initial value will be applicable, with respect to maximum allowed 
window for prescreening. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT  
During a regional or national emergency declared by a governmental agency, the Investigator/site 
should assess the site’s capacity to conduct procedures for a new participant to be enrolled into the 
study before initiating any screening procedures. Site capacity also should be ensured before 
randomization of a participant. If the site is unable to adequately follow protocol mandated 
procedures, contingency measures proposed in Appendix 9 (Section 10.9) should be applicable to 
prescreening/screening/enrollment/administration of study treatment. 
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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. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 5 - Overview of study interventions administered  
Intervention 
label 
tusamitamab ravtansine (SAR408701) 
gemcitabine 
Intervention 
name 
tusamitamab ravtansine (SAR408701) 
gemcitabine 
Type 
Drug 
Drug 
Dose 
formulation 
Concentrated solution for IV 
lyophilized powder for reconstitution for IVa 
Unit dose 
strength(s) 
5 mg/mL 
not applicable 
Dosage level(s) 
Loading dose 170 mg/m2 (or 135 mg/m2 only for Cohort 
C) over 1 hour 30 minutes on Day 1 of Cycle 1 
Other doses 100 mg/m2 Q2W  
For participants with a BSA >2.20 m², the dose will be 
calculated based on a BSA of 2.20 m² 
1000 mg/m² over 30 minutes on Day 1, 
Day 8, and Day 15, Q4W  
Route of 
administration 
IV infusionb 
IV infusionb 
Use 
experimental 
experimental 
IMP or NIMP 
IMP 
IMP  
Packaging and 
labeling 
Supplied in a 30 mL glass vial containing 125 mg/25 mL 
tusamitamab ravtansine (SAR408701). Packaging is in 
accordance with the administration schedule. The 
content of the labeling at vial and box level is in 
accordance with the local regulatory specifications and 
requirements.  
Per specifications for locally 
available/marketed source, where local 
sourcing is possible 
Current/Former 
name(s) or 
alias(es) 
Not applicable 
As per locally marketed formulation  
a. For locally sourced IMP, if the recommended formulation is not available. Local approved formation can be used after confirmed with the 
Sponsor.  
b. Infusion via a central line is preferred (line will be flushed before infusion), if available. Prior to dosing, each participant's dose will be 
individually prepared by the study pharmacist and labeled with protocol number, participant number, and treatment description.  
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Table 6 - Arms and associated interventions  
Arm name 
Cohort A (mBC) 
Cohort B (mPAC) 
Cohort C (mPAC) 
Associated interventions 
(intervention label[s]) 
Tusamitamab ravtansine 
(SAR408701) 
Tusamitamab ravtansine 
(SAR408701) 
Tusamitamab ravtansine 
(SAR408701) + 
gemcitabine 
 
After the study cut-off date for the secondary efficacy endpoints (see Section 9.3.1), 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. 
Noninvestigational medicinal product (NIMP): Premedication for tusamitamab ravtansine 
Tusamitamab ravtansine (SAR408701) has a potential risk of infusion-related reaction and 
premedication should be used. All the drugs used as premedication will be entered to the 
concomitant premedication page. 
Premedication with a histamine H1 antagonist (oral diphenhydramine 50 mg or equivalent 
[eg, dexchlorpheniramine] given approximately 15 minutes to 1 hour before tusamitamab 
ravtansine (SAR408701) administration depending on the administration form - IV or oral 
[15 minutes prior for IV and 1 hour prior for oral]) is required for all participants before the 
administration of tusamitamab ravtansine (SAR408701). If a participant has experienced an 
infusion reaction following previous tusamitamab ravtansine (SAR408701) 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. 
Premedication for gemcitabine: Antiemetic preventive therapy must be given according to ASCO 
guidelines and the local practice. Gemcitabine is known as a low-emetic-risk antineoplastic agent. 
According to ASCO anti-emetics guidelines updated on May 6th, 2020, adults treated with low-
emetic-risk antineoplastic agents should be offered a single dose of a 5-HT3 receptor antagonist or 
a single 8◦mg dose of dexamethasone before antineoplastic treatment (8). 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
A complete description of the IMPs and their proper handling will be provided in a Pharmacy 
Manual available at the investigational site.  
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. 
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4. 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. 
5. 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). 
6. Further guidance and information for the final disposition of used and unused study 
interventions are provided in the pharmacy manual and/or monitoring plan. 
Any quality issue noticed with the receipt or use of an IMP (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.  
6.4 
STUDY INTERVENTION COMPLIANCE  
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the study site staff. 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. 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 date and time of each 
dose administered in the clinic will be recorded in the source documents and recorded in the case 
report form (CRF). Deviation(s) from the prescribed dosage regimen should be recorded in the 
electronic case report form (eCRF). 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.  
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6.5 
DOSE MODIFICATION  
6.5.1 Determination of recommended dose for Cohort C  
During Part 1 of Cohort C, recommended dose of tusamitamab ravtansine in combination with 
gemcitabine will be determined according to the DLTs observed in participants according to the 
algorithm shown in Figure 1: 
• If 0/3 participants experiences a DLT at the starting loading dose, the starting loading dose 
will be RP2D. 
• If 1/3 participants experiences a DLT at the starting dose, the next 3 participants of the 
combination arm will be treated at the same DL to confirm the tolerability of the 
combination at the starting dose.  
- 
If ≤1/6 participants treated at the starting dose experiences a DLT, the starting dose 
will be the RP2D. 
- 
If ≥2/6 participants treated at the starting dose experience a DLT, the dose will be  
de-escalated to DL-1 for the next 3 participants of the combination arm. 
• If ≥2/3 participants experience a DLT at the starting dose, the dose will be de-escalated to 
DL-1 for the next 3 participants of the combination arm. 
- 
If ≤1/3 participants treated at the DL-1 experiences a DLT, the next 3 participants of 
the combination arm will be treated at the same DL to confirm the tolerability of the 
combination at DL-1. 
- 
If ≤1/6 participant treated at the DL-1 experiences a DLT, the DL-1 will be the 
RP2D. 
- 
If ≥2/6 participants treated at the DL-1 experience a DLT, an alternative dosage 
might be considered or the study part may be stopped. 
- 
If ≥2/3 participants treated at DL-1 experience a DLT, an alternative dosage might be 
considered or the study part may be stopped.  
The tolerability of the combinations will be assessed in 3 to 12 participants depending on DLTs 
observed. Dose modification and dose schedules are shown in Table 4. The Study Committee will 
review clinical data regularly during the study (Section 10.1.5). The dosage decision for the 
combination will be made during this meeting. Definitions of DLTs are provided in Table 7. 
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Table 7- Dose-limiting toxicities  
Hematological abnormalities 
Grade 4 neutropenia for 7 or more consecutive days. 
Grade 3 to 4 neutropenia complicated by fever (temperature ≥38.5°C on more than 1 occasion) or microbiologically or 
radiographically documented infection 
Grade ≥3 thrombocytopenia associated with clinically significant bleeding requiring clinical intervention 
Nonhematological abnormalities 
Grade 4 nonhematologic AE 
Grade ≥3 keratopathy 
In addition, any other AE that the recruiting Investigators and Sponsor deem to be dose limiting, regardless of its grade, may 
also be considered as DLT. 
Abbreviations: AE = adverse event; DLT = dose-limiting toxicity. 
All AEs specified in Table 7 occurring during the first cycle of treatment, unless due to disease 
progression or to a cause obviously unrelated to IMP, will be considered DLTs. During the DLT 
evaluation period in the safety run-in part, IMPs can be delayed but not omitted; the DLT 
evaluation period will be prolonged in such cases. The duration of the DLT observation period 
will be longer for a participant who delays initiation of Cycle 2 due to a treatment-related AE for 
which the event’s duration would determine whether the AE meets the definition of a DLT. The 
DLTs will be confirmed by the Study Commitee. The severity of AEs will be assessed according 
to NCI CTCAE Version 5.0. Causal relationships are to be determined by the Investigator.  
6.5.2 
Individual dose adjustment/dose delay: Cohort A, Cohort B and Cohort C Part 2  
Dose adjustment and/or cycle delays are permitted in case of adverse reactions. In case of toxicity, 
cycle delays and dose modifications should be implemented according to 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 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. 
All changes to study treatment administration must be recorded in the eCRF. 
In the event of neutropenia, therapeutic granulocyte colony-stimulating factor (G-CSF) should be 
administered according to the current American Society of Clinical Oncology (ASCO) guidelines 
(25). In the event of neutropenia or febrile neutropenia, prophylactic G-CSF should be started, and 
in the event of a second episode beside prophylactic G-CSF, the dose should be reduced 
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(Section 10.6).  The acceptable treatment window is ±2 days for Cohort A and B and ±3 days for 
Cohort C. 
One dose reduction of tusamitamab ravtansine and 2 dose reductions of gemcitabine are allowed 
during the conduct of the study for safety reasons. If a second dose reduction of tusamitamab 
ravtansine is considered necessary, this will be decided on a case-by-case basis following 
discussion with the Sponsor. In the event of a dose reduction, the study intervention will be 
administered as shown in Table 8. Dose delays are allowed for safety management. Retreatment 
of participants that requires more than a 1 month dose delay must be justified following a 
case-by-case risk benefit assessment (see Section 6.5.3). See Table 15 in Appendix 10.6 for 
guidance on dose modification or discontinuation.  
Table 8 - Dose modification for toxicity  
Drug name 
Dose 
1st dose reduction 
2nd dose reduction 
tusamitamab ravtansinea 
100 mg/m2 Q2W 
80 mg/m2 Q2W 
(not permitted) 
gemcitabine 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
a Dose modification is applicable from Cycle 2. The loading dose will remain 170 mg/m2  (or 135 mg/m2 in Cohort C).  
If appropriate, and if in the opinion of the Investigator, the toxicity is related to 1 of the 2 drugs 
(tusamitamab ravtansine or gemcitabine) instead of the combination, and more than 1 cycle delay 
is needed, the unrelated drug can be continued, and the related drug may be omitted if the delay 
exceeds 7 days, upon discussion with the Sponsor, and administration resumed at following 
recovery from the toxicity to Grade ≤1. If the toxicity is related to the combination, both agents 
should be reduced (if applicable), omitted, or definitively discontinued according to the 
recommended dose modifications (Section 10.6). If 1 of the 2 drugs (tusamitamab ravtansine or 
gemcitabine) is prematurely permanently discontinued, the other drug can be continued until 
disease progression.  
6.5.3 Retreatment criteria  
All participants entered into the study will be treated at Day 1 of each cycle, and participants in 
Cohort C, also at Day 8 and Day 15 of each cycle. A participant may receive additional study 
interventions if he/she meets the retreatment criteria as determined by the Investigator and agrees 
to be retreated.  
For the retreatment of all participants on Day 1 (or, for Cohort C, on Day 15) 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  
• Hemoglobin ≥9 mg/dL 
• Total bilirubin ≤1.5 × ULN (except participants with Gilbert's syndrome, for whom total 
bilirubin ≤3.0 × ULN with direct bilirubin ≤1.5 × ULN is allowed) 
• AST, ALT ≤2.5 × ULN or ≤5 × ULN in case of documented liver metastasis 
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• No IMP-related toxicity Grade >1 (except for alopecia) or baseline severity. 
For the treatment of participants on Day 8 of each cycle in Cohort C, the participant must meet all 
of the following criteria to be eligible for retreatment: 
• Neutrophil count ≥1 × 109/L 
• Platelets ≥75 × 109/L  
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
After the end of the study (see definition in Section 4.4), interventions should be decided by the 
Investigator per clinical practice. 
6.7 
TREATMENT OF OVERDOSE  
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Sponsor or Sponsor representative(s) immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Obtain a plasma sample for PK analysis if requested by the Sponsor or Sponsor 
representative(s) (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor or Sponsor representative(s) based on the clinical evaluation of the 
participant. 
6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
The Sponsor or Sponsor representative(s) should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the participant’s welfare and are unlikely to interfere with the IMP, they 
may be given at the discretion of the Investigator and recorded in the eCRF. Concomitant 
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medication will be recorded in the eCRF from 28 days prior to the first study intervention 
administration, before every cycle during the study treatment period, and for up to 30 days after 
the final dose of study intervention. Once the participant has withdrawn from study treatment, 
concomitant medication should only be recorded if used to treat new or unresolved study 
treatment-related adverse events. 
Concomitant medication may be considered on a case-by-case basis by the Investigator, in 
accordance with the following guidelines:  
• Palliative radiotherapy may be given for control of pain for palliative intents. Approval 
should be obtained from the Sponsor prior to initiating treatment if palliative radiotherapy 
is being considered, and prior to resuming therapy on the study. The irradiated area should 
be as small as possible and should never involve more than 20% of the bone marrow in 
any given 3-week period. In all such cases, the possibility of tumor progression should be 
ruled out by physical and radiological assessments of the tumor. If the only evaluable 
lesions are to be irradiated, the participant will stop the study intervention. The irradiated 
area cannot be used as a parameter for response assessment. 
• Any background therapy taken by the participant for concomitant illnesses other than 
cancer (eg, 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 concomitant treatments are not permitted during this study: 
• Concurrent treatment with other investigational drugs. 
• Concurrent treatment with any other anti-cancer therapy not specified in the protocol, 
including immunotherapy, hormonal therapy, targeted therapy or biological therapies. 
• The primary prophylactic use of Granulocyte-Colony Stimulating Factor is not allowed 
during the first cycle but secondary prophylaxis or therapeutic administration is allowed. 
• The use of prophylactic erythropoietin during the first cycle.  
• Participants treated or intended to be treated with drugs presented as CYP substrates with a 
narrow therapeutic range should be carefully monitored (See Section 10.10). 
• Concomitant use of strong CYP3A inhibitors should be avoided from 2 weeks before 
tusamitamab ravtansine administration up to the last tusamitamab ravtansine 
administration (See Section 10.10). 
• The use of contact lenses will not be permitted during the study treatment period. 
6.8.1 Rescue medicine  
Not applicable. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
   
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
The study intervention should be continued until the confirmed progression of disease whenever 
possible. Permanent study intervention discontinuation before disease progression should be 
discussed with the Investigator. Any study intervention discontinuation must be fully documented 
in the eCRF. 
If study intervention is permanently discontinued, the participant will remain in the study for 
tumor assessments as described in Section 8.1.  
Study intervention should be discontinued in any of the following cases: 
• At the participant’s request, at any time and irrespective of the reason (consent’s 
withdrawal), or at the request of their legally authorized representative. “Legally 
authorized representative” is considered to be an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective participant to the 
patient’s participation in the procedure(s) involved in the research.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the participant’s well-being, such as:  
- 
Unacceptable AE. 
- 
Confirmed disease progression. 
- 
Poor compliance to the study protocol. 
- 
Other, such as concurrent illness, that prevents further administration of study 
intervention. 
• Participant is lost to follow-up. 
• Sponsor decision to discontinue the study. 
See Appendix 6 (Section 10.6) for more details on discontinuation. 
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
      
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE/SAE/AESI to 
be followed-up as specified in this protocol, whichever comes last. 
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If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including 
tumor assessment, safety laboratory test, and immunogenicity sample, if appropriate. 
All cases of definitive 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). For all temporary intervention 
discontinuations, the duration should be recorded by the Investigator in the appropriate pages of 
the eCRF.  
7.1.2.1 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator has considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely and if the retreatment 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 Appendix 9 (Section 10.9). 
During a regional or national emergency declared by a governmental agency, reinitiation of IMP 
after temporary discontinuation can occur only once the Investigator has determined, according to 
his/her best judgment, that the participant would likely benefit from continued study treatment, 
and the IMP(s) was unlikely to contribute to the occurrence of an event of epidemic 
(eg, COVID-19 [COVID-19]). The Investigator should discuss the restart of IMP after prolonged 
cycle delay with the Sponsor or Sponsor’s representative(s). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an EOT 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. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
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• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
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 participate 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 and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. 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) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• During the screening period demography and medical/surgical/disease history will be 
evaluated. Demography includes age, gender, race, and ethnicity. Medical/surgical/disease 
history includes histologic types, stage at diagnosis, disease extent at study entry and 
specific mutations.  
• CEACAM5 expression status (archival or fresh tumor tissue) and circulating CEA will be 
evaluated during prescreening period after prescreening informed consent is signed. Once 
the participants are confirmed to have positive CEACAM5 tumors, they can continue with 
screening procedures. 
• After the study cut-off date for the primary analysis (see Section 9.3.1), participants will 
continue to undergo all assessments as per the SoA (Section 1.3). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
8.1 
EFFICACY ASSESSMENTS   
All efficacy endpoints are based on tumor assessments. The schedule of tumor assessments is 
provided in the SoA (Section 1.3). Tumor assessments will be done at screening, and then every 
8 weeks (±7 days) until EOT, and then every 12 weeks until progressive disease, new anti-cancer 
therapy, death, withdrawal of participant’s consent, or study cut-off date for secondary efficacy 
endpoints, whichever comes first. The scheduled assessment time point will not be modified in the 
event of a cycle delay. 
The tumor assessment method per RECIST v1.1 is detailed in Section 10.11. Chest, abdominal, 
pelvic CT-scan or MRI and any other examinations as clinically indicated will be performed to 
assess disease status. 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 the past 4 weeks. Bone 
CT-scan or MRI and other examinations should be performed if clinically indicated. Brain 
CT-scan or MRI should be performed at baseline and followed during treatment only for 
participants with brain lesions at baseline. 
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Imaging assessments are to be scheduled using the Cycle 1, Day 1 date as the reference for all 
time points and are not to be scheduled based on the date of the previous imaging time point. 
Imaging assessment delays to conform to treatment delays are not permitted. The same tumor 
assessment technique must be used throughout the study for a given lesion/participant. 
Objective response rate will be determined by the proportion of participants with confirmed CR or 
PR. ORR per RECIST v1.1 is the primary endpoint of this study and PFS, DCR, and DOR per 
RECIST v1.1 are secondary endpoints. Objective response rate will be derived based on 
Investigator review at each time point at which a response assessment occurred using the 
RECIST v1.1 (see Section 10.11).  
8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, central nervous systems, hepatomegaly, 
splenomegaly, and lymphadenopathy.  
• Height (at screening only) and weight will also be measured and recorded. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new adverse 
event. 
8.2.2 Vital signs  
• Temperature and blood pressure will be assessed. 
• Blood pressure will be assessed with a completely automated device. Manual techniques 
will be used only if 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). 
8.2.3 Electrocardiograms  
• Single 12-lead electrocardiogram (ECG) 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, QT, and QTc intervals.  
• ECG is to be repeated as clinically indicated. This test can be performed before the study 
intervention administration on the same day or the day before. 
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8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition. Laboratory abnormalities are to be recorded as AEs only if they 
lead to treatment discontinuation and/or dose modification and/or fulfill a seriousness 
criterion and/or are defined as an AESI.  
• 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 or Sponsor or Sponsor representative(s). 
- 
If such 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 assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA.  
- 
If laboratory values from non-protocol specified laboratory assessments 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 in the CRF.  
8.2.5 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 
for inclusion of a female participant with an early undetected pregnancy. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
monthly intervals during intervention (at study visits and if needed, at home in between 
visits). 
• Pregnancy testing (urine or serum as required by local regulations) must be conducted 
corresponding with the time frame for female participant contraception in Section 5.1. 
• 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. 
8.2.6 Performance status  
Performance status will be evaluated using ECOG scale (26). 
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8.2.7 Specific ocular test  
Standard specific ocular tests include: 
• Assessment of ocular/visual symptoms, (ie, blurred vision, photophobia, dry eye, etc) 
• Visual acuity 
• Slit lamp under dilatation 
• Schirmer’s test 
Standard specific ocular tests are planned at screening and EOT but can also be performed 
whenever clinically indicated. Assessment of ocular/visual symptoms should be performed at each 
visit before each study intervention. 
In participants with any ocular/visual symptom(s) (eg, blurred vision, photophobia) the complete 
ocular tests will be repeated at the time of the occurrence of the ocular toxicity, if any, regardless 
of the grade. Then, visual acuity, slit-lamp examination under dilatation, and Schirmer’s test will 
be repeated once weekly (if not recommended to have less frequent assessments by the 
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. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3 (Section 10.3). The definition of AESI is provided in Section 8.3.8. Adverse events 
will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (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).   
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs and SAEs will be collected from the signing of the screening ICF until the follow-up visit 
at the time points specified in the SoA (Section 1.3). During prescreening, 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. 
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All SAEs and AESIs 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 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  
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). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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/AESIs and 
IMP-related AEs (as defined in Section 8.3.8), 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 a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Adverse events that are considered expected will be specified in the reference safety 
information (refer IB).  
• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days. 
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- 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor. 
• An Investigator who receives an Investigator safety report describing a 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 dose 
of study intervention. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy of female participant or female partner of male participant (after 
obtaining the necessary signed informed consent from the female partner). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
• 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 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 
study participants /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. 
8.3.6 Cardiovascular and death events  
Cardiovascular events will be treated as regular events.  
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not Applicable.  
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8.3.8 Adverse event of special interest  
Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by a 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 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 Section 8.3.5). 
• Grade ≥3 keratopathy. 
• Bundle branch blocks or any conduction defects. 
• Grade ≥3 liver enzyme increased (symptomatic or asymptomatic). 
• Symptomatic overdose (serious or non-serious) 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.  
• Dose-limiting toxicity as defined in Section 6.5.1. 
8.3.9 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. 
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8.3.10 Guidelines for managing specific adverse events  
8.3.10.1 Hypersensitivity reactions  
Premedication treatments provided for treatment of hypersensitivity reactions are detailed in 
Section 6.1. 
8.3.10.2 Ocular toxicity  
It is recommended that topical artificial tears (and/or hyaluronic ophthalmic gel) are used 
regularly in all participants treated with tusamitamab ravtansine during the study treatment period.  
The participant 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 according to the SoA (Section 1.3). If ocular symptoms are present before IMP 
infusion, then a formal ocular examination should be performed. In participants with any 
ocular/visual symptom(s) (eg, blurred vision, photophobia, etc), the ocular evaluation should be 
repeated once weekly unless less frequent assessment is recommended by the ophthalmologist 
based on lesion characteristics, until resolution to Grade 1. 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 the ophthalmologist when applicable. 
8.3.10.2.1 Keratopathy/keratitis management  
Reversible non-inflammatory, microcystic keratopathy was identified as the DLT during the 
dose-escalation phase in the TED13751 study with tusamitamab ravtansine. At slit-lamp 
examination, it presents as lesions consisting of 100s to 1000s microcysts and/or deposits that are 
initially observed at the periphery of the cornea, the limbus being preserved. The lesions have a 
centripetal distribution and evolve towards the center of the corneal upon resolution, following the 
natural keratinocyte regeneration process. 
For standardization of AE verbatim, keratopathy should be a PT unless otherwise specified by the 
ophthalmologist due to inflammatory findings on eye exams leading to the diagnosis of keratitis. 
The potential ocular/visual toxicity symptoms could include, but are not limited to, blurred vision, 
dry eye, and photophobia. Curative treatment may be used as recommended by an 
ophthalmologist. 
No primary prophylaxis is recommended but prevention of dry eye with artificial tears and 
avoidance of using contact lenses should be ensured during the treatment period. 
Corticosteroid-containing ocular drugs are recommended in case ocular symptoms occur for the 
management of keratopathy/keratitis; treatment will be performed at the discretion of the 
ophthalmologist. Dose modification and recommendations are further described in Table 15. 
Grade ≥3 keratopathy should be reported as AESI. 
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8.3.10.3 Management of anemia  
Participants should not start Cycle 1 of treatment if hemoglobin levels are <9.0 mg/dL. Red blood 
cell transfusion is allowed during the screening window, but a 2-week washout period should be 
applied. During the treatment, erythrocyte transfusion can be given, upon Investigator decision. 
Erythropoietin can be given at the discretion of the Investigator, except during screening and 
Cycle 1. Current clinical practice should be followed for the management of anemia. 
8.3.10.4 Management of neutropenia  
In participants who experienced either febrile neutropenia or neutrophil count <1000 cells/mm3 
for more than one week during study intervention, prophylactic G-CSF should be implemented to 
ensure dose intensity and the dose should be reduced in case of recurrent events even after 
prophylactic G-CSF use.  
If the participant continues to experience these reactions at a lower dose, treatment should be 
discontinued as described in Section 7.1.1. 
Dose modification and discontinuation recommendations are further described in Appendix 6 
(Section 10.6). 
8.3.10.5 Liver function tests  
Hepatic enzyme increase has been reported with tusamitamab ravtansine monotherapy. 
Participants should be carefully followed and in the event of Grade ≥3 abnormal liver function 
tests, additional liver function tests will be done every 2 to 3 days until recovery to the baseline 
value. Tusamitamab ravtansine should be permanently discontinued in the event of drug-induced 
Grade 4 liver enzyme increase.  
Grade ≥3 liver enzymes increase events should be reported as AESIs. 
Drug-induced liver injury, including liver failure and death, has been reported in patients 
receiving gemcitabine alone or with other potentially hepatotoxic drugs. Administration of 
gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of 
hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic 
insufficiency. Assess hepatic function prior to initiation of gemcitabine and periodically during 
treatment. Permanently discontinue gemcitabine in patients who develop severe hepatic toxicity. 
8.3.10.6 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 Section 10.6.  
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8.3.10.7 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. Cycle delays or modifications for symptoms of colitis should be compliant with 
Section 6.5. 
8.3.10.8 Management of thrombocytopenia  
Gemcitabine can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, 
and anemia, and myelosuppression is usually the DLT. Patients should be monitored for platelets 
during therapy.  
Dose modification and discontinuation recommendations are further described in Appendix 6 
(Section 10.6). 
8.3.10.9 Pulmonary toxicity and respiratory failure  
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and 
adult respiratory distress syndrome (ARDS), has been reported with gemcitabine. In some cases, 
these pulmonary events can lead to fatal respiratory failure despite the discontinuation of therapy. 
The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine. 
Permanently discontinue gemcitabine in patients who develop unexplained dyspnea, with or 
without bronchospasm, or evidence of severe pulmonary toxicity. 
8.3.10.10 
Hemolytic uremic syndrome  
Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for 
dialysis, can occur with gemcitabine. In clinical trials, HUS occurred in 0.25% of 2429 patients. 
Most fatal cases of renal failure were due to HUS. Serious cases of thrombotic microangiopathy 
other than HUS have been reported with gemcitabine. 
Assess renal function prior to initiation of gemcitabine and periodically during treatment. 
Consider the diagnosis of HUS in patients who develop anemia with evidence of 
microangiopathic hemolysis; increased bilirubin or LDH; reticulocytosis; severe 
thrombocytopenia; or renal failure (increased serum creatinine or BUN). Permanently discontinue 
gemcitabine in patients with HUS or severe renal impairment. Renal failure may not be reversible 
even with the discontinuation of therapy. 
8.3.10.11 
Capillary leak syndrome  
Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving 
gemcitabine as a single agent or in combination with other chemotherapeutic agents. Permanently 
discontinue gemcitabine if CLS develops during therapy. 
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8.3.10.12 
Posterior reversible encephalopathy syndrome  
Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving 
gemcitabine as a single agent or in combination with other chemotherapeutic agents. PRES can 
present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and 
neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI). 
Permanently discontinue gemcitabine if PRES develops during therapy. 
8.4 
PHARMACOKINETICS  
Blood samples will be collected for the measurement of tusamitamab ravtansine (SAR408701), 
gemcitabine and its metabolite (dFdU) concentrations as described in the PK/ATA flowcharts 
(Section 1.3.3). The actual date and time of each sample will be recorded. Instructions for the 
collection and handling of PK samples will be provided by the Sponsor’s designee in a separate 
laboratory manual. These samples will be tested by the Sponsor or Sponsor’s designee. 
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. 
8.4.1 Noncompartmental analysis  
Pharmacokinetic parameters of SAR408701, gemcitabine, and dFdU will be calculated using 
noncompartmental methods from concentrations obtained after administration assayed in the first 
10 participants. The parameters will include, but may not be limited to, those listed in Table 9.   
Table 9 - List of pharmacokinetic parameters and definitions  
Analyte 
Cycle/Day 
Parameter 
Definition 
tusamitamab ravtansine 
1/1 
Cmax 
Maximum concentration observed after infusion 
 
 
AUC0-14d 
Area under the plasma concentration versus time curve 
calculated using the trapezoidal method from time 0 to 14 days. 
gemcitabine 
1/1 
CL 
Total body clearance of a drug from plasma calculated using the 
following equation from AUC: CL=dose/AUC 
dFdU 
1/1 
Cmax 
Maximum concentration observed after infusion 
 
8.4.2 Population approach  
Data from plasma concentrations of tusamitamab ravtansine may be used for population PK 
analysis by nonlinear, mixed-effects modeling. Empirical Bayesian estimation of individual 
exposure parameters such as maximum concentration (Cmax), trough concentration (Ctrough), and 
area under the curve (AUC) will be derived. The population PK analysis will be reported in a 
standalone report (s). 
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8.5 
GENETICS  
8.5.1 Circulating tumor DNA analysis  
A 20 mL blood sample corresponding to about 10 mL of plasma for tumor circulating free 
deoxyribonucleic acid (cfDNA) isolation and an additional 2 mL blood sample for germline DNA 
will be collected at pre-infusion of Cycle 1 Day 1. 
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 circulating tumor DNA or 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. 
The 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, and TP53. 
8.5.2 Tumor DNA and RNA analyses  
Although tumor CEACAM5 expression is a major parameter driving the activity of an anti-
CEACAM5 ADC such as tusamitamab ravtansine, other factors may significantly contribute. 
Tumor tissue will therefore also be requested to explore the potential relationship between clinical 
endpoints following tusamitamab ravtansine therapy and potential sets of biomarkers besides 
target expression that could be predictive of response. 
For that purpose, 3 × 10 μm slides (or equivalent such as 6 × 5 μm or other) from the same sample 
as the one sent for CEACAM5 assessment at prescreening are requested at screening or Cycle 1 
Day 1. 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 (mRNA and miRNA), and proteomic 
profiling. 
See Appendix 5 (Section 10.5) 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  
Samples collected for biomarker analyses and their derivatives will be stored for a period of up to 
15 years after last participant last visit for potential re-analyses. 
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8.6.1 Pharmacodynamics  
Circulating carcinoembryonic antigen (CEA) levels will be collected at prescreening, baseline, 
during the treatment (every 8 weeks), EOT, and follow-up period (every 12 weeks) at the time of 
laboratory assessment as close as possible to tumor assessment (and no more than 2 weeks from 
the tumor assessment) until confirmed disease progression. It will be assessed using local testing. 
Venous blood samples of approximately 3 mL (volume may change depending on local laboratory 
assay) will be collected for measurement at the local laboratory. 
8.6.2 Other 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 and assayed for CEACAM5 expression to 
determine eligibility for this study. For mBC, a tissue sample collected at the 
metastatic site is mandatory. For mPAC, a tissue sample collected at the metastatic site 
is preferable but primary tumor samples are also accepted. 
- 
Additionally, for mBC and if available, 3 × 5-µm slides from the surgery material at 
the breast cancer diagnosis (primary tumor or local lymph nodes) are requested for 
CEACAM5 assessment.  
- 
Blood sample will be collected for CTC detection to assess the expression of 
CEACAM5 on these cells (optional for Cohort A and Cohort B). 
- 
Blood sample will be collected for IgG dosage to explore impact of IgG level on PK of 
tusamitamab ravtansine (only for Cohort C). 
• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in a separate laboratory manual. 
• The level of CEACAM5 expression in tumor tissues will be determined by a central 
laboratory using a specific anti-CEACAM5 antibody (clone 769). 
Assessment of CTC at pre-infusion of Cycle 1 Day 1 will be determined by a central laboratory. 
For this test, 10 mL of blood will be collected. Samples will be taken from approximately 
5 participants per Cohort (Cohorts A and Cohort B). 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Blood samples will be collected for assessing the presence of ATA against tusamitamab 
ravtansine in plasma from all participants as described in SoA (Section 1.3). These samples will 
be tested by the Sponsor’s designee. The remaining plasma volume may also be used for further 
investigations (including pharmacokinetic assessment) if deemed relevant.  
Refer to the laboratory manual for details regarding sample collection, processing, storage, and 
shipment.  
Plasma samples will be screened for antibodies binding to tusamitamab ravtansine and the titer of 
confirmed positive samples will be reported.  
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8.8 
HEALTH ECONOMICS  
No health economics data will be collected. 
8.9 
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. 
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  
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. 
9.1 
SAMPLE SIZE DETERMINATION  
Assuming a prescreening failure rate of 90% for the mBC Cohort A, 85% for mPAC Cohort B, 
and 58% for mPAC Cohort C, and a screening failure rate of 20% for the 3 cohorts, 
approximately 440 participants for the mBC Cohort A, 242 participants for the mPAC Cohort B, 
and 90 participants for mPAC Cohort C will be prescreened to achieve up to approximately 
35 treated participants evaluable for activity (at least 1 postbaseline tumor assessment, early 
progression, or death due to progressive disease) for the mBC Cohort A, 29 treated participants 
evaluable for activity for mPAC Cohort B, and 30 participants evaluable for activity in mPAC 
Cohort C. 
For Cohort C safety run-in (Part 1), the actual sample size is expected to vary depending on DLTs 
observed. It is anticipated that around 3 to 12 DLT-evaluable participants will be enrolled. 
Table 10 and Table 11 list the estimated ORRs and 95% exact CIs by the numbers of responders 
from a sample size of 35 treated participants evaluable for activity for the mBC cohort, 29 treated 
participants evaluable for activity for mPAC cohort, and Table 12 lists the estimated ORRs and 
CIs 30 treated participants evaluable for activity for combination cohort. 
Table 10 -
 
 
 
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Table 11 -
 
    
Table 12 - 
  
 
 
9.2 
POPULATIONS FOR ANALYSES  
The following populations are defined in Table 13: 
Table 13 - Populations for analyses  
Population 
Description 
Prescreened 
All participants who signed the prescreening informed consent for CEACAM5 assay 
assessment of their biopsy. 
Screened 
All participants who signed screening informed consent for study participation. 
DLT-Evaluable (Cohort C Part 1)  
Participants who received 1 cycle with at least 80% of the intended dose for tusamitamab 
ravtansine at each of the first 2 infusions and gemcitabine at each of the first 3 infusions 
unless they discontinued the study intervention before the end of Cycle 1 due to a DLT. 
All-treated  
All registered participants exposed to the study treatment, regardless of the amount of 
treatment administered. This population is the primary population for all efficacy 
parameters. 
Activity 
All treated participants who have measurable disease at study entry and at least one post-
baseline evaluable tumor assessment. Participants with no post-baseline 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. 
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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 safety population. 
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. 
 
9.3 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
9.3.1 General considerations  
This study is designed to obtain preliminary efficacy and safety data on the use of tusamitamab 
ravtansine administered to participants with CEACAM5-positive tumors known to be sensitive to 
anti-tubulin agents at a loading dose of 170 mg/m² on Day 1 of Cycle 1, followed by 100 mg/m² 
Q2W for Cohorts A and B, and at a loading dose of 170 mg/m² (or 135 mg/m²) on Day 1 of 
Cycle 1, followed by 100 mg/m² Q2W, combined with gemcitabine 1000 mg/m² on Day 1, Day 8, 
and Day 15 every 4 weeks (Q4W), for Cohort C.   
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; 95% CIs will be provided for the primary and secondary 
efficacy endpoints. Each cohort will be analyzed separately. 
All efficacy analyses will be performed on the All-treated population (primary population for all 
efficacy parameters). In addition, the primary endpoint (ORR as per RECIST v1.1) and DCR will 
be analyzed on the activity population (secondary population). Objective response rate, as well as 
PFS, DCR and DOR, will be derived using the local radiologist’s/Investigator’s assessment. 
The study cut-off for the primary analysis (ORR) for each cohort corresponds to the date on which 
all treated evaluable participants of the cohort 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 
PK 
All treated participants with at least 1 postbaseline PK result with adequate documentation 
of dosing and sampling dates and times. 
ATA 
All treated participants with at least one post-baseline ATA result (negative, positive, or 
inconclusive). 
CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; ATA = antittherapeutic antibodies. 
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post-baseline tumor assessment, it will also include the confirmatory assessment. An interim 
analysis will be performed when the first 15 treated evaluable participants in Cohort C have had at 
least 2 postbaseline tumor assessments, experienced confirmed objective response, or have 
discontinued the study for any reason. Once 15 participants have been treated, enrollment may be 
paused until a decision regarding the interim analysis can be made. 
The analysis cut-off date for secondary efficacy endpoints including DOR and PFS (final cut-off 
date) will be 6 months after the cut-off date of the primary analysis. The primary analysis of ORR 
and DCR will also be updated at that time. 
All safety analyses will be performed on the All-treated population. Summaries of safety data will 
be provided by participant. For each safety parameter, the baseline value will be defined as the 
latest value or measurement taken before the first administration of the IMP.  
The observation period will be divided into 4 segments: 
• The prescreening period is defined as the time from when the participants give 
prescreening informed consent to the day before the screening informed consent. 
• The screening period is defined as the time from when the participants give screening 
informed consent to the first administration of the IMP. 
• The treatment period is defined as the time from the first administration of IMP up to 
30 days after the last administration of IMP. 
• The post-treatment period is defined as the time from the 31st day after the last 
administration of IMP to study closure or death, whichever occurs first. 
9.3.2 Primary endpoint(s)  
The primary efficacy endpoint is the ORR. The ORR will be estimated by dividing the number of 
participants with confirmed objective response (CR or PR as best overall response [BOR]), 
determined according to RECIST v1.1, by the number of participants from the analysis 
population.  
The BOR is the best tumor response observed from the date of first IMP administration until 
disease progression, death, cut-off date or initiation of post-treatment anti-cancer therapy, 
whichever occurs first. 
ORR will be summarized for the All-treated population with descriptive statistics. In addition, 
2-sided 95% CIs will be computed using the Clopper-Pearson method. 
ORR will also be summarized on the activity population as a supplementary analysis. 
A primary endpoint for Part 1 of Cohort C is DLTs observed during the 28 day DLT observation 
period (Cycle 1); incidences of DLTs will be summarized on the DLT-evaluable population, by 
dose level. In addition, AEs that meet the DLT criteria in subsequent cycles will be summarized 
on the all-treated population. Details will be provided by participant. 
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9.3.3 Secondary endpoint(s)  
The safety and efficacy secondary endpoints include safety, PFS, DCR, DOR per RECIST v1.1, 
PK and immunogenicity. 
9.3.3.1 Adverse events  
Adverse events will be collected from the time prescreening informed consent is signed until at 
least 30 days after the last infusion of the study treatment. All AEs will be categorized according 
to NCI-CTCAE v5.0 and classified by SOC and PT according to the latest available version of the 
medical dictionary for regulatory activities (MedDRA). 
• Prescreening AEs are defined as AEs occurring during the prescreening period. 
• Screening AEs are defined as any AEs occurring during the screening period. 
• Treatment-emergent AEs are defined as AEs that develop, worsen (according to the 
Investigator’s opinion), or become serious during the treatment period.  
• Post-treatment AEs are defined as AEs that are reported during the post-treatment period.  
The NCI-CTCAE grade will be taken into account in the summary of AEs. For participants with 
multiple occurrences of the same PT, the maximum grade will be used. 
The primary focus of AE reporting will be on TEAEs. Prescreening, screening, and post-treatment 
AEs will be described separately. 
Treatment-emergent adverse events: 
An overall summary of TEAEs will be provided. The number and percentage of participants 
experiencing any of the following will be provided: 
• TEAEs 
• Grade ≥3 TEAEs 
• Grade 5 TEAEs (any TEAE with a fatal outcome during the treatment period) 
• Serious TEAEs 
• TEAEs leading to definitive treatment discontinuation 
• Treatment-related TEAEs 
• Treatment-related Grade ≥3 TEAEs 
• Serious treatment-related TEAEs 
• AESI 
The number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE v5.0 grade (all grades and Grade ≥3) for the All-treated population. 
Similar summaries will be prepared for treatment-related TEAEs, TEAEs leading to definitive 
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discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, 
AESIs, and AEs/SAEs occurring during the post-treatment period. In addition, the number and 
percentage of participants with any Grade 5 AE (TEAE and post-treatment) will be summarized.  
9.3.3.2 Deaths  
The following deaths summaries will be generated: 
• Number and percentage of participants who died by study period (treatment, post-
treatment) and reasons for death (disease progression, AE, or other reason). 
• Deaths in registered but not treated participants. 
• All TEAEs leading to death by primary SOC and PT showing the number and percentage 
of participants. 
9.3.3.3 Clinical laboratory evaluations  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
Hematology and clinical chemistry results will be graded according to the NCI-CTCAE v5.0, 
when applicable. The number and percentage of participants with laboratory abnormalities (all 
grades and by grade) using the worst grade during the treatment period will be summarized for the 
All-treated population.  
When the NCI-CTCAE v5.0 grading scale is not applicable, the number of participants with a 
laboratory abnormality out-of-normal range value will be displayed. 
9.3.3.4 Progression-free survival  
Progression-free survival is defined as the time from the date of first IMP administration to the 
date of the first radiological documentation of progressive disease according to RECIST v1.1 or 
death due to any cause before the analysis cut-off date, whichever occurs first.  
The analysis of PFS will be based on the following censoring rules: 
• If progression or death is not observed before the cut-off date and prior to the initiation of 
a further anti-cancer therapy, then PFS will be censored at the date of the last valid tumor 
assessment performed before the analysis cut-off date or date of initiation of a further anti-
cancer therapy, whichever is earlier. 
• A participant without an event (death or disease progression) and without any valid post-
baseline tumor assessment will be censored at the day of first IMP administration (Day 1). 
Progression-free survival will be summarized on the All-treated population using Kaplan-Meier 
methods. The median PFS time and associated 95% CI will be provided along with probabilities 
of being progression-free at different time points. 
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9.3.3.5 Disease control rate  
The DCR will be estimated by dividing the number of participants with confirmed objective 
response or stable disease (CR or PR or stable disease as BOR), determined according to 
RECIST v1.1, by the number of participants from the analysis population. 
The DCR will be summarized for the All-treated population with descriptive statistics. In 
addition, 2-sided 95% CIs will be computed using the Clopper-Pearson method. 
Disease control rate will also be summarized on the activity population as a supplementary 
analysis. 
9.3.3.6 Duration of response  
The DOR will be defined as the time from the date of first initial occurrence of the confirmed CR 
or PR to the date of first radiological documentation of progressive disease according to 
RECIST v1.1 before the initiation of any post-treatment anti-cancer therapy or death due to any 
cause, whichever occurs first. 
In the absence of disease progression or death before the cut-off date, DOR will be censored at the 
date of the last valid tumor assessment performed before the analysis cut-off date or date of 
initiation of new anti-cancer therapy, whichever is earlier. Duration of response will be 
summarized with descriptive statistics using Kaplan-Meier methods. The median DOR and 
associated 95% CI will be provided. 
The DOR will only be summarized on the subgroup of participants who have achieved confirmed 
objective response in the All-treated population. 
9.3.3.7 Immunogenicity  
Immunogenicity analyses and the potential impact on safety and efficacy will be described in the 
statistical analysis plan (SAP); analyses will be performed on the ATA population. 
9.3.3.8 Pharmacokinetics  
Pharmacokinetic analyses are described briefly in Section 8.4.1, and will be described in the 
statistical analysis plan.  
The population PK methodology is described briefly in Section 8.4.2, and will be described in a 
separate report provided by the Pharmacokinetics, Dynamics, and Metabolism (PKDM) Modeling 
and Simulation group. 
9.3.4 Tertiary/exploratory endpoint(s)  
Biomarker analyses will be described in the SAP.  
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9.3.5 Other analyses  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
9.4 
INTERIM ANALYSES   
An interim analysis based on the number of responses observed in the Activity population for the 
cohort of patients with metastatic pancreatic cancer will be performed. 
The cut-off date for the interim analysis corresponds to the date when the first 15 treated 
evaluable participants in Cohort C who have had at least 2 postbaseline tumor assessments or 
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. Approximately 
up to 20 participants may be enrolled to reach the 15 treated evaluable participants, if needed. 
For Cohort C, if 1 or 0 confirmed response is observed among the first 15 treated participants 
evaluable for activity, the cohort will be closed. 
The statistical analysis plan will describe the planned interim analyses in greater detail. 
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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 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 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
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- 
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 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 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, Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• 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 
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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 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).  
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 and 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. 
Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response/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.  
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• 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. 
• 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.  
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• 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 
e-mail, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
The SC includes the Investigators or designees and Sponsor team members and, when 
appropriate, ad hoc experts. Decisions to continue the enrollment at a DL or to reduce the dose to 
be tested will be made after the appropriate data are collected and reviewed by the SC. The SC 
will convene regularly (eg, every 2 weeks) during Part 1 of Cohort C; and may meet ad hoc for 
specific discussions. Meeting minutes will be documented. 
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 patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to https://vivli.org. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
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privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address:https://vivli.org. 
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 “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. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• 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 
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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 (SD). The 
Investigator/delegated site staff will report all the original data in the participant’s medical 
chart or in a study specific SD created by him/her. If such document is used, the template 
should be reviewed by the CRA. A list of SD and their location will be filed in the 
Investigator Study File. 
• 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 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. 
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. 
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- 
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 multi-center 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 14 will be performed by the local laboratory with the exception 
of CEACAM5 immunohistochemistry, CTC evaluation (optional), ATA, cfDNA/Germline 
DNA, and tumor DNA/RNA analysis, 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. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• Pregnancy testing (urine or serum as required by local regulation) should be conducted in 
all WOCBP at Screening, then every 4 weeks from Cycle 2, 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). Additionally, during the 
treatment period, serum/urine pregnancy tests will be performed at the beginning of the 
visit every 4 weeks. 
 
 
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Table 14 - Protocol-required laboratory tests  
 
Laboratory assessments 
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 
 
Potassium 
 
Sodium 
 
Calcium 
 
Phosphate  
 
Chloride  
 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
 
Lactate dehydrogenase (LDH) 
 
Glucose 
 
Alkaline phosphatase 
 
Total and direct bilirubin 
 
Albumin 
 
Total protein 
 
Circulating carcinoembryonic antigen (CEA) 
Other screening tests 
• 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)c 
• 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg] or hepatitis B viral 
DNA, and hepatitis C virus antibody or HCV RNA) if applicable as per local 
regulatory requirement 
• 
CEACAM5 expression status on tumor tissue 
• 
CEACAM5 expression on CTCs in blood (Cycle 1 Day 1 pre-infusion) – optional 
• 
cfDNA/Germline DNA analysis 
• 
Tumor DNA/RNA analysis 
• 
ATA 
All study-required laboratory assessments will be performed by a local laboratory, with the 
exception of CEACAM5 expression, cfDNA/Germline DNA analysis, tumor DNA/RNA 
analysis, and ATA. The results of each test must be entered into the CRF 
NOTES: 
a If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 x 109/L. 
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b Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are given 
in Section 8.3.10.5. All events of ≥ Grade 3 ALT/AST increase must be reported as an AESI. Investigators must document their review of 
each laboratory safety report. 
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
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 non-serious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, or emergency room visit, or visit to/by a health care provider). The 
participant 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. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during interview with participant and by review of available medical 
records at the next visit. 
• Solicited AEs are pre-defined 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  
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- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• 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. 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 which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
An SAE is defined as any adverse event that, at any dose: 
a) Results in death 
c) 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. 
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d) 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. 
e) 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) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
f) 
Is a congenital anomaly/birth defect 
g) Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
h) 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. 
- 
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 
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- 
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 1 of the following categories according to NCI-CTCAE v5.0. 
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. 
• 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. 
• The Investigator will use clinical judgment to determine the relationship. 
• 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 IB and/or Product Information, for marketed 
products, in his/her assessment. 
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• 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. 
• 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 post-mortem 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 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the Investigator study file. 
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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 CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator study file. 
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. 
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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 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/RNA 
• 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 
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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 
advanced solid tumor and related diseases. They may also be used to develop tests/assays 
including diagnostic tests related to CEACAM5 targeting drug and advanced solid tumor. 
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. 
• 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/RNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
10.6 
APPENDIX 6: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS  
Table 15 - Recommended dose modification or discontinuation for tusamitamab ravtansine  
Event 
Symptoms 
severity 
(NCI-CTCAE 
v5.0) 
Dose modification 
(tusamitamab 
ravtansine) 
Dose modification 
(gemcitabine) 
Supportive care 
guidelines 
Infusion-related 
reaction  
Grade 1-2 
eg, Grade ≤2 
nausea, headache, 
tachycardia, 
hypotension, rash, 
shortness of breath. 
Interrupt tusamitamab 
ravtansine infusion. 
Tusamitamab ravtansine 
may be resumed only 
after participant 
recovery, at half the 
previous infusion ratea. 
Interrupt gemcitabine 
infusion and start 
appropriate treatment.  
 
Reduce infusion rate by 
50% 
Give diphenhydramine 
50 mg IV and/or 
dexamethasone 
10 mg IV.  
Dexamethasone can 
be added as 
premedication for 
upcoming cycles for 
tusamitamab 
ravtansine 
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Event 
Symptoms 
severity 
(NCI-CTCAE 
v5.0) 
Dose modification 
(tusamitamab 
ravtansine) 
Dose modification 
(gemcitabine) 
Supportive care 
guidelines 
Grade 3-4 
eg, symptomatic 
bronchospasm, 
urticaria lesions 
covering >30% BSA, 
hypotension, 
angioedema. 
Interrupt tusamitamab 
ravtansine infusion and 
definitively discontinue 
tusamitamab ravtansine. 
Interrupt gemcitabine 
infusion and definitively 
discontinue gemcitabine 
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 
tusamitamab 
ravtansine 
Grade 1 
Asymptomatic, 
Corneal lesions only 
observed on routine 
ocular examination 
and not requiring 
topical treatment. 
Next infusion of 
tusamitamab ravtansine 
at the same dose, with 
or without cycle delay, 
depending on the 
recommendation from 
the ophthalmologist 
(nature and extent of the 
lesion). 
Administer gemcitabine 
as planned 
Standard ocular 
examination is 
planned as 
recommended by the 
ophthalmologist. 
 
Grade 2 
Symptomatic, 
moderate decrease 
in visual acuity (best 
corrected visual 
acuity 20/40 and 
better or 3 lines or 
less decreased vision 
from known baseline) 
1st episode: tusamitamab 
ravtansine cycle delay 
until resolution to 
Grade 1 (asymptomatic) 
and restart tusamitamab 
ravtansine at the same 
dose. 
2nd episode: delay cycle 
until resolution to Grade 
1 (asymptomatic) and 
tusamitamab ravtansine 
dose reduction. 
Administer gemcitabine 
the same day as 
tusamitamab ravtansine 
Standard ocular 
examination weekly 
until resolutionc d. 
Start curative 
treatment per 
ophthalmologist 
recommendation.  
After resuming study 
treatment, participant 
should be followed 
with standard ocular 
examination by every 
two cycles, even 
asymptomatic during 
next four cycles. If no 
recurrence, standard 
process with follow-up 
with ocular symptom 
is resumed.  
Management of study 
drug and follow-up 
process upon 
recurrence to be 
discussed according 
to Grade of the event 
at recurrence, clinical 
benefit from study 
drug and 
recommendation from 
the ophthalmologist.  
Grade 3 
Symptomatic with 
marked decrease in 
visual acuity (best 
corrected visual 
acuity worse than 
20/40 or more than 3 
lines of decreased 
vision from known 
baseline, up to 
20/200); corneal 
ulcer; limiting 
self-care ADL. 
1st episode: tusamitamab 
ravtansine cycle delay 
until resolution 
(asymptomatic) and 
restart tusamitamab 
ravtansine with dose 
reduction. 
2nd episode: definitive 
discontinuation of 
tusamitamab ravtansine.  
Administer gemcitabine 
as planned if definitive 
discontinuation of 
tusamitamab ravtansine 
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Event 
Symptoms 
severity 
(NCI-CTCAE 
v5.0) 
Dose modification 
(tusamitamab 
ravtansine) 
Dose modification 
(gemcitabine) 
Supportive care 
guidelines 
 
Grade 4 
Perforation, best 
corrected visual 
acuity of 20/200 or 
worse in the affected 
eye 
Definitive 
discontinuation of 
tusamitamab ravtansine. 
 
Administer gemcitabine 
as planned.  
Complete the corneal 
examination as 
recommended by 
ophthalmologist. 
Repeat the standard 
ocular examination 
weeklyc until 
resolutiond. 
Start curative 
treatment per 
ophthalmologist 
recommendation.  
Conduction disorder 
associated with 
tusamitamab 
ravtansine 
Grade 1 
Mild symptoms 
tusamitamab ravtansine 
administration to be 
continued upon decision 
by the Investigator and 
Sponsor, depending on 
the nature of the 
conduction disorder. 
No action 
ECG performed once 
weekly until event 
resolution. 
Additional evaluations 
such as LVEF and 
Holter monitoring 
should be performed 
when relevant. 
Grade ≥2 
Definitive 
discontinuation of 
tusamitamab ravtansine. 
No action 
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. 
Grade≥3 
Definitive 
discontinuation of 
tusamitamab ravtansine. 
Decrease gemcitabine 
to next lower dose level 
per Table 8  
Grade≥4 
Definitive 
discontinuation of 
tusamitamab ravtansine. 
Definitive 
discontinuation of 
gemcitabine 
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Event 
Symptoms 
severity 
(NCI-CTCAE 
v5.0) 
Dose modification 
(tusamitamab 
ravtansine) 
Dose modification 
(gemcitabine) 
Supportive care 
guidelines 
Neutrophil count 
decreased 
Grade 1 
<LLN-1500/mm3 ; 
<LLN-1.5 × 109/L 
No change in 
tusamitamab ravtansine 
administration. 
No change in 
gemcitabine 
administration 
No intervention. 
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 change in 
gemcitabine 
administration 
No intervention. 
Grade 3 
<1000-500/mm3; 
<1.0-0.5 × 109/L 
Or 
Grade 4 (≤7 days) 
<500/mm3; 
<0.5 × 109/L 
Delay the cycle. 
Restart the treatment 
when ANC ≥1500/mm3 
at the same dose on the 
same day as 
gemcitabine (only for 
Cohort C). Prophylactic 
G-CSF can be 
considered in all 
subsequent cycles 
Delay the cycle and 
administer on the same 
day as tusamitamab 
ravtansine when 
ANC ≥1500/mm3 on 
Day 1 and Day 15, until 
ANC ≥1000/mm3 on 
Day 8, at dose reduced 
per Table 8  
Administer prophylactic 
G-CSF and in all 
subsequent cycles. 
Follow ASCO 
guidelines on usage 
G-CSF and 
antibiotherapy (25). 
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 
tusamitamab ravtansine 
at reduced dose 
3rd episode: definitive 
discontinuation 
1st episode: Delay the 
cycle and administer on 
the same day as 
tusamitamab ravtansine 
when ANC ≥1500/mm3 
on Day 1 and Day 15, 
until ANC ≥1000/mm3 
on Day 8, at dose 
reduced per Table 8  
Administer prophylactic 
G-CSF and in all 
subsequent cycles. 
2nd episode: Delay the 
cycle and administer on 
the same day as 
tusamitamab ravtansine 
when ANC ≥1500/mm3 
on Day 1 and Day 15, 
until ANC ≥1000/mm3 
on Day 8, and decrease 
2 dose levels per 
Table 8. Administer 
prophylactic G-CSF and 
in all subsequent 
cycles. 
3rd episode: definitive 
discontinuation 
Follow ASCO 
guidelines on usage of 
G-CSF and 
antibiotherapy (25). 
Repeat the test every 
3 days.  
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Event 
Symptoms 
severity 
(NCI-CTCAE 
v5.0) 
Dose modification 
(tusamitamab 
ravtansine) 
Dose modification 
(gemcitabine) 
Supportive care 
guidelines 
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 
tusamitamab ravtansine 
at reduced dose 
3rd episode: definitive 
discontinuation  
1st episode:  
Delay the cycle and 
administer when 
ANC ≥1500/mm3 on 
Day 1 and Day 15, until 
ANC ≥1000/mm3 on 
Day 8, and decrease to 
next lower dose level 
per Table 8  
Administer prophylactic 
G-CSF and in all 
subsequent cycles. 
2nd episode: Delay the 
cycle and administer 
when ANC ≥1500/mm3 
on Day 1 and Day 15, 
until ANC ≥1000/mm3 
on Day 8, and decrease 
2 dose levels per 
Table 8 (to 600 mg/m2) 
Administer prophylactic 
G-CSF and in all 
subsequent cycles. 
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 (25). 
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  
1st episode: Delay the 
administration until 
ANC ≥1500/mm3 on 
Day 1 and Day 15, until 
ANC ≥1000/mm3 on 
Day 8, and decrease to 
next lower dose level 
per Table 8.  
Administer prophylactic 
G-CSF and in all 
subsequent cycles. 
2nd 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 (25). 
Thrombocytopenia 
Grade 1 
Platelets <LLN-
75 000/mm3; 
<LLN-75.0 × 109/L 
Delay until 
platelets ≥100.0 × 109/L. 
Restart at the same 
dose. 
Delay the administration 
until 
platelets ≥100.0 × 109/L 
on Day 1 and Day 15, 
administer gemcitabine 
as planned on Day 8. 
Restart at the same 
dose. 
No intervention. 
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Event 
Symptoms 
severity 
(NCI-CTCAE 
v5.0) 
Dose modification 
(tusamitamab 
ravtansine) 
Dose modification 
(gemcitabine) 
Supportive care 
guidelines 
Grade 2 
Platelets 
<75 000-50 000/mm3; 
<75.0-50.0 × 109/L 
Delay until recovery of 
platelets ≥100.0 × 109/L. 
Restart at the same 
dose. 
Delay the administration 
until 
platelets ≥100.0 × 109/L 
on Day 1 and Day 15, 
until 
platelets ≥75.0 × 109/L 
on Day 8, and decrease 
to next lower dose level 
per Table 8. 
No intervention. 
Grade≥3 
Platelets 
<50 000/mm3; 
<50.0 × 109/L 
Administration changes 
to be decided at the 
Investigator’s discretion. 
1st episode: administer 
next cycle at reduced 
dose or definitively 
discontinue  
2nd episode: definitive 
discontinuation  
1st episode: Delay the 
administration until 
platelets ≥100.0 × 109/L 
on Day 1 and Day 15, 
until 
platelets ≥75.0 × 109/L 
on Day 8, and decrease 
to next lower dose level 
per Table 8. 
2nd episode: definitive 
discontinuation.  
Additional hematology 
tests will be done 
every 2-3 days until 
recovery to baseline 
value. 
Platelet transfusions 
can be considered per 
clinical practice. 
Hepatic enzyme 
increase 
Grade 1-2 
Administer tusamitamab 
ravtansine as planned. 
Administer gemcitabine 
as planned 
No intervention. 
Grade 3 
Delay the cycle. 
Restart the treatment 
until recovery to Grade 
1. 
Withhold gemcitabine 
until recovery to 
Grade 1 and decrease 
to next lower dose level 
per Table 8  
Additional liver 
function tests will be 
done every 2-3 days 
until recovery to 
baseline value. 
Grade 4 
Tusamitamab ravtansine 
should be permanently 
discontinued. 
Gemcitabine 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  
No action  
Participant who has 
ongoing grade 1 
neuropathy has high 
risk of worsening of 
his/her symptoms and 
should be closely 
followed.  
Grade 2 
Moderate symptoms; 
limiting instrumental 
Activities of Daily 
Living  
Delay cycle, dose 
reduction if no 
improvement with dose 
delay  
No action  
Grade 3 
Severe symptoms; 
limiting self-care 
Activities of Daily 
Living  
Definitive 
discontinuation  
 
No action  
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Event 
Symptoms 
severity 
(NCI-CTCAE 
v5.0) 
Dose modification 
(tusamitamab 
ravtansine) 
Dose modification 
(gemcitabine) 
Supportive care 
guidelines 
Grade 4 
Life-threatening 
consequences; 
urgent 
Definitive 
discontinuation 
No action  
Hemorrhage 
Grade 3 
Definitive 
discontinuation 
Decrease gemcitabine 
to next lower dose level 
per Table 8  
 
Grade 4 
Definitive 
discontinuation 
Definitive 
discontinuation of 
gemcitabine 
ASCO = American Society of Clinical Oncology, ASOCT = Anterior segment optical coherence, BSA = Body surface area, 
ECG = Electrocardiogram, G-CSF = Granulocyte colony-stimulating factor, Hb = Hemoglobin, IMP = Investigational medicinal product, 
IV = Intravenous; LLN = Lower limit of normal, LVEF = Left ventricular ejection fraction, NCI-CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events, RBC = Red blood cell. 
a Tusamitamab ravtansine is stable at least 7.5 hours in the infusion bag at room temperature. If necessary, a new infusion should be prepared 
with the remaining dose to be administered. 
b The NCI-CTCAE v5.0 grading is to be applied to keratopathy. 
c Standard ocular examination per protocol includes visual acuity, slit-lamp examination, Schirmer’s test, and enquiring for ocular/visual 
symptoms. 
d When possible at the site, photographs should be done when findings are first documented and to follow progression when relevant. Any 
additional relevant ocular examination can be done if indicated. 
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  
Not applicable. 
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 9.3.5, 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 
prescreening/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 prescreening process  
If there is no other way to conduct prescreening procedures during a regional or national 
emergency declared by a governmental agency (eg, due to a COVID-19 pandemic), the site may 
consider implementing a remote prescreening 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 prescreening is planned to be implemented at site:  
• The Investigator/delegate should contact each participant to inquire regarding the 
participant’s willingness to participate in the prescreening process. 
• If participant agrees to prescreening, the Investigator/delegate should send the 
prescreening ICF via e-mail to the participant’s personal e-mail address (as allowed by 
local regulation) or by postal mail. The Investigator/delegate should provide an overview 
of the study (eg, tusamitamab ravtansine mechanism of action; design of the study in terms 
of treatment groups, visits, and prescreening procedures; and rationale for assessment of 
CEACAM5 expression). The Investigator/delegate should respond to any question raised 
by a participant, and this correspondence should be documented in detail in the 
participant’s source file. 
• If a participant agrees to participate in the prescreening phase, the participant should print 
out, sign, and date 2 copies of the ICF. A scan of a signed ICF should be sent via secured 
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 prepare and send the slides for CEACAM5 
assessment. 
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 on-site status, if needed, Cycle 1 and Cycle 2 weekly safety laboratory assessment 
for Cohorts A and B (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 or legally authorized 
representative should be informed verbally prior to initiating any change that is to be implemented 
for the duration of the emergency (eg, study visit delays, use of back-up sites for safety laboratory 
or tumor assessment). 
 
10.10 APPENDIX 10: CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE AND 
STRONG CYP3A INHIBITORS  
Table 16 - List of CYP substrates with narrow therapeutic range  
In vivo CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A Narrow Therapeutic Range 
(NTR) Substrates 
CYP enzyme 
NTR Substratesa 
CYP1A2 
Theophylline, tizanidine 
CYP2C8 
Paclitaxel 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP2D6 
Thioridazine 
CYP3A 
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, quinidine, sirolimus, 
tacrolimus, cisapride, astemizole, terfenadine, pimozide 
a CYP Substrates with a narrow therapeutic range - drugs with an exposure-response relationship that indicates that relatively small 
increases in their exposure levels by co-administered CYP inhibitors may lead to safety concerns. 
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Table 17 - 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  
pharmacokinetic enhancer 
midazolam 
19.03 
indinavir  
protease inhibitors 
vardenafil 
9.67 
ketoconazole  
antifungals 
midazolam 
17.08 
troleandomycin  
antibiotics 
midazolam 
14.80 
saquinavir/rit  
protease inhibitors 
midazolam 
12.48 
itraconazole  
antifungals 
midazolam 
10.80 
voriconazole 
antifungals 
midazolam 
9.63 
mibefradil  
calcium channel blockers 
midazolam 
8.86 
clarithromycin  
antibiotics 
midazolam 
8.39 
danoprevir/rit  
antivirals 
midazolam 
13.42 
lopinavir/rit  
protease inhibitors 
alfentanil 
11.47 
elvitegravir/rit  
treatments of AIDS 
midazolam 
12.8 
posaconazole  
antifungals 
midazolam 
6.23 
telithromycin  
antibiotics 
midazolam 
6.2 
conivaptan  
vasopressin antagonists 
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 
5.42 
ribociclib  
kinase inhibitors 
midazolam 
5.17 
josamycin  
antibiotics 
ivabradine 
7.70 
tucatinib  
kinase inhibitors 
midazolam 
5.74 
lonafarnib 
other 
midazolam 
7.39 
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 2022 and from 
FDA (https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm) updated in 
June 2020. 
Abbreviations: AIDS = acquired immune deficiency syndrome, AUC = area under the curve, CYP = cytochrome P450, RIT = ritonavir. 
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10.11 APPENDIX 11: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
VERSION 1.1  
Details provided in bibliographic reference (27). 
10.11.1 
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. 
10.11.2 
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 18. 
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Table 18 - 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 19 provides a summary of the overall response status calculation at each time point for 
participants who have measurable disease at baseline. 
Table 19 - 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 20 is to be 
used. 
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Table 20 - 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; PR = partial response; SD = stable disease. 
Missing assessments and inevaluable designation: When no imaging/measurement is done at all at 
a particular time point, the 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. (27). 
10.12 APPENDIX 12: ABBREVIATIONS  
 
ADC: 
antibody-drug conjugate 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AIDS: 
acquired immunodeficiency syndrome 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
AP: 
alkaline phosphatase 
ASCO: 
American Society of Clinical Oncology 
AST: 
aspartate aminotransferase 
ATA: 
anti-therapeutic antibodies 
BOR: 
best overall response 
BSA: 
body surface area 
BUN: 
blood urea nitrogen 
CEA: 
carcinoembryonic antigen 
CEACAM5: 
carcinoembryonic antigen-related cell adhesion molecule 5 
cfDNA: 
circulating free deoxyribonucleic acid 
CI: 
confidence interval 
COVID-19: 
Coronavirus Disease 
CR: 
complete response 
CRF: 
case report form 
CSICF: 
Core Study Informed Consent Form 
CT: 
computed tomography 
CTC: 
circulating tumoral cells 
CTCAE: 
Common Terminology Criteria for Adverse Events 
CYP450: 
Cytochrome P450 
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DCR: 
disease control rate 
DL: 
dose level, dose level 
DLT: 
dose-limiting toxicity 
DM4: 
ravtansine 
DNA: 
deoxyribonucleic acid 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end-of-treatment 
FDA: 
United States Food and Drug Administration 
FDG-PET: 
fluorodeoxyglucose-positron emission tomography 
FFPE: 
formalin-fixed, paraffin embedded 
GCP: 
Good Clinical Practice 
G-CSF: 
granulocyte colony-stimulating factor 
GDPR: 
General Data Protection Regulation 
HCV: 
hepatitis C virus 
HER2: 
human epidermal growth factor receptor 2 
HIV: 
human immunodeficiency virus 
HRT: 
hormone replacement therapy 
IB: 
Investigator’s Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC: 
Independent Ethics Committees 
IHC: 
immunohistochemistry 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
IV: 
intravenous, intravenous 
LDH: 
lactate dehydrogenase 
mBC: 
metastatic breast cancer 
MDRD: 
modification of diet in renal disease 
MedDRA: 
medical dictionary for regulatory activities 
mPAC: 
metastatic pancreatic adenocarcinoma 
MRI: 
magnetic resonance imaging 
MTD: 
maximum tolerated dose, maximum tolerated dose 
NCI: 
National Cancer Institute 
NE: 
not evaluable 
NIMP: 
noninvestigational medicinal product 
NSCLC: 
non-small-cell lung carcinoma 
NSQ: 
non-squamous 
ORR: 
objective response rate 
OS: 
overall survival 
PAC: 
pancreatic adenocarcinoma 
PD1: 
programmed cell death protein 1 
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PD-L1: 
programmed death-ligand 1 
PFS: 
progression-free survival 
PR: 
partial response 
PT: 
preferred term 
Q2W: 
every 2 weeks, every 2 weeks, every 2 weeks, every 2 weeks, every 2 weeks, 
every 2 weeks 
RECIST: 
Response Evaluation Criteria In Solid Tumors 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
source document 
SoA: 
Schedule of Activities 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
TNBC: 
triple-negative breast cancer 
ULN: 
upper limit of normal 
US: 
United States 
WBC: 
white blood cell 
WOCBP: 
woman of childbearing potential 
     
10.13 APPENDIX 13: PROTOCOL AMENDMENT HISTORY  
This is the second protocol amendment. Details of this amendment are detailed in the Protocol 
Amendment Summary of Changes preceding the Table of Contents. Details of amended 
protocol 01 are presented in this section. 
AMENDMENT 01 (01 October 2021) 
This amended protocol 01 (amendment 01) is considered to be non-substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amendment is to cancel the interim analysis after ten participants treated and 
to continue enrolling and treating pancreatic cancer patients who have been prescreened and have 
CEACAM5 positive. Here are the reasons: 
- 
The prescreening was higher and faster than expected, so the prescreening was stopped in 
July 2021. 
- 
The incidence of high CEACAM5 expression was greater than initially expected; 
approximately 40% instead of 15%. 
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- 
Given the very limited treatment options in these patients along with the unmet medical 
need of this population, patients with positive CEACAM5 expression should be allowed to 
continue participation in this study.  
- 
The interim analysis was removed in order to better assess the efficacy in this patient 
population in a larger sample size. 
Beside this change, further modifications to protocol wording were implemented, as detailed 
below.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
INN name, tusamitamab ravtansine was added 
The newly approved INN name 
was added 
NCT number added 
NCT number is available 
1.1 Synopsis (Intervention groups 
and duration), 
1.3 Schedule of activities (SoA) 
(footnote ‘b’ for screening) 
Deleted the suggestion for consideration of 
approximately 10 days between screening visit 
and initiation of therapy. 
Backup IMP available at sites  
1.1 Synopsis (objectives and 
endpoints), 
3 Objectives and endpoints 
Added the word “confirmed” for CR and PR for 
DCR and DOR definitions 
To clarify 
1.1 Synopsis (Premedication), 
6.1 Study intervention(s) 
administered 
“15 minutes to”; “depending on the administration 
form IV or oral [15 minutes prior for IV and 1 hour 
prior for oral]” were added 
To provide detailed NIMP 
instructions 
1.1 Synopsis, 
9.3.1 General considerations, 
9.4 Interim Analyses  
Added confirmatory assessment of tumor 
assessment for interim analysis and primary 
analysis 
To clarify 
1.2 Schema 
Updated details for cohort B 
To reflect the change of removing 
the interim analysis for the 
pancreas cohort 
1.3 Schedule of activities (SoA), 
8 Study Assessments and 
Procedures, 
8.6.1 Pharmacodynamics 
Added circulating CEA during prescreening 
To evaluate circulating CEA 
levels at prescreening 
1.3 Schedule of activities (SoA) 
(footnote ‘l’ for Tumor assessment), 
8.1 Efficacy assessments   
Added text to continue tumor assessment until 
death, withdrawal of participant’s consent, or 
study cut-off date for secondary efficacy 
endpoints, whichever comes first. 
To clarify 
Deleted option for tumor assessment every 12 
weeks for new anti-cancer therapy patients ‘if the 
discontinuation is due to other reason than 
progressive disease’ 
To clarify 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities (SoA) 
Added window period for tumor assessments in 
footnote ‘l’ 
To clarify 
3 Objectives and endpoints 
Added “and to evaluate circulating CEA levels at 
prescreening” to tertiary/exploratory objectives 
To evaluate circulating CEA 
levels at prescreening 
4.2 Scientific Rationale for Study 
Design, 
9.4 Interim analyses 
Removed specifications of interim analysis 
planning for the pancreas cohort and deleted 
"For the mPAC cohort, if no confirmed response 
is observed among the first 10 treated 
participants evaluable for activity, the cohort will 
be closed." 
To remove the interim analysis 
for the pancreas cohort and 
continue enrolling and treating 
pancreatic cancer patients who 
have been prescreened and have 
CEACAM5 positive 
4.2 Scientific Rationale for Study 
Design, 
9.3.1 General considerations, 
9.4 Interim analyses 
Removed specifications of interim analysis in 
mPAC cohort “and 10 treated evaluable 
participants in mPAC cohort” 
To continue screening and 
treating pancreatic cancer 
patients 
5.2 Exclusion Criteria 
Deleted specification for German sites in E07 
Not applicable as German site 
are not in the study 
5.4 Screen Failures 
Clarified re-screening process 
To clarify 
8.3 Adverse events (AEs), Serious 
adverse events (SAEs) and Other 
Safety Reporting 
Added reference to protocol sections for 
definitions, method of recording, evaluating, and 
assessing causality of AEs, SAEs, and AESIs. 
To clarify 
8.3.1 Time period and frequency for 
collecting AE and SAE information 
Updated collection of AEs and SAEs from 
screening instead of prescreening. 
To clarify 
 
Added text for collection of only AEs related to 
fresh biopsy procedure at prescreening. 
To clarify 
8.3.5 Pregnancy 
Added text for follow up of outcome of the 
pregnancy, post-study pregnancy-related SAE, 
and discontinue study intervention or be 
withdrawn from study on pregnancy. 
To clarify 
8.3.10.6 Peripheral neuropathy 
New section with guidance for managing 
peripheral neuropathy. 
For clarity of safety management 
guidelines. 
8.3.10.7 Colitis (including 
hemorrhagic) 
New section for managing GI toxicity. 
For clarity of safety management 
guidelines. 
8.9 Use of biological samples and 
data for future research 
The phrase ''drug response and toxicity'' is 
replaced with ''mechanism of action, or possible 
toxicity''. 
Updated as per new template text 
Added text for collection and utilization of 
remaining leftover samples and additional/extra 
samples. 
Updated as per new template text 
Updated time frame for storage of relating data 
and biological samples for future research from 
15 years to 25 years. 
Updated as per new template text 
Deleted text for storage of study participant 
coded data. 
Updated as per new template text 
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Section # and Name 
Description of Change 
Brief Rationale 
9.2 Populations for Analyses 
Updated definition of activity population 
To clarify 
Deleted text for concomitant consideration of 
CEACAM5 positivity for screened participant 
population. 
Updated to take into all 
CEACAM5 patients in screened 
population. 
Added text for exclusion of participants exposed 
to study intervention before or without being 
enrolled, from analysis populations and only to 
be considered in safety population. 
To clarify 
Added below text: 
Enrolled participants for whom it is unclear 
whether they took the study intervention will be 
considered as exposed and will be included in 
the safety population. 
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. 
To clarify 
10.1.3 Informed consent process 
Updated ICF process for re-screening   
For clarity 
Deleted repeated wording from section 5.4 
For clarity 
10.1.7 Data quality assurance  
Removed the paragraph of quality tolerance 
limits 
Not applicable 
10.6 Appendix 6: Recommended 
supportive care and/or dose 
modification guidelines for drug-
related adverse events 
New section for managing hemorrhage. 
For clarity of safety management 
guidelines. 
10.10 Appendix 10: CYP substrates 
with narrow therapeutic range and 
strong CYP3A inhibitors, Table 13 
Updated list of strong CYP3A inhibitors 
Drug interaction list updated  
Throughout 
Minor editorial, typographical error corrections 
and standardization of wording 
For clarity 
 
SAR408701 replaced by tusamitamab ravtansine 
The approved product name was 
added 
 
 
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11 
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25. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations 
for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice 
Guideline Update. J Clin Oncol. 2015;33(28):3199-212. 
26. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5(6):649-
55. 
27. Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the 
recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication 
or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ 
meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, 
partnership or other entity 
 
According to template: Sanofi eSAP Version 1.0, dated 24-MAR-2021 
Page 1 
 
STATISTICAL ANALYSIS PLAN  
Protocol title: 
Open-label, multi-cohort, Phase 2 trial, evaluating the 
efficacy and safety of tusamitamab ravtansine 
(SAR408701) monotherapy and in combination in 
patients with CEACAM5-positive advanced solid 
tumors 
Protocol number: 
ACT16432 
Compound number 
(INN/Trademark): 
SAR408701 
tusamitamab ravtansine/Not applicable 
Study phase: 
Phase 2 
Short Title: 
Tusamitamab ravtansine monotherapy and in 
combination in patients with CEACAM5-positive 
advanced solid tumors 
(CARMEN-BT01)  
Statistician: 
Statistical project leader: 
Date of issue: 
11-Dec-2023 
Regulatory agency identifier number(s): 
IND: 
144484 
EudraCT: 
2020-003096-18 
NCT: 
NCT04659603 
WHO: 
U1111-1244-1644 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Date: 
11-Dec-2023 
Total number of pages: 49 
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Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS  
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 6 
1.1 
STUDY DESIGN ................................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS.......................................................................................................... 7 
1.2.1 
Estimands ............................................................................................................................................ 8 
2 
SAMPLE SIZE DETERMINATION ..................................................................................................... 9 
3 
ANALYSIS POPULATIONS ............................................................................................................. 11 
4 
STATISTICAL ANALYSES .............................................................................................................. 13 
4.1 
GENERAL CONSIDERATIONS........................................................................................................ 13 
4.2 
PARTICIPANT DISPOSITIONS ........................................................................................................ 14 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................... 15 
4.3.1 
Definition of endpoint ........................................................................................................................ 15 
4.3.1.1 Study-drug related DLT at Cycle 1 (Cohort C – Part 1) .................................................................... 15 
4.3.1.2 Confirmed objective response (Cohort A, Cohort B and Cohort C – Part 2) .................................... 15 
4.3.2 
Main analytical approach .................................................................................................................. 15 
4.3.3 
Sensitivity analysis ............................................................................................................................ 16 
4.3.4 
Supplementary analyses ................................................................................................................... 16 
4.3.5 
Subgroup analyses ........................................................................................................................... 16 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ........................................................................................ 17 
4.4.1 
Key/Confirmatory secondary endpoint(s) .......................................................................................... 17 
4.4.2 
Supportive secondary endpoint(s) .................................................................................................... 18 
4.4.2.1 Definition of endpoints ....................................................................................................................... 18 
4.4.2.2 Main analytical approach .................................................................................................................. 18 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS ................................................................. 21 
4.6 
MULTIPLICITY ISSUES .................................................................................................................... 21 
4.7 
SAFETY ANALYSES ........................................................................................................................ 21 
4.7.1 
Extent of exposure ............................................................................................................................ 21 
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4.7.1.1 Overall exposure ............................................................................................................................... 21 
4.7.1.2 Tusamitamab ravtansine ................................................................................................................... 22 
4.7.1.3 Gemcitabine ...................................................................................................................................... 23 
4.7.2 
Adverse events.................................................................................................................................. 25 
4.7.3 
Additional safety assessments .......................................................................................................... 30 
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs) .................................................... 30 
4.7.3.2 Ophthalmological examinations ........................................................................................................ 32 
4.8 
OTHER ANALYSES .......................................................................................................................... 34 
4.8.1 
Immunogenicity analyses .................................................................................................................. 34 
4.8.2 
PK analyses (for mPAC Cohort C) .................................................................................................... 35 
4.8.2.1 Noncompartmental analysis .............................................................................................................. 35 
4.8.2.2 Ctrough and Ceoi over cycles ................................................................................................................ 38 
4.8.2.3 Population PK analyses .................................................................................................................... 38 
4.8.2.4 IgG ..................................................................................................................................................... 38 
4.8.3 
Biomarker analyses ........................................................................................................................... 38 
4.8.3.1 CEACAM5 by IHC ............................................................................................................................. 39 
4.8.3.2 Circulating CEA ................................................................................................................................. 39 
4.8.3.3 Circulating free DNA (cfDNA) ............................................................................................................ 40 
4.8.3.4 To explore potential sets of biomarkers from tumor DNA and RNA analyses as potential 
biomarkers of response to tusamitamab ravtansine ......................................................................... 40 
4.8.3.5 CEACAM5 expression on circulating tumoral cells (CTCs) .............................................................. 40 
4.9 
INTERIM ANALYSES ....................................................................................................................... 40 
5 
SUPPORTING DOCUMENTATION ................................................................................................. 42 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ........................................................................................ 42 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ................................................ 43 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS ..................................................................................................... 44 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................... 47 
5.5 
APPENDIX 5 SANOFI SPONSOR GENERIC RANGES FOR HEMATOLOGICAL AND 
BIOCHEMISTRY PARAMETERS ..................................................................................................... 47 
6 
REFERENCES  ................................................................................................................................. 49 
 
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LIST OF TABLES  
Table 1 - Dose levels for Part 1 (safety run-in) ............................................................................................... 6 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Summary of primary estimand for main endpoints .......................................................................... 8 
Table 4 -
......................... 9 
Table 5 - 
....................... 9 
Table 6 - 
 ..................... 10 
Table 7 - Populations for analyses ................................................................................................................ 11 
Table 8 - Tusamitamab ravtansine dose reduction criteria ........................................................................... 23 
Table 9 - Gemcitabine dose reduction criteria .............................................................................................. 24 
Table 10 - Sorting of AE tables ..................................................................................................................... 26 
Table 11 - Analyses of adverse events ......................................................................................................... 27 
Table 12 - Selections for AESIs and other AEs of interest ............................................................................ 28 
Table 13 - List of PK parameters and definitions .......................................................................................... 35 
Table 14 - List of PK parameters and definitions .......................................................................................... 37 
Table 15 - Generic ranges for hematological and coagulation parameters .................................................. 47 
Table 16 - Generic ranges for biochemistry parameters ............................................................................... 48 
 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for study ACT16432 is based on the amended protocol 02 
dated 25-Jul-2022. The first participant was enrolled on 12-Apr-2021. This SAP is approved 
before the interim analysis for the pancreatic cancer cohort in combination is conducted.  
Major changes in statistical analysis plan 
SAP 
Version 
Approval 
Date 
Changes 
Rationale 
1 
17-Dec-2021 
Not applicable 
Original version 
2 
Current 
version 
Addition of analyses applicable to Cohort C (pancreatic 
cancer with SAR408701 in combination with 
gemcitabine) 
Protocol amendment 02 
 
 
Subgroup analyses updated  
To provide more details on the 
ORR according to tumor location 
 
 
Criteria on overdose added in the definition of the DLT-
evaluable population (change versus protocol) 
To better evaluate the intended 
dose 
 
 
Modification of AE groupings for AESIs and other AEs 
of interest 
To be aligned with other 
Tusamitamab ravtansine studies 
 
 
Addition of safety analyses (Ocular/visual symptoms 
TEAE in overview TEAE table, ECOG, QTcF) 
To be aligned with other 
Tusamitamab ravtansine studies 
 
 
Analyses on visual acuity test and slit lamp 
examination further detailed 
To provide more details and be 
aligned with other Tusamitamab 
ravtansine studies 
 
 
Update of Immunogenicity section 
To be aligned with other 
Tusamitamab ravtansine studies 
 
 
Removed mention of interim analysis for mBC Cohort A 
The mBC cohort A stopped 
enrollment 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 2, open-label, multi-cohort, multi-center study assessing the efficacy (antitumor 
activity), safety, and immunogenicity of tusamitamab ravtansine in the treatment of participants 
with metastatic Breast Cancer (mBC, Cohort A [monotherapy]) and metastatic Pancreatic 
Adenocarcinoma [(mPAC, Cohort B [monotherapy] and Cohort C (in combination with 
gemcitabine])] with CEACAM5-positive tumors (defined as CEACAM5 IHC intensity ≥2+ in 
≥50% of tumor cells). 
During the pre-screening phase, participants’ tumor samples will be collected to evaluate 
CEACAM5 status (central assessment by IHC). During the screening phase (up to 28 days), only 
participants with mBC and mPAC determined to be CEACAM5-positive will go through protocol 
screening procedures. 
Treatment allocation will be performed using an Interactive Response Technology (IRT). 
After being screened, the eligible participants will receive tusamitamab ravtansine as single agent 
treatment or receive tusamitamab ravtansine and gemcitabine combined treatment until 
documented disease progression, unacceptable toxicity, new anti-cancer therapy initiation, or the 
participant’s or Investigator’s decision to stop the treatment. 
In Cohorts A and B, participants will receive a tusamitamab ravtansine loading dose at 170 mg/m² 
on Day 1 of Cycle 1, followed by 100 mg/m² every 2 weeks (Q2W) from Cycle 2 and in all other 
cycles. 
In Cohort C, each treatment cycle will be 28 days (4 weeks). Cohort C will comprise 2 parts: 
• Part 1 (Safety Run-In): In Part 1, participants will receive a tusamitamab ravantasine 
loading dose at 170 mg/m2 on Day 1, followed by 100 mg/m2 Q2W, participants will also 
receive gemcitabine 1000 mg/m2 on Day 1, Day 8, and Day 15 every 4 weeks (Q4W). 
In the case that it is decided to reduce the initial loading dose of tusamitamab ravtansine to 
Dose Level (DL) – 1 (Table 1), a tusamitamab ravtansine loading dose of 135 mg/m2 will 
be administered to participants on Day 1 of Cycle 1. 
Table 1 - Dose levels for Part 1 (safety run-in)  
Dose level (DL) 
Tusamitamab ravtansine 
Gemcitabine 
Starting dose 
170 mg/m2 on D1; 100 mg/m2 Q2W thereafter 
1000 mg/m2 on D1, D8, and D15 Q4W 
Minus -1 (DL -1) 
135 mg/m2 on D1; 100 mg/m2 Q2W thereafter 
1000 mg/m2 on D1, D8, and D15 Q4W 
BSA = body surface area; DL -1=dose level -1; Q2W = every 2 weeks; Q4W = every 4 weeks. 
For participants with a BSA >2.2 m2, the tusamitamab ravtansine dose will be calculated based on a BSA of 2.2 m2. 
• Part 2: the recommended dose (RD) confirmed in Part 1 will be evaluated for activity 
in 24 to 27 additional participants. A total of 30 participants, including participants treated 
at the RD in Part 1, will be evaluated for activity.  
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The expected duration of study treatment for participants may vary, based on the progression date 
and cohort; the median expected duration of the study per participant is estimated to be 8 months 
for Cohorts A and C and 6 months for the Cohort B (up to 1 month for screening, a median of 4 or 
2 months for treatment in Cohorts A (breast cancer) and Cohort B/C (pancreatic cancer), 
respectively, a median of 1 month for EOT, and follow-up visit 90 days after the last IMP 
administration). 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
For Cohort A, Cohort B and Cohort C Part 2: To 
assess the antitumor activity of tusamitamab 
ravtansine in mBC and tusamitamab ravtansine 
monotherapy and in combination with gemcitabine 
in mPAC 
• 
For Cohort C Part 1: To confirm the recommended 
tusamitamab ravtansine dose when administered in 
combination with gemcitabine 
• 
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 per Response Evaluation 
Criteria In Solid Tumors (RECIST) v1.1 
• 
Incidence of dose-limiting toxicities (DLTs) in the 
28 Day DLT observation period (Cycle 1) 
Secondary 
To assess the safety and tolerability of tusamitamab 
ravtansine administered as monotherapy and in combination 
with gemcitabine 
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 administered as monotherapy and in combination 
with gemcitabine 
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 CR, PR or stable disease as 
per RECIST v1.1 
Duration of response (DOR), defined as the time from first 
documented evidence of CR or PR until progressive disease 
determined per RECIST v1.1 or death from any cause, 
whichever occurs first 
To assess the immunogenicity of tusamitamab ravtansine 
To assess the pharmacokinetics (PK) of tusamitamab 
ravtansine and gemcitabine when given in combination 
Incidence of participants with anti-therapeutic antibodies 
(ATAs) against tusamitamab ravtansine 
Pharmacokinetic parameters of tusamitamab ravtansine and 
gemcitabine 
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Objectives 
Endpoints 
Tertiary/exploratory 
To explore CEACAM5 expression on circulating tumoral cells 
(CTCs) 
CEACAM5 expression assessment on CTCs from participants 
with positive CEACAM5 expression on tumor tissue 
To explore modulations of circulating CEA as a potential 
pharmacodynamics biomarker of response to tusamitamab 
ravtansine treatment 
Circulating CEA at baseline and during the treatment period 
To assess 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 from tumor DNA and 
RNA analyses, beside target expression, as potential 
biomarkers of response to tusamitamab ravtansine treatment  
Biomarker annotation for tumor DNA and RNA at baseline 
 
 
 
1.2.1 Estimands  
Primary estimand defined for main endpoints are summarized below in Table 3. More details are 
provided in Section 4. 
Table 3 - Summary of primary estimand for main endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level summary  
(Analysis and missing 
data handling) 
Primary objective:  
For Cohort A, Cohort B and Cohort C Part 2: To assess the antitumor activity of tusamitamab ravtansine in mBC and 
tusamitamab ravtansine monotherapy and in combination with gemcitabine in mPAC 
Primary 
endpoint 
(primary 
estimand) 
Confirmed 
objective 
response 
(confirmed CR 
or PR as BOR), 
determined 
according to 
RECIST 1.1  
All-treated 
population 
Regardless of 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 missing 
or non-evaluable BOR). 
 
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2 
SAMPLE SIZE DETERMINATION  
Assuming a prescreening failure rate of 90% for Cohort A, 85% for Cohort B, and 58% for 
Cohort C, and a screening failure rate of 20% for the 3 cohorts, approximately 440 participants for 
the Cohort A, 242 participants for Cohort B, and 90 participants for Cohort C will be prescreened 
to achieve up to approximately 35 treated participants evaluable for activity (at least one 
postbaseline tumor assessment, early progression, or death due to progressive disease) for the 
mBC Cohort A, 29 treated participants evaluable for activity for mPAC Cohort B, and 30 treated 
participants evaluable for activity in mPAC Cohort C. 
For Cohort C safety run-in (Part 1), the actual sample size is expected to vary depending on DLTs 
observed. It is anticipated that around 3 to 12 DLT-evaluable participants will be enrolled. Table 4 
and Table 5 list the estimated ORRs and 95% exact CIs by the numbers of responders from a 
sample size of 35 treated participants evaluable for activity for the mBC cohort and 29 treated 
participants evaluable for activity for mPAC cohort, and Table 6 lists the estimated ORRs and CIs 
30 treated participants evaluable for activity for combination cohort. 
Table 4 - 
  
 
Table 5 - 
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Table 6 -
 
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3 
ANALYSIS POPULATIONS  
The following populations are defined (Table 7): 
Table 7 - Populations for analyses  
Population 
Description 
Pre-screened 
All participants who signed the pre-screening informed consent for CEACAM5 assay 
assessment of their biopsy. 
Screened 
All participants who signed screening informed consent for study participation. 
Enrolled 
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.  
DLT-Evaluable (Cohort C Part 1) 
All participants who have completed DLT observation period and who received 1 cycle 
with at least 80% of the intended dose for both tusamitamab ravtansine at each of 
the first 2 infusions and gemcitabine at each of the 3 first infusions. Any participant who 
experienced a DLT during that period will also be DLT-evaluable, except in case of 
overdose (defined as a dose received of at least 30% above the intended dose) of 
tusamitamab ravtansine or gemcitabine at any of the infusions of Cycle 1.  
Activity 
All treated participants who have measurable disease at study entry and at least one 
post-baseline evaluable tumor assessment. Participants with no post-baseline evaluable 
tumor assessment but with an early progression or who died due to disease progression 
will also be included in this set. This population is the secondary population for analysis of 
efficacy parameters 
Pharmacokinetic (PK) 
All treated participants with at least 1 postbaseline PK result with adequate documentation 
of dosing and sampling dates and times 
ATA 
All treated participants with at least one post-baseline ATA result (negative, positive, or 
inconclusive). 
Population without trial impact 
(disruption) due to COVID-19 
All treated participants: 
• 
without any critical or major deviation related to COVID-19, 
• 
and who did not permanently discontinue study intervention due to COVID-19, 
• 
and who did not permanently discontinue study due to COVID-19. 
CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; ATA = anti-therapeutic antibodies. 
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” e-CRF page. 
In practice, a participant will be included in the DLT-evaluable population (applicable to mPAC 
Cohort C Part 1 if a “Dose Limiting Toxicities” e-CRF page has been filled in at the end of 
Cycle 1. This includes any participant followed up to the end of the DLT observation period, or 
having experienced a DLT before the end of the DLT observation period and validated by the 
Study Committee. A participant with an overdose (defined as a dose received at least 30% above 
the intended dose) of tusamitamab ravtansine or gemcitabine at any of the infusions of Cycle 1 
will be excluded from the DLT-evaluable population. 
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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. 
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. 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
This study is designed to obtain preliminary efficacy and safety data on the use of tusamitamab 
ravtansine administered to participants with CEACAM5-positive tumors known to be sensitive to 
antitubulin agents at a loading dose of 170 mg/m² on Day 1 of Cycle 1, followed by  
100 mg/m² Q2W for Cohorts A and B, and at a loading dose of 170 mg/m2 (or 135 mg/m2) 
on Day 1 of Cycle 1, followed by 100 mg/m2 Q2W, combined with gemcitabine 1000 mg/m2 
on Day 1, Day 8, and Day 15 Q4W, for Cohort C.  
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; 95% CIs will be provided for the primary and secondary 
efficacy endpoints.  
Objective response rate, as well as PFS, DCR and DOR, will be derived using the local 
radiologist’s/Investigator’s assessment. 
Unless otherwise specified, analyses will be performed by cohort. 
The study cut-off for the primary analysis (ORR) for each cohort corresponds to the date on which 
all treated evaluable participants of the cohort had at least 2 postbaseline tumor assessments, 
experienced confirmed objective response, or discontinued the study 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.  
An interim analysis will be performed when the first 15 treated evaluable participants in Cohort C 
have had at least 2 postbaseline tumor assessments, experienced confirmed objective response, or 
discontinued the study for any reason. Once 15 participants have been treated, enrollment may be 
paused until a decision regarding the interim analysis can be made. 
The analysis cut-off date for secondary efficacy endpoints including DOR and PFS (final cut-off 
date) will be 6 months after the study cut-off for the primary analysis. The primary analysis of 
ORR and DCR will also be updated at that time.  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, Q1, Q3, minimum, and maximum. Categorical and ordinal data 
will be summarized using the count and percentage of participants. 
The baseline value will be defined as the last available value before the first dose IMP.  
Observation period  
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the period up to the first IMP administration. 
- 
The pre-screening period is defined as the time from when the participants give 
pre-screening informed consent to the day before the screening informed consent. 
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- 
The screening period is defined as the time from when the participants give screening 
informed consent to the first administration of the IMP.  
• The on-treatment period (ie, treatment-emergent (TE) period) is defined as the period 
from the first IMP administration to the last IMP administration + 30 days.  
• The post-treatment period is defined as the period from the end of the on-treatment 
period. 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 7 will 
be summarized. Reasons for exclusion from the population without trial impact (disruption) due to 
COVID-19 will be summarized. 
Prescreen failures are defined as participants who consent to participate in the prescreening phase 
of the study but are not subsequently screened. The number (%) of prescreen failures and reasons 
for prescreen failures will be provided in the prescreened population.  
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently enrolled. The number (%) of screen failures and reasons for screen failures will be 
provided in the screened population. 
Regarding intervention discontinuation, the following definitions will be used: 
• Permanent partial intervention discontinuation is defined as the discontinuation of one of 
the study drugs (tusamitamab ravtansine or gemcitabine) but the other is continued 
(mPAC cohort C) 
• Permanent full intervention discontinuation is defined as the discontinuation of 
SAR408701 (cohorts other than mPAC Cohort C) or both tusamitamab ravtansine and 
gemcitabine (mPAC cohort C) 
The number (%) of participants in the following categories will be provided:  
• Enrolled participants. 
• Enrolled but not exposed participants.  
• Enrolled and exposed participants. 
• Participants who fully discontinued the study intervention and main reason for permanent 
full intervention discontinuation.  
• Participants who partially discontinued the study intervention, and main reason for 
permanent discontinuation of tusamitamab ravtansine (mPAC Cohort C) 
• Participants who partially discontinued the study intervention, and main reason for 
permanent discontinuation of gemcitabine (mPAC Cohort C) 
• Participants still on study intervention. 
• Participants who discontinued the study and main reason for study discontinuation. 
Reasons for permanent study intervention and study discontinuation “adverse event” and 
“other reasons” will be split as related versus not related to COVID-19, if applicable. 
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The number (%) of exposed and not enrolled participants will also be summarized.  
In addition, the number (%) of participants prescreened, prescreen-failed, screened, 
screened-failed, enrolled, enrolled and exposed, with permanent intervention discontinuation, and 
with study discontinuation will be provided by country and site.  
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the all-treated 
population as well as displayed separately as related versus not related to COVID-19 if applicable. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
4.3.1 Definition of endpoint  
4.3.1.1 Study-drug related DLT at Cycle 1 (Cohort C – Part 1)  
For mPAC Cohort C Part 1, the primary safety endpoint is study-drug related DLTs during the 
DLT observation period (ie, approximately 28 days). For analysis purpose, DLTs will be 
identified based on the Adverse Events (AEs) reported on the e-CRF DLT page during DLT 
observation period in Part 1.  
4.3.1.2 Confirmed objective response (Cohort A, Cohort B and Cohort C – Part 2)  
The primary efficacy endpoint is confirmed objective response determined according to 
RECIST 1.1. A confirmed objective response is defined as a confirmed CR or PR as best overall 
response. 
The BOR will be derived according to RECIST 1.1 (1, 2) 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. 
4.3.2 Main analytical approach  
Statistical analysis for DLTs for Cohort C – Part 1 is described in Section 4.7.2. 
The primary efficacy analysis is based on the primary estimand introduced in Section 1.2.1. 
This primary estimand is defined according to the following attributes: 
• The endpoint is confirmed objective response (confirmed CR or PR as BOR) as per 
RECIST 1.1. 
• The treatment condition of interest is tusamitamab ravtansine Q2W with a loading dose for 
Cohorts A and B and in combination with gemcitabine for Cohort C. 
• The analysis population is the participants from the all-treated population (defined in 
Section 3). 
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• 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 (including further systemic anticancer therapies and 
radiotherapies with curative intent) intercurrent event will be handled with the “while 
not initiating further anticancer therapy” strategy. Confirmed objective response will 
be assessed based on tumor assessments up to the time of initiation of further 
anticancer therapy. 
• The population-level summary will include the objective response rate, defined as the rate 
of participants with confirmed objective response and two-sided 95% confidence intervals 
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 best overall response). 
4.3.3 Sensitivity analysis  
No sensitivity analysis is planned in this study. 
4.3.4 Supplementary analyses  
Number (%) of participants within each BOR category, including not evaluable as per RECIST 
1.1 and reason for being not evaluable will be provided on participants from all-treated 
population. 
As a supplementary analysis, confirmed objective response as per RECIST 1.1 will also be 
summarized on the participants from activity population (defined in Section 3). The same 
analytical approach as primary efficacy analysis defined in Section 4.3.1.2 will be used. 
In addition, the best relative tumor change from baseline, defined as the smallest relative tumor 
change from baseline (where tumor change at time t is the difference between sum of the longest 
diameters of the target lesions at time t and baseline, resulting in a negative value in case of 
decrease), will be summarized using a waterfall plot on the participants from the activity 
population (defined in Section 3). A swimmer plot will also be provided reporting the duration of 
treatment for all patients with their overall response, the baseline characteristics. This plot will 
differentiate responders from non-responders.  
4.3.5 Subgroup analyses  
To assess the homogeneity of the treatment effect across various subgroups, analyses will be 
performed on the primary endpoint across the following subgroups (categories with fewer than 
5 participants may be combined with other categories): 
• Race (White, Other) 
• Age group (<65, ≥65 years) 
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• Sex (Male, Female) 
• ECOG PS at baseline (0, 1) 
• Region (South America, Asia, Europe, North America) 
• mBC subtype (non-triple-negative Breast Carcinoma, triple-negative Breast Carcinoma) 
(mBC cohort) 
• Circulating CEA at baseline (<100, ≥100 µg/L) and (<80, ≥80 µg/L)  
• Time from initial diagnosis (<12 months, ≥12 months for both mPAC cohorts and 
<5 years, ≥5 years for mBC cohort) 
• Brain metastases (Yes, No) 
• Liver and Lung metastases (Yes, No) 
• Number of organs involved (including primary tumor location) (≤2, >2) 
• Primary tumor location (for both mPAC cohorts) (Head, Body, Tail, Other) 
• Tumor burden at baseline, ie, sum of the longest diameters of the target lesions (<100,  
≥100 mm) 
• Prior chemotherapy treatment as advanced intent (≤1, >1 for both mPAC cohorts, and  
<2, ≥2 for mBC cohort) 
• Prior Taxane (Yes, No) (cohorts mBC and mPAC B)  
• Prior T-DM1 (mBC cohort) (Yes, No) 
• Refractory to taxane/anthracyclines/T-DM1 (defined as progression within 60 days after 
last administration) (Yes, No) 
• Sensitivity to first-line chemotherapy line (duration of treatment 4-6 months Yes/No;  
≥6 months Yes/NO) 
• Sensitivity to second-line chemotherapy line (duration of treatment 4-6 months Yes/No; 
≥6 months Yes/NO) 
If a sufficient number of responses is observed tables will be provided, otherwise subgroup 
information will be displayed in listings only. For tables, objective response rate estimate and the 
corresponding 95% confidence interval will be provided for each subgroup using the same 
method as applied to the primary analysis. Forest plots will be provided. In addition, analysis of 
DOR and DCR will be conducted by mBC subtype (TNBC vs non-TNBC).  
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints detailed in this section are the progression-free survival, the duration of 
response and the disease control rate. Other secondary endpoints analyses are defined in  
Section 4.7.2 (AE, SAE, laboratory abnormalities) and Section 4.8 (PK and immunogenicity).   
4.4.1 Key/Confirmatory secondary endpoint(s)  
No key/confirmatory secondary endpoint is defined. 
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4.4.2 Supportive secondary endpoint(s)  
4.4.2.1 Definition of endpoints  
4.4.2.1.1 Progression-free survival  
PFS is defined as the time from the date of the first administration of IMP to the date of first 
documentation of objective progressive disease according to RECIST 1.1 definitions (1, 2) or 
death due to any cause, whichever occurs first. 
4.4.2.1.2 Disease control rate  
The DCR will be estimated by dividing the number of participants with confirmed objective 
response or stable disease (CR or PR or stable disease (SD) as BOR), determined according to 
RECIST v1.1, by the number of participants from the analysis population. 
4.4.2.1.3 Duration of response  
DOR is 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 progressive disease according to RECIST 1.1 
definitions (1, 2) or death due to any cause, whichever occurs first. 
4.4.2.2 Main analytical approach  
4.4.2.2.1 Progression-free survival  
PFS analysis is based on an estimand defined according to the following attributes: 
• The endpoint is progression-free survival. 
• The treatment condition of interest is tusamitamab ravtansine Q2W with a loading dose for 
Cohorts A and B and in combination with gemcitabine for Cohort C. 
• The analysis population is the participants from the all-treated population (defined in 
Section 3). 
• Intercurrent events: 
- 
The study intervention discontinuation will be handled with the treatment policy 
strategy. PFS will be assessed based on tumor assessments regardless of study 
intervention discontinuation. 
- 
The further anti-cancer therapy (including further systemic anticancer therapies and 
radiotherapies with curative intent) intercurrent event will be handled with the 
hypothetical strategy. PFS will be assessed based on tumor assessments had a further 
anticancer therapy not been 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 two consecutive tumor assessments not been 
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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% confidence intervals using a log-log transformation of the survival function and 
the method of Brookmeyer and Crowley. 
- 
Number (%) of participants at risk as well as the probabilities of being event-free at 
least at 2, 4, 6, 8, 10 and 12 months with 95% CIs using the Kaplan-Meier method and 
a log-log approach based on a normal approximation following the Greenwood’s 
formula.  
- 
Kaplan-Meier curve 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 (document disease 
progression or death without documented disease progression) and the number (%) of censored 
participants and reason for censoring (no baseline tumor assessment, no evaluable post-baseline 
tumor assessment, alive without documented disease progression, event occurred after two 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) 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 has been done. 
4.4.2.2.2 Disease control rate  
DCR analysis is based on an estimand defined according to the following attributes: 
• The endpoint is disease control response (confirmed CR or PR or stable disease (SD) as 
BOR) as per RECIST 1.1. 
• The treatment condition of interest is tusamitamab ravtansine Q2W with a loading dose for 
Cohorts A and B and in combination with gemcitabine for Cohort C. 
• The analysis population is the participants from all-treated population (defined in  
Section 3). 
• Intercurrent events: 
- 
The study intervention discontinuation will be handled with the treatment policy 
strategy. Confirmed objective response or stable disease will be assessed based on 
tumor assessments regardless of study intervention discontinuation. 
- 
The further anticancer therapy (defined as all further anti-cancer treatments and 
radiotherapies with curative intent) 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. 
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• The population-level summary will include the objective response rate, defined as the rate 
of participants with disease control response and two-sided 95% confidence intervals 
using the Clopper-Pearson method.  
In the absence of confirmed objective response and SD before the analysis cut-off date (taking 
into account the intercurrent event handling strategies), participants will be considered as non-
DCR, whatever the reason (including participants with non-evaluable best overall response). 
Disease control rate will also be summarized on the activity population as a supplementary 
analysis. 
4.4.2.2.3 Duration of response  
Duration of response (DOR) analysis is based on an estimand defined according to the following 
attributes: 
• The endpoint is duration of response. 
• The treatment condition of interest is tusamitamab ravtansine Q2W with a loading dose for 
Cohorts A and B and in combination with gemcitabine for Cohort C. 
• The analysis population is the participants from the all-treated population (defined in 
Section 3), limited to participants 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. 
- 
The further anticancer therapy (including further systemic anticancer therapies and 
radiotherapies with curative intent) 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 two 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% 
confidence interval using Kaplan-Meier methods. 
In the absence of documented disease progression or death before the study 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. 
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4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
Analyses of tertiary/exploratory endpoints (ie, biomarkers) are defined in Section 4.8.3.   
4.6 
MULTIPLICITY ISSUES  
No multiplicity issues are handled in this study. 
4.7 
SAFETY ANALYSES  
All safety analyses will be performed on the all-treated population as defined in Section 3, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
• Safety data in participants who do not belong to the all-treated population (eg, treated but 
not enrolled) will be provided separately. 
4.7.1 Extent of exposure  
4.7.1.1 Overall exposure  
The dose information will be assessed by the following variables: 
• Overall number of cycles started, defined by the number of cycles in which at least one 
dose of any study intervention is administered. 
• Duration of overall exposure (in weeks) is defined as (Last day of exposure – first day of 
exposure +1)/7. 
- 
The first day of exposure is defined as the first administration date with non-zero dose 
for at least one of the IMPs (tusamitamab ravtansine or gemcitabine for Cohort C) 
- 
The last day of exposure is the day before the theoretical date of the next 
administration (after the last administration), defined as the maximum between: 
- 
The last administration date + number of theoretical days until the next 
administration - 1 for tusamitamab ravtansine, 
- 
The last administration date + the number of theoretical days until the next 
administration -1 for gemcitabine for Cohort C. 
The total number of cycles started, and the number of cycles started by participants will be 
summarized as a quantitative variable and by category (number (%) of participants receiving at 
least 1 cycle, at least 2 cycles, etc). The duration of overall exposure will be summarized 
quantitatively. 
The following variable will be computed to describe overall dose modification (cycle delay): 
• Cycle delay: A cycle is deemed as delayed if the start date of the current cycle – 
theoretical cycle duration – start date of the previous cycle is >3 days. Cycle delay is not 
defined for the first cycle. 
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Cycle delay will be analyzed at the participant (with number of participants used as denominator) 
and cycle (with number of cycles used as denominator) levels, as follows: 
• Number (%) of participants with a least 1 cycle delayed 
- 
Number (%) of participants with a cycle delayed between 4 and 7 days (using 
maximum delay across all cycles),  
- 
Number (%) of participants with a cycle delayed >7 days (using maximum delay 
across all cycles). 
• Number (%) of cycles delayed 
- 
Number (%) of cycles delayed between 4 and 7 days, 
- 
Number (%) of cycles delayed between 8 and 28 days, 
- 
Number (%) of cycles delayed >28 days. 
In addition, summaries will be provided by trial impact (disruption) due to COVID-19 
(if applicable). 
4.7.1.2 Tusamitamab ravtansine  
The dose information will be assessed by the following: 
• Total number of cycles started. 
• Number of cycles started per participant.  
• Duration of exposure (in weeks) is defined by (date of last administration of tusamitamab 
ravtansine + 14 days – date of first administration of the tusamitamab ravtansine)/7. 
• Actual dose (in mg/m²). In case of dose interruption, actual dose will be the sum of the 
actual doses administered before and after the dose interruption.  
• Cumulative dose (in mg/m²): the cumulative dose is the sum of all actual doses of 
tusamitamab ravtansine, given from first to last administration. 
• Actual dose intensity (ADI in mg/m²/week): defined as the cumulative dose divided by the 
duration of tusamitamab ravtansine exposure (in weeks). 
• Planned dose intensity (PDI in mg/m²/week): corresponds to the planned dose at C1D1 + 
planned dose at subsequent cycles multiplied by the theoretical total number of doses 
started - 1 and divided by the theoretical cycle duration expressed in weeks (ie, 2 weeks 
per cycle started). 
• Relative dose intensity (RDI, in %):100 ×
ADI ([mg/m²/week]) 
PDI ([mg/m²/week]). 
The total number of cycles started, number of cycles started by participant will be summarized as 
a quantitative variable and by category (number [%] of participants receiving at least 1 cycle, at 
least 2 cycles, etc). Duration of tusamitamab ravtansine exposure, cumulative dose, ADI and RDI 
will be summarized quantitatively. 
The following variables will be derived to describe dose modifications and dose interruptions:  
• Dose reduction: The first administration (loading dose) and second administration 
(first 100 mg/m2 infusion) will not be counted as a dose reduction. For the third and 
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subsequent tusamitamab ravtansine administrations, dose reduction will be determined 
using the dose level intervals provided in Table 8, by comparing the current dose level to 
the previous dose level. If the current dose level is below the dose level interval of the 
previous dose administration, then the current dose level is considered reduced. 
Table 8 - Tusamitamab ravtansine dose reduction criteria  
Actual dose level 
Dose level interval 
 100 mg/m² 
>90 mg/m²   
Dose level -1 (80 mg/m²)  
>72.5 mg/m² and ≤90 mg/m²  
Low dose  
>0 mg/m² and ≤72.5 mg/m²  
• Dose delay: within a cycle, dose delay for tusamitamab ravtansine is deemed as delayed if 
the actual start date of the dose - theoretical start date of a doseis >2 days.  
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
• Dose interruption: A dose will be considered as interrupted if the tusamitamab ravtansine 
administration is stopped during an infusion regardless of whether it is restarted or not.  
Dose modifications and dose interruptions will be analyzed by participant and cycle as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 cycle delayed  
- 
Number (%) of participants with at least 1 dose reduction  
- 
Number (%) of participants with a least 1 dose interruption  
• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of cycles with at least 1 cycle delayed  
- 
Number (%) of cycles with at least 1 dose reduction  
- 
Number (%) of cycles with at least 1 dose interruption  
If applicable, summaries will be provided by trial impact (disruption) due to COVID-19.  
4.7.1.3 Gemcitabine  
For Cohort C only, the dose information will be assessed by the following: 
• Total number of cycles started. 
• Number of cycles started per participant. 
• Duration of gemcitabine exposure (in weeks) is defined by date of last administration of 
gemcitabine + number of theoretical days until the next administration – date of 
first administration of gemcitabine /7. 
• Actual dose (in mg/m²). In case of dose interruption, actual dose will be the sum of the 
actual doses administered before and after the dose interruption.   
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• Cumulative dose (mg/m²): the cumulative dose is the sum of all actual doses of 
gemcitabine, given from first to last administration.  
• Actual dose intensity (ADI in mg/m²/week): defined as the cumulative dose divided by the 
duration of gemcitabine exposure (in weeks). 
• Planned dose intensity (PDI in mg/m²/week): corresponds to the planned dose multiplied 
by the theoretical total number of doses started and divided by the theoretical cycle 
duration expressed in weeks (ie, 2 weeks per cycle started). Note: Theoretical total number 
of doses started is derived based on cycles where at least one IMP is administered (even in 
case of dose omission), up to the end of treatment of gemcitabine. 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/m²/week) 
PDI (mg/m²/week) . 
The total number of cycles started, number of cycles started by participant will be summarized as 
a quantitative variable and by category (number [%] of participants receiving at least 1 cycle, at 
least 2 cycles, etc). Duration of gemcitabine exposure, cumulative dose, ADI and RDI will be 
summarized quantitatively. 
The following variables will be derived to describe dose modifications and dose interruptions:  
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent gemcitabine administrations, dose reduction will be determined 
using the dose level intervals provided in Table 9, by comparing the current dose level to 
the previous dose level. 
Table 9 - Gemcitabine dose reduction criteria  
Actual dose level 
Dose level interval 
Starting dose (1000 mg/m2) 
>=900 and <1100 
Dose level -1 (800 mg/m2)  
>=700 and <900 
Dose level -2 (600 mg/m2) 
>=500 and <700 
Low dose 
<500  
• Within a cycle, dose delay for gemcitabine: a dose is deemed as delayed if the actual start 
date of the dose – theoretical start date of a dose is >2 days.  
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
• Dose interruption: A dose will be considered as interrupted if the gemcitabine 
administration is stopped during an infusion regardless of whether it is restarted or not.  
Dose modifications and dose interruptions will be analyzed by participant and cycle as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption  
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• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of cycles with at least 1 cycle delayed 
- 
Number (%) of cycles with at least 1 dose reduction 
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
4.7.2 Adverse events  
General common rules for adverse events 
All AEs will be graded according to National cancer institute common terminology for adverse 
events (NCI-CTCAE version 5.0) and coded to a lower-level term (LLT), preferred term (PT), 
high-level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock.  
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. 
• Treatment-emergent adverse events (TEAE)s: 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, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
The primary AE analyses will be on TEAEs.  Pre-treatment and post-treatment AEs will be 
described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is 
a pre-treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. Missing grade will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase, using the maximum (worst) grade by treatment phase. 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.  
The AE tables will be sorted as indicated in Table 10. 
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Table 10 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa 
PT 
By decreasing frequency of PTs 
a The table of all TEAEs presented by primary SOC and PT will define the presentation order for all other tables (eg, treatment-emergent 
SAE) presented by SOC and PT, unless otherwise specified.   
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE  
• Any grade ≥3 TEAE  
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment-emergent period)  
• Any treatment emergent SAE 
• Any treatment emergent AESI 
• Any TEAE leading to permanent full study intervention discontinuation  
• Any TEAE leading to permanent partial intervention discontinuation (discontinuation of 
tusamitamab ravtansine) (Cohort C only) 
• Any TEAE leading to permanent partial intervention discontinuation (discontinuation of 
gemcitabine) (Cohort C only) 
• Any TEAE related to IMP 
• Any Grade ≥3 TEAE related to IMP   
• Any serious TEAE related to IMP 
• Any Treatment-emergent Corneal events (with CMQ as defined in Table 12) 
• Any Treatment-emergent Peripheral neuropathy events (with SMQ 
“Peripheral neuropathy” (Narrow and Broad)) 
• Any ocular/visual symptoms TEAE (CMQ (“Eye disorders exclude corneal disorders”) 
The AE summaries of Table 11 will be generated with number (%) of participants experiencing at 
least one event. The analyses will be performed for all grades combined and for grades ≥3. The all 
TEAE summary by Primary SOC and PT (and other safety summaries (eg, SAEs, deaths), if 
deemed needed after TEAE evaluation) will be performed by trial impact (disruption) due to 
COVID-19.  
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Table 11 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HGLT, HLT and PT 
 
Primary SOC and PT 
 
PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC and PT  
TEAE related to tusmitamab ravtansine as per Investigator’s judgment (Cohort C only) 
Primary SOC and PT 
TEAE related to gemcitabine as per Investigator’s judgment (Cohort C only) 
Primary SOC and PT 
Treatment emergent SAE 
Primary SOC, HGLT, HLT and PT 
 
Primary SOC and PT 
Treatment emergent SAE related to IMP as per Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE related to tusamitamab ravtansine as per Investigator’s 
judgement (Cohort C only) 
Primary SOC and PT 
Treatment emergent SAE related to gemcitabine as per Investigator’s judgement 
(Cohort C only) 
Primary SOC and PT 
TEAE leading to permanent full study intervention discontinuation  
Primary SOC and PT  
TEAE leading to permanent partial intervention discontinuation (discontinuation of 
tusamitamab ravtansine) (Cohort C only) 
Primary SOC and PT 
TEAE leading to permanent partial intervention discontinuation (discontinuation of 
gemcitabine) (Cohort C only) 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported by the Investigator in 
the AE page) 
Primary SOC and PT  
TEAE related to tusamitamab ravtansine and leading to deathb 
Primary SOC and PT 
TEAE related to gemcitabine and leading to deathb (Cohort C only) 
Primary SOC and PT 
Pre-treatment AE 
Overviewa 
 
Primary SOC and PT 
Pre-treatment SAE 
Primary SOC and PT 
Post-treatment AE 
Overviewa 
 
Primary SOC and PT 
Post-treatment SAE 
Primary SOC and PT 
TEAE leading to dose modification of tusamitamab ravtansine (including dose delay and 
dose reduction) 
Primary SOC and PT  
TEAE leading to dose modification of gemcitabine (including dose delay and dose 
reduction) (Cohort C only) 
Primary SOC and PT  
TEAE leading to dose interruption of tusamitamab ravtansine 
Primary SOC and PT  
TEAE leading to dose interruption of gemcitabine (Cohort C only) 
Primary SOC and PT  
a Will include the following AE categories: any AEs, any serious AEs, any AEs leading to death, any AEs leading to permanent intervention 
discontinuation 
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Analysis of deaths 
In addition to the analyses of deaths included in Table 11 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods by study period and 
reason for death  
• Summary of fatal AEs, by primary SOC and PT 
- 
In context of disease progression (death within 30 days from last study intervention 
administration and the cause of death is disease progression), 
- 
In context other than disease progression (death within 30 days from last study 
intervention administration and for whom cause of death is not disease progression or 
the death occurred more than 30 days from last study intervention administration and 
the cause of death is AE). 
• An overview of Grade 5 AEs will be provided with the following categories: 
- 
Grade 5 AE (TEAE and post-treatment). 
- 
Fatal TEAE (regardless date of death/period). 
- 
Grade 5 TEAE with a fatal outcome during the treatment period,  
- 
Any Grade TEAE with a fatal outcome during the post-treatment period.  
- 
Post-treatment Grade 5 AE (excluding a TEAE that worsened to Grade 5 during the 
post-treatment period). 
• Deaths in non-enrolled participants or enrolled but not treated participants 
Analysis of adverse events of special interest (AESIs) and other AEs of interest 
Adverse events of special interest (AESIs) and other AEs of interest will be selected for analyses 
as indicated in Table 12. Number (%) of participants experiencing at least one treatment-emergent 
event will be provided for each event of interest, by SOC and PT (if applicable).  Tables will be 
sorted as indicated in Table 10. DLT observed during the DLT observation period will be listed in 
the DLT-evaluable population (for Cohort C Part 1 only). 
Table 12 - Selections for AESIs and other AEs of interest  
AESIs and other AEs of interest 
Selection 
AESIs 
 
Grade ≥3 keratopathy  
e-CRF AESI specific tick box on the AE page. It could include Grade ≥3 
events with PTs from CMQ of corneal events 
Bundle branch blocks or any conduction defects 
e-CRF AESI specific tick box on the AE page. It could include events with 
PTs from SMQ “Conduction defects” 
Grade ≥3 liver enzyme increased (symptomatic 
or asymptomatic) 
e-CRF AESI specific tick box on the AE page. It could include Grade ≥3 
events PTs from the SMQ “Hepatic disorders” (Narrow and Broad) 
Symptomatic overdose (serious or nonserious) 
with IMP/NIMP 
e-CRF symptomatic overdose specific tick box on the Overdose page 
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AESIs and other AEs of interest 
Selection 
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/NIMP 
e-CRF specific tick box for adverse events linked to pregnancy on the 
Pregnancy page 
DLT during DLT observation period (Cohort C 
Part 1 only) 
e-CRF specific DLT page 
Other AEs of interest 
 
Any AE meeting DLT criteria beyond DLT 
observation period (Cohort C) 
AEs reported on the e-CRF specific DLT page outside the DLT observation 
period 
Corneal events (reported as AEs) 
CMQ “Corneal events compound level” containing the PTs included in 
both SOC “Eye disorders” and SMQ “Corneal disorders” (Narrow) 
Ocular/visual adverse events (excluding 
corneal disorders) 
CMQ “Eye disorders exclude corneal disorders” containing PTs included in 
SOC “Eye disorders” and excluding PTs in SMQ “Corneal disorders” 
(Narrow)  
Cardiac conduction defects 
SMQ “Conduction defects” (Narrow) 
Peripheral neuropathy events 
SMQ “Peripheral neuropathy” (Narrow and Broad) 
Colitis events (excluding infective) 
CMQ “Colitis (excluding infective)” containing PTs included in HLT “Colitis 
(excl infective)” 
Hypersensitivity events 
SMQ “Hypersensitivity” (Narrow) and adverse event occurring on the day or 
the day after infusion 
Hepatic disorders events 
SMQ “Hepatic Disorders” (Narrow and Broad) 
Hematological events 
SMQ “Haematopoietic cytopenias” (Narrow and Broad) 
AE related to COVID-19 illness 
SMQ “COVID-19” (Narrow) 
An overview of corneal TEAEs will be provided with the following AE categories: any corneal 
TEAEs, Grade ≥3 corneal TEAEs, treatment-emergent corneal SAE, corneal TEAE leading to 
permanent full intervention discontinuation, corneal TEAE leading to permanent partial 
intervention discontinuation (discontinuation of tusamitamab ravtansine), corneal TEAEs related 
to IMP, Grade ≥3 corneal TEAEs related to IMP, and corneal TEAEs leading to dose 
modification of tusamitamab ravtansine. 
In addition, descriptive analyses will be provided on ocular/visual symptoms reported as 
associated with the corneal adverse events. These analyses will be performed based on the 
Investigator’s reporting of ocular toxicities (using Investigator’s terms collected in the category 
“Ocular/visual symptoms” in the AE page and using associated symptoms reported in the 
ocular/visual symptoms page during each corneal event). 
A summary of treatment-emergent corneal events will be provided. 
• Number (%) of participants by worst grade 
• Cycle of first occurrence regardless of the grade 
• Cycle of first occurrence of the worst grade 
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• Relationship to study intervention: in case of multiple occurrences with different 
relationships, if any event is related, then the relationship will be considered as related 
• Action taken with the study intervention: in case of multiple occurrences with different 
actions, the most severe action taken will be tabulated and selected according to the 
following order of severity: drug withdrawn, dose reduced, drug interrupted, dose not 
changed 
• Outcome: in case of multiple occurrences with different outcomes, the most severe 
outcome will be tabulated and selected according to the following order of severity: fatal, 
not recovered or resolved, recovering or resolving, recovered or resolved with sequelae, 
recovered or resolved, unknown 
In addition, analyses on occurrence and recurrence of corneal events will be provided. 
An occurrence of corneal event will be defined as one or a group of concomitant corneal events. 
A recurrence will be defined as any occurrence of corneal event starting after a previous resolved 
occurrence.  
• The number of occurrences by participant 
• The time to first onset of corneal event will be described using Kaplan-Meier curves. Time 
to first onset is defined as the time from the date of first IMP administration to the date of 
the first occurrence of the event. In the absence of an event before the analysis cut-off 
date, it will be censored at the end date of the treatment-emergent period, analysis cut-off 
date or date of death, whichever occurs first. 
• The time to recovery will be summarized using descriptive statistics in participants who 
have had at least one recovered or resolved occurrence of corneal event (with or without 
sequelae), considering the longest duration, and the longest duration of the worst grade 
among all occurrences by participant. 
• The time to recurrence will be summarized using descriptive statistics in participants who 
have had at least one recurrence, considering the shortest time among all recurrences by 
participant. 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units. 
• Hematology and coagulation:  
- 
Red blood cells, platelets and coagulation: hemoglobin, hematocrit, red blood cell 
count, platelet count and prothrombin time (expressed as international normalized ratio 
[INR]).  
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils and eosinophils 
• Clinical chemistry: 
- 
Metabolism: glucose, total protein and albumin. 
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- 
Electrolytes: sodium, potassium, chloride, phosphate and corrected calcium. Corrected 
calcium (mmol/L) will be derived using the following formula: measured total calcium 
(mmol/L) + 0.8 × 0.25 × (4.0 – [serum albumin (g/L) × 0.1]), where 4.0 represents the 
average albumin level.  
- 
Renal function: creatinine, blood urea nitrogen (BUN), urea. 
- 
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, lactate dehydrogenase, total and direct bilirubin. 
- 
Circulating carcinoembryonic antigen (CEA) 
• Vital signs: heart rate, temperature, systolic and diastolic blood pressure, weight, 
ECOG Performance status (PS) and body surface area (BSA) 
• ECG variables: PR, QRS, QT and QTc (according to Fridericia). 
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification (ULOQ) will be replaced by ULOQ value. 
For hematological parameters and some selected coagulation and biochemistry parameters, 
Sanofi sponsor generic ranges (LLN, ULN) are defined and will be used for grading (see list of 
parameters in Section 5.5). For other biochemistry and coagulation parameters, grading will be 
derived using local laboratory normal ranges. 
Quantitative analyses 
For vital signs and ECG variables above, descriptive statistics for results and changes from 
baseline will be provided for each planned visit, and 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.  
For QRS and QTc variables blood pressure and heart rate, mean changes from baseline with the 
corresponding standard error will be plotted over time. 
Analyses according to potentially clinically significant abnormalities (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 above, 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 
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The number (%) of participants with QTcF abnormality worsening during the on-treatment period 
(worst value per participant) according to baseline value will be displayed. 
For laboratory variables graded by NCI-CTCAE, 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade (except for liver function).   
• 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.  
• For liver function, baseline status will be provided according to multiples of ULN.  
For laboratory variables not graded by NCI-CTCAE or by PCSA, the number (%) of participants 
with laboratory tests outside normal ranges will be provided. 
For ECOG PS, the number (%) of participants in each grade (considering the worst grade during 
the TE period) will be provided according to baseline. 
Additional analyses for drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury:  
• An e-DISH-like plot of peak bilirubin/ULN versus peak alanine aminotransferase or 
aspartate aminotransferase (worst value)/ULN will be provided. The graph will be divided 
into 4 quadrants with a vertical line corresponding to 3 ULN for ALT/AST and a 
horizontal line corresponding to 2 ULN for total bilirubin.  
• For each liver function test (eg, ALT), participants having experienced a PCSA  
(eg, ALT >5 ULN) will be summarized using the following categories: Returned to 
baseline PCSA status (or returned to value ≤ULN in case of missing baseline) before 
last IMP dose, Returned to baseline PCSA status after last IMP dose, Never returned to 
baseline PCSA status, No assessment after elevation. This summary will be performed by 
categories of elevation (ALT >3, >5, >10, >20 ULN). 
4.7.3.2 Ophthalmological examinations  
Schirmer test 
Participants reported Schirmer’s test will be classified into three classes at baseline: normal 
≥10 mm, moderate >5 and <10 mm, severe ≤5 mm. The worst classification between the laterality 
will be considered. A frequency table of the baseline status with and without anaesthetics will be 
provided by treatment group for the participants with corneal events (CMQ) during the treatment-
emergent period and for the participants without event. 
Visual acuity test 
Analyses are done on the best corrected visual acuity assessed using Snellen Chart method. 
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Frequency tables on best corrected visual acuity (BCVA) measured during on-treatment period 
will be performed separately on all participants and on participants who experienced at 
least one treatment-emergent corneal event: 
• On the worst change from baseline: No worsening versus baseline (no line decrease), 
Worsening versus baseline (1 to 3 lines decrease versus baseline, or >3 lines decrease 
versus baseline). 
• On the worst absolute value: No change versus baseline, Worsening versus baseline: 
BCVA equals to 20/40 or better, BCVA worse than 20/40 up to 20/200, BCVA 20/200 or 
worse. 
• On the CTCAE worst vision decrease: BCVA equals to 20/40 or better or 1 to 3 lines 
decrease versus baseline, BCVA worse than 20/40 up to 20/200 or >3 lines decrease 
versus baseline, BCVA 20/200 or worse.  
• For participants who had worsening versus baseline (at least one line decrease) on BCVA, 
the worst outcome on the last BCVA will be displayed: Recovered to baseline, 
Not recovered to baseline, Lost to follow-up or dead with ongoing corneal events.  
A participant will be considered as lost to follow-up if the participant discontinued the study and 
did not perform any follow-up visit. 
A shift table of the category of the last BCVA value (Normal (20/20 or better), worse than 20/20 
up to 20/40, worse than 20/40 up to 20/200 or 20/200 or worse) versus the category of the worst 
BCVA value (20/40 or better, worse than 20/40 up to 20/200, 20/200 or worse) will be performed 
for participants who experienced at least one treatment-emergent corneal event. 
For the summary table on participants who experienced at least one treatment-emergent corneal 
event, the worst value and the worst change from baseline are measured during any of the 
treatment-emergent corneal events experienced by the participant (between start date and end date 
of the corneal events). For the summary table on all participants, all on-treatment BCVA values 
are considered. 
The worst classification between the laterality will be considered for the worst value of participant 
either left or right eye then the change from baseline and the last value will be measured from 
same eye with worst value. If the worst absolute value is the same for both eyes, then the eye with 
the worst change from baseline is considered, and if identical, then the eye with the worst 
last value is considered. 
Participants whose baseline visual acuity had been reported in naked eye instead of BCVA 
(ie, whenever baseline value was worse than the values reported during the during the treatment 
period/treatment-emergent corneal events) will be excluded from this analysis. 
Slit lamp examination 
Descriptive statistics of slit lamp examination will be provided separately at baseline and at 
the time of first abnormal slit lamp after occurrence of a treatment-emergent corneal event and at 
the time of the worst BCVA value during a treatment-emergent corneal event for participants 
experiencing treatment-emergent corneal events (CMQ). The outcome (normal, abnormal), and 
for abnormal findings, the type of lesions and the distribution will be described by laterality 
(unilateral, bilateral, all). 
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4.8 
OTHER ANALYSES  
4.8.1 Immunogenicity analyses  
Participant’s ATA status, response variable, and kinetics of ATA responses (see definitions 
below) will be summarized on the ATA population.  
Kinetics of ATA responses will be described for participants with treatment-induced ATA and 
for participants with treatment-boosted ATA, separately. Time to ATA onset and duration of ATA 
will be described with minimum, Q1, median, Q3, and maximum statistics.  
Peak titer will be described with minimum, Q1, median, Q3, and maximum statistics for 
participants with treatment-induced ATA and for participants with treatment-boosted ATA, 
separately.  
Sample status (negative, positive, inconclusive) and titers will also be described overtime using 
descriptive statistics.  
The impact of positive immune response on efficacy, PK, and safety variables may be further 
explored, depending on ATA incidence. 
Participant’s ATA status 
• Participants with pre-existing ATAs correspond to participants with ATAs present in 
samples drawn before first administration of intervention. Participants with missing ATA 
sample at baseline will be considered as without pre-existing ATA. 
• Participants with treatment-emergent ATA correspond to participants with at least 
1 treatment-induced/boosted ATA: 
- 
Participants with treatment-induced ATAs correspond to participants with ATAs that 
developed at any time after first IMP administration and without pre-existing ATA 
(including participants without pre-treatment samples).  
- 
Participants with treatment-boosted ATAs correspond to participants with 
pre-existing ATAs that are boosted at any time after first IMP administration to a 
significant higher titer than the baseline. A 2-fold serial dilution schema is used during 
titration, so at least a 4-fold increase will be considered as significant. 
• Participants with unclassified ATA correspond to participants with pre-existing ATAs 
that cannot be classified as treatment-boosted ATA because of missing titer(s)  
(ie, a positive ATA sample at any time after first IMP administration in a participant with 
pre-existing ATA but with missing titer at this sample or at baseline). 
• Participants without treatment-emergent ATA correspond to participants without 
treatment-induced/boosted ATA and without any inconclusive sample nor unclassified 
ATA at any time after first IMP administration.  
• Participants with inconclusive ATA are defined as participants which cannot irrefutably 
be classified as with or without treatment-emergent ATA. 
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Kinetics of ATA response 
Kinetics of ATA response will be derived for participants with treatment-induced/boosted ATA.  
• Time to onset of ATA response is defined as the time period between the first IMP 
administration and the first treatment-induced/boosted ATA.  
• Duration of ATA response is defined as the time between the first treatment-induced/ 
boosted ATA and the last treatment-induced/boosted ATA, irrespective of negative 
samples or positive samples not reaching the boosted threshold in-between. ATA duration 
will be summarized only for participants with persistent ATA response. 
• Persistent ATA response is defined by treatment-induced/boosted ATA with a duration 
of ATA response of at least 16 weeks. 
• Transient ATA response is defined by treatment-induced/boosted ATA with a duration 
of ATA response of less than 16 weeks and the last sample is not treatment-
induced/boosted. 
• Indeterminate ATA response is defined by treatment-induced/boosted ATA that are 
neither persistent nor transient. 
ATA response variable 
• ATA incidence is defined as the proportion of participants found to have seroconverted 
(treatment-induced ATAs) or boosted their pre-existing ATA response (treatment-boosted 
ATAs) at any time after first IMP administration. 
4.8.2 PK analyses (for mPAC Cohort C)  
4.8.2.1 Noncompartmental analysis  
4.8.2.1.1 Tusamitamab ravtansine  
The PK parameters will be calculated using non-compartmental methods from tusamitamab 
ravtansine concentrations will include, but may not be limited to, those listed in Table 13. 
Table 13 - List of PK parameters and definitions  
Parameters 
After Cycle 1 
Day 1 
administration 
After Cycle 2 
Day 15 
administration 
Definition 
Ceoi 
✓ 
✓ 
Concentration observed at the end of IV infusion 
Cmax 
✓ 
✓ 
Maximum concentration observed after infusion 
tmax 
✓ 
✓ 
Time to reach Cmax 
Clast 
✓ 
✓ 
Last concentration observed above the lower limit of quantitation 
after infusion 
tlast 
✓ 
✓ 
Time of Clast 
AUClast 
✓ 
✓ 
Area under the plasma concentration versus time curve 
calculated using the trapezoidal method from time zero to tlast 
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Parameters 
After Cycle 1 
Day 1 
administration 
After Cycle 2 
Day 15 
administration 
Definition 
AUCtau 
✓ 
✓ 
Area under the plasma concentration versus time curve 
calculated using the trapezoidal method from time 0 to 14 days 
AUC 
✓ 
 
AUC from time zero extrapolated to infinity according to the 
following equation: 
AUC = AUClast+(Clast/λz) 
Extrapolation should not exceed more than 30% of total AUC. If 
AUCex >30%, the value will be reported and not taken into 
account in descriptive statistics and derived parameters will not 
be calculated. 
CL 
✓ 
 
Total body clearance of a drug from plasma calculated using the 
following equation from AUC, after single dose: 
CL = Dose/AUC 
CLss 
 
✓ 
Total body clearance of the drug from the plasma after IV 
administration calculated after repeated dosing, using the 
following equation:  
CLss = Dose/AUC0- τ, τ being the dosing time interval (14 days) 
Vss 
✓ 
 
Volume of distribution in the terminal phase calculated according 
to the following equation: 
Vss = CL × MRT 
with MRT = AUMC/AUC(-Tinf /2 if infusion) 
MRT being the Mean Residence Time of a molecule in the body; 
AUMC is the area under the curve of the moments and Tinf is the 
duration of infusion. 
t1/2z 
✓ 
✓ 
Terminal half-life associated with the terminal slope determined 
according to the following equation: 
t1/2z = 0.693/λz 
Where λz is the slope of the regression line of the terminal phase 
of the plasma concentration versus time curve, in semi-
logarithmic scale. Half-life is calculated by taking the regression 
of at least 3 points on the terminal slope. 
4.8.2.1.2 Gemcitabine  
The PK parameters for gemcitabine and dFdU (gemcitabine metabolite) will be calculated using 
non-compartmental methods from concentrations will include, but may not be limited to, those 
listed in Table 14. 
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Table 14 - List of PK parameters and definitions  
Parameters 
gemcitabine and 
dFdU (gemcitabine 
metabolite) 
After Cycle 1 Day 
1 administration 
After Cycle 1 Day 1 
administration 
Definition 
Cmax 
✓ 
✓ 
Maximum concentration observed after infusion 
tmax 
✓ 
✓ 
Time to reach Cmax 
Clast 
✓ 
✓ 
Last concentration observed above the lower 
limit of quantitation after infusion 
tlast 
✓ 
✓ 
Time of Clast 
AUClast 
✓ 
✓ 
Area under the plasma concentration versus time 
curve calculated using the trapezoidal method 
from time zero to tlast 
AUC (gemcitabine only) 
 
 
✓ 
✓ 
AUC from time zero extrapolated to infinity 
according to the following equation: 
AUC = AUClast +(Clast/λz) 
Extrapolation should not exceed more than 30% 
of total AUC. If AUCex >30%, the value will be 
reported and not taken into account in 
descriptive statistics and derived parameters will 
not be calculated. 
CL (gemcitabine only) 
✓ 
✓ 
Total body clearance of a drug from plasma 
calculated using the following equation from 
AUC, after single dose: 
CL = Dose/AUC 
Vss (gemcitabine only) 
 
 
✓ 
✓ 
Volume of distribution in the terminal phase 
calculated according to the following equation: 
Vss = CL × MRT 
with MRT = AUMC/AUC(-Tinf /2 if infusion) 
MRT being the Mean Residence Time of a 
molecule in the body; AUMC is the area under 
the curve of the moments and Tinf is the duration 
of infusion. 
t1/2z (gemcitabine only) 
 
 
✓ 
✓ 
Terminal half-life associated with the terminal 
slope determined according to the following 
equation: 
t1/2z = 0.693/λz 
Where λz is the slope of the regression line of the 
terminal phase of the plasma concentration 
versus time curve, in semi-logarithmic scale. 
Half-life is calculated by taking the regression of 
at least 3 points on the terminal slope. 
Individual concentrations and PK parameters of tusamitamab ravtansine, gemcitabine and dFdU 
(gemcitabine metabolite) will be listed and summarized by dose level (if applicable) using 
descriptive statistics (such as the number of observations, arithmetic and geometric means, 
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median, standard deviation, standard error (SE), coefficient of variation (CV), minimum, and 
maximum). 
In addition, individual and mean concentration profiles over time will be plotted by dose level 
(if applicable). 
These descriptive statistics will be provided by PKDM department at Sanofi. 
4.8.2.2 Ctrough and Ceoi over cycles  
All concentration values below the LLOQ will be treated as zero in individual listing and 
respective descriptive statistics. Geometric mean will not be computed in case at least one 
concentration is below LLOQ. 
Individual observed predose concentrations (Ctrough) and concentrations observed at the end of 
infusion (Ceoi, Ceoi+1h if any) of tusamitamab ravtansine will be listed and summarized with 
standard descriptive statistics (such as the number of observations, arithmetic and geometric 
means, median, standard deviation, coefficient of variation, minimum, and maximum) by visit and 
by dose level (if applicable). 
For the descriptive statistics, Ctrough following any dose modifications (delay or reduction as 
defined in Section 4.7.1.2) will be excluded. Ceoi and Ceoi+1h will be excluded following dose 
reduction. 
A graphical representation of mean Ctrough (±SD) profile over time, by dose level superimposed in 
the same figure (if applicable), will be provided throughout the course of treatment. 
4.8.2.3 Population PK analyses  
The population PK analyses will be described in a specific document and the results will be 
presented separately from the clinical study report. 
4.8.2.4 IgG  
In the all-treated population, the level of IgG in blood at pre-infusion of Cycle 1 Day 1 will be 
summarized with standard descriptive statistics (such as number of observations, arithmetic and 
geometric means, median, standard deviation, coefficient of variation, minimum and maximum) 
for tusamitamab ravtansine. A listing will also be provided. 
4.8.3 Biomarker analyses  
Several exploratory objectives related to pharmacodynamic/genomic endpoints will be considered 
in this study. 
Unless otherwise specified, biomarkers analyses will be performed on participants with available 
data from the all-treated population. 
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4.8.3.1 CEACAM5 by IHC  
In the pre-screened population, the CEACAM5 expression (prevalence of the three categories 
[negative, moderate and high expressers] and possibly H-score) will be presented using 
descriptive statistics. 
4.8.3.2 Circulating CEA  
The circulating CEA will be considered as a quantitative variable or as a binary variable when 
considering different binary thresholds: <3, <5, <50, <80 or <100 µg/L. 
Circulating CEA values below the LLOQ will be replaced by half of the LLOQ. 
4.8.3.2.1 Circulating CEA levels before IMP and CEACAM5 IHC  
Circulating CEA levels before IMP will be correlated with IHC CEACAM5 expression status 
(for prescreened participants). To this end, the closest circulating CEA assessment to biopsy 
(or the oldest value before IMP if the date of the biopsy is missing) will be considered. The 
circulating CEA levels (quantitative and by thresholds) will be presented using descriptive 
statistics, by IHC CEACAM5 expression status. The correlation between the circulating CEA 
levels (quantitative) and the CEACAM5 expression will be also assessed, and visualized 
graphically. To this end, Pearson correlation, Spearman’s rank, or Kendall's tau coefficient will be 
considered depending on the nature of the data. The time from tumor biopsy collection and 
circulating CEA assessment (the closest to biopsy) will be also described and investigated in the 
correlation between circulating CEA levels and IHC CEACAM5 expression. 
In order to evaluate the variability of circulating CEA values, an intraclass correlation coefficient 
will be calculated between circulating CEA values before IMP and baseline (when both 
available). A graphical visualization may be provided to observe the degree of concordance. 
4.8.3.2.2 Circulating CEA levels at baseline and clinical response  
Circulating CEA levels at baseline will be correlated with confirmed objective response 
(for all-treated participants). To this end, the last circulating CEA assessment before (closest to) 
IMP will be considered and reported as the baseline value. 
The circulating CEA level will be presented using descriptive statistics, by response status, part, 
dose level and overall. The confirmed objective response rate and two-sided 95% confidence 
intervals using the Clopper-Pearson method will be presented for each circulating CEA subgroups 
(based on the predefined thresholds) by part, and overall. 
The correlation between the circulating CEA levels (quantitative) and the tumor burden at 
baseline will be also assessed and visualized graphically. To this end, Pearson correlation, 
Spearman’s rank, or Kendall's tau coefficient will be considered depending on the nature of 
the data. 
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4.8.3.2.3 Modulations of circulating CEA as a potential PD biomarker of response to 
tusamitamab ravtansine treatment  
A graphical visualization (spaghetti plot) will be presented to visualize the relative change from 
baseline of circulating CEA values for each participant, annotated with the best overall response.  
4.8.3.3 Circulating free DNA (cfDNA)  
4.8.3.3.1 Relationship between the tumor mutation profiles detected in the cfDNA at baseline 
with efficacy outcomes  
Genomic alterations collected locally from the eCRF at pre-screening will be described. For each 
gene, participants will be grouped into two groups: “altered” (ie, participants with at least one 
alteration for the gene) and “wild-type” (ie, participants without alteration for the gene) and 
described using descriptive statistics by part, dose level and overall in the pre-screened 
population. The confirmed objective response rate and two-sided 95% confidence intervals using 
the Clopper-Pearson method will be presented for each gene in the all-treated population. 
Circulating-free DNA (cfDNA) centrally assessed will be collected and analyzed in the same way 
as local data from eCRF. 
4.8.3.4 To explore potential sets of biomarkers from tumor DNA and RNA analyses as 
potential biomarkers of response to tusamitamab ravtansine  
The same tumor biopsy as the one sent for CEACAM5 assessment at pre-screening may be used 
for additional tumor DNA and/or RNA analyses, if enough relevant data is collected. 
Tumor DNA data from the TSO500 (+CEACAM5) panel will be generated. These data will be 
analyzed similarly to cfDNA data. For key genes, the concordance between tumor DNA and 
cfDNA can be investigated. 
RNAseq data will be also generated, and may be used to evaluate the abundance of expression of 
specific genes in this targeted population (ie, CEACAM5 high expression based on IHC), and 
explore patterns on response to tusamitamab ravtansine. 
4.8.3.5 CEACAM5 expression on circulating tumoral cells (CTCs)  
CEACAM5 expression on CTCs have been analyzed for some samples for feasibility purpose. 
A listing will be provided with the subject ID and associated level of CEACAM5 detected on 
CTCs. 
4.9 
INTERIM ANALYSES  
An interim analysis based on the number of responses observed in the Activity population for the 
patients in the mPAC Cohort C will be performed. 
The study cut-off for the interim analysis corresponds to the date when the first 15 treated 
evaluable participants in Cohort C have had at least 2 post-baseline tumor assessments or 
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experienced confirmed objective response or have discontinued the study for any reason. 
For participants with 2 post-baseline tumor assessments and occurrence of response at the second 
post-baseline tumor assessment, the confirmatory assessment will also be included.  
For Cohort C, if 1 or 0 confirmed response is observed among the first 15 treated participants 
evaluable for activity, the cohort will be closed. 
In addition, the study analysis will then be conducted in three steps for each cohort.  
• The first step analysis will be conducted for each cohort when all treated evaluable 
participants of the cohort have had at least 2 post-baseline tumor assessments, experienced 
confirmed objective response, or have discontinued the study for any reason. The study 
cut-off for the first-step analysis can be up to approximately 20 weeks after the date of the 
first IMP administration of the last participant of the cohort: 16 weeks for 2 tumor 
assessments and at least 4 weeks if a confirmation of response is needed.  
• The second step analysis will be based on the study cut-off for secondary efficacy 
endpoints including DOR and PFS (final cut-off date), 6 months after the study cut-off for 
the primary analysis. The primary analysis of ORR and DCR will also be updated at that 
time. 
• The final analysis will be conducted at the end of the study. Only safety analyses will be 
updated at this time. 
For the interim analysis and each analysis step, the analysis cut-off date will be defined as the date 
of the database extraction that will be performed for the analysis after the cut-off (study cut-off for 
the interim analysis, or study cut-off for the first analysis step and second analysis step). 
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply at interim analysis, 
first analysis step and second analysis step: 
• Participants without end of treatment status performed at the time of the analysis cut-off 
date will be considered as ongoing. Therefore: 
- 
Participants who did not prematurely discontinue the study intervention at analysis  
cut-off date will be analyzed as “ongoing” in the disposition summary. 
- 
Their treatment-emergent (TE) period, and concomitant medication period will end at 
the analysis cut-off date.  
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADC: 
antibody drug conjugate 
ADI: 
actual dose intensity 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATAs: 
antitherapeutic antibody 
AUC: 
area under the curve, area under the curve 
BCVA: 
best corrected visual acuity 
BOR: 
best overall response 
BSA: 
body surface area 
BUN: 
blood urea nitrogen 
CEA: 
carcinoembryoonic agent 
CEACAM5: 
carcinoembryonic antigen-related cell adhesion molecule 5 
cfDNA: 
circulating free DNA 
CI: 
confidence interval 
COVID-19: 
coronavirus disease 2019 
CR: 
complete response 
CTCs: 
circulating tumoral cells 
CV: 
coefficient of variation 
DCR: 
disease control rate 
DNA: 
deoxyribonucleic acid 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
e-CRF: 
electronic case report form 
EGFR: 
estimated glomerular filtration rate 
EOT: 
end-of-treatment 
HGLT: 
high level group term 
HLGT: 
high-level group term 
HLT: 
high-level term 
ICI: 
immune checkpoint inhibitor 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRT: 
interactive response technology 
LLN: 
lower limit of normal 
LLOQ: 
lower limit of quantitation 
LLT: 
lower-level term 
MedDRA: 
Medical Dictionary for Regulatory Activities 
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NCI-CTCAE: 
National cancer institute common terminology for adverse events 
ORR: 
objective response rate 
PCSA: 
potentially clinically significant abnormalities 
PD: 
progressive disease 
PDI: 
planned dose intensity 
PFS: 
progression-free survival 
PR: 
partial response 
PS: 
performance status 
PT: 
preferred term 
Q1: 
quartile 1 
Q2W: 
every 2 weeks 
Q3: 
quartile 3 
RBC: 
red blood cells 
RDI: 
relative dose intensity 
RECIST: 
response evaluation criteria in solid tumors 
RNA: 
ribonucleic acid 
SAEs: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SE: 
standard error 
SOC: 
system organ class 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
TKI: 
tyrosine kinase inhibitor 
TNBC: 
triple-negative breast cancer 
ULN: 
upper limit of normal 
ULOQ: 
upper limit of quantification 
WBC: 
white blood cell 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
Major statistical changes in protocol amendment(s) 
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
1 
01-Oct-2021 
Added the word “confirmed” for CR and 
PR for DCR and DOR definitions 
To clarify 
 
 
Removed specifications of interim 
analysis planning for the mPAC Cohort B 
To remove the interim analysis for the mPAC 
Cohort B  
 
 
Updated definition of activity population 
To clarify 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
2 
25-Jul-2022 
Removed mention of interim analysis for 
mBC Cohort A 
The mBC Cohort A stopped enrollment 
 
 
mPAC Cohort C and corresponding 
analyses added 
To evaluable Tusamitamab ravtansine in 
combination with gemcitabine in participants 
with pancreatic adenocarcinoma 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
 Demographics, baseline characteristics, medical and surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the all-treated 
population. 
Demographic and baseline characteristics  
• Age in years as quantitative variable and in categories (<65, [65-75[, ≥75)  
• Sex (Male, Female) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not reported, Unknown)  
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not reported, Unknown) 
• ECOG PS (0,1) 
• Weight in kg as quantitative variable 
• BSA in m² as quantitative variable 
• Primary tumor site (Head, body, tail, head and body, body and tail) 
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries.  
Medical (or surgical) history includes relevant history of previous pathologies and surgeries. 
Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, and associated primary 
SOC using the MedDRA version currently in effect at Sanofi at the time of database lock.  
Specific disease history includes primary tumor site, histology or histopathology type, mBC 
subtype (TNBC/non-TNBC), specific mutations and local protein expression (Her2 status, 
ER status, PgR status), TNM, staging, time from initial diagnosis to first administration of IMP 
(in years).  
Specific disease status at study entry includes extent of diseases, number and type of organs 
involved (including primary tumor location), time from relapse to first administration of IMP, 
circulating CEA (<100 µg/L, ≥100 µg/L and <80 µg/L, ≥80 µg/L).  
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Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock.  
• Prior medications are those the participant received prior to first IMP intake. Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any medications received by the participant concomitantly to 
the IMP from the first administration of IMP to the last IMP intake + 30 days. 
• Post-treatment medications are those the participant received in the period running from 
the end of the concomitant medications period up to the end of the study.  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether a 
given medication was received prior or concomitantly or post, it will be considered as 
prior, concomitant, and post-treatment medication. 
The prior and concomitant medications will be summarized for the all-treated population, by 
anatomic and therapeutic level. The summaries will be sorted by decreasing frequency of 
anatomic category (ATC) based on the overall incidence in the “All group”.   In case of equal 
frequency, alphabetical order will be used. Participants will be counted once in each ATC 
category (anatomic or therapeutic) linked to the medication.  
Premedications  
As defined in Section 6.1 of the study protocol, participants receive premedications prior to IMP 
administration to prevent related allergic reactions to tusamitamab ravtansine. Premedications are 
defined as non-investigational medicinal products and are reported on a specific e-CRF page.  
Anticancer therapies  
Prior anticancer therapies include anticancer treatment, surgery and radiotherapy.  
• Number (%) of prior anticancer therapies including neoadjuvant/adjuvant/radiosensitizer 
and advanced regimen 
• Number (%) of participants with intent: 
- 
neoadjuvant and adjuvant and chemoradiotherapy and advanced 
- 
neoadjuvant or adjuvant and advanced 
- 
chemoradiotherapy and advanced, 
- 
neoadjuvant or adjuvant or chemoradiotherapy only 
- 
advanced only 
• Number (%) of prior anticancer therapies in the advanced setting. 
A regimen in the advanced setting consists of a single agent, combination, or a sequential 
therapeutic strategy with several drugs, given until a PD is documented.  
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Adjuvant/neoadjuvant treatment for a participant who relapsed with metastatic disease during or 
within 6 months of treatment will be considered as first line treatment in the advanced setting. 
• Type of prior anticancer treatment including neoadjuvant, adjuvant and advanced 
regimens: 
- 
Biologics and small molecules 
- 
Tyrosine kinase inhibitor (TKI): EGFR inhibitors, Anti VEGF/VEGFR (anti-
angiogenic), BRAF kinase inhibitors, ALK inhibitors, RAS/RAF/MEK/ERK 
signaling pathway inhibitors, ROS1 inhibitors 
- 
Immune checkpoint inhibitor (ICI) 
- 
Others 
- 
Chemotherapy: Taxane, anthracyclines, platinum, pemetrexed, antimicrobules, 
gemcitabine, fluoropyrimidine (5-FU or capecitabine), others 
- 
Antibody drug conjugate (ADC) 
- 
Hormonal therapy for breast 
- 
Others 
• Prior immune checkpoint inhibitor: Single or Combination with chemotherapy 
• Summary of last prior anticancer therapy: 
- 
Time from completion of last regimen to first administration of IMP (in weeks) 
- 
Main treatments of last regimen: 
- 
ICI monotherapy 
- 
ICI in combination with chemotherapy 
- 
ICI and other biologics and small molecules 
- 
No ICI: Chemotherapy (Taxane, anthracyclines), Biologics, or Chemotherapy, or 
hormonal therapy, and Biologics 
- 
Best response to the last regimen 
- 
Reason for discontinuation of the last line 
- 
Sensitivity to previous lines (<4 months, 4 to 6 months, >6 months): 
- 
To first line (duration of first line prior anti-cancer therapy other than 
adjuvant/neoadjuvant) for both mPAC cohorts 
- 
To second line (duration of second line prior anti-cancer therapy) for both mPAC 
cohorts 
- 
To last line (duration of last line prior anti-cancer therapy) for all cohorts 
- 
To Taxane therapy for all cohorts 
• Prior surgery: number (%) of participants with any prior surgery (including biliary stent), 
type of surgery and time from the last surgery to the first administration of IMP 
(in months). 
• Prior radiotherapy: number (%) of participants with any prior radiotherapy, intent, 
analgesic intent if palliative and time from last dose of radiotherapy to first administration 
of IMP (in months). 
Further anticancer therapies after discontinuation of intervention will be summarized based on 
WHO-DD coding. 
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5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Unscheduled visits 
Unscheduled visit measurements will be used for computation of baseline and worst on-treatment 
values and/or grades. 
Unscheduled tumor assessments will be used for computation of efficacy endpoints based on 
radiological assessments of tumor burden. 
Corrected QT formula 
QTc parameter will be derived following the Fridericia method: 
QTcF = QT/RR0.33 
Where RR interval (in seconds) is 60 divided by heart rate. 
5.5 
APPENDIX 5 SANOFI SPONSOR GENERIC RANGES FOR HEMATOLOGICAL AND 
BIOCHEMISTRY PARAMETERS   
The current list of generic ranges (for adults) for hematological, coagulation and biochemistry 
parameters (3) are provided in tables below. 
Table 15 - Generic ranges for hematological and coagulation parameters  
Parameter 
Gender 
Unit 
LLN 
ULN 
Basophils 
 
10^9/L 
0 
0.15 
Eosinophils 
 
10^9/L 
0 
0.4 
Erythrocytes (RBC) count 
M 
10^12/L 
4.5 
5.9 
Erythrocytes (RBC) count 
F 
10^12/L 
4 
5.2 
Hematocrit 
M 
Fraction of 1 
0.41 
0.53 
Hematocrit 
F 
Fraction of 1 
0.36 
0.46 
Hemoglobin 
M 
g/L 
135 
175 
Hemoglobin 
F 
g/L 
120 
160 
Leukocytes (WBC) count 
 
10^9/L 
4.5 
11 
Lymphocytes 
 
10^9/L 
1 
2 
Monocytes 
 
10^9/L 
0.18 
0.5 
Neutrophils 
 
10^9/L 
1.8 
3.15 
Platelets count 
 
10^9/L 
150 
350 
Prothrombin time 
 
INR 
0.8 
1.2 
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Table 16 - Generic ranges for biochemistry parameters  
Parameter 
Unit 
LLN 
ULN 
Albumin 
g/L 
35 
55 
Blood Urea Nitrogen 
mmol/L 
3.6 
7.1 
Corrected calcium 
mmol/L 
2.2 
2.6 
Glucose 
mmol/L 
3.9 
7 
Potassium 
mmol/L 
3.5 
5 
Sodium 
mmol/L 
136 
145 
Protein 
g/L 
55 
80 
Urea 
mmol/L 
3.6 
7.1 
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6 
REFERENCES   
1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New 
guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 
2000;92(3):205-16. 
2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
3. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory reference values. N Engl J 
Med. 2004;351(15):1548-63. 
 
 
 
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